What is the recommended dosing for brexiprazole (atypical antipsychotic) in older adults?

Brexiprazole Dosing in Older Adults

For older adults (≥65 years), initiate brexiprazole at 0.5-1 mg once daily and titrate slowly to a target dose of 2 mg/day for depression augmentation or 2-3 mg/day for schizophrenia, with dose adjustments required for renal/hepatic impairment and CYP2D6 poor metabolizers. 1, 2

Initial Dosing Strategy

• Start at 0.5-1 mg once daily in elderly patients, which is lower than the standard adult starting dose 1, 2
• Titrate gradually over 10-12 days to reach steady-state concentrations, as brexiprazole has a long half-life of 91 hours 1
• The FDA label indicates that systemic exposure in elderly patients may be higher, particularly in those with moderate renal impairment 1

Target Maintenance Doses

For Major Depressive Disorder (Adjunctive Treatment)

• Target dose: 2 mg/day is optimal for depression augmentation 3, 4
• A dose-response meta-analysis demonstrated that 1-2 mg achieves the best balance between efficacy (OR 1.52,95% CI 1.12-2.06) and tolerability, with diminishing returns at 3 mg 3
• In a 26-week study of elderly patients (≥65 years) with MDD, flexible dosing of 1-3 mg/day was well tolerated, with 66.7% completing the study 2

For Schizophrenia

• Target dose: 2-4 mg/day for acute and maintenance treatment 1, 4
• Number needed to treat (NNT) is 7 for response in acute schizophrenia and 4 for relapse prevention 5, 4
• Consider starting at the lower end (2 mg) in elderly patients given increased exposure 1

Critical Dose Adjustments

CYP450 Metabolism Considerations

• Reduce dose by 50% in known CYP2D6 poor metabolizers 1
• Reduce dose by 50% when co-administered with strong CYP3A4 inhibitors 1
• Reduce dose by 75% (to one-quarter of usual dose) when co-administered with both strong CYP2D6 AND CYP3A4 inhibitors, as this produces a 5.1-fold increase in drug exposure 1

Renal and Hepatic Impairment

• Population pharmacokinetic analysis showed higher exposure in moderate renal impairment compared to normal renal function 1
• Dose adjustments should be considered in hepatic or renal dysfunction, though specific recommendations are not provided in the label 4
• This is particularly relevant since 26% of adults >70 years have chronic kidney disease that may be unrecognized 6

Administration Details

• Can be taken with or without food - a high-fat meal does not significantly affect absorption 1
• Once-daily dosing is appropriate given the 91-hour half-life 1
• Peak plasma concentrations occur within 4 hours, with 95% oral bioavailability 1

Safety Profile in Elderly Patients

Common Adverse Events

• In the elderly MDD study, the most common treatment-emergent adverse events were fatigue (15.2%) and restlessness (12.9%) 2
• Akathisia occurred in 8.6% of MDD patients (NNH of 15) but was less common than with aripiprazole 5, 4
• Discontinuation due to adverse events was 18.2% in the 26-week elderly study, with fatigue being the most common reason (3.0%) 2

Metabolic and Cardiovascular Effects

• Weight gain is moderate - more than aripiprazole or cariprazine but requires monitoring, especially in long-term treatment 4, 7
• Minimal effects on prolactin, glucose, and lipids in short-term studies 5, 7
• No clinically relevant QT prolongation 5, 7
• Small changes in metabolic parameters were not clinically significant 7

Movement Disorders

• Lower rates of extrapyramidal symptoms compared to aripiprazole due to less intrinsic activity at D2 receptors 4, 7
• No consistent clinically relevant findings on movement disorder scales in the elderly study 2

Special Considerations for Geriatric Prescribing

Avoid in Certain Contexts

• Antipsychotics in elderly patients with dementia carry a black box warning for increased mortality and stroke risk 6
• Use should be reserved for situations where behavioral interventions have failed and patients pose serious risk of harm 6
• The inadvertent chronic continuation of antipsychotics after acute treatment is a significant harm - 47% continued after ICU discharge and 33% as outpatients without clear indication 6

Monitoring Requirements

• Daily in-person evaluation when used for acute agitation, with ongoing assessment of need 6
• Monitor for anticholinergic burden, as older adults are more susceptible to these effects 8
• Assess cumulative medication burden, as polypharmacy (≥5 medications) increases delirium risk 6

Clinical Efficacy in Elderly

• Mean MADRS total score improved by -14.5 points from baseline to week 26 in elderly patients with MDD 2
• CGI-Severity improved by -1.8 points and social functioning (SASS) improved by 3.2 points over 26 weeks 2
• These improvements suggest clinically meaningful benefits in both depressive symptoms and psychosocial functioning 2