How antipsychotics are tested on Step 1
Expect a patient who develops a movement disorder, a fever with rigidity, galactorrhea, weight gain, or QT prolongation after starting an antipsychotic, and a question about the mechanism or management.
High-potency typicals (haloperidol) bind D2 tightly → more EPS. Low-potency typicals (chlorpromazine) bind D2 weakly but block muscarinic, α1, and H1 receptors → anticholinergic effects, orthostasis, and sedation.
Four dopamine pathways
Antipsychotics block D2 receptors in every dopamine pathway, not just the one that causes psychosis.
| Receptor blocked | Result |
|---|---|
| D2 (mesolimbic) | Antipsychotic effect |
| D2 (nigrostriatal) | EPS |
| D2 (pituitary) | Hyperprolactinemia |
| 5-HT2A | Fewer EPS, may improve negative symptoms (atypicals) |
| Muscarinic M1 | Dry mouth, constipation, urinary retention, confusion |
| α1 | Orthostatic hypotension |
| H1 | Sedation, weight gain |
Aripiprazole is a D2 partial agonist — little prolactin elevation or EPS, but akathisia is common.
Typical vs atypical antipsychotics
The two generations trade movement side effects for metabolic ones.
| Agent | Notable feature |
|---|---|
| Haloperidol | High potency; IV for delirium and agitation; most EPS and NMS |
| Clozapine | Most effective for refractory schizophrenia; agranulocytosis, seizures, myocarditis, sialorrhea |
| Olanzapine | Most weight gain and metabolic syndrome among commonly used agents |
| Quetiapine | Sedating; cataracts (animal data); low EPS |
| Risperidone | Highest prolactin elevation among atypicals |
| Aripiprazole | D2 partial agonist; weight-neutral; akathisia |
| Ziprasidone | QT prolongation |
Clozapine requires absolute neutrophil count monitoring because of agranulocytosis.
Movement disorders and NMS
Extrapyramidal symptoms follow a predictable timeline after starting a D2 blocker.
| Syndrome | Timing | Features | Treatment |
|---|---|---|---|
| Acute dystonia | Hours to days | Torticollis, oculogyric crisis, laryngospasm | Benztropine or diphenhydramine |
| Akathisia | Days to weeks | Inner restlessness, pacing | Lower dose, propranolol, benzodiazepine |
| Drug-induced parkinsonism | Weeks | Bradykinesia, rigidity, tremor | Lower dose, benztropine, or switch |
| Tardive dyskinesia | Months to years | Choreoathetoid orofacial movements; may be irreversible | Stop or switch (clozapine); VMAT2 inhibitors (valbenazine) |
Anticholinergics help acute dystonia and parkinsonism but can worsen tardive dyskinesia.
Clinical application
Recognize NMS early; it can be fatal.
Three days after starting IV haloperidol for agitation, a man has temperature 40.1 °C, blood pressure swinging between 170/100 and 90/50, diffuse lead-pipe rigidity, confusion, and CK 28,000 U/L. What is the diagnosis and treatment?
- Onset over days after a high-potency D2 blocker suggests neuroleptic malignant syndrome.
- Lead-pipe rigidity (not clonus), hyperthermia, autonomic instability, and very high CK confirm it.
- Dopamine blockade in the hypothalamus and striatum causes hyperthermia and rigidity.
Answer. Neuroleptic malignant syndrome. Stop haloperidol, cool aggressively, give IV fluids (rhabdomyolysis), and use dantrolene (muscle relaxant) and bromocriptine (dopamine agonist).