Antipsychotics: Receptor Profiles & Adverse Effects
Every antipsychotic blocks D2; the side effects depend on what else it hits, and when
Mechanism and dopamine pathways
D2 blockade. Every antipsychotic blocks (or, for partial agonists, dampens) dopamine D2 receptors. Blocking D2 in the mesolimbic pathway relieves positive symptoms such as hallucinations and delusions; clinical response needs roughly 65–80% striatal D2 occupancy, and above about 80% extrapyramidal effects become likely. Because the drugs cannot choose a pathway, the same blockade elsewhere causes predictable adverse effects: extrapyramidal symptoms from the nigrostriatal tract, hyperprolactinemia from the tuberoinfundibular tract, and possible worsening of negative and cognitive symptoms from the mesocortical tract.
Off-target receptors. The remaining adverse effects come from other receptors: muscarinic blockade (dry mouth, constipation, urinary retention, blurred vision, confusion), H1 blockade (sedation, weight gain), and α1 blockade (orthostatic hypotension). Second-generation agents add 5-HT2A antagonism.
First-generation antipsychotics
Potency. "Potency" refers to the dose needed, not efficacy; at equivalent doses all typicals control psychosis about equally. High-potency agents bind D2 tightly at low doses, so extrapyramidal effects and NMS dominate. Low-potency agents require large doses that also block muscarinic, H1, and α1 receptors, and they lower the seizure threshold the most.
| Feature | High potency | Low potency |
|---|---|---|
| Examples | Haloperidol, fluphenazine | Chlorpromazine, thioridazine |
| EPS and NMS | More | Fewer |
| Anticholinergic, H1, α1 effects | Few | Many: dry mouth, sedation, orthostasis |
| Unique toxicities | — | Thioridazine: pigmentary retinopathy, QT prolongation; chlorpromazine: corneal and lens deposits, photosensitivity, blue-gray skin, cholestatic jaundice |
Extrapyramidal syndromes
A predictable clock. Extrapyramidal syndromes follow a typical order after a D2 blocker is started or its dose raised, and each has its own treatment.
| Syndrome | Onset | Features | Treatment |
|---|---|---|---|
| Acute dystonia | Hours–days | Torticollis, oculogyric crisis, trismus, tongue protrusion, rarely laryngospasm; young men | IM/IV benztropine or diphenhydramine |
| Akathisia | Days–weeks | Inner restlessness, pacing, rocking; linked to suicidality | Lower dose or switch; propranolol, benzodiazepine |
| Parkinsonism | Weeks–months | Symmetric bradykinesia, rigidity, masked face, shuffling gait, tremor | Lower dose or switch; benztropine or amantadine (not levodopa) |
| Tardive dyskinesia | Months–years | Orofacial choreoathetosis: lip smacking, chewing, tongue darting | Stop or switch (clozapine); valbenazine, deutetrabenazine |
Clinical nuances. Akathisia is often mistaken for agitation and wrongly treated with more antipsychotic. Drug-induced parkinsonism is usually symmetric, unlike idiopathic Parkinson disease, which begins on one side; rabbit syndrome, a fine rapid perioral tremor, is a late parkinsonian variant that responds to anticholinergics. Tardive dyskinesia is attributed to dopamine receptor supersensitivity after long-term blockade, is often permanent, and may be worsened by anticholinergics; the VMAT2 inhibitors valbenazine and deutetrabenazine deplete presynaptic dopamine and are approved for it. Clozapine carries the lowest tardive dyskinesia risk.
Neuroleptic malignant syndrome and hyperprolactinemia
Neuroleptic malignant syndrome (NMS). An idiosyncratic, potentially fatal reaction to any D2 blocker, most often a high-potency agent early in treatment or after a dose increase. It evolves over 1–3 days with lead-pipe rigidity, fever, autonomic instability (labile blood pressure, tachycardia, diaphoresis), and altered mental status. Labs show a very high CK, myoglobinuria, and leukocytosis. Management is to stop the drug, cool, hydrate, and give dantrolene (acts on muscle) and/or bromocriptine (a D2 agonist). A similar syndrome follows abrupt withdrawal of levodopa in Parkinson disease.
NMS vs serotonin syndrome: NMS follows dopamine blockers, develops over days, and causes lead-pipe rigidity with normal or reduced reflexes; serotonin syndrome follows serotonergic drugs, develops within hours, and causes clonus and hyperreflexia (treated with cyproheptadine).
Hyperprolactinemia. Dopamine from the tuberoinfundibular tract tonically inhibits pituitary lactotrophs, so D2 blockade releases prolactin. The results are galactorrhea, amenorrhea, infertility, low libido, erectile dysfunction, gynecomastia, and long-term bone loss. Risperidone (and its metabolite paliperidone) and high-potency typicals are the worst offenders; aripiprazole spares or even lowers prolactin.
Second-generation antipsychotics
Mechanism and trade-off. Atypicals block 5-HT2A as well as D2. Serotonin normally restrains dopamine release in the nigrostriatal and mesocortical pathways, so 5-HT2A blockade lowers extrapyramidal risk. The price is metabolic syndrome: weight gain, insulin resistance and diabetes, and dyslipidemia, worst with clozapine and olanzapine. Weight or BMI, waist circumference, fasting glucose or HbA1c, and lipids are monitored at baseline and periodically.
Clozapine. Reserved for treatment-resistant schizophrenia (failure of at least two adequate antipsychotic trials) and for persistent suicidality, where it is the only agent shown to reduce suicidal behavior. It has the lowest EPS and tardive dyskinesia risk. Its hazards are agranulocytosis (requiring ANC monitoring, most frequent early in therapy), dose-related seizures, myocarditis and cardiomyopathy, sialorrhea, severe constipation progressing to ileus, orthostasis, and marked weight gain with diabetes.
| Drug | Signature adverse effect(s) |
|---|---|
| Clozapine | Agranulocytosis, seizures, myocarditis, sialorrhea, constipation, metabolic syndrome |
| Olanzapine | Weight gain, diabetes, dyslipidemia (second only to clozapine) |
| Quetiapine | Sedation (H1), orthostasis (α1); little EPS |
| Ziprasidone | QT prolongation; taken with food for absorption |
| Risperidone | Most prolactin elevation and EPS among atypicals, rising with dose |
| Aripiprazole, brexpiprazole | Akathisia; minimal prolactin and metabolic effects |
D2 partial agonists. Aripiprazole and brexpiprazole are D2 partial agonists that also act as 5-HT1A partial agonists and 5-HT2A antagonists. They damp dopamine signaling where it is excessive but provide some where it is low, which spares prolactin and metabolic parameters. Akathisia is their signature side effect. They are used for schizophrenia, bipolar disorder, and as adjuncts in depression.
Long-acting injectables. Nonadherence is the leading cause of relapse in schizophrenia. Depot formulations (haloperidol and fluphenazine decanoate; risperidone, paliperidone, aripiprazole, and olanzapine) are injected every 2 weeks to 6 months and reduce relapse and rehospitalization. Olanzapine pamoate can cause a post-injection delirium/sedation syndrome, so patients are observed for 3 hours after each dose.