Atypical antipsychotics — their uses and side effects in the elderly

Definition and mechanism. Second-generation ("atypical") antipsychotics act by combined dopamine D2 and serotonin 5-HT2A antagonism, with looser, more transient D2 binding than conventional agents. This gives them a lower risk of extrapyramidal symptoms and tardive dyskinesia, at the cost of a higher metabolic burden. Atypical antipsychotics are preferred over conventional antipsychotics in older adults.

Evidence-based indications. Schizophrenia and late-onset schizophrenia / VLOSLP (amisulpride 100 mg has RCT support); delusional disorder and late-life psychosis; acute mania in bipolar disorder (quetiapine, aripiprazole, risperidone at one-third to one-half adult dose); augmentation of antidepressants in treatment-resistant depression; psychotic depression combined with an antidepressant; Parkinson's disease psychosis (quetiapine, clozapine, or pimavanserin); and severe, distressing or dangerous agitation and psychosis in dementia after non-drug measures have failed.

Choosing the agent. Quetiapine — the drug of choice where parkinsonism or DLB is present; sedating, causes orthostatic hypotension. Risperidone 0.25–1 mg — most evidence in dementia-related psychosis, but dose-dependent EPS and hyperprolactinaemia. Olanzapine 2.5–5 mg — sedating, most metabolic burden, strongly anticholinergic. Aripiprazole 2–5 mg — partial D2 agonist, least metabolic effect, may cause akathisia. Clozapine — reserved for treatment-resistant schizophrenia and Parkinson's disease psychosis; requires mandatory neutrophil monitoring.

Adverse effects — the geriatric list. Metabolic — weight gain, hyperglycaemia, dyslipidaemia (worst with olanzapine and clozapine). Cardiovascular — orthostatic hypotension and falls, QTc prolongation and torsades. Neurological — EPS, tardive dyskinesia (risk rises with age), neuroleptic malignant syndrome, sedation, worsening of cognition. Anticholinergic — dry mouth, constipation, urinary retention, delirium (olanzapine, clozapine). Endocrine — hyperprolactinaemia (risperidone). Others — aspiration pneumonia, venous thromboembolism, agranulocytosis with clozapine, and severe neuroleptic sensitivity in DLB (sedation, worsening parkinsonism, autonomic instability — may be irreversible).

The boxed warning — must be written. All antipsychotics, typical and atypical, carry a boxed warning of increased mortality and cerebrovascular events when used for behavioural symptoms of dementia (roughly a 1.6–1.7 fold increase in death, mainly cardiac and infective). No medication is FDA-approved for treating the neuropsychiatric symptoms of dementia. Use therefore requires documented failure of non-pharmacological measures, informed consent from the patient or nominated representative, the lowest effective dose, and a defined review and withdrawal date.

Safe prescribing rules. Start at one-quarter to one-third of the adult dose and titrate slowly. Baseline and periodic monitoring of weight and waist circumference, fasting glucose (mg/dL), lipid profile, ECG for QTc, blood pressure lying and standing, prolactin if symptomatic, and an EPS/tardive dyskinesia examination (AIMS). Review for deprescribing every 3 months — most patients with dementia can be withdrawn without symptom recurrence. Avoid combining with other QT-prolonging or anticholinergic drugs. Note that antipsychotics such as quetiapine should generally not be used for anxiety disorders, as the risks outweigh the benefits. The AGS Beers Criteria list antipsychotics as potentially inappropriate unless the indication is schizophrenia, bipolar disorder or short-term antiemesis.

Brexpiprazole (FDA-approved May 2023) — the first drug ever approved for agitation associated with dementia due to Alzheimer's disease, at 2–3 mg daily. It remains subject to the class boxed warning on mortality in dementia-related psychosis, effect sizes are modest, and it must still follow rather than replace non-pharmacological management. Alongside this, xanomeline–trospium (KarXT, 2024) introduces a non-dopaminergic muscarinic mechanism with no EPS, prolactin rise or weight gain — potentially a major advance for older adults, with dementia-related psychosis trials ongoing.