Role of COMT, 5-HT1A, and SERT genetic polymorphisms on antidepressant response to transcranial magnetic stimulation

Malaguti, Alessia; Rossini, David; Lucca, A.; Magri, Lorenzo; Lorenzi, Cristina; Pirovano, Adele; Colombo, Cristina; Smeraldi, Enrico; Zanardi, Raffaella

doi:10.1002/da.20815

Cited by 46 publications

(33 citation statements)

References 57 publications

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“…In humans, PET imaging of 5-HT1A availability in regions such as the prefrontal cortex (PFC) and insula- areas highly involved in pain regulation- has been associated with the capacity of central suppression of pain [72]. Further attesting to the clinical relevance of such supraspinal 5-HT1A variation, G-carriers were recently reported to experience reduced antidepressant effect of transcranial magnetic stimulation (TMS) focused on the prefrontal cortex (PFC) [27]. These results are paralleled by experiments in rats, where activation of 5-HT1A-receptors in the ventrolateral orbital cortex (VLO) was shown to contribute to descending antinociception [73].…”

Section: Discussionmentioning

confidence: 99%

“…In congruence with the outlined effects, the G-allele has been suggested to increase the risk of depression [25], possibly impacting the response to antidepressants [26] and related therapies [27]. There is a substantial comorbidity beween affective disorders and chronic pain [28], [29], [30], indicating overlapping neurobiological mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Serotonin-1A Receptor Polymorphism (rs6295) Associated with Thermal Pain Perception

et al. 2012

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BackgroundSerotonin (5-HT) is highly involved in pain regulation and serotonin-1A (5-HT1A) receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A) may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP) rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities.MethodsFourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C–49°C). Nociceptive-flexion reflex (NFR) thresholds were also assessed.ResultsVolunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged.Conclusion/SignificanceTo the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a ‘hypo- to hyperalgesic’ response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain pathologies. Further investigations are therefore warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serotonin-1A Receptor Polymorphism (rs6295) Associated with Thermal Pain Perception

et al. 2012

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“…In the clinical domain, one study investigated the influence of this polymorphism on the antidepressant response in a TMS protocol. Although no effect of the COMT polymorphism was found, the 5-HT1A serotonergic receptor promoter region polymorphism predicted the treatment outcome (Malaguti et al, 2011). In the context of another clinical application, Shivakumar et al (2015) reported a better reduction of auditory hallucinations in schizophrenic patients by tDCS treatment in COMT Val allele homozygous individuals compared to Met allele carriers.…”

Section: Tdcs and The Catechol-o-methyltransferase (Comt)mentioning

confidence: 96%

Genetic Modulation of Transcranial Direct Current Stimulation Effects on Cognition

Wiegand

Nieratschker

Plewnia

2016

Front. Hum. Neurosci.

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High inter-individual variability substantially challenges the explanatory power of studies on the modulation of cognitive functions with transcranial direct current stimulation (tDCS). These differences in responsivity have been linked with a critical state-dependency of stimulation effects. In general, genetic diversity is a decisive biological basis of variations in neuronal network functioning. Therefore, it is most likely that inter-individual variability of tDCS-induced changes in cognitive functions is due to specific interactions between genetically determined network properties and the specific type of stimulation. In this context, predominantly the brain-derived neurotrophic factor (BDNF) Val66Met and the catechol-O-methyltransferase (COMT) Val108/158Met polymorphisms have been investigated. The studies on the interaction between the BDNF Val66Met polymorphism and the effect of brain stimulation indicate a critical but yet heterogeneous interaction. But up to now, data on the interplay between this polymorphism and tDCS on cognitive functioning are not available. However, recently, the functional Val(108/158)Met polymorphism in the COMT gene, that is particularly involved in the regulation of executive functions by means of the dopaminergic tone in frontal brain areas, has been demonstrated to specifically predict the effect of tDCS on cognitive control. Following an inverted U-shaped function, the high dopaminergic activity in Met allele homozygous individuals has been shown to be associated with a reduction of executive functioning by anodal tDCS to the prefrontal cortex. Consistently, Val homozygous individuals with lower dopaminergic tone show a clear reduction of response inhibition with cathodal tDCS. These findings exemplify the notion of a complex but neurophysiologically consistent interaction between genetically determined variations of neuronal activity and tDCS, particularly in the cognitive domain. Consequently, a systematic analysis and consideration of genetic modulators of tDCS effects will be helpful to improve the efficacy of brain stimulation and particularly tDCS in the investigation and treatment of cognitive functions.

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“…They found that improvement following left sided 10 Hz rTMS treatment correlated positively with changes in 5-HT(2A) receptor binding indices in the DLPFC bilaterally and negatively with right hippocampal binding. Several small case series have implicated genetic polymorphisms that affect serotonin transporter expression, the 5-HT(1A) receptor, or BDNF in modulating the likelihood of response to rTMS, but results have been inconsistent (Zanardi et al, 2007; Bocchio-Chiavetto et al, 2008; Malaguti et al, 2011). In one study, rapid tryptophan depletion did not lead to reemergence of depressive symptoms in adults who had responded to a course of rTMS (O'Reardon et al, 2007), suggesting that the therapeutic effects of rTMS do not depend critically upon central serotonergic tone.…”

Section: Cellular and Neurochemical Effects Of Rtms In Mddmentioning

confidence: 99%

The relationship between brain oscillatory activity and therapeutic effectiveness of transcranial magnetic stimulation in the treatment of major depressive disorder

Leuchter¹,

Cook²,

Jin³

et al. 2013

Front. Hum. Neurosci.

113

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Major depressive disorder (MDD) is marked by disturbances in brain functional connectivity. This connectivity is modulated by rhythmic oscillations of brain electrical activity, which enable coordinated functions across brain regions. Oscillatory activity plays a central role in regulating thinking and memory, mood, cerebral blood flow, and neurotransmitter levels, and restoration of normal oscillatory patterns is associated with effective treatment of MDD. Repetitive transcranial magnetic stimulation (rTMS) is a robust treatment for MDD, but the mechanism of action (MOA) of its benefits for mood disorders remains incompletely understood. Benefits of rTMS have been tied to enhanced neuroplasticity in specific brain pathways. We summarize here the evidence that rTMS entrains and resets thalamocortical oscillators, normalizes regulation and facilitates reemergence of intrinsic cerebral rhythms, and through this mechanism restores normal brain function. This entrainment and resetting may be a critical step in engendering neuroplastic changes and the antidepressant effects of rTMS. It may be possible to modify the method of rTMS administration to enhance this MOA and achieve better antidepressant effectiveness. We propose that rTMS can be administered: (1) synchronized to a patient's individual alpha frequency (IAF), or synchronized rTMS (sTMS); (2) as a low magnetic field strength sinusoidal waveform; and, (3) broadly to multiple brain areas simultaneously. We present here the theory and evidence indicating that these modifications could enhance the therapeutic effectiveness of rTMS for the treatment of MDD.

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Role of COMT, 5-HT1A, and SERT genetic polymorphisms on antidepressant response to transcranial magnetic stimulation

Abstract: According to our data, 5-HT(1A) polymorphism may play a role in influencing TMS response. The effect of COMT and SERTPR did not reach statistical significance. The analysis of these and other candidate genes in larger samples could help explain genetic influence on TMS response.

Cited by 46 publications

References 57 publications

Serotonin-1A Receptor Polymorphism (rs6295) Associated with Thermal Pain Perception

Serotonin-1A Receptor Polymorphism (rs6295) Associated with Thermal Pain Perception

Genetic Modulation of Transcranial Direct Current Stimulation Effects on Cognition

The relationship between brain oscillatory activity and therapeutic effectiveness of transcranial magnetic stimulation in the treatment of major depressive disorder

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