Atypical Antipsychotics

Introduction & Pathophysiology

• Antipsychotics (neuroleptics) — reduce psychotic symptoms across schizophrenia, bipolar disorder, psychotic depression and drug-induced psychosis; they are symptomatic, not curative.
• Atypical = second-generation (SGA) — newer agents with weak D₂ blockade but potent 5-HT_2a antagonism, defined operationally by a low liability for extrapyramidal symptoms (EPS) at effective doses — the original "atypicality" criterion derived from clozapine (1959).
• "Neuroleptic" — reserved for chlorpromazine/haloperidol-type conventional agents — potent D₂ blockers producing emotional quietening and EPS; a neuroleptic causes EPS at effective doses or catalepsy in animals.
• SGAs largely replaced FGAs — as first-line — chiefly for a more favourable neurological side-effect profile, not for superior antipsychotic efficacy (clozapine excepted).
• Dopamine hypothesis — excess D₂-mediated transmission in the associative/sensorimotor striatum drives positive symptoms; supported by DA-agonists (levodopa, amphetamine) provoking psychosis and ↑ striatal D₂ density/DA synthesis on imaging. It is incomplete — it fails to explain negative/cognitive symptoms or weak-D₂ atypicals.
• Serotonin & glutamate hypotheses — indole hallucinogens (LSD) are 5-HT_2a agonists — 5-HT_2a blockade is the key SGA mechanism; NMDA antagonists (ketamine, PCP) reproduce cognitive deficits + psychosis (glutamate hypofunction).
• Five dopaminergic pathways — frame the whole mechanism/ADR picture — mesolimbic-mesocortical (D₂ block → antipsychotic effect), nigrostriatal (→ EPS), tuberoinfundibular (→ hyperprolactinaemia), medullary-periventricular (appetite), incertohypothalamic.