Failure to Replicate Genetic Associations with Antidepressant Treatment Response in Duloxetine-Treated Patients

Perlis, Roy H.; Fijal, Bonnie; Dharia, Sweta; Heinloth, Alexandra N.; Houston, John P.

doi:10.1016/j.biopsych.2009.12.010

Cited by 82 publications

(57 citation statements)

References 16 publications

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“…Our results are consistent with those of some [9][10][11][12][13] but not all studies [1][2][3][4][5][6][7][8] . These conflicting data may result from the difficulties in the replication of candidate gene association studies.…”

Section: Discussionsupporting

confidence: 94%

“…However, as is frequently observed in complex diseases like MDD, the results from these studies are often contradictory. While several studies have shown an association between some polymorphisms within these genes and response to antidepressant treatment [1][2][3][4][5][6][7][8] , no association was found in other studies [9][10][11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…Studies investigating treatment outcomes of patients with low-expressing SERT gene variants treated with TCAs are limited. Reports using duloxetine (a SERT and NET blocker) and nortriptyline (a NET-selective blocker) have failed to show any association with treatment outcome and low-expressing SERT gene variants (Rajewska-Rager et al, 2008;Perlis et al, 2010). Our results from P28 SERT1/2 mice suggest that DMI may have especially limited therapeutic efficacy in adolescents harboring low-expressing SERT gene variants, although the exact mechanism for this remains unknown.…”

Section: Discussionmentioning

confidence: 57%

“…Amitriptyline poisoning, a condition that is more dangerous in children than in adults, is one example (Paksu et al, 2014). Given that studies on the therapeutic benefit experienced by juveniles and adolescents and by carriers of low-expressing SERT gene variants from TCA treatment have reported mixed results (Hazell et al, 1995;Rajewska-Rager et al, 2008;Perlis et al, 2010;Hazell and Mirzaie, 2013), there is a need to better understand the age and SERT gene variant dependence of TCA efficacy as a first step toward developing improved antidepressants for these populations.…”

Section: Introductionmentioning

confidence: 99%

Ontogeny of Norepinephrine Transporter Expression and Antidepressant-Like Response to Desipramine in Wild-Type and Serotonin Transporter Mutant Mice

Mitchell

Bowman

Gould

et al. 2016

J Pharmacol Exp Ther

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Depression is a major public health concern with symptoms that are often poorly controlled by treatment with common antidepressants. This problem is compounded in juveniles and adolescents, because therapeutic options are limited to selective serotonin reuptake inhibitors (SSRIs). Moreover, therapeutic benefits of SSRIs are often especially limited in certain subpopulations of depressed patients, including children and carriers of low-expressing serotonin transporter (SERT) gene variants. Tricyclic antidepressants (TCAs) offer an alternative to SSRIs; however, how age and SERT expression influence antidepressant response to TCAs is not understood. We investigated the relation between antidepressant-like response to the TCA desipramine using the tail suspension test and saturation binding of [P21]), adolescent (P28), and adult (P90) wild-type (SERT1/1) mice. To model carriers of low-expressing SERT gene variants, we used mice with reduced SERT expression (SERT1/2) or lacking SERT (SERT2/2). The potency and maximal antidepressant-like effect of desipramine was greater in P21 mice than in P90 mice and was SERT genotype independent. NET expression decreased with age in the locus coeruleus and increased with age in several terminal regions (e.g., the cornu ammonis CA1 and CA3 regions of the hippocampus). Binding affinity of [ 3 H]nisoxetine did not vary as a function of age or SERT genotype. These data show age-dependent shifts for desipramine to produce antidepressant-like effects that correlate with NET expression in the locus coeruleus and suggest that drugs with NET-blocking activity may be an effective alternative to SSRIs in juveniles.

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“…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). In contrast, GRIK4 was not associated with treatment response to 6 weeks of duloxetine in a sample of 250 mostly Caucasian MDD patients (Perlis et al, 2010). GRIK4 was also not associated with response to antidepressants, risk for MDD, or phenotypic characteristics in a sample of 223 Caucasian MDD patients and 76 healthy controls (Serretti et al, 2012).…”

Section: Ampa Receptormentioning

confidence: 91%

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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Failure to Replicate Genetic Associations with Antidepressant Treatment Response in Duloxetine-Treated Patients

Cited by 82 publications

References 16 publications

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

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

Ontogeny of Norepinephrine Transporter Expression and Antidepressant-Like Response to Desipramine in Wild-Type and Serotonin Transporter Mutant Mice

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

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