The serotonin transporter and the activity regulated cytoskeleton‐associated protein genes in antidepressant response and resistance: 5‐HTTLPR and other variants

Abstract

Objective Previous evidence suggested the involvement of serotonin transporter (SLC6A4) and activity regulated cytoskeleton‐associated protein (ARC) in antidepressant action. This study investigated their role in antidepressant efficacy and treatment‐resistant depression (TRD). Methods Three samples (n total = 648) were investigated to test the association between treatment outcomes (response, remission, symptom improvement, and TRD) and 11 polymorphisms within SLC6A4 and ARC genes. The possible modulating effect of age and gender was considered. Response and remission were also investigated using a fixed‐effects meta‐analysis of the three samples. Results SLC6A4 5‐HTTLPR/rs25531 effects on symptom improvement were modulated by age (better improvement in L/LA carriers in older subjects) and gender (better improvement in L/LA female carriers). SLC6A4 STin2 long alleles were associated with remission and lower risk of TRD. Preliminary evidence of association between ARC rs11167152/rs10110456 and different outcomes was found. Conclusions 5‐HTTLPR/rs25531 effect on antidepressant efficacy was modulated by age, in line with previous literature data. STin2 effect on antidepressant efficacy was in line with previous meta‐analyses. A new possible effect of ARC variants on antidepressant efficacy was observed; however, further studies in larger samples are needed to confirm their role.

Possible Modulatory Role of ARC Gene Variants in Mood Disorders

“…According to our main analyses, we did not find significant associations involving ARC polymorphisms with treatment outcomes in either of the investigated samples. Thus, we did not replicate our previous findings on rs10110456 and rs11167152 ARC SNPs [13]. We did detect some data indicating ARC polymorphisms being able to influence symptoms severity at baseline in both samples.…”

“…In this paper we focused on ARC possible influence on treatment efficacy and other clinical features in two samples of different ethnicity. The reason for this choice is based on previous research on possible associations of this gene with antidepressant efficacy (in particular with response and remission outcomes for rs10110456 and rs11167152) [13]. Unfortunately, despite the previous data, ARC variants do not seem to have any effect on treatment efficacy according to our principal data.…”

“…Among the genes showing an interesting link with psychiatric disorders there is ARC (activity regulated cytoskeleton associated protein) [10][11][12]. In particular, its potential association with Mood Disorders and antidepressant efficacy was already hinted in a previous work by our group [13]. ARC is an early onset gene that encodes for a protein likely to be involved in the regulation of the actin cytoskeleton [14,15] and microtubules [16].…”

“…In this paper we focused on ARC and in particular on the role of 4 single nucleotide polymorphisms (SNPs), namely rs10110456, rs11167152, rs7465272, rs10097505, on treatment efficacy In this paper our aim was to further contribute to the literature regarding ARC role in mood disorders, in particular we evaluated the same SNPs we investigated in a precedent work [13] in two samples of moderate size and of different ethnicity. At the same time, we attempted to find possible similarities between two genetically distinct populations.…”

Constitutive Serotonin Tone Modulates Molecular and Behavioral Response to Chronic Fluoxetine Treatment: A Study on Genetic Rat Model

“…One of the most promising lines of research has focused on functional genetic variants in the human serotonin transporter gene (3). Thus, a long (L) variant of the upstream regulatory region of the 5HTT gene, conferring higher 5HTT activity compared to the short (S) variant, has been associated with better response to SSRI treatment in Caucasian populations (4,5). Additionally, lower DNA methylation levels in the 5HTT promoter region, associated with higher gene expression levels (6), were also found to predict better response to SSRI treatment (7).…”