Genetic Variants May Account for Poorer ECT Response in Treatment-Resistant Patients

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Polymorphisms of the GRIK4 gene modulate the response to electroconvulsive therapy.

Patients with specific variants of a gene involved in the glutamatergic system respond more poorly to electroconvulsive therapy (ECT), reveals new research published in Neuroscience Letters. The reduced response to ECT among individuals with 1 of 3 polymorphisms of the glutamate receptor ionotropic kainate 4 (GRIK4) gene indicates that modulation of kainate receptors may influence treatment effectiveness.

“The particular localization of GRIK4 in specific brain areas makes it critical for learning and memory along with complex cognitive behaviors, mood and personality,” wrote Alessandra Minelli, PsyD, PhD, of the University of Brescia in Italy, and her colleagues. “Moreover, it is involved in the rapid transmission of an excitatory synapsis and plays an important role in excitotoxicity neural death. All of these peculiar functions make GRIK4 intriguing to study as it is related to ECT activity mechanisms.”

The researchers administered ECT sessions 3 mornings a week, for a mean 7.6 sessions, to 92 patients with major depressive disorder (MDD) and 8 with bipolar disorder (BP) in a severe depressive state, all of whom had been resistant to pharmacologic treatments. None of the 100 participants had a history of schizoaffective, personality, eating, or cognitive disorders. Participants were also genotyped for three GRIK4 variants: rs1954787, rs4936554 and rs11218030.

Although 69% of participants responded to the therapy, those least likely to respond carried the G allele for rs11218030. These patients had more than 5 times greater odds (OR, 5.62 [95% CI, 2.17-14.61]) of not responding to ECT compared to those carrying AA alleles, with failure beginning as early as one month post-treatment.

Those with GG homozygous rs1954787 similarly had more than double the odds of not responding to ECT (OR, 2.70 [95% CI, 1.24-7.13]) compared to those carrying an A allele. Likewise, A allele carriers for rs4936554 had more than twice the odds (OR, 2.52 [95% CI, 1.03-6.16]) of not responding to ECT compared to GG homozygotes. All these effects except that of the rs4936554 variant remained significant following adjustment for multiple comparisons in terms of how many single nucleotide polymorphisms (SNPs) were analyzed.

Previous research has shown ECT to normalize glutamate deficits in the brain, and the treatment mechanism may therefore result partly from regulation of the glutamate to GABA ratio, the authors suggest.

“Genetic marker information might improve the already demonstrated cost-effectiveness of ECT treatment, by contributing to the develop of algorithm tools for the prevision of the efficacy that takes into consideration several factors, such as clinical, pharmacological, technical and biological variables,” the authors concluded.

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Minelli A, Congiu C, Ventriglia M, et al. Influence of GRIK4 genetic variants on the electroconvulsive therapy response. Neurosci Lett. 2016;626:94-98.