Chlorpromazine. Background. Adverse Effects

Drug Approvals

(British Approved Name, rINN)

Drug Approvals

(British Approved Name Modified, rINNM)

Drug Approvals

(British Approved Name Modified, rINNM)

Pharmacopoeias. In China, Europe, International, Japan US.

European Pharmacopoeia, 6th ed. (Chlorpromazine Hydrochloride). A white or almost white crystalline powder. It decomposes on exposure to air and light. Very soluble in water freely soluble in alcohol. A freshly prepared 10% solution in water has a pH of 3.5 to 4.5. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Chlorpromazine Hydrochloride). A white or slightly creamy-white odourless crystalline powder. It darkens on prolonged exposure to light. Soluble 1 in 1 of water, 1 in 1.5 of alcohol, and 1 in 1.5 of chloroform insoluble in ether and in benzene. Store in airtight containers. Protect from light.

Dilution. Solutions containing 2.5% of chlorpromazine hydrochloride may be diluted to 100 rriL with 0.9%) sodium chloride solution provided the pH of the saline solution is such that the pH of the dilution does not exceed the critical range of pH 6.7 to 6.8.^l With saline of pH 7.0 or 7.2, the final solution had a pH of 6.4.

Incompatibility. Incompatibility has been reported between chlorpromazine hydrochloride injection and several other compounds precipitation of chlorpromazine base from solution is particularly likely if the final pH is increased. Compounds reported to be incompatible with chlorpromazine hydrochloride include aminophylline, amphotericin B, aztreonam, some barbiturates, chloramphenicol sodium succinate, chlorothiazide sodium, dimenhydrinate, heparin sodium, morphine sulfate (when preserved with chlorocresol), some penicillins, and remifentanil.

For a warning about incompatibility between chlorpromazine solution (Thorazine GSK, USA) and carbamazepine suspension (Tegretol-Novartts, USA).

Sorption. There was a 41%> loss of chlorpromazine hydrochloride from solution when infused for 7 hours via a plastic infusion set (cellulose propionate burette with PVC tubing), and a 79%> loss after infusion for 1 hour from a glass syringe through silastic tubing. Loss was negligible after infusion for 1 hour from a system comprising a glass syringe with polyethylene tubing.

Adverse Effects

Chlorpromazine generally produces less central depression than the barbiturates or benzodiazepines, and tolerance to its initial sedative effects develops fairly quickly in most patients. It has antimuscarinic properties and may cause adverse effects such as dry mouth, constipation, difficulty with micturition, blurred vision, and mydriasis. Tachycardia, ECG changes (particularly Q- and T-wave abnormalities), and, rarely, cardiac arrhythmias may occur hypotension (usually orthostatic) is common.

Other adverse effects include delirium, agitation and, rarely, catatonic-like states, insomnia or drowsiness, nightmares, depression, miosis, EEG changes and convulsions, nasal congestion, minor abnormalities in liver function tests, inhibition of ejaculation, impotence, and priapism. Hypersensitivity reactions include urticaria, exfoliative dermatitis, erythema multiforme, and contact sensitivity. A syndrome resembling SLE has been reported. Jaundice has occurred, and probably has an immuno-logical origin. Prolonged therapy may lead to deposition of pigment in the skin, or more frequently the eyes corneal and lens opacities have occurred.

Pigmentary retinopathy has occurred only rarely with chlorpromazine. Photosensitivity reactions are more common with chlorpromazine than with other antipsychotics. Haematological disorders, including haemolytic anaemia, aplastic anaemia, thrombocytopenic purpura, eosinophilia, and a potentially fatal agranulocytosis have occasionally been reported they may be manifestations of a hypersensitivity reaction. Most cases of agranulocytosis have occurred within 4 to 10 weeks of starting treatment, and symptoms such as sore throat or fever should be watched for and white cell counts instituted should they appear. Mild leucopenia has been stated to occur in up to 30% of patients on prolonged high dosage.

Extrapyramidal dysfunction and resultant disorders include acute dystonia, a parkinsonism-like syndrome, and akathisia late effects include tardive dyskinesia and perioral tremor. The neuroleptic malignant syndrome may also occur.

Chlorpromazine alters endocrine and metabolic functions. Patients have experienced amenorrhoea, galactorrhoea, and gynaecomastia due to hyperprolactinaemia, weight gain, and hyperglycaemia and altered glucose tolerance. Body temperature regulation is impaired and may result in hypo- or hyperthermia depending on environment. There have also been reports ofhypercholesterolaemia.

There have been isolated reports of sudden death with chlorpromazine possible causes include cardiac arrhythmias or aspiration and asphyxia due to suppression of the cough and gag reflexes. Pain and irritation at the injection site may occur on injection. Nodule formation may occur after intramuscular injection.

Phenothiazines do not cause dependence of the type encountered with barbiturates or benzodiazepines. However, withdrawal symptoms have been seen on abrupt withdrawal in patients receiving prolonged and/or high-dose maintenance therapy. Although the adverse effects of other phenothiazines are broadly similar in nature to those of chlorpromazine, their frequency and pattern tend to fall into 3 groups:

• group 1 (e.g. chlorpromazine, levomepromazine, and promazine) are generally characterised by pronounced sedative effects and moderate antimuscarinic and extrapyramidal effects
• group 2 (e.g. pericyazine, pipotiazine, and thioridazine) are generally characterised by moderate sedative effects, marked antimuscarinic effects, and fewer extrapyramidal effects than groups 1 or 3
• group 3 (e.g. fluphenazine, perphenazine, prochlorperazine, and trifluoperazine) are generally characterised by fewer sedative and antimuscarinic effects but more pronounced extrapyramidal effects than groups 1 or 2

Classical antipsychotics of other chemical groups tend to resemble the phenothiazines of group 3. They include the butyrophenones (e.g. benperidol and haloperidol) diphenylbutylpiperidines (e.g. pimozide) thioxanthenes (flupentixol and zuclopenthixol) substituted benzamides (e.g. sulpiride) oxypertine and loxapine.

Carcinogenicity.

See Effects on Endocrine Function, below.

Convulsions.

Treatment with antipsychotics can result in EEG abnormalities and lowered seizure threshold.^l Seizures can be induced particularly in patients with a history of epilepsy or drug-induced seizures, abnormal EEG, previous electroconvulsive therapy, or pre-existing CNS abnormalities. The risk appears to be greatest at the start of antipsychotic therapy, or with high doses, or abrupt increases of dose, or with the use of more than one antipsychotic. The incidence of antipsychotic-induced convulsions is, however, probably less than 1 %.

In general, the epileptic potential has been correlated with the propensity of the antipsychotic to cause sedation. Phenothiazines with marked sedative effects [group 1 ] such as chlorpromazine appear to present a higher risk than those with strong extrapyramidal effects [group 3]. Haloperidol appears to carry a relatively low risk of seizures. The following drugs have been suggested when classical antipsychotic therapy is considered necessary in patients at risk of seizures or being treated for epilepsy: fluphenazine, haloperidol, pimozide, or trifluoperazine. Antipsychotic dosage should be increased slowly and the possibility of interactions with antiepileptic therapy considered (see under Interactions, below).

The atypical antipsychotic clozapine appears to be associated with a particularly high risk of seizures (see Effects on the Nervous System, under Clozapine). Risperidone may be preferred if an atypical antipsychotic is to be used in patients at risk of seizures.

Effects on the blood.

The UK CSM provided data on the reports it had received between July 1963 and January 1993 on agranulocytosis and neutropenia. Several groups of drugs were commonly implicated, among them phenothiazines for which there were 87reports of agranulocytosis (42 fatal) and 33 of neutropenia (22 fatal). The most frequently implicated phenothiazines were chlorpromazine with 51 reports of agranulocytosis (26 fatal) and 12 of neutropenia (2 fatal) and thioridazine with 20 reports of agranulocytosis (9 fatal) and 10 of neutropenia (none fatal).

Effects on body-weight.

Most antipsychotic drugs are associated with weight gain. A meta-analysis found evidence of weight gain in patients receiving both classical (chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine, thioridazine, tiotixene, or trifluoperazine) and atypical (clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone) antipsychotics. Two drugs, molindone and pimozide, appeared in contrast to be associated with weight loss, although in the case of pimozide this could not be confirmed statistically. Placebo treatment was also associated with weight loss. For further details, see Effects on Body-weight, in Clozapine.

Effects on the cardiovascular system.

Orthostatic hypotension is a common problem in patients taking psychotropic drugs and is particularly pronounced with low-potency antipsychotics.

Various EEG changes or frank arrhythmias have occurred in patients receiving antipsychotics. T-wave changes have been reported with low-potency antipsychotics they are usually benign and reversible, and subject to diurnal fluctuations. Low-potency antipsychotics, particularly thioridazine and mesoridazine, and the high-potency drug pimozide, prolong the QT interval in a similar manner to class I antiarrhythmics such as quinidine or procainamide their use is therefore contra-indicated in patients taking such antiarrhythmics.

Droperidol, another high-potency drug, has also been reported to prolong the QT interval. Thioridazine is most frequently discussed in case reports of psychotropic drug-induced torsade de pointes, which has led to restrictions on its use (see Precautions, and Uses and Administration of Thioridazine) chlorpromazine and pimozide have also been implicated. Torsade de pointes has also been reported after overdosage with, or high intravenous doses of, the high-potency antipsychotic haloperidol.

There are also isolated reports of cardiac arrhythmias after attempts at rapid control with high doses of haloperidol. Melperone, a butyrophenone antipsychotic related to haloperidol, has been reported to have class III electrophysiologic and antiarrhythmic activity. In the UK, the risk of arrhythmias with antipsychotic treatment has been considered by an expert working group of the CSM the following recommendations were made regarding ECG monitoring:

• the need for an ECG should be based on a patient’s relevant medical history, family history, and clinical examination the elderly and those with a personal or family history of heart disease or any cardiac abnormalities would benefit the most from a baseline ECG
• during treatment an ECG should be performed in patients who experience palpitations or other symptoms suggestive of cardiac disease if the QT interval is prolonged then a reduction in dose may be required, if it exceeds 500 milliseconds treatment may need to be stopped
• an ECG should be considered during dose increases
• potassium levels should be monitored before and during treatment and in particular during periods of acute illnesses

Sudden unexpected deaths have long been reported in patients receiving antipsychotics. Whether this is due to the disease being treated or to the treatment is still unclear. However, in a retrospective cohort study involving about 482 000 patients, analysis of 1487 sudden cardiac deaths indicated that patients receiving antipsychotics in doses of more than 100 mg of thioridazine or its equivalent had a 2.4-fold increase in the rate of sudden cardiac death, rising to a 3.53-fold increase in those patients with pre-existing severe cardiovascular disease. A later case-control study in 5 UK psychiatric hospitals found that sudden unexplained death in psychiatric patients was associated with hypertension, ischaemic heart disease, and current treatment with thioridazine. Although several mechanisms have been suggested for the effect, prolongation of the QT interval has been implicated in a proportion of the cases.

Results from a case-control study have suggested that use of classical antipsychotics may be associated with an increased risk of idiopathic venous thromboembolism. The risk was most pronounced during the first 3 months of treatment, and was higher for low potency than high potency antipsychotics. This study did not examine the risk of venous thromboembolism with atypical antipsychotics, but see under Clozapine.

Effects on endocrine function.

Antipsychotics can alter the secretion of prolactin, growth hormone, and thyrotrophin from the anterior pituitary via their ability to block central dopamine-D₂ receptors. Therapeutic doses of classical antipsychotics (and some atypical antipsychotics such as amisulpride and risperidone) increase serum-prolactin concentrations this effect occurs at lower doses and after shorter latent periods than the antipsychotic effects. However, partial tolerance to the hyperprolactinaemic effect may develop on long-term use. Serum prolactin declines to normal values within 3 weeks of stopping oral antipsychotic therapy but may remain raised for 6 months after an intramuscular depot injection.

The long-term consequences of gonadal hormone deficiency, secondary to raised prolactin concentrations, have caused concern. There is evidence that patients taking long-term prolactin-raising antipsychotics are at high risk of osteoporosis associated with hypogonadism. Long-term antipsychotic treatment has also been shown to increase the incidence of mammary tumours in the rat. Although early studies’ found little or no evidence that chronic use in humans alters the risk of breast cancer among women with schizophrenia, a later retrospective cohort study found a modest dose-related increase in the risk of breast cancer in women using antipsychotic dopamine antagonists. A similar increase was seen in women receiving antiemetic dopamine antagonists. Fears that pituitary abnormalities, including pituitary tumours, might develop in patients on long-term phenothiazine therapy have not been confirmed.

Antipsychotics can in some circumstances reduce both basal and stimulated growth-hormone secretion but attempts to use them to treat dysfunctions in growth-hormone regulation have not been successful. Although a number of clinical studies show that acute dosage of antipsychotics increased both basal and stimulated thyrotrophin secretion, the majority of studies find either no change or only a small increase in thyrotrophin secretion following long-term use.

A small study has suggested that thioridazine may be more likely than other antipsychotics to decrease serum concentrations of testosterone or luteinising hormone in men. However, concentrations were within the normal range in most patients taking antipsychotics.

See also Effects on Fluid and Electrolyte Homoeostasis, below and Effects on Sexual Function, below.

Effects on the eyes.

Phenothiazines may induce a pigmentary retinopathy which is dependent on both the dose and the duration of treatment. Those phenothiazine derivatives with piperidine side-chains such as thioridazine have a higher risk of inducing retinal toxicity than other phenothiazine derivatives, with relatively few cases reported for those with aliphatic side-chains such as chlorpromazine the piperazine group does not appear to exert direct ocular toxicity. The retinopathy may present either acutely, (sudden loss of vision associated with retinal oedema and hyperaemia of the optic disc), or chronically, (a fine pigment scatter appearing in the central area of the fundus, extending peripherally but sparing the macula).

Chronic paracentral and peri-central scotomas may be found. Although pigmentary disturbances may progress after withdrawal of thioridazine, they are not always paralleled by deterioration in visual function nonetheless, some cases have led to progressive chorioretinopathy. The critical ocular toxic dose of thioridazine is reported to be 800 mg daily and UK licensed product information has recommended that a daily dose of 600 mg should not usually be exceeded. However, there is a report of pigmentary retinopathy in a patient who received long-term thioridazine in daily doses not exceeding 400 mg the total dose was 752 g.

Pigmentation may also occur in the cornea, lens, and conjunctiva following use of phenothiazines. It may occur in association with pigmentary changes in the skin and is dose-related. In a study of 100 Malaysian patients, ocular pigmentation was observed in slightly more than half of those who had received a total dose of chlorpromazine of 100 to 299 g and in 13 of 15 who had received 300 to 599 g. All those who had received more than 600 g of chlorpromazine or thioridazine had ocular pigmentation. Cataract formation, mainly of an anterior polar variety, has been observed rarely, mainly in patients on chlorpromazine. It does not appear to be dose-related.

A patient who had received fortnightly injections of fluphenazine 12.5 mg for 10 years (total dose 3.25 g) developed bilateral maculopathy following unprotected exposure of less than 2-minute’s duration to a welding arc. It was postulated that accumulation of phenothiazine in the retinal epithelium sensitised the patient to photic damage. However, another patient who had received fortnightly injections of fluphenazine 25 mg for 25 years (total dose 16.25 g) developed bilateral maculopathy without exposure to any extreme photochemical sources. The authors concluded that this was due to a direct effect of fluphenazine secondary to its accumulation in the retinal epithelium.

Effects on fluid and electrolyte homoeostasis.

There have been occasional reports of water intoxication in patients taking antipsychotics. A review of hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion associated with psychotropics summarised 20 such reports for antipsychotics in the literature. The drugs implicated were thioridazine (8 reports), haloperidol (3 reports), chlorpromazine, trifluoperazine, and fluphenazine (2 reports each), and flupentixol, tiotixene, and clozapine (1 report each). The majority of reports did not permit clear conclusions and, particularly in the cases of prolonged treatment, the role of the medication was unclear. However, at least 3 of the cases were well documented and supported the view that antipsychotics could cause hyponatraemia.

A report not considered by the above review described water retention and peripheral oedema associated with chlorpromazine. A small controlled study found that 5 of 10 evaluated patients receiving haloperidol decanoate had impaired fluid homoeostasis.

Effects on lipid metabolism.

Most antipsychotics are associated with hyperlipidaemia. A review found evidence of a higher risk of hyperlipidaemia in patients receiving low-potency classical antipsychotics, such as chlorpromazine and thioridazine, or the atypical antipsychotics, clozapine, olanzapine, and quetiap-ine. High-potency classical antipsychotics, such as haloperidol, and the atypical antipsychotics aripiprazole, risperidone, and ziprasidone, appeared to be associated with a lower risk of hyper-lipidaemia. Possible mechanisms for dyslipidaemia associated with antipsychotic therapy include the development of glucose intolerance, weight gain, and dietary changes. For further details, see Effects on Body-weight under Adverse Effects of Clozapine and Effects on Body-weight, above.

Effects on the liver.

Chlorpromazine and other phenothiazines may cause hepatocanalicular cholestasis often with hepatocyte damage suggestive of immunological liver injury. Only a small number of patients taking the drug are affected and the onset is usually in the first 4 weeks of therapy. The drug or one of its metabolites may induce alteration in the liver-cell membrane so that it becomes antigenic there is also good evidence for direct hepatotoxicity related to the production of free drug radical. There may be an individual idiosyncrasy in the metabolism of chlorpromazine and in the production of these radicals. A study has suggested that patients who have poor sulfoxidation status combined with unimpaired hydroxylation capacity may be most likely to develop jaundice with chlorpromazine.

A preliminary study showing a high incidence of gallstones in psychiatric inpatients in Japan found a correlation between the presence of gallstones and the duration of illness and use of antipsychotics. It was speculated that gallstones could be a consequence of phenothiazine-induced cholestasis.

Effects on sexual function.

The phenothiazines can cause both impotence and ejaculatory dysfunction. Thioridazine has been frequently implicated, and in an early report 60% of 57 male patients taking the drug reported sexual dysfunction compared with 25% of 64 men taking other antipsychotics. There are also several reports of priapism with phenothiazines alpha-adrenoceptor blocking properties of these compounds may be partly responsible. Male sexual dysfunction, including priapism, has been reported only rarely with other classical antipsychotics such as the butyrophenones, diphenylbutylpiperidines, and thioxanthenes. Priapism has also been reported with clozapine and other atypical antipsychotics. The effects of antipsychotics on female sexual function are less well studied. Orgasmic dysfunction has been reported with thioridazine, trifluoperazine, and fluphenazine.

The effects of hyperprolactinaemia (see Effects on Endocrine Function, above) on sexual function are described.

Effects on the skin, depot injection.

Of 217 patients who received a combined total of 2354 depot antipsychotic injections 42 (19.4%) had local problems at the site of injection 18 (8.3%) experienced chronic complications and 30 (13.8%) acute reactions. Acute problems reported included 31 episodes of unusual pain, 21 of bleeding or haematoma, 19 of clinically important leakage of drug from injection site, 11 of acute inflammatory indurations, and 2 of transient nodules. Complications were more common in patients receiving concentrated preparations, higher doses, weekly injections, haloperidol decanoate or zuclopenthixol decanoate, and injection volumes greater than 1 mL and in those treated for more than 5 years. Chronic reactions were more common in patients aged over 50 years.

PHOTOSENSITIVITY.

Testing in 7 subjects taking chlorpromazine revealed that photosensitivity reactions manifested primarily as immediate erythema and that sensitivity was primarily to light in the long ultraviolet (UVA) and visible wavebands. Sensitivity to UVB was normal.

The incidence of photosensitivity reactions to chlorpromazine has been given as 3%. However, a higher incidence of 16-25% has also been reported. See also Effects on the Eyes, above.

PIGMENTATION.

The pigment found in the skin of patients treated with chlorpromazine was considered to be a chlor-promazine-melanin polymer formed in a light-catalysed anaerobic reaction. Hydrogen chloride liberated during the reaction could account for the skin irritation. Intracutaneous injection of a preparation of the polymer into 2 volunteers produced a bluish-purple discoloration which faded in 3 days.

Extrapyramidal disorders.

Antipsychotics and a number of other drugs, including antiemetics such as metoclopramide and some antidepressants, can produce a range of dyskinesias or involuntary movement disorders involving the extrapyramidal motor system, including parkinsonism, akathisia, acute dystonia, and chronic tardive dyskinesia. Such reactions are a major problem in the clinical management of patients receiving antipsychotics.

Reactions of this type can occur with any antipsychotic, but (excluding tardive dyskinesia) are particularly prominent during treatment with high-potency drugs such as the tricyclic piperazines and butyrophenones. Antipsychotics such as clozapine carry a low risk of extrapyramidal effects and are therefore described as atypical antipsychotics. The incidence of tardive dyskinesia does appear to be minimal with clozapine, although there is less evidence for other atypical antipsychotics.

Of 2811 patients studied in the first few months of therapy with prochlorperazine (a drug with a high propensity to cause extrapyramidal reactions), 57 reported adverse effects, 16 of which involved the extrapyramidal system. There were 4 dystonic-dyskinesic reactions (an incidence of 1 in 464 and 1 in 707 for patients aged under and over 30 years respectively), 9 reports of parkinsonism (under 60 years, 1 in 1555 over 60 years, 1 in 159), and 3 reports of akathisia (1 in 562).

One explanation of extrapyramidal disorders is an imbalance between dopaminergic and cholinergic systems in the brain. However, this simple model fails to explain the co-existence of a variety of extrapyramidal effects, and several alternative mechanisms have been proposed. Hypotheses based on interactions between different dopamine receptor types may help to explain the decreased tendency of some antipsychotic drugs to induce these reactions (see Action under Uses and Administration, below).

AKATHISIA.

Akathisia is a condition of mental and motor restlessness in which there is an urge to move about constantly and an inability to sit or stand still. It is the most common motor adverse effect of treatment with antipsychotics. Acute akathisia is dose-dependent, usually develops within a few days of beginning treatment or after a rapid increase in dose, and usually improves if the drug is stopped or the dose reduced. Antimuscarinic antiparkinsonian drugs appear to provide only limited benefit, although success may be more likely in patients with concomitant parkinsonism.

A low dose of a beta blocker such as propranolol (although good evidence is lacking) or a benzodiazepine may be helpful. Improvement has also been reported with clonidine and amantadine but the usefulness of these drugs may be limited by adverse effects or development of tolerance, respectively. The tardive form, like tardive dyskinesia (see below), which appears after several months of treatment, does not respond to antimuscarinics and is difficult to treat.

DYSTONIA.

Acute dystonic reactions, which mainly affect the muscles of the face, neck, and trunk and include jaw clenching (trismus), torticollis, and oculogyric crisis are reported to occur in up to 10% of patients taking antipsychotics. Laryngeal dystonia is rare, but potentially fatal. Dystonias usually occur within the first few days of treatment or after a dosage increase but may also develop on withdrawal. They are transitory, and are most common in children and young adults. Dystonic reactions may be controlled by antimuscarinics such as biperiden or procyclidine, or antihisiamines such as diphenhydramine or promethazine Benzodiazepines such as diazepam can also be used.

Prophylactic antimuscarinics can prevent the development of dystonias, but routine use is not recommended as not all patients require them and tardive dyskinesia may be unmasked or worsened (see below) such a strategy should probably be reserved for short-term use in those at high risk of developing dystonic reactions, such as young adults starting treatment with high-potency antipsychotics or in patients with a history of drug-induced dystonias. Some patients may develop tardive dystonia. A range of drugs has been tried in this condition but without consistent benefit.

PARKINSONISM.

Parkinsonism, often indistinguishable from idiopathic Parkinson’s disease, may develop during therapy with antipsychotics, usually after the first few weeks or months of treatment. It is generally stated to be more common in adults and the elderly, although a retrospective study with haloperidol found an inverse relationship between drug-induced parkinsonism and age. This parkinsonism is generally reversible on drug withdrawal or dose reduction, and may sometimes disappear gradually despite continued drug therapy. Antimuscarinic antiparkinsonian drugs are used to suppress the symptoms of parkinsonism. However, they are often minimally effective and commonly cause adverse effects. Routine use for prophylaxis is not recommended because of the risk of unmasking or exacerbating tardive dyskinesia (see below). Amantadine is an alternative to the antimuscarinics.

TARDIVE DYSKINESIA.

The central feature of tardive dyskinesia is orofacial dyskinesia characterised by protrusion of the tongue (‘fly catching’), lipsmacking, sucking, lateral chewing, and pouting of the lips and cheeks. The trunk and limbs also become involved with choreiform movements such as repetitive ‘piano-playing’ hand movements, shoulder shrugging, foot tapping, or rocking movements. The prevalence of tardive dyskinesia among those receiving antipsychotics varies widely but up to 60% of patients may develop symptoms. In most cases the condition is mild and not progressive and tends to wax and wane.

Although tardive dyskinesia usually develops after many years of antipsychotic therapy no clear correlation has been shown between development of the condition and the length of drug treatment or the type and class of drug. However, clozapine does not appear to be associated with the condition and in some cases use has resulted in improvement of established tardive dyskinesia (see Schizophrenia under Clozapine). Whether other atypical antipsychotics also have a lower incidence of tardive dyskinesia remains to be established, although there are some data to suggest that this may be the case. Symptoms of tardive dyskinesia often develop after stopping the antipsychotic or after dose reduction. Risk factors include old age, female sex, affective disorder, schizophrenia characterised by negative symptoms, and organic brain damage.

Suggested causes of tardive dyskinesia include dopaminergic overactivity, imbalance between dopaminergic and cholinergic activity, supersensitivity of postsynaptic dopamine receptors, pre-synaptic catecholaminergic hyperfunction, and alterations of the gamma-aminobutyric acid (GABA) system. Options in the management of tardive dyskinesia include attempts at treatment while maintaining antipsychotic therapy, or withdrawal of antimuscarinic therapy, and either withdrawal of the antipsychotic or reduction of the dosage to the minimum required or transfer to an atypical antipsychotic.

Although many drugs have been tried in the treatment of tardive dyskinesia there have been relatively few double-blind studies. Reviews of tardive dyskinesia have concluded that there appeared to be no reliable or safe treatment. Overall, classical antipsychotics appeared to be the most effective in masking symptoms of tardive dyskinesia but tolerance may develop and a worsening of the underlying pathophysiology by antipsychotics had to be assumed on theoretical grounds. Other drugs with anti-dopaminergic actions which were probably of comparable efficacy included reserpine, oxypertine, tetrabenazine, and metirosine.

The next most effective drugs were considered to be noradrenergic antagonists such as clonidine. Some encouraging results had also been obtained with GAB Aergic drugs such as the benzodiazepines, baclofen, progabide, valproate, and vigabatrin, although systematic reviews of studies of some GABAer-gic drugs including benzodiazepines found the evidence inconclusive and/or unconvincing. The efficacy of cholinergics could not be confirmed. Dopaminergics and antimuscarinics mostly exacerbated symptoms but others had commented that there was no convincing evidence that long-term use of antimuscarinics increased the risk of developing the condition. Other drugs whose value is unclear include vitamin E and some calcium-channel blockers.

Withdrawal of the causative drug usually worsens the condition although symptoms often diminish or disappear over a period of weeks or sometimes a year or so. Success is most likely in younger patients. During withdrawal, drugs such as diazepam or clonazepam may be given to alleviate symptoms. Although classical antipsychotics are effective, their routine use to suppress symptoms is not recommended but they may be required for acute distressing or life-threatening reactions or in chronic tardive dyskinesia unresponsive to other treatment.

In extremely severe resistant cases some have used an antipsychotic with valproate or carbamazepine or reserpine with metirosine. In view of the unsatisfactory management of tardive dyskinesia, emphasis is placed on its prevention. Antipsychotics should be prescribed only when clearly indicated, should be given in the minimum dose, and continued only when there is evidence of benefit. Although drug holidays have been suggested for reducing the risk of tardive dyskinesia, the limited evidence indicates that interruptions in drug treatment may increase the risk of both persistent dyskinesia and psychotic relapse. Increasing the dose of antipsychotic generally improves the condition, but only temporarily.

Neuroleptic malignant syndrome.

The neuroleptic malignant syndrome (NMS) is a potentially fatal reaction to a number of drugs including antipsychotics and other dopamine antagonists such as metoclopr amide. The clinical features of the classic syndrome are usually considered to include hyperthermia, severe extrapyramidal symptoms including muscular rigidity, autonom-ic dysfunction, and altered levels of consciousness. Skeletal muscle damage may occur and the resulting myoglobinuria may lead to renal failure. However, there appear to be no universal criteria for diagnosis. Some believe the classic syndrome to be the extreme of a range of effects associated with antipsychotics and have introduced the concept of milder variants or incomplete forms.

Others consider it to be a rare idiosyncratic reaction and suggest that the term neuroleptic malignant syndrome should be reserved for the full-blown reaction. Consequently, estimates of the incidence vary greatly and recent estimates have ranged from 0.02 to 2.5%. The mortality rate has been substantial although it has decreased over the years with improved diagnosis and management, this may also be due to the detection and inclusion of the milder or incomplete variants. Possible risk factors include dehydration, pre-existing organic brain disease, and a history of a previous episode young males have also been reported to be particularly susceptible.

The pathogenesis of NMS is still unclear. Blockade of dopaminergic receptors in the corpus striatum is thought to cause muscular contraction and rigidity generating heat while blockade of dopaminergic receptors in the hypothalamus leads to impaired heat dissipation. Peripheral mechanisms such as vasomotor paralysis may also play a role. Also a syndrome resembling NMS has been seen after withdrawal of treatment with dopamine agonists such as levodopa (see p.806). Symptoms develop rapidly over 24 to 72 hours and may occur days to months after starting antipsychotic medication or increase in dosage, but no consistent correlation with dosage or length of therapy has been found.

Symptoms may last for up to 14 days after stopping oral antipsychotics, or for up to 4 weeks after stopping depot preparations. All antipsychotics are capable of inducing NMS depot preparations may, however, be associated with prolonged recovery once it develops, and hence a higher mortality rate. Use with lithium carbonate or antimuscarinics may increase the likelihood of developing the syndrome.

Antipsychotic medication should be withdrawn immediately once the diagnosis of the classic syndrome is made this should be followed by symptomatic and supportive therapy including cooling measures, correction of dehydration, and treatment of cardiovascular, respiratory, and renal complications. Whether antipsychotics should be withdrawn from patients with mild attacks and how they should be managed is a matter of debate. The efficacy of specific drug therapy remains to be proven, and justification for use is based mainly on case reports.

• Dantrolene was first used because of its effectiveness in malignant hyperthermia. It has a direct action on skeletal muscle and may be particularly effective for the reversal of hyperthermia of muscle origin.
• In contrast, dopaminergic agonists may resolve hyperthermia of central origin, restoring dopaminergic transmission and hence alleviating extrapyramidal symptoms. There have been isolated reports of success with amantadine and levodopa but bromocriptine is generally preferred. Any underlying psychosis may, however, be aggravated by dopaminergic drugs.
• Since dantrolene and dopaminergics act in different ways a combination of the two might be useful, but any advantage remains to be demonstrated.
• Antimuscarinics are generally considered to be of little use and may aggravate the associated hyperthermia.
• Benzodiazepines may be used for sedation in agitated patients and may be of use against concomitant catatonia. EOT may be an alternative in refractory cases of NMS or when catatonic symptoms are present.

Re-introduction of antipsychotic therapy may be possible but is not always successful and extreme caution is advised. It has been recommended that a gap of at least 5 to 14 days should be left after resolution of the symptoms before attempting re-introduction.

Withdrawal.

Stopping treatment with an antipsychotic abruptly may produce withdrawal symptoms, the most common of which are nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgias, paraesthesias, insomnia, restlessness, anxiety, and agitation. Patients may also experience vertigo, alternate feelings of warmth and coldness, and tremor. Symptoms generally begin within 1 to 4 days of withdrawal and abate within 7 to 14 days. They are more severe and frequent when antimuscarinics are stopped simultaneously.

Treatment of Adverse Effects

After an overdose of chlorpromazine, patients should be managed with intensive symptomatic and supportive therapy. Activated charcoal should be given by mouth if a substantial amount of the phenothiazine has been taken within 1 hour of presentation, provided that the airway can be protected emptying the stomach by gastric lavage has sometimes been recommended. Dialysis is of little or no value in poisoning by phenothiazines.

Hypotension should be corrected by raising the patient’s legs, or in severe cases by intravascular volume expansion. An inotrope such as dopamine may be considered in refractory cases. If a vasoconstrictor is considered necessary in the management of phenothiazine-induced hypotension the use of adrenaline or other sympathomimetics with high beta-adrenergic agonist properties should be avoided since the alpha-blocking effects of phenothiazine s may impair the usual alpha-mediated vasoconstriction of these drugs, resulting in unopposed beta-adrenergic stimulation and increased hypotension.

The treatment of neuroleptic malignant syndrome and the difficulties of treating extrapyramidal adverse effects, especially tardive dyskinesia, are discussed above.