STEPTRACKERPHARMACOLOGY + PSYCHIATRY | PSYCHIATRY | HIGH-YIELD REVIEW

Antipsychotics

Every antipsychotic blocks D2 receptors; first-generation drugs cause more movement problems, second-generation drugs more metabolic problems. Clozapine stands apart.

FOCUS ON
Typical (1st gen): high potency (haloperidol, fluphenazine, pimozide) → more EPS, NMS; low potency (chlorpromazine, thioridazine) → more anticholinergic, α1, H1 effects; thioridazine retinal deposits, QT; chlorpromazine corneal deposits. Atypical (2nd gen): D2 + 5-HT2A block — risperidone (hyperprolactinemia), olanzapine and clozapine (weight gain, diabetes, dyslipidemia), quetiapine (sedation), ziprasidone (QT), aripiprazole/brexpiprazole/cariprazine (D2 partial agonists; akathisia), lurasidone (pregnancy-friendlier). Clozapine: treatment-resistant schizophrenia, suicidality; agranulocytosis (ANC monitoring), seizures, myocarditis, sialorrhea, constipation. EPS timeline: acute dystonia (hours–days) → benztropine/diphenhydramine; akathisia (days–weeks) → propranolol; parkinsonism (weeks) → benztropine; tardive dyskinesia (months–years) → valbenazine, switch to clozapine. NMS: fever, lead-pipe rigidity, autonomic instability, ↑ CK → stop drug, dantrolene, bromocriptine.
DRUG · GROUP
KEY RECEPTORS
DISTINCT USE
SIGNATURE ADVERSE
Haloperidol · fluphenazine
Strong D2 block (high potency)
Acute agitation, delirium, Tourette; depot injection
EPS, NMS, hyperprolactinemia, QT (IV haloperidol)
Chlorpromazine · thioridazine
Weak D2; strong M, α1, H1
Psychosis (rare now), intractable hiccups
Sedation, orthostasis, anticholinergic; thioridazine retinitis pigmentosa, QT
Risperidone · paliperidone
D2 + 5-HT2A
Schizophrenia, bipolar mania, autism irritability
Hyperprolactinemia (galactorrhea, amenorrhea, gynecomastia), EPS at high dose
Olanzapine
D2 + 5-HT2A + H1, M
Schizophrenia, bipolar, agitation
Marked weight gain, diabetes, dyslipidemia
Quetiapine
Weak D2, strong H1
Bipolar depression, PD psychosis, adjunct MDD
Sedation, orthostasis, metabolic effects, cataracts (animal)
Ziprasidone · lurasidone
D2 + 5-HT2A
Schizophrenia, bipolar depression (lurasidone)
QT (ziprasidone); take with food; low metabolic risk
Aripiprazole · brexpiprazole · cariprazine
D2 partial agonists
Schizophrenia, bipolar, adjunct MDD, Tourette
Akathisia; low prolactin and metabolic effects
Clozapine
Weak D2, D4, 5-HT2A, many others
Treatment-resistant schizophrenia, suicidal patients, PD psychosis
Agranulocytosis (ANC monitoring), seizures, myocarditis, sialorrhea, ileus, weight gain
Acute dystonia
Sudden D2 block in nigrostriatal pathway
Hours–days: torticollis, oculogyric crisis
Benztropine or diphenhydramine
Akathisia
Inner restlessness
Days–weeks
Propranolol, benzodiazepine, lower dose
Drug-induced parkinsonism
Nigrostriatal D2 block
Weeks: bradykinesia, rigidity, tremor
Benztropine, amantadine
Tardive dyskinesia
D2 receptor upregulation after chronic block
Months–years: orofacial chewing, lip smacking
Valbenazine/deutetrabenazine; switch to clozapine; often irreversible
Neuroleptic malignant syndrome
Sudden profound D2 block
Fever, lead-pipe rigidity, delirium, labile BP, ↑ CK, myoglobinuria
Stop drug, cool, dantrolene, bromocriptine

Mechanism — four dopamine pathways

MesolimbicBlock → ↓ positive symptoms (goal)
MesocorticalBlock → worse negative symptoms
NigrostriatalBlock → EPS
TuberoinfundibularBlock → ↑ prolactin

Typical vs atypical

FEATURE
TYPICAL
ATYPICAL
EPS / TD
More
Less
Metabolic
Less
More (olanzapine, clozapine)
Negative symptoms
Little help
Some help
Prolactin
↑
↑ risperidone only

How it's tested

COMMON CONFUSIONAkathisia looks like agitation from psychosis — increasing the antipsychotic makes it worse; lower the dose or add propranolol.
THE TRAPFever and sore throat on clozapine → check ANC immediately (agranulocytosis), not just treat as a cold.
YOUR APPROACHTiming of the movement problem → name it → treat it. Metabolic patient → avoid olanzapine/clozapine; pick aripiprazole, lurasidone, ziprasidone.

If you see… think…

Neck twisting, eyes rolled up hours after haloperidol → acute dystonia → benztropine
Restlessness, can't sit still on antipsychotic → akathisia → propranolol
Lip-smacking after years of treatment → tardive dyskinesia
Fever, rigidity, ↑ CK, confusion → NMS → dantrolene, bromocriptine
Galactorrhea on atypical antipsychotic → risperidone
Weight gain, new diabetes → olanzapine or clozapine
Treatment-resistant schizophrenia → clozapine
Weekly blood counts on an antipsychotic → clozapine (agranulocytosis)
Retinal pigmentation on an old antipsychotic → thioridazine
D2 partial agonist → aripiprazole