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.
. 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.
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