Abstract: Prevalence of major depressive disorder runs 2 to 3 times higher in people with HIV infection than in the general population. Yet depression often goes undiagnosed or untreated in HIV populations. One analysis calculated that fewer than half of depression cases get recognized clinically in people with HIV, only 18% get treated, only 7% get treated adequately, and only 5% achieve remission through treatment. Depressive symptoms may affect two thirds of people with newly diagnosed HIV infection. Research in US and Swiss cohorts links depression to greater HIV mortality and all-cause mortality. Diverse studies document the baneful impact of depression on antiretroviral adherence and, at least partly in consequence, on CD4-cell and virologic response to antiretroviral therapy. Treating depression with selective serotonin reuptake inhibitors (SSRIs) ameliorates the impact of depression on these outcomes.
More than 1 in 3 people infected with HIV in the United States has major depressive disorder, according to analysis of a national probability sample of people in care.1 But almost half of the 488 people with major depressive disorder determined by the Composite International Diagnostic Interview, 45%, did not have a depression diagnosis in their medical record. An 8-site US study of 803 HIV-positive people with mental health and substance abuse disorders found that only 59% received any mental health treatment in the past 3 months.2 And among 551 people diagnosed with mood disorders, only 40% took an antidepressant. In a Veterans Administration analysis of 434 HIV-positive and 298 HIV-negative veterans with test-determined depression, only 38% of the HIV group and 34% of the HIV-negative group took a selective serotonin reuptake inhibitor (SSRI).3 Fewer than half in each group got an SSRI or mental health counseling.
HIV depression experts at Duke University and other centers recently underlined three troubling facts about depression care in HIV populations:4
- Although highly prevalent in people with HIV, depression remains widely unrecognized.
- When recognized clinically, depression often goes untreated.
- When treated, the therapeutic strategy typically does not follow best-practices guidelines.
Duke's Brian Pence and depression collaborators4 collected and parsed data from the cited studies1,2 and others to describe a depression treatment cascade for people with HIV. The end of the cascade looks more like a trickle. They calculated that of all cases of major depressive disorder in 1 year, only 45% are recognized clinically, only 40% of those recognized get treated, only 40% of those treated are treated adequately, and 70% of those treated adequately achieve remission. To state these estimates another way, only 18% of HIV-positive people with major depressive disorder get treated, only 7% receive adequate treatment, and only 5% emerge from their depression (Figure 1). That means 82% of HIV-positive people with depression receive no treatment, 93% do not get adequate treatment, and 95% do not attain remission.
How can healthcare professionals coax more flow through this ever-narrowing HIV depression care cascade? Pence and colleagues propose working collaboratively on multiple cascade steps, for example, "combining routine depression screening with collaborative care models that give HIV providers decision support in prescribing and adjusting antidepressants within the HIV 'medical home.'"4 (See the three models of such support.) This issue of RITA! aims to abet this process by helping clinicians understand (1) depression prevalence and clinical impact in people with HIV, (2) risk factors and keys to screening for and diagnosing depression, and (3) effective treatment.
Depression Rate 2 to 3 Times Higher With HIV
Major depressive disorder affects 17% of US adults in their lifetime, according to the 2001-2003 National Comorbidity Survey of 9282 people.5 Depression prevalence in people with HIV may stand 2 or 3 times higher, depending on the population studied and how depression is determined.
A 2001 comparison of a nationally representative sample of 2864 HIV-positive US adults and 22,181 people in the National Household Survey on Drug Abuse charted nearly a 5 times higher prevalence of major depression in the HIV group (36.0% versus 7.6%).6 In other HIV populations, prevalence of major depressive disorder or moderate to major depression has ranged from 26% among 212 people in Denmark,7 to 28% among 4422 people in the Swiss HIV Cohort Study,8 to 38% among 210 people in California.9 Depressive symptoms affected 15.7% of 2863 HIV-positive people in Western Europe and Canada10 and 48.8% of 690 people in Italy.11 Among 180 people with newly diagnosed HIV infection in Houston, 67% had depressive symptoms.12
Centers for Disease Control and Prevention (CDC) researchers used the simple 8-item Patient Health Questionnaire to identify current major depression in a nationally representative sample of 4168 people in care for HIV infection in 2009.13 They compared that prevalence with the rate in 267,584 people in the Behavioral Risk Factors Surveillance System. Current major depression affected 12% of adults with HIV, a prevalence 3.1-fold higher than current major depression in the general population. That prevalence ratio changed little in analyses controlled for age, race/ethnicity, or education. Controlling for both female gender and lower annual household income cut the prevalence ratio to 1.5 (95% confidence interval [CI] 1.4 to 1.7).
A 2001 meta-analysis of 10 studies comparing prevalence of major depressive disorder in 2596 HIV-positive or negative men who have sex with men (MSM) calculated an aggregated prevalence of 9.4% in men with HIV versus 5.2% in men without HIV.14 Those rates translated into a doubled chance of major depressive disorder in MSM with HIV (odds ratio [OR] 1.99, 95% CI 1.32 to 3.00). None of the individual studies -- reported from 1988 through 1998 in the United States, Canada, Australia, and Japan -- found higher odds of major depressive disorder in men with HIV, probably because none of the studies had enough participants to yield the needed statistical power to show a doubled chance of depression.
Fewer studies address depression incidence in people with HIV. Among 4422 people without a history of psychiatric disorders or depression in the Swiss HIV Cohort Study, depression developed at a rate of 3.9 cases per 100 person-years.8 A comparison of 297 HIV-positive men and 90 HIV-negative men in the HIV Neurobehavioral Research Center at the University of California, San Diego focused on men who did not have major depression, anxiety, or substance dependence when starting 2 years of follow-up.15 Men with symptomatic HIV disease proved significantly more likely to have a major depressive episode during those 2 years than asymptomatic HIV-positive men or HIV-negative men (about 40% versus 20%).
Research also shows that high proportions of people with HIV ponder suicide and sometimes attempt it. A review of studies published from 1995 through 2015 figured that 13.6% to 31% of HIV-positive people think about suicide and 3.9% to 32.7% try it.16 Analysis of 1560 HIV-positive people in the US CHARTER cohort determined that 26% thought about suicide and 13% tried it.17
Impact From Quality of Life to End of Life
Depression wields a sledgehammer impact on the clinical course of people with HIV infection. Dozens of studies confirm links between depression and dangerous risk behavior, poor HIV control, comorbidities including cardiovascular disease, and -- at the end of this trainwreck scenario -- death. Glenn Treisman, a depression expert at Johns Hopkins University, lists 10 life-changing, or life-ending, consequences of depression in people with HIV:18
- Impaired quality of life
- Decreased cognition
- Increased risk behaviors
- More frequent medical visits
- Longer hospital stays
- Higher treatment costs
- Decreased antiretroviral adherence
- Decreased survival
Five studies link depression to higher mortality in people with HIV.8,19-22 Three of these five studies took place in the United States early in the combination antiretroviral era,19-21 when regimens were less effective and many people shunned antiretroviral therapy (ART) at higher CD4 counts for fear of toxicity. And these older studies19-21 had HIV-related death, not all-cause mortality, as an endpoint. But the most recent studies, in Switzerland8 and the United States,22 ran up to the most recent antiretroviral era (from 2004 to 2014) and focused on all-cause mortality.
Compared with HIV-positive women without depressive symptoms, those with chronic symptoms had a doubled risk of HIV-related death (adjusted relative risk [aRR] 2.0, 95% CI 1.0 to 3.8) in a US analysis controlled for clinical and other risk factors.19 This analysis focused on 765 women seen from 1993 through 2000 in the prospective 4-city US HIV Epidemiologic Research Study (HERS) cohort. The HERS team also linked chronic depressive symptoms to greater drops in CD4 count. Only 38% of these women had taken ART for at least 1 year.
Prospective analysis of 1716 HIV-positive women in the US Women's Interagency HIV Study (WIHS) in the same era (1994-2001) found that women with chronic depressive symptoms had a 70% higher risk of AIDS death than women with limited or no depressive symptoms (aRR 1.7, 95% CI 1.1 to 2.7).20 Half of these women had taken ART for 1 year or more. Using mental health services halved the risk of AIDS mortality in these women (aRR 0.5, 95% CI 0.3 to 0.7).
Depressive symptoms boosted the risk of AIDS death by half (adjusted hazard ratio [aHR] 1.49, 95% CI 1.00 to 2.21, P = 0.05) in a prospective study of 338 men and 152 women, two thirds of them nonwhite, seen in five Southeastern US states in the early 2000s.21 There was no association between depressive symptoms and allcause mortality. Four in 5 people were taking ART when follow-up began.
The biggest assessment of depression and mortality used all-cause mortality as the endpoint and ran from January 2010 through July 2013 in the Swiss HIV Cohort Study (SHCS).8 This analysis of 4422 SHCS members without initial depression involved 3294 men (74%), 1934 MSM (44%), 1128 women (26%), and 432 injection drug users (10%). The researchers identified depression through diagnosis by a psychiatrist (63%) or an SHCS infectious diseases specialist. HIV care is free and accessible to all in Switzerland.
During follow-up 193 people died, mostly from non-AIDS deaths (59%), AIDS deaths (11%), or suicide (9%). Overall mortality measured 0.96 per 100 person-years, and mortality proved more than one third higher in people with than without depression (1.17 versus 0.86 per 100 person-years, P = 0.033). Eliminating drug injectors from the analysis rendered this difference nonsignificant. The researchers did not perform an adjusted analysis.
The most recent and most convincing study linking depression to a higher risk of death involved 4001 HIV-positive adults in a prospective US study, the CFAR Network of Integrated Clinical System (CNICS) Cohort.22 Participants entered care in 2004 or later and follow-up continued for up to 10 years. About 15% of cohort members were women, about 30% black, and about 17% Hispanic.
Defining depression as a Patient Health Questionnaire-9 (PHQ-9) score at or above 10, the investigators determined that 1246 people (31%) had depression in their first year of CNICS enrollment.22 At the end of follow-up, 121 people (3%) had died of any cause. A Cox proportional hazards model adjusted for adherence, CD4 count, HIV suppression, and other variables determined that people with depression had almost a two thirds higher risk of death (adjusted hazard ratio 1.64, 95% CI 1.06 to 2.53).
The Swiss and US studies8,22 offer strong contemporary evidence that depression shortens survival, and the intuitive strength of that conclusion speaks for itself. As the CDC observes, depression has strong associations with undeniable correlates of mortality such as smoking, drinking, and a sedentary lifestyle.23
Depression, Heart Failure, and the HIV Care Cascade
It's easy to add other factors that correlate with both depression and mortality, like injecting drugs, abusing other substances, and multiple comorbidities. A recent US general-population trial randomized 20 primary care practices to evidence-based depression care or usual care.24 During 2 years of follow-up involving 1204 older primary care patients, those in usual-care practices with the highest comorbidity and depression levels had a tripled risk of death compared with depressed patients who had minimal comorbidities (HR 3.02, 95% CI 1.32 to 8.72). In contrast, patients in depression-care practices with the highest levels of comorbidity and depression did not run a higher death risk than depressed patients with minimal comorbidity. The bottom line is that active depression management contributes to prolonged survival in older people with a list of comorbid diseases -- like a growing proportion of people with HIV infection.
One US study tied major depressive disorder to heart failure in people with HIV.25 This Veterans Aging Cohort Study (VACS) involved 26,908 veterans with HIV and 54,519 without HIV. After 5.8 years of follow-up, HIV-positive vets with major depressive disorder had a two thirds higher risk of heart failure than HIV-negative vets without depression (aHR 1.68, 95% CI 1.45 to 1.95). A separate fully adjusted analysis limited to veterans with HIV determined that major depressive disorder independently boosted heart failure risk (aHR 1.29, 95% CI 1.11 to 1.51). Among veterans with major depressive disorder, those taking antidepressants when follow-up began had a 24% lower risk of heart failure (aHR 0.76, 95% CI 0.58 to 0.99).
And for people with HIV, comorbidities represent only one set of hurdles to healthy longevity. To control HIV and comorbidities, they have to get into care, stay in care, start and adhere to antiretroviral therapy, gain CD4 cells, and make their viral load undetectable. Research from the past decade offers evidence that depression can narrow passage through each of these gateways in the HIV care continuum -- starting with linkage to care12 and retention in care,26 and proceeding through antiretroviral adherence,7,27-32 CD4 gains,19,32,33 and viral control.32-35
Retrospective analysis of 3359 HIV patients in the Kaiser Permanente healthcare system addressed the last three intertwined outcomes in people starting their first antiretroviral regimen from January 2000 through December 2003.32 This 8-state analysis included 1961 people (58%) starting ART without depression and 1398 (42%) starting ART with depression. Among people diagnosed with depression, only 508 (36%) got a prescription for a selective serotonin reuptake inhibitor (SSRI) antidepressant. Most study participants, 83%, were men, and median age stood at 40 when followup began. The Kaiser team calculated adherence by pharmacy refills.
An analysis adjusted for age, gender, antiretroviral regimen, and temporal trend determined that people with depression but not taking an SSRI had about a 20% lower chance of at least 90% antiretroviral adherence than the control group of people starting ART without depression (adjusted odds ratio [aOR] 0.81, 95% CI 0.70 to 0.98, P = 0.03) (Figure 2). But antiretroviral adherence did not differ significantly between the control group and people with depression taking an SSRI.
In an analysis adjusting for the same variables plus baseline CD4 count, odds of reaching a viral load below 500 copies/mL 12 months after starting ART proved 23% lower in people with depression and not taking an SSRI than in the control group of HIV-positive people without depression (aOR 0.77, 95% CI 0.62 to 0.95, P = 0.02). Chances of viral control in 12 months did not differ significantly between SSRI takers with depression and the control group. Twelve-month CD4 responses were similar in people with and without depression. But among people with depression, those with better than 80% SSRI adherence had significantly greater 12-month CD4 gains than people not taking an SSRI (+19 versus -19 cells/mm3, P = 0.01).
CDC analysis of a nationally representative sample also linked depression to lower chances of reaching an undetectable viral load.35 Among 18,095 HIV-positive people in the Medical Monitoring Project in 2009-2012, 25% had a depression diagnosis, 91% took antiretroviral therapy, and 69% had a viral load below 200 copies/mL on all measures in the past 12 months. An analysis adjusted for antiretroviral adherence and race determined that a depression diagnosis independently conferred a 7% lower chance of attaining sustained viral suppression (adjusted prevalence ratio 0.93, 95% CI 0.91 to 0.96).
The Worse the Depression, the Worse the Adherence
The link between depression and poor antiretroviral adherence appears to grow stronger as depression deepens. That conclusion emerged from a cross-sectional study of 624 HIV-positive adults at the Washington University HIV Clinic in 2009.33 Participants completed the Patient Health Questionnaire-9 (PHQ-9), which focuses on nine diagnostic criteria for DSM-IV depressive disorders, and researchers used responses to rate patients as having no depression, minimal depression, mild depression, moderate depression, moderately severe depression, or severe depression.
Ninety-six people (15%) had symptoms of major depressive disorder. Statistical analysis adjusted for age, race, tobacco use, and treatment with a protease inhibitor versus a nonnucleoside determined that more severe depression predicted a greater chance of worse than 95% antiretroviral adherence. For example, probability of poor adherence lay around 20% or lower in people with minimal or mild depression, above 20% in those with moderate or moderately severe depression, and as high as 40% in people with severe depression (P < 0.05).
If depression fosters poor adherence, one might assume treating depression improves adherence. Meta-analysis of 29 studies involving 12,243 people with HIV confirms that assumption.27 Overall odds of antiretroviral adherence proved 83% greater in people treated for depression (standardized odds ratio 1.83, 95% CI 1.27 to 2.55). In contrast, people not treated for depression ran a 35% higher risk of nonadherence (standardized relative risk 1.35, 95% CI 1.13 to 1.60). Compared with people not treated for depression, treated people had a doubled chance of improvement in depressive symptoms (standardized odds ratio 2.07, 95% CI 1.38 to 3.30). Adherence definitions varied from study to study.
In a review of major depression and other psychiatric disorders, Andrew Angelino and Glenn Treisman from Johns Hopkins call these conditions "a vector for infection with HIV and a barrier to its successful treatment."36 Evidence like that reviewed in this article led them "to conclude that treatment of these disorders greatly improves patient adherence and outcomes of HIV infection."
- Asch SM, Kilbourne AM, Gifford AL, et al. Underdiagnosis of depression in HIV: who are we missing? J Gen Intern Med. 2003;18:450-460.
- Weaver MR, Conover CJ, Proescholdbell RJ, Arno PS, Ang A, Ettner SL. Utilization of mental health and substance abuse care for people living with HIV/AIDS, chronic mental illness, and substance abuse disorders. J Acquir Immune Defic Syndr. 2008;47:449-458.
- Sueoka K, Goulet JL, Fiellin DA, et al. Depression symptoms and treatment among HIV infected and uninfected veterans. AIDS Behav. 2010;14:272-279.
- Pence BW, O'Donnell JK, Gaynes BN. Falling through the cracks: the gaps between depression prevalence, diagnosis, treatment, and response in HIV care. AIDS. 2012;26:656-658.
- Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-596. Erratum in: Arch Gen Psychiatry. 2005;62:768. Merikangas, Kathleen R [added].
- Bing EG, Burnam MA, Longshore D, et al. Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States. Arch Gen Psychiatry. 2001;58:721-728.
- Slot M, Sodemann M, Gabel C, Holmskov J, Laursen T, Rodkjaer L. Factors associated with risk of depression and relevant predictors of screening for depression in clinical practice: a cross-sectional study among HIV-infected individuals in Denmark. HIV Med. 2015; 16:393-402.
- Anagnostopoulos A, Ledergerber B, Jaccard R, et al. Frequency of and risk factors for depression among participants in the Swiss HIV Cohort Study (SHCS). PLoS One. 2015;10:e0140943.
- Israelski DM, Prentiss DE, Lubega S, et al. Psychiatric comorbidity in vulnerable populations receiving primary care for HIV/AIDS. AIDS Care. 2007;19:220-225.
- Robertson K, Bayon C, Molina JM, et al. Screening for neurocognitive impairment, depression, and anxiety in HIV-infected patients in Western Europe and Canada. AIDS Care. 2014;26:1555-1561.
- Marando F, Gualberti G, Costanzo AM, et al. Discrepancies between physician's perception of depression in HIV patients and self-reported CES-D-20 assessment: the DHIVA study. AIDS Care. 2016;28:147-159.
- Bhatia R, Hartman C, Kallen MA, Graham J, Giordano TP. Persons newly diagnosed with HIV infection are at high risk for depression and poor linkage to care: results from the Steps Study. AIDS Behav. 2011;15:1161-1170.
- Do AN, Rosenberg ES, Sullivan PS, et al. Excess burden of depression among HIV-infected persons receiving medical care in the United States: data from the Medical Monitoring Project and the Behavioral Risk Factor Surveillance System. PLoS One. 2014;9:e92842.
- Ciesla JA, Roberts JE. Meta-analysis of the relationship between HIV infection and risk for depressive disorders. Am J Psychiatry. 2001;158:725-730.
- Atkinson JH, Heaton RK, Patterson TL, et al. Two-year prospective study of major depressive disorder in HIV-infected men. J Affect Disord. 2008;108:225-234.
- Serafini G, Montebovi F, Lamis DA, et al. Associations among depression, suicidal behavior, and quality of life in patients with human immunodeficiency virus. World J Virol. 2015;4:303-312.
- Badiee J, Moore DJ, Atkinson JH, et al. Lifetime suicidal ideation and attempt are common among HIV+ individuals. J Affect Disord. 2012;136:993-999.
- Treisman G. HIV, depression and aging. 5th International Workshop on HIV and Aging. October 20-21, 2014, Baltimore.
- Ickovics JR, Hamburger ME, Vlahov D, et al. Mortality, CD4 cell count decline, and depressive symptoms among HIV-seropositive women: longitudinal analysis from the HIV Epidemiology Research Study. JAMA. 2001;285:1466-1474.
- Cook JA, Grey D, Burke J, et al. Depressive symptoms and AIDS-related mortality among a multisite cohort of HIV-positive women. Am J Public Health. 2004;94:1133-1140.
- Leserman J, Pence BW, Whetten K, et al. Relation of lifetime trauma and depressive symptoms to mortality in HIV. Am J Psychiatry. 2007;164:1707-1713.
- Bengtson A, Pence BW, Crane HM, et al. Depression increases the risk of mortality in a large cohort of HIV-infected adults. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 920.
- Centers for Disease Control and Prevention. Mental health. Depression.
- Gallo JJ, Hwang S, Joo JH, et al. Multimorbidity, depression, and mortality in primary care: randomized clinical trial of an evidence-based depression care management program on mortality risk. J Gen Intern Med. 2016;31:380-386.
- White JR, Chang CC, So-Armah KA, et al. Depression and human immunodeficiency virus infection are risk factors for incident heart failure among veterans: Veterans Aging Cohort Study. Circulation. 2015;132:1630-1638.
- Zuniga JA, Yoo-Jeong M, Tian D, Ying G, Drenna WV. The role of depression in retention in care for persons living with HIV. AIDS Patient Care STD. 2016;30:34-38.
- Sin NL, DiMatteo MR. Depression treatment enhances adherence to antiretroviral therapy: a meta-analysis. Ann Behav Med. 2014; 47:259-269.
- Gonzalez JS, Batchelder AW, Psaros C, Safren SA. Depression and HIV/AIDS treatment nonadherence: a review and meta-analysis. J Acquir Immune Defic Syndr. 2011;58:181-187.
- Tedaldi EM, van den Berg-Wolf M, Richardson J, et al. Sadness in the SUN: using computerized screening to analyze correlates of depression and adherence in HIV-infected adults in the United States. AIDS Patient Care STD. 2012;26:718-729.
- Kacanek D, Jacobson DL, Spiegelman D, Wanke C, Isaac R, Wilson IB. Incident depression symptoms are associated with poorer HAART adherence: a longitudinal analysis from the Nutrition for Healthy Living study. J Acquir Immune Defic Syndr. 2010;53:266-272.
- Sheth SS, Coleman J, Cannon T, et al. Association between depression and nonadherence to antiretroviral therapy in pregnant women with perinatally acquired HIV. AIDS Care. 2015;27:350-354.
- Horberg MA, Silverberg MJ, Hurley LB, et al. Effects of depression and selective serotonin reuptake inhibitor use on adherence to highly active antiretroviral therapy and on clinical outcomes in HIV-infected patients. J Acquir Immune Defic Syndr. 2008;47:384-390.
- Taniguchi T, Shacham E, Onen NF, Grubb JR, Overton ET. Depression severity is associated with increased risk behaviors and decreased CD4 cell counts. AIDS Care. 2014;26:1004-1012.
- Shacham E, Nurutdinova D, Satyanarayana V, Stamm K, Overton ET. Routine screening for depression: identifying a challenge for successful HIV care. AIDS Patient Care STD. 2009;23:949-955.
- Gokhale R, Bradley H, Garg S, Shouse RL. HIV viral suppression among adults diagnosed with depression in the United States. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 1037.
- Angelino AF, Treisman GJ. Management of psychiatric disorders in patients infected with human immunodeficiency virus. Clin Infect Dis. 2001;33:847-856.