Combination therapy of brexpiprazole and aripiprazole for an adolescent patient with a first episode of schizophrenia: A case report.

Abstract

One year before admission to our facility, an 18-year-old female high school student had presented with cognitive decline and reduced executive function. She presented grossly disorganized behavior accompanied by a mild fever and was tentatively diagnosed with encephalitis. She had no developmental issues, no history of illegal drug use, and no family history of psychiatric disorders. Neurologists conducted various tests, including tests of autoantibodies, cerebrospinal fluid, electroencephalography, and head MRI. Neither infection nor autoimmune disease was observed. Acyclovir infusion and steroid pulse therapy were performed as diagnostic treatments, but they were ineffective. The findings in total ruled out encephalitis. She gradually developed catatonic symptoms, and was transferred to our department. She was treated with lorazepam 1 mg/day, which led to partial relief of catatonic symptoms. Upon further communication with the patient, other symptoms, such as auditory hallucinations, loosening of association, and ego disorder as a delusion of control, were reported. She was then diagnosed with schizophrenia, and was initially treated with brexpiprazole, based on its tolerability, 1 mg/day, which was increased to 2 mg/day over a period of 1 week. She reported partial amelioration of her hallucinations. Brexpiprazole was increased to 4 mg/day. While brexpiprazole treatment was provided over a 4-week period, there was no further improvement in her symptoms. To improve her symptoms further, aripiprazole was added, 12 mg/day, and her hallucinations dramatically improved over a few days. She achieved remission with a combination of brexpiprazole (2 mg/day) and aripiprazole (12 mg/day). The combination therapy was continued until her discharge; the total length of her hospitalization was 3 months. Following discharge, she continued combination therapy, but aripiprazole was gradually discontinued over a period of 3 months because the patient complained of drowsiness. Treatment, then, was only with brexpiprazole, for a period 6 months. She has remained in remission on brexpiprazole treatment until the present. Patient consent was obtained for this report. For treating adolescent girls with their first episode of schizophrenia, both brexpiprazole and aripiprazole are suitable in terms of low risk for weight gain, prolactin increase, and extrapyramidal symptoms.1, 2 In this case, brexpiprazole was selected based its lower potential to induce adverse effects, compared to aripiprazole, which are mediated by partial agonism of the D2 receptor. Our patient reported no adverse effects of brexpiprazole, but her symptoms were only partially improved with brexpiprazole alone. Brexpiprazole, 2 mg/day and greater, demonstrated efficacy in patients with schizophrenia over a 6-week period.1, 3, 4 This suggests that in a subgroup of patients, as suggested in the current case, it could take more than 4–6 weeks for efficacy to occur with brexpiprazole monotherapy. Therefore, combination therapy of brexpiprazole with another second-generation antipsychotic (SGA) could be utilized as short-term treatment for first-episode schizophrenia patients. The mechanism of action of the current combination is unknown. The affinities of brexpiprazole and aripiprazole to D2 receptors as antagonists are similar. However, aripiprazole's partial agonism at the D2 receptor is greater than that of brexpiprazole, and brexpiprazole's antagonism of the 5-HT2A receptors is an order of magnitude greater than that of aripiprazole.5 In our patient, it is speculated that the addition of aripiprazole compensated for brexpiprazole's weak D2 receptor agonism and any adverse effects mediated by D2 receptor antagonism by aripiprazole were suppressed by brexpiprazole's potent antagonism of the 5-HT2A receptor. It is possible that modulating dopaminergic functioning in this manner allowed for efficacy and reduced adverse effects. Furthermore, both brexpiprazole and aripiprazole have been reported to have antidepressant effects. The effects of brexpiprazole and aripiprazole on the dopamine system might have acted on affective components, such as anxiety and emotional stability, to improve our patient's condition.6 In this case, a combination treatment of brexpiprazole and aripiprazole led to a shortened treatment period during the acute phase of schizophrenia, without side-effects. As remission was maintained with brexpiprazole alone, the findings suggest that aripiprazole could be effective as an additive treatment, with brexpiprazole, for acute treatment of schizophrenia. In this case, there were no apparent adverse events with the combination therapy other than drowsiness. Although there are limited reports of adverse events with combination therapy used in psychiatric medicine, brexpiprazole in combination with antidepressants has been reported to lead to akathisia and tardive dyskinesia.7 Atypical antipsychotics are generally prone to affect metabolism, electrolyte imbalance, and induced cardiovascular adverse effects.8 Such side-effects could occur when brexpiprazole is used in combination with other atypical antipsychotics, including aripiprazole. Further studies are needed to establish an optimal treatment regime and to evaluate other combinations of SGA that show both efficacy and markedly reduced adverse effects compared to monotherapy. The authors have no conflicts of interest to declare.