Antipsychotics

Classification

Antipsychotics are classified as first-generation (typical) - predominantly dopamine D2 receptor antagonism, higher extrapyramidal side effect burden - and second-generation (atypical) - broader receptor action (serotonin plus dopamine antagonism), generally lower extrapyramidal risk but higher metabolic adverse effect burden - this trade-off shapes agent selection and monitoring priorities

Used across psychotic disorders, bipolar disorder, and increasingly for other indications, with second-generation agents now generally preferred first-line given the more favourable extrapyramidal side effect profile despite metabolic trade-offs

D2 receptor blockade in the mesolimbic pathway underlies antipsychotic efficacy, while blockade in the nigrostriatal pathway causes extrapyramidal side effects (parkinsonism, dystonia, akathisia, and with chronic use, tardive dyskinesia) - the relatively lower nigrostriatal D2 affinity/faster dissociation of second-generation agents explains their generally reduced extrapyramidal burden compared with first-generation agents
Second-generation agents' additional serotonin and other receptor activity contributes to their broader efficacy profile but also to their distinct metabolic adverse effect profile (weight gain, dyslipidaemia, impaired glucose tolerance) via mechanisms less well characterised than the dopaminergic pathway effects

Baseline and regular metabolic monitoring (weight, waist circumference, lipids, glucose/HbA1c) is essential with second-generation agents given the significant metabolic risk
Extrapyramidal symptom assessment (rigidity, tremor, akathisia) should accompany routine review with any agent, and neuroleptic malignant syndrome (rigidity, hyperthermia, autonomic instability) requires urgent recognition given its life-threatening potential

Second-generation agents are generally preferred first-line given the more favourable extrapyramidal profile, with agent choice otherwise guided by individual metabolic risk, sedation profile, and specific indication
Clozapine (reserved for treatment-resistant psychosis) requires mandatory regular blood count monitoring given agranulocytosis risk, a specific, non-negotiable safety requirement distinct from routine antipsychotic monitoring

Metabolic syndrome (weight gain, dyslipidaemia, impaired glucose tolerance - highest with olanzapine/clozapine), tardive dyskinesia with chronic use (a potentially irreversible late complication), clozapine-associated agranulocytosis requiring lifelong monitoring
Neuroleptic malignant syndrome and serotonin syndrome share overlapping features (hyperthermia, autonomic instability, altered mental state) but require distinguishing - NMS typically develops over days with prominent lead-pipe rigidity and a clear antipsychotic exposure history, while serotonin syndrome develops more rapidly (hours) with hyperreflexia/clonus and a serotonergic drug exposure history - this distinction matters since specific management differs

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