Reduced use of illicit substances, even without abstinence, is associated with improved depressive symptoms among people living with HIV

Abstract

Purpose:

Substance use is linked with poor outcomes among people living with HIV (PLWH) and is associated with mental health disorders. This analysis examines the impact of decreasing substance use, even without abstinence, on depressive symptoms among PLWH.

Methods:

Data are from PLWH enrolled in the Centers for AIDS Research Network of Integrated Clinical Sites (CNICS) cohort. Participants completed longitudinal assessments of substance use (modified ASSIST) and depressive symptoms (PHQ-9). Changes in substance use frequency were categorized as abstinence, reduced use, and non-decreasing use. Adjusted linear mixed models with time-updated change in substance use frequency and depressive symptom scores were used to examine associations between changes in the use of individual substances and depressive symptoms. Analyses were repeated using joint longitudinal survival models to examine associations with a high (PHQ-9≥10) score.

Results:

Among 9,905 PLWH, 728 used cocaine/crack, 1,016 used amphetamine-type substances (ATS), 290 used illicit opiates, and 3,277 used marijuana at baseline. Changes in ATS use were associated with the greatest improvements in depressive symptoms: stopping ATS led to a mean decrease of PHQ-9 by 2.2 points (95%CI: 1.8–2.7) and a 61% lower odds of PHQ-9 score≥10 (95%CI: 0.30–0.52); decreasing ATS use led to a mean decrease of 1.7 points (95% CI:1.2–2.3) and a 62% lower odds of PHQ-9 score≥10 (95%CI: 0.25–0.56). Stopping and reducing marijuana and stopping cocaine/crack use were also associated with improvement in depressive symptoms.

Conclusions:

We demonstrated that both substance use reduction and abstinence are associated with improvements in depressive symptoms over time.

Introduction

Substance use is a public health challenge in the United States among many different vulnerable populations. Substance use is associated with a range of comorbidities among people living with HIV (PLWH), including viral hepatitis, tuberculosis, bacterial infections, kidney disease, atherosclerosis, cancer, and mental health disorders¹.

In particular, current substance use is associated with increased rates of depressive symptoms and depression among PLWH^2–7. Managing mental health disorders is challenging and, if untreated, the mental health disease will negatively impact HIV care along the HIV care continuum, including delayed linkage to care, delayed initiation of antiretroviral therapy, suboptimal medication adherence, and worse clinical outcomes³. Achieving abstinence in PLWH with substance use disorders is challenging⁸, often requiring multifaceted and interdisciplinary approaches. Addressing substance use, however, is a key intervention for improving depressive symptoms in PLWH, especially since these conditions often co-occur and impact the HIV care continuum^1–7.

We hypothesized that a reduction in substance use may have benefits in terms of depressive symptoms, even if abstinence is not achieved. Substance use can be considered a process of negative reinforcement, due to a decrease in the function of normal reward-related neurocircuitry, which results in increased depressive symptoms among users⁹. Prior studies, however, have predominantly focused on achieving complete abstinence, which is often the main goal of substance use treatment. Harm reduction, the reduction in drug use, remains an important goal, but it is crucial to determine if such reductions have resultant improvements in health, including depression outcomes. Our objective was to evaluate the impact on depressive symptoms of reducing substance use, with or without achieving abstinence. We considered this question in PLWH enrolled in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort¹⁰.

Methods

This study includes PLWH who were eighteen years of age or older and enrolled at one of six CNICS sites (Johns Hopkins University; University of Alabama at Birmingham; University of California, San Diego; University of California, San Francisco; University of North Carolina at Chapel Hill; and University of Washington, Seattle). CNICS is a longitudinal observational study of PLWH receiving primary care at CNICS sites from 1/1/1995 to the present¹⁰. In total, 9,905 participants were eligible for inclusion in analyses.

All participants completed longitudinal assessments of substance use frequency including cocaine/crack; amphetamine-type substances (ATS) which included methamphetamines; illicit opioids; and marijuana. Participants had to have two or more substance use assessments during cohort follow-up to be eligible for this study. We formed sub-cohorts of participants who were using a specific substance to ensure measurement of reduced use or abstinence were done among participants eligible to reduce use due to current use.

As a sensitivity analysis, to enrich the number of opioid users, we also pooled CNICS with Project STRIDE¹¹ from the Seek, Test, Treat, and Retain cohort¹¹. Project STRIDE is a randomized controlled trial of PLWH with substance use disorders that includes a buprenorphine plus naloxone (BPN) intervention, is registered at www.clinicaltrials.gov (NCT01550341), and has similar measures of depressive symptoms and substance use (making it ideal for pooling).

Substance Use

In the CNICS cohort, PLWH completed an approximately 10 minute clinical assessment with touch-screen tablets, with a planned frequency of every ~6 months, as part of routine clinical care¹². The CNICS clinical assessment includes measures of substance use (modified Alcohol, Smoking, and Substance Involvement Screening Test)¹³ as well as a broad group of other patient reported measures and outcomes (including alcohol use). Assessments of substance use included a Likert scale for frequency of use in the past 30 days.

We categorized frequency of use into less than weekly, 1–3 times per week, and daily or almost daily, based on participant responses to the study instruments. Changes in substance use frequency were defined as a change from one category to another. Possible changes included abstinence (change to no use), reduced use (change to a lower frequency category), and non-decreasing or increasing use (the same or higher category of use, as compared to baseline).

Depressive Symptoms

Depressive symptom scores were assessed using the Patient Health Questionnaire (PHQ)-9. CNICS administered the PHQ-9 to participants repeatedly over follow-up, via a Computer-Assisted Self-Interview (CASI) system. The PHQ-9 has been validated as a scale for detecting depressive symptoms both in outpatient populations¹⁴ and in diverse/international populations¹⁵. It has high screening utility and is used in clinical care to screen for depression among PLWH^16–17.

Statistical Models

Linear mixed models with time-updated change in substance use frequency and depressive symptom scores were used to examine associations between changes in the use of individual substances and depressive symptoms. For each substance, a specific cohort was formed of participants who were users at study baseline. These models were adjusted for other substance use, with random slopes and intercepts at the participant level to handle repeated measures over follow-up of both substance use and depressive symptoms. This type of mixed model approach to link changes in drug exposure levels to changes in continuous outcomes has been used in pharmacoepidemiology contexts¹⁸ and is a well-known approach to handle irregular data collection and participants loss to follow-up^19–20. All estimates were adjusted for age, sex, use of other substances, alcohol use, and calendar year.

We were also interested in whether findings were the same if the outcome of interest was screening positive for depression rather than change in depression symptom score as a continuous variable. Therefore, we dichotomized depression scores using a cut-off point of ≥10 (high PHQ-9) to indicate high predictive-value for screening positive for depression²¹ and repeated analyses using a joint longitudinal survival model²² to examine the impact of decreasing drug use and of abstinence for each drug due to known limitations with less complex models²³.

We also considered the possibility of a bidirectional association. We examined change in days of substance use among participants experiencing a drop in PHQ-9 score over follow-up, using a linear mixed model approach. All statistical analysis was done in STATA 14 (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC).

Results

CNICS enrolled patients in clinical care, resulting in a large diverse cohort. Among 9,905 PLWH, the mean age was 44 years, 16% of participants were female, and 40% used a substance at baseline [Table 1]. Overall, 728 participants reported cocaine/crack use, 1,016 ATS use, 290 illicit opioid use, and 3,277 reported marijuana use at baseline.

Table 1.

Demographic and clinical characteristics for 9,905 people living with HIV from the CNICS cohort, including days of use scaled to a 30 day period.

		CNICS
Age at baseline, mean (SD)		44 (11)
Female		16%
Race/Ethnicity	White	48%
	Black	33%
	Hispanic	14%
	Other/missing	5%
Current use of cocaine/crack		7%
Mean days of cocaine/crack use (among users)		3 (7)
Current use of amphetamine-type substances (ATS)		10%
Mean days of ATS (among users)		6 (11)
Current illicit opiate use		3%
Mean days of illicit opiate use (among users)		6 (11)
Current marijuana use		33%
Mean days of marijuana use (among users)		12 (14)
Current alcohol use		67%
Mean days of alcohol use (among users)		5 (6)
Current binge alcohol use		34%
Mean days of binge alcohol use (among users)		2 (6)
Depression (PHQ-9 score)		6 (6)

Changes in ATS use were associated with the greatest improvements in depressive symptoms. Abstinence from ATS was associated with a mean difference in the depressive symptom score of Δ −2.2 PHQ-9 points (95% Confidence Interval (CI): −2.7 to −1.8) or a 61% lower odds of screening positive for depression (95% CI: 0.30–0.52) compared with those who continued their ATS use without a decrease in frequency. Decreasing ATS without abstinence was associated with a mean difference of Δ −1.7 PHQ-9 points (95% CI: −2.3 to −1.2) or 62% lower odds of screening positive for depression (95% CI: 0.25–0.56) compared with those who did not decrease their use [Table 2].

Table 2.

The association of substance use change with depressive symptoms as measured with the PHQ-9 (screen positive PHQ-9 score or linear PHQ-9 score) among persons living with HIV in clinical care across the US in the CNICS cohort between 2010–2017. All estimates are adjusted for baseline frequency of use of other substances (amphetamine-type substances (ATS), cocaine/crack, opiates, marijuana), alcohol use, binge alcohol use, age, sex, and time (years) since baseline. The number of baseline users in each sub-cohort varied based on number of active substance users: Cocaine/crack N=728, ATS N=1,016, Opiates N=290, Marijuana N=3,277.

		Joint longitudinal and survival model (PHQ-9 Score≥10 outcome)			Linear mixed models (Linear PHQ-9 Score outcome)
		OR	95% CI	P- value	ΔPHQ-9 Score	95% CI	P- value
Cocaine/crack	Decrease	0.97	0.60, 1.58	0.912	−0.53	−1.36, 0.31	0.215
	Quit	0.76	0.56, 1.03	0.080	−0.80	−1.26, −0.35	0.001
ATS	Decrease	0.38	0.25, 0.56	<0.001	−1.73	−2.27, −1.20	<0.001
	Quit	0.39	0.30, 0.52	<0.001	−2.23	−2.65, −1.81	<0.001
Opiods	Decrease	1.20	0.39, 3.72	0.746	−0.17	−1.82, 1.47	0.838
	Quit	0.79	0.48, 1.29	0.352	−0.60	−1.35, 0.14	0.112
Marijuana	Decrease	0.72	0.58, 0.88	0.002	−0.40	−0.66, −0.13	0.003
	Quit	0.70	0.59, 0.84	<0.001	−0.50	−0.72, −0.27	<0.001

ATS: amphetamine-type substance; OR: odds ratio; 95% CI: 95% confidence interval

Decrease in use of other substances had more modest associations with depressive symptoms. Stopping marijuana was associated with a mean decrease in the depressive symptom score of Δ −0.5 PHQ-9 points (95% CI: −0.7 to −0.3) or 28% lower odds of screening positive for depression (95% CI: 0.58–0.88), and decreasing marijuana use was associated with a mean decrease of Δ −0.4 PHQ-9 points (95% CI: −0.7 to −0.1) or 30% lower odds of screening positive for depression (95% CI: 0.59–0.84). Stopping cocaine/crack was associated with a mean difference in the PHQ-9 score of Δ −0.8 points (95% CI: −1.3 to −0.4) or 24% lower odds of screening positive for depression (95% CI: 0.56–1.03), however decreasing cocaine/crack use without abstinence was not associated with a significant change in PHQ-9 score or the odds of screening positive for depression (ΔPHQ-9 score=−0.5 points / OR=0.97). Finally, neither stopping or reducing use of opiates over follow-up was associated with a significant reduction of depressive symptom (ΔPHQ-9 score=−0.6 points / OR=0.79 and ΔPHQ-9 score=−0.5 / OR=1.20, respectively) [Table 2]. Results for opioids use were similar to the CNICS-only results [Table 2] when we included an additional study, Project STRIDE, with a high-level of opioid use to improve precision on the illicit opioid estimates [Supplemental Table 1].

Looking for a bidirectional association, we considered the association between reducing PHQ-9 score over follow-up and frequency of substance use. There was an association for cocaine/crack (Δdays of cocaine/crack use −0.07; 95% CI: −0.12 to −0.02), ATS (Δdays of ATS use −0.21; 95% CI: −0.30 to −0.13), and marijuana (Δdays of marijuana use −0.25; 95% CI: −0.44 to −0.06) but not for opiates (Δdays of opiate use −0.03; 95% CI: −0.08 to 0.02) [Supplemental Table 2].

Discussion

We demonstrated that both substance use reduction and abstinence are associated with improvements in depressive symptoms over longitudinal follow-up in PLWH. Relative to other substances, reducing ATS use was more strongly associated with alleviation of depressive symptoms, perhaps suggesting that it has greater detrimental clinical impact, including on depression, than other drugs in this population.

Our results showing that cessation of substance use is associated with improved depression scores are not surprising, although it was reassuring to see the level of concrete improvement in routine care environments. It is well known that depression is associated with substance use^24–26. There is also evidence that substance use may interfere with pharmacologic treatment for depression in PLWH, resulting in less benefit of depression treatment in randomized trials²⁷, although there may be less impact for cognitive-behavioral therapy^28–29.

Treatment for depression in PLWH is important, as depression is a known barrier to HIV medication adherence^30–31 and a source of morbidity and mortality in its own right^32–33. Substance use interferes with improving depression and should be addressed as a part of any treatment plan. Our results should provide additional support for studying interventions that lead to reductions in substance use among PLWH even when complete abstinence is not feasible.

Bidirectional associations appear to be present, in that participants who reduced their PHQ-9 score over follow-up also had fewer days of substance use for most substances. While in clinical care there is often an emphasis on substance use cessation prior to diagnosis and treatment of mental health disorders due to the confounding impact of substance use on diagnosis of mental health disorders, treatment for depression can be effective in people with substance use disorders³⁴, including PLWH³⁵. These results suggest that there may also be a role for treating depression in parallel with efforts to treat substance use disorders.

Our study had key strengths including the longitudinal nature of the data and the high-quality measures of both our exposure and outcome. The use of linear mixed models allowed us to account for the irregular nature of the data and loss to follow-up in this population.

Our study had several key limitations. The population in these studies had lower levels of opioid use than other substances so we may have been underpowered to detect opioid associations. The study is inherently observational and while we adjusted our estimates for obvious confounders, the possibility of residual confounding remains. The measures of substance use were self-reported and were collected using categories of frequency of use, preventing us from establishing a clear threshold for reduction in order for participants to show benefit.

The results of this study suggest that reduction in substance use can result in better psychological outcomes for PLWH dealing with depressive symptoms. These benefits are particularly striking among ATS users (mostly methamphetamine), who showed the greatest benefits from cessation or reduction of use. While clearly cessation of substance use should remain the target of public health interventions, our findings show that reduction in level of use also confers benefit for PLWH dealing with substance use issues.