A Preliminary Study of Association of Genetic Variants with Early Response to Olanzapine in Schizophrenia

By Singh, Anmol; Beniwal, Ram et al. | Indian Journal of Psychiatry, January-March 2018 | Go to article overview

A Preliminary Study of Association of Genetic Variants with Early Response to Olanzapine in Schizophrenia


Singh, Anmol, Beniwal, Ram, Kukshal, Prachi, Bhatia, Triptish, Thelma, B., Deshpande, Smita, Indian Journal of Psychiatry


Byline: Anmol. Singh, Ram. Beniwal, Prachi. Kukshal, Triptish. Bhatia, B. Thelma, Smita. Deshpande

Background: Treatment response can be predicted in schizophrenia by DNA information in the drug metabolism pathways. This study aimed to examine clinical characteristics and genetic determinant (s) of early response to olanzapine treatment in schizophrenia using specified drug metabolizing genes. Materials and Methods: Consenting participants (n = 33) suffering from schizophrenia were diagnosed on Diagnostic Interview for Genetic Studies. Oral olanzapine was administered in an incremental dose up to 10 mg (2 weeks) and 20 mg (6 weeks). All participants were tested on Positive and Negative Syndrome Scale, Clinical Global Impressions, and Global Assessment of Functioning at 0, 2, and 6 weeks. Side effects were also evaluated. After 2 weeks, 11 (33.33%) fulfilled criteria for early response, whereas 17 (51.52%) responded at 6 weeks. We investigated the contribution of clinical factors and five polymorphisms (rs2740574, rs2470890, rs762551, rs3892097, and rs1065852) in predicting response to olanzapine at 2 and 6 weeks of treatment with a standard dose. Results: Severity of positive symptoms at baseline was associated with response at 2 weeks (P = 0.01) while higher scores on Scale for the Assessment of Negative Symptoms (SANS) at baseline was associated with response at both 2 (P = 0.04) and 6 weeks (P = 0.03). None of the five single nucleotide polymorphisms (SNPs) selected were significantly associated with response to olanzapine. Conclusions: Olanzapine is an effective and safe drug. Positive and Negative Syndrome Scale positive score and SANS score were variably associated with response at 2 and/or 6 weeks. Replicate studies with bigger sample size are warranted for conclusive results in the Indian population for genetic association.

Introduction

Schizophrenia affects many aspects of mental function-cognition, perception, behavior, and emotion, leading to debilitating severe mental illness.[1] Response to treatment in schizophrenia is heterogeneous.[2] "Atypical" or second-generation antipsychotics, mainstay of the treatment for schizophrenia, have improved its long-term prognosis and reduced side effects such as extrapyramidal symptoms and tardive dyskinesia.[3] Olanzapine is considered more effective among the second-generation antipsychotics, but it can cause weight gain and metabolic side effects.[4] Substantial heterogeneity has been observed in olanzapine response. Such differences are influenced by a number of factors such as duration and severity of illness, duration of treatment, average drug dose, and compliance-related factors. Environmental (smoking and diet), demographic (sex and ethnicity), illness-related (illness onset and duration and comorbidities), and genetic factors contribute to this variability.[5] Comparatively few Asian studies investigating the efficacy and tolerability of olanzapine, especially among Indians have been reported.[6],[7],[8] Cytochrome P450 3A4 is one of the most abundant P450s expressed in the liver, metabolizing more than 50% of all known drugs.[9] The gene is inducible and wide interindividual variation (up to 40-fold) exists in the level of expression, but few significant functional polymorphisms which could explain this variability have been found.

Olanzapine is metabolized primarily by CYP1A2[10] and to a lesser extent by CYP2D6.[11] In vitro studies suggest that olanzapine is metabolized to N-desmethylolanzapine by the action CYP1A2.[12] This metabolite is correlated significantly with olanzapine clearance rates in v itro. [13] CYP1A2*1F polymorphism may be associated with olanzapine serum concentrations, which can influence response to treatment in schizophrenia.[14] CYP1A2 1545 C > T was found to be associated with schizophrenia; however, it was rendered insignificant after corrections for multiple comparisons.[10]

CYP2D6*4 (G > A) accounts for more than 75% of the poor metabolizer (PM) phenotype among Europeans. …

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