What are the potential side effects of brexiprazole (antipsychotic medication)?

Brexiprazole Side Effects and Adverse Effects to Monitor

Brexiprazole is associated with akathisia, weight gain, and somnolence as the most common adverse effects, with rates generally lower than many other antipsychotics but requiring systematic monitoring, particularly for metabolic changes and movement disorders. 1

Most Common Adverse Effects (≥5% Incidence)

The FDA-approved labeling identifies the following most frequent adverse reactions across clinical trials 1:

In Adults

• Weight gain (7% in schizophrenia trials, 2-8% in MDD trials)
• Akathisia (6-9% in schizophrenia, 4-9% in MDD adjunctive therapy)
• Headache (6-7% across indications)
• Somnolence/sedation (5% in schizophrenia, 4-5% in MDD)
• Insomnia (variable across studies)

In Pediatric Patients (13-17 years)

• Weight gain (most common)
• Somnolence (notably higher in autism trials at 16% vs 5% in placebo)
• Headache
• Akathisia
• Nasopharyngitis 1

Movement Disorders (Extrapyramidal Symptoms)

Akathisia is the primary movement-related concern with brexiprazole, though rates are lower than with aripiprazole. 2, 3

Specific Movement Disorders to Monitor

• Akathisia: Risk ratio 1.72 compared to placebo; dose-dependent (lower at 2 mg vs 4 mg) 2
• Tremor: 2-3% incidence in clinical trials 1
• Tardive dyskinesia: Risk exists with all antipsychotics; requires regular monitoring with AIMS every 3-6 months 4, 1
• Dystonia: Possible but less common than with high-potency typical antipsychotics 4
• Parkinsonism: Can occur but rates are low 4

Metabolic and Endocrine Effects

Weight gain and metabolic changes require systematic monitoring, though brexiprazole shows a more favorable profile than olanzapine or clozapine. 5, 6

Weight and Metabolic Parameters

• Weight increase: 4-7% incidence; mean increase 1.1 kg in both short- and long-term studies 1, 7
• Blood glucose changes: Small changes observed; requires baseline and follow-up monitoring 5
• Lipid changes: Small alterations in lipid profiles, not clinically significant in most cases 7
• Blood creatinine phosphokinase elevation: 2% incidence 1

Monitoring Schedule

Before starting treatment, obtain: BMI, waist circumference, blood pressure, HbA1c, glucose, lipids, prolactin, liver function tests, urea and electrolytes, full blood count, and electrocardiogram 5

Follow-up monitoring:

• Fasting glucose at 4 weeks
• BMI, waist circumference, blood pressure weekly for 6 weeks
• Comprehensive metabolic panel at 3 months, then annually 5

Cardiovascular Effects

• Orthostatic hypotension: Possible, particularly during dose initiation 1
• QTc prolongation: Minimal effect (0-5 ms); favorable compared to other antipsychotics 4, 7
• Tachycardia: Can occur but rates are low 1

Neurological and Cognitive Effects

• Sedation/somnolence: 2-5% in adults; significantly higher (16%) in pediatric autism trials 1
• Cognitive impairment: Potential concern with all antipsychotics, though data specific to brexiprazole are limited 5
• Seizures: Risk exists but rates are low; brexiprazole does not significantly lower seizure threshold 1

Patients should be cautioned about operating hazardous machinery or driving until they know how brexiprazole affects them. 1

Serious but Rare Adverse Effects

Neuroleptic Malignant Syndrome (NMS)

• Presentation: Hyperthermia, muscle rigidity, altered mental status, autonomic instability 5, 1
• Incidence: Rare (0.02-3% with antipsychotics generally) 5
• Management: Immediate discontinuation, supportive care, possible ICU admission 5

Hematologic Effects

• Leukopenia/neutropenia/agranulocytosis: Possible with all antipsychotics; requires monitoring if risk factors present 1
• Unlike clozapine, brexiprazole does not require routine blood count monitoring in the absence of risk factors 5

Gastrointestinal Effects

• Constipation: 1-2% incidence 1
• Dyspepsia: 2-3% incidence 1
• Diarrhea: 1-3% incidence 1
• Nausea: Reported but rates similar to placebo 8

Psychiatric and Behavioral Effects

• Restlessness: 2-3% incidence, distinct from akathisia 1
• Anxiety: 2-4% incidence 1
• Pathological gambling and compulsive behaviors: Rare but documented risk with dopamine partial agonists 1
• Suicidal thoughts: Black box warning for adolescents and young adults, particularly in depression treatment 1

Special Population Considerations

Pregnancy and Lactation

• Third trimester exposure: Neonates at risk for extrapyramidal symptoms and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder) 1
• Monitoring: Neonates require observation for extrapyramidal and withdrawal symptoms 1
• Lactation: Brexiprazole presence in human milk unknown; present in rat milk 1

Elderly Patients

• Increased mortality: Black box warning for elderly patients with dementia-related psychosis 1
• Falls risk: Increased due to somnolence, orthostatic hypotension, and motor effects 1
• Cerebrovascular events: Increased risk in elderly with dementia 1

Dose-Dependent Effects

The 2 mg dose demonstrates better tolerability than 4 mg, with lower rates of akathisia and somnolence, while maintaining efficacy. 2, 3

• Akathisia and restlessness increase with dose escalation 1
• Discontinuation rates due to adverse effects: 1.3-3.5% in depression studies (dose-dependent) vs 0-1.4% for placebo 3
• In schizophrenia trials: 7.1-9.2% discontinuation in treatment groups vs 14.7% in placebo 3

Comparative Tolerability Profile

Brexiprazole shows lower akathisia rates than aripiprazole and cariprazine, less sedation than aripiprazole, but more weight gain than aripiprazole, cariprazine, or ziprasidone. 3, 9

The lower intrinsic activity at D2 receptors compared to aripiprazole, combined with stronger antihistaminic activity, translates to reduced akathisia risk but potentially increased sedation and weight gain 9

Clinical Monitoring Pitfalls

• Akathisia misinterpretation: Often mistaken for psychotic agitation or anxiety, leading to inappropriate dose increases rather than reduction or treatment 5, 4
• Pediatric somnolence: Significantly higher rates in younger patients, particularly in autism trials; requires careful dose titration 1
• Metabolic monitoring gaps: Failure to obtain baseline and follow-up metabolic parameters is common but increases long-term morbidity risk 5
• Tardive dyskinesia surveillance: Regular AIMS assessments often neglected despite being essential for early detection 4