The Boston Collaborative Survey indicated that adverse reactions are most common in patients receiving high doses, and that they usually occur soon after starting treatment. The most common serious reactions were fits, coma, severe hypotension, leukopenia, thrombocytopenia and cardiac arrest. Contraindications and cautions These include the following: • coma due to cerebral depressants, bone marrow depression, phaeochromocytoma, epilepsy, chronic respiratory disease, hepatic impairment or Parkinson’s disease; • caution is needed in the elderly, especially in hot or cold weather; • pregnancy, lactation; • alcoholism. Pharmacokinetics The pharmacokinetics of conventional antipsychotic drugs have been little studied. They have multiple metabolites and their large apparent volumes of distribution (Vd) (e.g. for chlorpromazine Vd � 22 L/kg) result in low plasma concentrations, presenting technical difficulties in estimation. Most is known about chlorpromazine, see Box 19.4. Drug interactions These include the following: • alcohol and other CNS depressants – enhanced sedation; • hypotensive drugs and anaesthetics – enhanced hypotension; • increased risk of cardiac arrhythmias with drugs that prolong the QT interval (e.g. amiodarone, sotalol); • tricyclic antidepressants – increased antimuscarinic actions; • metoclopramide – increased extrapyramidal effects and akathisia; • antagonism of anti-Parkinsonian dopamine agonists (e.g. L-dopa) (these are in any case contraindicated in schizophrenia). Box 19.4: Pharmacokinetics (chlorpromazine) • Dose regimes are largely empirical. • There is variable absorption. • There are �70 metabolites, some of which are active. • Enterohepatic circulation is involved. • There is enormous variability in plasma concentrations and t 1/2. • There is a vast volume of distribution. • Brain:plasma concentration is 5:1. • Reduced doses should be prescribed in the elderly (for both pharmacokinetic and pharmacodynamic differences). Case history SCHIZOPHRENIA 113 A 50-year-old woman whose schizophrenia is treated with oral haloperidol is admitted to the Accident and Emergency Department with a high fever, fluctuating level of consciousness, muscular rigidity, pallor, tachycardia, labile blood pressure and urinary incontinence. Question 1 What is the likely diagnosis? Question 2 How should this patient be managed? Answer 1 Neuroleptic malignant syndrome. Answer 2 1. Stop the haloperidol. 2. Initiate supportive therapy. 3. Bromocriptine (value uncertain). 4. Dantrolene (value uncertain). ATYPICAL ANTIPSYCHOTIC DRUGS The term ‘atyptical antipsychotic’ is used very imprecisely. ‘Newer’ or ‘second-generation’ antipsychotics are synonymous in some texts. In comparison to the conventional antipsychotics where potency is closely related to D2 receptor blockade, atypical antipsychotics bind less tightly to D2 receptors and have additional pharmacological activity which varies with the drug. Efficacy against negative symptoms, as well as less extrapyramidal side effects, are characteristic. These may be the result of the transient (‘hit and run’) binding to D2 receptors. Clozapine is the original ‘atypical’ antipsychotic and is described below. Its use is limited to resistant patients due to the risk of agranulocytosis. A variety of other atypical antipsychotic drugs are available. Features of clozapine are: • D 4 � 5HT 2 blockade; • D 1 � D 2 blockade; • α-adrenoceptor blockade; • effective in resistant patients; • effective against negative and positive symptoms; • virtually free from extrapyramidal effects; • agranulocytosis (3%) – use is restricted to patients licensed with a monitoring service: blood count (weekly for first 18 weeks, then every two weeks till one year, then every four weeks); • severe postural hypotension – initiate therapy under supervision; • sedation, dizziness, hypersalivation; • weight gain, glucose intolerance, possible intestinal obstruction; • myocarditis and cardiomyopathy; • pulmonary embolism; • seizures. Many newer alternatives, but none with the unique properties of clozapine, e.g. risperidone, olanzapine, aripiprazole, amisulpride, quetiapine and zotepine, have been introduced. Their pharmacology, efficacy and adverse effects vary. Although more expensive, in June 2002 NICE recommended
114 SCHIZOPHRENIA AND BEHAVIOURAL EMERGENCIES that atypical antipsychotics should be considered in newly diagnosed schizophrenic patients and in those who have unacceptable effects from, or inadequate response to, conventional antipsychotic drugs. Risperidone blocks D 2, D 4 and in particular 5HT 2 receptors. Careful dose titration reduces the risk of adverse effects, but extrapyramidal side effects are common at high doses. It is available as an intramuscular injection for acute control of agitation and disturbed behaviour. Weight gain and, more worryingly, an increased incidence of stroke in elderly patients with dementia have been reported wih both risperidone and olanzapine. Aripiprazole is a long-acting atypical antipsychotic which is a partial agonist at D 2 receptors, as well as blocking 5HT 2. It is not associated with extrapyramidal effects, prolactin secretion or weight gain. Key points Pharmacological treatment • Receptor blockade: – D 2, D 4, 5HT 2. • Although there may be a rapid behavioural benefit, a delay (usually of the order of weeks) in reduction of many symptoms implies secondary effects (e.g. receptor up/downregulation). • Conventional antipsychotics (e.g. chlorpromazine, haloperidol, fluphenazine), act predominantly by D 2 blockade. • Atypical antipsychotics (e.g. clozapine, risperidone, olanzapine) are less likely to cause extrapyramidal side effects. Key points Adverse effects of antipsychotic drugs • Extrapyramidal motor disturbances, related to dopamine blockade. • Endocrine distributions (e.g. gynaecomastia), related to prolactin release secondary to dopamine blockade. • Autonomic effects, dry mouth, blurred vision, constipation due to antimuscarinic action and postural hypotension due to α-blockade. • Cardiac dysrhythmias, which may be related to prolonged QT, e.g. sertindole (an atypical antipsychotic), pimozide. • Sedation. • Impaired temperature homeostasis. • Weight gain. • Idiosyncratic reactions; – jaundice (e.g. chlorpromazine); – leukopenia and agranulocytosis (e.g. clozapine); – skin reactions; – neuroleptic malignant syndrome. BEHAVIOURAL EMERGENCIES MANIA Acute attacks are managed with antipsychotics, but lithium is a common and well-established long-term prophylactic treatment. The control of hypomanic and manic episodes with chlorpromazine is often dramatic. ACUTE PSYCHOTIC EPISODES Patients with organic disorders may experience fluctuating confusion, hallucinations and transient paranoid delusions. Violent incidents sometimes complicate schizophrenic illness. Case history A 60-year-old man with schizophrenia who has been treated for 30 years with chlorpromazine develops involuntary (choreo-athetoid) movements of the face and tongue. Question 1 What drug-induced movement disorder has developed? Question 2 Will an anticholinergic drug improve the symptoms? Question 3 Name three other drug-induced movement disorders associated with antipsychotic drugs. Answer 1 Tardive dyskinesia. Answer 2 No. Anticholinergic drugs may unmask or worsen tardive dyskinesia. Answer 3 1. Akathisia. 2. Acute dystonias. 3. Chronic dystonias. 4. Pseudo-parkinsonism. MANAGEMENT Antipsychotics and benzodiazepines, either separately or together, are effective in the treatment of patients with violent and disturbed behaviour. Lorazepam by mouth or parenteral injection is most frequently used to treat severely disturbed behaviour as an in-patient. Haloperidol can rapidly terminate violent and psychotic behaviour, but hypotension, although uncommon, can be severe, particularly in patients who are already critically ill. Doses should be reduced in the elderly. Intramuscular olanzapine or liquid risperidone are gradually supplanting more conventional antipsychotics in the acute management of psychosis. When treating violent patients, large doses of antipsychotics may be sometimes needed. Consequently, extrapyramidal toxicity, in particular acute dystonias, develops in up to one-third of patients. Prophylactic anti-parkinsonian drugs, such as procyclidine, may be given, especially in patients who are particularly prone to movement disorders. The combination of lorazepam and haloperidol has been successful in treating otherwise resistant delirious behaviour.