Reuptake inhibition at monoaminergic synapses

An action common to all tricyclic antidepressants is inhibition of the high affinity, energy-dependent uptake of monoamines into cytoplasmic stores within the presynaptic membrane. Since this reuptake system normally terminates monoaminergic transmitter activity on synaptic neurones following nerve-stimulated release, the effect of its inhibition by tricyclic antidepressants is to prolong the actions of monoamines released at synapses, and to enhance their stimulation of pre- and postsynaptic receptors (Fig. 11.1). Among the tricyclic antidepressants, secondary amines have more potent effects on the uptake of noradrenaline, while tertiary amines are more potent in blocking the reuptake of serotonin. The reuptake of dopamine is much less affected by these drugs though all inhibit it to some degree.

Monoamine uptake block explains many of the pharmacological actions of the tricyclic antidepressants, and it has been widely accepted that it underlies their antidepressant effect. This possibility provided the main impetus for the monoamine hypothesis of affective disorders (Chapter 11). Both tricyclic antidepressants and monoamine oxidase in inhibitors (see below) increase the availability of active monoamines at receptor sites and reverse the biochemical, physiological, and behavioural effects of reserpine, a drug which depletes monoamine stores at nerve terminals, causes behavioural depression in animals, and can precipitate a depressive syndrome in man.

(p. 258 )

(p. 259 )

Fig. 12.1 Time course of therapeutic effect of tricyclic antidepressant drugs. Improvement in depression is considerably delayed compared with attainment of maximum plasma concentration (and biochemical effects). (From Oswald et al. 1972.)

However, several of the newer, clinically effective, antidepressants are neither reuptake blockers nor monoamine oxidase inhibitors; thus, such an action does not appear to be a prerequisite for an antidepressant effect. In addition, inhibition of monoamine uptake can be demonstrated within minutes of the administration of tricyclic antidepressants while the clinical antidepressant effect takes weeks to develop (Fig. 12.1). It has recently become apparent that, with chronic administration, the initial reuptake blocking effect gives rise to a number of secondary effects, both on monoamine synthesis and turnover, and on receptor sensitivity. At present, the long-term effects on receptor sensitivity appear to have the most clinical relevance.

Other effects on monoamine systems

Animal studies indicate that the increased synaptic concentration of noradrenaline and serotonin, induced acutely by the tricyclic antidepressants, inhibits the synthesis of the respective monoamines through negative feedback mechanisms, resulting in decreased cerebral turnover of noradrenaline or serotonin. Thus, tertiary amines have been observed to depress the firing of serotonergic raphe neurones (Koe 1983) while secondary amines depress the firing of noradrenergic locus coeruleus (p. 260 ) neurones (Sulser and Mobley 1980). These actions may be relevant to their anxiolytic effects (Chapter 4).

Monoamine receptor modulation with chronic administration

Chronic administration of tricyclic antidepressants leads to changes in the sensitivity of a number of receptors for monoamines. These changes may represent, at least partially, a homeostatic response to the initial monoamine uptake blocking action of the drugs. Receptor adaptations to long-term antidepressant medication have been discussed (Chapter 11) and are reviewed by Heninger and Charney (1987). In general, it appears that tricyclic antidepressants, a number of non-tricyclic antidepressant drugs, and perhaps various other treatments for depression including lithium and electroconvulsive therapy, can produce some or all of the following changes in monoamine receptor activity in the brain:

1. (i) Down-regulation of α₂-adrenergic receptors (Chapter 11).

2. (ii) Down-regulation of β3-adrenergic receptors (Chapter 11).

3. (iii) For post-synaptic α₁-receptors, the evidence is conflicting: increases, decreases, and no change after antidepressant treatment have all been reported.

4. (iv) Down-regulation of dopamine autoreceptors has been shown to occur in animals. There is little information in man and there have been few investigations of post-synaptic dopamine receptor density after antidepressants.

5. (v) Increase in density in human platelet imipramine binding sites; the importance of these binding sites in depression is still debatable (Marcusson and Ross 1990).

6. (vi) Down-regulation of 5-HT₂ receptors with inconsistent effects on 5-HT, receptors.

The effects of chronic antidepressant treatment on receptor sensitivity may vary in different parts of the brain, and adaptive receptor changes probably involve co-modulation by several different neurotransmitters. It seems likely that the therapeutic effects of chronic tricyclic antidepressant treatment stem from complex adaptive changes which ultimately result in greater synaptic efficiency and stability in several neurotransmitter systems.

Effects on other neurotransmitter systems

The tricyclic antidepressants are structurally related to the phenothiazines, and share with them both anticholinergic and antihistaminic effects. The anticholinergic effects do not correlate with antidepressant effects, and many of the newer antidepressants are almost devoid of anticholinergic activity. Antihistaminic effects are attributed to blockade of histamine receptors in the brain; there is no relationship between antihistaminic potency and antidepressant effect.

(p. 261 ) Long-term administration of many tricyclic antidepressants produces an up-regulation of GABA_B binding sites in the rat frontal cortex and it has been suggested that an interaction with GABA_B neurotransmission may be involved in the therapeutic effects of antidepressant treatments including tricyclic drugs, monoamine oxidase inhibitors, some benzodiazepines and electroconvulsive therapy (Heninger and Charney 1987).

Therapeutic efficacy of tricyclic antidepressants

Tricyclic antidepressants undoubtedly improve the prognosis in depression, but the degree to which they do this has been difficult to estimate. The drugs terminate attacks of depression in 60–80 per cent depending on the selection criteria for treatment (Amsterdam et al. 1980; Asberg and Sjoquist 1981), and most placebo-controlled trials show that tricyclic antidepressants are more effective than placebo. No particular tricyclic drug appears to have greater overall therapeutic efficacy, although the incidence and severity of adverse effects varies between drugs. Tricyclic agents have become the standard drugs against which new antidepressant drugs are compared for efficacy.

Continued administration of tricyclic antidepressants also reduces the likelihood of recurrence of depressive episodes. About 30–50 per cent of depressed patients relapse in 6 months after treatment with electroconvulsive therapy alone, while the relapse rate after 6 months of drug treatment is 10–20 per cent (Rogers et al. 1981). Three large collaborative studies cited by Berger (1977) have confirmed the finding that continued (6 months) tricyclic depressants treatment reduces the relapse rate compared with short-term treatment (6 weeks).

Reasons for failure of therapeutic response are discussed by Amsterdam et al. (1980). They include non-compliance, inappropriate dosage, and selective response to a particular tricyclic drug. There remains a core of depressed patients who do not respond to tricyclic antidepressants. These non-responders are clinically heterogeneous and there is no indication that their depression reflects a different aetiology from that of responders.

(p. 264 ) Adverse effects

Many tricyclic antidepressants have anticholinergic effects (Table 12.1). Cardiovascular effects include hypo- or hypertension, tachycardia, and cardiac arrhythmias which are probably due to peripheral monoamine reuptake blockade. Direct cardiac depressant effects may cause cardiac failure in some elderly subjects. In acute overdose a combination of central nervous system and cardiovascular toxic effects, due to both anticholinergic actions and increased adrenergic activity, are seen. Self-poisoning with antidepressant drugs is common and may be fatal. The relative toxicity of antidepressant drugs is reviewed by Henry and Martin (1987) and Pinder (1988).

Some of the tricyclic agents have sedative effects (Table 12.1) while others have stimulant effects and may cause restlessness or insomnia. Occasionally the drugs may precipitate mania in bipolar disorders, acute psychosis in schizophrenia or toxic confusional states in the elderly. Paradoxical worsening of depression has been reported (Damluji and Ferguson 1988) and it is debatable whether suicide may be promoted in some patients (Montgomery and Pinder 1987). Increased appetite with carbohydrate craving occurs in some patients and may lead to considerable weight gain; amenorrhoea and menstrual irregularities may also occur.

Several drugs interact with tricyclic antidepressants at their sites of action. Monoamine oxidase inhibitors potentiate the increase of mono-aminergic activity at synapses and the use of the two types of drugs together can precipitate excitement and hyperpyrexia. Rarely, this combination can also cause convulsions and coma, and the use of tricyclic antidepressants with monoamine oxidase inhibitors is generally contrain-dicated. Sympathomimetic amines may produce similar potentiation and give rise to a hypertensive reaction. On the other hand, the effects of certain antihypertensive drugs may be reversed. Drugs with anticholinergic effects may potentiate the central and peripheral anticholinergic effects of tricyclic antidepressants and at toxic concentrations produce a syndrome of hyperpyrexia, agitation and convulsions. Sedative/ hypnotic drugs, including alcohol, have additive effects with sedative tricyclic antidepressants.

Withdrawal syndrome

Tolerance develops to the anticholinergic effects of the tricyclic antidepressants and a number of adaptive changes result from the monoamine uptake inhibition, as discussed above. No doubt as a result of these changes, a variety of withdrawal effects can occur when the drugs are discontinued after chronic use. Signs of cholinergic hyperactivity (p. 265 ) after withdrawal include malaise, chills, coryza, muscular aches, nausea and vomiting, and occasionally movement disorders (Dilsaver 1989; Dilsaver et al. 1987a, b). Signs of monoaminergic overactivity include anxiety, panic, irritability, restlessness, insomnia, nightmares and occasionally mania (Dilsaver et al. 1987a, b; Tyrer 1984; Bialos et al. 1982; Charney et al. 1982). In some cases (Tyrer 1984), the syndrome is similar to the benzodiazepine withdrawal syndrome (Chapter 11) and may be related to the anxiolytic effects of the drugs. Withdrawal symptoms emerge during the first two weeks after drug withdrawal and subside during the next two weeks (Ayd 1986). The symptoms are relieved if the drug is resumed. The incidence of the withdrawal syndrome appears to be about 30 per cent in patients with neurotic depression and phobic neuroses (Tyrer 1984). Similar withdrawal symptoms may occur in neonates whose mothers received antidepressants during pregnancy (Webster 1973).

New generation antidepressants

Following the apparent therapeutic success of the classical tricyclic antidepressants, a new generation of drugs was developed with the hope of finding agents with increased antidepressant potency, a more rapid onset of action, and fewer adverse effects. In spite of their diverse chemical structures, most of these new drugs have very similar therapeutic effects to the original tricyclics, including a delayed onset of action. On the other hand many have fewer adverse effects and are safer in overdose.

Newer antidepressants are reviewed by Enna and Eison (1987). Maprotiline is a bridged tricyclic and is a relatively selective inhibitor of noradrenaline reuptake. It has sedative properties and its adverse and toxic effects are similar to those of the tricyclics. Mianserin has a tetracyclic structure. It appears to have a different biochemical action from the tricyclic antidepressants since it has no effect on monoamine reuptake, no sympathomimetic activity, and no significant anticholinergic effects. There is some evidence that it blocks α₂-receptors, thus increasing noradrenaline release. It also has anxiolytic, sedative and antihistamine effects. Adverse effects are uncommon although it can produce blood dyscrasias especially in the elderly. The virtual lack of cardiotoxic and anticholinergic effects make this drug relatively safe in overdose.

Monoamine oxidase inhibitors

The monoamine oxidase inhibitors were introduced as antidepressants in the 1950s at about the same time as the tricyclic compounds, but they were soon superseded by the tricyclics which had a wider therapeutic range and less severe adverse effects. Monoamine oxidase inhibitors are as effective as tricyclic antidepressants for most types of depression including some which do not respond to tricyclics (Tyrer 1989). They are also effective in depression accompanied by anxiety, and in phobic states. The drugs most often used clinically are the hydrazine derivatives phenelzine and isocarboxazid and the non-hydrazine tranylcypromine. These drugs are reviewed by Tyrer (1982) and Murphy et al. (1987). A shorter-acting derivative, moclobemide has recently been introduced.

Monoamine oxidase inhibition

As their name implies, the monoamine oxidase inhibitors inhibit the enzyme monoamine oxidase in brain and peripheral tissues. The hydrazines produce irreversible inhibition while that produced by nonhydrazines (p. 267 ) is slowly reversible; with moclobemide, enzyme activity recovers completely in 24 h after stopping the drug (Warrington et al. 1991). Monoamine oxidase exists in at least two forms in the body, MAO-A and MAO-B. These forms have different substrate specificities. The preferred substrate for MAO-A is serotonin, but it also deaminates noradrenaline and dopamine. The preferred substrate for MAO-B is benzylamine. Tyramine and tryptamine are substrates for both types. MAO-A is thought to be more relevant to the activity of antidepressant drugs.

At monoaminergic nerve terminals, MAO-A appears to control the amount of transmitter which is held in synaptic storage vesicles. A stabilizing system seems to exist whereby the quantity of transmitter stored at these sites is kept roughly constant, any excess being deaminated by the enzyme and returned to the metabolic pool. Thus, the activity of monoamine oxidase determines the quantity of monoamine released into the synaptic cleft by a nerve impulse and the consequence of monoamine oxidase inhibition is an increase in the concentration of monoamine transmitter available to act on synaptic receptors following nerve stimulation (Fig. 11.1). This effect leads to enhancement of activity of serotonin, noradrenaline and dopamine, both centrally and peripherally. The effect persists for some weeks after the elimination of the drug from the body, because of the irreversible or only slowly reversible nature of the enzyme inhibition.

Monoamine oxidase inhibitors also have some catecholamine uptake blocking activity which adds to their effect (Kline and Cooper 1980). The non-hydrazine derivatives are similar in structure to amphetamine and have additional amphetamine-like effects including dopamine release.

In animal tests, monoamine oxidase inhibitors, like many other antidepressants, reverse the behavioural and physiological effects of reserpine, increase brain concentrations of monoamines, enhance intracranial self-stimulation, inhibit the development of learned helplessness and behavioural despair, and normalize the behaviour of bulbectomized rats.

Receptor modulation

On chronic administration, the monoamine oxidase inhibitors produce alterations in receptor sensitivity similar to those which have been observed with many of the tricyclic antidepressants, including down-regulation of α₂- and β-adrenergic receptors and of serotonergic 5-HT₂ receptors, although serotonin reuptake sites are not affected (Sulser 1981; Sulser et al. 1983; Sugrue 1981; Chamey et al. 1981a). Similar adaptive receptor changes occur with pargyline which in clinical trials has little if any antidepressant effect (Tyrer 1982).

(p. 268 ) Relationship of biochemical effects to antidepressant action

It is not clear how much of the antidepressant effects of these drugs is related to secondary changes in receptor sensitivity and how much to inhibition of monoamine oxidase activity itself. The onset of antidepressant action is often delayed, but this may be partly due to pharmacokinetic factors. The offset of antidepressant activity on discontinuation occurs after a period of weeks and coincides with resynthesis of monoamine oxidase. Some monoamine oxidase inhibitors (particularly nonhydrazine derivatives) have additional amphetamine-like actions with a rapid onset of mood elevation. Like amphetamine, the drugs can precipitate mania or a schizophreniform psychosis and can aggravate symptoms in schizophrenia. As with tricyclic antidepressants, the crucial change produced by monoamine oxidase inhibitors may be an increase in stability in interacting central monoaminergic synapses. The drugs are particularly effective in disorders characterized by anxiety, rapid changes in mood in response to external events, diurnal mood swings, and phobic symptoms, and Tyrer (1982) notes from clinical observations that response to monoamine oxidase inhibitors, when it occurs, does not typically consist of a gradual improvement of symptoms, but of a sudden dramatic change which occurs over 24 h. ‘It seems that a “switch mechanism” in the brain must be operating to produce such a qualitative change in such a short time’ (Tyrer 1982, pp. 259–60).

Drug interactions

Indirectly acting sympathomimetic amines, including those contained in certain foods (Stewart 1976), can give rise to a serious interaction with monoamine oxidase inhibitors, due to increased release of catecholamines. The reaction consists of severe hypertension and hyperthermia and may terminate in fatal subarachnoid haemorrhage. The risk of these interactions appears to be much less with moclobemide (Warrington et al. 1991). Hypertensive reactions have been reported with intravenous adrenaline and noradrenaline presumably because of additive effects at catecholaminergic receptors. The combination of monoamine oxidase inhibitors with tricyclic, and related tetracyclic antidepressants can interact to produce cerebral excitement which may be followed by coma and severe hyperthermia, and sometimes a hypertensive reaction. Reserpine, methyldopa and L-dopa can also precipitate hypertension.

The inactivation of some drugs which are normally metabolized by oxidizing enzymes is inhibited by monoamine oxidase inhibitors, with the result that the effects of these drugs are potentiated and prolonged. Such drugs include narcotic analgesics, barbiturates, and to a lesser extent other hypnotics and sedatives. The effects of general anaesthetics, suxamethonium, anticholinergic drugs, and caffeine may also be potentiated.

Drug dependence

Drug dependence can occur with monoamine oxidase inhibitors, especially those with amphetamine-like structure. Tolerance develops and (p. 270 ) some patients take large doses in order to maintain the stimulant and occasionally euphoric effects. A severe withdrawal reaction similar to that of amphetamine and cocaine withdrawal (Chapter 7) can occur on sudden cessation of these drugs. In addition, anxiety reactions with sudden onset of panic, shaking, sweating, headache, paraesthesiae and perceptual disturbances have been described (Drug and Therapeutics Bulletin 1986). A rebound of REMS with sleep disturbance and severe nightmares have also been noted. The incidence of withdrawal symptoms after chronic use is greater with monoamine oxidase inhibitors than with tricyclics (Tyrer 1984).

Pharmacokinetics

Carbamazepine is slowly but well absorbed although plasma concentrations fluctuate during absorption. It has a plasma elimination half-life of 25–60 h after single dosage, falling to 10 h on chronic administration, possibly due to enzyme induction. It is metabolized to an epoxide derivative which has anti-epileptic activity but a half-life of only 2h.

Biochemical effects

The biochemical actions of carbamazepine are complex and not well understood; they are reviewed by Post and Uhde (1983) and Post (1978). Carbamazepine is a weak noradrenaline reuptake blocker and also blocks stimulation-induced noradrenaline release in peripheral animal tissues. It increases the firing of the locus coeruleus, in action which may be relevant to its antidepressant effects. Carbamazepine also increases plasma concentrations of total and free tryptophan in humans, another action which may possibly be relevant to antidepressant effects. Despite its antimanic actions, carbamazepine does not block dopamine receptors like neuroleptics (Chapter 14). Effects on GABA mechanisms, adenosine, glutamate and calcium and sodium channels appear to relate to anticonvulsant effects.

Carbamazepine has several effects on endocrine activity. It decreases circulating concentrations of tri- and tetraiodothyronine, but does not alter concentrations of thyroid stimulating hormone. It may act as a direct vasopressin agonist and has antidiuretic effects which have been used in the treatment of diabetes insipidus. In addition, it induces escape from dexamethasone suppression of Cortisol (Chapter 11). This effect may be partly due to enzyme induction which enhances the metabolism of dexamethasone, but it also alters the circadian rhythm of urinary cortiosteroid excretion and increases the 24-h excretion of Cortisol in normal subjects and depressed patients. A possible effect on endogenous opioid systems is suggested by the observation that carbamazepine facilitates opiate and enkephalin-induced motor activity in the mouse, (p. 272 ) and it has also been observed to decrease cerebrospinal somatostatin concentration in patients with affective disorders.

Behavioural and neurophysiological effects in animals

Carbamazepine has a distinctive profile of effects on animal behaviour: it is active in some antidepressant tests but does not reverse the effects of reserpine. It is also active on some anxiolytic tests, showing a positive action in conflict procedures (Chapter 3). It has little or no dopamine or acetylcholine antagonist activity, but is active in inhibiting aggressive behaviour. Electrophysiological studies show that carbamazepine has marked effects on the limbic system. It inhibits after-discharges elicited by electrical stimulation from a variety of limbic areas. It is the most effective anticonvulsant in stabilizing limbic electrical activity, followed by valproic acid, phenobarbitone, and the benzodiazepines and succinimides.

Clinical effects

Lithium

Lithium is usually administered as lithium carbonate, and has been shown to have therapeutic actions in mania and depression and in the prophylaxis of affective disorders (reviewed by Tyrer and Shaw (1982, and Bunney and Garland-Bunney 1987).

(p. 274 ) Effects on noradrenaline

In isolated tissues, lithium decreases the release of exogenously administered ³H-noradrenaline in response to electrical stimulation. This effect can be prevented by raising the concentration of calcium in the perfusing fluid, suggesting that lithium may interfere with the action of calcium in the stimulation-mediated release of noradrenaline. In man, chronic lithium treatment produces little overall change in the excretion of noradrenaline metabolites, but there is some evidence that it causes down-regulation of α₂-adrenergic receptors, an effect similar to that induced by chronic treatment with tricyclic antidepressants. The mechanisms for these effects of lithium are not known but lithium may compete with calcium and magnesium in various catecholamine transport and release systems. The net effect of lithium administration appears to be a decrease in the amount of noradrenaline available to receptors. Such an effect might possibly be a basis for its actions, at least in mania, while effects on α₂ receptors may be involved in the antidepressant actions.

Effects on dopamine

The effects of lithium on dopaminergic systems are not clear, but inhibition of dopamine synthesis has been demonstrated in rats treated with lithium for 2 weeks. The electrically stimulated, calcium dependent, release of dopamine from nerve terminals is inhibited by lithium. The development of Parkinsonian symptoms in patients maintained on lithium also suggests dopaminergic underactivity (Tyrer 1982) and lithium also appears to prevent the development of dopamine receptor supersensitivity in patients treated with haloperidol (Chapter 14) and may block the euphoriant effects of amphetamine and cocaine. Decreased dopaminergic activity may be relevant to the therapeutic action in mania.

Effects on serotonin

Short-term (1–5 days) administration of lithium to rats increases the high affinity uptake of tryptophan into forebrain synaptosomes. There is an associated increase in serotonin synthesis and turnover. The concentration of 5-HIAA in the forebrain in response to electrical stimulation of the raphe nuclei is increased. The effect of chronic treatment on concentrations of serotonin varies between different parts of the brain: decreased serotonin concentrations have been reported in hypothalamus and brainstem, but increased concentrations and turnover with increased release on electrical stimulation, in the forebrain. Bunney and Garland-Bunney (1987), and Price et al. (1990) conclude from a review of human and animal studies that chronic lithium treatment probably enhances serotonergic activity and that this may be important in its antidepressant (p. 275 ) action. The effect on serotonergic receptors is not clear: animal studies suggest a down-regulation of 5-HT₂ receptors in the frontal cortex and of 5-HT₁ receptors in the hippocampus.

Effects on other systems

The effects of lithium on other neurotransmitters are not clear. It may decrease the synthesis and release of acetylcholine in the cortex (Friedman 1973), and it appears to increase GABA concentrations in several brain areas. In addition, it appears to inhibit cyclic AMP and phosphoinositol second messenger systems in the brain in both animals and man (Bunney and Garland-Bunney 1987; Drummond 1987), an action which may account for some of its endocrine effects and possibly its antimanic action.

Clinical effects

Lithium in clinically used doses produces no discernible psychotropic effects in normal subjects. However, it has potent effects in a variety of affective disorders reviewed by Tyrer and Shaw (1982) and Bunney and Garland-Bunney (1987).

(p. 276 ) Effects in mania

Lithium is effective in 60 per cent of patients with acute mania, although the onset of therapeutic effects may be delayed for up to 2 weeks. Several controlled trials have compared lithium with neuroleptics, usually chlorpromazine (Prien et al. 1972; Johnson et al. 1971). The general conclusion has been that neuroleptics are superior: the symptoms are controlled more rapidly, within days as opposed to 2 weeks, and the adverse effects are less dangerous. However, both neuroleptics and lithium terminate manic episodes within 3 weeks in patients who continue treatment.

Although the neuroleptics are clearly more practical drugs to use initially in the management of acute mania because of their more rapid onset of action, there are some interesting qualitative differences in the response to neuroleptics and lithium (Gerbino et al. 1978). The neuroleptics produce an early decrease in motor activity but this effect is accompanied by considerable central nervous system depression. There is no clear early break in the mania, and euphoria and excitement may still be apparent despite the drug effects which, initially at least, appear to allow the patient to be ‘quietly manic’. In contrast, the mood change with lithium appears to be much sharper and more specific. Hyperactivity and affect return to normal without sedation, and once normality is achieved it is virtually complete with no accompanying central nervous system depression. These qualitative differences, which are difficult to rate objectively, have suggested that lithium affects some underlying neuronal dysfunction fundamental to mania, while neuroleptics merely override some of the symptoms, chiefly the overactivity.

Effects in depression

Lithium has been investigated as a treatment for depression in several trials in which it has been compared with tricyclic antidepressants or placebo. In mixed groups of depressed patients, it was found to be as effective as imipramine, with a therapeutic effect appearing in the second or third week of treatment. Later studies suggest that lithium is of particular value in patients with bipolar disorders, and when used in combination with other antidepressant drugs.

Prevention of recurrence

Several prolonged placebo controlled trials continued over several months to years have shown that long-term lithium treatment has a significant prophylactic effect in preventing, in attenuating the length or severity, or in reducing the frequency of relapses of affective illness. This effect appears to apply almost equally to recurrences of mania or depression, and to unipolar and bipolar depression. Nevertheless, the relapse (p. 277 ) rate of affective disorders, even with maintenance drug treatment, is of the order of 30 per cent and debate continues concerning the long-term value of lithium prophylaxis (Coppen et al. 1990; Cowen 1988; Lancet 1987a; Maj et al. 1989). There is no clear way of predicting response to the prophylactic effect of lithium and the high incidence of adverse effects limits the use of lithium in some patients.

Other disorders of affect

Lithium has been used in a number of other disorders associated with changes of affect, discussed by Tyrer and Shaw (1982). In milder cases of schizoaffective disorder lithium has a possible therapeutic effect, but it is less effective than neuroleptics in more severe cases. Anti-aggressive actions of lithium have been demonstrated in impulsively aggressive male prisoners, and possibly in aggressive epileptics and mentally subnormal individuals. It has also been used in character disorders with emotional instability, hyperactive children, affective disorders associated with alcoholism, amphetamine abuse, prementrual tension, Kleine-Levin syndrome, and cluster headaches.

(p. 278 ) Electroconvulsive therapy

Electroconvulsive therapy is mentioned briefly here since it remains an important treatment for patients in whom a rapid response is required because of the severity of the depression or the risk of suicide, and for those who have not responded adequately to drugs. It is effective in depressive disorders, as shown by numerous trials in which it has been compared with sham electroconvulsive therapy and antidepressant drugs. It is more effective than drugs in terminating attacks of depression and has a much quicker onset of action, although repeated treatments may be necessary. It is less effective in preventing recurrent episodes but the treatment can be combined with drugs which may potentiate its effects.

The mode of action of electroconvulsive therapy is not clear, but it appears to increase post-synaptic responsiveness to noradrenaline, serotonin and dopamine, possibly by increasing receptor sensitivity. The treatment is sometimes followed by a dramatic switch from a grossly abnormal to an apparently normal clinical state, and Lerer (1987, p. 585) remarks: ‘the fact that a series of electrically induced seizures may so effectively alleviate the most severely disturbed mood states is one of the most intriguing phenomena in biological psychiatry’. Possibly such treatment acts like antidepressant drugs to restore a degree of stability at central monoaminergic synapses.