What is the difference between typical and atypical antipsychotics?
First-generation (typical) antipsychotics are dopamine receptor antagonists. They work best when they occupy about 72% of D2 receptors and also block noradrenergic, cholinergic and histamine receptors. Second-generation (atypical) antipsychotics are serotonin-dopamine antagonists — they block D2 plus the 5-HT2A serotonin receptor, which is thought to lower the risk of extrapyramidal effects.
| Feature | Typical (first-generation) | Atypical (second-generation) |
|---|---|---|
| Receptor action | D2 antagonism (plus α1, M1, H1) | D2 + 5-HT2A antagonism (aripiprazole: D2 partial agonist) |
| Examples | Haloperidol, chlorpromazine, fluphenazine, thioridazine, pimozide, trifluoperazine | Risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, lurasidone, clozapine |
| Symptoms treated | Better for positive symptoms | Positive and negative symptoms |
| Extrapyramidal effects | Common (61.6% in one institutional study) | Less common (risperidone highest, clozapine lowest) |
| Prolactin rise | Common | Risperidone, paliperidone, amisulpride |
| Metabolic effects | Less | Weight gain, diabetes, dyslipidaemia — worst with olanzapine and clozapine |
| Depot forms | Haloperidol, fluphenazine | Risperidone, paliperidone, olanzapine, aripiprazole |
What are the four dopamine pathways and why do they matter?
Four dopamine pathways explain both the benefit and the side effects of D2 blockade. Overactive dopamine in the mesolimbic pathway is linked to positive symptoms; reduced dopamine in the mesocortical pathway to negative and cognitive symptoms. Blocking D2 everywhere therefore helps positive symptoms but also hits the motor and hormonal pathways.
| Pathway | Route | Normal role | Effect of D2 blockade |
|---|---|---|---|
| Mesolimbic | Ventral tegmental area → nucleus accumbens / limbic system | Reward, motivation | ↓ Positive symptoms (hallucinations, delusions) — the therapeutic effect |
| Mesocortical | Ventral tegmental area → prefrontal cortex | Cognition; low dopamine here is linked to negative symptoms | Not the therapeutic target — D2 blockade does little for negative symptoms |
| Nigrostriatal | Substantia nigra → dorsal striatum | Voluntary movement | Extrapyramidal side effects |
| Tuberoinfundibular | Hypothalamus → anterior pituitary | Dopamine inhibits prolactin | Hyperprolactinaemia |
When do the extrapyramidal side effects appear and how are they treated?
Extrapyramidal side effects (EPS) are drug-induced movement disorders from D2 blockade in the basal ganglia. They are dose-dependent and appear in a predictable time order — the most-asked part of this topic.
| Type | Typical onset | Features | Treatment |
|---|---|---|---|
| Acute dystonia | Hours to days — 50% within 48 h, 90% within 5 days | Torticollis, oculogyric crisis, trismus, opisthotonus, laryngeal dystonia (airway emergency); young men | Parenteral anticholinergic — IM benztropine 1–2 mg; IV for laryngeal dystonia |
| Akathisia | Days to weeks — usually within 4 weeks | Inner restlessness, urge to move, pacing; mistaken for agitation; linked to suicidality | Reduce dose or switch; propranolol, benzodiazepine, low-dose mirtazapine |
| Drug-induced parkinsonism | Weeks | Bradykinesia, rigidity, tremor, masked face, shuffling gait; older women | Reduce dose or switch; anticholinergic or amantadine |
| Tardive dyskinesia | Months to years of exposure | Choreoathetoid orofacial movements — lip-smacking, tongue protrusion, grimacing; may be permanent; older women | Taper or switch (clozapine, quetiapine); VMAT2 inhibitors valbenazine or deutetrabenazine; stop anticholinergics |
Tardive dyskinesia arises from chronic D2 blockade causing compensatory up-regulation and hypersensitivity of striatal dopamine receptors — the opposite of the acute blockade that causes parkinsonism. Mean prevalence among antipsychotic-treated people is about 20% to 25%; in older populations cumulative rates of about 25% after 1 year and 53% after 3 years have been reported.
How is neuroleptic malignant syndrome recognised and treated?
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal reaction to dopamine blockade (or abrupt withdrawal of dopaminergic drugs such as levodopa). The sudden fall in central dopaminergic activity produces the core features. The main risk factor is starting or increasing a neuroleptic; high-potency and depot drugs, rapid escalation, multiple neuroleptics and lithium add risk. Symptoms develop over 1 to 3 days.
- Fever (hyperthermia)
- Severe muscle rigidity
- Altered mental status — confusion, mutism
- Autonomic instability — tachycardia, labile blood pressure, diaphoresis
- Labs: very high creatine kinase (correlates with severity), leukocytosis, myoglobinuria, raised transaminases, acute kidney injury
| Step | Action |
|---|---|
| 1 | Stop all antipsychotics immediately |
| 2 | Aggressive IV fluids, cooling, electrolyte correction, intensive care monitoring |
| 3 | Moderate to severe cases: dantrolene (muscle relaxant) and/or bromocriptine (dopamine agonist); benzodiazepines may help |
| 4 | Refractory NMS: electroconvulsive therapy (ECT) |
| 5 | Rechallenge only after at least 2 weeks of resolution, with a lower-potency drug at low dose, avoiding lithium |
Which antipsychotics cause hyperprolactinaemia, metabolic syndrome and QT prolongation?
| Adverse effect | Mechanism | Classic culprits | Lowest risk |
|---|---|---|---|
| Hyperprolactinaemia — galactorrhoea, amenorrhoea, gynaecomastia, sexual dysfunction, low bone density | D2 block in the tuberoinfundibular pathway / pituitary | High-potency typicals, risperidone, paliperidone, amisulpride | Aripiprazole (lowers prolactin) |
| Weight gain and metabolic syndrome | Mainly second-generation drugs | Olanzapine, clozapine | Ziprasidone, aripiprazole |
| QTc prolongation / torsades | Delayed cardiac repolarisation | Thioridazine (sudden death warning), IV haloperidol, ziprasidone, pimozide, paliperidone | — |
| Orthostatic hypotension | α1 blockade | Chlorpromazine, thioridazine, clozapine, quetiapine | — |
| Anticholinergic effects | Muscarinic blockade | Chlorpromazine, thioridazine, clozapine | — |
| Sedation | H1 blockade | Chlorpromazine, quetiapine, olanzapine | Fluphenazine, haloperidol, pimozide (among typicals) |
| Eye / skin | Drug-specific | Chlorpromazine (blue-grey skin, lens/corneal deposits, photosensitivity); thioridazine (retinal pigmentation) | — |
All antipsychotics carry a boxed warning of increased mortality in elderly patients with dementia-related psychosis; second-generation drugs also carry a warning of increased stroke in this group.
Why is clozapine special and how is it monitored?
Clozapine is the drug for treatment-resistant schizophrenia. NICE CG178 says: offer clozapine when the illness has not responded to adequate doses of at least 2 different antipsychotics used sequentially, at least one of them a non-clozapine second-generation antipsychotic. Each trial should run at optimum dose for 4 to 6 weeks. Clozapine also reduces suicidal behaviour, causes the fewest EPS and can improve tardive dyskinesia. It binds the D4 receptor with higher affinity than D2.
| Adverse effect | Key facts |
|---|---|
| Agranulocytosis / severe neutropenia | About 1%; dose-independent; mostly within 6 weeks to 6 months. ANC monitored weekly for the first 6 months, every 2 weeks for months 6–12, then monthly if normal (per prescribing information). Agranulocytosis = ANC < 500/mm³ |
| Myocarditis / cardiomyopathy | Myocarditis in under 3%, usually in the first 4 weeks; dose-independent and potentially fatal |
| Seizures | Dose-dependent, about 1–6%, more with rapid titration; valproate may be added |
| Hypersalivation (sialorrhoea) | Dose-dependent, usually benign; risk of aspiration pneumonia |
| Metabolic | Major weight gain, diabetes, dyslipidaemia |
| Others | Tachycardia, hypotension, anticholinergic effects, venous thromboembolism |
Which individual antipsychotics have unique exam facts?
| Drug | Unique fact |
|---|---|
| Aripiprazole | Partial agonist at D2 and 5-HT1A, antagonist at 5-HT2A; low weight gain and lowers prolactin; akathisia common |
| Risperidone | Highest EPS among atypicals and marked prolactin elevation; long-acting injection available |
| Olanzapine | Most weight gain and somnolence; olanzapine + fluoxetine for treatment-resistant depression |
| Quetiapine | Least likely to cause EPS (after clozapine); sedation, orthostatic hypotension |
| Ziprasidone | Almost no weight gain but QTc prolongation |
| Clozapine | Treatment-resistant schizophrenia, suicidality; agranulocytosis, myocarditis, seizures, sialorrhoea |
| Haloperidol | High-potency butyrophenone; EPS; used in delirium agitation; IV route linked to torsades; Tourette disorder (with pimozide) |
| Chlorpromazine | Most sedating typical; allergic dermatitis, photosensitivity, blue-grey skin, corneal/lens deposits |
| Thioridazine | Retinal pigmentation; FDA warning for sudden cardiac death (QT) |
What baseline tests are needed before starting an antipsychotic?
NICE CG178 lists baseline investigations before starting antipsychotic medication, and asks for regular monitoring during treatment, especially during titration.
- Weight (plotted on a chart) and waist circumference
- Pulse and blood pressure
- Fasting blood glucose or HbA1c
- Lipid profile and prolactin
- Movement disorder assessment (e.g. AIMS scale)
- Nutritional status, diet and physical activity
- ECG if specified in the drug's SPC, if examination shows cardiovascular risk (e.g. hypertension), with a personal history of cardiovascular disease, or on inpatient admission