Antipsychotics
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Direct answer
Blockade of dopamine D2 receptors in the mesolimbic pathway relieves psychosis, but the same blockade in the nigrostriatal pathway produces extrapyramidal syndromes and in the tuberoinfundibular pathway raises prolactin — one mechanism, four clinical faces, and the entire exam logic of this chapter. Acute dystonia appears in the first days (treat with intramuscular anticholinergic or promethazine), akathisia within weeks (a beta blocker, never a higher antipsychotic dose), parkinsonism within months, and tardive dyskinesia after months to years of treatment, when it demands a switch to clozapine rather than more anticholinergic. Clozapine itself is the treatment-resistant option with a mandatory blood-count programme: roughly 1 per cent agranulocytosis, weekly neutrophil monitoring in the initial months, plus seizure, myocarditis and metabolic risks. Neuroleptic malignant syndrome — rigidity, hyperthermia, autonomic instability and creatine kinase elevation — is the emergency, treated by stopping the drug, cooling and dantrolene or bromocriptine.
What you must remember
- The four extrapyramidal syndromes in order of appearance: acute dystonia (days — IM benztropine or promethazine), akathisia (weeks — propranolol, dose reduction), drug-induced parkinsonism (months — anticholinergic, dose reduction), tardive dyskinesia (months-years — withdraw the culprit, switch to clozapine; anticholinergics worsen it).
- High-potency typicals (haloperidol): more extrapyramidal syndrome, less sedation; low-potency (chlorpromazine): sedation, postural hypotension, anticholinergic load, photosensitivity with slate-grey skin and corneal-lens deposits.
- Hyperprolactinaemia (galactorrhoea, amenorrhoea, infertility) is worst with risperidone and typicals; aripiprazole and quetiapine are prolactin-sparing.
- Clozapine: about 30 per cent of treatment-resistant patients respond when nothing else worked; agranulocytosis risk (roughly 1 per cent, highest in the first months — weekly full blood counts initially), dose-related seizures, myocarditis in the early weeks, hypersalivation, constipation that can become fatal ileus, and the heaviest metabolic burden.
- Atypical profiles: olanzapine — weight gain and dyslipidaemia; quetiapine — sedation, the safest in Parkinson disease psychosis; aripiprazole — partial D2 agonist with akathisia but least metabolic effect; ziprasidone — QT prolongation.
- Intramuscular olanzapine must not be given within an hour of a parenteral benzodiazepine — respiratory depression deaths drove the rule.
- First-episode schizophrenia is treated for 1–2 years after remission; long-acting injectables serve adherence, not severity.
- Neuroleptic malignant syndrome versus serotonin syndrome: NMS shows lead-pipe rigidity, hyporeflexia and slow onset over days with a soaring creatine kinase; serotonin syndrome shows clonus, hyperreflexia and onset within a day.
- Smoking induces clozapine metabolism (CYP1A2) — smoking cessation, including hospital no-smoking rules, can raise clozapine to toxic levels.
Worked example: first-episode psychosis
A 22-year-old student is admitted with three months of auditory hallucinations and persecutory ideas, agitated but medically well. The pathway: acute agitation is controlled with intramuscular haloperidol plus promethazine (or oral risperidone with lorazepam where accepted), then a structured start of an oral atypical — risperidone 2 mg or olanzapine 5 mg nightly — titrated over a fortnight. Baseline weight, waist, fasting glucose, lipids and an ECG are recorded before the first tablet, because the metabolic effects are predictable and the follow-up depends on this baseline. By week four the examiner plants the side-effect: he paces the corridor, unable to sit — akathisia, misread by the team as worsening psychosis. The correct move is propranolol (or a benzodiazepine) and a dose review, never escalation, because more D2 blockade deepens the restlessness.
At six months he is well; the maintenance conversation is 1–2 years for a first episode, with gradual withdrawal only after that, and a long-acting injectable considered at the first relapse rather than promised from day one. His male sex and young age flag the highest dystonia risk in his first treatment week — the reason the promethazine travels with the haloperidol.
Where students slip
Akathisia read as worsening illness is the most expensive error in the chapter: doubling the antipsychotic converts an uncomfortable side-effect into an emergency. Second, anticholinergics are prescribed for tardive dyskinesia, which they aggravate; the answer is withdrawal and clozapine. Third, neuroleptic malignant syndrome is called "infection" and treated with antibiotics while the antipsychotic continues — the creatine kinase and lead-pipe rigidity should stop both errors. Fourth, clozapine's constipation is dismissed until bowel ischaemia; it is a serious adverse effect, monitored like the blood count. Fifth, the prolactin question: a young woman on risperidone with amenorrhoea and galactorrhoea is switched (aripiprazole or quetiapine) rather than investigated endlessly. Finally, the IM olanzapine–benzodiazepine hour rule is a pure recall question with a mortality behind it.
Frequently asked questions
What is the treatment for acute antipsychotic-induced dystonia?
Intramuscular or intravenous anticholinergic (benztropine or biperiden) or promethazine, with oral anticholinergic cover for several days to prevent recurrence.
How do neuroleptic malignant syndrome and serotonin syndrome differ?
NMS: lead-pipe rigidity, hyporeflexia, hyperthermia, autonomic instability, marked creatine kinase rise, onset over days; serotonin syndrome: tremor, clonus, hyperreflexia, diarrhoea, onset within 24 hours of a serotonergic change.
What monitoring does clozapine require?
Regular neutrophil counts — weekly in the initial months with defined thresholds for withholding — plus early vigilance for myocarditis, seizure threshold, constipation and ileus, weight and glucose.
Which atypical antipsychotic raises prolactin most?
Risperidone (and paliperidone), producing galactorrhoea, amenorrhoea and sexual dysfunction; aripiprazole, quetiapine and clozapine are prolactin-sparing.
How is akathisia managed?
With dose reduction and a beta blocker such as propranolol (benzodiazepines as an alternative) — the antipsychotic dose must not be increased.
Why can hospital admission destabilise clozapine levels?
Inpatient no-smoking removes CYP1A2 induction abruptly, so clozapine rises — sedation, seizure and toxicity follow unless the dose is adjusted.