Key Facts

Antipsychotics are the mainstay of treatment for schizophrenia and are widely used in other psychiatric and medical conditions. Understanding the distinction between typical and atypical agents, and their respective side effect profiles, is essential.

Epidemiology

• Schizophrenia: ~1% lifetime prevalence
• Antipsychotics prescribed to ~1.5 million people in England (including non-psychotic indications)

Classification

First-generation (typical):

• Haloperidol, chlorpromazine, flupentixol, zuclopenthixol, sulpiride
• Potent D2 blockade → effective but high EPS risk

Second-generation (atypical):

• Olanzapine, quetiapine, risperidone, aripiprazole, amisulpride, clozapine
• D2 + 5-HT2A blockade → fewer EPS but more metabolic effects

Aripiprazole: D2 partial agonist — unique mechanism; fewer metabolic effects; less sedation

Clozapine: reserved for treatment-resistant schizophrenia; most effective antipsychotic but agranulocytosis risk (~1%)

Pathophysiology

• Dopamine hypothesis: psychosis associated with excess dopamine activity in mesolimbic pathway
• Mesolimbic blockade: reduces positive symptoms (hallucinations, delusions)
• Mesocortical blockade: may worsen negative symptoms (apathy, flat affect)
• Nigrostriatal blockade: causes EPS (parkinsonism, dystonia, tardive dyskinesia)
• Tuberoinfundibular blockade: causes hyperprolactinaemia → galactorrhoea, amenorrhoea, sexual dysfunction
• Metabolic effects: 5-HT2C/H1 antagonism → weight gain, insulin resistance, dyslipidaemia

Indications

• Schizophrenia: first-line — oral antipsychotic (NICE CG178); choice based on side effect profile and patient preference
• Bipolar disorder: olanzapine, quetiapine, aripiprazole — acute mania and maintenance
• Psychotic depression: antidepressant + antipsychotic
• Acute agitation/aggression: rapid tranquillisation — haloperidol 5 mg IM or lorazepam 1–2 mg IM (NICE NG10)
• Antiemesis: prochlorperazine, haloperidol (low dose)
• Delirium: haloperidol 0.5–1 mg (cautious use in elderly)

Side Effects by Class

EPS (worse with typicals):

• Acute dystonia: sustained muscle spasm (neck, jaw, eyes — oculogyric crisis); onset hours–days; treat with procyclidine 5–10 mg IM
• Akathisia: inner restlessness, inability to sit still; onset days–weeks; treat by reducing dose, propranolol, or switching drug
• Drug-induced parkinsonism: bradykinesia, rigidity, tremor; onset weeks–months; treat with anticholinergic (procyclidine) or reduce dose
• Tardive dyskinesia: involuntary choreoathetoid movements (orofacial); onset months–years; may be irreversible; reduce/stop causative drug

Metabolic (worse with atypicals — especially olanzapine, clozapine):

• Weight gain, type 2 diabetes, dyslipidaemia, metabolic syndrome
• Monitor: weight, BMI, waist circumference, glucose/HbA1c, lipids at baseline, 3 months, then annually

Hyperprolactinaemia (risperidone worst):

• Galactorrhoea, amenorrhoea, sexual dysfunction, reduced bone density

Red Flags

• NMS: rigidity, hyperthermia >38°C, autonomic instability, altered consciousness, raised CK (often >1000) → stop antipsychotic immediately; ICU; IV fluids, cooling, dantrolene 1 mg/kg IV
• Agranulocytosis on clozapine: sore throat, fever → URGENT FBC → if neutrophils <1.5 → stop clozapine
• QT prolongation: ECG before and during treatment with haloperidol, pimozide; risk of torsades
• Clozapine-induced myocarditis: chest pain, tachycardia, fever in first month → troponin, echo

Before Starting

• Baseline: weight, BMI, waist circumference, BP, fasting glucose/HbA1c, lipid profile
• ECG: before haloperidol, pimozide, amisulpride (QTc)
• FBC: baseline (mandatory for clozapine)
• LFTs, U&Es: baseline
• Prolactin: if relevant symptoms develop

Monitoring

• Metabolic parameters: at 3 months, 12 months, then annually — weight, glucose/HbA1c, lipids, BP
• ECG: if on QT-prolonging agent or if dose increased
• Prolactin: if amenorrhoea, galactorrhoea, sexual dysfunction
• EPS assessment: clinical at each review

Clozapine-Specific Monitoring (CPMS)

• FBC: weekly for 18 weeks → fortnightly for 1 year → monthly lifelong
• Must not dispense unless blood result registered and satisfactory
• Metabolic monitoring: as above but more frequent
• Troponin and CRP: if chest pain/tachycardia (myocarditis screening)

Special Tests

• Clozapine levels: therapeutic range 0.35–0.5 mg/L; toxicity >1.0 mg/L; affected by smoking (CYP1A2 induction — levels fall if smoking; RISE if stopped)
• CK: if NMS suspected

Schizophrenia (NICE CG178)

First episode:

• Oral atypical antipsychotic + psychological interventions (CBT, family therapy)
• Choice guided by side effect profile and patient preference
• Aripiprazole: least metabolic/sedative effects
• Olanzapine: effective but metabolic risk
• Risperidone: effective but hyperprolactinaemia
• Quetiapine: sedating; useful if insomnia/agitation

Treatment-resistant schizophrenia:

• Failed 2 adequate trials of different antipsychotics (at least 1 atypical) → clozapine
• Clozapine: start 12.5 mg OD → slow titration to 300–450 mg/day
• Register with Clozapine Patient Monitoring Service (CPMS)

Depot/Long-Acting Injectable (LAI)

• For adherence difficulties: flupentixol decanoate, zuclopenthixol decanoate, paliperidone palmitate, aripiprazole LAI

Managing Side Effects

• EPS: reduce dose; anticholinergic (procyclidine 5 mg PO/IM) for acute dystonia/parkinsonism; propranolol for akathisia
• Metabolic syndrome: lifestyle advice, switch to less metabolically active drug (aripiprazole); metformin if weight gain significant
• Hyperprolactinaemia: switch to aripiprazole (D2 partial agonist — reduces prolactin)
• NMS: stop antipsychotic immediately; ICU; IV fluids, cooling; dantrolene 1 mg/kg IV, bromocriptine 2.5 mg TDS

Referral Criteria

• Psychiatry: all psychotic disorders; clozapine initiation
• Urgent/crisis team: acute psychosis, NMS, aggression

• ~75% of first-episode psychosis patients respond to antipsychotics
• Clozapine: effective in ~30–60% of treatment-resistant patients
• Relapse: ~80% within 5 years if medication stopped; ~20% if continued
• Metabolic syndrome: significant long-term morbidity — CVD risk increased 2–3× in schizophrenia
• NMS mortality: ~5–10% with treatment; higher if not recognised
• Tardive dyskinesia: may be irreversible — prevention is key (use lowest effective dose, regular monitoring)
• Life expectancy in schizophrenia: reduced by ~15–20 years (CVD, metabolic disease, suicide)

Antipsychotic Side Effect Summary

NMS vs Serotonin Syndrome