Failure to Replicate Influence of GRIK4 and GNB3 Polymorphisms on Treatment Outcome in Major Depression

Serretti, Alessandro; Chiesa, Alberto; Crisafulli, Concetta; Massat, Isabelle; Linotte, Sylvie; Calati, Raffaella; Kasper, Siegfried; Bailer, Ursula F.; Lecrubier, Y.; Fink, Martin; Antonijevic, Irina A.; Forray, Carlos; Snyder, Lenore; Bollen, Joseph; Zohar, Joseph; Ronchi, Diana De; Souery, Daniel; Mendlewicz, Julien

doi:10.1159/000329553

Cited by 24 publications

(11 citation statements)

References 43 publications

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“…Furthermore, some studies allowed concomitant drug treatment, such as anxiolytics, mood stabilizers and (in one study) antipsychotics [12]. Finally, one study [11] defined treatment response in a different manner from the remaining four studies. Our ability to detect consistent and significant associations of treatment response with the C allele and CC homozygosity by meta-analysis is perhaps more impressive in light of these differences, which may also indicate the robustness of these effects.…”

Section: Discussionmentioning

confidence: 99%

GRIK4 Polymorphism and its Association with Antidepressant Response in Depressed Patients: A Meta-Analysis

Kawaguchi

Glatt

2014

Pharmacogenomics

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Aim This study aimed to evaluate the relationship between a human GRIK4 gene polymorphism (rs1954787) and responsiveness to antidepressant treatment in depressed patients. Methods A meta-analysis was carried out on five studies. Pooled odds ratios (ORs), 95% CIs and a χ2 test measuring heterogeneity were calculated. A test of publication bias was also conducted. Results Alleles and genotypes from a total of 2169 depressed patients were analyzed. The results showed that the C allele appeared more frequently than the T allele in responders to treatment (OR: 1.22; 95% CI: 1.035–1.445; z = 2.36; p = 0.018). Similarly, CC homozygotes were more likely than TT homozygotes to respond to treatment (OR: 1.45; 95% CI: 1.107–1.913; z = 2.69; p = 0.007). No evidence of publication bias was detected. Conclusion Subjects possessing the C allele or CC genotype of the GRIK4 polymorphism rs1954787 are more likely to respond to antidepressant treatment relative to subjects harboring the T allele and TT genotype. Additional replication of this result is required before this association can be considered definitive, after which it may become possible to employ this marker in conjunction with other known predictors in order to anticipate the outcomes of treatment with antidepressant medications.

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Section: Discussionmentioning

confidence: 99%

GRIK4 Polymorphism and its Association with Antidepressant Response in Depressed Patients: A Meta-Analysis

Kawaguchi

Glatt

2014

Pharmacogenomics

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“…A subsequent study of 82 GRIK4 SNPs in another sample identified a polymorphism with a stronger effect, also enhanced in its effect when combined with HTR2A . While a multicentre study was unable to replicate an effect of this gene on antidepressant response, the Chinese study of Pu et al . also found a significant effect of rs1954787 in GRIK4 on the outcome of antidepressant treatment.…”

Section: Glutamate and Gaba Systemsmentioning

confidence: 97%

Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms

Reynolds

McGowan

Dalton

2014

Brit J Clinical Pharma

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The treatment of severe mental illness, and of psychiatric disorders in general, is limited in its efficacy and tolerability. There appear to be substantial interindividual differences in response to psychiatric drug treatments that are generally far greater than the differences between individual drugs; likewise, the occurrence of adverse effects also varies profoundly between individuals. These differences are thought to reflect, at least in part, genetic variability. The action of psychiatric drugs primarily involves effects on synaptic neurotransmission; the genes for neurotransmitter receptors and transporters have provided strong candidates in pharmacogenetic research in psychiatry. This paper reviews some aspects of the pharmacogenetics of neurotransmitter receptors and transporters in the treatment of psychiatric disorders. A focus on serotonin, catecholamines and amino acid transmitter systems reflects the direction of research efforts, while relevant results from some genome-wide association studies are also presented. There are many inconsistencies, particularly between candidate gene and genome-wide association studies. However, some consistency is seen in candidate gene studies supporting established pharmacological mechanisms of antipsychotic and antidepressant response with associations of functional genetic polymorphisms in, respectively, the dopamine D 2 receptor and serotonin transporter and receptors. More recently identified effects of genes related to amino acid neurotransmission on the outcome of treatment of schizophrenia, bipolar illness or depression reflect the growing understanding of the roles of glutamate and γ-aminobutyric acid dysfunction in severe mental illness. A complete understanding of psychiatric pharmacogenomics will also need to take into account epigenetic factors, such as DNA methylation, that influence individual responses to drugs.

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“…Pharmacogenetic results are nevertheless inconsistent. Indeed, different SNPs were associated with antidepressant efficacy without any replicated result (rs1954787 [Paddock et al, ], rs12800734 [Horstmann et al, ]), while further studies provided negative findings [Perlis et al, ; Serretti et al, ]. The heterogeneity of treatments may have contributed to the inconsistency among results, since in only one study [Paddock et al, ] citalopram monotherapy was used, while the others allowed mixed regimens, or combinations with mood stabilizers/antipsychotics [Horstmann et al, ].…”

Section: Glutamatergic Systemmentioning

confidence: 99%

Pharmacogenetics of antidepressant drugs: An update after almost 20 years of research

Fabbri

Girolamo

Serretti

2013

American J of Med Genetics Pt B

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Major depressive disorder (MDD) is an emergent cause of personal and socio-economic burden, both for the high prevalence of the disorder and the unsatisfying response rate of the available antidepressant treatments. No reliable predictor of treatment efficacy and tolerance in the single patient is available, thus drug choice is based on a trial and error principle with poor clinical efficiency. Among modulators of treatment outcome, genetic polymorphisms are thought to explain a significant share of the inter-individual variability. The present review collected the main pharmacogenetic findings primarily about antidepressant response and secondly about antidepressant induced side effects, and discussed the main strengths and limits of both candidate and genome-wide association studies and the most promising methodological opportunities and challenges of the field. Despite clinical applications of antidepressant pharmacogenetics are not available yet, previous findings suggest that genotyping may be applied in the clinical practice. In order to reach this objective, further rigorous pharmacogenetic studies (adequate sample size, study of better defined clinical subtypes of MDD, adequate covering of the genetic variability), their combination with the results obtained through complementary methodologies (e.g., pathway analysis, epigenetics, transcriptomics, and proteomics), and finally cost-effectiveness trials are required.

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Failure to Replicate Influence of GRIK4 and GNB3 Polymorphisms on Treatment Outcome in Major Depression

Cited by 24 publications

References 43 publications

GRIK4 Polymorphism and its Association with Antidepressant Response in Depressed Patients: A Meta-Analysis

GRIK4 Polymorphism and its Association with Antidepressant Response in Depressed Patients: A Meta-Analysis

Pharmacogenomics in psychiatry: the relevance of receptor and transporter polymorphisms

Pharmacogenetics of antidepressant drugs: An update after almost 20 years of research

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