Essentials

Psychotropic drugs are widely used in medical practice, hence most clinicians are likely to have under their care a number of patients receiving treatment with psychoactive medication (Table 1). Practitioners therefore need to have an understanding of the uses and unwanted effects of psychotropic drugs, particularly of the way in which such medication can interact with drugs used to treat other medical disorders.

Most psychotropic drugs are prescribed for the treatment of depressive and anxiety disorders. This reflects the frequency of these conditions in both primary care and general hospital settings; accordingly, drug treatment for anxiety and depression will often be instituted both by general practitioners and hospital clinicians. Similarly, while the principal use of antipsychotic drugs is in the treatment of schizophrenia, such agents are also frequently used in general hospitals in the management of organic psychoses. Finally, while treatment with mood stabilizing drugs, such as lithium, will generally be initiated by psychiatrists, patients receiving long-term therapy may well require treatment for coexisting medical disorders; because of which, a knowledge of the effects of lithium on different body systems and its liability to produce adverse drug interactions will be required.

Table 1  Classification of clinical psychotropic drugs

 

Name	Examples of classes	Indications
Antipsychotic	Phenothiazines Butyrophenones Substituted benzamides	Acute treatment of schizophrenia and mania, prophylaxis of schizophrenia
Antidepressant	Tricyclic antidepressants Monoamine oxidase inhibitors Selective serotonin reuptake inhibitors (SSRIs)	Major depression (acute treatment and prophylaxis), anxiety disorders, obsessive–compulsive disorder (SSRIs)
Mood stabilizer	Lithium Carbamazepine Valproate	Acute treatment of mania, prophylaxis of recurrent mood disorder
Anxiolytic	Benzodiazepines Azapirones (buspirone)	Generalized anxiety disorder
Hypnotic	Benzodiazepines Cyclopyrrolones (zopiclone) Imidazopyridines (zolpidem)	Insomnia

5-HT, 5-hydroxytryptamine.

For many psychiatric conditions, particularly anxiety and depressive disorders, psychological treatments are as effective as psychotropic drugs and may have other advantages (Bullet list 1). Hence, if appropriate psychological treatments are available they may be considered before the use of drug therapy.

Drug overdose

The effects of deliberate or accidental overdose of psychotropic drugs will also involve physicians. Related to this is the general point that when prescribing psychotropic drugs, particularly for depressed patients, the risk of overdose should always be considered. If such a risk is present, the practitioner should: (1) ensure that medication is dispensed in small amounts; (2) consider asking a close relative to supervise the medication; (3) use a relatively nontoxic drug, if possible.

Pharmacokinetic factors

Most psychotropic drugs are highly lipophilic and well absorbed from the gastrointestinal tract. They are metabolized by the liver to water-soluble derivatives that are eliminated by the kidneys. Therefore, their half-life will be prolonged in patients with hepatic or renal impairment and in older patients. Where psychotropic medication is added to another drug treatment the possibility of drug interaction must be considered. For example, some selective serotonin reuptake inhibitors (SSRIs) are potent inhibitors of hepatic cytochrome P450 enzymes and can thereby increase plasma levels of coadministered drugs such as warfarin.

Bullet list 1 Possible advantages of cognitive behavioural therapy (CBT) compared to psychotropic drugs

Bullet list 2  Effects of sudden discontinuation of an SSRI

Withdrawal of psychotropic medication

Psychotropic and many other classes of drugs produce neuroadaptive changes during their repeated administration. Readjustment has to occur when drug treatment is stopped, and this may appear clinically as a withdrawal or abstinence syndrome. Characteristic abstinence syndromes have been described for the antidepressants, particularly SSRIs (Bullet list 2) and anxiolytics, while the sudden discontinuation of lithium can provoke a ‘rebound’ mania. It is therefore prudent to withdraw psychotropic drugs slowly whenever possible. It is also important to be able to distinguish withdrawal syndromes from relapse of the disorder being treated.

Compliance and concordance with treatment

Compliance is an even greater problem when prescribing psychotropic drugs than it is in general therapeutics. Psychoactive drugs frequently have unpleasant side effects and, while side effects are experienced early in treatment, several days may elapse before a therapeutic response is evident. In addition, patients may not see the need for treatment or believe that it can help them. Careful explanation accompanied by written instructions can help to ensure that necessary medication is taken.

It is increasingly recognized that the successful and safe use of medication requires a collaborative relationship between patient and doctor. The term ‘concordance’ may be preferred to ‘compliance’, which carries the implicit assumption that the patient’s task is to obey instructions. It is therefore important to acquire an understanding of the patient’s attitude to their illness as well as its treatment. For example, discussion that helps patients to weigh the advantages and disadvantages of drug treatment (‘compliance therapy’) has been shown to benefit those with schizophrenia.

Antidepressant drugs

Currently employed antidepressant drugs increase the activity of serotoninergic (5-hydroxytryptamine, 5-HT) and/or noradrenergic neurons in the CNS through one mechanism or another. The pharmacological actions of both noradrenaline (norepinephrine) and 5-HT in the synapse are terminated by specific reuptake pumps that draw these neurotransmitters back into the presynaptic nerve ending. Most antidepressants potentiate the action of 5-HT and noradrenaline by blocking this reuptake process.

Serotonin reuptake inhibitors (SSRIs)

The actions of SSRIs are confined to blockade of the reuptake of 5-HT and their use is associated with a sustained increase in brain 5-HT neurotransmission.

Principal drugs

These are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

Indications and use

With the availability of generic forms of citalopram, sertraline and fluoxetine, SSRIs are now first-line treatment for moderate to severe depression. They are modestly better tolerated than tricyclic antidepressants, lack significant cardiotoxicity, and are relatively safe in overdose. They are generally nonsedating and can be given in a single dose once daily. There are few important therapeutic differences between them. If treatment is successful, it is usual to continue the antidepressant for 4 to 6 months (so called ‘continuation therapy’). This reduces the risk of early relapse by about half. Some patients with recurrent depressive illness require long-term prophylactic treatment with antidepressant drugs. This should be considered in those who have had more than two episodes of depression in the previous 5 years, particularly if the episodes have been severe in terms of symptomatology and impact on work and social functioning.

Adverse effects

The main adverse effects of SSRIs are shown in Table 2. They can cause activation and agitation early in treatment and there has been controversy as to whether this might be associated with an increased risk of suicidal behaviour when therapy is initiated. There is some evidence for an effect of this nature in young people and, with the exception of fluoxetine, SSRIs are contraindicated in the treatment of depression in patients less than 18 years of age. The evidence for a prosuicidal effect of SSRIs in adults is more equivocal and, at a population level, some studies show a decreased suicide rate correlating with SSRI prescription. However, it does seem likely that the initiation of antidepressant drug treatment of any kind is associated with an increased risk of self-harm in the first weeks of treatment. Whether this represents a specific pharmacological effect is unclear. In practical terms, however, it suggests that depressed patients should be carefully monitored in the days after starting antidepressant medication and that medication should be prescribed in limited amounts.

Table 2  Newer antidepressants

 

Drug	Mechanism	Adverse effects
SSRIs	5-HT reuptake blockade	Nausea, insomnia, headache, anxiety, rash, sweating, sexual dysfunction, low sodium state, extrapyramidal movement disorders (rare), seizure (rare)
Venlafaxine, duloxetine	5-HT and noradrenaline reuptake blockade	Nausea, headache, insomnia, sweating, anxiety, hypertension, sexual dysfunction, seizure (rare), overdose toxicity (venlafaxine)
Reboxetine	Noradrenaline reuptake blockade	Dry mouth, sweating, constipation, insomnia
Trazodone	5-HT2-receptor antagonism α1-Aadrenoceptor blockade	Sedation, dizziness, nausea, postural hypotension, priapism (rare), cardiac arrhythmias (rare), seizure (rare)
Mirtazapine	5-HT2/ α2-receptor agonist	Sedation, weight gain, abnormal liver function tests, reversible agranulocytosis (rare), seizure (rare)

5-HT, 5-hydroxytryptamine; SSRI, selective serotonin reuptake inhibitor.

Drug interactions

SSRIs, with the exception of citalopram and escitalopram, slow the metabolism of numerous other drugs including warfarin, theophylline, anticonvulsants, antipsychotics, and tricyclic antidepressants. Dangerous interactions, characterized by 5-HT neurotoxicity, have been reported between SSRIs and monoamine oxidase inhibitors. This may be particularly problematic with fluoxetine, whose active metabolite norfluoxetine has a half-life of 7 to 10 days. At least 5 weeks should therefore elapse between stopping fluoxetine and prescribing a monoamine oxidase inhibitor. SSRIs may also produce 5-HT toxicity in combination with lithium. SSRIs may increase the risk of upper gastrointestinal bleeding, particularly if given in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs).

Other, newer antidepressants

Principal drugs

These can be classified as follows:

• ◆ selective noradrenaline reuptake inhibitors—reboxetine
• ◆ selective serotonin-noradrenaline reuptake inhibitors—duloxetine, venlafaxine
• ◆ monoamine receptor antagonists—mirtazapine, trazodone

Reboxetine inhibits only the reuptake of noradrenaline. Venlafaxine is a potent blocker of 5-HT reuptake and at higher doses blocks the reuptake of noradrenaline as well. Duloxetine has a similar action. Both trazodone and mirtazapine are 5-HT₂ receptor antagonists and block α₁-adrenoceptors in addition, which gives them a sedating profile. Mirtazapine also blocks inhibitory presynaptic α₂-adrenoceptors, resulting in an increased release of noradrenaline.

Indications and use

These antidepressants can be used to treat patients in whom SSRIs are poorly tolerated or ineffective. The lack of sedation associated with reboxetine, duloxetine, and venlafaxine can be beneficial in outpatients striving to carry out their usual activities. With the exception of venlafaxine these drugs lack significant cardiotoxicity and are relatively safe in overdose.

Adverse effects

The main adverse effects of the other, newer antidepressants are shown in Table 2. The major distinction between compounds is whether or not they are sedating. The sedating antidepressants have the advantage of improving sleep at an early stage, but they may impair cognitive function, while the reverse is true for duloxetine, venlafaxine, and reboxetine which may impair sleep.

Drug interactions

Duloxetine and venlafaxine, like SSRIs, potentiate 5-HT function and therefore can cause serious 5-HT neurotoxicity when combined with monoamine oxidase inhibitors (MAOIs). Toxicity can also occur in combination with lithium. Trazodone and mirtazapine may increase the sedative effects of other centrally acting drugs. Reboxetine should not be given with other agents that might potentiate noradrenaline function (such as MAOIs) or increase blood pressure (such as ergot derivatives).

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) inhibit the neuronal uptake of noradrenaline and 5-HT. They have numerous other pharmacological properties, but these are thought to contribute to their adverse effect profile rather than their therapeutic activity. However, some of these adverse effects, e.g. sedation, can prove beneficial in certain circumstances.

Principal drugs

Indications and use

TCAs are now prescribed somewhat less for depression than are SSRIs, but they still retain a role in patients with severe or treatment-resistant depression or in those who have shown a good previous clinical response. Many tricyclics are sedating, which can be helpful in patients with sleep disturbance and anxiety. To obtain tolerance to side effects, it is usual to begin treatment at a low dose, e.g. 25 to 50 mg of amitriptyline at night, and to increase the amount over about 2 to 3 weeks to the usual therapeutic dose, which ranges between 75 and 150 mg daily for amitriptyline and imipramine.

Adverse effects

TCAs possess antagonist properties at a variety of neurotransmitter receptors, including muscarinic cholinergic receptors, α₁-adrenoceptors, and H1 histamine receptors. These receptor antagonist effects account for much of the adverse effect profile of these agents, particularly their anticholinergic properties (Table 3). TCAs also possess membrane stabilizing effects; these underlie their most serious side effect of cardiotoxicity, which can be particularly problematic in tricyclic overdose, where ingestion of less than 1 g can sometimes prove fatal. Lofepramine, however, is relatively safe in overdose. TCAs should be used with caution in patients with cardiovascular disease. They also lower the seizure threshold and can thereby aggravate pre-existing epilepsy or sometimes cause seizures de novo.

Drug interactions

TCAs antagonize the hypotensive effects of α2-adrenoceptor agonists such as clonidine, but can be safely combined with thiazides and angiotensin-converting enzyme (ACE) inhibitors. The ability of TCAs to block noradrenaline reuptake can lead to hypertension with systemically administered noradrenaline and adrenaline (epinephrine). TCAs should not be used in conjunction with antiarrhythmic drugs, particularly amiodarone. Plasma levels of TCAs can be increased by numerous other drugs including cimetidine, sodium valproate, calcium channel blockers, and selective serotonin reuptake inhibitors (SSRIs).

Table 3  Some adverse effects of tricyclic antidepressants

 

Pharmacological action	Adverse effects
Muscarinic receptor blockade (anticholinergic)	Dry mouth, tachycardia, blurred vision, glaucoma, constipation, urinary retention, sexual dysfunction, cognitive impairment
α1-Adrenoceptor blockade	Drowsiness, postural hypotension, sexual dysfunction, cognitive impairment
Histamine H1 receptor blockade	Drowsiness, weight gain
Membrane stabilizing properties	Cardiac conduction defects, cardiac arrhythmias, epileptic seizures, overdose toxicity
Other	Rash, oedema, leucopenia, elevated liver enzymes

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors (MAOIs) block the enzyme monoamine oxidase, which deaminates the neurotransmitters 5-HT, noradrenaline, and dopamine. There are two forms of monoamine oxidase, known as type A (which deaminates noradrenaline and 5-HT) and type B (which preferentially deaminates dopamine and tyramine). Conventional MAOIs irreversibly deactivate both type A and type B monoamine oxidase. This has two main consequences of importance for MAOI use: (1) there is a potential for serious food and drug interactions; and (2) the consequent drug and food restrictions need to be continued for 2 weeks after cessation of MAOI treatment so that new monoamine oxidase can be synthesized.

Moclobemide is a reversible MAOI that selectively inhibits type A monoamine oxidase only. This leads to an increase in brain noradrenaline and 5-HT levels, but other amines such as tyramine are little affected. These factors make moclobemide much less likely than the older MAOIs to produce adverse food and drug interactions, giving it a significant safety advantage. However, while moclobemide has been shown to be effective in the treatment of moderately depressed outpatients, studies have not thus far demonstrated its efficacy in the patient groups for whom conventional MAOI treatment is currently reserved (see below).

Principal drugs

These are isocarboxazid, phenelzine, tranylcypromine, and moclobemide.

Indications and use

Conventional MAOIs are now regarded as third-line antidepressant treatment and are reserved for depressed patients who have failed to respond to multiple drug and other treatments. However, MAOIs can have useful effects in such patients, which is why they have retained a therapeutic role.

Phenelzine and tranylcypromine are the two most commonly prescribed MAOIs, the usual therapeutic dose for phenelzine being between 30 and 90 mg daily. As with TCAs, patients should be informed about side effects and advised that a therapeutic response from MAOIs may not be apparent for 3 to 4 weeks. Once a response is obtained, it is usually necessary to continue treatment for several months.

Adverse effects

MAOIs may cause the following side effects:

• ◆ central nervous system—dizziness, muscular twitching, insomnia, confusion, mania
• ◆ cardiovascular—tachycardia, postural hypotension, hypertension
• ◆ other—dry mouth, blurred vision, impotence, peripheral oedema, hepatocellular damage, leucopenia

Food and drug interactions

The main hazard of conventional MAOI treatment is through interaction with indirect sympathomimetics, i.e. agents that release noradrenaline from nerve endings. The usual source of interaction is tyramine in certain foodstuffs, especially cheese and meat extracts. Tyramine is usually metabolized by monoamine oxidase in the gut wall and liver, but in patients taking MAOIs large amounts may enter the systemic circulation, resulting in hypertension and even cerebrovascular accidents. Similar adverse effects have been reported when sympathomimetic drugs, e.g. amphetamines or ephedrine, are administered to patients taking MAOIs. Ephedrine or its derivatives are frequently present in cold cures: patients must therefore be warned against self-medication without seeking advice.

Hypertensive episodes resulting from the interaction of sympathomimetic drugs and MAOIs are best treated with an α1-adrenoceptor antagonist. Chlorpromazine is an alternative, if a selective agent is unavailable.

MAOIs also produce important interactions with other commonly used drugs, including opioids, insulin, and oral hypoglycaemic agents. Except in special circumstances, combination with TCAs is best avoided. Combination with clomipramine, SSRIs, and venlafaxine can cause a 5-HT neurotoxicity syndrome and is contraindicated.

From the foregoing, it will be apparent that conventional MAOIs should only be prescribed to patients capable of adhering to the necessary dietary restrictions. Written instructions listing prohibited foods should be provided. No additional medication should be given until the possibility of an adverse drug interaction has been excluded.

Moclobemide

Moclobemide is well tolerated, although insomnia and nausea may occur. Unlike conventional MAOIs, it does not cause significant interaction with tyramine, and adverse drug interactions also seem to be less likely. However, caution is recommended when prescribing with opioids, and combined use with SSRIs and sympathomimetic agents should be avoided. Because of the reversible nature of moclobemide’s interaction with monoamine oxidase and its short half-life (about 3 h), normal monoamine oxidase activity is restored within a day of stopping treatment.

Mood stabilising drugs

Lithium

Lithium salts have inhibitory effects on receptor-transduction systems, particularly second messengers such as cAMP and phosphoinositol. Lithium also produces marked increases in some aspects of brain 5-HT function.

The main uses of lithium are:

• ◆ prophylaxis of recurrent affective disorders, especially manic depressive illness
• ◆ acute treatment of mania
• ◆ augmentation of antidepressant medication in patients with resistant depression

Lithium remains a leading pharmacological treatment for the maintenance phase of bipolar disorder. However, because of its potential toxicity and limited tolerability, anticonvulsant treatments are being used more widely for this purpose, particularly in the United States of America.

The excretion of lithium from the body is critically dependent on the kidneys. Since there is little margin between therapeutic plasma levels of lithium (0.5–0.8 mmol/litre) and those causing toxicity (>1.2 mmol/litre), the introduction of lithium therapy should be preceded by clinical and laboratory assessment of renal function. Renal function tests should include urinalysis and measurement of plasma creatinine and electrolyte levels: note should be taken if there is any suggestion of impaired renal function (reduced estimated GFR (eGFR)).

Patients should initially be treated with 200 to 400 mg daily of lithium carbonate, usually as a single dose at night. Slow-release preparations of lithium are available, but their pharmacokinetics in vivo are very similar to those of the standard preparation. Dosage should be adjusted every 5 to 7 days on the basis of plasma lithium determinations obtained approximately 12 h after the last dose. Plasma levels of 0.5 to 0.8 mmol/litre are usually satisfactory for prophylaxis of recurrent mood disorders, but some patients—particularly those with an acute manic episode—may require higher levels (0.8–1.0 mmol/litre). Most patients achieve adequate plasma levels with lithium carbonate dosages of between 600 and 1200 mg daily, and following this their lithium requirement is generally stable.

In the absence of clinical indications, it is usually sufficient to check lithium levels every 2 to 3 months and repeat renal function tests every 6 months. Lithium can also cause hypothyroidism, so thyroid function tests should be performed prior to treatment and at 6-monthly intervals thereafter. If necessary, lithium can be combined with thyroxine replacement therapy. Sudden withdrawal of lithium in bipolar patients can cause an acute rebound mania and should be avoided if at all possible.

Adverse effects

Side effects of lithium are shown in Table 4. The most important concern the effects of lithium on the kidneys. Some degree of thirst and polyuria is common, and a few patients develop nephrogenic diabetes insipidus, probably caused by lithium blocking the effect of ADH on the renal tubule. Most patients taking lithium have a demonstrable impairment of tubular concentrating ability, although this is rarely of clinical significance. Glomerular function is less affected by lithium, but glomerular damage and interstitial fibrosis have been reported following lithium toxicity. There are also reports that long-term lithium treatment, even at therapeutic plasma levels, can occasionally cause long-term renal impairment and renal failure. However, this risk is manageable provided the plasma concentration of lithium is kept within the therapeutic range and episodes of toxicity avoided. An increasing level of creatinine/decreasing level of eGFR (a fall of more than 5 ml/min per year, or to a value <45 ml/min) should prompt referral to a renal physician.

Table 4  Some adverse effects of lithium

 

Central nervous system	Drowsiness, lethargy, headache, memory impairment, fine tremor
Cardiovascular system	Conduction defects (rare)
Gastrointestinal system	Nausea, vomiting, diarrhoea
Genitourinary system	Polydipsia, polyuria, nephrogenic diabetes insipidus
Endocrine system	Hypothyroidism (T4 ↓ TSH ↑), hyperglycaemia, hyperparathyroidism
Other	Leucocytosis, skin rash, weight gain
Signs of toxicity (plasma level: >1.2 mmol/litre)	Nausea, vomiting, coarse tremor, drowsiness, dysarthria, seizures, coma, renal failure, cardiovascular collapse

T4, thyroxine; TSH, thyroid stimulating hormone.

Up to 80% of the lithium filtered by the renal glomerulus is reabsorbed by the proximal tubule. Conditions such as diarrhoea and excessive sweating, which induce renal sodium retention, also result in increased lithium reabsorption by the kidney and elevated plasma lithium levels.

Drug interactions

As noted above, the narrow therapeutic index of lithium means that drug interactions that raise plasma lithium levels can have serious clinical consequences (see below). Important interactions can occur with:

• ◆ Diuretics—through their effect on sodium excretion, thiazides increase lithium reabsorption and can produce lithium toxicity unless the dose of lithium is reduced and plasma concentration carefully monitored. Loop and potassium-sparing diuretics are less likely to alter lithium clearance, but it is prudent to monitor lithium levels carefully when using these drugs.
• ◆ NSAIDs—plasma lithium levels may be increased by concomitant administration of NSAIDs
• ◆ Antihypertensives—lithium levels can be increased by ACE inhibitors and angiotensin II receptor antagonists.
• ◆ Other—lithium levels may be increased by metronidazole and lowered by theophylline and antacids. While the effects of lithium on cardiac conduction are usually considered benign, the effects of cardiac glycosides on conduction may be potentiated. Lithium can cause neurotoxicity (at normal plasma levels) with calcium channel blockers and carbamazepine, and may also increase the liability of antipsychotic drugs to cause extrapyramidal movement disorders.

Toxicity

Acute lithium toxicity usually appears at a plasma level above 1.2 mmol/litre. Early signs are coarse tremor, drowsiness, and dysarthria. Higher plasma concentrations (>2.0 mmol/litre) can lead to seizures, coma, and death. Since lithium toxicity is potentially fatal, any suspicion of intoxication should lead to the immediate withdrawal of lithium treatment and close monitoring of serum lithium and plasma electrolyte and creatinine concentrations. Severely ill patients with high serum lithium levels may require dialysis.

Carbamazepine

Carbamazepine blocks neuronal sodium channels, as do certain other anticonvulsant drugs. The relationship of this effect to its therapeutic actions in affective disorder is uncertain.

Indications and use

Carbamazepine is effective in the acute treatment of mania and in the prophylaxis of bipolar affective disorder. It is used in patients who have difficulty tolerating or fail to respond to lithium therapy, when it may be given in combination with lithium.

The dose range of carbamazepine employed to treat patients with affective illness is similar to that used in the treatment of seizure disorders. Initial treatment should be with 100 mg of carbamazepine twice daily, with the dose increased according to tolerance over the next 2 to 4 weeks. The effective dose range in the treatment of bipolar disorder is generally between 600 and 1200 mg daily, although some patients require higher doses. Plasma level monitoring may be used to help avoid toxicity.

Side effects

Dizziness, drowsiness, and nausea are common early in treatment, particularly with rapid dose titration, but tolerance to these effects usually develops. Persistent ataxia and diplopia may indicate plasma carbamazepine levels in the toxic range. A moderate degree of leucopenia is often seen during carbamazepine treatment and agranulocytosis can occasionally develop, such that it is prudent to monitor the white cell count as well as the carbamazepine level during treatment. Skin rashes are also quite common. Other rarer adverse effects include hyponatraemia and liver cell damage. Circulating thyroid hormone level may be lowered by carbamazepine treatment, but thyroid-stimulating hormone (TSH) levels generally remain in the normal range and clinical hypothyroidism is unusual. Carbamazepine can impair cardiac conduction and should be used with caution in patients with cardiovascular disease.

Drug interactions

Carbamazepine increases the metabolism of a number of other drugs, including TCAs, haloperidol, oral contraceptive agents, warfarin, and other anticonvulsants. A similar mechanism may underlie the decline in the plasma carbamazepine level sometimes seen during continued treatment. The carbamazepine level may be increased by erythromycin and by some calcium channel blockers, such as diltiazem and verapamil. Neurotoxicity has been reported when carbamazepine is combined with lithium.

Sodium valproate

Valproate is a simple branched-chain fatty acid with a mode of action that is unclear, although there is some evidence that it can slow the breakdown of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). This action could account for its anticonvulsant properties, but whether it also underlies the psychotropic effects is unclear.

Indications and use

Like carbamazepine, sodium valproate was first introduced as an anticonvulsant. Recent studies have shown that it is effective in the management of acute mania. In the United States of America valproate is widely used in the longer term prophylaxis of bipolar disorder, but the evidence for this indication from randomized trials is not particularly strong.

Valproate can be started at a dose of 200 to 400 mg daily, which may be increased once or twice weekly to between 1 and 2 g daily. Plasma levels of valproate do not correlate well with either its anticonvulsant or mood stabilizing effects, but it has been suggested that efficacy in the treatment of mood disorders is usually apparent when plasma levels are above 50 µg/ml.

Side effects

Common side effects of valproate include gastrointestinal disturbances, tremor, sedation, weight gain, and transient hair loss. Serious side effects are rare, but fatal hepatic toxicity has been reported, as has acute pancreatitis. Valproate may also cause thrombocytopenia and inhibit platelet aggregation, and increases in plasma ammonia have been reported.

Drug interactions

Valproate potentiates the effects of central sedatives. It has been reported to increase the side effects of other anticonvulsants (without necessarily improving anticonvulsant control). It may increase plasma levels of phenytoin and TCAs.

Other drugs

Although not licensed for this indication in the United Kingdom, the anticonvulsant drug lamotrigine is increasingly used to treat depression in patients with bipolar disorder. Atypical antipsychotic drugs such as olanzapine and quetiapine (see below) are also employed in the treatment of bipolar illness.

Antipsychotic drugs

Antipsychotic drugs, also known as major tranquillizers or neuroleptics, are a group of agents of varied structure that are used to treat schizophrenia and other psychoses. Conventional or typical antipsychotic agents have in common the ability to block dopamine receptors in the central nervous system, and it is likely that their antipsychotic effect is caused by blockade of dopamine D₂ receptors in mesolimbic regions of the brain. Blockade of D₂ receptors in striatum explains the common occurrence of various kinds of extrapyramidal movement disorders.

Atypical antipsychotic drugs have been developed more recently. These have a varied pharmacology, but a lower likelihood than conventional agents of producing extrapyramidal side effects at therapeutic doses. Some are highly selective dopamine D₂ receptor antagonists with selectivity for mesolimbic dopamine receptors, e.g. amisulpride. Others (e.g. risperidone, olanzapine, and quetiapine) have high affinities for the 5-HT₂ receptor that exceed their affinities for the D₂ receptor. Finally, clozapine is also a potent 5-HT₂ receptor antagonist but a weak D₂ receptor antagonist, which accounts for its particularly low risk of inducing extrapyramidal movement disorders.

Principal drugs

These are:

• ◆ conventional (typical) antipsychotic drugs—chlorpromazine, haloperidol, flupentixol, fluphenazine, loxapine, pimozide, thioridazine, and trifluoperazine
• ◆ atypical antipsychotic drugs—amisulpride, aripiprazole, olanzapine, quetiapine, and risperidone

Indications and use

Antipsychotic drugs are used mainly in the management of schizophrenia. They are also used to treat mania and are sometimes given to depressed patients who have psychotic symptoms or who are particularly agitated. Some atypical antipsychotic drugs (for example, olanzapine and quetiapine), are helpful in the maintenance treatment of bipolar disorder and quetiapine has useful effects in the treatment of bipolar depression. Antipsychotic drugs are also used in the management of disturbed behaviour arising from other medical causes (e.g. confusional states), but their use as nonspecific tranquillizing agents should be limited to short-term use because of potentially serious side effects. In this respect it is worth noting that some groups of demented patients (particularly those with Lewy body type dementia) may suffer severe extrapyramidal effects from comparatively low doses of antipsychotic drugs, and patients with dementia also appear to be at increased risk of adverse cardiovascular events, particularly stroke, during antipsychotic drug treatment.

The treatment of patients with schizophrenia or mania with antipsychotic drugs requires careful monitoring and persistence because the full therapeutic response may be delayed for some weeks. Furthermore, the dose of antipsychotic drug required may vary considerably from patient to patient, and also within the same patient at different stages of the illness. Lower doses of conventional antipsychotic drugs are now employed for the treatment of these disorders, since positron emission tomography (PET) imaging studies have revealed that an adequate blockade of dopamine D₂ receptors can be obtained with oral doses of 5 to 10 mg of haloperidol daily or 200 to 400 mg of chlorpromazine. Higher doses of these agents can produce sedation and behavioural calming, but at the expense of movement disorders and decreased compliance subsequently.

If a patient has responded to an antipsychotic drug, it is usual to continue the medication for a number of months into remission. It is frequently necessary to administer medication on a long-term basis to prevent relapse, in which case the use of long-acting intramuscular preparations will improve compliance. The decanoates of fluphenazine, flupentixol, and haloperidol are most commonly used, and a depot preparation of the atypical agent risperidone is also available.

Atypical antipsychotic drugs are generally used for new cases of schizophrenia and are also indicated when patients experience extrapyramidal movement disorders on modest doses of typical agents. Clozapine can be effective in up to 30% of patients with schizophrenia whose symptoms have not responded to other antipsychotic drugs (both typical and atypical). It is effective in the treatment of both positive and negative symptoms of schizophrenia; the latter often showing a poor response to other antipsychotic drugs.

Adverse effects

Movement disorders

Through their blockade of brain dopamine receptors, typical antipsychotic drugs produce a variety of extrapyramidal movement disorders that can mimic signs of basal ganglia disease (Table 5). Many patients exhibit symptoms of parkinsonism very similar to those of the idiopathic disorder, although tremor is less prominent. A side effect that appears early in treatment is acute dystonia, which can present with abnormal postures or dramatic muscular spasms involving the face and limbs. Laryngeal spasm with respiratory distress can also occur. A history of recent antipsychotic drug use can help avoid misdiagnoses (e.g. it is not unusual for such reactions to be viewed as ‘hysterical’). Another movement disorder that patients find very distressing is akathisia, which is a state of motor restlessness, often with agitation and dysphoria. Distinguishing this reaction from symptoms arising from the underlying psychiatric disorder may not be easy.

Table 5  Extrapyramidal disorders and antipsychotic drugs

 

Disorder	Description	Treatments employed
Dystonic reaction	Involuntary muscle contraction, especially face and jaw, oculogyric crisis	1. Benzatropine (1–2 mg IM or IV) 2. Diazepam (10 mg IV)
Akathisia	Sense of subjective motor restlessness, continual pacing	1. Reduce dose of antipsychotic drug 2. Benzatropine (1–6 mg daily) 3. Propranolol (40–120 mg daily) 4. Diazepam (10–30 mg daily)
Parkinsonism	Rigidity, bradykinesia, tremor	1. Reduce dose of neuroleptic 2. Benzatropine (1–6 mg daily)
Tardive dyskinesia (late onset)	Choreoathetoid movements, especially tongue, lips, and jaw	1. Withdraw antipsychotic drug 2. Vitamin E 3. Atypical antipsychotic drug
Neuroleptic malignant syndrome (rare)	Fever, muscular rigidity, coma, death	1. Discontinue neuroleptic 2. Intensive care support 3. Bromocriptine 4. Dantrolene

IM, intramuscular; IV, intravenous.

All these movement disorders may be treated by a reduction in dosage of the antipsychotic drug or by the introduction of anticholinergic medication such as benztropine. However, anticholinergic drugs should not be prescribed routinely with antipsychotic medication because of the risk of misuse for their euphoriant effects.

Later in treatment, tardive dyskinesia may develop. This consists of involuntary repetitive movements, usually involving the tongue and lips, though other parts of the body may be involved. The condition may be associated with a supersensitivity of postsynaptic dopamine receptors in the basal ganglia. Unfortunately, this disorder cannot be treated easily, and anticholinergic medication may make it worse. If possible, the antipsychotic drug should be stopped, but this decision is often difficult because of the risk of relapse of the psychiatric disorder.

Atypical antipsychotic drugs are less likely to cause movement disorders. Risperidone, however, is a potent D₂ receptor antagonist as well as a 5-HT₂ receptor antagonist and can produce some movement disorders at the upper end of its dose range (above 4–6 mg daily). Atypical antipsychotic drugs, particularly clozapine, are generally less likely to cause tardive dyskinesia.

A rare, but potentially very serious, reaction to antipsychotic drugs is the neuroleptic malignant syndrome (Table 5). This is characterized by fever, rigidity, and altered consciousness, together with tachycardia and labile blood pressure. Laboratory investigations usually reveal a leucocytosis together with a markedly raised serum level of creatinine phosphokinase. Antipsychotic drug treatment should be withdrawn immediately if the neuroleptic malignant syndrome is suspected. Management in an intensive care facility may be needed to deal with cardiovascular, respiratory, and renal complications. Treatment with a dopamine receptor agonist such as bromocriptine and the antispasticity agent dantrolene may be beneficial.

Many antipsychotic drugs can cause weight gain, but the risk is greater with certain atypical agents, particularly clozapine, olanzapine, and quetiapine. These drugs are also associated with a greater risk of type 2 diabetes than conventional agents, as well as disturbances in lipid profile. Patients taking atypical antipsychotics should therefore be monitored regularly for weight gain and disturbances in glucose and lipid metabolism.

Antipsychotic drugs such as chlorpromazine can produce a variety of side effects due to blockade of muscarinic receptors and α-adrenoceptors (Table 2). Other side effects include:

• ◆ endocrine—elevated prolactin levels, amenorrhoea, and galactorrhoea (not seen with atypical agents except amisulpride and risperidone)
• ◆ skin—rashes, pigmentation, and photosensitivity (especially phenothiazines)
• ◆ other—precipitation of seizures, hypothermia (especially chlorpromazine), cardiac arrhythmias (pimozide, thioridazine), weight gain, cholestatic hepatitis, leucopenia, and retinitis pigmentosa (thioridazine in doses >800 mg daily)

The most common side effects of atypical antipsychotic drugs are shown in Table 6.

Drug interactions

Antipsychotic drugs potentiate the effects of other central sedatives. They may delay the hepatic metabolism of TCAs and antiepileptic drugs, leading to increased plasma levels of these agents. The hypotensive properties of chlorpromazine and thioridazine may enhance the effects of antihypertensive drugs. Antipsychotic drugs, particularly pimozide and thioridazine, can increase the QT interval and should not be given with other drugs likely to potentiate this effect, such as antiarrhythmics, astemizole, terfenadine, and TCAs. There are also reports of an increased risk of cardiac arrhythmias when pimozide has been combined with clarithromycin and erythromycin. Clozapine should not be given with any agent likely to potentiate its depressant effect on the white cell count such as carbamazepine, co-trimoxazole, and penicillamine. SSRIs slow the hepatic metabolism and increase blood levels of several antipsychotic drugs, including haloperidol, risperidone, and clozapine.

Table 6  Atypical antipsychotics

 

Drug	EPS	Prolactin	Weight gain	Adverse effects
Amisulpiride	+	↑	+	Insomnia, agitation, nausea, constipation, QT prolongation (rare)
Clozapine	0	0	+++	Agranulocytosis—white cell monitoring mandatory, myocarditis and myopathy (rare), fatigue, drowsiness, hypersalivation, sweating, tachycardia, postural hypotension, nausea, constipation, ileus, urinary retention, diabetes
Olanzapine	+/0	0	+++	Somnolence, dizziness, oedema, hypotension, dry mouth, constipation, diabetes
Quetiapine	0	0	++	Somnolence, dizziness, postural hypotension, dry mouth, abnormal liver function tests, QT prolongation (transient), diabetes
Risperidone	+	↑	+	Insomnia, agitation, anxiety, headache, impaired concentration, nausea, abdominal pain

0, not present; +, sometimes; ++, often; +++, can be excessive; EPS, extrapyramidal symptoms.

Antianxiety agents

Benzodiazepines

Benzodiazepines enhance the action of the neurotransmitter γ-aminobutyric acid (GABA) in the central nervous system by binding to a specific benzodiazepine receptor located in a complex with a GABA receptor and a chloride ion channel. The pharmacological effects of benzodiazepines are attributed to the facilitation of GABA neurotransmission.

Principal drugs

These are alprazolam, chlordiazepoxide, diazepam, flurazepam, lorazepam, lormetazepam, nitrazepam, and temazepam.

Indications and use

The prescription of benzodiazepines is decreasing following concern about their liability to produce dependence. Alternative therapies are available for most anxiety related disorders, and it is recommended that the drug treatment of anxiety and insomnia should be limited to a few weeks’ duration. The main indication for the use of benzodiazepines is to help patients in a crisis, when generalized anxiety and insomnia are causing functional impairment and reducing their ability to cope. Patients should be advised that the drug treatment will be of short duration to help them manage their immediate difficulties.

All benzodiazepines have hypnotic and anxiolytic properties, the main difference between them of clinical importance being their length of action. Derivatives with short half-lives, such as temazepam, are suitable hypnotics because of their relative lack of a hangover effect. Other benzodiazepines, e.g. diazepam, have long half-lives and are metabolized to active compounds. These may be used for the treatment of anxiety, either in the form of regular dosing, or on the now preferred ‘as required’ basis with an agreed maximum daily dose.

Side effects and interactions

Benzodiazepines have a low acute toxicity. Their adverse effects are extensions of their clinical effects and include the following: drowsiness, psychomotor impairment, dizziness, ataxia, and paradoxical aggression (rare). Benzodiazepines potentiate the effects of other centrally acting sedatives, particularly alcohol. The effects of benzodiazepines are potentiated by cimetidine.

Patients who have taken clinical doses of a benzodiazepine for more than a few weeks may show a withdrawal syndrome when the medication is stopped. In many respects this syndrome resembles an anxiety state, but perceptual disturbances and acute dysphoria may also occur. It is thus apparent that benzodiazepines can cause physical dependence, and although the withdrawal syndrome is less severe than that seen following the cessation of barbiturates, patients frequently find it difficult to stop their medication. A gradual reduction is usually best. Generally, withdrawal from a long-acting benzodiazepine is easier than from a short-acting preparation, and if patients taking short-acting benzodiazepines have difficulty withdrawing, then a switch to a long-acting preparation may be helpful.

Other drugs that increase brain GABA function

A number of nonbenzodiazepine agents with short half-lives (the Z drugs) also increase GABA function and are licensed as hypnotics. Whether the Z drugs have advantages over short-acting benzodiazepines such as temazepam is disputed. The treatment of insomnia with either benzodiazepines or the Z drugs should be short-term to avoid dependence.

Zopiclone is a cyclopyrrolone derivative marketed for the treatment of insomnia. It binds to a site close to the benzodiazepine receptor and thereby facilitates brain GABA function. By contrast to the benzodiazepines, which reduce the amount of slow-wave (deep) sleep at night, zopiclone has little effect on sleep architecture and is relatively free from a daytime ‘hangover’ effect. It is claimed to be less likely than benzodiazepine hypnotics to produce tolerance and withdrawal effects, but cases have been reported. The most common adverse effects of zopiclone include bitter taste, nausea, dry mouth, irritability, and headache.

Zolpidem is an imidazopyridine derivative that also binds to a site close to the benzodiazepine receptor. It has a very short duration of action and, like zopiclone, has little effect on sleep architecture or daytime performance. Its possible adverse effects include nausea, dizziness, headaches, and diarrhoea. Zaleplon is a pyrazolopyrimidine derivative with pharmacological properties similar to zopiclone and zolpidem, but its half-life is only about an hour such that it can be used to reinduce sleep after nocturnal waking.

Clomethiazole also binds at the GABA receptor complex, but its clinical effects resemble those of barbiturates rather more than those of the benzodiazepines. It can cause serious respiratory depression in overdose, particularly in combination with alcohol. Because of its short half-life (4–5 h), clomethiazole is used as a hypnotic in older people, but again only short-term use is recommended.

Drugs altering monoamine function

Buspirone is a 5-HT_1A receptor agonist structurally unrelated to benzodiazepines. It is effective in the treatment of generalized anxiety disorder (less so in patients previously exposed to benzodiazepines), but has a slow onset of action (1–3 weeks). Unlike benzodiazepines, buspirone does not cause significant sedation or cognitive impairment and appears unlikely to cause dependence. It does not have hypnotic properties. Side effects include nervousness, dizziness, and headache.

Other drugs

SSRIs and TCAs are effective in the management of patients with a range of anxiety disorders, including generalized anxiety and phobic states. They are generally preferred to benzodiazepines for the treatment of agoraphobia with and without panic attacks. SSRIs are also effective in the treatment of obsessive–compulsive disorder and social phobia, but TCAs (with the exception of clomipramine) are not.

Further reading

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