Discontinue Rexulti Immediately and Reassess the Underlying Condition
If a patient experiences increased hallucinations while taking Rexulti (brexpiprazole), the medication should be discontinued immediately, as this represents either treatment failure, paradoxical worsening, or an underlying condition requiring different management. 1
Immediate Actions
Stop Rexulti and Evaluate the Clinical Context
Discontinue brexpiprazole immediately when hallucinations worsen, as antipsychotics are intended to reduce—not increase—psychotic symptoms. 1, 2
Rule out medical causes of worsening hallucinations including metabolic derangements, infections, substance withdrawal (especially alcohol or benzodiazepines), or medication interactions before attributing symptoms to psychiatric disease progression. 3, 4
The FDA label for brexpiprazole warns of serious neuropsychiatric risks including neuroleptic malignant syndrome and metabolic changes that could contribute to delirium and secondary hallucinations. 1
Assess for Drug-Induced Complications
Check for serotonin syndrome if the patient is on concurrent SSRIs, SNRIs, or other serotonergic agents, as this can cause altered mental status and perceptual disturbances. 5
Evaluate for akathisia, which brexpiprazole can cause and which may be misinterpreted as worsening psychosis or agitation. 6, 7
Monitor for metabolic derangements (hyperglycemia, electrolyte abnormalities) that brexpiprazole can induce and which may precipitate delirium with hallucinations. 1
Transition to Alternative Antipsychotic Therapy
First-Line Alternatives for Acute Hallucinations
Switch to olanzapine 2.5-10 mg daily as the preferred atypical antipsychotic for acute hallucinations, given its rapid onset, superior efficacy, and favorable side effect profile compared to other agents. 4, 8
Olanzapine demonstrates specific efficacy in reducing hallucinations in schizophrenia spectrum disorders, with 92% of first-episode patients achieving remission of hallucinations within one year of treatment. 2
Alternative options include risperidone 0.25-2 mg daily (caution: extrapyramidal symptoms at ≥2 mg/day) or quetiapine 12.5-200 mg twice daily (more sedating, monitor for orthostasis). 4, 8
Dosing Strategy for New Antipsychotic
Start with the lowest effective dose and titrate slowly over 14-21 day intervals to minimize side effects and optimize adherence. 8
For risperidone, target 2 mg/day initially with maximum 4 mg/day in first-episode psychosis; doses above 4-6 mg/day increase side effects without improving efficacy. 8
Avoid exceeding maximum recommended doses, as this only increases adverse effects without therapeutic benefit. 8
Special Considerations Based on Clinical Context
If Hallucinations Are Distressing or Patient Is Agitated
The Society of Critical Care Medicine acknowledges that patients experiencing significant distress from hallucinations, anxiety, or fearfulness may benefit from short-term antipsychotic use until symptoms resolve, despite general recommendations against routine antipsychotic use for delirium. 3
For severely agitated patients with hallucinations, consider intramuscular olanzapine 10 mg as first-line, or haloperidol 5 mg IM plus lorazepam 2 mg IM for more rapid sedation. 8
If Patient Has Treatment-Resistant Symptoms
After failure of two first-line atypical antipsychotics (including the failed brexpiprazole trial), clozapine becomes the drug of choice with target blood levels of 350-450 μg/mL for maximal effect. 2
Consider augmentation with cognitive-behavioral therapy (CBT) to reduce catastrophic appraisals and emotional distress associated with auditory hallucinations. 2
Critical Pitfalls to Avoid
Do not continue brexpiprazole hoping symptoms will improve—worsening hallucinations on an antipsychotic indicate treatment failure or an alternative diagnosis requiring immediate intervention. 1, 2
Do not use typical antipsychotics (haloperidol, fluphenazine) as first-line alternatives in elderly patients due to 50% risk of irreversible tardive dyskinesia after 2 years of continuous use. 8, 5
Avoid prescribing antipsychotics to patients at significant risk for torsades de pointes (baseline QTc prolongation, concurrent QTc-prolonging medications, history of arrhythmia). 3
Do not attribute all hallucinations to primary psychiatric disease—delirium from medical causes requires specific treatment of the underlying condition, not escalation of antipsychotics. 3, 4