False: Clozapine, quetiapine, amisulpride and other atypical antipsychotics bind less strongly to the D₂ receptor and dissociate more rapidly from the D₂ receptor than the typical antipsychotics or dopamine. This may facilitate more ‘normal’ dopamine transmission by allowing endogenously released brief pulses of dopamine to compete with these drugs for occupancy of the receptor. This may explain why atypical antipsychotics cause fewer extrapyramidal symptoms than the typical antipsychotics (King 2004, p. 325; Sadock & Sadock 2005, p. 2918).

False: Clozapine binds more loosely to and has only modest affinity for the D₂ receptor compared to the older typical antipsychotic drugs (King 2004, p. 323; Sadock & Sadock 2005, p. 2918).

False: Clozapine is the archetypal atypical antipsychotic drug. One explanation for its low propensity to cause extrapyramidal side-effects is that it binds less strongly to the D₂ receptor than dopamine which may allow more ‘normal’ dopamine transmission (King 2004, p. 325; Sadock & Sadock 2005, p. 2918).

True: Clozapine antagonizes D₂-like (D₂, D₃, D₄) and D₁-like (D₁, D₅) receptors. Clozapine has the lowest affinity for D₂ receptor and a 10-fold higher affinity for D₄ receptor compared to other antipsychotics (Cookson et al 2002, p. 312; Sadock & Sadock 2005, p. 2918).

False: Clozapine and most typical and atypical antipsychotics cause postural hypotension due to a₁ adrenergic receptor blockade. Postural hypotension is less marked with amisulpride, sulpiride, haloperidol, trifluoperazine and aripiprazole. Even though, ‘typical antipsychotics’ are a large group that includes drugs with widely differing hypotensive effects, postural hypotension is particularly problematic with clozapine (Gelder et al 2006, p. 536; King 2004, p. 351; Taylor et al 2005, p. 27).

False: Clozapine is more sedative than the most sedative typical antipsychotics, e.g. thioridazine, chlorpromazine, mesoridazine, trifluoperazine, etc. Clozapine is the most sedative atypical antipsychotic. Sedation is the most common side-effect of clozapine. Sedation occurs early in treatment and tends to subside over time (BNF 2005 4.2.1; Sadock & Sadock 2005, p. 2923).

False: Clozapine is not commonly used in the elderly due to its sedative, hypotensive, anticholinergic and haematological side-effects. It may be cautiously considered for treatment-resistant schizophrenia. The usual dose range is 12.5–100 mg (Sadock & Sadock 2005, p. 3729).

True: Clozapine reduces seizure threshold in a dose-dependent fashion. The risk starts increasing at doses above 300 mg and increases sharply at doses above 600 mg.

EEG changes occur in 75% and paroxysmal discharges in 40% of patients on clozapine. Rapid increase in dose, pre-existing seizure disorder and history of head injury increase the risk. Monitoring blood clozapine levels and doing an EEG before increasing the dose above 600 mg may help reduce the risk. Sodium valproate is often used concomitantly as an anticonvulsant (Gelder et al 2000, p.1322; Johnstone et al 2004, p. 267; King 2004, p. 350).

True: Aripiprazole is a partial agonist at both 5-HT_1A and D₂ receptors and an antagonist at 5-HT_2A receptors. Partial agonists bind to receptor sites to give a partial response which is less than that of a full agonist but greater than an antagonist. Partial agonists compete with endogenous ligand and therefore give an attenuated response if the ligand is in excess, whilst increasing response where there is a deficit (Sadock & Sadock 2005, p. 2933).

False: Various degrees of glucose intolerance including hyperglycaemia, type II diabetes mellitus and even diabetic keto-acidosis can occur with atypical antipsychotics, especially clozapine and olanzapine. Most cases of hyperglycaemia occur within 6 months of initiating treatment. The exact mechanism is unknown but does not seem to be dose-related (King 2004, p. 533; Sadock & Sadock 2005, p. 2927; Taylor et al 2005, p. 10).

False: Quetiapine, ziprasidone, sertindole, aripiprazole, olanzapine and clozapine do not cause clinically meaningful elevation of prolactin (Taylor et al 2005, p. 92).

True: Quetiapine has its highest affinity for H₁ receptors. H₁ antagonism is considered responsible for its sedative effects (King 2004, pp. 328, 349).

True: The steady state half-life is 6.9 hours (Sadock & Sadock 2005, p. 2929.

False: Clozapine, risperidone and other atypical antipsychotics have low propensity to cause extrapyramidal side-effects. However, risperidone is more likely to cause extrapyramidal side-effects than clozapine. This may be related to clozapine’s lower affinity for the D₂ receptors. Risperidone-induced extrapyramidal side-effects tend to be dose-related (Sadock & Sadock 2005, p. 2914).

True: Akathisia usually quickly follows initiating or increasing the dose of antipsychotic drugs, often within hours of oral administration and within 30 minutes of parenteral administration (Johnstone et al 2004, p. 268; Sadock & Sadock 2005, p. 2716).

False: Neuroleptic malignant syndrome is generally considered to be an acute, severe syndrome that develops rapidly over 1–3 days and lasts 5–10 days. However, the onset may appear more gradual if one monitors creatinine phosphokinase (CPK), blood pressure and white cell counts (King 2004, p. 579; David Taylor, personal communication).

False: The diagnostic features include:

False: The definitive treatments include stopping the offending drug, excluding other possible causes for the presentation and general supportive measures. No drug treatment is of proven value. Treatments that have been used include amantidine, bromocriptine, L-dopa (dopamine agonists), dantrolene (muscle relaxant), benzodiazepines (sedative, muscle relaxant) and antimuscarinic drugs. There have only been anecdotal reports of using calcium channel blockers. Some centres use nifedipine as a prophylactic agent when restarting antipsychotics in patients who had neuroleptic malignant syndrome (King 2004, p. 579; Robert Kerwin, personal communication).

False: Spontaneous dyskinesias indistinguishable from neuroleptic-induced tardive dyskinesia have been recorded in 5% of patients with schizophrenia prior to the introduction of antipsychotic drugs and occur in 2% of the normal elderly. However, strictly speaking, the term tardive dyskinesia is used only for dyskinesias developing secondary to exposure to antipsychotic drugs (Taylor et al 2005, p. 8).

False: Although some studies report rates as high as 56%, most studies report rates of 15–20% prevalence of tardive dyskinesia in chronic institutionalized patients. Rates are higher (up to 40%) in the over 65s on long-term treatment (Gelder et al 2006, p. 535; King 2004, p. 347; Sadock & Sadock 2005, p. 2716).

True: Tardive dyskinesia disappears during sleep. It can be temporarily suppressed voluntarily or by purposeful action or distraction. Some other movement disorders (e.g. the chorea associated with Huntington’s disease) also decrease during sleep (Sadock & Sadock 2005, p. 997).

True: Antimuscarinic agents can cause acute organic reactions in the elderly. In adults they can cause delirium in high doses. Symptoms include confusion, excitement, agitation, paranoid delusions and hallucinations (Gelder et al 2000, p. 1323; Gelder et al 2006, p. 539; Lishman 1997, p. 657).

True: Tolerance, withdrawal symptoms and psychological and physical dependence can occur. Abrupt discontinuation may cause akinesia, rigidity and cholinergic rebound, i.e. nausea, diarrhoea, restlessness and agitation (Cookson et al 2002, p. 305; Gelder et al 2006, p. 540).

True: The acute dystonias, e.g. oculogyric crisis and torticollis, respond rapidly to antimuscarinic drugs such as procyclidine. Acute dystonia is caused by relative excess cholinergic activity compared to dopaminergic activity in the nigrostriatal pathway following blockade of dopamine receptors. Acute dystonias are more common in men and in younger patients, with high potency drugs, higher doses and rapid increase in dose. 90% of cases occur within 5 days of exposure or dose increment (Johnstone et al 2004, p. 267; King 2004, p. 345).

False: On treatment with typical antipsychotic drugs 15–40% of patients develop Parkinsonian symptoms such as bradykinesia, tremor and rigidity. The risk increases with age, drug potency and the rate of dose increments. In drug-induced Parkinsonism, bradykinesia is more prominent and more disabling than rigidity and tremor. Unfortunately, antimuscarinic drugs have least effect on bradykinesia (Johnstone et al 2004, p. 269; Neal 1992, p. 57).