Antipsychotic Side Effects
Antipsychotic side effects are common, dose-related, and a major cause of non-adherence. They include metabolic syndrome, extrapyramidal symptoms, QTc prolongation, and hyperprolactinaemia.
Key Facts
Metabolic syndrome (weight gain, dyslipidaemia, hyperglycaemia) — highest with olanzapine and clozapine Extrapyramidal symptoms (EPS): Acute dystonia, parkinsonism, akathisia, tardive dyskinesia — highest with typical antipsychotics Tardive dyskinesia: Involuntary orofacial movements; may be irreversible; risk increases with duration of treatment QTc prolongation: Can lead to torsades de pointes; monitor ECG — especially haloperidol, pimozide, ziprasidone Hyperprolactinaemia: Amenorrhoea, galactorrhoea, sexual dysfunction, osteoporosis — highest with risperidone, paliperidone, amisulpride Clozapine-specific: Agranulocytosis (~1%), myocarditis (~1-3% in first 2 months), constipation (can be fatal), sedation, metabolic syndrome Monitoring: Metabolic parameters at baseline, 6 weeks, 3 months, 6 months, then annually Weight gain is the most common reason for patient non-adherence to antipsychotic medication
Overview
Key Facts
Antipsychotic side effects are a major clinical concern, affecting adherence, quality of life, and physical health outcomes. Proactive monitoring and management are essential.
Epidemiology
Up to 80% of patients on antipsychotics experience at least one side effect. Weight gain occurs in ~50-80% of patients on olanzapine/clozapine. Metabolic syndrome develops in ~30-50% of patients on atypical antipsychotics. EPS affects ~25-50% of patients on typical antipsychotics.
Aetiology
Side effects result from dopamine, serotonin, histamine, muscarinic, and alpha-adrenergic receptor blockade across multiple brain and peripheral pathways.
Pathophysiology
- EPS: D2 blockade in nigrostriatal pathway → loss of dopaminergic modulation of basal ganglia → movement disorders
- Hyperprolactinaemia: D2 blockade in tuberoinfundibular pathway → loss of prolactin inhibition → raised prolactin
- Metabolic: H1 and 5-HT2C receptor blockade → increased appetite and weight gain; insulin resistance; dyslipidaemia
- QTc prolongation: Blockade of cardiac hERG potassium channels → delayed repolarisation → risk of torsades de pointes
- Anticholinergic effects: Muscarinic receptor blockade → dry mouth, constipation, urinary retention, blurred vision
Clinical Presentation
Extrapyramidal Symptoms
- Acute dystonia: Hours-days; sustained involuntary muscle contraction (torticollis, oculogyric crisis, trismus); Rx: procyclidine 5-10mg IM/IV
- Parkinsonism: Days-weeks; bradykinesia, rigidity, tremor; Rx: reduce dose, switch, procyclidine 5mg TDS
- Akathisia: Days-weeks; subjective restlessness, inability to sit still; Rx: reduce dose, switch, propranolol 30-80mg/day
- Tardive dyskinesia: Months-years; involuntary orofacial movements (lip-smacking, tongue protrusion, choreiform); Rx: stop or switch antipsychotic; valbenazine (not widely available UK)
Metabolic Effects
- Weight gain (especially olanzapine, clozapine, quetiapine)
- Type 2 diabetes, dyslipidaemia
- Metabolic syndrome (central obesity + 2 of: raised TG, low HDL, raised BP, raised glucose)
Other Side Effects
- Sedation: Clozapine, olanzapine, quetiapine
- Postural hypotension: Alpha-1 blockade — clozapine, quetiapine
- Anticholinergic: Dry mouth, constipation, urinary retention, blurred vision — clozapine, chlorpromazine
- Sexual dysfunction: Reduced libido, erectile dysfunction, anorgasmia — especially with raised prolactin
Red Flags
- NMS (see separate topic): Rigidity, hyperthermia, autonomic instability, raised CK — stop antipsychotic immediately
- QTc >500ms — stop drug, cardiology review
- Neutrophils <1.5 × 10⁹/L on clozapine — withhold and contact CPMS
- Severe constipation on clozapine — can cause ileus and death
Differential Diagnosis
| Side Effect | Common Culprits | Differential |
|---|---|---|
| Parkinsonism | Haloperidol, risperidone | Parkinson's disease (age, unilateral onset) |
| Akathisia | Aripiprazole, haloperidol | Anxiety, restless legs syndrome |
| Tardive dyskinesia | Long-term typical antipsychotics | Huntington's, Wilson's disease |
| Weight gain | Olanzapine, clozapine | Hypothyroidism, Cushing's |
| Hyperprolactinaemia | Risperidone, amisulpride | Prolactinoma |
Diagnosis / Investigation
Monitoring Schedule (NICE CG178)
- Baseline: Weight, BMI, waist circumference, BP, fasting glucose/HbA1c, lipids, FBC, ECG, prolactin
- 6 weeks: Weight, fasting glucose
- 3 months: Weight, BMI, waist, BP, fasting glucose, lipids
- 6 months: All metabolic parameters
- Annually: Full metabolic screen, movement disorder assessment
- Clozapine: FBC weekly × 18 weeks → fortnightly × 1 year → monthly
- Lithium: See separate topic
Specific Tests
- ECG: QTc measurement (prolonged >450ms male, >470ms female — caution; >500ms — stop drug)
- Prolactin: If symptoms of hyperprolactinaemia
- CK: If NMS suspected
- Fasting lipids and glucose: Metabolic monitoring
Management
Prevention
- Choose antipsychotic based on side effect profile and patient factors
- Lowest effective dose
- Lifestyle intervention (diet, exercise) from outset
- Regular metabolic monitoring
Treatment of Side Effects
- Acute dystonia: Procyclidine 5-10mg IM/IV (onset within minutes)
- Parkinsonism: Reduce dose, switch; procyclidine 5mg TDS if needed
- Akathisia: Reduce dose, switch to lower-EPS drug; propranolol 30-80mg/day; mirtazapine
- Tardive dyskinesia: Stop/reduce offending agent, switch to clozapine or quetiapine (lowest EPS risk)
- Weight gain: Lifestyle intervention; consider switching to aripiprazole; metformin 500mg BD (off-label)
- Hyperprolactinaemia: Switch to aripiprazole (partial D2 agonist — reduces prolactin)
- Constipation (clozapine): Proactive laxative regimen — docusate + senna; monitor regularly
- QTc prolongation: Stop offending drug, check and correct K⁺ and Mg²⁺, cardiology review if >500ms
Referral Criteria
- NMS — emergency medical management, stop antipsychotic
- Tardive dyskinesia — specialist review, consider clozapine
- Severe metabolic complications — endocrinology/cardiology
- Agranulocytosis on clozapine — haematology, stop clozapine
Prognosis
- Most side effects are reversible on dose reduction or drug switching
- Tardive dyskinesia: May be irreversible in ~50% of cases; risk increases with duration and cumulative dose
- Metabolic syndrome: Increases cardiovascular mortality — antipsychotic users have 2-3× increased CV risk
- Clozapine agranulocytosis: Mortality <1% with monitoring; recovery expected on drug withdrawal
- NMS: Mortality ~5-10% (historically higher); recovery over 1-2 weeks after drug withdrawal
- Proactive monitoring and management significantly reduce morbidity from antipsychotic side effects
Other Relevant Information
EPS by Type
| Type | Onset | Features | Treatment |
|---|---|---|---|
| Acute dystonia | Hours-days | Sustained contraction, torticollis | Procyclidine 5-10mg IM |
| Parkinsonism | Days-weeks | Bradykinesia, rigidity, tremor | Dose reduction, procyclidine |
| Akathisia | Days-weeks | Restlessness, inability to sit still | Propranolol, dose reduction |
| Tardive dyskinesia | Months-years | Orofacial movements, choreiform | Stop/switch, clozapine |