Psychological Resources

Post-Tsunami The Influence of Context on Children's Subjective Wellbeing

2011-09-24T11:26:00.001+05:30

Journal of the Indian Academy of Applied Psychology

July 2010, Vol.36, No.2, 207-213.

Post-Tsunami: The Influence of Context on Children's Subjective

Well-being

Silvia Exenberger and Barbara Juen

University of Innsbruck, Austria

This paper presents the first work-package of the project "Post-tsunami" funded by the European Commission. It aims to develop indicators of children's well-being living in the affected areas and focuses on contextual influences on children's well-being. Fifty-six caregivers participated in focus group discussions in order to answer questions regarding their children's well-being. 112 children spoke in same-sex and same-age groups for themselves what makes them feel happy and sad, and what helps them to feel better when they feel unpleasant. On the basis of the qualitative research methodology "Grounded Theory" the transcribed interviews are analysed. The children are single and double orphans, either living with their biological parent or in an out-of-home care organisation providing family based care. Out of caregivers' and children's statements five domains of well-being are distinguished: cognitive, social, psychological, physical and economic. Especially in the social, psychological and economic domains the context plays an important role in determining children's subjective well-being.

Reflections on Repetitive Intrusive Thoughts: Diagnostic Dilemmas and Beyond

2011-09-24T11:25:00.001+05:30

Journal of the Indian Academy of Applied Psychology

July 2010, Vol.36, No.2, 197-206.

Reflections on Repetitive Intrusive Thoughts: Diagnostic Dilemmas and Beyond

R. Tripathi and S. Mehrotra

National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore

Abstract

Repetitive thoughts (RTs) are normal phenomena; however, these also form essential features of various psychiatric syndromes. This paper describes two unusual adult cases of repetitive thoughts. Both the cases were characterized by emergence of repetitive images and thoughts that were intrinsically pleasurable and were in consonance with developmental concerns in early adulthood. The RTs were not considered irrational by the individuals. The immediate consequences described were that of pleasure and relief. The RTs acquired an intrusive quality overtime. The increasing frequency of intrusions was accompanied by decreasing sense of control, heightened impairment in overall functioning and distress although the RTs continued to be described as giving pleasure during their occurrence. Despite warranting clinical attention, the presentation of the cases was atypical in various ways and did not adequately match the criteria for any diagnosis. The phenomeno\og'ica\ description highlights the evo\ut\on of repetitive thoughts in terms of qualities such as intrusiveness, ego-syntonicity as well as co-occurrence of positive & negative affective tones. Using existing theoretical frameworks, the possible psychological mechanisms underlying these presentations are discussed. The paper raises several questions on repetitive, intrusive thoughts that need to be addressed through further research.

Emotional Labour, Emotional Intelligence, and Psychological Distress

2011-09-23T19:01:00.003+05:30

Jahanvash Karim and Robert Weisz
Universite de Paul Cezane, France

abstract
The purpose of the study was to explore (1) whether employees differing in emotional

intelligence level would differ in their emotional labour styles and (2) whether these

styles would mediate the impact of emotional labour on psychological distress. To test

the relationships, data was collected from employees of three public sector

organizations situated in Quetta, Pakistan. After establishing the psychometric

properties of the scales hypotheses were tested through Partial Least Squares (PLS) path

modelling algorithm. The results of this study indicated that (a) emotional intelligence

was positively and significantly related to deep acting; (b) surface acting was

positively and significantly related to psychological distress, and; (c) neither surface

acting nor deep acting mediated the relationship between emotional intelligence and

psychological distress.

Keywords: Emotional Labour, Emotional

Hochschild (1983) coined the term emotional labour and defined EL as 'the management of

feelings to create a publicly observable facial and bodily display to keep up with job

requirements. EL is sold for a wage and therefore has exchange value'. Since 1983, EL

has become an increasingly popular topic within the fields of psychology and management

(e.g., Ashforth & Tomiuk, 2000; Grandey, 2000; Grandey & Brauburger, 2002; Rafaeli &

Sutton, 1987; Zapf, 2002). In explanatory models of emotional labour (e.g., Brotheridge

& Lee, 2003; Grandey, 2000), surface (SA) and deep acting (DA) are the two most

frequently studied EL strategies. In DA, employee attempts to deeply modify internal

feelings to match the required organizational display rules. DA involves changing inner

feelings by altering something more than outward appearance. Rafaeli and Sutton (1987)

referred to this act as "faking in good faith" because employees' intent is to seem

authentic to the audience. In SA, employee modifies outward displays to be consistent

with display rules without shaping innerfeelings. In other words, employee hide felt

emotions or fake unfelt emotions. Hence, SA is termed as "faking in bad faith "(Rafaeli

& Sutton, 1987).
EL has been found to be associated with emotional intelligence (El) (Austin, Dore, &

O'Donovan, 2008; Giardini & Frese, 2006; Johnson, 2007; Johnson & Spector, 2007;

Mikolajczak, Menil, & Lumient, 2007; Totterdell & Holman, 2003). Mayer and Salovey

(1997) defined El as "the ability to perceive accurately, appraise, and express emotion;

the ability to access and/or generate feelings when they facilitate thought; the ability

to understand emotion and emotional knowledge; and the ability to regulate emotions to

promote emotional and intellectual growth". There is accumulating evidence that El

abilities and traits influence numerous psychological adjustment variables such as

psychological distress and depression (e.g., Besharat, 2007; Dawda & Hart, 2000; Slaski

& Cartwright, 2002; Tsaousis & Nikolaou, 2005; Martinez-Pons, 1997). However, to our

knowledge, there is no study testing the extent to which EL strategies may mediate such

a connection. Theories of EL (e.g., Brotheridge & Lee, 2003; Diefendorff, Croyle, &

Gosserand, 2005; Grandey, 2000; Zapf, Seifert, Schmutte, Mertini, & Holz, 2001) suggest

that EL strategies at work are key vehicles of personality and organizational influences

on numerous psychological adjustment variables (e.g., distress, anxiety, stress,

coping).

The main objective of this study was to build and test on prior research the theoretical

links between EL, El, and psychological distress. In general, (1) employees with higher

levels of El were expected to engage more in the less destructive form of EL (i.e., DA)

and; (2) EL strategies were expected to mediate the relationship between El and

psychological distress.
EL and El
Various, empirical studies have explored the association between El and EL strategies

(e.g., Austin et al., 2008; Giardini & Frese, 2006; Johnson, 2007; Johnson & Spector,

2007; Mikolajczak et al., 2007; Totterdell & Holman, 2003). Austin et al. (2008) found

no association between El and DA and negative relationship between El and SA. Giardini

and Frese (2006) found that emotional competence was a significant personal resource in

moderating associations between EL and job/health outcome. Johnson (2007) found a

significant positive relationship between El and DA. Johnson and Spector (2007) found

that El did not moderate the relationship between the EL strategies and personal

outcomes (well-being). Mikolajczak et al. (2007) found negative relationship between El

and DA. Thus, further investigation is needed to unravel associations between El and

different EL strategies.
While there are numerous models and measures of El, a number of El dimensions are common

across measures. In particular, self-emotion appraisal, others' emotional appraisal, the

regulation of emotion, and the use of emotion are dimensions that appear on almost every

El measure (e.g., Salovey & Mayer, 1990; Mayer & Salovey, 1997; Wong & Law, 2002).
Self-emotional appraisal relates to the individual's ability to understand their deep

emotions and be able to express these emotions naturally, whereas others' emotional

appraisal relates to peoples' ability to perceive and understand the emotions of those

people around them (Wong & Law, 2002). These abilities form the major aspects of

emotional work (Zapf et al., 2001). It is expected that emotionally intelligent

employees will deep.act more because they are better able to perceive the emotional

display rules cues within the work settings, have knowledge what people around them

feel, read people emotions accurately, and don't always maintain neutral expressions

(i.e., smiles when happy or pleasant) (Caruso & Salovey, 2004).

The regulation of emotion relates to the ability of people to regulate their emotions,

which enables them to recover rapidly from psychological distress (Wong & Law, 2002).

Emotionally Intelligent people effectively manage emotions in oneself and others by

moderating negative emotions and enhancing pleasant ones (Mayer & Salovey, 1997).

Effective regulation of emotions allows an individual to induce and sustain a positive

affective state, which subsequently promotes helping behaviour and motivation (Joseph &

Newman, 2010). According to Butler et al. (2003), people with high ability to regulate

emotions are less likely to adopt the strategy of emotion suppression (i.e., SA) and

instead engage in a more effective strategy, such as cognitive appraisal. It is expected

that emotionally intelligent employees would be more prone toward employing the DA

strategy, because they can "psych up", calm down, or maintain a good mood as desirable

and can cheers others up, calm others down, or manage others feelings appropriately

(Caruso & Salovey, 2004).

Finally, the use of emotion relates to the ability of individuals to make use of their

emotions by directing them towards constructive activities and personal performance

(Wong & Law, 2002). Emotionally intelligent employees are better able to prioritize

thinking with the help of emotions, generate emotions as an aid to judgment, and

consider multiple points of view (Mayer & Salovey, 1997). It is expected that

emotionally intelligent people would engage themselves more in deep acting (than surface

acting) because by effectively using emotions they are able to swing their moods from

negative to positive in order to enhance persistence during difficult times (e.g.;

encountering a difficult customer) or stimulating creativity in solving difficult

problems (e.g., choosing among different atternatives for satisfying the difficult

customer) (Carmeli, 2003).
Hypothesis 1a. Individuals with high emotional intelligence will be less likely than to

surface act.
Hypothesis 1b: Individuals with high al intelligence will be more likely than to deep

act.
EL and Psychological Distress
SA(i.e., modification of facial expression) requires more attention and effort than does

DA (i.e., modification of inner feelings) Brotheridge & Lee, 2003; Brotheridge &

Grandey. 2002; Grandey, 2003). SA is positively related to emotional dissonance and

felt inauthenticity (Liu, Prati, Perrewe, & Ferris, 2008). Emotional dissonance is an

aversive psychological state in which one experiences a sense of discrepancy between

one's real self and expressed emotions. According to Wharton (1999), the major reason

for this discrepancy is that, the organizational display rules prevent employees from

interacting with customers based on spontaneous intuition, which compel employees to

replace and supress their own emotional response by an organizationally sanctioned

response.Because individuals are motivated to maintain or enhance a sense of oneness and

SA leads to inauthentic/fake emotional displays (increases emotional dissonance), it has

been argued that SA results in psychological distress (i.e., depression) (Liu et al.,

2008). Grandey (2003) asserts that, "DA minimizes emotional dissonance by bringing

feelings in line with expressions, so DA's relationship with emotional exhaustion should

be weaker than the relationship between SA and emotional exhaustion" (p. 89). Emotional

exhaustion (a key component of burnout) closely resembles traditional stress reactions

that are studied in occupational stress research, such as job-related depression and

anxiety (Demerouti, Bakker, Nachreiner, & Schaufeli, 2001). Research has demonstrated

that SA is more positively and strongly related to emotional exhaustion than DA (Kruml &

Geddes, 2000; Totterdell & Hoiman, 2003).

Hypothesis 2: DA's relationship with psychological distress is weaker than the

relationship between SA and psychological distress.

In general, a given variable functions as a mediator to the extent that it accounts for

the relationship between the predictor and the criterion (Baron & Kenny, 1986). This

study predicts that DA and SA will mediate the relationship between El and psychological

distress.
Research suggests that El abilities and traits contribute to good physical and

psychological health (e.g., Salovey, Bedell, Detweiler, & Mayer, 1999). For example,

people who do not recognize and understand their own emotions well are more prone to

depression and anxiety (Ciarrochi, Scott, Deane, & Heaven, 2003), substance use

disorders, eating disorders, and somatic complaints (Taylor, 2001; Conrad, Schilling,

Langenbuch, Haidl, & Liedtke, 2001). In a study conducted on clinically depressed

patients, Downey et al. (2008) found significant associations between severity of

depression and the El dimensions of Emotional Management (r= -0.56) and Emotional

Control (r = -0.62). In addition, various empirical studies have well documented the

significant negative relationship between overall El and psychological distress (e.g.,

Besharat, 2007; Tsaousis & Nikolaou, 2005).
As noted above, the primary value of understanding El lies in the prediction of certain

outcomes such as psychological distress. The previous discussion about the relationship

between EL strategies and psychological distress shows that EL strategies may affect the

level of psychological distress. Thus, El is related to psychological distress because

El affects emotional labour, in that El is a vital characteristic that enables an

individual to appropriately match the EL strategy (DA vs. SA) to the situation.

Consequently, the EL has a direct impact on the psychological distress level. The above

discussion suggests the hypothesis that EL will mediate the effects of El on

psychological distress.
Hypothesis 3a. SA will mediate the relationship between El and psychological distress
Hypothesis 3b: DA will mediate the relationship between El and psychological distress
Method
Participants:
The sample for this study consisted of 200 employees from three public sector

organizations situated in the province of Balochistan, Pakistan. 92 participants of the

total sampie (46 percent) were males and 108 (54 percent) were females. The mean age for

this sample was 31.48 years (SD = 8.10). All participants were treated in accordance

with the "Ethical principles of Psychologists and Code of Conduct" (American

Psychological Association, 2002). Administration of the questionnaires was carried out

by post graduate students who acted as research assistants and no monetary incentive was

provided.
Measures:
Psychological distress. Psychological distress was measured by Chan's (2005) twenty item

scale. This scale measures psychological distress in terms of current non-psychotic

symptoms in the five symptom areas represented by scales of health concerns, sleep

problems, anxiety, dysphoria, and suicidal ideas. Respondents were requested to rate

each symptom statement on a 5-point scale (not at all to extremely) by comparing

themselves during the past 2 weeks with their 'usual selves'. Coefficients alphas for

the five dimensions were: health concerns: .75; sleep problems: .68; anxiety: .60;

dysphoria: .86; and suicidal ideas: .78.

Emotional Labour. SA was measured by three items adopted from Grandey's (2003) EL scale.

The sample items include, "I just pretend to have the emotions I need to display for my

job". DA was measured by three items adopted from Brotheridge and Lee (1998) EL scale.

The sample items include, "I make an effort to actually feel the emotions that l need to

display to others". The response scale has been seven point Likert-type scale ranging

from one (strongly disagree) to seven (strongly agree).
Emotional intelligence. Wong and Law Emotional Intelligence Scale (WLEIS: Wong & Law,

2002), one of self-report measures based on Saloveyand Mayer's model (1990), taps

individuals' knowledge about their emotional abilities. Specifically, the WLEIS is a

measure of beliefs concerning self-emotional appraisal (ability to understand one's deep

emotions and be able to express these emotions naturally), others' emotional appraisal

(ability to perceive and understand the emotions of other people), regulation of emotion

(ability to regulate one's own emotions), and use of emotion (ability to make use of

one's emotions by directing them toward constructive activities and personal

performance). The response scale has been seven point Likert-type scale ranging from one

(strongly disagree) to seven (strongly agree).
Design and Analysis
Inspection of skewness and kurtosis statistics revealed non normality for most of the

items. Because of nonnormal data we resorted to Partial Least Squares (PLS) path

modelling algorithm. PLS is far less restrictive in its distributional assumptions and

sample size restrictions as compared to covariance-based structural equation modelling

(CBSEM) (Fornell & Cha, 1994).
In line with Henseler, Ringle, and Sinkovics (2009) recommendations, PLS model was

analyzed and interpreted in two stages: the measurement model and the structural model.

The measurement model relates to the relations between manifest variables (observed

items) and latent variables. The measurement model is tested by assessing the validity

and reliability of the items and constructs in the model. Individual ■rem reliability

was assessed by examining the
oadings of respective items on their respective latent construct (Hulland, 1999),

whereas Composite reliability (nc) (Werts, Linn, & Joreskog, 1974) and Cronbach's alpha

(1951) were used to assess the reliability of scales. Convergent and discriminant

validity of constructs were assessed via Fornell and Larcker's (1981) AVE test. An AVE

value greater than 0.50 indicates that a latent variable is able to explain more than

half of the variance of its indicators on average. E. ;ence of the discriminant validity

occurs when square root of the variance extracted estimation exceed the correlations

between the factors making each pair (Fornell & Larcker, 1981). Regarding structural

model,
"r -cnparametric bootstrapping procedure using 1000 subsamples was performed to evaluate

the statistical significance of each path coefficient and to provide confidence

intervals for all parameter estimates.
3::3ness-of-fit (GoF) (Tenenhaus. Esposito Vinzi, Chatelin, & Lauro, 2005) was employed

to assess the overall fit of the model. GoF is normed between 0 and 1, where a higher

value represents better path model estimations.
Results
Measurement Model
The factor loadings from the final PLS measurement models are reported in Figure 1. PD5

(Sleep problem) due to factor loading of less than .50 was dropped from further

analysis. All remaining items loaded significantly (> .50) on their respective factors

which was an indication of indicator reliability. Composite reliability (hc) (Werts et

al., 1974) and Cronbach's alpha (1951) values for all scales exceeded the minimum

threshold level of 0.70 , thus indicating the reliability of all scales used in this

study (Table 1). Results revealed that the variance extracted for all factors exceeded

the minimum threshold value of 0.50 which was an indication of convergent validity of

all scales. Fornell and Larcker's (1981) test for discriminant validity

revealed relatively high variances extracted for each factor compared to the inter-scale

correlations, which was an indication of discriminant validity of four constructs (i.e.,

El, psychological distress, SA, and DA)

Structural Model
The results shown in Figure 1 supported hypothesis 1a and 1b: the coefficient of the

path from El to SAwas insignificant [a =-.03, t =0.21, p<.05, 95% CI:(-.26)-(.21)] and the coefficient of the path from El to DA was significant [a =.23, t= 3.16, p<,05, 95% CI: (.08) - (.39)]. Regarding hypothesis 2, SA had a significant direct impact on psychological distress [a =.30, f=5.56, p<001, 95% CI: (.20)-(.41), ^=.067] and the impact of DA on psychological distress was insignificant [3= .09, f =1.51, p>05, 95%

CI:(-.02) - (.22), F = .0101.

Exogenous variables in the model (i.e., DA, and SA) explained low amounts of variance of

psychological distress (R2 = .12). The value of R2may be decomposed in terms of the

multiple regression coefficients and correlations between the dependent variable and the

explanatory ones (Tenanhaus et al., 2005). This decomposition allows understanding the

contribution of each explanatory variable to the prediction of the dependent one. For

this model, SA was the most important variable in the prediction of psychological

distress, contributing to 82.5 %of the R2. On the contrary, DA contribution was only

16.33 % (far less than SA) (Table 2). The goodness-of-fit (GoF) (Tenanhaus et al., 2005)

index for the PLS model was 0.21, which indicated an acceptable data-model fit.

To test Hypothesis 3a and 3b proposing that emotional labour mediates the effect of El

on psychological distress, multiple mediator model (Preacher and Hayes, 2008) was tested

with case values of composite latent variables obtained in the PLS analysis. As can be

seen in Table 3, the 95 percent confidence intervals for both paths included zero,

therefore both SA and DA did not mediate the relationship between El and psychological

distress.

Discussion
The purpose of this study was to examine the relationships among EL, El, and

psychological distress in a sample of employees working in public sector organizations.

A specific objective was to determine the mediatory role of EL in the relationship

between El and psychological distress. The majority of proposed hypothesis received

considerable support, clearly demonstrating the relationships of the EL with EI and

psychological distress. This is the first empirical study (to my knowledge) in a South

Asian context to assess the relationship of EL strategies with other variables.
It was hypothesized that El would be differentially related to the EL strategies, that

is, emotionally intelligent employees would engage more in DA (modification of internal

feelings) than SA (faking or suppression of feelings). In line with previous studies

(Cote, 2005; Johnson, 2007) support was found for this hypothesis. This finding

indicates that El is a vital characteristic that enables an individual to appropriately

match the EL strategy to the situation (Feldman Barrrett, & Gross, 2001). Furthermore,

El enables people to deep act more that is, to understand people, be empathetic to their

circumstances, and internalizes their feelings. Conversely employees low on El are more

inclined to surface act, because they are unable to accurately perceive, appraise,

understand, and express emotions in order to comply with the demands of the situation as

well as to internalize others feelings. In other words, it s easy for employees low on

El to suppress or fake emotions than to generate positive emotions via perceiving,

understanding and regulating emotions (El abilities).
It was hypothesized that individuals performing SA would be more susceptible to

psychological distress than individuals T-; = :e: In DA. in line with previous studies

fe.g.r Johnson, 2007; Kruml & Geddes, 2000; "fctterdell & Holman, 2003) support was

foundforthis hypothesis. SAwas the most important variable in the prediction of

psychological distress, contributing to 82.25 % of the R2. This finding corroborates the

assertion that emotional dissonance (the difference between felt and expressed emotions)

is the direct outcome of SA and leads to emotional exhaustion (Grandey, 2003), which in

turn positively influences many negative outcomes such as psychological distress

(Panagopoulou, Kersbergen, & Maes, 2002). Furthermore, there was no relationship between

DA and psychological distress and this finding was consistent with previous findings

(Brotheridge & Grandey, 2002; Grandey, 2003). This finding suggest that employees who

engage themselves in DA are better able to avoid psychological distress by actively

changing their emotions (rather than just simply modifying outer expressions as in SA)

in order to comply with organizational display rules.
Finally no support was found for the mediatory role of EL in the relationship between El

and psychological distress, in order to gain further understanding of the situation,

second model was tested by adding an additional path from El to psychological distress.

The results indicated significant direct impact of El on psychological distress [a =

-.24, i = 3.10, p < .05, 95% CI: (-.36) - (-.09), f = .06], This shows that El directly

impacts psychological distress rather than through other mediatory variables.
Implications
The current study provides several implications for practice. It is evident from the

results of current study that in order to promote DA, organizations must find ways to

enhance employees' El level. This could be accomplished via cultivating a service-

oriented organizational climate, training and socialization of employees. Training

programs focusing on emotional regulation skills and DA techniques to cope with

emotional demands of work can help in reducing the deleterious effects of SA. Organizations must find ways to hire emotionally intelligence people against jobs that require substantial amounts of emotional work. Finally, employers can help employees to internalize their roles rather to fake the emotions (Ashforth & Humphrey, 1993) by providing them adequate resources needed to meet the demands of the job.
Limitations
There are few limitations in this study that must be mentioned. First, the results are specific to organizations in one geographical area and may or may not be generalizable to other areas. Second, we used a cross-sectional design, which limited our ability to draw any causal references regarding the relationships found among variables in the study. The direction of causality (in cross-sectional studies) cannot be established and will have to be examined using longitudinal data. Finally, all respondents were full-time employees and these findings may not be applicable to part-time employees.
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Jahanvash Karim, Doctoral Student, des Entreprises d'Aix-en-Province, Ut Puyricard - BP 30063, France
Robert Weisz, PhD, Universite de Paul Cezane, Clos Guiot Puyricard - BP 30063, France

Clinical implications of Psychopharmacology

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Clinical implications
Schizophrenia
Following the discovery that some antipsychotic drugs bind to sigma receptors, the suggestion arose that sigma receptors may be involved in schizophrenia and in the mode of action of antipsychotic drugs. Support for this hypothesis arose from the observation that the density of sigma receptors was dramatically reduced in several brain regions of post-mortem brains from schizophrenic patients. Such changes appeared to be restricted to the sigma receptor and did not involve the NMDA receptor or the PCP receptor. Whether such findings implicate alterations in sigma receptor function in schizophrenia is uncertain as it is possible that the changes in the density of these receptors is a function of the duration of treatment with neuroleptics. Support for the possible involvement of sigma receptors in schizophrenia, and in the action of antipsychotic drugs comes from the observation that haloperidol had a high affinity for these receptors in rat brain. Furthermore rimcazole, a putative neuroleptic, was found to have a high affinity for sigma receptors with little action on dopamine receptors. Several other sigma-selective ligands were also developed as possible neuroleptics. Unfortunately, despite convincing pre-clinical data showing that many of the sigma-selective ligands were active in animal models predictive of antipsychotic activity, none proved to have efficacy in clinical trials. It would therefore seem that the sigma ligands so far developed are unlikely to become the novel neuroleptics of the future.

Movement disorders
The most common symptomatic dystonias result from the administration of neuroleptics and occur as acute dystonic reactions or as tardive dyskinesia. The dystonias are disorders that involve sustained, involuntary muscle contractions and abnormal posture which interferes with normal motor function. Dystonias can be focal, as in the case of torticollis in which the neck involuntarily rotates, or they may be progressive and generalized as in torsion dystonia in which the body slowly becomes contorted. Torsian dystonia is familial and recent studies have identified a defective gene which may be responsible. Acute dystonic reactions occurring following the administration of potent neuroleptics are reported primarily in young men and usually develop shortly after the start of therapy. By contrast, tardive dystonia occurs following chronic neuroleptic treatments; as with tardive dyskinesia, symptoms often begin after the abrupt withdrawal of the neuroleptic. Although less severe than acute dystonic reactions, tardive dystonia is frequently permanent and difficult to treat. Until recently, the cause of dystonia has been assumed to involve a dysfunction of the basal ganglia. However, it is now known that most patients with lesions of the basal ganglia show no evidence of dystonia while those patients with dystonia exhibit little biochemical or anatomical change in basal ganglia function. More recently, there is clinical evidence that dystonia is associated with lesions of the brainstem and the cerebellum. The cerebellum is closely linked to the red nucleus which contains a high density of sigma receptors but few dopamine, serotonin or glutamate receptors. The brainstem region is also implicated in the hereditary mutant mouse model of dystonia in which the symptoms are known to be associated with both brainstem and cerebellar lesions. The presence of sigma receptors in anatomical structures that control movement and posture provides indirect evidence for the link between sigma receptors and dystonia. Further support for the involvement of these receptors is provided by the effects induced by the direct administration of sigma ligands into the red nucleus of rats; the degree of dystonia produced is directly proportional to the affinity of the drug for the sigma receptors. Additional experimental support for the involvement of sigma receptors in idiopathic dystonias comes from studies on a strain of rats which can develop a lethal dystonia but which are free of any identifiable anatomical lesions. It would appear that the density of sigma receptors is dramatically reduced compared to their non-affected litter-mates.

Regarding neuroleptic-induced dystonias, it is well known that typical neuroleptics cause catalepsy in rats and movement disorders in man. By contrast, the atypical neuroleptics clozapine and sulpiride have a low propensity to cause movement disorders in man even though they have established antipsychotic effects. These atypical neuroleptics, unlike many of the typical neuroleptics, have a low affinity for sigma receptors which lends support to the hypothesis that the dystonias produced by typical neuroleptics are related to their affinity for sigma receptors in the brainstem–cerebellar region.

Neurodegenerative disorders
So far all the evidence implicating the neuroprotective action of sigma ligands has been based on animal models of stroke or neurodegeneration. Several sigma ligands such as igmesine (JO 1784), NPC26377, ifenprodil and eliprodil have been shown to protect gerbils against ischaemic insult resulting from the bilateral occlusion of the carotid arteries; this is a popular experimental model of stroke. Similarly, ifenprodil and eliprodil, which have high affinity for sigma receptors in rat brain, are effective in protecting the mouse against focal cerebral ischaemia when administered after the induction of ischaemia. It would appear that the neuroprotective action is due to modulation of the polyamine site on the NMDA-glutamate receptor. However, as sigma ligands such as DTG, 3-PPP and BM4 14802 (which lack affinity for the NMDA glutamate receptor) have no neuroprotective action in the mouse model of focal cerebral ischaemia, it is uncertain whether highly selective sigma ligands would be effective in focal ischae mia in man. In other experimental studies, the potent sigma ligand igmesine has been shown to potentiate the potassium-evoked release of acetylcholine from rat hippocampal slices in vitro, an effect which is blocked by haloperidol. This suggests that igmesine may act as a sigma-1 agonist and may facilitate memory formation. Further evidence for this possibility is provided by the anti-amnestic action of igmesine in scopolamine-treated rats. These experimental studies suggest that sigma ligands, particularly sigma-1 agonists, may have therapeutic potential in the treatment of stroke and possibly in facilitating memory formation in the aged brain. Only doubleblind clinical trials of drugs such as igmesine, which appear to be relatively devoid of peripheral organ toxicity, will determine whether the various animal models of memory deficit and neurodegeneration are really predictive of potential therapeutic activity.

Anxiety and depression
There is experimental evidence to show that representative drugs for most classes of antidepressants have a modest affinity for sigma-1 receptors in vitro. Some antidepressants, such as sertraline and the monoamine oxidase- A inhibitor clorgyline, are moderately potent ligands for their receptor site. However, more recent studies have indicated that the most important final common pathway for the action of antidepressants involves the modulation of the NMDA-glutamate receptor possibly via the sigma receptor. It therefore seems uncertain that potent and selective sigma ligands will form the basis of a new group of antidepressants. However, there is more convincing experimental evidence to suggest that sigma ligands could have anxiolytic or anti-stress activity. Thus igmesine and DTG have been shown to block environmentally induced stress or corticotrophin-releasing factor induced colonic activity in the rat. Recently there has been renewed interest in the clinical development of igmesine as an antidepressant. Other experimental studies have shown that selective sigma ligands such as Lu 28-178 are potent anxiolytics in rodent models of anxiety.

The future of sigma receptor ligands
Besides the obvious need to develop highly potent and selective drugs for the sigma-1 and sigma-2 receptor sites, knowledge of the precise structures of the sigma receptors is required in order to establish firmly their identity. The presence of sigma receptors in the brain, in the gastrointestinal tract and endocrine and immune systems suggests that there must be endogenous factors that act as agonists and antagonists for these receptors. To date the nature of these endogenous factors is unknown but there is experimental evidence to implicate some neuropeptides (such as neuropeptides- Y and PYY) and steroids such as progesterone and deoxycorticosterone as putative ligands. In addition to the need for more detailed experimental studies to characterize the cellular mechanism of action of the different types of sigma receptors it is also essential to broaden the clinical profile of these drugs. So far, attention has been almost exclusively directed at the action of relatively non-selective sigma ligands in the treatment of psychotic disorders. The experimental findings that sigma compounds may have putative neuroprotective and anxiolytic/anti-stress effects will hopefully encourage the further development of the highly selective sigma compounds for their therapeutic application.

Endocoids and their Role in Psychopharmacology

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The empirical evidence implicating naturally occurring substances which occur within the mammalian brain and which appear to produce their psychotropic effects by activating specific receptors within the brain. Such substances are termed endocoids and they include the enkephalins and endorphins, which activate specific opioid receptors, the anandamide related compounds, which activate cannabinoid receptors, the endopsychosins and related compounds that activate sigma receptors and natural agonists and antagonists that show an affinity for the benzodiazepine receptors. These different types of endocoids will be discussed in terms of their possible physiological effects.

Endogenous cannabinoids and cannabinoid receptors
The Chinese emperor Shen Nung is believed to have produced the first written account of the medicinal properties of cannabis over 2000 years ago and various formulations of herbal cannabis have been used over the centuries to treat seizures, neuralgia, dysmenorrhoea, insomnia and even gonorrhoea. The hemp plant, Cannabis sativa, from which cannabis and many of the related compounds are obtained, has a long history in medicine. Thus over the centuries the cannabinoids have been used for the treatment of pain, asthma, dysentery, as sedatives, for the suppression of nausea and vomiting and as anticonvulsants. Although the clinical uses of the cannabinoids declined in the 20th century there has been a renewed interest in these natural compounds in recent years for the control of spasticity associated with multiple sclerosis and in the treatment of chronic pain. Such renewed interest coincided with greater attention being paid by the medical profession and society at large to herbal remedies. Understanding the mec hanism of action of the cannabinoids has been advanced by the identification and cloning of specific cannabinoid receptors in the mammalian brain and spleen and the identification of endogenous substances which bind to these receptors. Thus the cannabinoid receptors in the brain are primarily of the CB1 type. These receptors are widely distributed in areas concerned with motor activity (basal ganglia and cerebellum), memory and cognition (cerebral cortex and hippocampus), emotion (amygdala and hippocampus), sensory perception (thalamus) and with endocrine function (hypothalamus and pons). The distribution of radio-labelled tetrahydrocannabinol, the main active ingredient of Cannabis sativa, is similar to the distribution of the CB1 receptors and there is good evidence that the cannabinoids exact their action through these receptors. In addition to the CB1 receptors, CB2 receptors have been identified on macrophages in the spleen where they probably mediate the immunological effects of the cannabinoids. CB1 receptors have also been detected in peripheral tissues.

The discovery of cannabinoid receptors has raised the possibility that therapeutic agents could be developed that may combine the therapeutic uses of the cannabinoids with lack of abuse and drug dependency. The first endogenous substances to be shown to have a high affinity for the cannabinoid receptors were the anandamides, named after the Sanskrit word for ‘‘bliss’’=ananda. Structurally the endogenous ligands for the cannabinoid receptors are unlike those of plant origin. The The system comprising the cannabinoid receptors and endogenous anandamide-related compounds is referred to as the anandamide system. However, it must be borne in mind that endogenous ligands for cannabinoid receptors may exist with properties that differ from those of the anandamide series of compounds. Endogenous parent compound is a derivative of the endogenous fatty acid arachidonic acid, arachidonyl ethanolamide. More recently, two other endogenous unsaturated fatty acid ethanolamides with a high affinity for cannabinoid receptors have been identified in brain tissue. These are homogamma-linolenylethanolamide and docotetraenylethanolamide. While there is convincing evidence that endogenous compounds exist in the mammalian brain that have properties which resemble those of tetrahydrocannabinol, the most potent cannabinoid from a plant source, the question arises regarding the need to postulate the existence of specific receptors for these natural ligands. After all, although opioid peptides have been isolated from brain extracts, the search for other receptor ligands, including those which bind to the benzodiazepine and sigma receptors, has not been nearly as successful. Nevertheless, due to the special nature of receptors which are coupled to G proteins, it is highly probable that there are natural ligands for all such receptors. This is because G proteins are single molecules that do not contain allosteric binding sites, unlike the benzodiazepine–GABA receptor where the benzodiazepine binding site is an allosteric regulatory site for GABA.

For all G protein-coupled receptors, every receptor has an endogenous ligand associated with its binding site. Thus it is reasonable to conclude that the binding sites for the anandamide system in the mammalian brain are true receptor sites through which the physiological changes initiated by the cannabinoids are expressed. Despite the recent advances in molecular biology, the mechanisms of action and the physiological functions of the anandamide system remain obscure. It would appear that the cannabinoid receptors and the anandamides reside within the neurons. Thus unlike the classical neurotransmitters noradrenaline and serotonin, the anandamides are not released into the synaptic cleft and are not involved in interneuronal communication. Instead the anandamides modulate the excitability and inhibitory responsiveness of neurons by acting on cannabinoid heteroceptors located on inhibitory and excitatory terminals. In this way, the cannabinoid receptors reduce the activity of these neurons by decreasing the i nflux of calcium through the calcium channels and increasing the efflux of potassium ions through the potassium channels located on the neuronal membrane. In some regions such as the cerebellum, there is a convergence of the G protein-linked receptors such as the GABA-B, adenosine A1, cannabinoid and kappa opioid receptors that inhibit the activity of adenylate cyclase thereby leading to a reduction in the release of glutamate. Thus it seems possible that the anandamide system modulates the activity of the major neurotransmitter systems including the opioid, prostenoid and glucocorticoid systems.

Sites of action of the cannabinoids
CB1 receptors are present in a high density in the hippocampus and cerebral cortex and the effects of cannabinoids on cognition and memory are undoubtedly related to their activation of the receptors in this brain region. These regions also mediate the effects of the cannabinoids on perception of time, sound, colour and taste. With regard to the motor effects, and effects on posture, of the cannabinoids it would appear that this is related to their agonist action on CB1 receptors located in the basal ganglia and cerebellum. Other central actions of the anandamide system include the hypothalamus (effect on body temperature), the spinal cord (antinociception) and the brain stem (suppression of nausea and vomiting). The discovery that cells of the immune system contain both cannabinoid binding sites and cannabinoid receptor mRNA suggests that the immunosuppressive actions of the naturally occurring cannabinoids are receptor mediated. There is now evidence that cannabinoid receptors occur on spleen cells in rodents and man and in human thymus cells and monocytes, but the receptor density is lower than that occurring in the brain. The B-lymphocytes have been shown to contain the highest quantity of cannabinoid receptor mRNA. The specific binding of cannabinoids to the small intestine and testis has also been reported to occur in different mammalian species. As the peripheral cannabinoid receptor appears to be of the CB2 type which appears to be absent from the brain, there have been attempts to develop selective agonists which would lack psychotropic properties but which would be of therapeutic value as immunosuppressants and in the control of such autoimmune diseases as rheumatoid arthritis. Conversely, CB2 receptor antagonists may act as drugs to enhance immune function. To date, no compounds have reached clinical application despite showing promising pharmacological profiles in the preclinical stages of their development. There is hope that a new approach in which analogues of the anandamides are developed will be more fruitful.

Physiological processes in that endogenous cannabinoids may be act as mediators
The possible physiological importance of the endogenous cannabinoids has largely been based on an extrapolation from the pharmacological properties of the THC-like compounds that are known for their psychotropic effects. Such drugs may differ in action from the endogenous cannabinoids because of their broad range of activity that follows the activation of both the CB1 and CB2 receptors, but also their ability to inhibit membrane bound enzymes and to cause a disruption of the normal function of the phospholipid compounds of neuronal and other membranes. Thus it would be anticipated that endogenous cannabinoids would show more selective actions both in the brain and periphery.

Tolerance is known to develop rapidly to many of the effects of the psychotropic cannabinoids but little is known regarding the mechanisms responsible for the development of tolerance to these drugs. One possibility to account for the development of tolerance is that compensatory decreases in the sensitivity or density of cannabinoid receptors occurs following the prolonged stimulation of these receptors, perhaps by inducing changes in the genetic expression of the receptor protein. This could occur as a result of a decrease in the signal transduction mechanism or in the affinity of the receptor sites for the cannabinoids. There are several in vitro and in vivo experimental studies in support of such mechanisms, but it is presently unproven whether such mechanisms apply to the components of the anandamide system.

Endozepines as endogenous anxiolytic and anxiogenic agents
It has been postulated that, at the cellular level, the symptoms of anxiety can arise because:
1. There is inadequate activity of an endogenous anxiolytic ligand.
2. There is excessive activity of an endogenous inverse agonist at the benzodiazepine receptor site.
3. There is a dysfunctional GABA-A receptor causing a shift in the GABAA complex towards inverse agonist activity.
It is uncertain which of these three possibilities apply to patients with anxiety disorders. There is evidence that the binding of the benzodiazepine receptor antagonist, flumazenil, is lower than normal in patients with panic disorder and that it increases the panic attack frequency in these patients but not in normal subjects. This has been interpreted as a slight shift in the benzodiazepine receptor towards the inverse agonist state.

Three types of endozapines have been isolated. It is known that the betacarbolines can be synthesized in the mammalian brain and that, in vitro, they act as inverse agonists at benzodiazepine receptor sites. Theoretically such compounds could induce anxiety. However, none of these compounds has been isolated in vivo and the original detection of a beta-carboline in the urine of anxious patients was later found to be an artifact, possibly caused by bacterial contamination. A diazepam binding inhibitor has been isolated from mammalian brain and found to be a mixture of two peptides (an octodecaneuropeptide and a trikontatetra neuropeptide) which stimulates neurosteroid synthesis by acting on peripheral benzodiazepine receptors. There are two main neurosteroids present in the mammalian brain which are antagonists of GABA-A receptors, namely dehydroepiandrosterone and its sulphate form (DHEA and DHEAS). These neurosteroids are also synthesized in the adrenal glands. These neurosteroids are known to have multiple effects of brain function by affecting mood, cognition and sleep; they also enhance neuronal plasticity and are neuroprotective. The third group of compounds are the naturally occurring benzodiazepines. Desmethyldiazepam has been isolated from human brains which were stored frozen in the 1930s, at least two decades before the benzodiazepines were developed. While there is no evidence that the benzodiazepine structure can be synthesized enzymatically in the mammalian brain, several other compounds of this type have since been isolated from cattle brain and from human breast milk. One possibility is that gastrointestinal flora can partially synthesize the benzodiazepine molecule and it is also known that plants such as wheat and potatoes are a potential source of diazepam, desmethyldiazepam and lormetazepam. If it is eventually shown that the local brain concentration of these benzodiazepines is sufficiently high to activate the benzodiazepine receptors then the possibility arises that anxiety disorders could result from a lack of these endozepines.

Several species of plant also contain compounds that have been shown to act as agonists on benzodiazepine receptors. These include: Valeriana officinalis which contains hydroxypinoresinol, Matricaria recutita which contains 5,7,4’-trihydroxyflavone, Passiflora coeruleus which contains chrysin and Karmelitter Geist which contains amentoflavin. Hypericum perforatum (St John’s Wort) also contains unknown compounds which have affinity for these receptors. Extracts of these drugs are commonly recommended by herbalists for the treatment of insomnia and anxiety.

Endogenous sleep factors
Early in the 20th century, Pierin in Paris infused the CSF of sleep-deprived dogs into normal dogs and showed that the CSF contained a sleep-inducing (somnogenic) factor. This was thought to be a muramyl peptide but later suggested to be the result of bacterial contamination as these peptides cannot be synthesized by the mammalian brain. Pro-inflammatory cytokines can also induce sleep, the effect depending on the concentration of the cytokine and the time of day. The effect on the sleep profile (increased non-REM and decreased REM sleep) appears to depend on the increased synthesis of prostaglandin D2 and nitric oxide which then alter the circadian rhythm. It is also known that some pro-inflammatory cytokines can affect the reuptake of 5-HT which plays an important role in regulating the sleep–wake profile. The endogenous fatty acid, oleamide, can cause sedation and induce sleep by activating cannabinoid receptors but also by potentiating the action of benzodiazepines on their receptor sites. Whether such action is of physiological relevance is presently unknown.

Function and therapeutic effects of sigma receptors
The sigma opiate receptor were originally proposed by the American neuropharmacologist William R. Martin as the site that mediates the psychotomimetic and stimulatory effects of cyclazocine, pentazocine, Nallyl normetazocine (SKF 10047) and related opiates in humans and dogs. However, there is now considerable evidence to suggest that these effects are not mediated by opioid receptors. Many of the opiates that have psychotomimetic properties also bind with a high affinity to phencyclidine (PCP) receptor sites situated in the channel of the N-methyl-D-aspartate (NMDA) receptor. It now appears from electrophysiological, biochemical, anatomical and molecular studies that there are two distinct sites that bind opioid analgesics that have an affinity for sigma receptors. One site is on the PCP receptor situated in the NMDA receptor. The other sigma site is defined as non-opioid, non-dopaminergic and shows a high affinity for haloperidol and N-allyl normetazocine. Using a highly selective ligand for sigma receptors such as ditolyguanidine (DTG), it has now been possible to separate sigma receptors into two major types. Sigma-1 receptors are the main neuronal type and exhibit a high affinity for centrally acting antitussive and anticonvulsant drugs. The other site has a low affinity for most sigma ligands except DTG and haloperidol. This site is found in the red nucleus and cerebellum (as well as many other brain regions) where it may mediate the motor (dystonic) effects of different types of sigma ligand. Biochemically the sigma-1 and sigma-2 receptors may also be distinguished by the nature of the second messenger to which they are attached. Thus the sigma-1 receptors appear to be linked to guanylyl nucleotide binding proteins (G proteins) whereas the sigma-2 sites are not and may bring about their physiological effects by modulating K+ channels.

Sigma receptors and psychosis
Some 20 years ago, Martin and coworkers proposed that the psychotomimetic effects of pentazocine and related opiate analgesics was due to their effect on sigma receptors. It is now known that the sigma receptors are quite distinct from PCP, opioid, serotonin and dopamine receptors. However, many psychotropic drugs that bind to dopamine, serotonin and PCP receptors also have a high affinity for sigma receptors. For example, haloperidol and the novel benzamide neuroleptic remoxipride bind with high affinity for both D2 and sigma receptors. Nevertheless, there are many potent neuroleptics that have a negligible affinity for sigma receptors and conversely, many sigma ligands that do not apparently have any neuroleptic activity, but it remains a possibility that there could be an involvement of sigma receptors in the pathology of schizophrenia. Thus receptor autoradiographic studies of post-mortem schizophrenic brain have demonstrated a significant reduction of sigma binding sites in the frontal cortex, amygdala and hippocampus without any significant change in the density of PCP binding sites. Therefore, the evidence linking a malfunctional sigma receptor system to schizophrenia, or the use of selective sigma receptor ligands as putative neuroleptics, is inconclusive.

Sigma receptors and the immune and endocrine systems
Experimental evidence suggests that sigma receptors play an important role in regulating and integrating both immune and endocrine functions. In experimental studies, it has been shown that the selective sigma ligand N-allyl-normetazocine stimulates the hypothalamic–pituitary–adrenal axis but suppresses luteinizing hormone and prolactin secretion. A high density of sigma receptors has been identified on human leucocytes and in the rat spleen, testis, ovary and adrenal gland. In human leucocytes it has also been shown that sigma receptors are involved in the second signalling mechanisms that are essential for cellular activation. In addition, sigma receptors have been identified on human and rat T and B cells. There is experimental evidence to show that the suppression of T cell replication, and enhanced activity of monocyte phagocytosis, that occurs in some rodent models of depression, can be effectively reversed by the chronic administration of selective sigma ligands such as igmesine. This suggests that such compounds may be of benefit in correcting the diverse immune and possibly endocrine defects that characterize depression.

Stress and the immune system

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All forms of stress result in the activation of the pituitary–adrenal axis, with a consequent rise in circulating catecholamines and glucocorticoid hormones from the adrenal gland. The secretion of ACTH from the pituitary gland, which is controlled by hypothalamic CRF, triggers the secretion of adrenal glucocorticoids, while stress-induced activation of the sympathetic system is responsible for the catecholamine secretion. It is now apparent that ACTH secretion can also be increased by thymic peptides (such as thymopoietin), while interleukin-1 (IL-alpha), a product of macrophage activity, has been shown to enhance ACTH secretion. Such events show how the immune, endocrine and central nervous systems are integrated in their responses to any form of stress. It is well established that physical or psychosocial stress causes increased secretions of prolactin, growth hormones, thyroid, and gonadal hormones, in addition to ACTH. Endogenous opioids are secreted under such conditions and function as immunomodulators, while also elevating the pain threshold. Receptors for such hormones exist on immunocompetent cells, along with receptors for catecholamines, serotonin and acetylcholine. In addition to the regulatory effects of the nervous system on the immune system, there is now convincing evidence that the immune system can influence brain function. Thus changes in the activity of specific nuclei in the hypothalamus of the rat have been described following the formation of antibodies to specific antigen challenges. Alterations in electrical activity appear to be linked to specific decreases in noradrenaline concentrations in these nuclei. Changes in the activity of the serotonergic neurons in the hippocampus also occur shortly after the occurrence of the immune response. These findings illustrate how the immune system, presumably via the release of immunoregulatory peptides (also called immunotransmitters) such as interleukins from macrophages, can influence the activity of the hypothalamic–pituitary axis and also higher centres of the brain (such as the hippocampus), which are involved in short-term memory processing.

The effect of stress on the endocrine and immune systems depends upon its duration and severity. Following acute stress, the rise in ACTH in response to the release of corticotrophin releasing factor (CRF) from the hypothalamus results in a rise in the synthesis and release of cortisol from the adrenals. The increase in the plasma cortisol concentration results in a temporary suppression of many aspects of cellular immunity. Due to the operation of an inhibitory feedback mechanism, stimulation of the central glucocorticoid receptors in the hypothalamus and pituitary causes a decrease in the further release of CRF, thereby decreasing the further synthesis and release of cortisol. Arginine vasopressin (AVP) also plays a role in activating the release of ACTH from the anterior pituitary gland. Following chronic stress, however, the regulatory feedback inhibitory mechanism is dysfunctional due to the desensitization of the central and peripheral glucocorticoid receptors. Thus cortisol continues to be secreted primarily due to the activation of the hypothalamic–pituitary axis by AVP and the elevated pro-inflammatory cytokines such as interleukin-1. Due to the desensitization of the glucocorticoid receptors on the immune cells and in the brain, and a lack of inhibition by glucocorticoids of central macrophage activity (the astrocytes and glial cells), glucocorticoids continue to be secreted.

Immune system in affective disorders
Susceptibility to bacterial and viral infections, and to the establishment of tumours, is reported to arise more frequently in those who are depressed than in those who are not. An analysis of the immune systems of those suffering the severe psychological stress of bereavement has shown that the activity of those immune cells that are fundamentally involved in the host defence against infections (e.g. NKCs and T-lymphocytes) is dramatically reduced. Such an effect can occur following chronic and subchronic stress. The past 20 years have witnessed a broad interest in the role of the hypothalamic–pituitary–adrenal axis in the psychobiology of affective disorders. In depressed patients, increases in serum cortisol are frequently reported in addition to disruptions of circadian patterns of cortisol secretion and an insensitivity of cortisol secretion to suppression by glucocorticoids such as dexamethasone. The potential association between the immune system and mood disorders has become a major topic of interest in biological psychiatry in the past decade. In general, three immune measures have been examined, namely white blood cell counts, functional measures of cellular immunity such as natural killer cell activity and immune cell markers as exemplified by human lymphoctye antigen (HLA). The cumulative data from these studies suggests that depressed patients have a decreased number of lymphocytes, reduced mitogen-induced lymphocyte proliferation and a reduction in the number of natural killer cells. However, this does not apply to all depressed patients. Furthermore, not all aspects of immune function are decreased despite the presence of hypercortisolaemia. Thus the activity of macrophages (that include the microglia and astrocytes in the brain which are part of the immune system) has been shown to increase in depression. These immune cells release cytokines that not only act as immunoregulators but also as neuromodulators of central neurotransmitters.

In general, the cytokines are either of the pro-inflammatory type (called Th-1 type, and largely stimulatory in their action) or anti-inflammatory type (called Th-2 type and largely inhibitory in their action). The proinflammatory cytokines are exemplified by interleukins (IL-) 1, 6 and tumour necrosis factor (TNF-) alpha while the anti-inflammatory cytokines are IL-4, 10 and 13. The presence of elevated blood concentrations of the pro-inflammatory cytokines, and in the concentration of IL-1 in the CSF, has led to the macrophage hypothesis of depression which suggests that the changes in brain neurotransmitter function are a consequence of the increase in inflammatory changes. The neural damage occurring in cortical and subcortical regions of the brain of depressed patients has been ascribed to the shift in the balance to proinflammatory cytokines from anti-inflammatory cytokines. These changes occur both in the brain and in the periphery and, in chronic depression, the brain damage is accentuated by the elevation of glucocorticoids which are hypersecreted due to the desensitization of the glucocorticoid receptors on neurons and on immune cells.

If a malfunctional immune system plays a role in the pathogenesis of depression, it would be anticipated that antidepressants have an immunoregulatory action. Because immune cells express neurotransmitter receptors, mediators such as noradrenaline and serotonin, as well as various neuropeptides, are able to modulate the immune response. Moreover, neurons and glial cells express cytokine receptors and the release and action of neurotransmitters are modulated by cytokines. Antidepressants appear to affect cytokine release from macrophages, monocytes and glial cells in addition to their well-known effects on monoamine synthesis. Antidepressants can also modulate intracellular signals such as cyclic AMP and neurotrophic factors and in this way alter the synthesis of the proinflammatory cytokines. The beneficial long-term effects of antidepressant treatments in depression may therefore result from a shift in the balance of the pro-inflammatory to the anti-inflammatory cytokines in addition to improving the brain repair mechanisms.

Clearly, more detailed studies must be undertaken to validate this hypothesis, but these preliminary findings link proven neurotransmitter changes in depressed patients with the delays in onset of action of antidepressants and the changes in cellular immunity. It now seems probable that specific disturbances occur in the immune system in psychiatric illness that are not artefacts of non-specific stress factor, institutionalization or medication. The known effects of the neuroendocrine system on the immune response, and the recent evidence that receptor sites for neurotransmitters and neuroendocrine factors occur on lymphocytes and macrophages, support the hypothesis that immunological abnormalities may assist in precipitating the symptoms of anxiety and depression, commonly symptoms of major affective disorders.

Changes in the immune system in schizophrenia
Evidence suggesting an abnormality in immune function in those subject to severe stress or suffering from depression largely relates to an abnormality in function. Such abnormalities do not appear to occur in schizophrenia. Possibly because of its well-established genetic component, many aspects of the immune system would appear to be deranged in schizophrenic patients. Thus abnormalities in the concentration of serum immunoglobulins and deficiencies in immune responsiveness have been reported to occur in such patients. Several investigators have reported a generalized increase in the immunoglobulins in both acute and chronic stages of schizophrenia, although not all investigators have been able to confirm this. There is some evidence that antibrain antibodies which could selectively destroy specific types of brain cells have been detected in schizophrenic patients. Some years ago, a factor was isolated from the serum of schizophrenic patients that produced catatonia and an abnormal electroencephalographic pattern when injected intravenously into monkeys or human volunteers; the electroencephalogram changes were similar to those seen in schizophrenic patients. The serum protein causing these abnormalities was termed taraxein. These findings were confimed by some researchers but not by those who used a more reliable radioimmunoassay method. However, in an extensive study of antibrain antibodies in 69 schizophrenics and 58 controls, it has been shown that if antibrain antibodies play any role in psychiatric disorders they are nonspecific and only present in a small percentage of patients. Allergic reactions entail disordered immune functioning, and controversy exists regarding allergies to various food substances and the incidence of schizophrenia. Some studies have suggested that schizophrenics have an increased incidence of allergies in childhood, especially involving an intolerance to wheat gluten. However, there are few adequately controlled studies to show that food allergies play any role in the aetiology of schizophrenia and, to date, there is little unequivocal evidence to support the view that allergies play a causal role in this illness.

There is evidence to suggest that there are at least two genetically determined components in those at risk from schizophrenia. One of these components facilitates a decrease in suppressor cells, while the other promotes the accumulation of antithymic immunoglobulins. The consequences of the resultant imbalance between the helper and suppressor mechanism which arises from these immune malfunctions are the occurrence of specific antitissue antibodies, the formation of which is normally controlled by a balance between helper and suppressor T cell mechanisms. There have been several suggestions whereby the negative symptoms of schizophrenia could represent an autoimmune encephalitis-like syndrome in which a viral infection, for example, could initiate an autoimmune response against dopaminergic pathways. One possibility is that dopamine receptor stimulating antibodies could be produced as part of the pathological processes that have a high affinity for the dopamine autoreceptors and thereby decrease the release of the neurotransmitter in specific dopaminergic pathways. However, it must be emphasized that the clinical data upon which many of these speculations are based have been obtained from patients on prolonged treatment with neuroleptics. These drugs are known to modify the immune system which could increase the subsequent vulnerability of the patient to viral infections.

It may be speculated that an inherited primary defect in the immune system could initiate schizophrenia by stimulating the production of antibrain antibodies or by increasing the vulnerability of the patient to a viral infection. Alternatively, a primary defect in central neurotransmitter metabolism, possibly involving dopamine, may cause the immune abnormalities which have been described. In this case it may be argued that the immune changes are an epiphenomenon of the disease and not necessarily the primary cause. Although there has been considerable interest in investigating the changes in the immune system of patients with depression, it is only more recently that researchers have turned their attention to the possible involvement of the immune system in the pathogenesis of schizophrenia. As has already been mentioned, antibrain antibodies have been detected in the CSF of chronic schizophrenic patients while the presence of an increase in the concentration of immunoglobulin G in the CSF, which correlates with the presence of negative symptoms, is a further suggestion that an inflammatory process is operational in the brain of the schizophrenic patient. With regard to the pro-inflammatory cytokines, IL-6 is increased in both the CSF and serum from medicated and unmedicated patients; this is reduced by effective antipsychotic drug treatment. Studies in children with schizophrenia have shown that interferon alpha is raised in the CSF and that this cytokine correlates both with the severity of the symptoms and in their refractoriness to drug treatment. It is of interest to note that the secretion of interferon is an important component of the antiviral immune response that may provide further evidence in favour of the viral hypothesis of schizophrenia. Unlike depression, IL-2 concentrations have been found to increase in the CSF of schizophrenic patients. As there is some evidence that this cytokine can increase the release of dopamine from central neurons, it is possible that IL-2 could contribute to the hyperdopaminergic state which characterizes the acute form of the disease. Support for a central inflammatory process being involved in the pathology of schizophrenia comes from the recent report that cyclo-oxygenase 2 inhibitors, such as celecoxib, potentiate the action of atypical antipsychotics such as clozapine in schizophrenic patients who appear to be resistant to the therapeutic effects of atypical antipsychotics.

Inter-relationship Between Psychopharmacology and Psychoneuroimmunology

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An adverse effects of stress and depression, the effects of bereavement, unemployment and social isolation on mental and physical health have been known since antiquity. Aristotle advised physicians, ‘‘Just as you ought not to attempt to cure eyes without head or head without body, so you should not treat body without soul.’’ One of the fathers of modern medicine put it more scientifically in the 19th century when he recommended that when attempting to predict health outcomes from tuberculosis in patients, it is just as important to know what is going on in a man’s head as it is in his chest. These are two of the numerous examples, largely anecdotal, that document the complex and intimate connection between the mind and the body. In the past 20 years this has given rise to a new science of psychoneuroimmunology that is devoted to the study of the inter-relationship between the brain, behaviour and the immune system. Interest in this area of neuroscience has undoubtedly been due to the impact of acquired immune deficiency syndrome (AIDS) in which it has been estimated that at least 10% of these patients will develop mood, behavioural, cognitive and memory changes before they develop somatic signs of the illness. Similarly, studies have shown that 6 months before patients with pancreatic cancer develop clinical signs of the disease, a significant proportion develop depression. Such observations suggest that not only does the brain influence the immune system by way of the endocrine and efferent neuronal pathways but also that products of immune cell activity, such as the cytokines, play a role in modifying human behaviour by directly modulating central neurotransmitter pathways.

Basic structure of the immune system
It is not the purpose of this short introduction to psychoneuroimmunology to give a comprehensive view of the immune system. Most of the cells comprising the immune system can be divided into one of two categories depending on the targets of their action. Thus the immune cells are either primed to eliminate specific pathogens or to respond to any type of cell that is not recognized as being a normal body component. The first category of cells comprises the different types of lymphocytes which are divided into the B-lymphocytes (B cells) that are responsible for antibody production, and the T-lymphocytes (T cells) that directly phagocytose pathogens or release specific biologically active proteins, the cytokines, that regulate the activity of other cells in the immune system. Both T and B cells respond in a highly specific manner when attacking pathogens. In addition to these specific immune cells, there are phagocytic cells, such as the monocytes and neutrophils, that respond to any cell type or foreign molecule that is not recognized as being a normal constituent of the body. The phagocytic cells such as the monocytes and neutrophils are basically scavenger white blood cells that ingest invading bacteria or viruses. Some of the monocytes also enter the tissues where they become macrophages. They can also provide signals enabling T cells to respond more efficiently to the pathogen. In this situation the antigen becomes attached to the monocyte membrane which is then presented to a T-lymphocyte together with the cytokine interleukin-1 (IL-1). This initiates a further activation of T-lymphocytes. Monocytes also produce mediators of inflammation, the complement proteins, which help to create a hostile environment for foreign organisms. In addition to complement proteins other mediators of the immune response include histamine (which acts as a local hormone to cause capillary dilatation), the prostaglandins and leukotrienes which act to initiate and terminate the activities of the macrophages and T cells.

Lymphocytes are derived from bone marrow but, whereas some of the cells remain in the bone marrow until they reach maturity (the B cells), others migrate early in their development to the thymus gland to become T cells. Thus B (from bursa) and T (from thymus) cells learn to distinguish between the normal constituent cells of the body and foreign objects, due to the presence of specific memory cells which are under genetic control. B and T cells circulate throughout the vascular system before concentrating in lymphoid tissue (spleen and lymph nodes) where they remain inactive until stimulated by specific antigens. Because of the specificity of function imparted on the T and B cells by the memory cells, the lymphocytes are highly selective in responding to relatively few antigens.

Main properties of the immune cells that are altered in psychiatric illnesses :
Natural killer cells (NKCs):
Recognize changes on cell-membrane virus-infected and cancer cells and destroy the cells. NKCs bind to surfaces of target cells and inject cytotoxic molecules into the cell membrane, destroying the cells. There are several types of cells that have NKC activity.

Phagocytes:
Two major classes of WBCs are involved in removing invading microorganisms by a process of phagocytosis. These are polymorphonuclear leukocytes and mononuclear phagocytes, or monocytes. In tissues, monocytes differentiate into macrophages and, in the brain, into microglia.

T and B lymphocytes:
Produced by lymphoid tissue. Lymphocytes represent about 20% of the WBCs in adults; they have a long life span (sometimes several years). They probably serve as memory cells for the immune system. These mononuclear cells may be small, agranular structures (T and B cells) or large, granular cells (NKCs). Different types of T cells may only be differentiated by their cell-surface markers (CD markers – clusters of differentiation). CD markers are identified using labelling antibodies.

T cells exist in several different forms. Thus the T-helper cells (Th cells) play a regulatory role by facilitating the antibody production by B cells and also activate the macrophages. Other types of T cells can directly attack pathogens or normal cells that have been infected with a virus or bacterium for example. These are the cytotoxic T cells, or natural killer cells (NKCs). Not only can such cells destroy pathogens but they also secrete such cytokines as IL-1 which have a key role to play in orchestrating the immune system both peripherally and in the brain. The immunoglobulins (the most important in man being IgM, IgG, IgE, IgD and IgA) are produced following the activation of B cells by specific antigens. Fever and sleep are important events which assist recovery following an infection by helping to destroy heat-sensitive foreign microorganisms. One of the key promoters of sleep and fever following an infection is IL-1. This cytokine can penetrate some areas of the blood–brain barrier and raise the temperature ‘‘set point’’ in the hypothalamus thereby producing a fever. Similarly IL-1 promotes slow-wave sleep and thereby facilitates tissue repair due to the secretion of growth hormone during that sleep phase. In addition to facilitating tissue repair, growth hormone can also boost the immune system. Whereas the precise mechanism whereby the cytokines can enter the brain and initiate subtle changes in brain function is uncertain, CNS changes initiated by peripherally produced IL-1 (and also by the microglial cells within the brain) provides convincing evidence that the immune system directly impacts upon the brain.

The endocrine immune relationship
One of the major pathways whereby the central nervous system regulates the immune system is via the hypothalamic–pituitary–adrenal (HPA) axis. Various neurotransmitters (e.g. serotonin, noradrenaline, acetylcholine) regulate the secretion of corticotrophin releasing factor (CRF) which controls the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. ACTH directly activates the adrenal cortex to produce glucocorticoids (e.g. cortisol). Following the rise in the plasma concentration of the glucocorticoids, a negative feedback mechanism normally operates to block the further release of ACTH from the pituitary. In depression, however, there would appear to be an insensitivity of the central glucocorticoid receptors to this feedback regulation. As a consequence, the plasma concentration remains elevated and cannot be easily suppressed by a potent synthetic glucocorticoid such as dexamethasone. This forms the basis of the dexamethasone suppression test (DST) which is often used as a biological marker of depression. T cells are particularly sensitive to the inhibitory effects of the glucocorticoids. In particular, the nascent T cells, which represent about 90% of all T cells in the thymus gland, are very sensitive to the inhibitory effects of these steroids; high steroid concentrations can also prematurely induce the migration of T cells from the thymus to other immune tissues. This leads to a decrease in the size of the thymus gland. It should be emphasized that the effects of the glucocorticoids on the immune system are biphasic; in high concentrations they suppress major components of the immune system whereas in low concentration they activate it. In addition to glucocorticoid receptors, T cells also contain receptors for prolactin and growth hormones which suggests ways in which the endocrine system can directly affect the immune system. The adrenal gland secretes glucocorticoids in a pulsatile rhythmical way with the highest plasma concentrations being reached during the day. It has been shown that the lowest plasma concentration of the glucocorticoids coincides with the time at which the lymphocytes respond most actively to antigens. As the hypersecretion of cortisol is a characteristic feature of depression and other psychiatric conditions, it is perhaps not surprising to find that components of the immune system are also abnormal in this condition.

Anatomical links between the brain and the immune system
What is the mechanism whereby the nervous system can influence the immune system? Two major routes serve to link the brain with the immune system. The first is via the HPA axis, already referred to. The second is via the autonomic nervous system. It has been known for over 20 years that there were adrenoceptors on T cells, B cells and macrophages. In addition, noradrenergic fibres directly innervate the bone marrow, thymus, spleen, lymph nodes and virtually all other immune organs. These sympathetic nerve terminals not only release noradrenaline but also possibly neuropeptides as well. There is evidence that many sympathetic nerve terminals innervating the immune organs make direct contact with the parenchyma, ending adjacent to the cells of the immune system. In the spleen for example, the sympathetic terminals penetrate the areas that contain a high density of helper T cells and also cytotoxic and suppressor T cells. Electron microscopic evidence suggests that the sympathetic nerve terminals can form direct physical contact with T-lymphocytes and macrophages.

The functional connection between the peripheral sympathetic system and the immune system can be illustrated by the changes which take place in ageing. It is known that in the aged animal the sympathetic innervation of the spleen is dramatically reduced. This appears to be associated with deficiencies in T cell function and in cellular immunity. At the cellular level, immunosenescence is associated with a change in responsiveness of the immune cells and in their ability to regulate the beta adrenoceptors on their cell surfaces. Such changes appear to shift the metabolism of the sympathetic nervous system to a state that encourages apoptosis (or programmed cell death) possibly by inducing an increase in the production of cytotoxic metabolites. Experimental evidence suggests that the monoamine oxidase-B (MAO-B) inhibitor deprenyl (selegiline) can reduce these neurodegenerative changes in the peripheral sympathetic system and lead to the restoration of sympathetic innervation of the spleen.

Geriatric Psychopharmacology

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An elderly person is likely to experience many socioeconomic, emotional and physiological changes which will have a major bearing on psychotropic drug treatment. Such a population is therefore more likely to be exposed to more types of drug treatment than younger age groups.

It is found that the vast majority of elderly patients being treated for a psychiatric disorder also have at least one physical disorder that requires medication; 80% of all elderly patients have at least one chronic physical illness. Thus the elderly are the most likely group to experience adverse drug reactions and interactions. Studies show that patients over the age of 70 years have approximately twice as many adverse drug reactions as those under 50 years. Another problem which particularly affects the elderly population concerns compliance with prescribed medication. Factors such as impaired vision, making it difficult for the patient to recognize the various medications, hearing, manual dexterity and cognition all contribute to the non-compliance. Perhaps one of the most important factors that governs non-compliance is the increased frequency and severity of the side effects that occur with most types of medication in the elderly. This may be illustrated by the tricyclic antidepressants and phenothiazine neuroleptics, both these classes of drugs having pronounced antimuscarinic activity even in the physically healthy young patient. In the elderly there is evidence of excessive sensitivity to the anticholinergic effects of drugs. This is compounded by the decline in cognitive function which accompanies ageing. Thus one must anticipate that patient compliance for any psychotropic drug with pronounced anticholinergic and sedative side effects will be low. Another problem which can compromise compliance concerns the hypotensive actions of many psychotropic drugs (e.g. tricyclic antidepressants, phenothiazine neuroleptics). Due to the alpha1 receptor antagonistic action of these drugs, they are likely to cause severe orthostatic hypotension in some elderly patients. This can cause patients to fall and damage themselves. The increased sensitivity of the elderly to the sedative effects of drugs is also well known. As hypnotics and anxiolytics are frequently administered to the elderly, the sedative effects of these drugs can be minimized by using drugs that have a short to medium half-life. There seems little justification for using the long half-life sedative hypnotics in the elderly patient.

Dementia
The pathological and clinical features of the various types of dementia. A variety of conditions that occur in the elderly must be differentiated from true dementia. Delirium, for example, is associated with an alteration in the level of consciousness, disordered thinking and fluctuating cognitive impairment. Such a delirious state can occur for a variety of reasons, including inadequately treated diabetes, hyperparathyroidism or hepatic encephalopathy. Dementia must also be distinguished from psychosis, in which the patient shows impairment of thinking but not impairment of memory. The term ‘‘pseudo-dementia’’ is often used to describe a depressive episode in which the patient presents with abnormalities of mood, appetite and sleep disturbance with cognitive dysfunction which is directly caused by the depression. The cognitive deficits usually resolve with treatment of the underlying condition. Finally cerebrovascular disease or carotid occlusion may be associated with episodic memory loss. It is therefore important to diagnose correctly the cause of the memory and cognitive impairment so that appropriate treatment may be given. Should the results of clinical and neurological investigation clearly establish the existence of Alzheimer’s disease, then the appropriate symptomatic therapy (e.g. a cholinesterase inhibitor) may be considered.

Pseudodementia
This is defined as any condition which mimics dementia. The commonest psychiatric disorder which mimics dementia is depression in which the retardation can be confused with the apathy of dementia. The guiding principle is careful clinical assessment and, if in doubt, a trial of an appropriate antidepressant.

Depression
A disturbance in the sleep pattern is a common symptom of depression but changes in the sleep pattern also occur as a consequence of ageing. Once depression has been diagnosed, there are several types of antidepressants which may be given. Because of their potent anticholinergic side effects, there seems little merit in prescribing the older tricyclic antidepressants (e.g. amitriptyline, imipramine) to such patients. There is now sufficient evidence to suggest that sedative antidepressants such as mianserin or trazodone given at night reduce the likelihood that the patient will require a sedative hypnotic. For the more retarded elderly patient, a non-sedative antidepressant such as lofepramine or one of the SSRIs (e.g. fluoxetine, fluvoxamine or sertraline) may be used. The side effects and cardiotoxicity of the tricyclic antidepressants have been discussed in detail elsewhere in this volume and, while there is ample evidence of their therapeutic efficacy, it seems difficult to justify their use, particularly in a group of patients who are most vulnerable to their detrimental side effects. Of the newer antidepressants, the reversible inhibitors of monoamine oxidase type A such as moclobemide may also be of value in the elderly depressed patient, particularly in those patients who fail to respond to the amine uptake inhibitor type of antidepressant. The safety of antidepressants should be the first priority for the elderly. For this reason, the second-generation antidepressants, or the atypical tricyclic antidepressant lofepramine, should be the drugs of choice. Undoubtedly the SSRI antidepressants have a major role to play and of these, citalopram and fluvoxamine have been extensively studied in the elderly depressed patient. It should also be remembered that electroconvulsive therapy (ECT) can be potentially life-saving in the elderly, particularly if the patient is suffering from delusions or is retarded and depressed. ECT should also be considered when antidepressant drug treatment has failed.

Psychosis
A variety of psychotic conditions occur in the elderly, but it is important to remember that an elderly person who develops agitation, paranoid ideation or delusions may be suffering from a drug-induced delirium. The most common causes of such a condition are drugs that have potent central muscarinic-blocking properties, such as the antiparkinsonian agents, antihistamines, tricyclic antidepressants and antipsychotics. Withholding all psychotropic drug medication for a few days may be the most judicious management for this type of toxic psychosis. Agitation and aggression are often symptoms of advanced Alzheimer’s disease and high potency atypical antipsychotics such as risperidone or olanzapine may be of value in demented patients. Drugs such as chlorpromazine and thioridazine are more likely to produce hypotension, cardiac abnormalities and excessive sedation in the elderly patient, and side effects are, of course, a problem with the high potency neuroleptics in the elderly; centrally acting anticholinergic agents that are used to reverse some of the symptoms of parkinsonism in such patients should be used as little as possible and in the lowest possible doses. Mania can occur in any age group. Acute manic episodes in the elderly may best be managed with high potency neuroleptics. The use of lithium is not contraindicated in the elderly provided renal clearance is reasonably normal. The dose administered should be carefully monitored, as the halflife of the drug is increased in the elderly to 36–48 hours in comparison to about 24 hours in the young adult. The serum lithium concentration in the elderly should be maintained at about 0.5mEq/litre. It is essential to ensure that the elderly patient is not on a salt-restricted diet before starting lithium therapy. The side effects and toxicity of lithium have been discussed in detail elsewhere (see p. 198 et seq.), and, apart from an increase in the frequency of confusional states in the elderly patient, the same adverse effects can be expected as in the younger patient.

Paranoid disorders
According to DSM–IV, it has abandoned the terms paranoia and paraphrenia and replaced them with the term delusional disorder to describe non-affective and nonbizarre delusional states. Neuroleptics have been the group of drugs most widely recommended for delusional states. Of the first-generation neuroleptics, the sedative, cognitive impairing and extrapyramidal side effects are likely to be particularly prominent in the elderly. The introduction of the atypical neuroleptics should improve the treatment of these disorders as they are generally better tolerated due to their improved side-effect profile. TCAs, together with neuroleptics should be avoided as they may aggravate psychotic symptoms and potentiate any anticholinergic side effects. In the case of the very aggressive patient, parenteral administration of lorazepam or diazepam will usually be sufficient to enable the patient to be managed.

Anxiety and insomnia
Anxiety states are often expressed somatically in the elderly and therefore it is important to exclude any physical disorder, such as cerebrovascular disease and thyroid dysfunction, which can be associated with apprehension and agitation.

Most psychotropic drugs are highly lipophilic, and the increased fat to lean body mass ratio and the decreased metabolism and excretion in the elderly patient mean that the half-lives of most psychotropic drugs are increased. The benzodiazepine anxiolytics and hypnotics are no exception. Following a single dose of chlordiazepoxide, diazepam or flurazepam, the time for elimination of the parent compounds and their active metabolites can be as long as 72 hours. For this reason, it is now general practice to administer a short-acting benzodiazepine (e.g. oxazepam, alprazolam or temazepam) only as needed and for as short a period as possible. Such drugs should only be used for a period not exceeding 6 weeks. Supportive psychotherapy, either as an adjunct to drug therapy or as an alternative, has an important role to play in treating mild anxiety states in the elderly. Insomnia is a common complaint in the elderly. As people age they require less sleep, and a variety of physical ailments to which the elderly are subject can cause a change in the sleep pattern (e.g. cerebral atherosclerosis, heart disease, decreased pulmonary function), as can depression. Providing sedative hypnotics are warranted, the judicious use of short half-life benzodiazepines such as temazepam, triazolam, oxazepam and alprazolam for a period not exceeding 1–2 months may be appropriate. Because of their side effects, there would appear to be little merit in using chloral hydrate or related drugs in the treatment of insomnia in the elderly. It should be noted that even benzodiazepines which have a relatively short half-life are likely to cause excessive day-time sedation.

In addition to the benzodiazepines, there may be a role for the nonbenzodiazepine drugs such as zalaplon, zolpidem or zopiclone in the treatment of anxiety and insomnia in the elderly. These drugs appear to be well tolerated in younger populations of patients, but it is essential to await the outcome of properly conducted trials of these drugs on a substantial number of elderly patients before any conclusions may be drawn regarding their value as alternatives to the benzodiazepines.

Application of Psychotropic Drugs in Specific Childhood Disorders

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Attention deficit hyperactivity disorder (ADHD)
This is a heterogeneous disorder of inattention, hyperactivity and impulsivity that starts in childhood and may persist into adulthood. Children with the disorder can be identified by their inattention which leads to daydreaming, distractability and difficulty in sustaining an effort to complete a task. Their impulsivity makes them accident prone and disruptive while their hyperactivity, combined with excessive talking, is poorly tolerated particularly in schools. As teenagers, the hyperactivity and impulsivity tend to diminish but other symptoms persist. The adolescent with ADHD often has low self-esteem, poor relationships with peers and often becomes subject to drug abuse. To what extent ADHD persists into adulthood is open to debate, but some longitudinal, family and genetic studies would favour this view. ADHD is often co-morbid with conduct, depressive, bipolar and anxiety disorders.

Psychopathology of ADHD
Evidence of fronto-limbic dysfunction with poor inhibitory control of the cortex over the limbic system would appear to account for many of the physical and psychological symptoms. Neuroimaging studies have implicated a disorder of the right frontal cortex while PET imaging studies have shown that there is an approximate increase of 70% in the dopamine transporter in this brain region. Genetic and twin studies have shown that the heritability of the hyperactivity of ADHD is greater than 65%, while that of the attention deficit is greater than 70%. In molecular genetic studies there is evidence of an association between ADHD and a defect in the D4 receptor gene, but it must be emphasized that not all studies have replicated this. D4 receptor ‘‘knock-out’’ mice show supersensitivity to cocaine and methamphetamine that may have some bearing on the pathology of ADHD in children. ADHD is also associated with an abnormal allelic form of the dopamine transporter protein.
The catecholamine hypothesis of ADHD is the most widely supported hypothesis at the present time. This is largely based on the efficacy of the drugs used to treat the disorder and which act on the noradrenergic and dopaminergic systems. The drugs would appear to be most effective during the initial phase of the daily treatment when the plasma drug concentration is rising. This parallels the acute release of noradrenaline and dopamine and it has been argued that these changes in the catecholamines increase the inhibitory effect of the pre-frontal cortex on the subcortical regions of the brain. There is less convincing evidence regarding the involvement of 5-HT in ADHD; SSRIs have little benefit in treating the disorder. Recently, evidence has emerged that the nicotinic cholinergic receptors are defective, a view which is supported by the finding that nicotine applied as transdermal patches can improve some of the symptoms of the disorder.

Nicotinic receptors can act as heteroceptors on dopaminergic terminals in the frontal cortex, which again serves to emphasize the importance of the dopaminergic system in the pathology of this disorder.

Pharmacological treatment of ADHD
The stimulants methamphetamine, dexamphetamine, methylphenidate and pemoline have been shown to improve the main symptoms of the disorder in up to 70% of children; they may be of some benefit in adults also.

Conduct disorders
The symptoms consist of a collection of symptoms such as defiance, disobedience, temper tantrums, fighting, destructiveness, stealing and lying. These disorders frequently lead to the child being brought to the child psychiatric clinic and requiring treatment as they predict potentially serious outcomes in terms of later psychiatric disorders. While there has been an emphasis on the use of different psychotherapeutic techniques for treating these disorders, there is increasing evidence that psychotropic drugs have an important role to play. Neuroleptics such as chlorpromazine and haloperidol have been used to treat aggressive behaviour in mentally handicapped children, but there is always a risk that such drugs have a negative impact on the cognitive, social, emotional and developmental aspects. Such side effects necessitate the use of such drugs for a very short period only. Whether the atypical antipsychotics such as risperidone could be used as safer alternatives to the first-generation neuroleptics is unnown but because of their better side effects, are worthy of consideration.

Anticonvulsants have sedative side effects and therefore drugs such as carbamazepine have occasionally been used to treat conduct disorders. There is no evidence that such drugs are useful in the control of aggressive symptoms.

Lithium may be of some value in the treatment of difficult, impulsive and aggressive adolescents and children but the results from the studies in which lithium was used are few and the outcome uncertain. Thus, at present, there is little evidence that psychotropic drugs have a major role to play in the treatment of conduct disorders.

Emotional disorders
These disorders in children are considered to be particularly amenable to psychological treatment and therefore there has been a reluctance to use psychotropic drugs to treat them. In addition, problems of diagnostic classification have confounded research into drug treatment. Nevertheless the benzodiazepines and tricyclic antidepressants have been used. Thus the benzodiazepines have been used for childhood emotional disorders but there are no satisfactory controlled studies regarding their efficacy. Clearly only the short-term use, using short half-life drugs such as temazepam, is acceptable. So far there is no evidence of benzodiazepine dependence occurring in children. Of the tricyclic antidepressants used, clomipramine has been shown to be effective in the treatment of children with obsessional symptoms, effects which have been shown to be independent of the antidepressant action of the drug. More recent studies have provided evidence that the SSRI antidepressants such as fluoxetine are as effective, with fewer side effects.

Tic disorders
These range from transient disorders lasting a few weeks or months to chronic conditions lasting more than a year. The most severe form of a tic disorder is Tourette’s syndrome. Neuroleptics are the drugs of choice in the treatment of tic disorders but they should only be considered in situations where the life of the child is seriously affected and when behavioural treatments have failed. Of the classical neuroleptics which have been used, haloperidol and pimozide have shown success but so far there have been no adequately controlled trials of any neuroleptic to objectively validate their efficacy. It would appear that only low doses of haloperidol are necessary (2–3mg/day) to obtain a significant reduction in tic frequency. It would seem reasonable to consider the use of the atypical antipsychotics for these disorders but, to date, there is no evidence of their efficacy in children. Recently there have been studies in which clonidine was used in the effective treatment of motor tics. The side effects are similar to those seen in the adult and include sedation, headache, irritability and sinus bradycardia.

Nocturnal enuresis
This is quite a common condition affecting some 7% of 7 year olds who continue to wet the bed at least once a week. The cause of nocturnal enuresis is complex and beyond the scope of this volume. It is evident, however, that various treatments are available including retention control, dry-bed training, enuretic night alarms and waking the child to urinate during the night. The most effective treatment (estimated at 80%) is the use of the enuretic night alarm. Drug treatments include sympathomimetic stimulants, anticholinergics, tricyclic antidepressants and synthetic antidiuretics. Of these, imipramine and desmopressin have been found to be the most effective. The efficacy of imipramine has been repeatedly demonstrated in controlled trials; about 85% of children treated within a week of the start of medication, but tolerance frequently develops after a number of weeks and relapse is high after discontinuation of the treatment. Relatively low doses of imipramine only are needed, but the typical side effects of tricyclic antidepressants limit the prolonged use of the drug. The mechanism of action of imipramine in the treatment of nocturnal enuresis is unclear but one possible action is through a direct anticholinergic action on the bladder wall.

The synthetic vasopressin peptide, desmopressin, has been extensively investigated and shown to be effective as tricyclic antidepressants in the control of nocturnal enuresis and to enhace the enuretic night alarm treatment. The side effects are relatively few (nasal pain, conjunctivitis) when given by nasal spray. The precise mechanism of action of this peptide is unknown.

Affective disorders of childhood and adolescence
There is much controversy regarding the occurrence of major depressive disorder in prepubertal children. However, several studies in both the United States and Britain have suggested that depressive disorder does exist, although the frequency appears to be lower than in adolescents. There is endocrinological evidence, based on the hypersecretion of cortisol and an abnormal growth hormone response to insulin-induced hypoglycaemia, to suggest that children with major depressive disorder show similar endocrine abnormalities to those of adolescents and adults. However, the number of patients in these studies is small and clearly more thorough investigations must be undertaken before any conclusion may be reached. Regarding the drug treatment of depression in children, there is so far a paucity of good clinical trials to show that antidepressants are effective. Several small studies suggest that daily doses of up to 5mg/kg of imipramine may be beneficial, but there is no data to show whether other types of antidepressant medication are effective. The side effects and toxicity of tricyclic antidepressants are legion and have been discussed in detail elsewhere. Undoubtedly the SSRIs should now be the drugs of first choice in the treatment of depression in children.

Manic disorders would appear to be extremely rare in young children and only single case reports have appeared in the clinical literature. They are more common in adolescence but not as frequent as among adults. Some authorities have argued that the extent of mania among adolescents is underestimated and that many patients have been misdiagnosed as schizophrenics. Regarding treatment, lithium would appear to be the drug of choice. Since children and adolescents appear to have a higher lithium renal clearance than adults, it is occasionally necessary to give the drug in a higher oral dose than would be usual for the adult. Apart from the possible detrimental effect of lithium on bone growth in children, the monitoring of the young patient should follow the same procedures as outlined for the adult.

Anxiety disorders
The DSM–IV classifies anxiety disorders in children into four categories, namely social anxiety, over-anxious disorder, phobias and separation anxiety. Only separation anxiety, a fear of losing a loved one or a close attachment, has been reasonably well studied from the point of view of drug treatment. School phobia is perhaps the most severe form of separation anxiety and there are several trials to show that imipramine, in daily doses of up to 5 mg/kg, is effective. Many patients require drug treatment for at least 6 to 8 weeks before an optimal response is achieved. Frequently, children remain symptom free after a 3–4 month course of treatment. In addition to the usual anticholinergic effects of imipramine, it should be noted that children are often susceptible to withdrawal symptoms such as nausea and gastrointestinal spasm. This may be reduced if the drug is slowly withdrawn over a 2-week period.

Obsessive–compulsive disorders
These occur only rarely in children but more frequently in adolescents. There have been no extensive studies of drug treatments of this condition in young patients, but anecdotal reports suggest that tricyclic antidepressants such as clomipramine may be as effective as they are in adults but the SSRI antidepressants should be considered as first line treatments.

Paediatric Psychopharmacology

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Psychotropic drug is to be given to either young or elderly patient, the general rule was to start with the lowest dose that is therapeutically beneficial in contrast to the standard dose that would be given to an adult. The rates of drug absorption, metabolism and distribution may differ. In the case of the child and aged one, hepatic microsomal enzyme metabolism, which is largely responsible for the metabolism of psychotropic drugs, were suboptimal.
There is also evidence that tissue sensitivity to many psychotropic drugs is altered at the extremes of age. Thus the general rule is to start at the lowest possible dose and, if necessary, increase the dose slowly until optimal therapeutic benefit is achieved. In the treatment of psychiatric disorders of children, the clinician is faced with a problem which is less apparent in the adult patient. In adult psychiatry, the diagnosis of the condition assists in ensuring optimal treatment.
As psychiatric diagnosis of childhood disorders is at a more elementary stage than it is in adult psychiatry, the diagnostic approach to treatment still leaves much to be desired. This chapter will therefore be confined to a discussion of those disorders of childhood for which there seems to be reasonable agreement over diagnosis and treatment. Despite the success in the use of psychotropic drugs for the treatment of psychiatric disorders in adults, and to some extent in adolescents, the application of psychotropic drugs for the treatment of children has been less encouraging. This has been due to the use of invalid diagnostic classifications, limitation of the methods for measuring response to treatment and the utilization of concepts drawn from adult psychiatry being inappropriately applied to children. These difficulties are reflected in the greater variability in the use of psychotropic drugs in children. This unfortunate situation is reflected in the fact that methylphenidate, imipramine and chlorpromazine still form the bulk of the prescriptions of child psychiatrists.There are four main areas where psychotropic drugs are useful in children:

1. To provide relief from symptoms until the child matures, for example, in enuresis.

2. As an adjunct to other treatments as, for example, when a child refuses to attend school.

3. To suppress symptoms and thereby prevent the negative effects on other psychogical parameters. An example of this would be a child who suffers from tic disorders which causes embarrassment.

4. In severe conduct disorders when other non-drug-based methods have been unsuccessful.

Short-term side effects of psychotropic drugs

As with all types of medication, the side effects of psychotropic drugs should be weighed against their benefits. Symptoms such as dizziness, appetite suppression and sleep disturbance occur quite commonly but often diminish following continual use. Other more serious side effects may involve changes in endocrine and cardiac function, effects which can sometimes be controlled by reducing the drug dose. Finally there are idiosyncratic and allergic reactions such as agranulocytosis which are difficult to predict and which can be fatal in some cases. Other side effects may only be manifest in the behaviour of individual patients. For example, benzodiazepines have a calming effect in most cases but can occasionally be associated with behavioural dysinhibition and lead to aggressiveness in a disturbed child. Similarly, neuroleptics can suppress aggression but also cause emotional flattening and cognitive dysfunction. Such side effects are particularly important in the younger child. Longer-term side effects such as growth retardation as a result of stimulants and tardive dyskinesia following the prolonged use of typical neuroleptics are particularly important. It is presently unclear whether the long-term use of stimulants leads to dependence, although there would appear to be little evidence that this is the case.

Specific Crimes ,Violent Offences

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Specific Crimes
Violent Offences
The Offence
· offence type does not accurately predict future offence category
· about 15 % of sexual offences are re-convicted, but re-conviction is just as
likely to be a non-sexual offence
Degree of violence
· degree increases with:
· low IQ
· mental illness
· intoxication
· low victim resistance
· family killings
· multiple killings
· when women killed
Quality of violence
· better indication of mental illness than quantity
· bizarre quality equates with mental illness or severe personality disorder
Disinhibiting factors
1. alcohol and drugs
· 86 % of victims assaulted are intoxicated at time of injury
· 63 % of offenders are intoxicated at time of offence
· 60 % of murderers have drunk alcohol prior to their offence
2. companions and groups
· e.g. football match
3. stress and fatigue
4. blood sugar
Criminal record
· the best predictor of future behaviour is past behaviour
1. predictors of repetition for dangerous offences include:
a) a juvenile record
b) number of previous offences
c) convictions for violence
i) one previous violent offence predicts 14 % chance of reconviction
ii) four previous violent offence predicts 60 % chance of reconviction
iii) the exception is over-controlled murder, where a ‘mildmannered’
person is ‘pushed over the edge’
d) severity of last offence
Personal data
1. Sex
· women less likely to seek violent solutions
· but when women do become violent, they can display the same level of
violence
· the most common offence committed by women is stealing
2. Age
· high rates of offending in youths
· sex crimes may decline with increasing age if offence is linked to orgasm
· exhibitionism may persist to later age
3. Marital status
· persistent failure to achieve sexual relationship and one or more violent
assaults on a woman is ominous
· of adult female victims of murder, 40 % were killed by their husband
4. Social circumstances
· association between homelessness and violence
Personality
· two broad types:
· over-controlled - feelings inhibited
· under-controlled - easily exhibits feelings and resorts to violence
· Helman’s triangle (in childhood) is a good predictor of future violence:
1. bedwetting
2. firesetting
3. cruelty to animals
· paranoid / suspicious
· suspicious is more likely to resort to verbal or physical aggression
Family and personal history
· violent behaviour is associated with:
· childhood deprivation
· poor parent / child relationships
· childhood beatings
· alcoholic fathers
· dominant mother
· isolation from peers
· deep hostility to authority
· childhood physical abuse is associated with:
· marital conflict and violence
· single parent families
· low socio-economic status
Past psychiatric history
· schizophrenia (esp. paranoid) is most likely diagnostic group to commit crimes of
violence
· mentally ill are more likely to be assaultative, and risk is increased if:
· male
· young
· low socio-economic status
· substance abusing
· rates of violent offending:
· schizophrenia = 5 in 10,000
· affective psychoses = 6 in 100,000
Predictors of repetition
1. History:
a) one or more previous episodes of violence
b) repeated impulsive behaviour
c) evidence of difficulty in coping with stress
d) previous unwillingness to delay gratification
e) sadistic or paranoid traits
2. The offence:
a) bizarre violence
b) lack of provocation
c) lack of remorse
d) continuing major denial
e) severity of violence
3. Mental State:
a) morbid jealousy
b) paranoid beliefs plus a wish to harm others
c) sadistic fantasy life
d) deceptiveness
e) lack of self control
f) threats to repeat violence
g) attitude to treatment/ lack of insight or willingness to comply
4. Circumstances:
a) provocation or precipitant is likely to reoccur
b) alcohol or drug abuse
c) social difficulties and lack of support
Shoplifting
· peak age = 10-18
· majority offend once and are not re-convicted
· in middle-aged women, depression is present in up to 30%
· associated with:
· phobic anxiety states
· chronically stressed
· personality disorder, in association with low mood
· chronic physical illness
· organic states
Arson
· M:F = 1:2.5
· more common in:
· subnormality
· alcoholism
· recurrence more likely if:
· multiple attempts
· psychotic
· demented
· mentally retarded
· alcoholic
· sexual excitement derived from the act
Stalking
· usually due to:
· personality disorder
· paranoid illnesses
Juvenile delinquency
· is law breaking behaviour by 10- to 20-year-olds
· associated with:
· unsatisfactory child rearing
· low IQ
· conduct disorder in childhood
· parental criminality
· large family size
· refers to the recurrent failure to resist irresistible impulses to steal objects not
needed for personal use nor for their monetary value
· it is classified under ICD-10 F63 ‘Habit and impulse disorders’
· it is rare – with less than 5% of shoplifters giving a history consistent with
kleptomania
· the average age of onset is 20 years
· the diagnosis is usually made 1-2 decades after the average age of onset
· stealing is impulsive, and done without the assistance of others

Automatism

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Automatism
· if a person has no control over an act, he cannot be held responsible for it – the
concept is similar to being ‘briefly insane’
· it is a legal term, and has no connection with epileptic automatisms
· verdicts of not guilty have been returned when acts of violence were judged to have
been committed as ‘sane automatisms’
· sane automatism:
· leads to a full acquittal
· seen to be due to an ‘external cause’
· includes:
· absent-mindednesss (in association with depression)
· insane automatism:
· automatism thought to arise from a ‘disease of the mind’ – the appropriate
defence is then insanity and the McNaghten rules apply
· are due to an ‘internal cause’ because the conditions may reoccur
· includes:
· epileptic automatism
· hypoglycaemia, hyperglycaemia
· sleep-walking
· arteriosclerosis
Amnesia
· in the absence of organic disease, the presence of amnesia is unlikely to carry any
legal implications

Intoxication

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Intoxication
· involuntary intoxication (as when someone unwittingly takes a drink to which a
drug has been added) or automatism occurring as a side-effect to medical treatment,
constitutes a valid defence
· self-induced intoxication is not a defence unless:
1. it is itself evidence of ‘disease of the mind’ under the McNaghten rules or
2. it is evidence of lack of intent in relation to those crimes for which ‘specific
intent’ must be proved (e.g. murder, theft, and burglary)
· intoxication has been accepted as a reason for diminished responsibility (Dingwall
1857) and for reducing murder charge to culpable homicide

Psychiatric defences

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Psychiatric defences
· a defence can be made that the person is not culpable because he did not have a
sufficient degree of mens rea due to:
1. not guilty by reason of insanity
2. diminished responsibility (not guilty of murder, but guilty of manslaughter,
which requires a lesser degree of criminal intent
3. incapacity to form an intent because of an automatism
4. if a mother kills her child in the first year of life, she is not usually held
legally responsible for murder, but for the lesser charge of infanticide
Not guilty by reason of insanity
· embodied in the McNaghten rules (in 1842 Daniel McNaghten, a wood turner from
Glasgow, shot and killed Edward Drummond, private secretary to the Prime
Minister, Sir Robert Peel)
· To establish a defence on the ground of insanity, it must be clearly proved
that, at the time of committing the act, the party accused was labouring
under such a defect of reason, from disease of the mind, as not to know the
nature and quality of the act he was doing, or, if he did know it, that he did
not know what he was doing was wrong
· the McNaghten rules due not apply in Scotland
· the burden of proof lies with the defence
· based on the opinions on 2 psychiatrists ‘on the balance of probability’
· it counts as an acquittal, but the disposal is as Insanity in bar of trial
Diminished responsibility
· the defence of diminished responsibility for murder was introduced in 1957
· the Homicide Act 1957 (Section 2) states:
· where a person kills or is party to a killing of another, he shall not be
convicted of murder if he was suffering from such abnormality of mind
(whether arising from a condition of arrested or retarded development of
mind or any inherent causes or induced by disease or injury) as substantially
impaired his mental responsibility for his acts and omissions in doing or
being party to the killing
· if the plea is acceptable to the judge and prosecution, there is no trial but a hearing
and a sentence of manslaughter (culpable homicide) is passed
· it refers only to sentencing, not responsibility for the act in terms of guilt
· “degrees of mental illness produce degrees of culpability”
· personality disorder is not sufficient in Scottish Law
Culpable homicide
· there is a lack of specific or evil intent to kill
· Involuntary culpable homicide – an unintended death occurs as a result of an
assault or other criminal act or as a result of culpable negligence
· Voluntary culpable homicide – death results from an intentional reckless act but
because of provocation or diminished responsibility, the offence is reduced from
murder to culpable homicide

Criminal responsibility ,Homicide

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Criminal responsibility
· in England and Wales, it starts at the age of 10 - children under 10 are excluded
because they are deemed incapable of criminal intent
· in Scotland, it begins at the age of 8
· children between 10 and 14 do not have mens rea unless it can be proved otherwise
– this is termed Dolci incapax and means that criminal responsibility is partial
· after the age of 14, an individual is legally responsible for their actions unless caused
by:
· a mistake
· an accident
· duress
· necessity
· mental disorder
Homicide
· in England and Wales, it may be:
· lawful and justifiable (e.g. killing on behalf of the state)
· lawful and excusable
· unlawful – this is ‘the unlawful killing of any reasonable creature in being and
under the Queen’s peace, the death following within a year and a day’
· causing death by dangerous driving
Insanity in bar of trial
Fitness to plead
· English law requires that the defendant must be in a fit condition to defend himself
· the issue can only be decided by a jury
· if the accused is found unfit to plead and the charge is murder, an order is made
committing him to any hospital specified by the Home Secretary where he may be
detained without limit of time and can be discharged only at the discretion of the
Home Secretary
· in determining fitness to plead, it is necessary to determine how far the defendant
can:
1. understand the nature of the charge
2. understand the difference between pleading guilty and not guilty
3. instruct counsel
4. challenge jurors
5. examine a witness
6. follow the proceedings in court
Disposal of those deemed insane in bar of trial
· three stage process:
1. Determine whether or not insane in bar of trial (evidence from two doctors, one
approved)
2. Examination of facts:
7
· as near as possible to an ordinary trial, but held in the presence of a sheriff or
judge alone
· if not satisfied beyond reasonable doubt, then acquitted
· if satisfied, then disposal
3. Disposal of insanity cases:
· hospital order +/- restrictions
· guardianship order
· new supervision and treatment order
· discharge with no order
· for murder, there is mandatory hospital and restriction orders

Psychiatric issues in the assessment of offenders

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Psychiatric issues in the assessment of offenders
Fitness to be interviewed
· factors to be considered include:
1. Does the detainee understand the police caution after it has been explained to
him or her?
2. Is the detainee fully oriented in time, place, and person and does he or she
recognize the key persons present during the police interview?
3. Is the detainee likely to give answers that can be seriously misconstrued by the
court? i.e. are they able to understand the consequences of their answers
The appropriate adult
· used when the detainee if found fit to be interviewed, but does have a mental illness
or learning disability
· an appropriate adult is:
1. a relative, guardian, or other person responsible for the care or custody of the
subject, or
2. someone with experience in dealing with mentally ill or handicapped people, or
3. some other responsible person who is not a police officer or someone who is
employed by the police
Mental state at the time of the offence
· before anyone can be convicted of a crime, the prosecution must prove the
following:
1. he carried out an unlawful act (actus reus)
2. he had at the time the state of mind necessary to commit a crime (mens rea)
· traffic offences only require actus reus
· the categories of mens rea (loosely translated as meaning a ‘guilty mind’) are:
1. Intent - the person perceives and intends that his act of omission will
produce unlawful consequences
2. Recklessness - ‘is the deliberate taking of an unjustifiable risk’. A man is
reckless with respect to the consequences of his act, when he foresees it may
occur but does not desire it (e.g. pulling the trigger of a gun that you do not
know whether it is loaded or not)
3. Negligence - ‘a man acts negligently when he brings about a consequence
which a reasonable and prudent man would have foreseen and avoided’
(Smith & Hogan 1988)
4. Blameless inadvertence - ‘a man may reasonably fail to foresee the
consequence of his act, as when a slight slap causes the death of an
apparently healthy person: or reasonably fail to consider the possibility of
the existence of a circumstance, as when goods, which are in fact stolen, are
bought in the normal course of business from a trader of high repute’ (Smith
& Hogan 1988)

Depression ,Bipolar Illness,Schizophrenia,Dementia

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Depression
· severe illness may lead to homicide
· the depressed person is usually acting on delusions
· family member is usually the victim in altruistic homicides
· the killer often commits suicide afterwards
· sometimes associated with shoplifting
Bipolar Illness
· offending is more common than in depression
· manic patients may spend excessively, hire cars and fail to return them, or steal cars
· may be charged with fraud or false pretences
· prone to irritability and aggression, though any resulting violence is seldom severe
Schizophrenia
· more likely to commit non-violent as well as violent crimes
· minor offences more likely than serious offences
· most criminal behaviour followed the onset of schizophrenia, although crime is
frequently a result of personality difficulties and social incompetence
· risk of homicide is moderately increased in schizophrenia compared to the general
population
· violence in schizophrenics may be associated with any of:
· great fear and loss of self control associated with non-systematized
delusions
· systematized paranoid delusions of persecution
· irresistible urges
· instructions from hallucinatory voices
· unaccountable frenzy
· risk of violence is greatest where delusions are accompanied by strong affect, and
when the person has made efforts to try to confirm the truth of the delusions
Dementia
· 44% are mildly aggressive
· 10% severely aggressive
· association between offending and dyspraxia
Episodic dyscontrol syndrome (Bach-y-Rita et al. 1971)
· repeated unprovoked episodes of violence
· excluded epilepsy, schizophrenia, pathological intoxication, drug intoxication
· unexplained violence preceded by a sequence of aura, headache, and drowsiness
· 50 % reported amnesia for the episode
· 50 % have EEG abnormalities, usually in the temporal lobes

Specific mental disorders and crime

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Specific mental disorders and crime
Psychopathic disorder
· in the Mental Health Act 1983 of England and Wales, the term psychopathic
disorder is employed and defined as a ‘persistent disorder or disability of mind
(whether or not including significant impairment of intelligence), which results in
abnormally aggressive or seriously irresponsible conduct’
· if a compulsory order is to be made on the grounds of psychopathy, then the Act
requires there to be evidence that treatment ‘is likely to alleviate or prevent a
deterioration of (the patient’s) condition’ as well as the requirement ‘that it is
necessary for the health and safety of the patient, or the protection of other persons’
· there is an increased likelihood of other psychiatric symptoms and disorders
· homicide risk is increased 10x in someone with an antisocial personality disorder
Alcohol dependence
· alcohol and crime are related in 3 important ways:
1. alcohol intoxication may lead to charges related to public drunkenness or to
driving offences
2. intoxication reduces inhibitions and is strongly associated with crimes of
violence, including murder
3. the neuropsychiatric complications of alcoholism may also be linked with
crime
Drug dependence
· offences against property are associated with the need to pay for drugs
· rates of drug abuse are increased among prisoners
Mental retardation
· about 1 % of the prison population are mentally retarded
· most offences committed by those in the borderline to mild ranges of learning
disability
· the mentally retarded are more likely to be caught
· they may commit offences because they do not understand the implications of their
behaviour, or they are susceptible to exploitation by others
· the closest association between mental retardation and crime is a high incidence of
sexual offences, especially indecent exposure by males
· the exposer is often known to the victim
· there is also said to be an association between MR and arson
· other associations:
· low socioeconomic status
· family history of criminality
· social disadvantage
· cerebral abnormality
· history of behavioural disorder as a child
· minor physical abnormality
· gullibility
· lack of self control

Forensic aspects of psychiatry

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Forensic aspects of psychiatry
Associations between psychiatric disorders and crime
Possible relationships between crime and mental disorder
1. coincidence
2. correlation
3. cause
· among male sentenced prisoners in England and Wales
· 37 % have diagnosable disorder
· 0.6 % have mental retardation
· 2 % have psychosis
· 6 % neurotic disorder
· 10 % personality disorder
· 12 % alcohol dependence
· 12 % drug dependence
· convicted prisoners:
· 5.2% major psychological disorder (Cooke 1994)
· remand prisoners:
· 2.3% major psychiatric disorder (Davidson et al. 1995)
· 14.1% depression
· 10.8% anxiety and agitation
· 22.4% alcohol problem
· 70% had abused drugs
· the disorders most likely to be associated with crime are:
· personality disorders
· alcohol and drug dependence
· mental retardation
State Hospital admission
· factors precipitating admission:
· alcohol or drug intoxication 21.2%
· non-compliance with medication and relapse 11.2%
· psychosis 54.8%
· ‘normal’ aggression 15.4%
Important studies
1. Hafner & Boker, 1982
· all homicides and attempted homicides in West Germany 1955-64
· mental disorder was associated with 5% of these
· the rate of mental disorder in the community was 3-5%
· homicidal violence rateschizophrenia = 5/10,000
· schizophrenics were 100x more likely to commit suicide than
homicide
· homicidal violence rateaffective disorder = 6/100,000
· affective disorders were 1000x more likely to commit suicide than
homicide
2. Swanson et al. 1990 ‘Violence and psychiatric disorder in the community:
evidence from the epidemiological catchment area survey’
· violence in last 12 months:
· non-substance use schizophrenia 8.3%
· substance abuse 21%
· substance abuse schizophrenia 30%
· active psychotic symptoms are associated with an increased risk of violence
Patterns of offending
· peak age of offending is:
· 14 in girls; there is another peak around the menopause
· 17-18 in boys
· 50% of all indictable crimes are committed by people under the age of 21
· the sex ratio of convicted men to women is approximately 5:1
· by the age of 30, around 30% of men have been convicted of an indictable offence

Cardiovascular System

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Cardiovascular System
 Transport system of the body.
 Consists of the heart, blood, and blood vessels
 Blood vessels consist of:
 Arteries that carry oxygenated (red) blood from the heart to the periphery and brain.
 Veins carries de-oxygenated (blue) blood back to the heart and lung
Heart
 Fist-sized muscle that circulates blood to and from the lungs to the body.
 Four chambers – atrium (right & left) and ventricles (right & left)
 Left side pumps oxygenated blood from lungs out to periphery and brain.
 Right side takes deoxygenated blood in to the lungs.
Blood pressure (BP)
 Pressure of blood in the arteries.
 As the heart contracts and pushed blood into the arteries (systolic cardiac cycle) the BP rises.
 As the heart rests between beats and no blood is pumped (diastolic cardiac cycle) BP is at its lowest.
Dynamics of Blood Pressure (BP)
 Cardiac output – force of contraction of the heart muscle
 Heart rate – speed of contraction
 Blood volume – amount of blood in the system
 Peripheral resistance – ease with which blood can pass through the arteries (as resistance increases, BP increases)
Dynamics of Blood Pressure (BP)
 Elasticity – is the give and take in the arterial walls. As elasticity decreases BP increases.
 Viscosity – thickness of the blood. BP increases when the thickness of the blood increases.
Blood pressure (BP) is Dynamic
 When arteries dilate (e.g., in heat) diastolic BP decreases.
 BP increases when heart rate or cardiac output increases in response to activity, change in posture, while talking, when under stress, temperature, etc.
 BP follows a circadian (daily) rhythm such that it is lowest when in deep sleep.
Hypertension
 Permanently high blood pressure
 Systolic blood pressure >= 140 mmHg; Diastolic blood pressure >= 90 mmHg
 Essential (primary) – no known physical cause (90-95% of cases are of this type)
 Secondary hypertension – due to specific cause, e.g., adrenal tumor.
Risk Factors for Essential Hypertension
 Lack of exercise, Body weight, Salt consumption, Stress, Age, Gender, Ethnicity (blacks at higher risk), Genetics

Blood
Two components
 Formed elements
 Plasma
Formed elements consist of three elements:
 Red blood cells
 Leukocytes (white blood cells)
 Platelets
Formed Blood – Red Blood Cells
 Most abundant cells
 Formed in bone marrow
 Contains hemoglobin – a protein that attaches to oxygen and transports it to the cells and tissue
 Anemia is when level of red blood cells are below normal.
Leukocytes (white blood cells)
 Serve a protective function (e.g., destroys bacteria).
 Produced in bone marrow and various organs of the body.
 Leukemia is when there is an excessive production of white blood cells that crowd out plasma and red blood cells.
Platelets
 Granular fragments that can clump together to prevent blood loss at site of cuts.
 Produced by bone marrow
 Hemophilia is when platelets don’t function properly to produce clotting and so if the person receives a cut could bleed excessively.

Plasma
 55% of the blood is plasma
 Composed of 90% water and 10% plasma protein and other organic and inorganic substances.
 Other substances include hormones, enzymes, waste products, vitamins, sugars, fatty material etc.
 An important fatty substance is lipids.
 Consist of:
 Cholesterol, Low and high-density lipoprotein, & Triglycerides
 High lipid content in the plasma can lead to plaque build-up on arteries and lipid deposits in arterial wall, causing hardening of the arteries.

Disorders of the Cardiovascular System – Hardening of Arteries
 Atherosclerosis – deposits of cholesterol and other substances on the arterial wall, forming plaques that can block the artery.
 Ateriosclerosis – calcium and other substances get deposited on the arterial wall leading to hardening of the plaques.
Risk Factors for Atherosclerosis
 Hypertension
 High fat intake leading to hyperlipidemia
 Smoking, Stress, Diabetes, Lack of exercise, Genetics, & Gender
Consequences of Atherosclerosis
 Angina pectoris – insufficient oxygen supply to the heart for its need and removal of waste products resulting in chest pain.
 Myocardial infarction (heart attack) – when there is a blockage of blood supply to an area of the heart cutting off oxygen supply to the tissue in the area and resulting in tissue death

Respiratory System

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Respiratory System
 Air enters the body through the nose and mouth.
 It travels past the larynx and down the trachea and bronchial tubes into the lung.
 Bronchial tubes divide into small branches called bronchioles, and then tiny sacs call alveoli.
Disorders of the Respiratory System
 Asphyxia – too little oxygen and too much carbon dioxide (can occur in small breathing space).
 Anoxia – shortage of oxygen (occurs at very high altitudes). Person looses judgment, pass into comma.
 Hyperventilation – deep rapid breaths that reduce the amount of carbon dioxide.
 Hay fever – seasonal allergic reactions. Body produces, histamines in response to the irritants entering the lungs.
 Asthma – more severe allergic reaction. Muscles surrounding the air tubes constrict.
 Viral infections (e.g., flu); Bacterial infections (e.g., strep throat)

Digestive system

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Digestive system
 Enzymes: break-downs food substances
 Commands from the brain stem activates the production of saliva. Saliva contains enzymes that breakdown starches.
 Esophagus pushes food to the stomach using peristalsis.
 Stomach uses gastric juices and churning to further breakdown food.
 Peristalsis moves food from the stomach to the duodenum (small intestine)
 Acid food mixture becomes chemically alkaline from secretions of the pancreas, gallbladder, and small intestine wall.
 Additional enzymes and bile continue the food breakdown.
 Absorption occurs.
 Large intestine (mainly colon) continues absorption of water and passes the remaining waste to the rectum for excretion.
Disorders of the Digestive System
 Peptic ulcers – open sores in the stomach or duodenum. Causes by excessive gastric juices and bacterial infection.
 Hepatitis – liver becomes inflamed.
 Cirrhosis – liver cells die and are replaced by scar tissue. Caused by hepatitis and heavy alcohol consumption.
Disorders of these Systems - Diabetes
 Type I – insulin-dependent diabetes where person has to take exogenous insulin to make up for the lack of insulin produced by the pancreas.
 Type II – non-insulin dependent diabetes where body is not sufficiently responsive to insulin
 Leading cause of blindness in adults and 50% of dialysis patients (kidney failure) have diabetes.

Neurotransmitters

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Neurotransmitters
 Electrochemical messengers:
 Catecholamines, consisting of epinephrine and norepinephrine
 Dopamine, Acetycholine, and Serotonin.

The Endocrine System
 Set of glands
 Works in close association with the autonomic nervous system
 Communicates via chemical substances like hormones
 Examples are adrenaline, cortisol, somatotropic hormone, gonadotropic hormone, etc.

Endocrine and autonomic systems work together
 Connection between the hypothalamus in the brain and the pituitary gland (“master gland”)
 The pituitary gland sends out hormones that communicates with other glands to send out hormones

Adrenal gland
 Located on top of each kidney
 Comprised of the adrenal medulla and the adrenal cortex.
 Adrenal medulla secretes adrenaline (epinephrine) and noradrenaline (norepinephrine)
 Adrenal cortex secretes steroids (including mineralocorticoids and glucocorticoids, androgens, and estrogens)
Thyroid gland
 Located in the neck
 Produces hormone (thyroxin) that regulates activity level and growth.
 Hypothyroidism: Insufficient thyroid hormones (leads to low activity levels and weight gain)
 Hyperthyroidism: Over-secretion of thyroid hormones (leads to hyperactivity and weight loss, insomnia, tremors, etc.)
Pancreas
 Located below the stomach
 Regulates level of blood sugar by producing insulin which absorbs blood sugar.
 Important gland in diabetes mellitus

Fight or Flight Response

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Fight or Flight Response
Increase in
 Epinephrine & norepinephrine
 Cortisol
 Heart rate & blood pressure
 Levels & mobilization of free fatty acids, cholesterol & triglycerides
 Platelet adhesiveness & aggregation
Decrease in
 Blood flow to the kidneys, skin and gut

Peripheral Nervous System ,Sympathetic nervous system

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Peripheral Nervous System
Autonomic nervous system and Somatic nervous system
Somatic nervous system
Involved in both sensory and motor functions, serving mainly the skin and skeletal muscles.
Efferent impulses: carry messages from the brain to the skeletal muscles
Afferent impulses: carry messages from the sensory organs to the brain
Autonomic nervous system
Controls what is generally involuntary, automatic activity
Consists of the sympathetic and parasympathetic nervous systems.

Sympathetic nervous system
Fight of flight response
Sends out messages (neurotransmitters) to the body preparing the body for fight or flight.
Also prepares the body for strenuous activity

Parasympathetic nervous system
Restores equilibrium in the body
Decreases arousal, slows breathing and heart rate, lowers heart rate and blood pressure, etc.

Reticular Activating System and Limbic System

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Reticular Activating System and Limbic System
 Reticular activating system runs from the medulla through the midbrain into the hypothalamus.
 Responsibility for activation of all areas of the brain and if damaged – coma ensues
 Limbic system controls emotion and it has three sub-circuits

Limbic System - emotions
 Amygdala and hippocampus – essential for self-preservation, includes aggression.
 Cingulate gyrus, the septum, and areas of the hypothalamus – pleasure and sexual excitement.
 Areas of the thalamus and hypothalamus – important to socially relevant behaviour

Diencephalon
Thalamus
Chief relay centre for directing sensory messages and helps regulate awareness.
Relays commands going to the skeletal muscles from the motor cortex.
Hypothalamus
Command for the control of autonomic functions such as heart rate, blood pressure, hunger, thirst.
Role in emotions and motivation (e.g., thoughts about fear get translated into arousal through hypothalamus.)

Cerebellum
 Maintains body balance and coordination of movement
 Damage to the cerebellum results motor disorders such as ataxia.
 Ataxia is a condition where our movements become jerky and uncoordinated.
Hindbrain
 Consists of:
 Pons – involved in eye movement, facial expressions and eye movement
 Medulla – controls breathing, heart rate, blood pressure
Midbrain
 Midbrain – top of brain stem, receives visual and auditory information, also important in muscle movement.
 Reticular formation – controls states of sleep, arousal, and attention.
Spinal cord
 Transmits messages from the brain to the other areas of the body.
 Efferent – away from the brain out to the body (Produces muscle action)
 Afferent – from the periphery to the brain (Relays information from the sensory organs)

Three sections of the brain

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Three sections of the brain
Hindbrain
Midbrain
Forebrain
Medulla -Pathway connecting Diencephalon (Thalamus, Hypothalamus)
Pons hindbrain and Forebrain.
Telecephalon (Cerebrum, Limbic system)
cerebellum

Telencephalon
 Upper and largest portion of the brain
 Involved in higher order intelligence, memory, and personality
 Composed of two hemispheres: Left hemisphere – language processes, etc. and
Right hemisphere – visual imagery, emotions, etc.

Four lobes of the cerebral cortex
Frontal
Parietal
Temporal
Occipital
Motor activity
Bodily sensations, Hearing Primary visual
Higher level intelligence e.g., pain, heat Vision area of the brain
Planning, Problem solving Body movement Smell
Emotions, Self-awareness Memory

2011-05-30T20:26:00.000+05:30

The Systems of the Body

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The Systems of the Body
Neuron
 Cell body – source of life of the cell
 Dendrites – branches on the cell bodies that act as receivers of messages from adjacent neurons.
 Axon – projection through which messages travel.
 Synaptic knobs: Tips of branches at end of axon. Sends messages to adjacent neurons.
 Synapse: Fluid filled gap between neurons.

Non-benzodiazepine hypnotics

2011-05-19T13:51:00.001+05:30

Non-benzodiazepine hypnotics
These drugs comprise the barbiturates, alcohols and a new class of cyclopyrrolone hypnotics. Because of the severity of their side effects and their dependence potential, the barbiturates should not be used to treat insomnia. The alcohol type of hypnotics include the chloral derivatives, of which chloral hydrate and chlormethiazole are still occasionally used in the elderly, and ethchlorvynol. Chloral hydrate is metabolized to another active sedative hypnotic trichlorethanol. These drugs all have a similar effect on the sleep profile. They are short half-life drugs (about 4–6 hours) that decrease the sleep latency and number of awakenings; slow-wave sleep is slightly depressed while the overall REM sleep time is largely unaffected, although the distribution of REM sleep may be disturbed. Chloral hydrate and its active metabolite have an unpleasant taste and cause epigastric distress and nausea. Undesirable effects of these drugs include lightheadedness, ataxia and nightmares, particularly in the elderly. Allergic skin reactions to chloral hydrate have been reported. Chronic use of these drugs can lead to tolerance and occasionally physical dependence. Like the barbiturates, overdosage can lead to respiratory and cardiovascular depression. Therapeutic use of these drugs has largely been superseded by the benzodiazepines.
Any new hypnotic should induce and maintain natural sleep without producing residual sedative effects during the day; it should not cause dependence or interact adversely with other sedatives, including alcohol. The ideal hypnotic should not cause respiratory depression or precipitate cardiovascular collapse when taken in overdose. So far no drug fulfils all these criteria. Several new anxiolytic and sedative drugs act at the benzodiazepine receptor site, or one of the subsets that comprise this receptor site even though the chemical structure of these molecules differs substantially from the benzodiazepines. One of the first of these compounds to be developed was the cyclopyrrolone zopiclone. A structurally somewhat similar moleculezolpidem, an imidazopyridine, has also been marketed recently as has the beta-carboline abercarnil. Of the newer benzodiazepines, the tetracyclic 2,4 benzodiazepine bretazenil has also been introduced as a short-acting sedative–hypnotic.

The therapeutic profile and adverse effects of the non-benzodiazepine sedative–hypnotics Zopiclone was the first of the new sedative–hypnotics to be launched in the late 1970s and has been shown to be equi-effective with the standard sedative–hypnotic benzodiazepines such as flurazepam and temazepam.
There is evidence that zopiclone may cause less ‘‘hang-over’’ effects than the conventional benzodiazepines but some studies have shown that this drug does produce performance decrement when this is tested shortly after treatment. A similar profile has been reported for zolpidem while abercarnilhas been reported to cause a performance decrement for the first few days of treatment that then largely disappears. Bretazenil has been shown to cause dose-related disruptions in psychomotor performance, but these effects are not as prominent as occurs following an equivalent dose of diazepam or alprazolam. A somewhat unusual side effect has been described by patients taking zopiclone – a bitter, unpleasant taste and a dry mouth. The cause of these effects is presently unknown. Regarding abuse liability, to date there have been only few studies in which newer sedative–hypnotics have been investigated. Nevertheless there is some evidence that those with a history of sedative abuse preferred high doses of triazolam and zopiclone to placebo. There is some evidence that bretazenil has a lower abuse potential than the benzodiazepines. Abuse liability of these novel sedative hypnotics has also been evaluated in primates. Abercarnil causes a lower incidence of withdrawal effects than conventional benzodiazepines. This may be due to the differences in the intrinsic efficacy rather than the bioavailability of these drugs for the brain. However, zopiclone and bretazenil did lower the seizure threshold to electroshock-induced seizures in mice whereas the seizure threshold was unaffected by zolpidem, tracozalate and C1 218,872. In baboons zolpidem may cause physiological dependence; similar studies in monkeys show that mild withdrawal effects occur after the abrupt withdrawal of zopiclone, whereas withdrawal from diazepam caused severe symptoms. It may be concluded that sedative–hypnotic drugs with a limited efficacy such as bretazenil and zolpidem are also limited in their ability to cause physiological dependence.
In human studies, there is some evidence that withdrawal signs such as nervousness, anxiety and vertigo occur following sub-chronic administration of zopiclone but the frequency and intensity of the withdrawal effects are greater after conventional 1, 4-benzodiazepines. No rebound effects have been seen in patients with insomnia who received zolpidem daily for 7–180 days. By contrast, after 3 weeks of abercarnil treatment of patients with generalized anxiety disorder possible signs of withdrawal resulted, the incidence of these withdrawal effects being related to doses of abercarnil administered. From the published clinical studies, it would appear that the partial agonists bretazenil and abercarnil are less likely to cause physiological dependence, have lower reinforcing effects and a lower incidence of subjective effects associated with abuse liability than the conventional 1, 4-benzodiazepine sedative–hypnotics. It is presently unclear whether the full agonists for the GABA-A receptor, zolpidem and zopiclone, offer a real advance in the treatment of insomnia although their adverse effect profiles and abuse liability may be lower than that of the conventional benzodiazepines.

Drugs used to treat insominia

2011-05-19T13:49:00.000+05:30

Drugs used to treat insominia
1. Benzodiazepine receptor agonists
Benzodiazepines (triazolam, temazepam, midazolam, lorazepam, estazolam). Non-benzodiazepines (imidazopyridines, e.g. zolpidem; pyrazopyrimidines, e.g. zaleplon; cyclopyrolones, e.g. zopiclone).
2. Pharmacological effects
Benzodiazepines – shorter latency to sleep, longer duration of sleep, decreased REM sleep, increased slow-wave sleep. Zopiclone – similar to benzodiazepines. Zaleplon and zolpidem – stated to have little adverse effect on sleep profile. There is evidence that the therapeutic efficacy is maintained even after several months of treatment.
3. Main side effects
Long half-life benzodiazepines cause day-time sedation. Dose-related anterograde amnesia. Impaired reaction time and vigilance. In elderly, cognitive impairment; falls causing fractures. Rebound insomnia can occur after withdrawal of short half-life drugs. Recurrence of original symptoms can occur when drug is stopped. Withdrawal effects on abrupt discontinuation of drug. These include:
dizziness, confusion and dysphoria.
Because of the frequency of side effects, benzodiazepine ligands are only recommended for the short-term (4 weeks) treatment of insomnia.
4. Other treatments include:
Sedative antidepressants (venlafaxine, trazodone, nefazodone, TCAs, mianserin, mirtazepine). Antihistamines (diphenhydramine, doxylamine). Melatonin (may shorten sleep latency but little effect on sleep time). Valerian extract (evidence of efficacy in double-blind studies). It should be noted that all these alternative treatments for insomnia also have side effects, some of which (e.g. TCAs) are potentially more serious than those occurring with the benzodiazepine group.

Use of hypnotics

2011-05-19T13:46:00.000+05:30

Use of hypnotics
Despite the fact that man spends approximately one-third of his life asleep, the purpose of sleep still remains a mystery. The clinical importance of sleep is reflected in the frequency and severity of complaints about insomnia, a condition that signifies unsatisfactory or insufficient sleep. Problems may involve difficulty in getting to sleep, disturbing dreams, early wakening, and day-time drowsiness due to poor sleep at night. In most cases, these symptoms are fairly transient and may be associated with a specific or identifiable event such as a family or work situation, a temporary financial problem, etc. Should the sleep disturbance persist for longer than 3 weeks, specific treatment may be indicated. The Association of Sleep Disorders Centres has classified sleep disorders into two broad classes – disorders of initiating and maintaining sleep (DIMS) and disorders of excessive somnolence (DOES); these definitions have now been appended to the DSM–IV. The hypnogram of a patient with an underlying psychiatric illness may be characterized by a delay in sleep onset, the presence of residual muscular activity causing frequent awakenings, fragmented sleep, reduced REM and slow-wave sleep, and day-time drowsiness. Such disorders are generally not associated with a recent or transient event and the cause cannot usually be identified. Often such changes in the sleep architecture are associated with major psychiatric disorders such as depression, mania, psychosis or severe anxiety states.
For the purpose of considering the prescribing of hypnotics, insomnia may be classified into three major types:
1. Transient insomnia. This occurs in normal sleepers who experience an acute stress or stressful situation lasting for a few days, for example, air travel to a different time zone or hospitalization.
2. Short-term insomnia. This is usually associated with situational stress caused, for example, by bereavement or which may be related to conflict at work or in the family.
3. Long-term insomnia. Studies suggest that insomnia in up to 50% of patients in this category is related to an underlying psychiatric illness.
Of the remainder of the patients in this category, chronic alcohol or drug abuse may be the cause of the sleep disruption. Whenever the use of hypnotics is considered appropriate, it is universally agreed that patients should be given the smallest effective dose for the shortest period of time necessary. This recommendation applies particularly to elderly patients. For transient and short-term insomnia there is no clear consensus, although in practice the use of a medium or short half-life hypnotic for a few days is sometimes recommended when sleep disturbance is associated with shift work or ‘‘jet-lag’’. For chronic insomnia, careful investigation of the underlying cause of the condition is essential before hypnotics are routinely prescribed. Should the insomnia be associated with a psychiatric condition or drug abuse, specific treatment of the core illness will often obviate the need for hypnotics.
For all practical purposes, the benzodiazepines are the group of drugs most widely used to treat insomnia. These may be divided into three classes based on their pharmacokinetic characteristics:
1. Short half-life drugs, such as triazolam, midazolam and brotizolam, with elimination half-lives of about 6 hours.
2. Intermediate half-life drugs, such as temazepam, lormetazepam and loprazolam, with half-lives of 6–12 hours.
3. Long half-life drugs, such as nitrazepam, flurazepam and flunitrazepam, with half-lives over 12 hours.
The elimination half-lives of a number of commonly used hypnotics. It should be noted that many of the drugs in current use have active metabolites which considerably prolong the duration of their pharmacological effect. This is particularly true for the elderly patient in whom the half-life of the hypnotic is prolonged due to decreased metabolism and renal clearance; such individuals are also more sensitive to the sedative effects of any psychotropic medication. In general, the efficacy of hypnotics for short-term use is well established and there is a close relationship between their pharmacokinetic and pharmacodynamic profiles. The most widely used hypnotic in the UK, for example, is temazepam, which is relatively slowly absorbed and therefore has only a marginal effect on the sleep latency but facilitates sleep duration.The short elimination half-lives of drugs such as brotizolam ensure that residual sedative effects do not occur during the day. In contrast, fast elimination hypnotics such as midazolam and triazolam, which are effective in treating sleep onset insomnia, often give rise to rebound insomnia on withdrawal. It should be emphasized that the abrupt withdrawal of hypnotics, particularly when they have been given for several weeks or longer, is generally accompanied by REM rebound which results in an increased frequency of dreams and nightmares and can precipitate disturbed sleep and anxiety. Slow reduction in the night-time dose of the hypnotic over several days may reduce the risk of such a rebound. Regarding the efficacy of hypnotics when used long-term, there is evidence that sleep latency shows more tolerance than sleep time. Furthermore, it is generally accepted that each hypnotic has a minimal effective dose and that increasing this does little to improve the duration of sleep but is more likely to increase the side effects.

Sleep and the EEG

2011-05-19T13:45:00.000+05:30

Sleep and the EEG
In general, the sleep cycle is synchronized via the SCN. All sensory stimuli activate the ascending reticular activating system, thereby causing cortical arousal and preventing the cortex reverting to its basic slow-wave oscillating rhythm. The excitatory, arousing mechanisms are complemented by inhibitory inputs from the hypothalamus. At least four different types of neurotransmitters are involved in regulating the EEG pattern in the sleep–wake cycle. Thus acetylcholine causes a desynchronization of the cortical EEG while REM sleep is induced by cholinomimetic drugs (such as arecoline and physostigmine) but blocked by atropine.
The central histamine 1 receptors are active in the posterior hypothalamus during the waking phase but inactive during the slow-wave sleep and REM stages of the sleep–wake cycle. Antagonists of the H1 histamine receptors cause sedation. There is evidence that the histaminergic tract that passes from the posterior hypothalamus to the cortex via the thalamus is inhibited by a GABAergic pathway. It is now known that H3 receptors act as autoreceptors on histaminergic neurons and that agonists of H3 receptors augment slowwave sleep. In addition, histamine can increase cortical arousal by enhancing excitatory cholinergic neurons from the basal forebrain and also inhibits the hypothalamic pre-optic area which normally promotes sleep. With respect to the control of the circadian rhythm, histamine has both excitatory (H1) and inhibitory (H2) effects on the SCN. Thus in addition to acetylcholine, noradrenaline and 5-HT, histamine would also appear to play a crucial role in regulating the sleep pattern. Noradrenaline – the EEG is aroused by stimulants such as the amphetamines and methylphenidate whereas drugs such as reserpine which deplete brain noradrenaline have the opposite effect. Similar effects to the stimulants may be obtained by the electrical stimulation of the locus coeruleus which has been shown to decrease in activity during the REM sleep phase of the sleep cycle. The precise role that noradrenaline plays in sleep is uncertain. While it may be involved in sleep induction, noradrenaline also has many other physiological functions including control of the heart rate, blood pressure, autonomic activity, etc. which play a role in the entraining process.
Dopamine – low doses of the dopamine agonist apomorphine increase slow-wave sleep and, like other dopaminometics, cause somnolence in patients with Parkinson’s disease. Conversely, dopamine autoreceptor antagonists, which enhance dopamine release, reduce both REM and non-REM sleep. Stimulants such as cocaine cause arousal by activating D2 postsynaptic receptors, effects which are blocked by most neuroleptics. Serotonin – the reduction in the release of 5-HT in the brain (for example, by blocking 5-HT synthesis with parachlorophenyl alanine) induces sleep while the electrical stimulation of the raphe´ nuclei causes excitation. It would appear that the activity of the raphe´ nuclei is decreased in slow-wave sleep. However, the role of specific 5-HT receptors in mediating the effects of 5-HT is unclear. This is due to the relative lack of specificity of the drugs available but also due to the fact that 5-HT modulates the activity of other neurotransmitter systems involved in the regulation of sleep. For example, 5-HT1A receptor agonists increase the frequency of slow-wave sleep which may be due to its inhibitory effect on the release of acetylcholine from the nucleus basalis. It would appear however that the serotonergic system is active during the waking phase but reduced during the sleep phase of the sleep–wake cycle.
In animals, two main types of sleep pattern may be identified termed nonrapid eye movement sleep (non-REM or slow-wave sleep) and rapid eye movement sleep (REM sleep). Normal sleep is composed of several REM and non-REM cycles. Non-REM sleep is divided into light sleep (stages 1 and 2) and slow-wave or delta sleep (stages 3 and 4). Stage 1 sleep is characterized by alpha rhythm on the EEG and forms the transition between wakefulness and sleep; it occupies approximately 5% of the time. Muscle tone is relatively weak and while a certain amount of mental activity persists, concentration and imagination fluctuate. As the sleep deepens, hypnagogic hallucinations may occur. Stage 2 sleep represents over 50% of the total sleeping time and is marked by characteristic sleep spindles and K complexes in the EEG; delta waves are also present occasionally. Muscle tone is weak and there are no eye movements. Stages 3 and 4, slow-wave sleep, occupy approximately 20% of the sleep time. The EEG is characterized by more than 50% of the sleep pattern being in the form of delta waves. This stage of sleep is the recuperative phase which is associated with growth hormone secretion and tissue repair; the secretion of prolactin is not associated with any specific phase of sleep. Dreaming may occur but tends to be of brief duration and of a rational nature. Nocturnal terrors and sleep walking are associated with stage 4 sleep.
REM sleep occupies approximately 20% of the sleep time in the normal adult, up to 30% in the young child and less than 20% in the aged or mentally handicapped. The cortical EEG activity resembles that of wakefulness, but is accompanied by muscular weakness; 4Hz ‘‘sawtooth’’ waves herald the onset of REM sleep. The precise physiological function of REM sleep is unknown but it is associated with dreaming sleep, the dreams being long, emotional and animated. The physiological changes accompanying REM sleep include hypertension, tachycardia alternating with bradycardia, pelvic congestion in the female and penile tumescence in the male. Cortisol secretion appears to peak during the latter part of the sleep cycle when REM sleep is most pronounced. This type of sleep is also characterized by bursts of eye movement and small sporadic muscular twitches of the face and extremities. The typical sleep pattern of the young adult is composed of four to six cycles of non-REM sleep alternating with REM sleep at approximately 90 minute intervals. The subject first goes into non-REM sleep and then gradually descends from stage 1 through to stage 4 sleep, the frequency of the waves becoming slower and their amplitude greater. The depth of sleep then briefly (for a few minutes) returns to stage 2, after which the first episode of REM sleep appears. Bodily movements often occur at this stage. This may be illustrated by means of a hypnogram.
It should be noted that stages 3 and 4 are more pronounced during the early part of the sleep period, whereas REM sleep tends to increase during the sleep cycle. The actual period of sleep is to some extent genetically determined, some individuals requiring at least 8 hours while others need only 4 hours to function normally. The sleep pattern becomes more fragile with advancing age, so that in the elderly the number of nocturnal awakenings increases and REM sleep becomes more evenly distributed throughout the night. The sleep architecture may be modified by disease and by certain drugs. In the healthy individual, the duration of the first phase of REM sleep is usually 3 minutes. In patients with depression or narcoplexy, the time of onset of the first REM phase is shorter than usual, while those with anxiety disorders have a delayed time of onset of the first REM phase. The duration of the first REM phase is also increased in depressed patients. All hypnotics in current clinical use alter the sleep architecture by reducing the quantity and quality of the REM sleep phase in particular. Thus a single dose of a hypnotic benzodiazepine suppresses REM during the period in which it is present, but for up to the two following nights the amount of REM sleep is generally increased (so-called REM rebound). When the hypnotic is given for a prolonged period, the REM sleep gradually returns to normal, but abrupt withdrawal can lead to prolonged rebound in REM sleep, which is often associated with intense and unpleasant dreams and anxiety on wakening. Most hypnotics also affect the quality of the non-REM sleep, particularly the slow-wave sleep pattern.
Thus stage 3 and stage 4 sleep are suppressed and remain so during the period of drug administration. following drug withdrawal, the slow-wave sleep gradually returns to normal, but this may take up to 15 days. However, no rebound effect appears to occur in slow-wave sleep. All hypnotics in current use also decrease stage 1 of non-REM sleep and prolong stage 2 sleep; this may be the reason why the nocturnal awakenings decrease, so that the individual feels that the quality of sleep under the influence of the hypnotic has improved! The effect of a hypnotic on the quality of the REM and slow-wave sleep is shown diagrammatically. Disturbance in the sleep pattern commonly occurs in the alcoholic. The sleep pattern in this type of patient is characterized by frequent awakenings and decreased REM and slow-wave sleep. Concomitantly, stages 1 and 2 are increased but shallower than usual. After withdrawal from alcohol, the patient experiences insomnia and REM rebound occurs. The sleep profile of the alcoholic often remains abnormal for 1–2 years following withdrawal. Most antidepressants decrease the quantity of REM sleep in the depressed patient, although it is difficult to say whether this is a reflection of the action of the drugs or due to the underlying pathology. Abrupt withdrawal of antidepressants, particularly the monoamine oxidase inhibitors, is often associated with REM rebound.

Physiology of sleep

2011-05-19T13:43:00.000+05:30

Physiology of sleep
Although there is no evidence for a specific sleep ‘‘centre’’ in the brain, it is generally accepted that the level of consciousness is located in the diffuse network of nerve cells that comprise the reticular formation. This region consists of tegmental parts of the medulla, pons and midbrain. Lesions of the reticular formation result in somnolence or coma, sensory stimuli failing to arouse the animal. Such observations led to the conclusion that the brain stem reticular activity system maintains alertness and wakefulness, while lack of sensory stimulation results in sleep. Arousal from sleep by sensory stimuli is attributed to collateral pathways that link the main sensory pathways to the reticular formation. Undoubtedly this is a gross simplification of the anatomical substrate for sleep and wakefulness. There is evidence, for example, that animals may recover consciousness following lesions of the reticular formation and that the forebrain is not completely dependent on inputs from the reticular formation to maintain consciousness. Nevertheless, it is generally accepted that the reticular formation plays an important, if not a key role, in sleep and wakefulness.
Physiological basis of sleep – circadian rhythmicity It is a well-known fact that the circadian rhythm is entrained for diurnal cues to approximately 24 hours. However, a non-entrained rhythm, which operates in the absence of external cues, lasts between 25 and 27 hours. Thus the human sleep–wake cycle normally shows a 24-hour rhythm but not all physiological processes (for example, body temperature) follow the sleep–wake cycle. It is now known that circadian rhythms are controlled by clock genes which are found in species as wide apart as insects and mammals. It would appear that the clock genes are activated by light falling on the retina. The activated retina neurons then stimulate the retinohypothalamic tract which projects to the suprachiasmatic nucleus and thence to the anterior pituitary.
This pathway is responsible for coupling the circadian rhythm with the light cycle. The lateral geniculate nucleus (LGN) activates the suprachiasmatic nucleus (SCN) in the case of the non-light-based stimuli such as motor activity. The raphe´ nuclei also impact on the SCN. Thus several pathways appear to be involved in the entraining process.

Drug Treatment of Insomnia

2011-05-19T13:41:00.000+05:30

Drug Treatment of Insomnia
Apart from the benzodiazepines, the sedative hypnotics are a group of drugs that depress the brain in a relatively non-selective manner. This results in a progressive change from drowsiness (sedation), sleep (hypnosis) to loss of consciousness, surgical anaesthesia, coma and finally cardiovascular and respiratory collapse and death. The central nervous system (CNS)depressant drugs include general anaesthetics, barbiturates and alcohols, including ethanol. Before the advent of the benzodiazepines, barbiturates in low doses were widely used as anxiolytics. A sedative drug is one that decreases CNS activity, moderates excitement and generally calms then individual, whereas a hypnotic produces drowsiness and facilitates the onset and maintenance of sleep from which the individual may be easily aroused. Historically the first sedative hypnotics to be introduced were the bromides in the mid 19th century, shortly followed by chloral hydrate, araldehyde and urethane. It was not until the early years of this century
that the first barbiturate, sodium barbitone, was developed and this was shortly followed by over 50 analogues, all with essentially similar pharmacological properties. The major breakthrough in the development of selective, relatively non-toxic sedative hypnotics followed the introduction of chlordiazepoxide in 1961. Most of the benzodiazepines in current use have been selected for their high anxiolytic potency relative to their central depressant effects. Because of their considerable safety, the benzodiazepines have now largely replaced the barbiturates and the alcohols, such as chloral hydrate and trichloroethanol, as the drugs of choice in the treatment of insomnia. The hypnotics are some of the most widely used drugs, over 15 million prescriptions being given for this group of drugs in Britain in 1985; the number of prescriptions for hypnotics has remained fairly constant over the last decade despite the reduction in anxiolytic prescriptions by about 50% over this same period. This situation is hard to reconcile with the fact that all benzodiazepines in current use have hypnotic properties if given in slightly higher therapeutic doses. This implies that what determines their use as anxiolytics, for day-time administration, or hypnotics, for night-time use, is largely a question of dose and marketing. As discussed in considerable detail elsewhere (see p. 213), there is a metabolic interrelationship between the commonly used 1,4-benzodiazepines and their mode of action is similar. It is of interest that the hypnotic benzodiazepines have received little media attention, in contrast to the anxiolytics of the same class, regarding their possible dependence-forming effects.

Treatment option of Depression

2011-05-05T13:05:00.002+05:30

Treatment decisions for unipolar depression
. Treatment of choice – second-generation antidepressants such as a SSRI, venlafaxine, mirtazepine, reboxetine, moclobemide.
. Switching – alternative second-generation antidepressant, usually from another group.
. Augmentation of antidepressant response – add lithium, thyroid hormone, an atypical antipsychotic (e.g. risperidone, olanzepine), pindolol, buspirone.
. Other options – ECT, St John’s Wort.
Note: In a survey of 13 studies, switching from an SSRI to either another SSRI or to imipramine, venlafaxine, mirtazepine or buproprion resulted in a response rate of 30–90%.

Electroconvulsive shock treatment
One of the pioneers in the application of electroconvulsive shock treatment (ECT) was the Italian clinician Cerletti who stated that the ‘‘. . . electricity itself is of little importance . . . the important and fundamental factor is the epileptic-like seizure no matter how it is obtained’’. ECT is undoubtedly an effective treatment for a range of psychiatric diseases varying from severe depression and mania to some forms of schizophrenia. Despite the considerable use of ECT over the last 50 years, it still arouses intense emotional and scientific debate. While the opposition to the use of ECT has been more evident in some Continental European countries and the United States than in Britain or Ireland, it was a British study of the use of ECT which, following a survey of over 100 centres, found that many units were badly equipped and had poor facilities and staff training. This report resulted in a considerable improvement in the application of ECT, with the establishment of guidelines governing the managemen and use of the technique; somewhat similar guidelines were instituted by the American Psychiatric Association. It is now generally agreed that ECT is singularly effective and useful. There has been controversy over the relative merits in using unilateral or bilateral ECT. In general, it would appear that unilateral ECT is effective in the treatment of most depressed patients, whereas manic patients appear to respond best to bilateral ECT. Following a course of treatment, twice weekly for several weeks, the success rate in treating depression is about 80%. This is more successful than using antidepressants (up to 70% for a single course of treatment). Seizure monitoring is essential to ensure an adequate response. The principal side effect of ECT is a temporary cognitive deficit, specifically memory loss. There is evidence that such impairment is reduced if unilateral ECT is applied to the non-dominant hemisphere. Brief pulse-current ECT machines are now favoured in Britain and the United States to ensure opt imal efficacy and minimal side effects. As Cerletti hypothesized in 1938, chemically induced seizures are equally effective as ECT and at one time pentamethylenetetrazole or flurothyl were used to produce seizures. However, the safety and ease of application of ECT means that such methods have been largely replaced. While there are various psychological, neurophysiological and neuroendocrine theories that have been developed to explain the beneficial effects of ECT, most attention has been given to the manner in which ECT causes changes in those neurotransmitters that have been implicated in psychiatric illness. It is known that the rise in the seizure threshold during the course of treatment, and the corresponding alteration in cerebral blood flow, may reflect profound changes in cerebral metabolism that could be of crucial importance regarding the action of ECT. Changes in the hypothalamo– pituitary–adrenal axis have also been reported, but most studies suggest that such changes are secondary to the clinica l response. The major emphasis of research has therefore been in the functional changes in brain neurotransmission, but it must be emphasized that most detailed studies have been conducted in rodents and therefore their precise relevance to changes in the human brain are a matter of conjecture.

Experimental studies in rodents have largely centred on the changes in biogenic amine neurotransmitters following chronic ECT treatments. Under these conditions, noradrenaline and 5-HT have been shown to be increased; the number of presynaptic alpha2 receptors and their functional activity has been shown to be decreased, as has the functional activity of the dopamine autoreceptors. Such changes have also been found following the chronic administration of antidepressant drugs. The most consistent changes reported have been those found in postsynaptic receptor function. The functional activity of the postsynaptic beta adrenoceptors is decreased, a change which is also found with antidepressants. The postsynaptic 5-HT2 receptor sensitivity is enhanced by chronic ECT and antidepressant treatment. Thus there appears to be a consistency between the chronic effects of both ECT and antidepressants in enhancing 5-HT responsiveness and diminishing that of noradrenaline. Regarding the dopaminergic system, while there is speculation that changes in the activity of this system may be important in the action of novel antidepressants such as bupropion, the only consistent changes found following chronic application of ECT and antidepressants is a functional decrease in the dopamine autoreceptor activity. This would lead to a reduction in the release of this transmitter. In contrast to the plethora of animal studies, few clinical studies have shown consistent changes in the biogenic amines. There is evidence that the urinary and CSF concentrations of the noradrenaline metabolites normetanephrine and MHPG are decreased, suggesting that the turnover of noradrenaline is decreased, the opposite to that found in animals. Neuroendocrine challenge tests that have been used as probes to assess central noradrenergic function (e.g. with clonidine) show no consistent changes in patients following chronic ECT. Consistent changes have been reported in serotonergic function, however, with enhanced prolactin release occurring in response to a thyroid-stimulating hormone challenge. This is in agreement with the view that chronic ECT sensitizes postsynaptic 5-HT2 receptors. Furthermore, platelet imipramine binding, which according to the results of some studies is increased in the untreated depressed patient, is attenuated by both antidepressant and ECT treatments, although it must be emphasized that not all investigators can replicate these findings. The transport of [3H]5-HT into the platelets of depressed patients is also normalized following ECT and chronic antidepressant treatments. There is no evidence of any change in the dopaminergic system in depressed patients following ECT. The central cholinergic system has been implicated in the pathogenesis of affective disorder and in memory function, which is frequently found to be malfunctioning in depressed patients. The memory deficit elicited by chronic ECT in both patients and animals may be related to the decreased density and function of central muscarinic receptors, but it should be emphasized that the changes reported in cholinergic function are small and their relevance to the clinical situation remains to be established. Brain GABA is closely associated with the induction of seizures. In animals, chronic ECT decreases GABA synthesis in the limbic regions. While consistent changes in GABA-A receptor activity have not been reported, it would appear that GABA-B receptor density increases in the limbic regions following chronic ECT. This is qualitatively similar to the changes that have been reported following antidepressant treatment. The recent interest in the involvement of GABA in the aetiology of depression and in the mode of action of antidepressants is based on the hypothesis that GABA plays a key role not only in the induction of seizures but also in modulating the changes in the serotonergic system that are induced by both antidepressants and ECT. Due to the ubiquitous distribution of peptides as cotransmitters and neuromodulators in the brain, it is not surprising to find that ECT produces changes in their concentrations and in their possible functional activity. Increased metenkephalin concentrations have been reported following chronic ECT. Such changes may be due to increased opioid receptor binding sites. Opioid-mediated behavioural changes such as catalepsy and reduced pain responses are increased following ECT in animals. Whether such changes are relevant to the effects of ECT and antidepressants in depressed patients is still unknown. Other possibilities that have been suggested as a cause of the antidepressant action of ECT include an enhanced adenosine1 receptor density in the cortex; agonists at these receptor sites are known to have anticonvulsant properties, while antagonists such as caffeine can cause convulsions, at least in high doses. Thyroid-stimulating hormone activity has also been shown to be enhanced. This peptide may exert antidepressant effects in its own right, but may also act by modulating both serotonergic and dopaminergic activity.

In general overview and summary, it would appear that ECT produces a number of changes in central neurotransmission that are common to antidepressants. These include a decrease in the functional activity of beta adrenoceptors and an enhanced activity of 5-HT2 and possibly GABA-B receptors. The functional defect in central muscarinic receptors may be associated with the memory deficits caused by ECT treatment. It must be emphasized that the changes reported have largely been derived from animal experiments and their precise relevance to the mode of action of ECT in man is still a matter of conjecture. Adverse effects of drug treatment for depression TCAs Significant side effects have been estimated to occur in about 5% of patients on TCAs, most of these effects being attributed to their antimuscarinic properties, for example, blurred vision, dry mouth, tachycardia and disturbed gastrointestinal and urinary tract function. Orthostatic hypotension due to the block of alpha1 adrenoceptors and sedation resulting from antihistaminic ac tivity frequently occur at therapeutic doses, particularly in the elderly. Excessive sweating is also a fairly common phenomenon, but its precise mechanism is uncertain. In the elderly patient, the precipitation of prostatic hypertrophy and glaucoma by the TCAs is also a frequent cause of concern.

Adverse effects of the TCAs on the brain include confusion, impaired memory and cognition and occasionally delirium; some of these effects have been reported to occur in up to 30% of patients over the age of 50. These effects may occasionally be confused with a recurrence of the symptoms of depression and are probably due to the central antimuscarinic activity of these drugs. Tremor also occurs frequently, particularly in the elderly, and may be controlled by the concurrent administration of propranolol. Neuroleptics are normally not recommended to be used in combination with TCAs as they are liable to accentuate the side effects of the latter drugs. The risk of seizures, and the switch from depression to mania in bipolar patients, has also been reported following TCA administration. Weight gain is a frequent side effect and is of considerable concern, particularly in the female patient, an effect probably associated with increased appetite. Other less common side effects include jaundice (particularly with imipramine), agranulocytosis and skin rashes.

Acute poisoning
This occurs all too frequently with the TCAs and can be life threatening. Death has been reported with doses of 2000mg of imipramine, or the equivalent quantity of other TCAs, which approximates to 10 daily doses or less! Severe intoxication has been reported at doses of 1000 mg. Because of the toxicity of these drugs and the nature of the illness, in which suicidal thoughts are a common feature, it is generally recommended that no more than a 1 week’s supply should be given at any one time to an acutely depressed patient. The symptoms of overdose are to some extent predictable from the antimuscarinic and adrenolytic activity of these drugs. Excitement and restlessness, sometimes associated with seizures, and rapidly followed by coma, depressed respiration, hypoxia, hypotension and hypothermia are clear signs of TCA overdose. Tachycardia and arrhythmias lead to diminished cardiac function and thus to reduced cerebral perfusion, which exacerbates the central toxic effects. It is generally accepted that dialysis and forced diuresis are useless in counteracting the toxicity, but activated charcoal may reduce the absorption of any unabsorbed drug. The risk of cardiac arrhythmias may extend for several days after the patient has recovered from a TCA overdose. It is partly due to the toxicity of the TCAs that the newer non-tricyclic drugs have been developed. All the evidence suggests that the non-tricyclics are much safer in overdose.

Drug interactions
Another area of concern regarding the use of the TCAs is their interaction with other drugs which may be given concurrently. Such interactions may arise due to the drugs competing for the plasma protein binding sites (e.g. phenytoin, aspirin and the phenothiazines) or for the liver microsomal enzyme system responsible for the common metabolism of the drugs (e.g. steroids, including the oral contraceptives, sedatives, apart from the benzodiazepines, and the neuroleptics). All of the TCAs potentiate the sedative effects of alcohol and any other psychotropic drug with sedative properties given concurrently. Smoking potentiates the metabolism of the TCAs. There is a well-established interaction between the TCAs and the adrenergic neuron blocking antihypertensives (e.g. bethanidine and guanethidine) which results from the TCA impeding the uptake of the neuron blocker into the sympathetic nerve terminal, thereby preventing it from exerting its pharmacological effects. There is also a rare, but occasionally fatal, interaction between TCAs and MAOIs in which hyperpyrexia, convulsions and coma can occur. The precise mechanism by which this is brought about is unclear, but it may be associated with a sudden release of 5-HT. Following prolonged TCA administration, abrupt withdrawal of the drug can lead to generalized somatic or gastrointestinal distress, which may be associated with anxiety, agitation, sleep disturbance, movement disorders and even mania. Such symptoms may be associated with central and peripheral cholinergic hyperactivity that is a consequence of the prolonged muscarinic receptor blockade caused by the TCAs.

MAOIs
The toxic effects of these drugs may arise shortly after an overdose, the effects including agitation, hallucinations, hyperreflexia and convulsions. Somewhat surprisingly, both hypo- and hypertension may occur, the former symptoms arising due to the accumulation of the inhibitory transmitter dopamine in the sympathetic ganglia leading to a marked reduction in ganglionic transmission, while hypertension can result from a dramatic release of noradrenaline from both central and peripheral sources. Such toxic effects are liable to be prolonged, particularly when the older irreversible inhibitors such as phenelzine and tranylcypromine are used.

Treatment of such adverse effects should be aimed at controlling the temperature, respiration and blood pressure.

The toxic effects of the MAOIs are more varied and potentially more serious than those of the other classes of antidepressants in common use. Hepatotoxicity has been reported to occur with the older hydrazine type of MAOIs and led to the early demise of iproniazid; the hepatotoxicity does not appear to be related to the dose or duration of the drug administered. Excessive central stimulation, usually exhibited as tremors, insomnia and hyperhidrosis, can occur following therapeutic doses of the MAOIs, as can agitation and hypomanic episodes. Peripheral neuropathy, which is largely restricted to the hydrazine type of MAOI, is rare and has been attributed to a drug-induced pyridoxine deficiency. Such side effects as dizziness and vertigo (presumably associated with hypotension), headache, inhibition of ejaculation (which is often also a problem with the TCAs), fatigue, dry mouth and constipation have also been reported. These side effects appear to be more frequently associated with phenelzine use. They are not associated with any antimuscarinic properties of the drug but presumably arise from the enhanced peripheral sympathetic activity which the MAOIs cause.

Drug interactions
Predictable interactions occur between the MAOIs and any amine precursors, or directly or indirectly acting sympathomimetic amines (e.g. the amphetamines, phenylephrine and tyramine). Such interactions can cause pronounced hypertension and, in extreme cases, stroke. MAOIs interfere with the metabolism of many different classes of drugs that may be given concurrently. They potentiate the actions of general anaesthetics, sedatives, including alcohol, antihistamines, centrally acting analgesics (particularly pethidine due to an enhanced release of 5-HT) and anticholinergic drugs. They also potentiate the actions of TCAs, which may provide an explanation for the use of such a combination in the treatment of therapy-resistant depression. The ‘‘cheese effect’’ is a well-established phenomenon whereby an aminerich food is consumed while the patient is being treated with an irreversible MAOI. Foods which cause such an effect include cheeses, pickled fish, yeast products (red wines and beers, including non-alcoholic v arieties), chocolate and pulses such as broad beans (which contain dopa). It appears that foods containing more than 10mg of tyramine must be consumed in order to produce a significant rise in blood pressure. Furthermore, it is now apparent that there is considerable variation in the tyramine content of many of these foods even when they are produced by the same manufacturer. Therefore it is essential that all patients on MAOIs should be provided with a list of foods and drinks that should be avoided.

Changing a patient from one MAOI to another, or to a TCA, requires a ‘‘wash-out’’ period of at least 2 weeks to avoid the possibility of a drug interaction. There is evidence to suggest that a combination of an MAOI with clomipramine is more likely to produce serious adverse effects than occurs with other TCAs. Regarding the newer non-tricyclic antidepressants, it is recommended that a ‘‘wash-out’’ period of at least 5 weeks be given before a patient on fluoxetine is given an MAOI; this is due to the very long half-life of the main fluoxetine metabolite norfluoxetine. Although it is widely acknowledged that the older MAOIs have the potential to produce serious adverse effects, the actual reported incidence is surprisingly low. Tranylcypromine was one of the most widely used drugs, involving several million patients by the mid 1970s, and yet only 50 patients were reported to have severe cerebrovascular accidents and, of these, only 15 deaths occurred. Nevertheless, it is generally recommended that this drug sh ould not be given to elderly patients or to other patients with hypertension or cardiovascular disease.

Second-generation antidepressants
With the possible exception of maprotiline, which is chemically a modified TCA with all the side effects attributable to such a molecule, all of the newer non-tricyclic drugs have fewer anticholinergic effects and are less cardiotoxic than the older tricyclics. Lofepramine is an example of a modified tricyclic that, due to the absence of a free NH2 group in the side chain, is relatively devoid of anticholinergic side effects. Thus by slightly modifying the structure of the side chain it is possible to retain the efficacy while reducing the cardiotoxicity.

Of the plethora of new 5-HT uptake inhibitor antidepressants (e.g. zimelidine, indalpine, fluoxetine, fluvoxamine, citalopram, sertraline and paroxetine), the most frequently mentioned side effects following therapeutic administration are mild gastrointestinal discomfort, which can lead to nausea and vomiting, occasional diarrhoea and headache. This appears to be more frequent with fluvoxamine than the other SSRI antidepressants. Such changes are attributable to increased peripheral serotonergic function. Some severe idiosyncratic and hypersensitivity reactions such as the Gullain–Barre´ syndrome and blood dyscrasias have led to the early withdrawal of zimelidine and indalpine. For the well-established antidepressants such as fluoxetine, the side effects appear to be mild and welltolerated, although akathisia and agitation have been reported and may be more pronounced in elderly patients. Nomifensine and bupropion are examples of non-tricyclic antidepressants that facilitate catecholaminergic function. These drugs have the advantage over the TCAs of being non-sedative in therapeutic doses. The rare, although fatal, occurrence of haemolytic anaemia and pyrexia following therapeutic administration of nomifensine led to its withdrawal from the market a few years ago. Bupropion was also temporarily withdrawn from clinical use following evidence of seizure induction, but it has now returned to the market in the United States. Idiosyncratic reactions have been reported to occur with the tetracyclic antidepressant mianserin, several cases of agranulocytosis have been reported in different countries. Elderly patients would appear to be most at risk from such adverse effects. Whether such side effects are a peculiarity of the mianserin structure or will also be found with the 6-aza derivative, mirtazepine, is uncertain but preliminary evidence from post-marketing surveys suggests that this is unlikely. Other frequent side effects associated with therapeutic doses of mianserin are sedation and orthostatic hypotension; sedation and weight gain are also problems with mirtazepine. Clearly the major advantage of all the recently introduced antidepressants lies in their relative safety in overdosage and reduced side effects. These factors are particularly important when considering the need for optimal patient compliance and in the treatment of the elderly depressed patient who is more likely to experience severe side effects from antidepressants.

Treatment-resistant depression
It has been estimated that at least 30% of patients with major depression fail to respond to a 6-week course of a TCA antidepressant. A major problem arises however in the definition of ‘‘treatment resistance’’. To date, there appears to be no internationally acceptable definition of the condition. A practical definition which many clinicians find useful is that treatment resistance occurs when the patient fails to respond to:
1. An antidepressant given at maximum dose for 6–8 weeks.
2. An antidepressant from another group administered for 6–8 weeks.
3. A full course of ECT.

The following possibilities may then be considered should the patient fail to respond:
1. Add lithium to a standard antidepressant (e.g. an SSRI) maintaining the plasma lithium concentration at 0.4–0.6mmol/l. This is a wellestablished method with approximately 50% of the patients responding.
However, the plasma lithium concentration must be monitored.
2. Administer a high therapeutic dose of a ‘‘dual action’’ antidepressant such as venlafaxine or possibly mirtazepine. A discontinuation syndrome may occur if venlafaxine is abruptly withdrawn. The symptoms of the discontinuation reaction, which also occur occasionally when some of the SSRIs are abruptly withdrawn, include dizziness, ‘‘electroshock’’ sensations, anxiety and agitation, insomnia, flu-like symptoms, diarrhoea and abdominal pain, parathesis, nausea.
3. Add tri-iodothyronine to a standard antidepressant. This combination is usually well tolerated but monitoring the plasma T3 concentration is important.
4. Add tryptophan to a standard antidepressant (usually an SSRI). There is a danger that the serotonin syndrome may occur however and occasionally the eosinophilia myalgia syndrome. The symptoms that occur with increasing severity are restlessness, diaphoresis, tremor, shivering, myoclonus, confusion, convulsions, death.
5. Add pindolol (a 5-HT1D antagonist as well as a beta adrenoceptor antagonist), which is well researched but there are contradictory findings in the literature with regard to its efficacy. So far, the clinical data suggest that the response to a standard antidepressant is accelerated.
6. Add dexamethasone to a standard antidepressant. This combination is well tolerated for a short course of treatment but so far there is only limited evidence of efficacy from the literature.
7. Add lamotrigine to a standard antidepressant. Again, the support for this approach is largely anecdotal.
8. Add buspirone to a standard antidepressant (usually an SSRI). The evidence in favour of this combination is largely anecdotal.
9. Add an atypical antipsychotic (e.g. olanzapine or risperidone). There is some ‘‘open trial’’ evidence in favour of such combinations.
10. Add mirtazepine to a standard antidepressant (usually an SSRI). Again, the evidence is largely anecdotal.
There are a number of other methods mentioned in the literature, some of which (such as the combination of a TCA with an MAOI) are potentially cardiotoxic and not to be recommended. More recently, a combination of an SSRI with a TCA has become popular but is not to be recommended because of the probability of metabolic interactions involving the cytochrome P450 system that can increase the tissue concentration of even a modest dose of a TCA to a cardiotoxic level.

Physical pain and depression

2011-05-05T13:04:00.001+05:30

Physical pain and depression
Major depression is a triad of psychological, somatic and physical symptoms. Over 75% of depressed patients report painful physical symptoms involving the neck, back, head, stomach and the skeletomuscular system. Not only can chronic pain lead to depression, but also vice versa. Fibromyalgia, accounting for 2–4% of the general population, is a common cause of chronic pain. It has been estimated that 20–40% of such patients have co-morbid depression with a lifetime prevalence of about 70%. This raises the question whether there is a common mechanism linking pain and depression. Neuroanatomically both the locus coeruleus and the raphe´ nuclei project to the spinal cord where they gate sensory pathways from the skeletomuscular areas. As there is evidence that both noradrenaline and 5-HT are dysfunctional in depression, it is perhaps not surprising to find that the pain threshold is often reduced in patients with depression. Conversely, different types of antidepressants have been shown to have an antinociceptive effect in both rodent models of neuropathic pain, and clinically in fibromyalgia, chronic fatigue syndrome, postherpetic neuralgia and diabetic neuropathy. In general, it would appear that the dual action antidepressants (such as the TCAs and SNRIs) are more effective than the SSRIs.

2011-05-05T13:04:00.000+05:30

Tricyclic antidepressants (TCAs), MAOIs(monoamine oxidase inhibitors), SSRI, Classification of antidepressants, and Other Drug Treatments

2011-05-05T12:59:00.003+05:30

Tricyclic antidepressants (TCAs)
This group of drugs was introduced during the early 1960s following the chance discovery of the antidepressant effects of imipramine. The therapeutic efficacy of the TCAs has been ascribed to their ability to inhibit the reuptake of noradrenaline and serotonin into the neuron following the release of these transmitters into the synaptic cleft. In addition, these drugs inhibit the muscarinic receptors (causing dry mouth, impaired vision, tachycardia, difficulty in micturition), histamine type-1 receptors (causing sedation) and alpha-1 adrenoceptor antagonism (causing postural hypotension). Such side effects often lead to non-compliance (estimated to be at least 40% in general practice situations) and are more frequent in the elderly. The excellent clinical efficacy of the TCAs has been well documented and the pharmacokinetic profiles are favourable. The most serious disadvantage of the TCAs lies in their cardiotoxicity. Thus, with the exception of lofepramine, all the tricyclic antidepressants, including mapro tiline, block the fast sodium channels in the heart which can lead to heart block and death. Approximately 15% of all patients with major depression die by suicide and a high proportion of these (up to 25%) do so by taking an overdose of TCAs. Such a dose can be as low as 5–10 times the recommended daily dose.Lofepramine differs from the other TCAs in that its structure seems to preclude it from causing the anticholinergic, antihistaminergic and antiadrenergic effects evident with the other TCAs. In addition, it does not appear to be any more cardiotoxic than most of the second-generation antidepressants. The reason for this is an enigma, as the main metabolite of lofepramine is desipramine, a typical cardiotoxic TCA. There is a suggestion that, due to its high lipophilicity, it impedes the access of desipramine to the sodium fast channels in the heart without interfering with their normal function. Thus lofepramine would appear to fulfil many of the requirements of a safe and effective TCA; it has been widely used, particularly in elderly depressed patients, in the past in both the UK and Ireland.

Irreversible inhibitors of monoamine oxidase (MAOIs)
Iproniazid, an MAOI no longer available because of its hepatotoxicity, was the first effective antidepressant to be discovered; it was introduced shortly before the discovery of imipramine. All MAOIs are presumed to have a similar mode of action, namely to inhibit the intra- and interneuronal metabolism of the biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin). These amines are primarily metabolized by MAO-A (noradrenaline and serotonin) or MAO-B (dopamine). The irreversible MAOIs are inhibitors of MAO-A while selegiline (deprenyl), used as an adjunctive treatment for Parkinson’s disease, is a selective, irreversible inhibitor of MAO-B. The main limitation to the clinical use of the MAOIs is due to their interaction with amine-containing foods such as cheeses, red wine, beers (including non-alcoholic beers), fermented and processed meat products, yeast products, soya and some vegetables. Some proprietary medicines such as cold cures contain phenylpropanolamine, ephedrine, etc. and will also interact with MAOIs. Such an interaction (termed the ‘‘cheese effect’’), is attributed to the dramatic rise in blood pressure due to the sudden release of noradrenaline from peripheral sympathetic terminals, an event due to the displacement of noradrenaline from its intraneuronal vesicles by the primary amine (usually tyramine). Under normal circumstances, any dietary amines would be metabolized by MAO in the wall of the gastrointestinal tract, in the liver, platelets, etc. The occurrence of hypertensive crises, and occasionally strokes, therefore limited the use of the MAOIs, despite their proven clinical efficacy, to the treatment of atypical depression and occasionally panic disorder. The side effects of the MAOIs include, somewhat surprisingly, orthostatic hypotension. This is thought to be due to the accumulation of dopamine in the sympathetic cervical ganglia where it acts as an inhibitory transmitter, thereby reducing peripheral vascular tone. Other side effects include psychomotor restlessness and sleep disorder. The MAOIs are cardiotoxic but probably less so than the TCAs. Potentially fatal interactions can however occur when MAOIs are combined with SSRIs or any type of drug which enhances serotonergic function. The interaction can give rise to hyperexcitability, increased muscular tone, myoclonus and loss of consciousness.Reversible inhibitors of monoamine oxidase (RIMAs) Antidepressants of this class, such as moclobemide, have a high selectivity and affinity for MAO-A. However, unlike the MAOIs, the RIMAs are reversible inhibitors of the enzyme and can easily be displaced from the enzyme surface by any primary amine which may be present in the diet. This means that the dietary amines are metabolized by MAO in the wall of the gastrointestinal tract while the enzyme in the brain and elsewhere remains inhibited. Thus the RIMAs have brought the MAOIs back into use as antidepressants in general practice. It is now evident that the RIMAs are not as potent as most currently available antidepressants.

Selective serotonin reuptake inhibitors
Zimelidine was the first SSRI antidepressant to be launched in Europe and, despite its therapeutic success, was withdrawn in the late 1980s due to severe abdominal toxicity. Zimelidine was soon replaced by fluvoxamine which only slowly received acceptance in Europe because of the high incidence of nausea and vomiting; the recommended starting dose was initially too high. Fluoxetine was the third SSRI to be launched in Europe with the advantage of a fixed daily dose (20 mg) and relatively few side effects. Sertraline, paroxetine and citalopram followed so that by the end of the 1980s, the five SSRIs were well established throughout Europe and most of the world.

As the name implies, these drugs have a high affinity for the serotonin transporter both on neuronal and also platelet membranes. There is abundant evidence that the SSRIs inhibit the reuptake of 3H-5-HT into platelets, brain slices and synaptosomal fractions, as illustrated in Table 7.10, but it is clear that there is no direct relationship between the potency of the drug to inhibit 5-HT reuptake in vitro and the dose necessary to relieve depression in the clinic. In experimental studies, it is clear that the increased release of 5-HT from the frontal cortex only occurs following the chronic (2 weeks or longer) administration of any of the SSRIs. Thus the inhibition of 5-HT reuptake may be a necessary condition for the antidepressant activity, but it is not sufficient in itself.

Despite their common ability to enhance serotonergic function in vivo, the SSRIs differ both in terms of their pharmacological profiles and their pharmacokinetics. Thus in addition to their direct inhibitory action on the serotonin transporter, they also affect other neurotransmitter systems which may have some clinical relevance. Citalopram has a modest antihistamine action which might account for its slightly sedative action. Sertraline has slight dopaminomimetic effect which may contribute to its alerting effect, while paroxetine is a muscarinic receptor antagonist. Both fluvoxamine and sertraline have affinity for sigma 1 receptors, the precise importance of which is uncertain but could contribute to the motor side effects which all the SSRIs are reputed to have, albeit very rarely. Fluoxetine, by activating 5-HT 2C receptors, may cause anxiety at least in some patients. Thus differences between the SSRIs are due not only to their different potencies as 5-HT reuptake inhibitors, but also because of their actions on other receptor systems. These differences may be of clinical importance in terms of the special populations to whom the drugs should be administered. Sertraline could also be considered for this group and while drug interactions could be more problematic it does have a slightly alerting profile which could be beneficial. Fluvoxamine has also been extensively studied in the elderly, but nausea could be a problem while fluoxetine, with its very long half-life (with its active metabolite norfluoxetine, amounting to 12 days in the elderly patient) could be beneficial for the non-compliant patient. In the elderly, fluoxetine could cause some anorexia and weight loss however. Paroxetine should be administered with more care in the elderly because of its anticholinergic action. In addition to their proven efficacy in the treatment of all types of depression, the SSRIs have been shown to be the drugs of choice in the treatment of panic disorder, obsessive–compulsive disorder, bulimia nervosa, and as an adjunct to the treatment of alcohol withdrawal and relapse prevention, premenstrual dysphoric disorder and post-traumatic stress disorder. The usefulness of these drugs in treating such a diverse group of disorders reflects the primary role of serotonin in the regulation of sleep, mood, impulsivity and food intake. All the SSRIs have qualitatively similar side effects that largely arise from the increase in serotonergic function and the resulting activation of the different 5-HT receptor types in the brain and periphery. There are differences in the frequency of these effects however which would not be anticipated if all the SSRIs were essentially the same! These effects include nausea, vomiting, diarrhoea or constipation, insomnia, tremor, initial anxiety, dizziness, sexual dysfunction and headache. Loss in body weight may occur but this is rare. The behavioural toxicity of the SSRIs as indicated by their effects on psychomotor function, memory and learning, is low, particularly when compared to the TCAs and same of the sedative secondgeneration antidepressants such as mianserin, mirtazepine and trazodone.

The SSRIs are not cardiotoxic and safety in overdose has been indicated for all these drugs. In general, the severity of the adverse effects is slight and seldom leads to non-compliance. In addition to the five SSRIs currently available, many more compounds are in development which will no doubt be marketed in the near future. Of the new arrivals, escitalopram, the S-enantiomer of citalopram, has already become available in many European countries.

Classification of antidepressants available in Europe
. Antidepressants that inhibit monoamine reuptake
Tricyclic antidepressants (TCAs) – first-generation antidepressants
Examples – tertiary amine type: imipramine, amitriptyline, dothiepin,
clomipramine
– secondary amine type: desipramine, nortriptyline
– other effects: potent antagonists of muscarinic, histaminic and
alpha-1 adrenergic receptors; cardiotoxic
Modified TCA-lofepramine – non-cardiotoxic; low affinity for muscarinic and
alpha-1 adrenoceptors
. Inhibitors of noradrenaline reuptake (NARIs)
Examples – maprotiline: a ‘‘bridged’’ tricyclic with affinity for histamine, H1,
and alpha-1 adrenoceptors. Causes seizures
– reboxetine: not cardiotoxic; does not have an affinity for any
neurotransmitter receptors
. Inhibitors of serotonin reuptake (SSRIs)
Examples – citalopram (1), sertraline (2), fluoxetine (3), paroxetine (4),
fluvoxamine
Slight affinity for (1) histamine, (2) dopamine, (3) serotonin, (4) muscarinic
receptors (see text)
. Specific inhibitors of noradrenaline and serotonin reuptake (SNRIs)
Examples – venlafaxine (more potent inhibitor of 5-HT than noradrenaline
reuptake)
– milnacipran (more potent inhibitor of noradrenaline than 5-HT
reuptake)
. Antidepressants that inhibit monoamine metabolism
Irreversible monoamine oxidase inhibitors (MAOIs)
Examples – phenelzine, pargyline, tranylcypromine, isocarboxazid. All
interact with dietary monoamine to cause the ‘‘cheese effect’’
(see text)
. Reversible inhibitors of monoamine oxidase A (RIMAs)
Examples – moclobemide, pirlindole. At therapeutic doses unlikely to interact
with dietary amines (see text)
. Tetracyclic antidepressants
Examples – mianserin (1), mirtazepine (6-aza-mianserin) (2)
(1) The first second-generation antidepressant; an alpha-2 adrenoceptor antagonist with some affinity for 5-HT1A, 5-HT2A and 5-HT3, alpha-1 adrenoceptors and H1 receptors
(2) Known as a noradrenaline and specific serotonin antidepressant (NaSSA).

More potent affinity for alpha-2 adrenoceptors and 5-HT receptors than mianserin; H1 antagonist
. Other antidepressants (sometimes called ‘‘atypical’’)
Examples – trazodone, nefazodone: 5-HT1A and 5-HT2 antagonists, weak SSRI activity; alpha-1 and H1 antagonism

Noradrenaline reuptake inhibitors (NRIs)
Reboxetine is the only selective and reasonably potent noradrenaline reuptake inhibitor available clinically at the present time. Reboxetine has a chemical structure not dissimilar from viloxazine, an antidepressant which was of only limited clinical interest in the 1970s because of its weak efficacy and unacceptable side effects (nausea, vomiting and occasionally seizures). Unlike the secondary amine TCA antidepressants, such as maprotiline, desipramine, nortriptyline and protriptyline, reboxetine does not affect any other transporter or receptor system and therefore is largely devoid of TCA and SSRI-like side effects. In clinical trials, reboxetine has been shown to be as effective as the SSRIs in the treatment of depression but, unlike the SSRIs, reboxetine does not inhibit any of the cytochrome P450 enzymes in the liver.

In contrast to the widespread interest in 5-HT in depression research and in the development of antidepressants, there would appear to be little interest in developing antidepressants that selectively modulate the noradrenergic system. At the present time, there do not appear to be any drugs of this type in development. For completeness, buproprion should be mentioned even though it is not widely registered as an antidepressant in Europe, partly because of its propensity to cause seizures in some patients. Buproprion, quite widely used in the USA as an antidepressant, appears to inhibit the reuptake of both dopamine and noradrenaline and therefore tends to have a slightly alerting action. In many European countries it has recently been introduced, at a lower than antidepressant dose, in the treatment of nicotine withdrawal in smoking cessation programmes. Lastly, nomifensine was an interesting antidepressant that also had noradrenaline, dopamine and, due to its 4-hydroxy metabolite, serotonin reuptake properties. It was withdrawn some years ago because of the occurrence of haemolytic anaemia in a small number of patients. It was a particularly effective drug in the treatment of depression in patients with epilepsy as, unlike many antidepressants available at that time, it did not affect the seizure threshold.

Selective serotonin and noradrenaline reuptake inhibitors (SNRIs)
In an attempt to combine the clinical efficacy of the TCAs with the tolerability and safety of the SSRIs and NRIs, drugs showing selectivity in inhibiting the reuptake of both noradrenaline and serotonin were developed. Being structurally unrelated to the TCAs however, they lacked their side effects including their cardiotoxicity. To date, venlafaxine is the most widely available of the SNRIs. Although it is known to enhance both serotonergic and noradrenergic function, at the lower clinical dose range it primarily enhances serotonergic function and therefore has the characteristic side effects of an SSRI. At higher therapeutic doses, venlafaxine also inhibits noradrenaline reuptake and therefore resembles a TCA antidepressant. While there is no evidence that venlafaxine is as cardiotoxic as the TCAs, recent studies have indicated that it is at least threefold more likely than the SSRIs to result in death if taken in overdose. Hypertension may occur in some patients when given a high therapeutic dose of venlafaxine. A more potent, but qualitatively similar antidepressant to venlafaxine, duloxetine, is currently in advanced clinical development. Milnacipran is also a dual-action antidepressant which, like venlafaxine, has been shown to be more effective than the SSRIs in the treatment of severe, hospitalized and suicidally depressed patients. At lower therapeutic doses, milnacipran blocks the noradrenaline transporters and therefore resembles the NRI antidepressants. Higher doses result in the serotonergic component becoming apparent (i.e. an SSRI-like action). The main problem with milnacipram appears to be its lack of linear kinetics with some evidence that it has a U-shaped dose–response curve.

Tetracyclic antidepressants
Mianserin was the first of the second-generation antidepressants to be developed. It lacked the amine reuptake inhibitory and MAOI actions of the first-generation drugs and also lacked the cardiotoxicity and anticholinergic activity of the TCAs. However, it was sedative (antihistaminic), caused postural hypotension (alpha-1 blockade) and also caused blood dyscrasias and agranulocytosis in a small number of patients. This has limited the use of mianserin in recent years. Mirtazepine (called a Noradrenaline and Selective Serotonin Antidepressant; NaSSA) is the 6-aza derivative of mianserin and shares several important pharmacological properties with its predecessor, namely its antihistaminic and alpha-1 adrenoceptor antagonistic actions. Like mianserin, mirtazepine also causes weight gain. Nevertheless, mirtazepine is better tolerated and there is no evidence of blood dyscrasias associated with its clinical use. Regarding the mode of action of these tetracyclic compounds, both are potent alpha-2 adrenoceptor antagonists which cause an enhanced release of noradrenaline. The action of mirtazepine on serotonin receptors (5- HT1A, 5-HT2A, 5-HT3) is both direct (5-HT2A and 5-HT3) and indirect (5- HT1A). The complexity of the interaction of the drug with both adrenoceptors and serotonin receptors helps to emphasize the importance of the ‘‘cross talk’’ between these two neurotransmitter systems. Thus the antidepressant effects of both mirtazepine and mianserin are related to the enhancement of noradrenaline release (alpha-2 blockade) and 5-HT2A receptor antagonism. In addition, mirtazepine (and to a lesser extent mianserin) blocks 5-HT3 receptors therefore reducing the anxiety and nausea normally associated with drugs that enhance serotonergic function. The anti-anxiety effect of mirtazepine is ascribed to its indirect activation of the 5-HT1A receptors, an effect also seen following the administration of an SSRI.

Other, or atypical, antidepressants
These include trazodone and a derivative of its metabolite nefazodone, both of which are strongly sedative, an effect which has been attributed to their potent alpha-1 receptor antagonism rather than to any antihistaminic effects. A main advantage of these drugs in the treatment of depression is that they appear to improve the sleep profile of the depressed patient. Their antidepressant activity is associated with their weak 5-HT reuptake inhibition and also a weak alpha-2 antagonism. However, unlike most of the second-generation antidepressants, neither drug is effective in the treatment of severely depressed patients. Furthermore, there is some evidence that trazodone can cause arrythmias, and priapism, in elderly patients.

Herbal antidepressants – St John’s Wort (Hypericum officinalis)
St John’s Wort in recent years has become widely used in Europe and North America for the treatment of mild depression. Unlike all other antidepressants mentioned above, St John’s Wort is obtained through herbalists and health food shops in such countries, the exception being Ireland where it can only be obtained on prescription like any other antidepressant. There are at least 12 placebo-controlled studies proving the efficacy of St John’s Wort against standard antidepressants; all these studies show that the mixture of compounds present in St John’s Wort is effective in mild to moderate, but not severe, depression. Of the main active ingredients of the plant, it would appear that hyperfolin is largely responsible for the antidepressant activity. This compound is an inhibitor of the reuptake of noradrenaline, dopamine and serotonin. In addition, it appears to have some NMDA-glutamate receptor antagonist activity, a property which it shares with many other antidepressants.

Antidepressants and changes in neuronal structure

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Antidepressants and changes in neuronal structure
Another possible mechanism whereby antidepressants may change the physical relationship between neurons in the brain is by inhibiting neurite outgrowth from nerve cells. In support of this view, it has been shown that the tricyclic antidepressant amitriptyline, at therapeutically relevant concentrations, inhibited neurite outgrowth from chick embryonic cerebral explants in vivo. While the relevance of such findings to the therapeutic effects of amitriptyline in man is unclear, they do suggest that a common mode of action of all antidepressants could be to modify the actual structure of nerve cells and possibly eliminate inappropriate synaptic contacts that are responsible for behavioural and psychological changes associated with depression. There are several mechanisms whereby antidepressants can modify intracellular events that occur proximal to the postsynaptic receptor sites. Most attention has been paid to the actions of antidepressants on those pathways that are controlled by receptor-coupled second messengers (such as cyclic AMP, inositol triphosphate, nitric oxide and calcium binding). However, it is also possible that chronic antidepressant treatment may affect those pathways that involve receptor interactions with protein tyrosine kinases, by increasing specific growth factor synthesis or by regulating the activity of proinflammatory cytokines. These pathways are particularly important because they control many aspects of neuronal function that ultimately underlie the ability of the brain to adapt and respond to pharmacological and environmental stimuli. One mechanism whereby antidepressants could increase the synthesis of trophic factors is by the activation of cyclic AMP-dependent protein kinase which indirectly increases the formation of the transcription factors. There is experimental evidence to show that the infusion of one of these transcription factors (brain derived neutrophic factor) into the midbrain of rats results in antidepressant-like activity, an action associated with an increase in the synthesis of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin.

Changes in neuronal structure in depression
1. There is evidence that inadequately treated, or untreated, major depression is associated with a decrease in the hippocampal volume. This could be a consequence of the increase in proinflammatory cytokines and hypercortisolaemia.
2. Experimental evidence suggests that chronic antidepressant treatments increase the formation of transcription factors within the brain which increases neuronal plasticity and leads to recovery.

The effects of antidepressants on endocrine-immune functions

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The effects of antidepressants on endocrine-immune functions
Stress is frequently a trigger factor for depression in vulnerable patients. There is clinical evidence to show that CRF is elevated in the cerebrospinal fluid of untreated depressed patients, which presumably leads to the hypercortisolaemia that usually accompanies the condition. One of the consequences of elevated plasma glucocorticoids is a suppression of some aspects of cellular immunity. It is now established that many cellular (for example, natural killer cell activity, T-cell replication) and non-cellular (for example, raised acute phase proteins) aspects are abnormal in the untreated depressed patient. Such observations could help to explain the susceptibility of depressed patients to physical ill health. A link between CRF, the cytokines which orchestrate many aspects of cellular immunity, and the prostaglandins of the E series has been the subject of considerable research in recent years. There is clinical evidence to show that prostaglandin E2 (PGE2) concentrations are raised in the plasma of untreated depressed patients and are normalized following effective treatment with tricyclic antidepressants. Raised PGE2 concentrations in the brain and periphery reflect increased proinflammatory cytokines (particularly tumour necrosis factor, interleukins 1 and 6) which occur as a consequence of increased macrophage activity in the blood and brain. In the brain the microglia functions as macrophages and produces such cytokines locally. Thus the increased synthesis of PGE2 may contribute to the reduction in amine release in the brain that appears to underlie the pathology of depression. It has recently been postulated that several types of antidepressants (e.g. tricyclics, monoamine oxidase inhibitors) normalize central neurotransmission by reducing brain concentrations of both the cytokines and PGE2 by inhibiting central and peripheral macrophage activity together with cyclooxygenase type 2 activity in the brain. Cyclooxygenase is the key enzyme in the synthesis of the prostaglandins. It is not without interest that the usefulness of tricyclic antidepressants in severe rheumatoid arthritis can now be explained by the inhibitory action of such drugs on cyclooxygenase activity in both the periphery and brain. Such changes, together with those in glucocorticoid receptor function, may therefore incrementally bring about the normalization of defective central neurotransmission as a consequence of antidepressant treatment. Whether the inhibition of cyclooxygenase is a common feature of all classes of antidepressants is presently unknown.

The possible role of prostaglandins and cytokines in depression
1. There is evidence that both cellular and non-cellular immunity are abnormal in the depressed patient.
2. The proinflammatory cytokines (interleukins 1 and 6 and tumour necrosis factor alpha) from macrophages are raised in depression. This leads to increased PGE2 synthesis and release which may lead to a reduction in central monoamine release.
3. Chronic antidepressant treatments reduce both the proinflammatory cytokines and PGE2.

The role of the glutamatergic system in the action of antidepressants

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The role of the glutamatergic system in the action of antidepressants
Whereas much emphasis has been placed on the monoamine neurotransmitters with respect to the mechanism of action of antidepressants, little attention has been paid to the changes in the glutamate system, the primary excitatory neurotransmitter pathway in the brain. Experimental evidence shows that tricyclic antidepressants inhibit the binding of dizolcipine to the ion channel of the main glutamate receptor, the N-methyl-D-aspartate receptor in the brain. The initial studies have more recently been extended to show that both typical and atypical antidepressants have a qualitatively similar effect by reducing the binding of dizolcipine to the NMDA receptors. Whether this is due to direct action of the antidepressants on the ion channel receptor sites, or an indirect effect possibly involving the modulation of the glycine receptor site, is uncertain, but there is evidence that glycine and drugs modulating the glycine site have antidepressant-like activity in animal models of depression. These results suggest that antidepressants act as functional NMDA receptor antagonists.

Intracellular changes that occur following chronic antidepressant treatment
The recent advances in molecular neurobiology have demonstrated how information is passed from the neurotransmitter receptors on the outer side of the neuronal membrane to the secondary messenger system on the inside. The coupling of this receptor to the secondary messenger is brought about by a member of the G protein family. Beta-adrenoceptors are linked to adenylate cyclase, and, depending on the subtype of receptors, 5-HT is linked to either adenylate cyclase (5-HT1A, 5-HT1B) or phospholipase (5-HT2A, 5-HT2C). Activation of phospholipase results in an intracellular increase in the secondary messengers diacylglycerol and inositol triphosphate (IP3), the IP3 then mobilizing intraneuronal calcium. The net result of the activation of the secondary messenger systems is to increase the activity of the various protein kinases that phosphorylate membrane-bound proteins to produce a physiological response. Some researchers have investigated the effect of chronic antidepressant treatment on the phosphorylation of proteins associated with the cytoskeletal structure of the nerve cell. Their studies suggest that antidepressants could affect the function of the cytoskeleton by changing the component of the associated protein phosphorylation system. In support of their hypothesis, these researchers showed that both typical (e.g. desipramine) and atypical (e.g. (+) oxaprotiline, a specific noradrenaline reuptake inhibitor, and fluoxetine, a selective 5-HT uptake inhibitor) antidepressants increased the synthesis of a microtubule fraction possibly by affecting the regulatory subunit of protein kinase type II. These changes in cytoskeletal protein synthesis occurred only after chronic antidepressant treatments and suggest that antidepressants, besides their well-established effects on pre- and postsynaptic receptors and amine uptake systems, might change neuronal signal transduction processes distal to the receptor. Glucocorticoid receptors: adaptive changes following antidepressant treatment Interest in the possible association of glucocorticoid receptors with central neurotransmitter function arose from the observation that such receptors have been identified in the nuclei of catecholamine and 5-HT-containing cell bodies in the brain. Experimental studies have shown that glucocorticoid receptors activate as DNA binding proteins which can modify the transcription of genes. The link to antidepressant treatments is indicated by the chronic administration of imipramine which increases glucocorticoid receptor immunoreactivity in rat brain, the changes being particularly pronounced in the noradrenergic and serotonergic cell body regions. Preliminary clinical studies have shown that lymphocyte glucocorticoid receptors are subsensitive in depressed patients. The failure of the negative feedback mechanism that regulates the secretion of adrenal glucocorticoids further suggests that the central glucocorticoid receptors are subsensitive.

This leads to the hypersecretion of cortisol, a characteristic feature of many patients with major depression. Such findings lend support to the hypothesis that the changes in central neurotransmission occurring in depression are a reflection of the effects of chronic glucocorticoids on the transcription of proteins that play a crucial role in neuronal structure and function. If the pituitary–adrenal axis plays such an important role in central neurotransmission, it may be speculated that glucocorticoid synthesis inhibitors (e.g. metyrapone) could reduce the abnormality in neurotransmitter function by decreasing the cortisol concentration. Recent in vitro hybridization studies in the rat have demonstrated that typical antidepressants increase the density of glucocorticoid receptors. Such an effect could increase the negative feedback mechanism and thereby reduce the synthesis and release of cortisol. In support of this hypothesis, there is preliminary clinical evidence that metyrapone (and the steroid synthes is inhibitor ketoconazole) may have antidepressant effects. Recently several lipophilic antagonists of corticotrophin releasing factor (CRF) type 1 receptor, which appears to be hyperactive in the brain of depressed patients, have been shown to be active in animal models of depression. Clearly this is a potentially important area for antidepressant development. Glucocorticoid receptors are present in a high density in the amygdala and neuroimaging studies have shown that the amygdala is the only structure in which the regional blood flow and glucose metabolism consistently correlate positively with the severity of depression. This hypermetabolism appears to reflect an underlying pathological process as it also occurs in asymptomatic patients and in the close relatives of the patients.

Possible role of excitatory amino acids and intracellular second messengers in the action of antidepressants
1. In experimental studies, chronic antidepressant treatments have been shown to reduce the behavioural effects of the NMDA-glutamate receptor antagonist dizolcipine. This suggests that antidepressants may act as functional NMDA receptor antagonists and thereby reduce excitatory glutamate transmission which is mediated by NMDA receptors.
2. Intracellular protein phosphorylation is enhanced by chronic antidepressant treatment. This leads to the increased synthesis of microtubules that form an important feature of the cellular cytoskeleton. Thus antidepressants might change signal transduction with the neurone.
3. Enhanced synthesis and transport of neurotransmitter synthesizing enzymes (e.g. tyrosine and tryptophan hydroxylase).

Role of glucocorticoids in modulating brain amines in depression
1. Glucocorticoid receptors occur on catecholamine and 5-HT cell bodies in the brain.
2. There is evidence that the glucocorticoid receptors are hyposensitive in the depressed patients.
3. Chronic antidepressant treatment sensitizes these receptors, thereby normalizing the noradrenergic and serotonergic function that is reduced by the hypercortisolaemia which occurs in major depression.

Link between the serotonergic and noradrenergic systems

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Link between the serotonergic and noradrenergic systems
Considerable attention has recently been focused on the interaction between serotonergic and beta-adrenergic receptors, which may be of particular relevance to our understanding of the therapeutic effect of antidepressants. Thus the chronic administration of antidepressants enhances the inhibitory response of forebrain neurons to micro-iontophoretically applied 5-HT. This enhanced response is blocked by lesions of the noradrenergic projections to the cortex. This dual effect could help to explain enhanced serotonergic function that arises after chronic administration of antidepressants or ECT. Conversely, impairment of serotonergic function by means of a selective neurotoxin (e.g. 5,7-dihydroxytryptamine) or 5-HT synthesis inhibitor (e.g. parachlorophenylalanine) largely prevents the decrease in functional activity of cortical beta-adrenoceptors that usually arises following chronic antidepressant treatment. 5-HT1B receptors are located on serotonergic nerve terminals that act as autoreceptors, and, on stimul ation by serotonin, decrease the further release of this amine. It has been hypothesized that the chronic administration of selective serotonin reuptake inhibitor antidepressants (such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine) slowly desensitize the inhibitory 5-HT1B receptors and thereby enhance serotonin release. In addition to the importance of the 5-HT1B autoreceptors in the regulation of serotonergic function, there is experimental and clinical evidence that the 5-HT1A receptors play a fundamental role in both anxiety and depression. In brief, the 5-HT1A somatodendritic receptors inhibit the release of serotonin and it is postulated that the enhanced release of the transmitter following the chronic administration of the selective serotonin reuptake inhibitors is a consequence of the adaptive down-regulation of the inhibitory 5-HT1A receptors. The validity of this hypothesis is supported by the pharmacological effect of 5-HT1A antagonists. Thus the beta-adrenoceptors antagonist an 5-HT1A antagonist pindolol, in combination with fluoxetine or paroxetine, enhance the therapeutic efficacy of the SSRI and, in some studies, reduce the time of onset of the peak therapeutic effect. However, several investigators have not been able to replicate such findings.

Both clinical and experimental studies have provided evidence that 5-HT can also regulate dopamine turnover. Thus several investigators have shown that a positive correlation exists in depressed patients between the homovanillic acid (HVA), a major metabolite of dopamine, and 5-HIAA concentrations in the CSF. In experimental studies, stimulation of the 5-HT cell bodies in the median raphe´ causes reduced firing of the substantia nigra where dopamine is the main neurotransmitter. There is thus convincing evidence that 5-HT plays an important role in modulating dopaminergic function in many regions of the brain, including the mesolimbic system. Such findings imply that the effects of some antidepressants that show an apparent selectivity for the serotonergic system could be equally ascribed to a change in dopaminergic function in mesolimbic and mesocortical regions of the brain. It has been postulated that the hedonic effect of antidepressants may be ascribed to the enhanced dopaminergic function in the mesocor ex.

Mechanism of action of antidepressants: changes in serotonergic function
1. There is experimental evidence that the chronic administration of antidepressants or ECT enhances the inhibitory effect of micro-iontophoretically applied 5-HT.
This effect is blocked by lesions of the noradrenergic projections to the frontal cortex.
2. SSRIs after chronic administration down-regulate the inhibitory 5-HT1A receptors on the serotonergic cell body, thereby leading to an enhanced release of the transmitter from the nerve terminal.
3. 5-HT can also decrease dopamine release from the substantia nigra (an important dopaminergic nucleus). This may account for the observation that some SSRIs may cause dystonias and precipitate the symptoms of parkinsonism if given to such patients who are responding to L-dopa. Sertraline appears to differ from other SSRIs in this respect and may slightly enhance dopaminergic function by reducing the reuptake of this transmitter.

Historical development of antidepressants

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Historical development of antidepressants
The use of cocaine, extracted in a crude form from the leaves of the Andean coca plant, has been used for centuries in South America to alleviate fatigue and elevate the mood. It was only relatively recently, however, that the same pharmacological effect was discovered when the amphetamines were introduced into Western medicine as anorexiants with stimulant properties. Opiates, generally as a galenical mixture, were also widely used for centuries for their mood-elevating effects throughout the world. It is not without interest that while such drugs would never now be used as antidepressants, there is evidence that most antidepressants do modulate the pain threshold, possibly via the enkephalins and endorphins. This may help to explain the use of antidepressants in the treatment of atypical pain syndromes and as an adjunct to the treatment of terminal cancer pain. Finally, alcohol in its various forms has been used to alleviate anguish and sorrow since antiquity. Whilst the opiates, alcohol and the stimulants offer some temporary relief to the patient, their long-term use inevitably leads to dependence and even to an exacerbation of the symptoms they were designed to cure. The development of specific drugs for the treatment of depression only occurred in the early 1950s with the accidental discovery of the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs). This period marked the beginning of the era of pharmacopsychiatry. Although the iminodibenzyl structure, which forms the chemical basis of the TCA series, was first synthesized in 1889, its biological activity was only evaluated in the early 1950s following the accidental discovery that the tricyclic compound chlorpromazine had antipsychotic properties. Imipramine is also chemically similar in structure to chlorpromazine, but was found to lack its antipsychotic effects. It was largely due to the persistence of the Swiss psychiatrist Kuhn that imipramine was not discarded and was shown to have specific antidepressant effects. It is not without interest that the first report of the antidepressant effects of imipramine was presented to an audience of 12 as part of the proceedings of the Second World Congress of Psychiatry in Zurich in 1957! The introduction of the first MAOI in the early 1950s was equally inauspicious. Iproniazid had been developed as an effective hydrazide antitubercular drug, but was subsequently found to exhibit mood-elevating effects. This was shown to be due to its ability to inhibit MAO activity and was unconnected with its antitubercular action. Thus by the late 1950s, psychiatrists had at their disposal two effective treatments for depression, a TCA and an MAOI. But it was only in attempting to discover how these drugs may work, together with the evidence that the recently introduced antipsychotic drug resperine caused depression in a small number of patients, that the hypothesis was developed that depression was due to a relative deficit of biogenic amine neurotransmitters in the synaptic cleft and that antidepressants reversed this deficit by preventing their inactivation.
While this hypothesis has been drastically revised in the light of research into the biochemical nature of depression, at that time it had the advantage of unifying a number of disparate clinical and experimental observations and in laying the basis for subsequent drug development. Aspects of the biochemical basis of depression Research into the chemical pathology of depression has mainly concentrated on four major areas:
1. Changes in biogenic amine neurotransmitters in post-mortem brains from suicide victims.
2. Changes in cerebrospinal fluid (CSF) concentrations of amine metabolites from patients with depression.
3. Endocrine disturbances which appear to be coincidentally related to the onset of the illness.
4. Changes in neurotransmitter receptor function and density on platelets and lymphocytes from patients before and following effective treatment.
Approximately 30 years ago, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. Evidence in favour of this hypothesis was provided by the observation that the antihypertensive drug reserpine, which depletes both the central and peripheral vesicular stores of catecholamines such as noradrenaline, is likely to precipitate depression in patients in remission. The experimental drug alpha-methylparatyrosine that blocks the synthesis of noradrenaline by inhibiting the rate-limiting enzyme tyrosine hydroxylase was also shown to precipitate depression in patients during remission. While such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression, more direct evidence is needed to substantiate the hypothesis. The most obvious approach would be to determine the concentration of noradrenaline and/or its major central metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brains of suicide victims. The problem with such post-mortem studies is that (a) the precise diagnosis may be uncertain, (b) there is usually a considerable postmortem delay before the brain is removed at autopsy and (c) suicide is often committed by taking an overdose of alcohol together with drugs which grossly affect central monoamine neurotransmitter function. Unless these variables are carefully controlled, the value of the results obtained from such analyses is uncertain. Nevertheless, there is evidence that the neurotransmitter receptors in post-mortem brain are less labile than the neurotransmitters that act upon them. The finding that the density of beta adrenoceptors is increased in cortical regions of the brains from suicide victims who had suffered from depression is evidence of disturbed noradrenergic function which is associated with some of the symptoms of the illness. Such observations are further supported by the increase in the density of beta adrenoceptors on the lymphocytes of untreated depressed patients. As t he density of these receptors is normalized by effective antidepressant treatment, it has been postulated that changes in the beta receptor density may be a state marker of the condition. Other studies have shown that the elevation of growth hormone in the plasma following the administration of the alpha-2 adrenoceptor agonist clonidine is diminished in depressed patients, which suggests that central postsynaptic alpha-2 adrenoceptors are also subfunctional in such patients. This is perhaps the most consistent finding to have emerged in studies of the hypothalamic–pituitary axis in depression. As the clonidine response does not return to normal after effective antidepressant treatment, this is possibly a trait marker of depression. It should be emphasized that the reduced growth hormone response to clonidine cannot be accounted for by drug treatment, age or gender of the patient, which supports the view that the noradrenergic system is dysregulated in depression. Lastly, determination of the urine or plasma concentrations of MHPG (an indicator of central noradrenergic activity) suggests that central noradrenergic function is suboptimal in depression. Taken together, these results suggest that central noradrenergic function is decreased in depression, an event leading to the increase in the density of the postsynaptic beta adrenoceptors that show adaptive changes in response to the diminished synaptic concentration of the transmitter. It should be emphasized however that none of the studies of noradrenergic function in post-mortem material or tissues from depressed patients are entirely satisfactory. Many of the findings cannot be replicated, the number of patients studied is relatively small and the tritiated ligands used to determine the receptor density for example vary in their selectivity.

There is also evidence that the density of muscarinic receptors is increased in limbic regions of depressed patients who have committed suicide. If it is assumed that such a change reflects an increased activity of the cholinergic system, it could help to explain the reduced noradrenergic function as there is both clinical and experimental evidence to suggest that increased central cholinergic activity can precipitate depression and reduce noradrenergic activity. The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in depressed patients. Whereas the overall psychophysiological effects of noradrenaline in the CNS appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood. It is not surprising therefore to find that the serotonergic system is abnormal in depression. This is indicated by a reduction in the main 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA), in the cerebrospinal fluid of severely depressed patients and a reduction in 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims. The 5-HT receptor function also appears to be abnormal in depression. This is indicated by an increase in the density of cortical 5-HT2A receptors in the brains of suicide victims and also on the platelet membrane of depressed patients. Platelets may be considered as accessible models of the nerve terminal. Thus platelets are, like neurons, of ectodermal origin and contain enzymes such as enolase that are otherwise restricted to neurons. In addition, platelets contain storage vesicles for 5-HT from which the amine is released by a calcium-dependent mechanism. An energy-dependent transport site for 5-HT also occurs on the platelet membrane, the structure of which is identical to that found on neurons in the brain. Furthermore, the platelet membrane contains 5-HT2A and alpha-2 adrenergic receptors that are functionally involved in platelet aggregation; there is evidence that the densities of these receptors are increased in depressed patients and largely normalized following effective treatment. Thus a number of important biochemical parameters may be determined from a platelet-rich plasma sample. It has been found, for example, that the transport of 3H-5-HT into the platelet is significantly reduced in the untreated depressed patient but largely returns to normal following effective treatment. This change occurs irrespective of the nature of the antidepressant used to treat the patient and may therefore be considered as a state marker of the illness. The function of the 5-HT2A receptor also appears to be subnormal in the untreated patient as shown by diminished aggregatory response to the addition of 5-HT in vitro, but normalizes when the patient recovers. As the number of 5-HT2A receptors on the platelet membrane of depressed patients is increased (as shown by the increased binding of a specific ligand such as 3H-ketanserin) this finding suggests that the G protein transducer mechanism, which links the receptor to the second messenger phosphatidyl inositol system within the platelet, is possibly defective in depression. There is also evidence that the modulatory site on the 5-HT transporter, the imipramine binding site, is decreased in depression, but unlike the changes in 5-HT uptake, remains unchanged by effective treatment. This suggests that the number of imipramine binding sites on the platelet membrane is a trait marker of the condition. However, the precise relevance of this finding is uncertain as the binding of the more specific ligand, 3H-paroxetine, is unchanged in depression. These studies of platelet function before, during and following treatment can give important information of the biochemical processes which may be causally related to depression. However, it is still uncertain how the changes in platelet function precisely reflect those occurring in the brain. Platelets are unconnected with the nervous system and therefore the changes observed could be a reflection of the hormonal changes (for example, glucocorticoids) that occur in depression. There is also evidence that some of the alterations in platelet function are a consequence of low molecular weight plasma factors that occur in the depressed patient and which are absent following effective antidepressant treatment.

Changes in brain and tissue amine neurotransmitters in depressed patients which may be indicative of the mechanism of action of antidepressants
. Evidence from the brains of depressed patients who committed suicide
. Increased density of beta adrenoceptors in cortical regions
. Increased density of 5-HT2A receptors in limbic regions
. Decreased concentration of 5-HIAA in several brain regions
. Increased muscarinic receptor density in limbic regions

Other clinical studies implicating an abnormal biogenic amine function in depression
. Decreased 5-HIAA concentration in CSF
. Decreased HVA (main dopamine metabolite) in CSF
. Decreased urinary excretion of the main central noradrenaline metabolite MHPG (?)
. Rapid relapse following administration of a tryptophan-free amino acid drink to depressed patients being treated with an SSRI
. Rapid relapse following administration of the tyrosine hydroxylase inhibitor alpha-methyl-tyrosine to depressed patients who respond to a noradrenaline reuptake inhibitor such as desipramine

While there has been considerable attention devoted to changes in noradrenergic and serotonergic function in depression, less attention has been paid to the possible involvement of dopamine in this disorder. This is surprising as anhedonia is a characteristic feature of major depression and a defect in dopaminergic function is thought to be causally involved in this symptom. Several studies have shown that the concentration of the main dopamine metabolite, homovanillic acid (HVA), is decreased in the CSF of depressed patients, particularly those with psychomotor retardation. These depressed patients who attempted suicide were also found to have a decreased urinary excretion of HVA and the second major dopamine metabolite, dihydroxyphenylacetic acid (DOPAC). It is of course possible that the dopamine deficit is more a reflection of the degree of retardation rather than the psychological state as similar changes in CSF HVA concentrations have been reported to occur in patients with Parkinson’s disease. This imp lies that the changes in the basal ganglia probably overshadow any changes in the mesolimbic dopaminergic system as the contribution of this area is relatively minor. With regard to the specific action of antidepressants on the dopaminergic system, there is evidence that buproprion (not marketed in most countries in Western Europe as an antidepressant but available in North America), amineptine and nomifensin (withdrawn because of the rare occurrence of haemolysis) owed their antidepressant efficacy to their ability to increase central dopaminergic function. There are also open label studies to suggest that the novel dopamine receptor agonist roxindole and the selective dopamine uptake inhibitor pramipexole may have antidepressant action. Thus when the results of the studies on platelets, lymphocytes, changes in cerebrospinal fluid metabolites of brain monoamines and the post-mortem studies are taken into account it may be concluded that a major abnormality in both noradrenergic and serotonergic function occu rs in depression, and that such changes could be causally related to the disease process.

Evidence from depressed patients
. Increased density of 5-HT2A receptors on the platelet membrane
. Decreased uptake of 3H-5-HT into platelet
. Increased beta adrenoceptor density on lymphocyte membrane
. Increased density of alpha-2 adrenoceptors on platelet membranes (*)
. Blunted growth hormone response to a clonidine challenge
. Blunted prolactin response to a fenfluramine challenge

Both clinical and experimental studies have shown that a number of transmitter receptors and amine transport processes show circadian changes. It is well established that depression is associated with a disruption of the circadian rhythm as shown by changes in a number of behavioural, autonomic and neuroendocrine aspects. One of the main consequences of effective treatment is a return of the circadian rhythm to normality. For example, it has been shown that the 5-HT uptake into the platelets of depressed patients is largely unchanged between 0600 and 1200 hours, whereas the 5-HT transport in control subjects shows a significant decrease over this period. The normal rhythm in 5-HT transport is only reestablished when the depressed patient responds to treatment. Thus it may be hypothesized that the mode of action of antidepressants is to normalize disrupted circadian rhythms. Only when the circadian rhythm has returned to normal can full clinical recovery be established. Chronobiological studies have shown tha circadian rhythms occur in the responsivity of animals to light, dark and psychotropic drugs. This implies that the timing of drug administration so that the drug reaches the target organ at its optimum sensitivity could help to improve its therapeutic efficiency. The results of experimental studies suggest that most antidepressants delay the circadian phase and lengthen the circadian period. These changes could be due to the drugs acting on the circadian pacemaker in the superchiasmatic nucleus. However, other brain regions could also be responsible together with antidepressantinduced changes in the retina which would lead to a modification of the processing of light stimuli; the lateral geniculate nucleus may also have a role to play. Seasonal affective disorder (SAD) generally consists of recurrent depressive episodes in autumn and winter that alternate with euthmia or hypomania in spring and summer. The seasonal rhythms of mood, sleep and weight change seen in SAD patients resemble hibernation seen in animals. This led to the hypothesis that extension of the photoperiod in winter could counteract the depressive symptoms. Exposure to bright light had indeed been shown to be efficacious. Clinical studies show that carbohydrate craving, a common feature of SAD, is possibly linked to a decreased serotonin turnover. Such a hypothesis is supported by the fact that the serotonin releasing agent D-fenfluramine is effective in treating SAD. Chronobiology is clearly an important area of research for the psychopharmacologist which needs more attention.

Why is there a delay in the onset of the antidepressant response?
In an attempt to explain the reason for the delay in the onset of the therapeutic effect of antidepressants, which is clearly unrelated to the acute actions of these drugs on monoamine reuptake transporters or intracellular metabolizing enzymes, emphasis has moved away from the presynaptic mechanism governing the release of the monoamine transmitters to the adaptive changes that occur in pre- and postsynaptic receptors that govern the physiological expression of neurotransmitter function. Antidepressant therapy is usually associated with a gradual onset of action over 2 to 3 weeks before the optimal beneficial effect is obtained. Much of the improvement seen early in the treatment with antidepressants is probably associated with a reduction in anxiety that often occurs in the depressed patient and improvement in sleep caused by the sedative action of many of these drugs. The delay in the onset of the therapeutic response cannot be easily explained by the pharmacokinetic profile of the drugs as peak plasma (and presumably brain) concentrations are usually reached in 7 to 10 days. Furthermore, the 2–3 weeks delay is also seen in many, though not all, patients given electroconvulsive therapy (ECT). It is apparent that adaptational changes occur in adrenoceptors, serotonin, dopamine and GABA-B receptors. There is evidence that GABA-B receptors play a role in enhancing noradrenaline release in the cortex and in this respect differ fundamentally from the inhibitory GABA-A receptors which facilitate central GABAergic transmission. A decrease in the activity of GABA-B receptors may therefore contribute to the reduced central noradrenergic tone reported to occur in depression.

Changes in cholinergic and aminergic receptors in depression and following antidepressant treatment
1. Evidence that central muscarinic receptors are supersensitive in depressed patients and that chronic antidepressant treatments normalize the supersensitivity of these receptors. This effect does not depend on any intrinsic anticholinergic activity of the antidepressant (i.e. it is an indirect, adaptive effect).
2. Following chronic administration to rats, there is evidence that most antidepressants cause adaptive changes in 5-HT1A, 5-HT2A alpha-1, alpha-2 and beta adrenoceptors, GABA-B receptors and possibly the NMDA-glutamate receptors.

Changes in cholinergic function
In addition to these changes, recent evidence has shown that a decrease in cortical muscarinic receptors occurs in the bulbectomized rat model of depression that, like most of the changes in biogenic amine receptors, returns to control values following treatment with either typical (e.g. tricyclic antidepressants) or atypical (e.g. mianserin) antidepressants. Such findings are of particular interest as the anticholinergic activity of the tricyclic antidepressants is usually associated with their unacceptable peripheral side effects and most second generation antidepressants have gained in therapeutic popularity because they lack such side effects. Nevertheless, support for the cholinergic hypothesis of depression is provided by the finding that the short-acting reversible cholinesterase inhibitor pyridostigmine, when administered to drug-free depressed patients, causes an enhanced activation of the anterior pituitary gland as shown by the release of growth hormone secretion. This suggests that the muscarinic receptors are supersensitive in the depressed patient. However, the mechanism whereby the receptors are normalized by chronic (but not acute) antidepressant treatment vary and in most cases are unlikely to be due to a direct anticholinergic action. It has been postulated that depression arises as the result of an imbalance between the central noradrenergic and cholinergic systems; in depression the activity of the former system is decreased and, conversely, in mania it is increased. As most antidepressants, irrespective of the presumed specificity of their action on the noradrenergic and serotonergic systems, have been shown to enhance noradrenergic function, it is hypothesized that the functional reduction in cholinergic activity arises as a consequence of the increase in central noradrenergic activity.

Drug Treatment of Depression

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Drug Treatment of Depression
The Oxford Dictionary defines depression as a state of ‘‘low spirits or vitality’’. Clearly, this state has been experienced by most people at some stage during their lives. However, the psychiatrist is seldom concerned with such a mood change unless it persists for such a long time that it incapacitates the individual. Should the depressed mood be associated with feelings of guilt, suicidal tendencies and disturbed bodily functions (such as weight loss, anorexia, loss of libido or a disturbed sleep pattern characterized by early morning wakening) and persist for weeks or even months, often with no initiatory cause, then psychiatric assistance is usually required. It is not proposed to discuss the various types of depression that have been identified because the drug treatment is essentially similar irrespective of whether or not there appears to be an initiatory cause. For example, bereavement is often associated with a severe depressive episode, particularly in the elderly, and while counselling may be of c onsiderable assistance in enabling the patient to adjust to the changed circumstances the use of an antidepressant is often advisable.

Many psychiatrists still divide depression into the endogenous (i.e. no apparent external cause) and reactive (i.e. an identifiable external cause) types and, while such a division may be of some value regarding ancillary treatment, there is presently no evidence to suggest that the biochemical changes that may be causally linked to the illness differ nor is there any evidence that the way in which the patient should be assisted by drugs differs substantially. Other international classifications of depression are based on the mono- and bipolar dichotomy, a system of classification that separates those patients with depressive symptoms only from those that fluctuate between depression and mania (i.e. manic-depression) or have only manic symptoms. In such cases treatment strategies differ as specific and antimanic drugs such as lithium or the neuroleptics would be used to abort an acute attack of mania, while antidepressants are the drugs of choice to treat the depressive episodes and anxiety associated with de pression. Readers are referred to the various classification manuals, such as the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (DSM-IV) or the International Classification of Diseases, 10th Revision (ICD10), for further details.

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Serotonin receptor subtypes and disease states
Physiological or pathological -- condition Serotonin receptor subtype implicated
Feeding behaviour: 5-HT1A agonists enhance food consumption in experimental animals
5-HT1B/5-HT2C agonists decrease food consumption in experimental animals
Thermoregulation: 5-HT1A agonists cause hypothermia in experimental animals
5-HT1B and 5-HT2 agonists cause hyperthermia in experimental animals
Sexual behaviour: 5-HT1A agonists both facilitate and inhibit sexual behaviour in male rats 5-HT1B agonists inhibit sexual behaviour in the male but facilitate this behaviour in the female rat Cardiovascular system: 5-HT1, 5-HT2 and 5-HT3 receptors may be involved in the complex action of serotonin on blood pressure 5-HT2 agonists appear to be hypertensive agents whereas the antagonists are hypotensives
Sleep: 5-HT1A agonists delay the onset of REM sleep
5-HT2 antagonists suppress REM sleep
Hallucinogenic activity: Most ‘‘classical’’ hallucinogens such as LSD and mescaline are antagonists at 5-HT2 receptors
Antipsychotic activity: Many atypical neuroleptics (e.g. amperozide and risperidone) are 5-HT2 receptor antagonists. In animals,
5-HT3 antagonists have profiles similar to chronically active neuroleptics
Anxiolytic activity: Several novel anxiolytics (e.g. buspirone, ipsapirone) are
5-HT1A partial agonists
5-HT2 and 5-HT3 antagonists have anxiolytic properties
Depression: 5-HT1A receptors are functionally sensitized by chronic antidepressant treatments in rats
5-HT2 receptor numbers are increased and activity decreased, in depression; return to control values in response to treatment

Distribution and selectivity of drugs for 5-HT receptor subtypes

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Distribution and selectivity of drugs for 5-HT receptor subtypes
5-HT1A receptors
Hippocampus, septum, amygdala, cortical limbic area
Agonists: buspirone, gepirone, ipsapirone, flesinoxan
Antagonists: WAY100135, BMY7378, NAN-190
Possible clinical use of agonists: anxiolytics, antidepressants
5-HT1B receptors
Substantia nigra, globus pallidus, dorsal subiculum, superior colliculi
Non-selective: pinodol, propanolol
? selective partial agonists: CP-93, 129
Possible clinical use of antagonists: antidepressants
5-HT1D receptors
Caudate nucleus but widely distributed in human dry and GP brain, similar to
5-HT1B of rat brain
Non-selective: rauwolscine, yohimbine
? selective: L-694, 247
Possible clinical use of antagonists: antidepressants
5-HT1E receptor
In mammalian brain
Possible clinical use: ?
5-HT2A
Neocortex but widely distributed in the mammalian brain
Agonists: DOI, DOB
Non-selective antagonists: ketanserin, ritanserin
Possible clinical use of antagonists: antidepressants, anxiolytics, ? neuroleptics
5-HT2B
In mammalian brain
Possible clinical use: ?
5-HT2C
Choroid plexus
Non-selective antagonists: spiperone, amperozide, pimozide
Possible clinical use of antagonists: neuroleptics
5-HT3
Area postrema, entorhinal and frontal cortex, hippocampus
Agonists: ondansetron, granisetron, zacopride
Possible clinical use of antagonists: antiemetics, anxiolytics, ? antidementia
5-HT4
Collicular and hippocampal neurons
Antagonists SC-205-557, SC-53606
Agonist: SC-49518
Possible clinical use: ?
---------------------
8-OHDPAT= Dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthylene
RU-24969 = 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl) 1H indol
mCPP = 1-(3 chlorophenyl) piperazine
TFMPP = 1-(m-trifluoromethylphenyl) piperazine
DOI = 1-(2,5-dimethoxy-1-iodophenyl) 2-aminopropane
MDL73005 = 8,2 (2,3-dihydro-1,4-benzodioxin-2yl) methylamino-ethyl-8-azaspirol (4,5) decan-7,9-dione
NAN190 = 1-(2-methoxyphenyl) 4-(4(2-phthalimido)entyl-piperazine)
5-CT = 5-carboxamidotryptamine
ICI 169369 = (2-(2-dimethylamino-ethylthio-3-phenylquinoline))
ICS 205-930 = (3-tropanyl)-IH-indole-2-carboxylic acid ester
DOM = 2,5-dimethoxy-4-dimethylbenzene ethamine

Principal methods used in molecular genetics

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Principal methods used in molecular genetics

Brain mRNAs
Reverse transcriptase transcribes these different mRNAs into single complementary strands of DNA

Single-stranded brain cDNAs formed
Single-stranded cDNAs form template for double-stranded DNA

Double-stranded brain cDNAs formed
Double-stranded cDNAs added to bacterial plasmids that insert the cDNA into the plasmid

Recombinant DNA plasmid containing the brain DNA
Recombinant DNA then inserted into bacteria which reproduce the brain DNA

cDNA library formed with each bacterium multiplying the specific cDNA it contains

Individual bacteria isolated and cultured to produce clones that yield
specific cDNAs
Specific cDNAs (for example a receptor) inserted in plasmid that transfects a mammalian cell (e.g. fibroblasts) in culture

Mammalian cell containing the specific cDNA then exposed in a culture medium to a toxin which destroys all non-transformed mammalian cells
Add radioligand that identifies the receptor of the mammalian cell

Identification and isolation of transformed cells which can then be cultured to provide unlimited quantities of the receptor protein

Molecular Genetics and Psychopharmacology

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Molecular Genetics and Psychopharmacology
Psychopharmacologist has paid increasing attention to the examination of brain proteins with which psychotropic drugs react, and also the molecular mechanisms that control the synthesis and cellular function of these proteins. For this reason, any understanding of psychopharmacology requires some knowledge of the basic techniques of molecular genetics.

Genes are composed of deoxyribonucleic acid (DNA) which is a long polymer composed of deoxyribonucleotides. Each deoxyribose nucleotide has one of the following purine or pyrimidine bases, namely adenosine, guanine, thymine or cystosine. A single gene may contain from a few thousand to several hundred thousand bases that are arranged in a specific sequence according to the information contained in the gene. It is this sequence of bases which determines the structure of the gene product which is a protein. In addition, the gene also contains information regarding the way in which the gene is expressed during development and in response to environmental stimuli. The role of DNA in storing and transferring genetic material is dependent on the properties of the four bases. These bases are complementary in that guanine is always associated with cytosine, and adenosine with thymine.
Watson and Crick, some 40 years ago, showed that the stability of DNA is due to the double helix structure of the molecule that protects it from major perturbations. Information is ultimately transferred by separating these strands which then act as templates for the synthesis of new nucleic acid molecules. There are two ways in which DNA molecules may act as templates.
Firstly, DNA is used as a template for replicating additional copies during cell division. This occurs by free deoxyribonucleotides binding to the complementary bases of the exposed DNA strand and then being linked by the enzyme DNA polymerase to form a new DNA double helix.
Secondly, small sections of the DNA molecule are used as a template for the synthesis of messenger ribonucleotides (mRNAs) which are responsible for carrying the message for the synthesis of specific proteins. mRNAs differ from DNA in that they are much shorter (generally 7000 base pairs in length) and are single stranded. mRNAs contain the information necessary for the synthesis of a specific protein and also contain the pentose sugar moiety ribose instead of deoxyribose found in DNA. In addition, thymine is replaced by the pyrimidine base uracil which, like thymine, is complementary to adenine.

The human genome contains approximately 100 000 genes which are distributed with a total DNA sequence of 3 billion nucleotides. The DNA of the human genome is divided into 24 exceptionally large molecules each of which is a constituent of a particular chromosome, of which 22 are autosomes and two are sex chromosomes (X and Y chromosomes). Translation of the information encoded in DNA, expressed as a particular nucleotide sequence, into a protein, expressed as an amino acid sequence, depends on the genetic code. In this code, sequences of three nucleotides (termed a codon) represent one of the 20 amino acids that compose the protein molecule. Because there are 64 codons which can be constructed for the four different bases, and only 20 different amino acids that are coded for, several amino acids may be coded for by more than one codon. There are also three codons, called stop codons, that terminate the transfer of information. Furthermore, although all cells contain the same complement of genes, certain cells (for example, the neurons) have specialized genes that encode specific proteins for the synthesis of specific transmitters. The expression of such genes is under the control of regulatory proteins called transcription factors which control the transcription of mRNAs from the genes they control.

The expression of enzymes that control neurotransmitter systems is controlled not only by factors operating during embryonic development, but also by the degree of neuronal activity. Thus the more active the nervous system, the greater the genetically controlled synthesis of the neurotransmitters which clearly play an important role in the behaviour of the organism. Regulation of the genes also determines the response of the brain to drugs, hence the importance of molecular genetics to psychopharmacology. One of the most important areas of molecular genetics concerns the role of specific base sequences, called regulatory sequences, that surrounded the sections of the gene that encode the amino acid sequence of a protein. These regulatory sequences are activated or inactivated by specific transcription factors and it is the complex interaction of regulatory sequences and transcription factors that underlies the adaptation of brain function to the effects of some psychotropic drugs. For example, it is well known that the optimal response to an antidepressant or neuroleptic drug requires several weeks of treatment. Such adaptive changes are probably a reflection of the molecular genetics of neurotransmitter function and may help to explain the lack of success in developing antidepressants or neuroleptics that have a rapid therapeutic action.

Manipulation of Genes
Molecular genetics is to determine the base sequence of the human genome. This is the purpose of the Human Genome Project, an international collaborative research programme aimed at providing a complete analysis of the human genome within the next decade. The first step in such an analysis is to isolate the small sequences of bases in DNA that are transcribed into mRNAs. The information contained in the mRNAs can be isolated and amplified by a technique called cDNA cloning. In this technique, mRNAs from brain tissue, for example, are purified and then treated with reverse transcriptase which converts mRNAs into single complementary strands of DNA. This is called complementary DNA (cDNA). The cDNA provides a template for producing a second strand that is complementary to the first. This double-stranded cDNA is then incubated with bacterial plasmids to produce recombination DNA plasmids. Plasmids may be considered as bacterial viruses that can reproduce themselves when inserted into the appropriate bacteria so that during the process of bacterial cell division multiple copies of the cDNA that had been inserted in the plasmid are formed. As each bacterium is likely to be infected with a plasmid, containing a different type of cDNA, the resulting medium will contain a mixed population of cDNAs from the original brain tissue. This is called a cDNA library.
The individual components of the cDNA library may be obtained by grouping individual bacteria on a culture medium so that they reproduce to form identical clones. This enables a large quantity of specific cDNAs to be produced in a pure form. The cDNA within these plasmid-containing bacteria can then be removed, and the precise nucleotide sequence determined by standard automated analytical procedures. Since the brain expresses many mRNAs that are also found in nonnervous tissue and are therefore of little interest to the psychopharmacologist, it is necessary to isolate only those cDNAs that, for example, encode for a specific enzyme or receptor protein. Several techniques have been developed to achieve this. For example, a specific cDNA plasmid may be inserted into cultured mammalian cells such as fibroblasts that can express the specific receptor or enzyme. Once this has been expressed in the culture medium, the receptor or enzyme can be identified by adding a specific ligand or substrate. This enables those cells that expressed the specific macromolecule of interest to be identified and subsequently isolated. Once a particular cDNA has been isolated in this way it can be used to make unlimited quantities of the macromolecule whose sequence it encodes. As mammalian cells are generally used for this method of amplification, the amino acid sequence is the same as that used in the limbic brain. Furthermore, if, for example, the cDNA encodes a neurotransmitter receptor, it is likely that it will be integrated into the plasma membrane of the cell surface and therefore largely reflect the portion of the receptor in the neuron. This enables such receptor-containing cells to be used for screening the affinity of putative psychotropic drugs on receptors that were derived from human brain. This method is now commonly used in the pharmaceutical industry to screen numerous compounds for their potential therapeutic application: for example, screening compounds for their affinity for the human D4 receptor as potential atypical neuroleptics.

Another important application of cDNAs is to identify specific proteins in a tissue homogenate or tissue section. Since cDNAs undergo complementary base pairing, adding a radioactively labelled cDNA to a homogenate or tissue slice will bind it to the complementary sequence by a process of hybridization. Thus the amount of radioactive cDNA that hybridizes to the tissue or tissue extract is a measure of the amount of mRNA that is complementary to it. When this procedure is undertaken on slices of brain, it is known as in situ hybridization. In this way it is possible to determine the distribution of specific receptors in a tissue by accurately determining the distribution of mRNA that encodes for the receptor protein. This is a particularly valuable technique for the administration of psychotropic drugs. A variety of techniques have now been developed to manipulate gene expression using cDNAs. For example, it is possible to introduce copies of a new gene (in the form of cDNAs) into a cultured cell line by a process of transfection. This is achieved by means of plasmids that transfect the human or mammalian cells in culture. Those cells that have had the DNA sequence integrated into their chromosomes can then be separated from those cells in which integration has not occurred by incubating the mixed cell population with a toxin to which the engineered cells are resistant whereas the normal cells are not. In this way clones of cells that contain the new genetic material can eventually be isolated.

A major advance in this technique has arisen through the development of transgenic mice. This technique involves injecting foreign DNA into the genome of the mouse embryo. As a consequence, the foreign DNA can give rise to a line of mice that contain the foreign DNA. Using this technique, mice have now been produced whose brains express the A4 protein – a marker for Alzheimer’s disease. A variant of this technique is to replace a normal gene with a foreign gene in the chromosome, thereby giving rise to a progeny that lack both the normal gene and its function. Sibling mating then gives rise to offspring which have two defective genes. This method has so far largely been confined to mice which are termed ‘‘knock-out’’ mice. This method could prove to be particularly useful for determining the physiological role of specific neurotransmitter receptors.

Decision-making in the choice of a psychotropic drug

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Decision-making in the choice of a psychotropic drug
Despite the considerable advances that have been made in psychopharmacological research, there are many areas in which objective decisions based on scientific evidence with regard to the choice of the appropriate drug are sparse. In an attempt to overcome this problem, several authors have recently produced prescribing guidelines based on the evidence of the most appropriate drug to use. Such evidence extends from studies that are supported by randomized control trials (highest category), those which are supported by limited controlled trials (alternative category if drugs of the first category are ineffective) to those based on uncontrolled or anecdotal evidence (lowest category, unproven usefulness). A summary of the treatment options for the major psychiatric disorders and for Alzheimer’s disease is found at the end of the appropriate chapter. General principles of prescribing psychotropic drugs

The decision to use a psychotropic drug must take into account the potential risks and benefits. This should be discussed with the patient and/ or carer. Before prescribing, a full evaluation of the symptoms should be made and the diagnosis confirmed. Polypharmacy should be avoided. If a drug combination is necessary, the pharmacodynamic and pharmacokinetic interactions should be considered. In general, the lowest effective dose of the drug should be used, particularly in elderly patients. Dose titration should be undertaken slowly. Similarly, on discontinuation of a drug, the dose should be reduced slowly, the rate of decrease being decided by the elimination half-life of the drug. Some psychotropic drugs produce a discontinuation syndrome that can usually be avoided by slow withdrawal. In particular, sedatives, anxiolytics and antidepressants can cause withdrawal effects. In switching drugs, the half-life of elimination that is being stopped should be considered if drug interactions are to be avoided. The time taken for the withdrawal of a drug depends on the duration of treatment; sedatives, antiepileptics and anxiolytics may take several weeks to withdraw.

Clinical trials

2011-05-05T12:32:00.002+05:30

Clinical trials
Once a decision has been made to develop a compound further following the extensive pre-clinical pharmacological and toxicological studies, approval for the first clinical studies must be sought from the regulatory authority (Medicines Board in Europe or the Food and Drug Administration in the USA). A clinical trial of a new drug is, in the words of Bradford Hill (in his Principles of Medical Statistics): a carefully, and ethically, designed experiment with the aim of answering some precisely framed questions. In its most vigorous form it demands equivalent groups of patients concurrently treated in different ways. These groups are formed by the random allocation of patients to one or other treatment. In principle, the method is applicable to any disease or type of treatment. It may also be applied on any scale.
Thus the purpose of a clinical trial is to describe (a) whether the new treatment is of therapeutic value, (b) how it compares with a ‘‘standard’’ drug, (c) what type of patient would benefit from the new drug, (d) what is the best route of administration, how frequently and in what dose range should it be used, (e) what are the side effects and disadvantages of the new drug. For the classical randomized control trial, the following points should be stressed:
(a) The use of equivalent groups of patients by random (chance) allocation to a placebo, standard drug or novel drug group. It is self-evident that if the treatment groups differ with respect to age, gender, race, duration and severity of the disease it will not be possible to attribute differences in outcome to the novel treatment. The randomization of patients is therefore used to eliminate systematic bias and to permit the use of appropriate statistical methods to correct for any bias.
(b) Time and place of treatment. Treatment must be undertaken concurrently and concomitantly. Using control data from past clinical studies (historical controls) is almost always unacceptable.
(c) Precisely formulated questions. These must be formulated before the start of the trial. For example, ‘‘is drug A capable of treating depression more rapidly and effectively, and with fewer side effects, than drug B?’’.
Some important concepts in evaluating clinical trials The null hypothesis postulates that there is no difference in outcome between a new and a standard drug. Thus when two groups of patients have been treated separately with the drugs (between-patient comparisons) or when each patient has received both drugs (within-patient comparisons) and the result of the outcome of treatment is apparently better with one drug than the other, it is essential to determine if this difference is statistically significant.

The test of statistical significance will enable the researcher to determine whether the differences observed between the two treatments are due to chance. In practice, it is generally agreed that if the difference between the two groups occurs five times, or less, in 100 trials then the null hypothesis is unlikely to hold true and there is a real difference between the treatment groups. The level of statistical significance which is usually considered to be acceptable is at the 5% level, or less. This is represented by a probability value P50.05 (the percentage divided by 100). If the probability of a result occurs only once in 100 trials then it is highly significant at P50.001. The confidence interval is a measure of the degree of assurance, or confidence, one may have in the process or power of the result. The confidence interval is expressed as a range of values about the mean and within which it is 95% certain that the true value of the result lies. The range may be wide, indicating uncertainty, or narrow, indicating relative certainty. If a result lacks statistical significance at the 5% level or less, it can only be interpreted as meaning that there is no clinically or experimentally useful difference between the treatments. Small numbers in experimental groups inevitably mean low precision or statistical power. Often small clinical trials are published without any statement of statistical power or the inclusion of confidence intervals which reveal their inadequacy.

Types of error
Type 1 errors arise when a difference is found between treatments when, in reality, the groups do not differ, whereas Type 2 errors commonly arise when treatments do differ but no statistical differences are found. It must be emphasized that statistical tests do not prove that there is a difference between two groups, but merely that there is a probability of this being the case. However, a difference may be statistically significant and have narrow confidence limits but yet be biologically insignificant. For example, there is experimental evidence to show that beta adrenoceptors on lymphocytes change by over 50% between midday and midnight in healthy adults yet such changes would appear to have no clinical significance. Similarly, the activity of the serotonin transporter on the platelet membrane is one-third greater at noon than at 6 a.m. without having any apparent effect on physiological functions. Thus the statistical significance of a result in any area of neuroscience must always be considered in conj unction with the biological relevance of the change. This is often overlooked, particularly when considering the variables that are linked to psychiatric and neurological disorders.

Types of clinical trial: single and double-blind trials
Because both the clinician and the patient are subject to bias as a result of their expectations of the outcome of the trial of a new drug, the doubleblind technique is usually applied to evaluate the efficacy of a new drug. In such a trial the randomized groups of patients are given identical capsules or tablets (containing either a placebo, unknown drug or standard comparator); the clinician undertaking the clinical assessment is also ‘‘blind’’ to the distribution of the different treatments. Occasionally a double-blind technique cannot be applied as, for example, when the side effects of one of the drugs is greater than that of the placebo or the second drug. A non-blinded clinical trial (i.e. lacking a placebo or standard comparator) is called an ‘‘open’’ trial and is usually used for the first clinical exposure of a novel compound once it has been approved for clinical trial by the regulatory authority. ‘‘Open’’ trials are useful for obtaining the dose range for a new drug and the frequency of side effec ts; healthy volunteers are usually involved in the first exposure to a new drug. Once the relative safety of the drug has been assessed, an ‘‘open’’ trial on a small group of well-defined patients is undertaken so that an idea of the therapeutic efficacy of the drug can be obtained. These are termed Phase 1 studies and they are followed by Phase 2 studies, which are double-blind and involve a comparator as a standard, and Phase 3 studies (usually multicentred studies involving a large number of patients under double-blind conditions). The Phase 1–Phase 3 studies would normally take at least 6 years to complete. It has also been estimated that it takes at least 12 years from the initial chemical synthesis of a novel compound to its clearance for clinical use by the regulatory authorities at a cost in excess of $230 million. In addition, for every 10 000 chemical entities that are synthesized, approximately 10 million will enter Phase 1 trials but only one would be expected to obtain regulatory approval. Use of placebos in clinical trials While serious ethical objections have been raised regarding the use of placebos in trials of drugs used in the treatment of psychiatric disorders (largely based on the possibility that the patients may commit suicide if they are inadequately treated, although such patients are usually excluded from placebo controlled trials), all regulatory authorities insist on properly conducted, placebo controlled trials as a basis for registering a new drug.

The placebo is useful in (a) distinguishing the pharmacodynamic effects of a drug from the psychological impact of the medication and the environment in which it is given (the ‘‘halo’’ effect of the enthusiastic, or pessimistic, research clinician). It is well known, for example, that the placebo effect in major depression is as high as 30% while that of an effective antidepressant is approximately 60% of the optimal response. This statistic illustrates the importance of placebo-based studies in evaluating the efficacy of a new psychotropic drug. The placebo also distinguishes drug effects from fluctuations in the disease, which is particularly relevant in the case of psychiatric disorders. Lastly, the placebo allows false negatives to be excluded. For example, if a placebo is compared to a novel drug and a standard drug and the outcome of all three treatments is the same, the conclusion reached would be that the trial design (for example, number of patients in each group) is incapable of distinguishing between an active and inactive drug and therefore should be modified. If a standard drug is not included, however, it can only be concluded that the new medication is inactive at the dose used or that the end point used for the clinical assessment is inadequate. Informed consent must always be obtained from a patient participating in any clinical trial. In the trial of a psychotropic drug, the mental status examination is critical for determining the capacity of the patient to consent and the ability to communicate is an absolute prerequisite. Both the memory and the orientation of the patient must be substantially intact if the patient is to give informed consent. Such studies may be undertaken in chronic, stable diseases that cannot be cured but whose symptoms may improve following drug treatment, for example, Parkinson’s disease and the dementias. In such cases, each patient is subject to the new drug and placebo in a random order, the patients acting as their own control. In such studies, it is important to ensure that any ‘‘carry-over’’ effects of the active drug are taken into account when the placebo, or a lower dose of the active drug, follows the highest dose of the drug.

The number of patients to be included in any trial is usually decided by a statistician. In the fixed-number type of trial, the total number of patients to be recruited is agreed before the start of the study and must be adhered to even if the result of the study does not quite reach an acceptable level of statistical significance. In such circumstances it is not permissible to add additional patients to the study in the hope that the 5% level of significance will be reached as this will not allow chance and the effect of treatment to be the sole factors involved in deciding the outcome of the study. To avoid this situation, trials are now designed so that the number of patients in each treatment group is not determined in advance but the trial design allows either continuous or intermittent assessment of the response, thereby allowing the trial to be stopped as soon as statistical difference between the groups is obtained or when such a result seems unlikely. Thus the trial can be terminated when the predete rmined result is obtained (for example, a 50% reduction in the Hamilton Depression score in an antidepressant drug trial). In such a modified sequence design study, formal analysis of the data is undertaken at several predetermined intervals. Such interim analyses may reduce the power of the statistical analysis however. Large, definitive clinical trials of the type that have been used for Phase 3 studies are difficult to organize, prolonged, very expensive to perform and often yield inconclusive results. This has led to the design of smaller, controlled trials which, while of more limited statistical power, are subject to meta-analyses. Where numerous controlled trials on a drug have been undertaken and the outcome varies, the data can be collected in a systematic review and the accumulated results analysed by appropriate statistical methods. The resultant meta (‘‘overall’’) analysis must meet the criteria for a good scientific study. Meta-analyses can involve 100 000 patients, or more, but problems may arise in identifying all the suitable trials of a new drug (and in assessing their standards from the published literature), added to which is the bias due to the fact that only positive results are usually published. Cost of treatment with psychotropic drugs It is self-evident that any new psychotropic drug is likely to be expensive. This situation also applied to the drugs used to treat other chronic illnesses such as cardiovascular disease, rheumatoid arthritis and diabetes. However, the cost of treatment implies more than the price of the drug. As most psychiatric disorders are chronic, costs must take into account the acute, maintenance and prophylactic phases of treatment. Thus in assessing the true cost, it is necessary to consider the ancillary procedures needed to monitor the patients’ response to treatment (laboratory tests, etc.), managing any adverse effects of the medication, the relative costs of inpatient versus out-patient treatment, costs saved to the social and health services as a result of imp roved compliance and better response to treatment and the comparative costs of alternative treatments. It has been estimated that the cost of a new psychotropic drug for the treatment of depression, bipolar disorder or schizophrenia is approximately 10–15% of the total cost of treatment. It is also necessary to take into account the costs of not providing adequate treatment. These factors include the risks of premature death, and the increased morbidity, including the loss of productivity and the adverse effect of the illness on the social life of the patient.

Thus despite the much higher cost of a new psychotropic drug, Quality of Life assessments, which take into account the true cost of treatment, consistently show that new antidepressants and antipsychotics are superior to the older, and cheaper, medications. Most importantly, when optimal total care is provided for the patient, the quality of life is substantially improved which surely must be the aim of clinical psychopharmacology. The limitation of pre-clinical studies on the development of novel psychotropic drugs Serendipity has played a major role in the discovery of most classes of psychotropic drugs. For example, the observation that the first antidepressants, the tricyclic antidepressants and the monoamine oxidase inhibitors, impeded the reuptake of biogenic amines into brain slices, or inhibited their metabolism, following their acute administration to rats, provided the experimenter with a mechanism that could be easily investigated in vitro. Such methods led to the development of numerous antidepressants that differed in their potency, and to some extent in their side effects (for example, the selective serotonin reuptake inhibitors) but did little to further the development of novel antidepressants showing greater therapeutic efficacy. The accidental discovery of atypical antidepressants such as mianserin led to the broadening of the basis of the animal models used to detect potential antidepressants with greater emphasis being placed on the chronic effects of the drugs in vivo. However, with few exceptions, all the in vitro and in vivo models in current use are based on the acute effects of novel compounds. Recently, with the impact of high-throughput screening methods based on the activity of compounds on multiple neurotransmitter receptors in vitro, even acute in vivo methods have been reduced in an attempt to decrease the time taken to proceed to the initial clinical assessment. Only time will tell whether the extensive use of genomics, microarray screens and receptor profiles of novel compounds will lead to genuinely novel psychotropic drugs. So far, there appears to be little advance in the therapeutic potential of the psychotropic drugs in development.

Limitation of clinical trials of new psychotropic drugs
A typical placebo controlled trial consists of 50–60 patients including a reference drug. Trials of new psychotropic drugs usually last for 6–8 weeks; the recommended duration of treatment in clinical practice is usually about 6 months. Most clinical protocols do not provide justification for the sample size used, or even specify the statistical power of the data obtained. As the proportion of non-responders for many psychotropic drugs may range from 20–30%, it can be argued that such limited trials (with a statistical power that is too low to show differences between treatments, conducted over too short a period in comparison with clinical practice and often excluding noncompliant patients from the final analysis) are unlikely to show any difference between a new and standard drug. This means that few studies are able to demonstrate an improved efficacy of a new drug over a standard drug. It has been calculated that the sample size that would be required to show a difference of 5% between two psychotropic dr ugs, assuming that approximately 20% will be non-responders or partial responders, would be between 1250 and 2380 patients per arm of the trial. The expense of such trials would, of course, be prohibitive! This does show that the apparent limited efficacy of most classes of psychotropic drugs is a reflection of the limitation of the clinical trial rather than their real potential differences, which could only be determined by using much larger numbers of patients in trials that last for several months.

Drug–protein interactions and human brain tissue in drug discovery

2011-05-05T12:30:00.000+05:30

Drug–protein interactions
In addition to metabolic interactions, consideration should be given to drug–protein binding interactions, although there is little clinical evidence to suggest that such interactions are of any consequence with the SSRIs. It must be stressed that many liver enzymes are non-specific for their substrates and that most drugs are metabolized by multiple pathways. Good therapeutic practice demands that drug interactions should be considered carefully, particularly in subpopulations of depressed patients such as the elderly or those with hepatic dysfunction or a history of alcoholism.

Use of human brain tissue in drug discovery
Despite the success in using animal models to develop drugs which have similar pharmacological properties to those drugs in clinical use, they are much less successful in detecting novel compounds that have pharmacological properties, and possible therapeutic indications, that differ from the drugs that are currently available. In an attempt to improve the chance of discovering novel drugs and, at the same time, reduce the cost and increase the number of compounds which may be screened for their potential therapeutic activity, in vitro models have recently been introduced in pharmaceutical and biotechnological companies based on sequences from the human genome. Such an approach has been encouraged by the need to introduce models based on human brain tissue at a much earlier stage in drug development. In support of this view, it has been estimated that man and chimpanzees share more than 98.9% of their genes in common. However, the expression of genes in the brain was more than fivefold greater in man than in the chimpanzee, whereas the differences in gene expression in the liver and blood were small. Differences between the gene expression of man and rodents were much greater than between man and primates. This suggests that whereas it is possible to model drug metabolism and distribution in such primates, it is less likely that disorders of higher mental function (such as depression and schizophrenia) could be modelled with the same degree of certainty. Drug discovery in recent years has moved away from the development of specific drugs (such as the SSRIs, 5-HT1A partial agonists, D4 receptor antagonists) which were presumed to act at single targets, to the realization that complex psychiatric disorders require multiple targets for their effective treatment. This change in emphasis in drug discovery is due to an increased knowledge of the interactions that take place between physiological processes in order to maintain homeostasis and the fact that diseases arise as a consequence of a loss of homeostasis. In addition, it is now recognized that many physiological systems have an inbuilt redundancy, whereby the effects of a drug on one system can be compensated by an adaptive change in a closely related system.

In an attempt to model such interactions, cDNA microassays have been developed. Microassay technologies are particularly suited for use with human tissues, including brain tissue, because the widest availability of genes on microchip assemblies has been obtained thanks to the human genome project. Rat and mouse microassays are now also becoming commercially available. Drug targets are usually proteins. To date, the high-throughput proteomic technologies are not as advanced as the microassay technologies in terms of their sensitivity and number of items which can be determined simultaneously. However, while neither proteomics nor gene expression analysis by microassays are ideal, they are powerful methods particularly when used in combination with in situ hybridization, antibody localization and PCR methods With regard to the use of human tissues for drug development, stem cells offer a unique advantage over blood cells which have been used as targets for drug discovery in the recent past. Stem cells have a unique property of being able to develop into any cell type, including brain cells. Stem cells have already been used for cell therapy and transplantation therapy (for example, in Parkinson’s disease) and more recently they have been used for target identification in drug discovery programmes. As a complementary approach, an analysis of the changes in gene expression using microassay assemblies that occur following the action of known drugs that have been administered acutely or chronically could lead to the development of new classes of drugs with improved therapeutic profiles.

Properties of single enantiomers in psychopharmacology

2011-05-05T12:23:00.000+05:30

Properties of single enantiomers in psychopharmacology
(1) Analgesics – methadone
This synthetic opiate was introduced in 1965 to manage opioid dependence and has been successfully used as an aid to abstinence since that time. Methadone is a racemate, the R-enantiomer being the pharmacologically active form of the drug. This isomer shows a 10-fold higher affinity for the mu and delta opioid receptors, and nearly 50 times the antinociceptive activity of the S-enantiomer. In addition, the R-isomer is less plasma protein bound than the S-form; the latter isomer being more tightly bound to alpha-1 acid glycoprotein. The plasma clearance of the R-form is slower than the S-isomer. Patients treated with the isomers of methadone showed considerable individual variability, with some parameters reaching 70%: this would not have been detected if the racemate had been administered. These pharmacokinetic differences could be crucially important when patients are being treated with methadone as part of an opiate withdrawal programme as relatively small decreases in the plasma concentration could produce marked changes in mood, thereby undermining the positive benefit of the methadone withdrawal programme.
(2) Sedative/hypnotics – zopiclone Zopiclone is widely used as a sedative–hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists.
(3) Neuroleptics – thioridazine Thioridazine is a complex first-generation antipsychotic agent that is metabolized to two other pharmacologically active drugs (mesoridazine and sulphoridazine) which have been introduced as neuroleptics in their own right. All three neuroleptics have chiral centres. Interest in thioridazine has arisen in recent years because of the higher incidence in sudden death, due to cardiotoxicity, found in patients who had been prescribed the drug.

Thioridazine-5-sulphoxide would appear to be the metabolite responsible for the cardiotoxicity. This metabolite alone has four chiral centres and knowledge is lacking concerning the toxicity of these enantiomers which serves to illustrate the complexity of the problem. Regarding the pharmacological activity of thioridazine, the R-enantiomer has been shown to be at least three times more potent than the R-isomer in binding to the D2 dopamine receptors and nearly five times more potent than an alpha-1 receptor antagonist. Conversely, the S-isomer has a 10-fold greater affinity for the D1 receptor than the R-form. Thus the pharmacological consequences of using a single enantiomer of thioridazine are, unlike the other three examples given, very complex. Thus if the S-enantiomer was selected, while the potency would undoubtedly increase (due to its D2 antagonism), the chances of postural hypotension (due to the alpha-1 receptor antagonism) would also be greater. Furthermore, the relative activity and toxicity of the individual enantiomers and their metabolites is unknown. With regard to the extrapyramidal side effects for example, experimental studies have shown that the R-isomer is more likely to cause catalepsy and is, in addition, far more toxic than the S-form. Dose–response relationships have also been undertaken on the individual enantiomers versus the racemate form of thioridazine and show that the racemate is 12 times more potent than the S-isomer and three times more potent than the R-isomer.

(4) Antidepressants It is widely agreed that there is little difference in the therapeutic efficacy between any of the first- and second-generation antidepressants. However, in terms of their tolerability and safety, the second-generation drugs are superior. Of these, the SSRI antidepressants are the most widely used but, despite their clear advantages over the tricyclic antidepressants which they have largely replaced in industrialized countries, they have such side effects as nausea and sexual dysfunction which can affect compliance. While there are clearly differences in the frequency of side effects between the SSRIs, no clear overall advantage emerges for any one of the drugs. Many currently used antidepressants are chiral drugs (for example, tricyclic antidepressants, mianserin, mirtazepine, venlafaxine, reboxetine, fluoxetine, paroxetine, sertraline, citalopram), some of which are administered as racemates (such as the tricyclics, mianserin, mirtazepine, fluoxetine, reboxetine, venlafaxine, citalopram) while others are given as single isomers (paroxetine and sertraline). The relative benefits of the enantiomers of antidepressants vary greatly. For example, when the therapeutic properties of the enantiomers are complementary (for example, mianserin) then use of the racemate is an advantage. However, if there are qualitative, but not quantitative, similarities then it would be beneficial to develop the active isomer. This has recently occurred with the development of citalopram.

The S-enantiomer of citalopram (escitalopram) is over 100 times more potent in inhibiting the reuptake of 5-HT into brain slices than the R-form and is devoid of any activity at the neurotransmitter of other receptor types (racemic citalopram has an affinity for histamine receptors and causes sedation). In in vivo studies, escitalopram is more potent than the R-form or the racemate in releasing 5-HT in the cortex of conscious rats; it has been shown to have antidepressant and anti-anxiety properties in both animal models and in patients. With regard to its side effects, the frequency of nausea and ejaculatory dysfunction after escitalopram is approximately the same as that of the racemate. From the results of the published clinical studies, it would appear that the tolerability of escitalopram is slightly better than the racemate and the time of onset of the clinical response may be slightly faster but this needs confirmation. In general, the adverse effects were mild and transient with a low patient withdrawal rate. Early clinical trials suggest that escitalopram is as effective as citalopram in the treatment of depression and anxiety disorders.

Possible advantages of the single stereoisomer over the racemic mixture

2011-05-04T09:27:00.000+05:30

Possible advantages of the single stereoisomer over the racemic mixture
1. Reduction in the therapeutic dose.
2. Reduction in the interpatient variability in metabolism and in response to treatment.
3. Simplification of the relationship between the dose and the response to treatment.
4. Reduction in the toxicity and side effects due to the greater specificity of action of the isomer with the relevant biological processes.

In addition to the possible advantages of the single enantiomer, the pharmacologically inactive enantiomer may reduce the efficacy of the active isomer by reducing its activity at its site of action or by interfering with its metabolism. Thus separating a racemic mixture into its enantiomers, and assessing the individual properties of the isomers would seem to be a reasonable approach to improving the clinical profile of many wellestablished psychotropic drugs. The process whereby a racemic mixture is reintroduced as a single enantiomer is termed ‘‘chiral switching’’. While there appears to be a compelling argument for using single enantiomers whenever possible in order to improve the efficacy and safety of a racemic drug, there is no certainty that chiral switching will always be beneficial. For example, in 1979 seven cases of inadvertent injection of the local anaesthetic racemic bupivacaine resulted in cardiovascular collapse in a few patients. The toxicity appeared to reside entirely in the R-isomer so th at, by chiral switching, a safer and less toxic local anaesthetic was produced. Other examples have not been so successful however. For example, the chiral switching of racemic fenfluramine to its R-enantiomer, dexfenfluramine (the nomenclature has changed recently so that Denantiomers, Dex enantiomers, are now termed R-enantiomers while the L-enantiomers, levoenantiomers, become S-enantiomers) was at first heralded as a successful new appetite suppressant. However, it was soon shown that, despite its improved efficacy, the R-enantiomer was more likely to cause pulmonary hypertension. This has resulted in the withdrawal of the drug.

Enantiomers: their importance in psychopharmacology

2011-05-04T09:26:00.001+05:30

Enantiomers: their importance in psychopharmacology

The majority of naturally occurring drugs and biologically active compounds are asymmetrical in their chemical structure. This means that the molecule is structured around one or more carbon atoms in such a way that the molecule is distributed mostly on the right (R=rectus) or left (S=sinister) of the symmetrical carbon atom, the so-called chiral centre of the molecule. Thus a large proportion of psychotropic drugs in current use possess one or more chiral centres and therefore exist in pairs of enantiomers which differ in terms of their three-dimensional structures. However, it must be remembered that chirality can apply not only to molecules but also to anatomical structures. For example, the left and right hands are chiral structures as is evident when one attempts to put a lefthanded glove on the right hand and vice versa. At the cellular level, the various types of receptor, transporter, enzyme and ion channel are all chiral in form. Thus although the enantiomers of a drug may have identical physicochemi cal properties, the way in which they may interact with chiral targets at the level of the cell will give rise to different pharmacodynamic and pharmacokinetic properties. A few simple examples will illustrate how taste and olfactory receptors can differentiate between enantiomers. Thus R-carvone tastes like spearmint whereas the S-isomer tastes like caraway. Similarly, R-limolene smells like lemon whereas the S-enantiomer tastes of orange. In psychopharmacology, interest in the properties of enantiomers has been aided by the need to improve the therapeutic efficacy and decrease the side effects and toxicity of drugs. For example, if the therapeutic activity resides entirely in one enantiomer (called a eutomer) then giving a racemic mixture which contains the active and the inactive enantiomer is clearly wasteful. Thus using the single enantiomer (isomer or eutomer) should enable the dose of the drug to be lowered, reduce the interpatient variability in the response and, hopefully, reduce the side effects and toxicity of the drug.

Drug–drug interactions

2011-05-04T09:24:00.000+05:30

Drug–drug interactions
There are two main types of drug interactions, pharmacodynamic and pharmacokinetic. Pharmacodynamic interactions arise when one drug increases or decreases the pharmacological effect caused by a second drug that may be given concurrently. Pharmacokinetic interactions occur when one drug alters a pharmacokinetic component of another drug thereby causing a change in its effective concentration at its site of action. The relationship between the pharmacodynamic and pharmacokinetic characteristics and the subsequent therapeutic response can be summarized by the following equations:
Magnitude of therapeutic response ¼ drug pharmacodynamics + drug
pharmacokinetics + individual biological variation
Magnitude of clinical response ¼ potency at site of action + drug
concentration at site of action + biological status of the patient With regard to the differences between the pharmacodynamic and pharmacokinetic drug interactions, it would appear that pharmacokinetic interaction produces the same result as a change in the dose of the drug. For example, combining the SSRI antidepressant fluoxetine with a sub-therapeutic dose of a tricyclic antidepressant could result in a two- to threefold elevation in the blood concentration of the tricyclic as fluoxetine inhibits its metabolism via the 2D6/3A4 isozymes. However this change in the pharmacodynamic response to the tricyclic antidepressant could (a) result in unexpected cardiotoxicity due to the abrupt increase in the concentration of the drug in the cardiac tissue resulting in the block of the fast sodium channels and (b) prolong the elimination half-life of the tricyclic antidepressant thereby resulting in a cumulative toxicity of the drug. Thus the SSRI, by inhibiting the metabolism of the tricyclic, has changed the clearan ce of the drug as illustrated by the equation:
Rate of dosing-Clearance!Steady-state concentration-Therapeutic response
By decreasing the clearance due to cytochrome P450 inhibition, but maintaining the same dose and rate of dosing, the steady-state concentration of the tricyclic antidepressant increases thereby enhancing the therapeutic or toxicological response. In clinical practice, pharmacokinetic drug interactions may be dismissed as an idiosyncrasy of the patient rather than a potential drug hazard.

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. In addition to the above examples, toxicity problems can also arise when one drug induces the metabolism of the second drug. Toxic metabolites, which are not normally present in a sufficiently high concentration to be noticeable, may increase due to the increase in their concentration as a consequence of enzyme induction. For example, carbamazepine induces P450 3A3/4 which enhances the metabolism of valproate. This leads to the increased production of the 4-ene metabolite of valproate which is hepatotoxic.

Main types of drug metabolized by cytochrome P450 isozymes

2011-05-04T09:23:00.000+05:30

Main types of drug metabolized by cytochrome P450 isozymes

CypP450 1A2
Antidepressants – tricyclics, mirtazepine, fluoxetine*
Antipsychotics – clozapine, haloperidol, olanzapine, phenothiazines
Sedative/hypnotics – zopiclone
Beta-blockers – propranolol, warfarin, theophylline

CypP450 2C19
Antidepressants – amitriptyline, clomipramine, imipramine, moclobemide, citalopram
Antipsychotics – olanzapine
Mood stabilizers – phenytoin, valproate, topiramate
Sedative/anxiolytics – diazepam, barbiturates
Beta-blockers – propranolol

CypP450 2D6
Antidepressants – tricyclics, fluoxetine*, paroxetine*, sertraline*, mirtazepine, venlafaxine, mianserin
Antipsychotics – phenothiazines, haloperidol, clozapine, olanzapine, quetiapine
Antiarrhythmics – encainide, flecainide, mexiletine
Beta-blockers – alprenolol, metoprolol, propranolol, timolol
Opiates – codeine, dextromethorphan, ethylmorphine

CypP450 3A3/4
Antidepressants – tricyclics, nefazodone*, fluoxetine*, fluvoxamine*, citalopram, mirtazepine, venlafaxine
Antipsychotics – chlorpromazine, clozapine, pimozide, quetiapine, risperidone
Anxiolytics – clonazepam, diazepam, temazepam, triazolam, alprazolam, midazolam, buspirone
Anticonvulsants – ethosuximide, carbamazepine
Calcium channel blockers – diltiazem, felodipine, nifedipine, verapamil
Antibiotics – clarithromycin, erythromycin
Others – omeprazole, cisapride, dapsone, lavastatin

Biotransformation of drugs by phase 1 and phase 2 reactions

2011-05-04T09:21:00.000+05:30

Biotransformation of drugs by phase 1 and phase 2 reactions
Phase 1 reactions Oxidative reactions involving N- and O-dealkylation, aliphatic and aromatic hydroxylation, N- and S-oxidation, deamination.
Phase 2 reactions Biotransformation reactions involving glucuronization, sulphation, acetylation.

Classification of the cytochrome P450 enzymes
These enzymes have been classified according to the degree of structural similarity in their amino acid structures (the so-called sequence homology). Thus the closer the enzymes are from both the phylogenic and functional point of view, the more likely they are to be a member of the same enzyme family with a sequence homology of at least 40%. The enzymes are further grouped into subfamilies (isozymes) which are designated by the letters A, B, C, D, E, F. All enzymes in the same subfamily have a sequence homology of at least 55%. The final number designates the gene that codes for a specific enzyme (1, 2, 3, 4, 5, 6, 7, etc.). With regard to the metabolism of the psychotropic drugs, cytokines 1A2, 2C19, 2D6, 3A3/4 are of primary importance.
The cytochrome P450 enzymes are divided into two major groups, namely the ‘‘steroidogenic’’ enzymes (which are the phylogenically older type and are responsible for the synthesis of steroids and related compounds comprising the cell wall) and the ‘‘xenobiotic’’ type (located in the smooth endoplasmic reticulum and involved in the metabolism of foreign, or xenobiotic, compounds which include all drugs). The following list summarizes the types of compounds metabolized by the main groups of P450 enzymes:
. Steroidogenic type – steroids, bile acids, cholesterol, prostaglandin biosynthesis.
. Xenobiotic type – drugs, toxins, carcinogens, mutagens.
It should be noted that the genetic information for the P450 enzymes is present throughout in all tissues, but knowledge of the role of the enzymes in tissues other than the liver and gastrointestinal tract is unclear. For example, cytochrome P450 2D6 is found in the brain where it is linked to the dopamine transporter. Whether a deficit in the activity of this enzyme is responsible for predisposing some individuals to Parkinson’s disease is a matter of conjecture.

The biochemical basis of drug interactions

2011-05-04T09:20:00.000+05:30

The biochemical basis of drug interactions
The biotransformation of a drug may either lead to the termination of its pharmacological activity or, occasionally, to its activation to a pharmacologically effective entity. It is also possible that a drug may be metabolized to form pharmacologically or toxicologically active metabolites. Whatever the outcome, the biotransformation of a drug ultimately involves its conversion to a more hydrophilic form thereby facilitating its excretion into the urine. However, some lipophilic drugs and their metabolites are excreted via the bile into the intestine while others, that are volatile, pass into the lungs and are thereby excreted in the expired air.

The biotransformation Phase 1 involves the oxidative catabolism of the drug. The end products of the phase 1 reactions are generally conjugated by uridine diphosphorylglucuronyl transferase, sulphatase or N-acetyltransferase to form polar, water-soluble products which are then excreted into the urine. These are the products of the phase 2 reactions. While it is well known that products of the phase 1 reactions are often pharmacologically active (for example, norfluoxetine which is a metabolic product of fluoxetine), it is also possible that the end product of phase 2 reactions can also be pharmacologically active. For example, morphine-6-glucuronide is as pharmacologically active as the parent compound. The primary site of biotransformation is the liver although the gastrointestinal tract, kidneys and the skin also contribute to a minor extent. Drugs that are orally administered often undergo first-pass metabolism. This involves their (generally partial) metabolism in the liver following their entry from the gastrointestinal tract via the portal circulation. This inevitably leads to a reduction in the effective blood concentration and must therefore be taken into account when the dose of the drug to be administered is calculated. In the liver, the microsomal enzymes that are responsible for catalysing the oxidative reactions are the cytochrome P450 family of enzymes. These enzymes are haem-containing membrane proteins that are bound to the smooth endoplasmic reticulum of the hepatocytes. Of the 12 gene families of the cytochrome P450 system that have been identified in man, those classified as cytochrome P450 types 1, 2 and 3 account for most of the drug biotransformations. In addition to the oxidative reactions undertaken by the P450 enzymes (also known as isozymes), hydrolytic reactions are carried out by epoxide hydrolase and several amidases, esterases, proteases and peptidases.

There are several important factors which may influence biotransformation reactions. Thus some drugs or toxins may induce the synthesis of microsomal oxidases by the liver (for example, a barbiturate) and thereby enhance the metabolism of the drug, or any other drug given concurrently which is metabolized by the same enzyme system (for example, warfarin). Nicotine in tobacco smoke is known to increase the activity of the cytochrome P450 1A2 isozyme which may predispose some individuals to a greater risk of cancer. Some drugs produce hepatotoxic metabolites which thereby impair the biotransformation of other drugs or toxins which may be present. For example, chronic alcohol intake can lead to the formation of hepatotoxic metabolites. Drugs may also selectively inhibit individual isozymes of the P450 system, thereby causing an unexpected rise in the blood and tissue concentrations of any drug given concurrently which is also metabolized by that isozyme. The SSRI antidepressants for example have been shown to act as inhibitors of some P450 isozymes, thereby not only reducing their own metabolism but also those of other drugs given concurrently. Some foods may also inhibit the P450 isozymes and thereby enhance the toxicity, or the duration and magnitude of the therapeutic response of a drug given concurrently. Grapefruit juice, for example, is a significant inhibitor of the P450 isozyme 3A4, an enzyme which is widely involved in the metabolism of psychotropic drugs. It is self-evident that biotransformation will be reduced in patients with liver or kidney disease, in the elderly and also in neonates. In addition, pharmacogenetic differences play a considerable role in the way an individual patient metabolizes a drug. Such differences often result from polymorphisms in the cytochrome P450 family of microsomal enzymes.