Pharmacogenetics and Schizophrenia—Can Genomics Improve the Treatment with Second-Generation Antipsychotics?

Abstract

Schizophrenia (SCZ) is a complex psychiatric disorder of multifactorial origin, in which both genetic and environmental factors have an impact on its onset, course, and outcome. Large variability in response and tolerability of medication among individuals makes it difficult to predict the efficacy of a chosen therapeutic method and create universal and precise guidelines for treatment. Pharmacogenetic research allows for the identification of genetic polymorphisms associated with response to a chosen antipsychotic, thus allowing for a more effective and personal approach to treatment. This review focuses on three frequently prescribed second-generation antipsychotics (SGAs), risperidone, olanzapine, and aripiprazole, and aims to analyze the current state and future perspectives in research dedicated to identifying genetic factors associated with antipsychotic response. Multiple alleles of genes involved in pharmacokinetics (particularly isoenzymes of cytochrome P450), as well as variants of genes involved in dopamine, serotonin, and glutamate neurotransmission, have already been identified as ones of significant impact on antipsychotic response. It must, however, be noted that although currently obtained results are promising, trials with bigger study groups and unified protocols are crucial for standardizing methods and determining objective antipsychotic response status.

Association of DRD2, DRD4 and COMT genes variants and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia

“…Furthermore, in cases where aripiprazole and CYP3A4 inhibitors are taken simultaneously, the FDA suggests a decrease in aripiprazole dose, with no determination of the patient’s phenotype. Nevertheless, these guidelines are advantageous, they are in no way adequate, therefore, more and more emphasizing the need for further research in this field [ 44 ].…”

A systematic review of pharmacogenetic testing to guide antipsychotic treatment

“…Antipsychotic drugs have demonstrated efficacy, and like almost every medication, they are prescribed in a prioritized order based on our knowledge of their tolerability and are adapted to the patient’s needs using clinical observations to identify the optimal medication and dose that will maximize response and minimize toxicity 3 . However, this process can lead to substantial delays in finding the drug and dose of choice for each patient 3 because the response to antipsychotics is highly variable among individuals 4 . While the majority of patients diagnosed with schizophrenia experience symptom improvements with antipsychotics, approximately 34% of patients are ‘treatment-resistant’, indicating a limited or lack of response to at least two trials of an antipsychotic therapy at an appropriate dose 4 , 5 .…”

“…However, this process can lead to substantial delays in finding the drug and dose of choice for each patient 3 because the response to antipsychotics is highly variable among individuals 4 . While the majority of patients diagnosed with schizophrenia experience symptom improvements with antipsychotics, approximately 34% of patients are ‘treatment-resistant’, indicating a limited or lack of response to at least two trials of an antipsychotic therapy at an appropriate dose 4 , 5 . In addition, antipsychotic drugs have a plethora of adverse drug reactions (ADRs), some of which are serious and thought to contribute to the excess mortality associated with severe mental illness 6 .…”

Impact of Pharmacogenetic Testing on Clozapine Treatment Efficacy in Patients with Treatment-Resistant Schizophrenia

“…The Taq1A (rs1800497) polymorphism has been observed to influence D 2 receptor expression, with the A1 allele associated with reduced D 2 receptor density in the caudate and putamen [ 15 , 16 ]. For that, A1/A1 carriers showed a significantly better response using different scales according to psychiatric symptoms in comparison to noncarriers in different antipsychotic treatments [ 17 , 18 ].…”