Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia

Abstract

Antipsychotic treatment response is highly heterogeneous and unpredictable in terms of both efficacy and side effects. A combination of factors influences treatment outcome, including clinical, demographic, environmental and genetic factors. No comprehensive studies have quantified the relative contributions of these factors to date. Two decades of pharmacogenetic and pharmacogenomic studies have attempted to identify key gene variants associated with antipsychotic response, with a dual goal of better understanding the mechanisms underlying drug response and guiding prescribing decisions in clinical care. Pharmacogenetic studies have succeeded in identifying several genes that are associated with antipsychotic treatment efficacy or side effects. However, the strength of these associations is modest and they are of limited clinical value. Genome-wide association studies, moving beyond hypothesis-based discovery, have greater potential to identify novel gene associations, although only a few genome-wide association studies have been conducted and they have not revealed clearly significant findings. The first pharmacogenetic tests to guide the selection or dosing of antipsychotic drugs are now commercially available. Their uptake has been limited by the modest level of prediction they offer, compounded by the lack of data supporting their clinical or economic benefits. Advances in genomic analysis techniques, the better characterization of larger subject cohorts and an improved understanding of the role of environmental factors and gene-environment interactions are renewing hope that future research will identify genetic variants with stronger associations with treatment outcome. Tests incorporating such genetic data, with environmental and clinical variables, may offer the potential to personalize medicine and significantly improve the efficacy and tolerability of antipsychotic treatment.

Pharmacogenetic Applications and Pharmacogenomic Approaches in Schizophrenia

“…FGA display strong affinity whereas SGA display moderate to high affinity for D2, D3 and D4 receptors. Numerous pharmacogenetic studies confirm the relevance of dopamine receptors for antipsychotic efficacy [2,8]. Figure 1 summarises the number of published reports associating genetic variants (grouped by gene) with level of antipsychotic efficacy.…”

“…Pharmacogenetic studies have proved that antipsychotic treatment variability has an important degree of heritability, although the later has not been quantified through systematic twin studies. Nevertheless, concordance in the response to antipsychotic treatment has been reported in a number of twin pairs suggesting a strong genetic contribution [2]. However, it is clear that genetic factors can only partly explain treatment variability, and that clinical and environmental factors have an important contribution to antipsychotic response.…”

Dopamine (DRD2) and Serotonin (HTR2A, 2C) Receptor Gene Polymorphisms do not influence early response to Risperidone in South Indian Patients with Schizophrenia

“…There are no biological markers available to predict therapeutic response and tolerance, thereby leading to lengthy empirical trials with an uncertain outcome. Genetic variation may play a role in AAP response variability and several lines of evidence suggest that polymorphisms within genes coding for proteins implicated in the dopamine and serotonin neurotransmission may influence the AAP efficacy in SCZ . In this context, several pharmacogenetic studies have been performed to investigate the implication of dopaminergic and serotonergic candidate genes in AAP response .…”

The identification of novel genetic variants associated with antipsychotic treatment response outcomes in first-episode schizophrenia patients

“…differences between antipsychotic drugs are less important than the greater variability in patient response' [5]. In general, the treatment outcomes of both First Generation Antipsychotics and Second Generation Antipsychotics are nonoptimal, unpredictable, and vary widely between patients, with only ∼ 60% of patients responding to antipsychotic treatment [5].…”

“…In general, the treatment outcomes of both First Generation Antipsychotics and Second Generation Antipsychotics are nonoptimal, unpredictable, and vary widely between patients, with only ∼ 60% of patients responding to antipsychotic treatment [5]. Thus, methods to optimize antipsychotic treatment decisions are urgently required.…”