Abstract: Independent risk factors for depression in people with HIV infection can be grouped into sociodemographic variables (including female gender, unemployment, and financial difficulties), behavioral factors (including injection drug use and other substance use and abuse), clinical factors (including less antiretroviral experience, poor antiretroviral adherence, and a detectable viral load), and psychological factors (including a family or personal history of depression and low self-efficacy). Research throughout the Western world shows that depression often goes undiagnosed and untreated in HIV-positive people. HIV health experts in the United States and Europe recommend screening everyone with HIV for depression. European AIDS Clinical Society (EACS) guidelines offer straightforward advice on screening for and diagnosing depression in people with HIV.
Why is depression so prevalent in people with HIV infection? One inescapable reason is that depression ranks high among risk factors for HIV infection, so depression often precedes HIV infection and the two coexist after seroconversion. Depression goes hand-in-hand with behaviors that boost HIV risk, such as injecting drugs, abusing alcohol and other substances,1 and frequent sex without condoms. The link between depression and HIV risk also holds true in people without a substance abuse history. One study from the first decade of the US HIV epidemic charted a 7-fold higher rate of lifetime mood disorders in nonabusers seeking HIV testing than in the general population.2
Thus any survey of depression risk in people with HIV must be read with the understanding that relevant research rarely establishes causality. But a grasp of which variables hold the strongest associations with depression in HIV populations can be a crucial step toward heightened awareness of depression in people with HIV -- and toward possible diagnosis and treatment.
Depression Risk Factors Fit in Four Bins
European AIDS Clinical Society (EACS) guideline writers believe depression poses such a threat to people with HIV that everyone infected should be screened for depression immediately after HIV diagnosis and every 1 to 2 years thereafter (see "Screening and Diagnosis Simplified" below).3 These guidelines offer a 7-point framework as a starting point for identifying HIV-positive people at high risk for depression:
- Family history of depression
- Personal history of depressive episode
- Older age
- History of drug addiction or psychiatric, neurologic, or severe somatic comorbidity
- Efavirenz use
- Use of neurotropic or recreational drugs
Specific depressive symptoms in men may include feeling stressed or burned out, venting feelings in angry outbursts, and coping through overwork and heavy drinking.3 But this list is hardly immutable. For example, some HIV research shows a diminishing risk of depression with age,4-6 and research does not consistently confirm a link between efavirenz and depression.7
Analysis of 11 studies from the combination antiretroviral era (Table 1)4-14 suggests several other variables independently associated with depression that fit into four broad bins: (1) sociodemographic, (2) behavioral, (3) clinical, and (4) psychological (Table 2). The research explored includes three prospective and eight cross-sectional studies involving 15,480 people with HIV infection. Six studies came from the United States (n = 4766), two from Denmark (n = 417), and one each from Switzerland (n = 4422), Spain (n = 5185), and Italy (n = 690) (Table 1). Participants in most of these 11 studies averaged about 40 years in age except for one study of people 50 or older10 and one study of US youth.14 About half of participants in the study of US youngsters were female,14 while women made up one quarter to one third of the other study groups.
|Table 1. Eleven US/European Studies Assessing Depression Risk Factors With HIV|
|First Author||Year(s)||n||Location||Type of Study, Age||How Depression Was Determined|
|Anagnostopoulos4||2010-2013||4422||Switzerland (SHCS)||Prospective||Psychiatrist or physician report|
|Bhatia8||2006-2007||200, 32% F||Houston||Prospective, mean age 38 (range 18-70)||CES-D-20|
|Carrico9||2000-2002||2902, 24% F||4 US cities||Cross-sectional, mean age 41||Suicidal ideation by BDI|
|Grov10||2005||914 >50 years old, 29% F||New York City||Cross-sectional, median age 54 (range 50-78)||CES-D >23|
|Gutierrez7||2004-2010||5185, 26% F||Spain, CoRIS cohort||Prospective, median age 41||"Clinically significant depression;" unclear how determined|
|Justice11||2001-2002||50||VACS 5 sites||Cross-sectional||PHQ-9|
|Marando12||Current ART era||690, 27% F||Italy||Cross-sectional, median age 45||CES-D-20|
|Rodkjaer5||2005||205, 24% F||Denmark||Cross-sectional, 83% 30 to 59 years old||BDI-II|
|Shacham6||2007||514, 32% F||St. Louis||Cross-sectional, mean age 42||PHQ-9|
|Slot13||2013||212||HIV clinic in Denmark||Cross-sectional||BDI-II|
|Tanney14||2000s||186 youth, ~50% F||5 US sites||Cross-sectional||BSI|
ART, antiretroviral therapy; BDI, Beck Depression Inventory; BSI, Brief Symptom Inventory; CES-D, Center for Epidemiologic Studies Depression; F, female; PHQ-9, Patient Health Questionnaire; SHCS, Swiss HIV Cohort Study; VACS, Veterans Aging Cohort Study.
|Table 2. Independent Predictors of Depression in 11 Cohort Studies|
|Check for Yes||Variable|
| ||Female gender4,8,12|
| ||Homosexual vs heterosexual orientation5,9|
| ||Behavioral vs perinatal HIV acquisition in youth14|
| ||Single (living alone,4 not in primary relationship9)|
| ||One or more minor dependents (vs none)6|
| ||Not working (unemployed/occasionally employed,6,12 decreased ability to work4)|
| ||Financial difficulty (low income,8 finances "hopeless,"5 low access to care8)|
| ||Injection drug use4|
| ||Other substance use or abuse (illicit drug use,12 recent substance abuse,8 regular marijuana,9 previous alcohol abuse,13 smoking12)|
| ||No physical activity4|
| ||Sexual activity4|
| ||More behavioral problems (in youth)14|
| ||Less ART experience (not starting ART,7 less ART exposure7)|
| ||Detectable viral load4,6|
| ||Lower CD4 nadir,4 baseline CD4 count below 2008|
| ||Poor antiretroviral adherence5,13|
| ||More severe HIV symptoms9|
| ||Decreased cognitive function10|
| ||Self-reported poor health13|
| ||Reduced energy10|
| ||Depression history (previous diagnosis,12 previously sought psychological help13)|
| ||Stigma;10,14 shame, guilt, double life with HIV5|
| ||Other psychological problems (loneliness,10 dissatisfaction with current life,13 self-reported stress13)|
| ||Low self-efficacy (belief in one's ability to accomplish things)8,9|
| ||Constant thoughts about HIV,5 perception that HIV affects all aspects of life13|
Among sociodemographic factors, certain variables consistently predict depression from study to study: female gender, homosexual orientation, living alone, and unemployment or low income (Table 2). Three studies found a consistent association between female gender and higher depression risk,4,8,12 though some experts question the strength of this link on the grounds that men are less likely than women to admit depressive symptoms on testing. Living without a spouse or partner boosted depression risk in the Swiss HIV Cohort Study4 and made suicidal ideation more likely in a 4-city US study.9 Unemployment or limited ability to work got tied to depression in the United States,6 Italy,12 and Switzerland.4 A single-center study in St. Louis, Missouri found that having one or more minor dependents (versus none) made depression more likely.6 Financial straits5,8 or low access to medical care8 contributed to depression in Houston8 and Denmark.5 Homosexual versus heterosexual orientation made depression5 or suicidal ideation9 more likely in Denmark or 4 US cities. In a study of 186 HIV-positive youngsters at five US sites, those behaviorally infected rather than perinatally infected ran a higher risk of depression.14
Analysis of these studies yields no tidy take-home on how age affects depression risk. The study of HIV-positive US youth found depression more likely in older youngsters,14 while a study of US HIV patients 50 or older found depression more likely in younger cohort members.10 A 4422-person Swiss HIV Cohort Study analysis found incident depression more frequent in people under 45 (versus over 55), while cumulative prevalent depression proved more frequent in people over 45 (versus under 45).4 Studies of middle-aged adults in St. Louis6 and Denmark5 found depression more likely in younger study participants. A comparison of HIV-positive and negative US veterans at five sites determined that depressive symptom frequency dropped with age in HIV-negative vets but not HIV-positive vets.11 Depression prevalence rose with age in veterans with HIV compared with HIV-negative veterans. The message from this drove of data may be to consider age a less reliable depression predictor than other factors.
Among behavioral factors tied to depression, injection drug use looms large. In the Swiss HIV Cohort Study, men who inject drugs ran a higher risk of incident depression and cumulative prevalent depression than white men who have sex with men (MSM), while women who inject drugs had a higher risk of cumulative prevalent depression.4 Research elsewhere in Europe and the United States also confirms illicit drug use,12 recent substance abuse,8 regular marijuana use,9 previous alcohol abuse,13 and smoking12 as depression risk factors. In the Swiss study, lack of physical activity boosted chances of incident or prevalent depression, and sexually active people ran higher risks of both incident and prevalent depression.4 The study of US youth found an unsurprising link between more behavioral problems and depression.14
These 11 US and European studies turned up several links between antiretroviral therapy, its benefits, and depression. In a 5185-person Spanish cohort, both starting ART and longer ART exposure (including longer efavirenz use) lowered the risk of clinically significant depression.7 Lower nadir CD4 count heightened risk of incident depression in Switzerland,4 while a pre-ART CD4 count below 200 cells/mm3 raised depression risk in a US study.8 Having a detectable viral load made depression more likely in Switzerland4 and the United States.6 Two studies in Denmark linked poor antiretroviral adherence to depression.5,13 Other clinical variables tied to depression or suicidal ideation include worse HIV symptom severity,9 decreased cognitive function,10 cirrhosis,12 self-reported poor health,13 and reduced energy.10
A previous depression diagnosis raised odds of a new episode almost 10-fold in the Italian cohort.12 Related variables that made depression more likely include previously seeking help for psychological problems;13 guilt, shame, stigma, or leading a double life with HIV;5,10,14 low self-efficacy (belief in one's ability to accomplish things);8,9 increased loneliness;10 dissatisfaction with one's current life;13 self-reported stress;13 constant thoughts about HIV;5 and the perception that HIV affects all aspects of life.13
Table 2 outlines the risk factors summarized in the preceding paragraphs, creating a checklist clinicians can use when evaluating a patient for depression.
Frequent Depression Underdiagnosis and Undertreatment
Research in the United States and Western Europe shows that clinicians routinely fail to diagnose or treat HIV patients who meet standard criteria for depression. The largest US study addressing this issue focused on a national probability sample of HIV-positive adults in the HIV Cost and Services Utilization Study (HCSUS) who completed the Composite International Diagnostic Interview (CIDI) in the first years of the combination antiretroviral era.15 Of the 1140 study participants, 76% were men, 59% white, 22% black, and 14% Hispanic. Two thirds were between 26 and 40 years old and 5% were younger.
Among 448 people (39% of 1140) with CIDI-defined depression, only 203 (45%) had a depression diagnosis on their chart.15 Compared with people who had a college education, those who did not complete high school had 2.5 times higher odds of a missed depression diagnosis. Older patients -- those with Medicare -- had a two thirds lower chance of a missed diagnosis than privately insured people. People with more clinic visits during the study period also had lower odds of a missed diagnosis.
A more recent US analysis looked at 803 HIV-positive adults with a baseline visit in 2000-2002 in the HIV/AIDS Treatment Adherence, Health Outcomes, and Cost Study.16 One third of participants were women and two thirds black. According to the Structured Clinical Interview for DSM IV Axis I Disorders (SCID), 69% of participants had a mood disorder, 57% a personality disorder, and 27% anxiety disorder. The SF-36 mental health composite score lay in the lowest (worst) quartile in 194 people (24%). Among people with both mental illness and substance use, only 59% received any mental health care in the past 3 months; among those with a mood disorder, only 40% were taking a psychotropic drug.
Analyzing these data15,16 and other findings, Duke University depression expert Brian Pence and colleagues estimate that only 45% of major depressive disorders in people with HIV get recognized clinically, only 40% of those recognized get treated, and only 40% of those treated get treated adequately.17
A single-center Danish study used the Beck Depression Inventory II (BDI-II) to determine how many HIV patients had symptoms of depression (BDI-II >14) or major depression (BDI-II >20).5 The 2005 study involved 205 people with HIV who reflected the general HIV population in Denmark (76% male, 83% 30 to 59 years old, 80% white). Seventy-seven people (38%) had symptoms of depression and 53 (26%) had major depression. Of these 53 people, 36 agreed to see a psychiatrist, and 18 of those 36 had untreated depression. Among the 17 people who declined a visit to a psychiatrist, 12 had not seen a mental health specialist before. Thus 30 of 53 people with major depression (57%) received no care for their illness.
A cross-sectional survey reported in 2015 involved HIV-positive adults seen at one of 24 centers across Italy.12 Of these 690 people, 155 (22%) had severe depression, defined as a Center for Epidemiologic Studies Depression (CES-D) score of 26 to 60. In contrast, physicians identified severe depression in only 6 patients (4%). Physician evaluations rated 135 of 155 severely depressed people (87%) as having no, mild, or moderate depression.
Screening and Diagnosis Simplified
Guidelines for primary care of people with HIV from the US HIV Medicine Association and the Infectious Diseases Society of America18 echo European guidelines3 in recommending depression screening for everyone with HIV. "All patients should be evaluated for depression and substance abuse, and if present, a management plan that addresses these problems should be developed and implemented in collaboration with appropriate providers," the US guidelines state. European AIDS Clinical Society (EACS) Guidelines call for a depression questionnaire at HIV diagnosis, before starting antiretroviral therapy, then "as indicated" for "at-risk persons."3
What depression screening options do HIV clinicians have? A multicenter study of 190 HIV-positive people in Ontario rated three short screening instruments -- and two of three ultrashort forms -- highly reliable in detecting depression identified by the Mini International Neuropsychiatric Interview.19 The six screening tools were the Center for Epidemiologic Depression Scale (CES-D-20), the Kessler Psychological Distress Scale (K-10), and the Patient Health Questionnaire depression scale (PHQ-9) and their ultrashort forms (CES-D-10, K-6, and PHQ-2). The three primary screening instruments had excellent accuracy and validity (defined at area under the curve >0.9) and good reliability (Kappa statistic 0.71 to 0.79 and Cronbach's alpha 0.87 to 0.93). Except for PHQ-2, all tools had good to excellent sensitivity (0.86 to 1.0) and specificity (0.81 to 0.87), excellent negative predictive value (>0.90), and moderate positive predictive value (0.49 to 0.58).
EACS guideline writers suggest two questions that can help clinicians identify depressed HIV patients:3
- Have you often felt depressed, sad, or without hope in the last few months?
- Have you lost interest in activities that you usually enjoy?
These guidelines then advise clinicians to rule out organic causes, which may include hypothyroidism, hypogonadism, Addison's disease, non-HIV drugs, and vitamin B12 deficiency.3
The MacArthur Foundation's Depression Management Tool Kit also suggests a simple two-question screen:20
During the past month, have you been bothered by:
- Little interest or pleasure in doing things?
- Feeling down, depressed, or hopeless?
A positive response to either question calls for further evaluation, perhaps with the PHQ-9 (see page 17 of reference 20).
The EACS also offers a straightforward scheme to diagnose depression and advises clinicians to evaluate symptoms regularly (Figure 1).3 (For a similar approach, see DSV-IV criteria for diagnosing depression on page 14 of reference 20.)
Johns Hopkins University depression expert Glenn Treisman advises clinicians to distinguish between major depressive disorder and demoralization (sadness or grief).1,21 Major depression is marked by persistent sadness and anhedonia (utter lack of pleasure). In contrast, demoralization is "a psychological reaction to life stresses" usually "related to a specific event or circumstance."1 People with demoralization say they feel fairly normal when distracted from the event that caused their sadness. But when they are reminded of that event, their sadness returns.1 Table 3 outlines the main features distinguishing major depressive disorder from demoralization.
|Table 3. Features Distinguishing Major Depressive Disorder From Demoralization Proposed by Glenn Treisman|
|Major Depressive Disorder||Demoralization (Sadness or Grief)|
|Anhedonia (pervasive loss of rewards from activity)||Can be distracted from loss (maintains rewards from activity)|
|Family history||No family history|
|History of similar episodes||Unique episode|
|Disrupted life course||Stable life course|
|Unresponsive to positive events||Responsive to positive events|
From Glenn Treisman, Johns Hopkins University.1,21
- Angelino AF, Treisman GJ. Management of psychiatric disorders in patients infected with human immunodeficiency virus. Clin Infect Dis. 2001;33:847-856.
- Perry S, Jacobsberg LD, Fishman B, Frances A, Bobo J, Jacobsberg BK. Psychiatric diagnosis before serological testing for the human immunodeficiency virus. Am J Psychiatry. 1990;147:89-93.
- EACS European AIDS Clinical Society. Guidelines. Version 8.0. October 2015.
- 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.
- Rodkjaer L, Laursen T, Balle N, Sodemann M. Depression in patients with HIV is under-diagnosed: a cross-sectional study in Denmark. HIV Med. 2010;11:46-53.
- 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.
- Gutierrez F, García L, Padilla S, et al. Risk of clinically significant depression in HIV-infected patients: effect of antiretroviral drugs. HIV Med. 2014;15:213-223.
- 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.
- Carrico AW, Johnson MO, Morin SF, et al. Correlates of suicidal ideation among HIV-positive persons. AIDS. 2007;21:1199-1203.
- Grov C, Golub SA, Parsons JT, Brennan M, Karpiak SE. Loneliness and HIV-related stigma explain depression among older HIV-positive adults. AIDS Care. 2010;22:630-639.
- Justice AC, McGinnis KA, Atkinson JH, et al. Psychiatric and neurocognitive disorders among HIV-positive and negative veterans in care: Veterans Aging Cohort Five-Site Study. AIDS. 2004;18(Suppl 1):S49-S59.
- 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.
- 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.
- Tanney MR, Naar-King S, MacDonnel K; Adolescent Trials Network for HIV/AIDS Interventions 004 Protocol Team. Depression and stigma in high-risk youth living with HIV: a multi-site study. J Pediatr Health Care. 2012;26:300-305.
- 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; Cost Subcommittee of the HIV/AIDS Treatment Adherence, Health Outcomes, and Cost Study Group. 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.
- 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.
- Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horben MA. Primary care guidelines for the management of persons infected with HIV: 2013 Update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58:e1-e34.
- Choi SK, Boyle E, Burchell AN, et al. Validation of six short and ultra-short screening instruments for depression for people living with HIV in Ontario: results from the Ontario HIV Treatment Network Cohort Study. PLoS One. 2015;10:e0142706.
- The MacArthur Foundation Initiative on Depression & Primary Care. Depression management tool kit. 2009.
- Treisman G. HIV, depression and aging. 5th International Workshop on HIV and Aging. October 20-21, 2014, Baltimore.