Antipsychotic Side Effects
Chapter notes (PDF)PDFAntipsychotic 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
D2 blockade in nigrostriatal pathway
loss of dopaminergic modulation of basal ganglia
movement disorders
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
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
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 |