First principle: one mechanism, location‑dependent consequences
Antipsychotic efficacy is anchored in post‑synaptic D2 antagonism, but dopamine serves four pathways — so blocking it everywhere is non‑selective:
| Pathway | Consequence of D2 blockade |
|---|---|
| Mesolimbic | ↓ positive symptoms (the therapeutic effect) |
| Mesocortical | Already hypodopaminergic → blockade can worsen negative/cognitive symptoms |
| Nigrostriatal | EPS: acute dystonia, parkinsonism, akathisia; tardive dyskinesia with chronic blockade |
| Tuberoinfundibular | Loss of prolactin inhibition → hyperprolactinaemia (galactorrhoea, amenorrhoea, sexual dysfunction, long‑term bone loss) |
This single table lets you predict side‑effects from where a drug acts, rather than memorising lists.
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Typical vs atypical — the trade‑off
- First‑generation (typical) — potent D2 blockade → more EPS and prolactin elevation. High‑potency (haloperidol) → EPS; low‑potency (chlorpromazine) → sedation, antimuscarinic, hypotension.
- Second‑generation (atypical) — 5‑HT2A antagonism disinhibits dopamine in nigrostriatal/mesocortical pathways → fewer EPS, but a metabolic liability (weight gain, dyslipidaemia, insulin resistance) that is now the dominant long‑term risk. Aripiprazole (D2 partial agonist) is prolactin‑sparing and metabolically lighter.
Adverse effects that must be recognised on sight 🚩
- NMS — fever, lead‑pipe rigidity, autonomic instability, ↑CK, altered mental state → stop antipsychotic, supportive care ± dantrolene/bromocriptine.
- Acute dystonia — young males, early → anticholinergic (procyclidine/benztropine).
- Akathisia — inner restlessness (often mistaken for agitation/anxiety → don't escalate the antipsychotic) → reduce dose, propranolol.
- Tardive dyskinesia — late, potentially irreversible → use lowest effective dose, consider VMAT2 inhibitors.
- QTc prolongation — baseline/periodic ECG for higher‑risk agents.
Monitoring you own
Baseline + scheduled weight/BMI, waist, fasting glucose/HbA1c, lipids, prolactin (if symptomatic), ECG. Prescribing = predicting + monitoring, not dispensing.
Pitfalls
- Reading akathisia as worsening psychosis and increasing the dose.
- Ignoring metabolic monitoring because the patient is young.
Pearls
- 🎯 Nigrostriatal → EPS; tuberoinfundibular → prolactin; mesolimbic → efficacy; mesocortical → negative symptoms. Pathway logic beats rote side‑effect lists.
- 🩺 Persistent restlessness on an antipsychotic is akathisia until proven otherwise — treat, don't escalate.
Next → Efficacy sits inside a phased management plan (Concept 14).