Pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report

Abstract

BackgroundGiven the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study.Case presentationA 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient’s symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles.ConclusionsWe report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism pathways but a DRD2 -141C variant that may influence brain D2 expression and antipsychotic responsiveness. The clinical utility of DRD2 information and what to do with genotyping results has not been previously addressed, despite availability on clinical test panels. Our case report suggests further investigations of altered dosing strategies and receptor genotype sensitivities to pharmacokinetic factors may be helpful in understanding symptom re-emergence observed in some patients taking LAI antipsychotics.

Clinical Utilization of Pharmacogenetics in Psychiatry – Perspectives of Pharmacists, Genetic Counselors, Implementation Science, Clinicians, and Industry

“…With respect to psychiatric treatment, a range of different types of clinical studies have also been conducted from RCTs to meta-analyses, retrospective cohort, and case studies [19,[26][27][28][29][30][31][32][100][101][102]. Due to the absence of biomarker-based diagnosis, variability in phe-notype and outcome measures may confound results and warrant larger sample sizes (compared to other disorders).…”

The pharmacogenetics of the new-generation antipsychotics – A scoping review focused on patients with severe psychiatric disorders

“…In a case report, oral, followed by the monohydrate LAI formula of aripiprazole, was initiated after failed trials of multiple antipsychotics in a 51-year-old patient with schizophrenia ( 78 ). A high dose of aripiprazole monohydrate LAI (400 mg every 3 weeks) still allowed exacerbation of psychosis 3 days before the next injection of the antipsychotic, which raised the question of resistance factors, including pharmacogenetic variables ( 78 ). The pharmacokinetic parameters possibly influenced by genetic factors have been excluded ( 78 ).…”

“…A high dose of aripiprazole monohydrate LAI (400 mg every 3 weeks) still allowed exacerbation of psychosis 3 days before the next injection of the antipsychotic, which raised the question of resistance factors, including pharmacogenetic variables ( 78 ). The pharmacokinetic parameters possibly influenced by genetic factors have been excluded ( 78 ). Still, a -141C Del variant of the D2 receptor gene was detected, which has been previously associated with treatment resistance in schizophrenia ( 78 ).…”

Pharmacogenomic Characterization in Bipolar Spectrum Disorders

“…When the Ins/Ins genotype is present, patients respond better to antipsychotic drugs than subjects carrying one or two copies of the Del allele. Subjects carrying the homozygous C allele with rs2514218 have been shown to respond better to antipsychotics than those homozygous for T allele, but they also present more side effects [84][85][86].…”