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Tuesday, July 19, 2011

Clinical implications of Psychopharmacology

Clinical implications
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

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

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

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.

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

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.

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.

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.

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.

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

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

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.