Using a marginal structural model to account for time-varying confounding by depression severity, we found that antidepressant medication treatment increased the probability of achieving viral suppression among a cohort of homeless and marginally housed persons living with HIV. In supplemental analyses, we found evidence of improved adherence along a continuum of HIV care: antidepressant medication treatment increased the probability of ART uptake by nearly fourfold and also resulted in a 25% percentage point increase in self-reported ART adherence and a nearly twofold-increased probability of achieving complete adherence. These results are consistent with prior studies linking depressive symptoms to reduced uptake 5, 6
and adherence 7–9
While changes in behavior are the most plausible explanation for our findings 49, 50
, some researchers have hypothesized that biological pathways may directly link depression to poorer HIV outcomes 51
. This is consistent with prior studies showing that, even after adjusting for ART adherence, depression is associated with worsened HIV outcomes, including CD4+ count decline 52
, incident AIDS-defining illness 53
, and AIDS-related mortality 54
. One study showed that resolution of a major depressive episode was associated with increased natural killer cell activity 55
. And more recently, a cross-sectional analysis of data from 658 HIV-positive men and women showed that participants taking serotonin reuptake inhibitors were less likely to have detectable cerebrospinal fluid HIV-1 RNA levels 56
. This relationship held even among those not concurrently taking ART, suggestive of a biologic effect and leading some to suggest that psychotropic medications could be useful as adjunctive treatment for persons living with HIV 57
. In our marginal structural model analysis, the estimated effect of antidepressant medication treatment became non-statistically significant when adjusted for ART adherence, suggesting that the effect of antidepressants on HIV treatment response is at least partially mediated by adherence. However, the attenuation of the treatment effect once adherence was added to the model could also have been due to the limitations of our relatively small sample size. Additional assumptions would be required to fully interpret the adjusted effect as a direct (non-mediated) effect of antidepressant medication treatment 58, 59
. In particular, we would need to assume that the baseline covariates alone capture all of the confounding from the effect of adherence on viral suppression, which is unlikely to be the case. Distinguishing the relative contributions of the two mechanisms, direct vs. indirect (biological vs. behavioral), through which antidepressant medication treatment could affect virologic outcomes was beyond the scope of our study and remains an important area for future work.
We observed greater effects of antidepressant medication on viral suppression among participants with more severe depressive symptoms at baseline. This finding is potentially analogous to results from a recently published meta-analysis of randomized controlled trials showing that the efficacy of antidepressant medication on mood is greater among those with more severe depressive symptoms at baseline 44–46
. In other clinical contexts, marginal structural models have also estimated treatment effects that closely approximate the findings from randomized controlled trials 16, 60–62
. Even though our estimates have a causal interpretation under certain assumptions, randomized controlled trial evidence is needed in order to definitively conclude that pharmacologic treatment of depression has beneficial effects on HIV treatment adherence and HIV treatment outcomes.
Despite these caveats, our study contributes to a sparse literature on how treatment of depression can result in improved HIV outcomes. No randomized controlled trials of antidepressant medication treatment alone have shown improvements in virologic outcomes. Safren et al. 63
studied the effect of individual cognitive behavioral therapy (CBT) among persons living with HIV and also diagnosed with a depressive mood disorder. The CBT intervention explicitly incorporated adherence training and improved ART adherence by more than 20% percentage points at 12 month follow up, but the small sample size limited the investigators’ ability to detect differences in viral load. Two randomized studies of group-based cognitive behavioral stress management for persons living with HIV have yielded mixed results, one positive 64
and one negative 65
, but those studies enrolled participants with minimal depressive symptoms(i.e., mean BDI<14 at baseline). Our study is notable in that it suggests that antidepressant medication treatment can improve HIV care and HIV treatment outcomes among persons with significant depressive symptoms.
Also in contrast to these studies, the participants in the REACH cohort are drawn from a population whose frequently changing living situations and medical and psychiatric comorbidities can make controlled study difficult. All REACH participants were either homeless or marginally housed, approximately one-half reported alcohol or illicit drug use, and more than one-third had been assigned to representative payeeship. Due to these complex comorbidities, many of our study participants would have been excluded from most randomized controlled trials of antidepressant efficacy 66, 67
. The clinical and public health importance of our work is further underscored by nationally representative evidence of underdiagnosis 68
and undertreatment 32
of depression among persons living with HIV/AIDS, as well as the fact that even incremental (e.g., 10%) increases in ART adherence can improve virologic 69, 70
and immunologic 71
outcomes in this population.
Despite these strengths, interpretation of our findings is subject to a number of limitations. Most participants in our study were female, which limits generalizability to the HIV epidemic in the United States 68, 72
. However, while not formally a random sample of HIV-infected, homeless and marginally housed persons, the parent cohort (REACH) was drawn from a systematic and reproducible venue-based sample 73
of homeless and marginally housed persons living with HIV. The REACH cohort was comprised of mostly men with a high prevalence of drug use, alcohol use, and mental illness and is roughly generalizable to the HIV-infected urban poor 17, 18
. The preponderance of females in our analytic sample may reflect the overall epidemiology of major depressive disorder in the general population 3, 74
. Although our sample may not represent patients seen in most clinical settings, it does reflect a population that has variable access to medical and mental health care services and which remains an important part of the national HIV epidemic 75, 76
. A second limitation is that our statistical analyses group antidepressant medications together into a single category, implicitly assuming equivalent treatment effects across medication classes. However, there is recent meta-analytic evidence to support this simplifying assumption 77–79
. Lack of power prevented us from studying individual drugs, but we conducted a sensitivity analysis for the most frequently prescribed medication class in our study (SSRIs) and observed qualitatively similar effects on viral suppression. And finally, our data did not permit us to account for dose escalation. Drug metabolism and clearance varies widely between individuals, and psychiatrists frequently compensate for this pharmacokinetic variability by tailoring antidepressant medication dosage to individual patients’ responses. Our marginal structural model analysis can be conceptualized as analogous to a flexible randomized controlled trial in which subjects are randomized to receive antidepressant medication treatment (or not), but the drug and dose are left up to physician and patient discretion. As noted previously, marginal structural models require several assumptions. First, consistency implies that each participant’s potential outcome under her observed antidepressant medication exposure history is precisely her observed outcome 80
. Although consistency may be problematic when the exposure is a feature such as obesity, it is plausible (although not empirically verifiable) in observational studies of medical treatments. Second, with regards to positivity, or the experimental treatment assumption 14
, there were no structural zeroes 43
in the setting of our data, i.e., factors that would be deterministic of either treatment or non-treatment with antidepressant medication. We were able to identify exposed and unexposed participants at each level of depressive severity as measured by the BDI-II, thereby ruling out the presence of potential random zeroes. In addition, we fitted a regression model using all of the baseline covariates and the time-varying covariate to compute predicted probabilities of treatment. We then visually inspected a plot of the log odds of treatment against both the observed treatment and predicted probabilities of treatment to ensure that there was an acceptable degree of variation of observed values across all levels of the predicted 81, 82
. Third, we assumed that conditioning on several baseline covariates and recent values of depression severity was sufficient to achieve exchangeability between those who did and did not initiate treatment with antidepressant medication during the follow-up period 83, 84
. This is not an empirically verifiable assumption, but we relied on prior studies to guide our inclusion of the most important confounders. Furthermore, we included a broad range of other covariates in an exhaustive sensitivity analysis, and our findings remained robust to these alternate specifications. Nonetheless, some unmeasured confounding could remain, e.g., receipt of adherence counseling. Subjects who received adherence counseling may be more likely to initiate antidepressant medication treatment due to greater interaction with the care team and greater awareness of depression severity, and they may also be more likely to adhere to ART. And fourth, we made the conservative “intent-to-treat” assumption, long recognized as the preferred approach to analysis of data from randomized controlled trials 35, 36, 85
. Thus, we anticipate some bias towards the null in our treatment estimates. Participants in the study cohort remained on antidepressant medications an average of 67% (median 73%) of the time following treatment intiation, which compares favorably with completion rates observed in long-term (i.e., 6–8 months in duration) randomized controlled trials of SSRIs 86
and is similar to completion rates observed in short-term trials of both SSRIs 87
and tricyclic antidepressant medications 88
In summary, we introduced the method of marginal structural modeling to the psychiatric literature to estimate the causal effect of antidepressant medication treatment on viral suppression among a longitudinal cohort of homeless and marginally housed persons living with HIV. Antidepressant medication treatment resulted in a twofold greater probability of achieving viral suppression, and this effect was likely due to improved adherence along a continuum of HIV care. The estimated effects are clinically meaningful and(under certain assumptions) have a causal interpretation, yet randomized controlled trials are needed to conclude definitively that antidepressant medication increases viral suppression in this population. Given the relatively high prevalence of under diagnosed and undertreated depressive mood disorders among persons living with HIV, our findings suggest that improved diagnosis and treatment of depression may have an important contribution to improving HIV treatment outcomes.