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Variation in the HTR1A and HTR2A Genes and Social Adjustment in Depressed Patients

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Variation in the HTR1A and HTR2A Genes and Social Adjustment in Depressed Patients Journal of Affective Disorders 150 (2013) 649–652 Contents lists available at ScienceDirect Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad Brief report Variation in the HTR1A and HTR2A genes and social adjustment in depressed patients Niki Antypa a, Raffaella Calati b, Daniel Souery c, Silvia Pellegrini d, Othman Sentissi e, Daniela Amital f, Ulrike Moser g, Stuart Montgomery h, Siegfried Kasper g, Joseph Zohar i, Diana De Ronchi a, Julien Mendlewicz j, Alessandro Serretti a,* a Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy b IRCCS Centro S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy c Laboratoire de Psychologie Medicale, Université Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels, Belgium d Department of Experimental Pathology, Medical Biotechnology, Epidemiology and Infectious diseases, University of Pisa, Pisa, Italy e Département de Psychiatrie Hôpitaux Universitaires de Genève, Faculté de Médecine de Genève, Geneva, Switzerland f Ness-Ziona Mental Health Center, Israel g Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria h Imperial College School of Medicine, London, UK i Chaim Sheba Medical Center, Tel-Hashomer, Israel j Université Libre de Bruxelles, Brussels, Belgium article info abstract Article history: Background: Social adjustment is impaired in depressed patients. The difficulty to adjust to social Received 14 June 2012 circumstances has been hypothesized to be one of the causes of depression, as well as a consequence of Received in revised form the disorder. Genetic variation in the serotonin transporter gene has been previously associated with 15 February 2013 social adjustment levels in patients with mood disorders. Accepted 18 February 2013 Methods: We investigated whether variations on the HTR1A (rs6295) and HTR2A (rs7997012) genes Available online 26 March 2013 were associated with levels of social adjustment using the Social Adjustment Scale in two samples of Keywords: depressed patients (total n¼156). Social adjustment Results: Patients carrying the GG genotype of the HTR2A-rs7997012 showed better social adjustment in Serotonin genes areas of work and family unit bonding. Depression Limitations: These findings did not survive correction for multiple testing and should be interpreted with caution. Conclusion: Our finding is in line with previous observations that have associated the G allele of the HTR2A-rs7997012 with higher rate of antidepressant response. The HTR2A-rs7997012 is worthy of further investigation in studies examining factors that are related to depression course and outcome. & 2013 Elsevier B.V. All rights reserved. 1. Introduction social maladjustment was considered to be a risk factor for recurrent affective episodes (Bauwens et al., 1998; Grunebaum et al., 2010)and Patients with mood disorders have impaired levels of social was associated with the recurrence of depressive symptoms in functioning, in particular during the acute phase of the disorder depressed patients treated with antidepressants (Reimherr et al., (Bauwens et al., 1991; Blairy et al., 2004). Although an improve- 2001). Social adjustment has also been examined as an outcome in ment in functioning is expected during remission, social adjust- depressive disorders. In a prospective study of a depressed cohort, ment problems also persist in the euthymic phase (Serretti et al., characteristics of the depressive episode, such as severity, recurrence 1999). The Social Adjustment Scale (SAS) (Weissman and Bothwell, before baseline and during follow-up, lack of full remission, and 1976; Weissman et al., 2001) has been extensively used to assess episode duration predicted current levels of social adjustment this area as a predictor of the depressive course. For example, (Rytsälä et al., 2006). Consequently, social maladjustment has been implicated both as a consequence and as a cause of depression. Current research on etiological mechanisms implicates both * Correspondence to: Department of Biomedical and Neuromotor Sciences, genetic and environmental variables as major contributors of University of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy. Tel.: þ39 051 depression. Research on the genetics of mood disorders has 6584233; fax: þ39 051 521030. E-mail address: [email protected] (A. Serretti). focused on the serotoninergic system as a reasonable source of 0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.02.036 650 N. Antypa et al. / Journal of Affective Disorders 150 (2013) 649–652 candidate genes, since this system is implicated in antidepressant 2.3. Statistical analyses pharmacodynamics, challenged by tryptophan depletion methods, and consequently affects mood states (Cowen, 2008). Variation in Descriptive characteristics were assessed with correlations, chi- the serotonin transporter promoter polymorphism (5-HTTLPR) has square tests or one-way ANOVAs as appropriate. Differences been associated with levels of social adjustment in healthy con- between genotype and allele groups on SAS scores were assessed trols and bipolar patients (Serretti et al., 2005). The 5-HT1A using analysis of co-variance (ANCOVA). Socio-demographic and receptor gene (HTR1A) has a polymorphism (rs6295) in the clinical variables that could influence the outcome were included promoter region, which has been associated with depression as covariates. In the whole sample, we had sufficient power (0.80) (Savitz et al., 2009). Furthermore, within the 5-HT2A receptor gene to detect an effect size of 0.22, with an alpha level of 0.05, that, as (HTR2A), the rs7997012 polymorphism has been mainly investi- an example, corresponds to a final difference in the total SAS score gated in relation to treatment response (Kato and Serretti, 2010). of 1.8 points between subjects carrying GG and AG genotypes of The purpose of this study was to investigate whether variations in rs7997012. For other SNPs power was lower (data not shown). the HTR1A and HTR2A genes were associated with social adjust- Genotype frequencies were consistent with Hardy Weinberg ment levels (SAS) of depressed patients. Equilibrium (rs7997012: AA¼13, AG ¼82, GG¼70, χ2(1)¼2.72, p¼0.10; rs6295: CC¼32, CG¼72, GG¼61, χ2(1)¼1.63, p¼0.20). There were no differences in genotype frequencies between 2. Methods European and Israeli samples (rs7997012: χ2(2)¼3.85, p¼0.15; rs6295: χ2(2)¼0.02, p¼0.99). Minor Allele Frequencies (MAFs) 2.1. Participants and assessments were in accordance with those reported for Caucasian populations (rs7997012 MAF:0.33; rs6295 MAF: 0.41). A Cochran-Mantel- One hundred and sixty five patients with a major depressive Haenszel test (McDonald, 2009) showed that there was no disorder were recruited. Of the 165 patients, 94 (56.97%) were difference in allele frequencies between the samples as well: recruited in the context of the European multicenter project (rs7997012: χ2(1)¼ 0.16, p¼0.69; rs6295: χ2 (1)¼2.59, p¼0.11). “Patterns of treatment resistance and switching strategies in uni- polar affective disorder”. Data was collected from the following centers: (1) Department of Psychiatry and Psychotherapy, Medical 3. Results University Vienna, Austria; (2) Department of Psychiatry, Chaim Sheba Medical Center, Tel-Hashomer, Israel; (3) Department of Demographic and clinical characteristics of the sample can be Psychiatry, Ness Ziona, Israel, (4) Department of Psychiatry, Erasme observed in Table 1. Genotypic data were available for 165 Hospital, Universite Libre de Bruxelles, Brussels, Belgium. The patients. Of those, 156 patients also filled in the SAS. SAS levels sample has been described in detail elsewhere (Souery et al., were not related to age, education level, occupation status, marital 2007). In brief, the main inclusion criterium was to be affected by status or number of episodes (all p>0.05), but only to gender and a primary mood disorder (i.e. mood disorder preexisting to any current level of symptoms (HAM-D). Women reported higher other psychiatric disorder). Exclusion criteria were: a mood disorder levels of social dysfunction on areas of work, leisure and marital secondary to any primary ‘non affective’ psychiatric condition. Only relationships (all p<0.05). Higher levels of symptoms were related to patients with a major depressive disorder (MDD) diagnosis were higher impairment in areas of work (r¼.54, p<0.001), leisure (r¼.46, included in this report. Diagnoses were obtained using the Mini p<0.001), family (all r¼.19 p¼0.02) and finances (r¼.18, p¼02). International Neuropsychiatric Interview (MINI) version 5.0.0. The duration of the received antidepressant treatment was marginally Of the 165 patients, 71 patients (43.03%) were recruited from related to the “family unit” area (r¼−.19, p¼0.05). the outpatient unit at the Institute of Psychiatry of Bologna University, Italy. Inclusion criterium was a primary MDD diagnosis Table 1 as assessed with the MINI. Sociodemographic and clinical characteristics of the sample(s). Both samples completed the Hamilton Rating Scale for Depres- sion (HAM-D) and the SAS (Weissman and Bothwell, 1976). The SAS Total Multicenter Bologna P* is a 54-item self-report scale, subdivided into the following subar- sample sample sample n¼165 n¼94 n¼71 eas: (1) work; (2) leisure; (3) extended family; (4) marital role; M±SD/N (%) M±SD/N(%) M±SD/N (%) (5) children; (6) family unit; and (7) finance. Social adjustment is assessed for each area (item range: 1–5). Higher scores reflect poorer Age 53.15±16.72 52.16±14.99 54.67±19.12 0.39 adjustment. The scale contains “skip-outs”, so that non-applicable Gender: females 118 (71.5%) 69 (73.4%) 49 (69.0%) 0.54 < items were not considered (Weissman et al., 2001). Scores for each Marital status 0.01 Single 33 (20.0%) 17 (20.0%) 16 (25.0%) area were calculated by averaging the scores for all answered items Married 84 (50.9%) 54 (63.5%) 30 (46.9%) within that area, and the total score was calculated by averaging all Separated 22 (13.3%) 13 (15.3%) 9 (14.1%) the applicable items (Weissman et al., 2001).
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