Influence of Genetic Polymorphisms in the Glutamatergic and GABAergic Systems and Their Interactions with Environmental Stressors on Antidepressant Response

Pu, Mengjia; Zhang, Zhijun; Xu, Zhi; Shi, Yue; Geng, Leiyu; Yuan, Yuan; Zhang, Xiangrong; Reynolds, Gavin P.

doi:10.2217/pgs.13.1

Cited by 46 publications

(36 citation statements)

References 58 publications

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“…In another Caucasian sample of 627 MDD patients, GRIK4 rs11218030 was associated with treatment resistance (corrected P = 0.025), while the G allele of GRIK4 rs1954787 was linked to the presence of psychotic symptoms (Milanesi et al, 2015). Consistent with the study by Paddock and colleagues , antidepressant response in a Chinese Han sample of 281 MDD patients receiving different SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs) for 6 weeks was directly and inversely associated with the G allele of the GRIK4 rs1954787 SNP and with the A-G-G HT of GRIK4 (rs1954787-rs2230297-rs2298725), respectively (Pu et al, 2013). GRIK4 SNPs analyzed in a Caucasian sample of 275 MDD patients were not significantly associated with response and remission within up to 5 weeks of treatment with several types of antidepressants, but the GG genotype of GRIK4 rs12800734 was associated with downregulation of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity (Horstmann et al, 2010).…”

Section: Ampa Receptorsupporting

confidence: 73%

“…GRM7 was also linked to BD in one large study (Kandaswamy et al, 2014) and to MDD in one medium-sized study (Pergadia et al, 2011). Finally, GRIK4 influenced treatment response in one large and two medium-sized studies in MDD (Horstmann et al, 2010;Paddock et al, 2007;Pu et al, 2013) and was associated with risk for BD in two medium-sized samples (Pickard et al, 2006(Pickard et al, , 2008. All four of these genes (GRIA3, GRIK2, GRIK4, and GRM7) stand out as highly interesting candidates for further study.…”

Section: Discussionmentioning

confidence: 90%

“…In a Chinese Han sample of 281 patients with MDD, the GRIA3 rs502434 and rs3761555 SNPs were also linked to early-onset adverse events and recent negative life stress that influenced treatment outcome, though the analyses did not withstand correction for multiple comparisons (Pu et al, 2013). In addition, a family study of 373 Caucasian individuals from 40 BD pedigrees from the US and Israel found no linkage between GRIA3 and BD (Gécz et al, 1999).…”

Section: Ampa Receptormentioning

confidence: 91%

“…For instance, no gene has been replicated in all the available studies to date, and associations in opposite directions have been reported for some single nucleotide polymorphisms (SNPs; Menke et al, 2008;Pu et al, 2013). Furthermore, genetic studies of glutamate-related genes have never been systematically reviewed, which hampers a synthesized view of the field and the identification of replicable targets on the glutamatergic pathway.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders

Loch

Carvalho

et al. 2016

Neuropsychopharmacol

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Both bipolar disorder (BD) and major depressive disorder (MDD) have high morbidity and share a genetic background. Treatment options for these mood disorders are currently suboptimal for many patients; however, specific genetic variables may be involved in both pathophysiology and response to treatment. Agents such as the glutamatergic modulator ketamine are effective in treatment-resistant mood disorders, underscoring the potential importance of the glutamatergic system as a target for improved therapeutics. Here we review genetic studies linking the glutamatergic system to the pathophysiology and therapeutics of mood disorders. We screened 763 original genetic studies of BD or MDD that investigated genes encoding targets of the pathway/mediators related to the so-called tripartite glutamate synapse, including pre-and post-synaptic neurons and glial cells; 60 papers were included in this review. The findings suggest the involvement of glutamate-related genes in risk for mood disorders, treatment response, and phenotypic characteristics, although there was no consistent evidence for a specific gene. Target genes of high interest included GRIA3 and GRIK2 (which likely play a role in emergent suicidal ideation after antidepressant treatment), GRIK4 (which may influence treatment response), and GRM7 (which potentially affects risk for mood disorders). There was stronger evidence that glutamate-related genes influence risk for BD compared with MDD. Taken together, the studies show a preliminary relationship between glutamate-related genes and risk for mood disorders, suicide, and treatment response, particularly with regard to targets on metabotropic and ionotropic receptors.

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Section: Ampa Receptorsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 90%

Section: Ampa Receptormentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders

Loch

Carvalho

et al. 2016

Neuropsychopharmacol

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“…Such interactions have been reported between stressful life events and genes involved in serotonergic [70,71] and glutamatergic transmission [72] and adrenal axis regulation [73], and between childhood trauma and genes involved in serotonin metabolism [71]. Similarly, a variant in the angiotensin I-converting enzyme (ACE) gene was found to influence antidepressant response in women, but not in men [74].…”

Section: Depressive Disordersmentioning

confidence: 96%

A patient-centered model of the action of psychotropic drugs

Rajkumar

2015

Personalized Medicine Universe

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a b s t r a c tBackground: Psychotropic medications are widely used to treat a variety of mental disorders, but a unifying explanation of their modes of action remains obscure. Objective: To examine the limitations of existing models of psychotropic drug action, and to propose an integrative, patient-oriented model that explains the wide spectrum of actions of psychotropic medications. Method: The traditional "disease-centered" model of psychotropic action, and its most logical contemporary alternative, the "drug-centered" model e are critically analysed, and their limitations identified. An alternate model, which acknowledges the importance of patient-related factors in determining drug effects is outlined. The two processes involved in this model, and the evidence in its support, are explained at length with reference to specific psychiatric disorders. Conclusion: The patient-centered model proposed in this paper, though provisional, provides a broadbased, unified framework for understanding the actions of psychotropic drugs, and can enhance clinical practice and research.

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A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder

Yin

Pantazatos

Galfalvy

et al. 2016

American J of Med Genetics Pt B

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Gamma-amino butyric acid (GABA) and glutamate are the major inhibitory and excitatory neurotransmitters in the mammalian central nervous system, respectively, and have been associated with suicidal behavior and major depressive disorder (MDD). We examined the relationship between genotype, brain transcriptome, and MDD/suicide for 24 genes involved in GABAergic and glutamatergic signaling. In part 1 of the study, 119 candidate SNPs in 24 genes (4 transporters, 4 enzymes, and 16 receptors) were tested for associations with MDD and suicidal behavior in 276 live participants (86 nonfatal suicide attempters with MDD and 190 non-attempters of whom 70% had MDD) and 209 postmortem cases (121 suicide deaths of whom 62% had MDD and 88 sudden death from other causes of whom 11% had MDD) using logistic regression adjusting for sex and age. In part 2, RNA-seq was used to assay isoform-level expression in dorsolateral prefrontal cortex of 59 postmortem samples (21 with MDD and suicide, 9 MDD without suicide, and 29 sudden death non-suicides and no psychiatric illness) using robust regression adjusting for sex, age, and RIN score. In part 3, SNPs with subthreshold (uncorrected) significance levels below 0.05 for an association with suicidal behavior and/or MDD in part 1 were tested for eQTL effects in prefrontal cortex using the Brain eQTL Almanac (www.braineac.org). No SNPs or transcripts were significant after adjustment for multiple comparisons. However, a protein coding transcript (ENST00000414552) of the GABA A receptor, gamma 2 (GABRG2) had lower brain expression postmortem in suicide (P = 0.01) and evidence for association with suicide death (P = 0.03) in a SNP that may be an eQTL in prefrontal cortex (rs424740, P = 0.02). These preliminary results implicate GABRG2 in suicide and warrant further investigation and replication in larger samples.

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Influence of Genetic Polymorphisms in the Glutamatergic and GABAergic Systems and Their Interactions with Environmental Stressors on Antidepressant Response

Abstract: Genetic polymorphisms in the glutamatergic and GABAergic systems and certain genetic interactions, as well as gene-environment interactions, are associated with antidepressant response.

Cited by 46 publications

References 58 publications

Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders

Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders

A patient-centered model of the action of psychotropic drugs

A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder

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