Antipsychotics

Mostly what these disorders are not treated with. In delirium there is no FDA-approved drug, and evidence "does not support the routine use of antipsychotics to shorten delirium duration, hasten cognitive recovery, or prevent new episodes" — use is restricted to severe agitation that threatens safety, at the lowest dose, adjusted daily, stopped as soon as feasible, with a baseline ECG and QTc monitoring; no pharmacotherapy is indicated for hypoactive delirium. In dementia they are the last step after pain, triggers, environment and non-drug measures, because of the boxed warning (≈ 1.6–1.7× mortality, 4.5% vs 2.6%) and stroke risk. Lewy body and Parkinson disease dementia: haloperidol is contraindicated; only quetiapine, pimavanserin or clozapine are considered. Benzodiazepines are worse still — they double falls and hip fractures and deepen delirium; their one delirium indication is alcohol or benzodiazepine withdrawal.

One of the two rapid-tranquilization classes — the goal is to calm, not to sedate. "For severely violent clients requiring immediate sedation, a rapid-acting first-generation antipsychotic (e.g., haloperidol or droperidol), benzodiazepine (e.g., midazolam), or a combination of both may be prescribed," and "Chemical restraint with antipsychotic and benzodiazepine medications has a long-standing safety and efficacy record." Project BETA: "The goal of medicating the agitated patient is not to sedate but to calm him." Offer oral medication first — "Oral medication is the preferred option when patients are willing to cooperate" — and "Giving the patient a choice in either oral or parenteral administration can help give the patient some control." Atypicals "offer greater tranquilization and less sedation than typical antipsychotics" and reduce extrapyramidal symptoms. Alcohol intoxication agitation "is best treated with an antipsychotic medication." Safety: QT prolongation (droperidol carries a boxed warning); akathisia can itself cause agitation; and "Both typical and atypical antipsychotic medications have black box warnings indicating that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death" — and the haloperidol label adds that "Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less haloperidol." Olanzapine is not combined with a benzodiazepine.

The class that covers both poles, which is why it is a maintenance mainstay. On the CANMAT/ISBD and WFSBP first-line lists for acute mania, as reported by StatPearls, the second-generation antipsychotics named are quetiapine, risperidone, aripiprazole, asenapine, cariprazine, olanzapine and paliperidone, alongside lithium and valproate, and a large meta-analysis found atypical antipsychotics more effective than mood stabilisers for acute mania — "but not necessarily for maintenance." Two are also first-line for acute bipolar depression — quetiapine and lurasidone (alone or added to lithium or divalproex), with cariprazine also listed — while olanzapine-fluoxetine "remains an evidence-supported option but is often reserved because of metabolic adverse effects." In maintenance, quetiapine, aripiprazole, olanzapine and long-acting injectable risperidone are among the evidence-supported options, with lithium the best-supported. (Any valproate/divalproex option carries the pregnancy restriction on the valproate row.) For escalating agitation in an acute manic episode, the nursing text describes "immediate administration of a prescribed antipsychotic and/or benzodiazepine," noting that an injectable combination of haloperidol and lorazepam is commonly used for rapid onset of action, and "the nurse must monitor for respiratory depression, hypotension, and oversedation" afterwards. Clozapine and electroconvulsive therapy "have shown many benefits for treatment-resistant mania but are less commonly used." One disorder-side interaction is worth carrying: neuroleptic malignant syndrome may be caused by low-potency and atypical antipsychotics, antiemetics, tricyclic antidepressants and lithium, and concurrent use of multiple neuroleptic agents or lithium increases the risk — so a bipolar patient on lithium plus an antipsychotic carries both risks at once. The rest of the antipsychotic adverse-effect burden — extrapyramidal symptoms, tardive dyskinesia, metabolic syndrome, prolactin elevation, QTc prolongation and the dementia-related-psychosis boxed warning — is taught on the Schizophrenia page and the class page, and is not re-derived here.

Olanzapine in anorexia — useful, and NOT FDA-approved. "There are currently no medications approved by the U.S. Food and Drug Administration (FDA) to treat the symptoms of anorexia nervosa or ARFID." For "acutely ill patients who do not respond to initial treatment, olanzapine is a first-line medication. Other antipsychotics have not demonstrated similar effects on weight gain," and Open RN notes it "has shown potential benefits by promoting weight gain and alleviating anxiety symptoms." Nutrition and psychotherapy remain the core — "Pharmacotherapy is not used initially."

Chorea with behavioral or psychotic symptoms; aggression (off-label). NINDS: "Antipsychotic medicines, such as risperidone and olanzapine, may help calm chorea movements and also treat psychiatric symptoms," but "Some antipsychotic medicines can make movement-related symptoms worse in people with HD." EHDN (2019): second-generation neuroleptics (Grade B) are first-line for chorea "in particular when the patients have associated personality and/or behavioral or psychotic disorders," and a neuroleptic is the first-line treatment for aggressive behavior (Grade C); monotherapy is preferred. StatPearls: evidence "is inconsistent," with extrapyramidal effects "including akathisia and tardive dyskinesia." Do not combine QTc-prolonging antipsychotics with tetrabenazine (XENAZINE label).

Augmentation only. "Augmentation with antipsychotics, especially risperidone and aripiprazole, shows some evidence of efficacy; however, only one-third of SSRI-resistant patients experience clinically meaningful improvements, warranting meticulous risk-benefit evaluations" (StatPearls). Open RN notes some respond "especially if they also have a tic disorder."

Low dose for cognitive-perceptual symptoms (Open RN). "Cognitive-perceptual symptoms (e.g., hallucinations and paranoid ideation): Treated with low-dose antipsychotics such as aripiprazole, risperidone, and quetiapine." "Medications that can be fatal in overdose should be avoided or used with caution."

The gold-standard treatment, with a precisely limited target. Antipsychotic medications "are typically used to treat psychosis." What they fix and what they do not is the sentence that organises the whole page: they are "most effective in positive symptoms of psychosis — hallucinations, delusions, disorganized thoughts and behavior — and less useful for negative symptoms," with "little evidence that antipsychotics substantially improve negative or cognitive symptoms" except where those are secondary to positive symptoms. Efficacy arrives when central concentrations occupy around 70% of dopamine D2 receptors — clozapine and quetiapine are the exceptions, working at lower occupancy. Teach the timeline (NIMH): "Some symptoms, such as agitation and hallucinations, typically go away within days of starting antipsychotic medication. Other symptoms, such as delusions, usually go away within a few weeks. However, people may not experience the full effects of antipsychotic medication for up to 6 weeks." On generations, resist the shortcut: second-generation agents cause fewer extrapyramidal and tardive effects while most carry a higher risk of metabolic syndrome. Beyond that trade-off, the second-generation drugs are not a homogeneous class: in a large meta-analysis only four of the nine compared (amisulpride, clozapine, olanzapine, risperidone) beat first-generation drugs on overall efficacy, and only by small-to-medium margins, while a later network meta-analysis in adults with multi-episode schizophrenia found efficacy differences between individual drugs mostly gradual and side-effect differences more marked — so the choice is made drug by drug, weighing the outcomes that matter most, the patient’s medical problems and preferences. Start low: young people in a first episode of psychosis seem to respond to low doses and are more susceptible to extrapyramidal effects and acute weight gain (first-episode review); older adults need lower doses, and in general, start at the lowest dose and titrate up slowly to reduce side effects, then give a typically effective dose for at least 4–6 weeks before judging it ineffective (WHO). Dose deliberately: the dose-response curve plateaus — doses above the approved range do not yield greater efficacy, only more adverse effects. Long-acting injectables address nonadherence. Clozapine is the answer for the roughly one-third with treatment-resistant schizophrenia — symptoms persisting despite two or more adequate trials with documented adherence — with about 40% responding — and its FDA indications are exactly those two groups: "severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment" and "Reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior." Despite that evidence, clozapine is widely underused and often started years late; the main barriers are the mandatory blood testing, fear of serious side effects, doubts about adherence, difficulty identifying suitable patients, fragmented services, and too little training. It requires absolute neutrophil count monitoring through the US Clozapine REMS program because of agranulocytosis risk — the schedule and the cut-offs belong to the class page. Clozapine’s other disorder-side burdens: seizure with high doses or rapid escalation, myocarditis, gastrointestinal hypomotility with constipation, fecal impaction, ileus and death requiring a prophylactic bowel regimen, and sialorrhea in 90% of patients, which must be managed to prevent discomfort, stigma and aspiration pneumonia. Never stop abruptly — abrupt withdrawal causes dizziness, nausea and vomiting, and uncontrolled movements of the mouth, tongue or jaw.

Potent pain control via µ-opioid receptor agonism. Watch for respiratory depression; reverse with naloxone.

Potentiate GABA for anxiety, seizures, and sedation. Additive CNS depression — deadly with opioids.

First-line antidepressants that raise synaptic serotonin. Delayed onset; watch for serotonin syndrome and early suicidality.

Stabilize neuronal firing to prevent seizures. Many are narrow-therapeutic-index — level monitoring and rash vigilance are essential.

A widely used fever/pain reliever with no anti-inflammatory or platelet effect — but hepatotoxic in overdose.

Lithium controls bipolar mania but has a tiny therapeutic window — levels are everything.