Combination loxapine and aripiprazole for refractory hallucinations in schizophrenia

To document the effects of combining loxapine with aripiprazole for refractory hallucinations in 2 patients with chronic schizophrenia.

Two patients with schizophrenia and auditory hallucinations that were unresponsive to what was considered adequate treatment with multiple typical and atypical antipsychotic medications given over several years were prescribed a combination of aripiprazole 20-30 mg and high-dose loxapine (100-300 mg/day). Both patients had refused clozapine and depot antipsychotics. Aripiprazole/loxapine therapy resolved hallucinations in both patients, and discontinuation of either medication resulted in a return of persecutory voices. Breakthrough hallucinations in both individuals responded to increasing the loxapine dosage. Adverse effects included hypersalivation and tremor, which were treated with benztropine and propranolol. The patients also reported mild sedation, which resolved after several weeks of treatment. Both patients continued to do well during 2 years after starting this combination of medications.

Recent research has indicated serotonergic and dopaminergic abnormalities in the superior temporal gyrus of patients with a history of chronic auditory hallucinations. Both loxapine and aripiprazole have effects on dopaminergic and postsynaptic serotonergic (5-HT₂A) receptor systems, which could account for synergistic effects in treating refractory hallucinations. The combination appears safe, even when loxapine is given in high dosages. Patients should be monitored for the development of parkinsonian tremors.

The combination of aripiprazole and high-dose loxapine should be considered in patients with schizophrenia who develop treatment-refractory hallucinations, particularly those who are unwilling to accept treatment with either depot antipsychotics or clozapine.