Risk of clinically significant depression in HIV-infected patients: effect of antiretroviral drugs

Authors


  • Presented in part at the 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, 3-6 March 2013 [Abstract 413].

Abstract

Objectives

We aimed to characterize depression in newly diagnosed HIV-infected patients, to determine the effect of antiretroviral therapy (ART) on its incidence, and to investigate whether efavirenz use was associated with a higher risk, compared with non-efavirenz-containing regimens, in the Spanish CoRIS cohort.

Methods

CoRIS is a contemporary, multicentre cohort of HIV-infected patients, antiretroviral-naïve at entry, launched in 2004. Poisson regression models were used to investigate demographic, clinical and treatment-related factors associated with a higher incidence of clinically significant depression to October 2010.

Results

In total, 5185 patients (13 089 person-years) participated in the study, of whom 3379 (65.2%) started ART during follow-up. The incidence rates of depression before and after starting ART were 11.68 [95% confidence interval (CI) 9.01–15.15] and 7.06 (95% CI 5.45–9.13) cases per 1000 person-years, respectively. After adjustment, there was an inverse association between the occurrence of depression and the initiation of ART [incidence rate ratio (IRR) 0.53; 95% CI 0.28–0.99], while the likelihood of depression increased in patients of age > 50 years (IRR 1.94; 95% CI 1.21–3.12). Longer exposure to ART was associated with a decreased IRR of depression in unadjusted and adjusted analyses. The IRR for patients receiving < 2, 2–4 and > 4 years of ART was 0.72 (95% CI 0.36–1.44), 0.10 (95% CI 0.04–0.25) and 0.05 (95% CI 0.01–0.17), respectively, compared with ART-naïve patients. This protective effect was also observed when durations of exposure to nonnucleoside reverse transcriptase inhibitor-based regimens and efavirenz-containing regimens were analysed separately.

Conclusions

The incidence of clinically significant depression was lower among HIV-infected patients on ART. The protective effect of ART was also observed with efavirenz-containing regimens.

Introduction

Mood and anxiety disorders, especially depression, are common among people living with HIV/AIDS [1-3]. Several studies have demonstrated higher rates of depressive disorders in HIV-infected patients compared with HIV-uninfected persons [2, 4]. In a cross-sectional study conducted in a large HIV clinic in the USA, an estimated 29% of patients had clinically relevant depression [3].

Mood disorders may negatively affect medication adherence, disease progression and mortality in HIV-infected patients [5-7]. Depressive symptoms at the time of initiating combined antiretroviral therapy (ART) have been associated with slower virological suppression [8] and more rapid virological failure in patients initially responding to nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens [9]. A number of studies have reported significantly worse outcomes in depressed compared with nondepressed HIV-infected persons, even after adjusting for adherence [9, 10].

Risk factors for mood disorders in HIV-infected individuals remain largely unknown and there is limited information about the effect that ART might have on their occurrence. A few small observational studies in the early era of combined ART reported a lower prevalence of depression among persons on ART than in those not receiving ART [11], and a possible improvement in depressive symptoms during therapy with protease inhibitors (PIs) was observed [12]. However, there have been no systematic studies assessing the impact of ART on the incidence of depression.

ART in persons with mood disorders is potentially complicated by side effects of antiretroviral medications, in particular neuropsychiatric adverse events associated with efavirenz, a potent and effective first-line NNRTI. Efavirenz induces depressive-like behaviour and increases stress response in rats [13], and treatment with this drug is often associated with acute central nervous system (CNS) adverse reactions, including insomnia, dizziness and vivid dreams [14, 15]. Although these symptoms generally resolve after a few weeks of efavirenz use, a minority of patients may show longer term neuropsychiatric problems [14-16].

The association of efavirenz use with depression or suicide remains controversial [17-20]. Unfortunately, investigations attempting to address this issue have been either cross-sectional studies or clinical trials with a relatively short follow-up period. While cases of acute depression and suicidal ideations have indeed been reported [21] and some studies have warned of a high prevalence of depression in efavirenz-treated patients [17, 22], others have found no association between efavirenz use and depressive disorders [18, 19, 23]. In the light of this uncertainty, providers may have doubts about the suitability of using efavirenz in individuals with mood disorders, or those considered to be at risk of depression.

We recently investigated non-AIDS events (NAEs) in a large prospective contemporary cohort, and found that psychiatric events, mainly depression, were the most common NAEs occurring in newly diagnosed HIV-infected patients [24]. This report is a subgroup analysis of all the patients who developed clinically relevant depression in the cohort, with the aim of assessing the rate and predictors of this disorder, and determining whether ART may have an effect on its incidence. The study also investigated whether efavirenz use was associated with a higher risk of depression, compared with non-efavirenz-containing regimens.

Methods

The clinical and epidemiological data used in the study were collected from patients included in the cohort of adults with HIV infection of the Spanish AIDS Research Network (CoRIS) launched in 2004. CoRIS is a multicentre cohort of patients newly diagnosed with HIV infection and naïve to ART. The cohort has been described in detail elsewhere [25]. Losses to follow-up in the cohort (< 20%) are more frequent in younger people, in injecting drug users, in subjects of non-Spanish origin, in persons with primary or lower educational level, and in those with better immunological and virological status at cohort entry (25).

ART is documented in detail, with the start and stop dates for each drug. Data are collected at baseline, and prospectively updated and sent to the coordinating centre. Patient follow-up ends when the patient dies or is transferred for follow-up care to another centre that is not in CoRIS and cannot provide follow-up data.

All centres were invited in February 2008 to provide data on incident NAEs, including non-AIDS-defining malignancies and cardiovascular, renal, liver, bone, metabolic and psychiatric events. Full details of the project have been published elsewhere [24]. Briefly, centres were asked to collect retrospectively all of the above NAEs occurring from the day of entry in the cohort to February 2008 (including patients who had died or were lost to follow-up prior to data collection), and to report them prospectively since then. Centres were provided with a structured event reporting form containing the list of events to be reported, and the precise definition of each NAE required for inclusion.

Within the category of psychiatric events, the following major events were reported: depression requiring drug therapy, suicide attempt, and psychosis. Events reported as depression requiring drug therapy and suicide attempts were considered as ‘clinically significant depression’.

The main analyses of the spectrum of NAEs were based only on the first NAE that occurred during follow-up (i.e. if the first NAE in a given patient was a liver complication and the patient subsequently developed a psychiatric event, only the liver event was included in the analyses) [24]. For the purpose of the current analyses, all the patients who developed clinically relevant depression during follow-up were included, irrespective of whether it was the first or a subsequent NAE.

Statistical analyses

Descriptive analyses were used to summarize the incidence rates of clinically significant depression, and the characteristics of the patients developing it. Incidence rates were calculated as the number of new events divided by the number of person-years of follow-up. Follow-up for the analysis of incident events accrued from the day of inclusion in the cohort to the date of the development of an event. Only events occurring after cohort entry were included in the analyses. Patients with pre-existing depression or those with depression at cohort entry were not included, unless it recurred during follow-up. Follow-up of patients not developing events accrued from the day of inclusion in the cohort to the date of last visit or death. Data were abstracted from the study database on 15 February 2011, and follow-up of patients was administratively censored after the last cohort merging on 31 October 2010. As the number of subsequent events developing in the same patient was limited, for simplicity, analyses were based on the first event of clinically significant depression that occurred during follow-up. Poisson regression models were used to determine the demographic, clinical and treatment-related factors associated with the development of a new event. To determine the effect of ART on the incidence of clinically significant depression, and to investigate whether therapy with certain drugs was associated with a higher risk, both exposure (ever treated) to ART and cumulative exposure to ART, to specific antiretroviral regimens and to specific drugs were calculated. Exposure to ART was included in the model as a time-dependent covariate. We split the ever ART-treated patients' follow-up into two periods of time [naïve and on treatment] by the day on which they started their first ART regimen, ignoring subsequent changes in treatment, including treatment interruptions and terminations, after starting the first ART regimen. Cumulative exposure to ART, to specific antiretroviral regimens, and to specific drugs during the follow-up period was calculated taking into account all the changes in treatment, interruptions and terminations. Cumulative exposures to different treatments were subsequently included in the models as categorical variables. Multivariable models were adjusted for the effect of all the variables included in univariate analyses.

Crude incidence rates of clinically significant depression were calculated per 1000 person-years of follow-up stratified by duration of exposure to ART [naïve to all ART drugs (reference), and < 2, 2–4 and > 4 years of exposure], duration of exposure to specific antiretroviral regimens and duration of exposure to specific drugs [naïve to all ART drugs (reference), no exposure to a specific drug, and < 2, 2–4 and > 4 years of exposure]. To study the associations between specific drugs and the risk of depression, we categorized ART regimens according to the third drug component of the regimen. Only regimens reaching an exposure time of at least 500 person-years of follow-up and a median individual post-exposure follow-up of > 12 months were analysed. Poisson regression models were fitted adjusting for sex, age at initiation of ART, educational level, HIV transmission category, CD4 cell count and HIV RNA at initiation of ART, prior clinical AIDS and hepatitis C virus (HCV) coinfection. Confidence intervals (CIs) were computed using robust error variance estimators clustered by centre. Time to the occurrence of depression was estimated by the use of Kaplan−Meier curves according to exposure to ART; patients' follow-up was measured from the date of inclusion in the cohort until clinically significant depression or last visit. All the analyses were conducted using stata software (V.11.2; Stata Corporation, College Station, TX).

Results

In total, 5185 patients (13 089 person-years of follow-up) were included in the main analysis [24]. Of these, 3379 (65.2%) patients (10 117 person-years of follow-up) started ART during follow-up, with a median total treatment duration of 1.94 [interquartile range (IQR) 0.83–3.52] years, accounting for 8214 person-years of ART. The median CD4 cell count at which ART was initiated increased steadily throughout the observation period, from 147 (IQR 56–271) cells/μL in 2004 to 278 (IQR 168–357) cells/μL in 2010 (P < 0.001; test for linear trend). At the last visit the most frequent antiretroviral regimens were based on NNRTIs (1922 patients; 56.9%; of these, 85% were receiving efavirenz), followed by PI-based regimens (1156 patients; 34.2%). Tenofovir was the most frequently used nucleoside reverse transcriptase inhibitor, received by 78.7% of the patients.

A total of 115 patients developed clinically significant depression during the follow-up period, with an incidence rate (IR) of 8.78 cases per 1000 person-years (95% CI 7.31–10.54). The main characteristics of the patients are shown in Table 1. The IRs (95% CIs) before and after starting ART were 11.68 (9.01–15.15) and 7.06 (5.45–9.13) cases per 1000 person-years, respectively. There were 92 cases of depression requiring drug therapy (IR 7.03; 95% CI 5.72–8.62) and 23 cases of suicide attempt (IR 1.75; 95% CI 1.16–2.64). The IR of clinically significant depression decreased over calendar time from 27.42 (95% CI 14.27–52.7) cases per 1000 person-years in 2004 to 4.76 (95% CI 2.63–8.59) cases per 1000 person-years in 2010 (P = 0.003; test for linear trend across the groups). During the same period, the percentage of HIV-infected patients who started ART with a CD4 cell count < 200 cells/μL decreased from 60.9% (95% CI 55.2–66.5%) in 2004 to 32.2% (95% CI 27.6–36.9%) in 2010.

Table 1. Baseline characteristics of patients developing clinically significant depression
VariableClinically significant depression
YesNo
  1. CI, confidence interval; IDU, injecting drug user; IQR, interquartile range; MSM, men who have sex with men; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
  2. *Data regarding hepatitis B and hepatitis C virus coinfection were available in 3113 and 3392 patients, respectively.
Patients [n (%)]115(2.22)5070(97.78)
Depression requiring drug therapy [n (%)]92(80) 
Suicide attempt [n (%)]23(20) 
Female [n (%)]30(26.09)1039(20.49)
Age at cohort entry (years) [median (IQR)]41(33–45)36(29–43)
HIV transmission group [n (%)]    
IDU25(21.74)673(13.27)
MSM45(39.13)2420(47.73)
Heterosexual41(35.65)1787(35.25)
Other/unknown4(3.48)190(3.75)
Prior clinical AIDS [n (%)]16(13.91)647(12.76)
CD4 count at cohort entry [n (%)]    
> 500 cells/μL38(33.4)1458(28.76)
350–500 cells/μL17(14.78)964(19.01)
200–349 cells/μL22(19.13)1034(20.39)
< 200 cells/μL32(27.83)1491(29.41)
Unknown6(5.22)123(2.43)
HIV RNA at cohort entry [n (%)]    
< 100 000 copies/ml73(63.48)3435(67.75)
≥ 100 000 copies/ml34(29.57)1489(29.37)
Unknown8(6.96)146(2.88)
Hepatitis C virus coinfection* [n (%)]18(27.69)594(17.85)
Hepatitis B virus coinfection* [n (%)]4(6.25)185(6.07)
Follow-up (years) [median (IQR)]1.32(0.33–2.64)2.21(0.93–3.83)
Antiretroviral therapy exposure [n (%)]    
No exposure57(49.57)1748(34.47)
Ever treated with NNRTI-based regimens33(28.70)2184(43.08)
Containing efavirenz29(25.22)1913(37.73)
Containing nevirapine7(6.09)402(7.93)
Ever treated with PI-based regimens36(31.30)1724(34.00)
Containing lopinavir25(21.74)1024(20.20)
Containing atazanavir8(6.96)469(9.25)
Containing fosamprenavir7(6.09)202(3.98)
Containing darunavir0(0)253(4.99)
Ever treated with regimens containing maraviroc0(0)27(0.53)
Ever treated with regimens containing raltegravir2(1.74)178(4.99)

Factors associated with the occurrence of clinically significant depression are shown in Table 2. In unadjusted analysis, there was a higher risk of clinically significant depression in patients of older age. Factors inversely associated with the development of clinically significant depression were HIV transmission categories men who have sex with men (MSM) and heterosexual, secondary or higher educational level and exposure to ART. After multivariate adjustment, there was an inverse association between the occurrence of clinically significant depression and initiation of ART [incidence rate ratio (IRR) 0.53; 95% CI 0.28–0.99; P = 0.048], while the likelihood of clinically significant depression significantly increased in patients of age > 50 years (IRR 1.94; 95% CI 1.21–3.12).

Table 2. Unadjusted and adjusted incidence rate ratios (IRRs) for the occurrence of clinically significant depression
   Univariable analysesMultivariable analysis
Number of eventsFollow-up (person-years)IRR (95% CI)PIRR (95% CI)P
  1. Multivariable models were adjusted for sex, age, HIV transmission group, educational level, prior AIDS, hepatitis C coinfection, CD4 count and HIV viral load at cohort entry, and antiretroviral therapy initiation.
  2. CI, confidence interval; IDU, injecting drug user; IRR, incidence rate ratio; MSM, men who have sex with men.
Female sex      
No8510126111
Yes3029631.20 (0.95–1.51)0.1121.45 (0.96–2.18)0.074
Age at cohort entry      
≤ 40 years57876311
41–50 years4230512.11 (1.50–2.97)0.0010.94 (0.55–1.60)0.826
> 50 years1612741.92 (1.06–3.48)0.0291.94 (1.21–3.12)0.006
HIV transmission group      
IDU25199911
MSM4557000.63 (0.40–0.97)0.0370.82 (0.43–1.53)0.536
Heterosexual4149580.66 (0.45–0.96)0.0340.62 (0.32–1.19)0.156
Other/unknown44310.74 (0.30–1.81)0.5130.68 (0.24–1.92)0.475
Educational level      
None/primary49482211
Secondary/university4158420.69 (0.47–1.01)0.0550.72 (0.44–1.17)0.193
Unknown2524241.01 (0.61–1.67)0.9540.99 (0.60–1.63)0.982
Prior clinical AIDS      
No991127411
Yes1618151.01 (0.67–1.50)0.9861.04 (0.64–1.69)0.863
Hepatitis C virus coinfection      
No47658111
Yes1817591.43 (0.76–2.67)0.2580.90 (0.38–2.09)0.815
Unknown5047481.47 (0.90–2.40)0.1211.31 (0.78–2.21)0.299
CD4 count at cohort entry      
> 500 cells/μL38374911
350–500 cells/μL1723980.69 (0.32–1.49)0.3560.76 (0.34–1.66)0.495
200–349 cells/μL2225610.84 (0.47–1.52)0.5811.04 (0.56–1.96)0.882
< 200 cells/μL3240580.77 (0.48–1.25)0.3020.93 (0.44–1.95)0.850
Unknown63211.84 (0.68–4.94)0.2240.79 (0.24–2.53)0.692
HIV RNA at cohort entry      
< 105 copies/mL73882311
≥ 105 copies/mL3439171.04 (0.77–1.41)0.7521.23 (0.83–1.83)0.285
Unknown83482.77 (1.08–7.04)0.0322.61 (0.72–9.43)0.141
Antiretroviral therapy      
No57487511
Yes5882140.60 (0.39–0.92)0.0190.53 (0.28–0.99)0.048

Unadjusted and adjusted IRRs of exposure to ART and exposure to different antiretroviral drugs for clinically significant depression in patients who received ART during follow-up compared with ART-naïve patients are shown in Table 3. Longer exposure to ART was associated with decreased IRR of depression in unadjusted and adjusted analysis. IRR (95% CI) for patients receiving < 2, 2–4 and > 4 years of ART therapy was 0.72 (0.36–1.44), 0.10 (0.04–0.25) and 0.05 (0.01–0.17), respectively, compared with ART-naïve patients. When time on ART was fitted as a continuous variable, there was a 54% decrease in the risk of clinically significant depression (IRR 0.46; 95% CI 0.35–0.59; P < 0.001) per additional year on ART. The protective effect of ART on the incidence of clinically significant depression was also observed when durations of exposure to NNRTI-based regimens and efavirenz-containing regimens were analysed separately (Fig. 1).

Figure 1.

Adjusted incidence rate ratios for the occurrence of clinically significant depression by exposure to antiretroviral therapy (ART) and different antiretroviral drugs. Multivariable models were adjusted for sex, age at initiation of ART, educational level, HIV transmission category, CD4 cell count and HIV RNA at initiation of ART, prior clinical AIDS and hepatitis C virus coinfection. ART exp., ART exposure; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; EFV, efavirenz; NEV, nevirapine; LPV, lopinavir; ATV, atazanavir.

Table 3. Unadjusted and adjusted incidence rate ratios (IRRs) for the occurrence of clinically significant depression in patients initiating antiretroviral therapy by cumulative exposure to antiretroviral drugs
    Univariable analysesMultivariable analysis
Number of patientsNumber of eventsFollow-up (person-years)IRR (95% CI)PIRR (95% CI)P
  1. Multivariable models were adjusted for sex, age at initiation of antiretroviral therapy, educational level, HIV transmission category, CD4 cell count and HIV RNA at initiation of antiretroviral therapy, prior clinical AIDS and hepatitis C virus coinfection.
  2. CI, confidence interval; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor.
cART exposure       
Naïve180557297211
< 2 years17104017961.16 (0.76–1.75)0.4780.72 (0.36–1.44)0.357
2–4 years10061129760.19 (0.09–0.38)0.0010.10 (0.04–0.25)0.001
> 4 years664734410.10 (0.04–0.24)0.0010.05 (0.01–0.17)0.001
Per year115111850.59 (0.50–0.68)0.0010.46 (0.35–0.59)0.001
cART exposure by family       
NNRTI-based       
Naïve180557297211
No exposure11632524890.52 (0.34–0.80)0.0030.32 (0.15–0.68)0.003
< 2 years13392523380.55 (0.33–0.91)0.0220.39 (0.18–0.81)0.012
2–4 years560617390.17 (0.07–0.44)0.0010.11 (0.03–0.39)0.001
> 4 years318216470.06 (0.02–0.20)0.0010.04 (0.01–0.19)0.001
Efavirenz       
Naïve180557297211
No exposure14382932560.46 (0.31–0.69)0.0000.29 (0.15–0.56)0.000
< 2 years12262222140.51 (0.27–0.96)0.0370.37 (0.14–0.92)0.034
2–4 years451513760.18 (0.07–0.48)0.0010.12 (0.04–0.40)0.001
> 4 years265213670.07 (0.02–0.25)0.0010.05 (0.01–0.24)0.001
Nevirapine       
Naïve180557297211
No exposure29715169850.38 (0.23–0.60)0.0010.25 (0.11–0.58)0.001
< 2 years26376320.57 (0.35–0.95)0.0310.41 (0.24–0.70)0.001
2–4 years1030366
> 4 years430230
PI-based       
Naïve180557297211
No exposure16202235900.31 (0.19–0.53)0.0010.23 (0.10–0.51)0.001
< 2 years9122015330.68 (0.41–1.12)0.1340.45 (0.19–1.07)0.074
2–4 years465513710.19 (0.06–0.53)0.0020.12 (0.03–0.41)0.001
> 4 years3831117180.33 (0.20–0.54)0.0010.20 (0.08–0.48)0.000
Lopinavir       
Naïve180557297211
No exposure23313351170.33 (0.21–0.52)0.0010.23 (0.11–0.51)0.001
< 2 years6781716360.54 (0.30–0.95)0.0360.35 (0.13–0.91)0.032
2–4 years26068780.35 (0.16–0.76)0.0080.23 (0.10–0.50)0.001
> 4 years11125810.17 (0.03–0.82)0.0270.11 (0.01–0.79)0.028
Atazanavir       
Naïve180557297211
No exposure29035069180.37 (0.24–0.57)0.0010.25 (0.11–0.55)0.001
< 2 years33536930.22 (0.87–0.58)0.0020.14 (0.06–0.33)0.001
2–4 years11054360.59 (0.19–1.80)0.3620.37 (0.09–1.56)0.180
> 4 years320167

Discussion

To our knowledge, the data presented here represent the first substantive evidence from a large cohort to inform the effect of ART on the incidence of depression in HIV-infected patients. The results indicate that the risk of clinically significant depression is lower in patients receiving ART. Consistent with the literature, age was also a strong determinant of depression. The study also provides information on the rate of and predictors for depression in patients with HIV infection in the current era. There was a decreasing incidence of clinically significant depression during the observation period, which is most remarkable considering the prospective collection of events in recent years. The reason for this decline remains unknown, although the documented earlier initiation of ART throughout the observation period could have played a role.

Data from experimental studies suggest that HIV per se and/or the associated proinflammatory and immune activation state may play an important role in HIV-associated depression. Both glycoprotein 120 (gp120) and Tat proteins administered into the brain can induce depressive-like behaviour in preclinical models with laboratory rodents, and they can activate glial cells, thus contributing to the propagation of inflammation [26, 27]. Several investigations have focused on potential mechanisms linking inflammation-induced depression to tryptophan metabolism, as a reduction in the bioavailability of tryptophan could affect serotoninergic neurotransmission in the brain, leading to depressive symptoms [28, 29]. Those studies have shown that the proinflammatory cytokines interleukin (IL)-1β, tumour necrosis factor (TNF)-α and interferon (IFN)-γ, and lipopolysaccharide (LPS), are capable of activating the enzyme indoleamine 2, 3-dioxygenase (IDO) [30-32], a tryptophan-degrading enzyme that oxidizes tryptophan to n-formylkynurenine.

A hallmark of HIV infection is the presence of abnormal levels of immune activation and inflammation with high concentrations of proinflammatory cytokines, and high plasma LPS levels [33]. Therefore, activation of IDO by inflammatory signals was expected in HIV infection. Indeed, studies conducted two decades ago by Fuchs et al. demonstrated an increased activity of the IDO/kynurenine pathway with reductions in tryptophan levels in the plasma of HIV-infected patients which were associated with neuropsychiatric manifestations [34]. Interestingly, a recent experimental study in mice has demonstrate that a single exposure to Tat in the brain is sufficient to induce brain cytokine signalling and increased expression of IDO mRNAs in the CNS tissue that culminates in depressive-like behaviour [27].

There is strong evidence that ART may deactivate the immune system in HIV-infected patients through its inhibition of HIV replication, usually resulting in a marked reduction of T-cell activation and a decrease of proinflammatory cytokine levels [33]. Therefore, effective ART might be expected to reduce the risk of depression in HIV-infected patients. However, while some small studies in the early ART era suggested an association between ART and decreased rates of depression [11], data from prospective cohort studies assessing the effect of ART on the incidence of depression were lacking. We found consistent associations between ART exposure and a reduction in the rate of clinically significant depression, thus indicating that ART has indeed a beneficial effect on the risk of depression in HIV-infected patients.

In the analyses of the effects of duration of exposure to ART and exposure to different antiretroviral drugs on the incidence of clinically significant depression in patients who received ART during follow-up, we again found a consistent protective effect of ART that was also observed when durations of exposure to NNRTI- and efavirenz-containing regimens were analysed separately. The effect of long-term NNRTI-based ART on the incidence of depression has been largely unknown to date. Although CNS toxicity is a common side effect of efavirenz, and significant rates of depression and suicidal ideation have been described in uncontrolled studies [17], most controlled, systematic evaluations of the impact of efavirenz on depression have found no evidence that efavirenz-based regimens resulted in an excess of depression [18, 19, 23]. In recent years, three clinical trials have investigated the impact of switching from efavirenz to another antiretroviral agent on CNS symptoms in patients on a stable, fully suppressive, efavirenz-based regimen [35-37]. Although some of these studies did show a significant reduction in CNS adverse events [35, 37], none of them demonstrated significant differences in depression scores between participants receiving efavirenz and patients receiving an alternative antiretroviral regimen. It should be noted that neither those results nor findings from the current study argue against the existence of idiosyncratic depression provoked by efavirenz.

The strengths of the present analyses are the contemporary nature of the cohort, with most patients being diagnosed in the current era and naïve at entrance, and the availability of accurate data for the use of antiretrovirals, and for demographic and HIV-related factors. Limitations are the observational nature of the study, the retrospective collection of events until February 2008, and the lack of data on risk factors for the development of depression. An indication bias as a result of a higher risk of depression in some patients cannot be excluded. As a previous history of mood disorders is not usually considered either a contraindication or a barrier to starting ART, delaying ART in this scenario is unlikely. However, patients with a higher underlying risk of depression might have been less likely to be initially placed on efavirenz-containing regimens, and thus our findings on the strong protective effect of this drug could be partially explained by indication bias. Finally, it is possible that those patients more predisposed to depression were more commonly lost to follow-up or less committed to start ART, leaving subjects at lower risk overrepresented in the treated group. Losses to follow-up in our cohort are more frequent in persons with primary or lower educational level and HIV transmission categories other than MSM and heterosexual, both characteristics associated with a higher risk of depression in unadjusted analysis (25). However, losses to follow-up in the cohort are more frequent in younger people (25), whereas the likelihood of depression increased with age, and older age and ART were the only variables associated with depression after multivariate adjustment. Given the large number of participating sites and the study design, we focused on cases with a definitive diagnosis of depression who were receiving treatment with antidepressants. Use of these criteria may underestimate the true prevalence of depression and limits our ability to make conclusions about depressive disorders. While recognizing that using screening tools for depression could have increased the number of patients diagnosed as having mood disorders, we feel that the criteria used allowed us to select for the most clinically significant cases.

In conclusion, this study suggests that ART decreases the risk of clinically significant depression. The protective effect of ART was also observed with efavirenz-containing regimens.

Acknowledgements

This study would not have been possible without the collaboration of all the patients, medical and nursing staff and data managers who have taken part in the project. The study was supported in part by Red Temática de Investigación Cooperativa en VIH/SIDA-ISC III-RETIC RD06/0027, RD12/0017/0023, and Instituto de Salud Carlos III-FIS (PI081893).

Author contributions

All authors contributed to the preparation of the manuscript. In addition, individual authors made the following contributions to the study: study design was performed by FG and MM, data entry and cleaning by DA, data analysis by SP and LG, and drafting of the paper by FG, MM, SP and LG. All authors reviewed and approved the final version of the manuscript.

Appendix: Appendix: Centres and investigators participating in CoRIS

Coordinating committee: Juan Berenguer, Julia del Amo, Federico García, Félix Gutiérrez, Pablo Labarga and Santiago Moreno y María Ángeles Muñoz.

Field work, data management and analysis: Paz Sobrino Vegas, Victoria Hernando Sebastián, Belén Alejos Ferreras, Débora Álvarez, Susana Monge, Inmaculada Jarrín and Adela Castelló.

BioBanco: M. Ángeles Muñoz-Fernández, Isabel García-Merino, Coral Gómez Rico and Jorge Gallego de la Fuente y Almudena García Torre.

Participating centres

Hospital General Universitario de Alicante (Alicante): Joaquín Portilla Sogorb, Esperanza Merino de Lucas, Sergio Reus Bañuls, Vicente Boix Martínez, Livia Giner Oncina, Carmen Gadea Pastor, Irene Portilla Tamarit and Patricia Arcaina Toledo. Hospital Universitario de Canarias (Santa Cruz de Tenerife): Juan Luis Gómez Sirvent, Patricia Rodríguez Fortúnez, María Remedios Alemán Valls, María del Mar Alonso Socas, Ana María López Lirola, María Inmaculada Hernández Hernández and Felicitas Díaz-Flores. Hospital Carlos III (Madrid): Vicente Soriano, Pablo Labarga, Pablo Barreiro, Pablo Rivas, Francisco Blanco, Luz Martín Carbonero, Eugenia Vispo and Carmen Solera. Hospital Universitario Central de Asturias (Oviedo): Victor Asensi, Eulalia Valle and José Antonio Cartón. Hospital Doce de Octubre (Madrid): Rafael Rubio, Federico Pulido, Silvana Fiorante, Jara Llenas, Violeta Rodríguez and Mariano Matarranz. Hospital Donostia (San Sebastián): José Antonio Iribarren, Julio Arrizabalaga, María José Aramburu, Xabier Camino, Francisco Rodríguez-Arrondo, Miguel Ángel von Wichmann, Lidia Pascual Tomé, Miguel Ángel Goenaga, Ma Jesús Bustinduy and Harkaitz Azkune Galparsoro. Hospital General Universitario de Elche (Elche): Félix Gutiérrez, Mar Masiá, Sergio Padilla, Catalina Robledano, Andrés Navarro, Cristina López, Joan Gregori and Fernando Montolio. Hospital Germans Trías i Pujol (Badalona): Bonaventura Clotet, Cristina Tural, Lidia Ruiz, Cristina Miranda, Roberto Muga, Jordi Tor and Arantza Sanvisens. Hospital General Universitario Gregorio Marañón (Madrid): Juan Berenguer, Juan Carlos López Bernaldo de Quirós, Pilar Miralles, Jaime Cosín Ochaíta, Isabel Gutiérrez Cuellar, Margarita Ramírez Schacke, Belén Padilla Ortega, Paloma Gijón Vidaurreta, Ana Carrero Gras and Teresa Aldamiz-Echevarría Lois y Francisco Tejerina Picado. Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili (Tarragona): Francesc Vidal, Joaquín Peraire, Consuelo Viladés, Sergio Veloso, Montserrat Vargas, Miguel López-Dupla, Montserrat Olona, Alba Aguilar, Joan Josep Sirvent, Verónica Alba and Olga Calavia. Hospital Universitario La Fe (Valencia): José López Aldeguer, Marino Blanes Juliá, José Lacruz Rodrigo, Miguel Salavert, Marta Montero, Eva Calabuig and Sandra Cuéllar. Hospital Universitario La Paz (Madrid): Juan González García, Ignacio Bernardino de la Serna, José Ramón Arribas López, María Luisa Montes Ramírez, Jose Ma Peña, Blanca Arribas, Juan Miguel Castro, Fco Javier Zamora Vargas, Ignacio Pérez Valero, Miriam Estébanez, Silvia García Bujalance and Marta Díaz. Hospital de la Princesa (Madrid): Ignacio de los Santos, Jesús Sanz Sanz, Ana Salas Aparicio and Cristina Sarriá Cepeda. Hospital San Pedro-CIBIR (Logroño): José Antonio Oteo, José Ramón Blanco, Valvanera Ibarra, Luis Metola, Mercedes Sanz and Laura Pérez-Martínez. Hospital de Navarra (Pamplona): María Rivero, Itziar Casado, Jorge Díaz, Javier Uriz, Jesús Repáraz, Carmen Irigoyen and María Jesús Arraiza. Hospital Parc Taulí (Sabadell): Ferrán Segura, María José Amengual, Eva Penelo, Gemma Navarro, Montserrat Sala, Manuel Cervantes and Valentín Pineda. Hospital Ramón y Cajal (Madrid): Santiago Moreno, José Luis Casado, Fernando Dronda, Ana Moreno, María Jesús Pérez Elías, Dolores López, Carolina Gutiérrez, Beatriz Hernández, María Pumares and Paloma Martí. Hospital Reina Sofía (Murcia): Alfredo Cano Sánchez, Enrique Bernal Morell and Ángeles Muñoz Pérez. Hospital San Cecilio (Granada): Federico García García, José Hernández Quero, Alejandro Peña Monje, Leopoldo Muñoz Medina and Jorge Parra Ruiz. Centro Sanitario Sandoval (Madrid): Jorge Del Romero Guerrero, Carmen Rodríguez Martín, Teresa Puerta López, Juan Carlos Carrió Montiel, Cristina González and Mar Vera. Hospital Universitario Santiago de Compostela (Santiago de Compostela): Antonio Antela, Arturo Prieto and Elena Losada. Hospital Son Espases (Palma de Mallorca): Melchor Riera, Javier Murillas, Maria Peñaranda, Maria Leyes, Ma Angels Ribas, Antoni Campins, Concepcion Villalonga and Carmen Vidal. Hospital Universitario de Valme (Sevilla): Juan Antonio Pineda, Eva Recio Sánchez, Fernando Lozano de León, Juan Macías, José del Valle and Jesús Gómez-Mateos. Hospital Virgen de la Victoria (Málaga): Jesús Santos González, Manuel Márquez Solero, Isabel Viciana Ramos and Rosario Palacios Muñoz. Hospital Universitario Virgen del Rocío (Sevilla): Pompeyo Viciana, Manuel Leal, Luis Fernando López-Cortés and Mónica Trastoy.

Ancillary