The pharmacotherapeutic use of clozapine in older adults: A narrative review

Abstract

Clozapine remains the gold-standard treatment for refractory schizophrenia, yet its use in older adults is often limited by concerns regarding tolerability, age-related pharmacokinetic changes, and the burden of medical comorbidities. This narrative review synthesises current evidence on clozapine use in older populations, with a focus on pharmacokinetic alterations, dosing strategies, comorbidity-related considerations, and clozapine’s therapeutic benefits, safety, and risks. A primary aim is to review the nature of age-related pharmacokinetic changes and their cumulative impact over time. Aging is associated with changes in drug absorption, increased volume of distribution due to altered body composition, reduced hepatic blood flow, decreased cytochrome P450 enzyme activity, and impaired clearance, all of which may elevate clozapine and norclozapine plasma concentrations and increase susceptibility to adverse effects. Older adults are particularly vulnerable to sedation, orthostatic hypotension, anticholinergic effects, gastrointestinal hypomotility, falls, and serious adverse events including agranulocytosis and pneumonia. Polypharmacy and comorbidities such as hepatic conditions, obesity and cognitive impairment further complicate treatment and elevate the risk of drug interactions. Evidence supports a conservative “start low, go slow” approach, guided by therapeutic drug monitoring to determine clozapine concentrations, with many older adults achieving therapeutic benefit at lower doses than younger patients, alongside careful monitoring and individualized risk–benefit assessment. Understanding these age-related pharmacokinetic and clinical considerations is essential to optimise dosing, minimise toxicity, and enhance therapeutic outcomes in older patients. Further research is required to strengthen the evidence base and develop clear clinical guidelines for this growing population.