title: Impact of 5-HTTLPR and BDNF polymorphisms on response to sertraline versus transcranial direct current stimulation: implications for the serotonergic system.
abstract: Transcranial direct current stimulation (tDCS) has been intensively investigated as a non-pharmacological treatment for major depressive disorder (MDD). While many studies have examined the genetic predictors of antidepressant medications, this issue remains to be investigated for tDCS. In the current study, we evaluated whether the BDNF Val66Met and the 5-HTT (5-HTTLPR) polymorphisms were associated with tDCS antidepressant response. We used data from a factorial trial that evaluated the efficacy of tDCS and sertraline and enrolled 120 moderate-to-severe, antidepressant-free participants. In the present study, we used analyses of variance to evaluate whether the BDNF (Val/Val vs. Met-carries) and 5-HTTLPR alleles (long/long vs short-carriers) were predictors of tDCS (active/sham) and sertraline (sertraline/placebo) response. Analyses were conducted on the polymorphisms separately and also on their interaction. Genotype frequencies were in Hardy-Weinberg equilibrium. BDNF polymorphism was not associated with treatment response. We found that 5-HTTLPR predicted tDCS effects as long/long homozygotes displayed a larger improvement comparing active vs. sham tDCS, while short-allele carriers did not. A dose-response relationship between active-sham differences with the long allele was also suggested. These results strengthen the role of the serotonergic system in the tDCS antidepressant effects and expand previous findings that reported that tDCS mechanisms of action partially involve serotonergic receptors. Therefore, we hypothesize that tDCS is a neuromodulation technique that acts over depression through the modulation of serotonergic system and that tDCS "top-down" antidepressant effects might not be optimal in brain networks with a hyperactive amygdala inducing bottom-up effects, such as occurs in short-carriers.
authors.affiliation: Hospital Universitário, University of São Paulo, São Paulo, Brazil; University of São Paulo Medical School, São Paulo, Brazil; Centro de Atenção Integrada em Saúde Mental, Faculdade de Ciências Médicas da Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil. Electronic address: brunoni@usp.br.
authors.forename: A R
authors.initials: AR
authors.lastname: Brunoni
authors.forename: A H
authors.initials: AH
authors.lastname: Kemp
authors.forename: P
authors.initials: P
authors.lastname: Shiozawa
authors.forename: Q
authors.initials: Q
authors.lastname: Cordeiro
authors.forename: L C L
authors.initials: LC
authors.lastname: Valiengo
authors.forename: A C
authors.initials: AC
authors.lastname: Goulart
authors.forename: B
authors.initials: B
authors.lastname: Coprerski
authors.forename: P A
authors.initials: PA
authors.lastname: Lotufo
authors.forename: D
authors.initials: D
authors.lastname: Brunoni
authors.forename: A B A
authors.initials: AB
authors.lastname: Perez
authors.forename: F
authors.initials: F
authors.lastname: Fregni
authors.forename: I M
authors.initials: IM
authors.lastname: Benseñor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003131:Combined Modality Therapy / Q000009:adverse effects; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics*; D004311:Double-Blind Method; D004599:Electric Stimulation Therapy; D004843:Epistasis, Genetic / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D020280:Sertraline / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; C579455:BDNF protein, human; D020280:Sertraline
keywords: Brain-derived neurotrophic factor polymorphism; Major depressive disorder; Serotonin selective reuptake blockers; Serotonin-transporter-linked-polymorphic region; Single-nucleotide polymorphism; Transcranial direct current stimulation