Depression following acute coronary syndrome: Time-specific interactions between stressful life events, social support deficits, and 5-HTTLPR

Subtitle: Genetic-environmental interactionson depression followingACS

Jae-Min Kima; Robert Stewartb, Hee-Ju Kanga, Kyung-Yeol Baea, Sung-Wan Kima, Il-Seon Shina, Young Joon Hongc, Youngkeun Ahnc, Myung Ho Jeongc, Hyuno Kangd, Jin-Sang Yoona

aDepartments of Psychiatry Chonnam National University Medical School, Korea,

bKing’s College London, Institute of Psychiatry, London, UK,

cDepartment of Cardiology, Chonnam National University Medical School, Korea,

dGwangju Center, Korea Basic Science Institute

Disclosure Statement: Prof. J-M Kim reported receiving grants from Ministry of Health and Welfare, Republic of Korea, Lundbeck, Lilly, and Otsuka. Prof. R Stewart reports research funding from Pfizer, Lundbeck, J&J and Roche. The other authors report no competing interests.

Address correspondence to Prof. Jae-Min Kim, Departments of Psychiatry, Chonnam National University Medical School, 160 Baekseoro, Dong-gu, Kwangju 501-757, Republic of Korea. Phone number: +82-62-220-6143; Fax number: +82-62-225-2351; E-mail: .

Depression is commonfollowing acute coronary syndrome (ACS), with shared risk factors including social exposures, such as stressful life events (SLEs) and social support deficits (SSDs)– associated withdepression [1], ACS [2], and their comorbidity[3]. The serotonin transporter gene-linked promoter region (5-HTTLPR) s/l polymorphism may modulate the association between psychosocial risk factors and depression, the s allele decreasing 5-HTT expression and increasing depression susceptibility to SLEs [4] and SSDs [5]. To our knowledge, this has not been investigated longitudinally for depressionfollowing ACS.

We consecutively recruited1,152 patients from 2006 to 2013 who were hospitalized at the Department of Cardiology, Chonnam National University Hospital (CNUH), Gwangju, South Korea within 2 weeks of ACS;all participants were re-approached 1 year after baseline evaluation toinvestigate both acute and chronic phases. At both examinations, depressive disorderdiagnoseswere determined by the study psychiatrists using the MINI, a structured diagnostic interview for DSM-IV,defining major and minor depressive disorder[6].From the two evaluations, we defined three binary variables: depressive disorder at baseline, depressive disorder at follow-up in those without depressive disorder at baseline, and depressive disorder at follow-up in those with depressive disorder at baseline. Since ACS patients are usually discharged from hospital within 2 weeks, after intensive medical treatment, criteria applied for depressive disorder diagnosisdid not require a 2-week minimum symptom durationat baseline, but required this at follow-up, as is conventional.At baseline, 969 (378 with DSM-IVdepressive disorder; 591 without)agreed to phlebotomy and represented the baseline sample. Of these, 711 were successfully followed at 1 year;depressive disorder at follow up was present in 53 (12%) of the 426 who did not have depressive disorderat baseline, and in, 130 (46%) of the 285 who had depressive disorder at baseline. The 258 who were lost to follow-up had significantly older age and higher Killip class (p-values<0.05) than those followed. Written informed consent was collected, and the study was approved by the CNUH Review Board.

SLEs were defined by the List of Threatening Events, designed to detect events carrying significant threat and of particular salience for depression.[7]. Specifically, the following nineSLEs during the3monthspreceding the acute coronary syndrome were enquired about: serious illness of self (prevalence 16%), serious illness of a close relative (13%), bereavement of a close family member (4%), bereavement of another relative or close friend (10%), marital separation (2%), end of relationship (9%), problem/disagreement with a close friend or relative (11%), severe economic problem (23%), and theft or loss (8%). Positive responses were totaled to generate a summary score, andbecause of the skewed distribution,were categorized into 2 groups (SLEs absent or present). SSDs were measured by the 6-item Social Support Scale including “someone appreciate what you do”and the 5-item Social Undermining Scale including “someone acted in a unpleasant manner toward you”[8]using 5-pointqualifiers (not at all/rarely/occasionally/often/a great deal). Lower scores indicate deficits of social support.Since there is no standard cutoff,summed scale scores were dichotomized at the medianinto low and high SSD groups.

5-HTTLPRgenotype was determined bypolymerase chain reaction (PCR) and PCR-based restriction fragment length polymorphism assays, categorized as ‘l/l,’ ‘l/s,’ or ‘s/s’.Baseline potential covariates comprised sociodemographic data, depression characteristics (personal / family histories of depression), cardiovascular risk factors, and current cardiac status considering previous research [2,3,9].Patients with and without depressive disorder at baseline were comparedusing t- or χ2 tests. SLEs, SSDs, and 5-HTTLPR genotypes were compared between groups of patients with and without baseline/follow-updepressive disorders using χ2 tests. To investigate interactive effects, associations of SLEs and SSDs with depressive status were initially stratified by5-HTTLPR genotype, followedby tests for interactions ofSLEs x 5-HTTLPR and SSDs x 5-HTTLPR in multivariate logistic regression models after adjusting for covariatesassociated with depressive disorder at baseline at p<0.05. All analyses were performed using SPSS 18.0.

Depressive disorder at baseline was significantly (p<0.05) associated with female sex, lower education, living alone, rented housing, current unemployment, hypertension, diabetes, and current smoking, and these were used as covariates in the adjusted analyses. SLEs and high SSDs were significantly associated with all baseline and follow-up depressive disorders (p<0.05). The 5-HTTLPR s allele was significantly associated with baseline depressive disorder and follow-up depressive disorder in those with baseline depressive disorder (p<0.05). Figure 1 presents data for relationships of SLEs and SSDs with depressive disorder status stratified by genotype. The presence of SLEs was significantly associated with baseline depressive disorder in the presence of the s/s genotype; andwith follow-up depressive disorder in both baseline groupsin the presence of the l/s and s/s genotypes. High SSDs were significantly associated with baseline depressive disorder in the presence of the s/s genotype and with follow-up depressive disorder in those with baseline depressive disorder in the presence of the l/s and s/s genotypes.There were significantinteractive effects of SLEs x 5-HTTLPR on baseline depressive disorder [interaction term OR=1.68 (95% CI 1.08-2.64); P=0.032] and of SSDs x 5-HTTLPR on follow-up depressive disorder in those with baseline depressive disorder [OR=1.92 (1.05-3.72); P=0.036] in the adjusted logistic regression models. All analyses were repeated after excluding participantsreporting a history of previous depression (N=34),and no substantial differences were found in any models (data not shown).

Our findings confirm the well-documented associations between unfavorable social environments anddepression risk, both in patients with ACS [4] and in the general population [1]. Our findings also replicate previous studies in the association between the 5-HTTLPR s allele and depression in ACS [9], and with respect to the interactive effects of genes and environment on depression risk[4,5].However, our study also presents novel findings with respect totime-specific interactions between social factors and 5-HTTLPR on depression at both acute and chronic phases post-ACS: there was a significantinteractive effectof SLEs and 5-HTTLPR on depressive disorder within 2 weeks of ACS and a significantinteractive effect of SSDs and 5-HTTLPR on depressive disorder at 1 year in those with baseline depressive disorder.

These different patterns of genetic-environmental interactions on depression at acute and chronic phases post-ACS may be explained by the nature of unfavorable environments. SLEs are strong risk factors for the onset of depression, but their long-term effects depend on the chronicity of these events [10]. Moreover, acute ACS itself represents a severe life stress when invasive diagnostic and treatment methods are involved. The synergistic effects of SLEs and the 5-HTTLPR s allele on depression may exert a powerful effect in the acute phase of ACS. In contrast, SSDs tend to be stable rather than variable over time, and are therefore well-known predictors of depression persistence [1]. The interaction of SSDs and the 5-HTTLPR s allele on depression may beparticularlyprominent in the chronic phase of ACS, when general health and functioning become stronger determinants of mood states.However, it is important to bear in mind the single follow-up examination which will not have captured depressive symptom trajectories over 1 year between examinations.Additionally, participants with more severe baseline pathology were more frequently lost to follow-up, which might obscure underlyingassociations. Moreover, symptoms-duration criteria for depressive disorder at baseline were not standard, although similar criteria have been used in previousevaluations of ACS patients in theacute phase.

Comorbid depression with ACS results in a high disease burden and is difficult to treat. Simple evaluations of SLEs and SSDs among ACS patients may be helpful in screening for depression not only at the acute phase but also at chronic phases. When combined with 5-HTTLPR genotyping, such screening may result in more focused and time-specific interventions for the prevention or management of depression in susceptible ACS subgroups.

Acknowledgements

The study was funded by a grant of National Research Foundation of Korea Grant (NRF-2015M3C7A1028899), and was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (NRF-2013R1A2A2A01067367) to Professor J.-M. Kim.

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Fig. 1. Depressive disorder status according to stressful life events, social support deficits, and serotonin transporter gene linked promoter region (5-HTTLPR).

Figure legends:

* p-value<0.05; † p-value<0.01; ‡ p-value<0.001usingχ2 tests to test the associations of stressful life events / social support deficits with depressive disorder outcomesfor each 5-HTTLPR genotype.

Interactions (Ix.) of SLEs x 5-HTTLPR and SSDs x 5-HTTLPR on depressive status were examined using multivariate logistic regression models after adjusting for gender, education, housing, current employment, hypertension, diabetes, and current smokingfor analyses on a) and b), and plus treatment status for analyses on c).