second-generation antipsychotic

**Mechanism:** SGAs block dopamine D2 receptors (mesolimbic pathway, which reduces positive symptoms) and serotonin 5-HT2A receptors. 5-HT2A antagonism increases dopamine release in the nigrostriatal and mesocortical pathways. This is thought to reduce EPS and may help negative symptoms. SGAs bind D2 less tightly (fast dissociation) than first-generation antipsychotics (FGAs). Aripiprazole, brexpiprazole, and cariprazine are D2 partial agonists ("dopamine system stabilizers"). Many SGAs also block H1, M1, and α1 receptors, which causes side effects.

**Common agents (mnemonic: names often end in "-apine" or "-idone"):** - Clozapine: D4 and 5-HT2A antagonist. Reserved for treatment-resistant schizophrenia and for reducing suicidality in schizophrenia. - Olanzapine, quetiapine: "-apines"; highest metabolic risk (olanzapine) and sedation. - Risperidone, paliperidone, ziprasidone, lurasidone, iloperidone, lumateperone: risperidone and paliperidone cause the most hyperprolactinemia of the SGAs. - Aripiprazole, brexpiprazole, cariprazine: partial D2 agonists with a low metabolic burden. Aripiprazole can cause akathisia. - Pimavanserin: selective 5-HT2A inverse agonist, used for Parkinson disease psychosis. - Newer non-D2 agent: xanomeline-trospium (muscarinic M1/M4 agonist plus peripheral anticholinergic) is approved for schizophrenia and is not a typical D2 blocker.

**Indications:** Schizophrenia (positive and negative symptoms), acute mania and maintenance in bipolar disorder, adjunct in treatment-resistant major depression (aripiprazole, quetiapine, brexpiprazole), irritability in autism, Tourette (risperidone, aripiprazole), and agitation or psychosis in various settings.

**Adverse effects (high-yield):** - Metabolic syndrome: weight gain, insulin resistance and diabetes, dyslipidemia. Greatest with clozapine and olanzapine. Monitor weight/BMI, waist circumference, BP, fasting glucose or HbA1c, and lipids. - QT prolongation: ziprasidone is the classic example. Also iloperidone, quetiapine, and others. Check baseline ECG and electrolytes. - Clozapine-specific: agranulocytosis (requires ANC monitoring through a REMS program, though requirements have been relaxed in recent years), seizures (dose-dependent lowering of seizure threshold), myocarditis and cardiomyopathy (early in therapy), sialorrhea, orthostatic hypotension, and constipation or ileus. - Hyperprolactinemia (gynecomastia, galactorrhea, amenorrhea, sexual dysfunction): most with risperidone and paliperidone. - Sedation, anticholinergic effects, and orthostatic hypotension via H1, M1, and α1 blockade. - EPS and tardive dyskinesia: lower risk than FGAs but not zero. Risperidone at higher doses carries the most EPS risk. - Neuroleptic malignant syndrome (NMS) can occur with any antipsychotic: fever, "lead-pipe" rigidity, autonomic instability, altered mental status, and elevated CK. Treat with stopping the drug, supportive care, dantrolene, and bromocriptine. - Boxed warning: increased mortality in elderly patients with dementia-related psychosis.

**SGA vs FGA comparison:** - FGAs (haloperidol, chlorpromazine, fluphenazine, etc.) are mainly D2 antagonists, with higher EPS, tardive dyskinesia, and prolactin elevation. Low-potency FGAs also have anticholinergic, antihistamine, and antiadrenergic effects. - SGAs have a lower EPS risk, with metabolic and cardiac effects as their main drawbacks. - Efficacy for positive symptoms is generally similar, except clozapine, which is superior for refractory illness.

**Test-taking pearls:** - Treatment-resistant schizophrenia (failure of 2 adequate antipsychotic trials) → clozapine. - A patient on an antipsychotic who develops diabetes or weight gain → suspect olanzapine or clozapine. - A patient with galactorrhea or amenorrhea on an antipsychotic → risperidone. - A patient with a prolonged QTc → ziprasidone. - Acute dystonia is treated with benztropine or diphenhydramine. Akathisia is treated with a β-blocker (propranolol) or benzodiazepine, or by dose reduction. Tardive dyskinesia is treated with VMAT2 inhibitors (valbenazine, deutetrabenazine). - Long-acting injectable formulations (e.g., risperidone, paliperidone, aripiprazole, olanzapine pamoate) are used for nonadherence.