The Swiss HIV Cohort Study (SHCS) is a prospective multicenter cohort study with continuous enrollment of HIV-positive persons in Switzerland, established in 1988 [19] (www.shcs.ch). Semiannual visits with standardized data collection of demographic, psychosocial, clinical, laboratory and treatment information are conducted in the outpatient clinics of the seven cohort centers, affiliated regional hospitals, and private practitioners collaborating with the cohort centers.

We analyzed participants from the main HIV transmission groups: men who have sex with men (MSM), heterosexually infected persons (HET) and injection drug users (IDU). We excluded persons on interferon-based therapy and pregnant women. The study period starts in January 2010 when items on depression were introduced in the semiannual cohort questionnaire, and ends in July 2013.

Prior to January 2010, the SHCS database included a single item on the diagnosis of "psychiatric illness within the last 6 months" which was not further specified. Since the start of the study period in January 2010, the database of the SHCS is recording whether the diagnosis of depression was made by a psychiatrist, and whether participants with a diagnosis of depression were prescribed anti-depressive medication. The SHCS does not request the use of a specific diagnostic tool for the diagnosis of depression; psychiatrists in Switzerland use the Diagnostic and Statistical Manual of Mental Disorders (DSM) whereas Infectious Diseases specialists at SHCS centers and HIV care physicians in private practice use clinical screening questions as previously described [20]. Among the SHCS participants in our study, the diagnosis of a depressive episode was established in 63% by psychiatrists.

The SHCS was approved by the local ethical committees of the participating centers: Kantonale Ethikkommission Zürich (KEK-ZH-NR: EK-793); Ethikkommission beider Basel ("Die Ethikkommission beider Basel hat die Dokumente zur Studie zustimmend zur Kenntnis genommen und genehmigt."); Kantonale Ethikkommission Bern (21/88); Comité departmental d'éthique des specialités médicales es de médecine communautarie et de premier recours, Hôpitaux Universitaires de Genève (01–142); Commission cantonale d'éthique de la recherche sur l'être humain, Canton de Vaud (131/01); Comitato etico cantonale, Repubblica e Cantone Ticino (CE 813); Ethikkommission des Kantons St. Gallen (EKSG 12/003), and written informed consent was obtained from all participants.

We used Stata/SE 14.0 (StataCorp, College Station, Texas, USA) for the analyses.

The selection process for the different analyses is shown in Fig 1. For the mortality analyses we included 8,271 individuals with at least one visit after January 2010. Of these, 6,756 (82%) had at least three visits (median 4, interquartile range (IQR) 3–5), and contributed to the cumulative prevalence analysis. For the incidence analysis we included 4,422 individuals with no history of psychiatric disorders and no depression at the first two visits after January 2010.

The characteristics of participants included in the incidence and cumulative prevalence analyses are shown in Table 1. Only 39.5% and 34.7% of male and female white IDU were free of depression at both baseline visits and without previous psychiatric disorders. Persons with no history of mental health disorders at the first two visits were more likely to report light alcohol consumption, no smoking, regular physical activity, fully preserved work ability, living together with a partner, and being sexually active. They less likely had an active HCV infection, and more likely had a normal BMI. Of note, 894/1327 (67.4%) of participants with depression at baseline had a history of previous psychiatric disorders.

A new-onset depression was diagnosed in 360 of 4,422 participants without prior depressive or other psychiatric disorder during 9,348 person-years of follow-up, resulting in an incidence rate (IR) of 3.85 per 100 patient-years (95% confidence intervals (CI) 3.48–4.28). Incidence was highest for white male IDU (IR 5.85, 4.20–8.15), followed by white female HET (5.71, 4.34–7.51) and white female IDU (5.16, 3.11–8.56), and lowest for white male HET (2.81, 2.10–3.85) (Table 2 and Fig 2, top panel). Antidepressants were prescribed for 57% of participants with a depression diagnosis; of those diagnosed by psychiatrists, 70% were receiving antidepressants, whereas only 39% of those diagnosed by infectious diseases specialists or general practitioners were treated. Results of the uni- and multivariable Poisson regression analyses are shown in Table 2. Due to strong correlations between the IDU transmission category and several variables, such as alcohol consumption, smoking, ability to work, HCV and HBV co-infection as well as current injection and non-injection illicit drug use, we have omitted these variables from the multivariable model in Table 2. As supporting information we provide S1 Table with a full multivariable model demonstrating the over adjustment. In addition we performed a sensitivity analysis (S2 Table) excluding IDU due to the strong correlation of illicit drug use with HCV co-infection and several psychosocial or life-style variables such as smoking, alcohol consumption and ability to work.

Consistent among all analyses was evidence for an increased incidence of depression among white female HET with incidence rate ratios (IRR) of 1.6–1.7 when compared to MSM. Similar increases were also observed among white male IDU while there was no evidence for increased depression incidence among non-white individuals when compared to MSM (Table 2). We further found associations of incident depression with cannabis consumption and illicit drug use, both, injection and non-injection. We observed decreased incidence of depression with older age, light alcohol consumption (compared to none) throughout all models, while the associations with higher ability to work, increased physical activity and being sexually active were evident only in a subset of analyses.

The increased rates of depression for individuals with active HCV infection in the analysis of the entire cohort is difficult to interpret because of the high prevalence of replicating HCV among IDU (60%) compared to only 3–4% among the other risk groups. In the sensitivity analyses limited to non-IDU participants (S2 Table), however, elevated depression rates for persons with active HCV co-infection were confirmed (adjusted IRR 1.87, 95% CI 1.11–3.16, P = 0.019).

Separate analyses in different HIV transmission groups showed significant declines in the incidence of depression per 10 years older age for white male HET (IRR 0.68, 95% CI 0.51–0.90) and MSM (0.79, 0.67–0.93), while no such trends were seen for the other HIV transmission groups. The different patterns of incident depression with age for the various risk groups are shown in Fig 2, bottom panel.

Among 6,756 persons with at least three follow-up visits spanning a median of 2.94 years (IQR 2.60–3.11) since January 2010, a total of 1,937 (28.7%) experienced a depressive disorder during follow-up. The diagnosis was made by a psychiatrist in 1212/1937 (62.6%) of participants with depression, and the prescription of anti-depressive medication was more frequent when a psychiatrist was involved compared to HIV care providers (70.1% vs. 40.3%, P<0.001). Characteristics of persons with a diagnosis made by a psychiatrist did not differ from those with a depression diagnosed by other HIV care providers of the SHCS centers (all P>0.2, details not shown).

Results from the analysis of the cumulative prevalence of depression with logistic regression models are shown in Table 3. Variables associated with incident depression were generally also associated with cumulative prevalence. In addition, we found evidence for associations of being single with increased prevalence of depression, and of suppressed HIV-1 viral load under ART with decreased prevalence of depression. The association with cannabis consumption seen in the incidence analysis was not reproduced. Similar to the incidence analysis we have added a fully adjusted model and a sensitivity analysis excluding the IDU transmission category as supportive information in S3 and S4 Tables.

At the last visit, the majority of individuals (95%) was on ART and had restored immunity with median CD4 cell counts of 595 cells/μL (IQR 438–788).

During 20,102 patient-years, 193 of 8,271 participants died, resulting in an overall mortality of 0.96 (95% CI 0.83–1.11) per 100 patient-years (PY). Mortality was higher among white male IDU (2.34, 1.78–3.09), white female IDU (2.33, 1.59–3.39) and white male HET (1.32, 0.94–1.84), compared to white female HET (0.53, 0.29–0.95) and MSM (0.71, 0.55–0.92). The lowest rates were observed among non-white males (0.31, 0.13–0.74) and non-white female (0.28, 0.12–0.61). Compared to participants free of depression, mortality was slightly increased among participants with a history of depression (1.17, 0.94–1.45 vs. 0.86, 0.71–1.03, P log rank test = 0.033). Causes of death included 113 non-AIDS events, 21 HIV-related conditions, 6 accidents, 18 suicides, 4 narcotics overdose and in 31 participants causes were unknown.

The overall suicide rate was 0.089 (95% Cl 0.056–0.14) per 100 PY. The majority of suicides (12/18) occurred among MSM resulting in rates of 0.14 (0.082–0.25) per 100 PY vs. 0.12 (0.037–0.36) for white male HET (3/18 suicides). However, numbers were too small to support evidence for significant difference between HIV transmission groups (log rank test P = 0.30). Twelve suicides were committed by participants with prior diagnosis of depression during follow-up, resulting in a rate of 0.18 (0.10–0.31) per 100 PY vs. 0.045 (0.020–0.10) among persons without depression (log rank test P = 0.003).

Rates of loss to follow-up differed between HIV transmission groups with the highest rates for non-white males (5.1 per 100 PY), followed by white female IDU (4.9), white male IDU (4.6), non-white female HET (3.6), white female HET (3.2), and white male HET and white MSM (both 2.8, log rank test P<0.001). However, there was no difference in drop-out rates between participants with or without depression during follow-up (log rank test P = 0.69).