When and How to Treat Depression -- and How to Make It Easier

Abstract: A simple symptom checklist can guide clinicians in deciding when and how to start treating depressive symptoms in people with HIV and when to refer a patient to a specialist. Among nondrug therapies, cognitive behavioral therapy has proved particularly effective in people with HIV, especially young adults. Systematic reviews establish the value of multiple antidepressant classes in people with HIV, but selective serotonin reuptake inhibitors (SSRIs) have become the mainstay of treatment. Besides relieving depression, SSRIs promote better antiretroviral adherence, better viral control, and higher CD4 counts. Three strategies tested in randomized trials show that measurement-guided care can help prescribing clinicians reach the optimal tolerable antidepressant dose with the aim of attaining remission of depressive symptoms in people with HIV. With appropriate therapy, HIV-positive people achieve remission of depression as often as or more often than people without HIV.

"Standard psychotherapeutic and pharmacological treatments work as well or better in achieving full remission from depression in HIV patients compared to the general population," according to Duke University depression expert Brian Pence and colleagues.1 Yet, they add, plentiful research confirms that depression remains undiagnosed and untreated or poorly treated in people with HIV infection.

Analyzing recent data, Pence and coauthors estimate that only 45% of major depressive disorder cases get recognized clinically in people with HIV, only 18% receive any treatment, only 7% receive adequate treatment, and only 5% achieve remission.1 But systematic reviews of clinical trials show that both psychotherapy2 and antidepressants2,3 can be effective in treating depression in people with HIV.

A decade ago the National Comorbidity Study Replication (NCS-R) figured that only 64% of the general US population in care with mental health specialists received adequate depression treatment, while only 41% of those treated in general practice got adequate treatment for depression.4 In a US national probability sample of people with HIV, more than one third had test-determined major depressive disorder.5 But 45% of those with depression did not have that diagnosis listed in their medical record.

Core Principles of Treating Depression

European AIDS Clinical Society (EACS) guidelines map out a straightforward approach to treating depression in people with HIV.6 The first step in planning treatment, EACS says, is determining the number of depressive symptoms a person has from a simple list of 10 (see Figure 1 of the preceding article):

  1. Depressed mood for at least 2 weeks
  2. Loss of interest
  3. Diminished sense of pleasure 4. 5% or greater weight gain in 1 month or persistent change in appetite 5. Insomnia or hypersomnia most days 6. Change in speed of thought and movements 7. Fatigue 8. Feelings of guilt and worthlessness 9. Diminished concentration and decisiveness 10. Suicidal ideation or suicide attempt From that point, it's a numbers game (Figure 1). A person with fewer than four of these 10 symptoms probably does not have depression and needs no treatment, the EACS advises. A person with four of the 10 symptoms may benefit from problem-focused consultation, physical activity, and possibly antidepressant therapy. A person with five or six symptoms should start antidepressant therapy. And a person with more than six symptoms must be referred to a specialist (Table 1).
EACS Guide to Treating Depression
EACS Guide to Treating Depression Figure 1. European AIDS Clinical Society (EACS) guidelines suggest a symptom-based approach to deciding whether and how to treat depression in people with HIV.6 Figure 1 describes the 10 symptoms.
Teresa B. Southwell/The Center for AIDS Information & Advocacy
Table 1. EACS Advice on When to Refer a Depressed Patient to a Specialist6
  • If treating clinician is unfamiliar with using antidepressants
  • If depression is not responding to treatment
  • If patient has suicidal ideation
  • If patient has more than six of 10 symptoms in this list
  • In complex situations including drug addiction, anxiety disorder, personality disorder, dementia, or acute severe life events

HIV depression mavens Brian Pence1 and Glenn Treisman7 stress a fundamental principle of treating people with antidepressants: "The first step in antidepressant treatment is to get the patient to consistently take the medicine," Treisman writes, "and to use an adequate therapeutic dose."7 Start with a low dose, Treisman and Pence advise, then evaluate patients regularly for response and side effects, escalating the dose slowly until a response becomes apparent. The final section of this article (see "Three Tested Measurement-Based Antidepressant Strategies") describes three models of treatment monitoring by a professional other than the prescribing clinician.)

EACS HIV care guidelines include an outline of doses, safety, and side effects of four selective serotonin reuptake inhibitors (SSRIs), the dual-action reuptake inhibitor venlafaxine, and the mixed-action agent mirtazapine (available online at reference 6). Finally, EACS offers a clear yet comprehensive list of interactions between major antidepressants and antiretrovirals.6

Psychological Treatment of Depression in HIV Populations

One systematic review analyzed diverse psychotherapies and related interventions for depression in people with HIV,2 while two other reviews focused on group psychotherapies for HIV-positive people.8,9

The diverse psychotherapy analysis examined 90 studies (81 from North America or Western Europe) published through September 2009 that assessed an intervention and a comparison group.2 Two thirds of the studies involved men, mostly men who have sex with men. Psychological interventions -- especially cognitive-behavioral stress management -- proved most effective in relieving depression, with 15 of 22 strategies (68%) having a significantly greater impact than control conditions. Three of four studies combining psychological and pharmacological therapy had a significantly greater impact than control conditions. Five of nine HIV-specific therapies proved effective; these approaches included adherence support, selfcare symptom management, enhanced risk prevention, and modified directly observed therapy. Studies of physical therapies (like exercise, acupuncture, and massage) yielded less clear-cut evidence of success, while psychosocial therapies (like art psychotherapy, life review, and mantra repetition) generally proved ineffective. This analysis also covered antidepressant interventions, summarized in the next section of this article.

A 2007 meta-analysis examined eight double-blind randomized controlled trials of group psychotherapy involving 665 people with HIV, including five studies of cognitive behavioral therapy, two studies of supportive therapy, and one study of coping effectiveness training.8 Supportive therapy and coping effectiveness training did not relieve depressive symptoms more than control strategies. Pooled analysis of the five group cognitive behavioral therapies found significant relief of depressive symptoms, but that impact did not reach significance in studies that excluded people with major depression. Almost all study participants were men, so these findings may not apply to women with HIV.

A 2013 analysis9 homed in on four randomized controlled trials10-13 of group cognitive behavioral therapy for HIV-positive adults -- always men -- with depressive symptoms. All trials were small, single-center studies, with the largest randomizing 95 people.12 One trial took place in Hong Kong10 and three in the United States. All four studies used waiting-list controls, and two also used active controls.11,12 Pooled analysis of the four trials determined that cognitive behavioral therapy reduced depressive symptoms. But an analysis limited to the two comparisons with active control arms found the impact of group therapy "less impressive."

Together these three analyses2,8,9 single out cognitive behavioral therapy as an effective way to ease depressive symptoms in adults (at least men) with HIV infection. Cognitive behavioral therapy also proved effective in a small trial of young adults with HIV (31% of them women). Experts define cognitive behavioral therapy as short-term, goal-oriented psychotherapy "that takes a hands-on, practical approach to problem-solving" and aims "to change patterns of thinking or behavior that are behind people's difficulties, and so change the way they feel."14

In their HIV-depression review article, Pence and colleagues advise that psychotherapy for depression "generally requires at least eight sessions."1 A US study of 399 adults who screened positive for depression on the 9-item Patient Health Questionnaire (PHQ-9) showed the value of each visit for psychiatric or psychological treatment.15 Most study participants (79%) were men taking antiretroviral therapy (81%); their age averaged 43.9 years, and 52% were nonwhite. Statistical analysis adjusted for demographics, antiretroviral adherence, and CD4 count calculated a 0.63 drop (improvement) in PHQ-9 with each additional depression treatment visit.

Insights on Antidepressant Therapy for People With HIV

A 2005 meta-analysis of randomized controlled trials in people with HIV found that antidepressant therapy has at least a moderate impact in relieving depression, but this analysis is dated.16 The 7 trials involving 494 adults with depression appeared from 1994 through 1999 and only 1 took place in the combination antiretroviral therapy era. Two studies tested the tricyclic antidepressant imipramine, 1 tested imipramine and the SSRI paroxetine, and 4 tested the SSRI fluoxetine. Three studies documented a significant benefit with antidepressant therapy, 2 testing fluoxetine or paroxetine and 1 testing imipramine. The 7-trial pooled effect size of 0.57 (95% confidence interval [CI] 0.28 to 0.85) indicated that these antidepressants have a moderate impact in relieving depression in people with HIV. Because the trials enrolled almost no women and few minorities, the findings cannot be applied to those groups.

A 2011 systematic review of depression therapy for people with HIV included a subanalysis of trials involving 10 psychotropic medications: the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline, the tricyclics desipramine and imipramine, the central nervous system stimulants dextroamphetamine and methylphenidate, the serotonin modulator trazodone, and the benzodiazepine clorazepate.2 Treatment proved effective in 6 of 11 placebo-controlled trials (55%). Effective antidepressants in these studies were fluoxetine, fluvoxamine, sertraline, desipramine, imipramine, dextroamphetamine, methylphenidate, and testosterone replacement (the last two of which were not effective in certain trials). In two trials (18%) antidepressant therapy had no impact, and in 3 trials (27%) the impact was unclear. Treatment also relieved depressive symptoms in 2 of 3 trials with a placebo or control group but without random allocation.

SSRIs have become the mainstay of antidepressant therapy for people with and without HIV. Four of the six antidepressants listed in EACS guidelines are SSRIs (citalopram, escitalopram, paroxetine, and sertraline).6 An open-label study of three SSRIs and three randomized trials comparing an SSRI with placebo or a tricyclic antidepressant establish the efficacy of SSRIs in men and women with HIV.17-20

Retrospective analysis of 3359 US patients with HIV linked SSRI therapy to better antiretroviral adherence, better viral control, and higher CD4 counts.21 Ample research links depression to faulty antiretroviral adherence (see page 10 of this issue). This US study in 8 states and Washington, DC is the largest to explore the impact of depression and SSRI therapy on antiretroviral adherence in people starting antiretrovirals.

The study involved 1961 people never diagnosed with depression and 1398 with depression, 508 of whom (36% of 1398) took at SSRI for more than 2 months. Most study participants (83%) were men, and median age stood at 40 years when antiretroviral therapy began. Depression without SSRI therapy lowered odds of antiretroviral adherence almost 20% (adjusted odds ratio [aOR] 0.81, 95% CI 0.70 to 0.98) and sliced the odds of reaching an undetectable viral load almost 25% in the first 12 months of treatment (aOR 0.77, 95% CI 0.62 to 0.95). In the same adjusted analysis, people taking an SSRI for depression did not differ from people without depression in antiretroviral adherence and viral control. Among study participants with depression, those taking an SSRI gained significantly more CD4 cells with antiretroviral therapy (adjusted CD4 change at 12 months -19 cells/mm3 without SSRI, +9 cells/mm3 with SSRI, +19 cells/mm3 with greater than 80% SSRI adherence, P = 0.01 comparing first and third groups).

Because depression remains highly prevalent in people with HIV (42% in this study group) these clinical investigators urge colleagues to screen HIV patients for depression and to offer SSRI therapy to those with depression.21 Although this study did not directly measure the impact of SSRIs on depressive symptoms, the HIV-related benefits linked to SSRIs suggest these antidepressants did relieve depression.

The MacArthur Foundation's Depression Management Tool Kit reviews most current SSRI and non-SSRI antidepressants in a concise table below.

Three Tested Measurement-Based Antidepressant Strategies

Low depression treatment rates in HIV-positive people1 underline a need for plans to assist clinicians in prescribing antidepressants with or without psychotherapy, tracking side effects and response, and titrating doses. Three US groups developed innovative collaborative care plans that can help primary HIV providers offer optimal antidepressant therapy to their patients (Table 2).

Table 2. Response-Driven Strategies to Support Treatment of Depression With HIV
 SLAM DUNC22HITIDES24ATN Plan25
What is it?Measurement-based care with antidepressantsMeasurement-based care with antidepressants plus phone supportCognitive behavioral therapy plus measurement-based care with antidepressants
What treatments are involved?Antidepressant therapyAntidepressant therapy, phone support by nurseCognitive behavioral therapy, antidepressant therapy
What staff is needed besides prescribing clinician?Depression case managerNurse depression care manager, clinical pharmacist, psychiatristPsychotherapist
How is response monitored?PHQ-9PHQ-9QIDS-SR
Plan details available?Strategy described in Pence;22 treatment algorithms online at Adams23Strategy described in Pyne;24 medical management algorithm not currently online*Strategy described in Brown;25 medical management algorithm
Test population?304 HIV+ US adults with depression249 HIV+ US veterans with depression44 HIV+ US 18- to 24-year-olds with depression
Length of test?12 months12 months24 weeks plus 24 weeks follow-up
How well did it work?Depressive severity similar with intervention and usual care at 12 months; 16% greater probability of depression remission and 29 more depression-free days in 12 months with interventionResponse and remission rates initially higher with intervention than usual care but not by 12 months; 19 more depression-free days through 12 months with HITIDES versus usual careSignificantly fewer depressive symptoms at 24 and 48 weeks with intervention than with usual care; significantly higher response rates and remission rates at 24 and 48 weeks

ATN, Adolescent Trials Network for HIV/AIDS Interventions; HITIDES, HIV Translating Initiatives for Depression Into Effective Solutions; PHQ-9, Patient Health Questionnaire-9; QIDS-SR, Quick Inventory of Depressive Symptomatology -- Self-Report.

* A similar system is available at https://aims.washington.edu/resource-library/care-management-tracking-system-cmts

A 304-person 4-clinic US trial that randomized HIV-positive people to measurement-based antidepressant therapy or enhanced standard care found that the measurement-based plan significantly improved some depression outcomes through 6 and 12 months.22 The 2010-2014 SLAM DUNC trial enrolled adults on or about to start antiretroviral therapy with depression indicated by the Patient Health Questionnaire-9 (PHQ-9) and the Mini International Neuropsychiatric Interview.

Measurement-based care follows straightforward antidepressant algorithms interpreted by trained depression case managers and emphasizes "vigorous antidepressant dosing."22 Cases managers can be medical assistants, nurses, clinical social workers, or other professionals. The algorithms, available online at reference 23, guide case managers through treatment steps at initial and follow-up visits. The case managers then relay antidepressant therapy recommendations to providers. The aim is depression remission, and decisions are driven by side effects and response on the PHQ-9 (Figure 2). The treatment plan follows six principles:22

  1. The goal of depression treatment is remission.
  2. Assess depressive symptoms systematically.
  3. Monitor side effects early and often.
  4. Start with a low dose.
  5. Increase the dose to remission, using the full dosing range if needed.
  6. Ensure an adequate trial before switching or referring.
Week-by-Week Measurement-Based Antidepressant Plan
Week-by-Week Measurement-Based Antidepressant Plan Figure 2. A measurement-based plan for antidepressant therapy relies on regular checkups by a case manager who makes recommendations to the prescribing clinician based on side effects and response to therapy gauged on Patient Health Questionnaire-9 (PHQ-9).22 Algorithms detailing decisions based on side effects and symptom response are online at reference 23.
Teresa B. Southwell/The Center for AIDS Information & Advocacy

Age averaged 42.8 years in the 149 people randomized to measurement-based care and 44.9 in the 155 randomized to usual care. Respective proportions of men were 75% and 64%, blacks 56% and 68%, whites 36% and 25%, and Hispanics 6% and 3%. Three quarters in both study groups were unemployed. Depression severity (by the Hamilton Depression Rating Scale) and psychiatric comorbidity prevalence were high. Participants in the measurement-based care arm averaged 8.9 contacts with case managers over 12 months.

Six months after randomization, the intervention arm did better in three measures of depression:

  • Depressive severity significantly lower (mean difference -3.7)
  • Probability of depression remission higher (relative advantage 13%)
  • Suicidal ideation lower (risk difference -18%)

By month 12 differences from the usual-care arm disappeared for two of these three outcomes. But the management-based care group maintained significant advantages by two measures:

  • Probability of depression remission higher (relative advantage 16%)
  • Depression-free days over 12 months (29 more days)

Measurement-based care had no impact on antiretroviral adherence at 6 months by unannounced telephone pill count, possibly because participants were not selected for low adherence and baseline adherence was high in both groups. Nor did the groups differ in appointment adherence, HIV symptoms, or viral load. The authors propose that depression treatment models like this one "efficiently leverage clinic staff time to provide antidepressant prescription decision support to HIV medical providers."22 They believe the trial "demonstrates that such a real-world strategy can significantly shorten the course of depressive illness for HIV patients and reduce overall morbidity from depression."

A randomized trial at three Veterans Affairs (VA) HIV clinics found that a collaborative team using a treatment decision system lessened symptom severity and yielded more depression-free days, though the intervention did no better than standard care in improving response rate or remission rate.24 The trial enrolled 249 HIV-positive veterans who screened positive for depression on the PHQ-9. Substance-dependent veterans could enroll. Researchers randomized them to standard care or to the HITIDES intervention, which relies on a three-person team -- a registered nurse depression care manager, a clinical pharmacist, and a psychiatrist. This trio makes treatment suggestions to prescribing clinicians via electronic medical record progress notes. These suggestions follow a stepped-care model that heightens treatment intensity when a participant does not respond. The provider makes all treatment decisions. The depression care manager supports each patient by phone, discussing treatment barriers and resolution, depression symptom and treatment monitoring, and substance abuse monitoring. The team monitors treatment response by PHQs completed by each participant and delivered at each clinic visit.

Both treatment groups averaged 49.8 years in age, and 97% were men. Almost two thirds of participants were black, and about 90% had at least a high school education. Three quarters of both groups had major depression verified by the Mini International Neuropsychiatric Interview, and about 80% had a current antiretroviral prescription.

Six months after randomization response rates (at least a 50% drop in the 20-item Hopkins Symptom Checklist [SCL-20]) measured 33.3% in the HITIDES group and 17.5% in the standard-care group. Those results yielded more than twice higher odds of response in the HITIDES group in an analysis adjusted for relevant variables (aOR 2.60, 95% CI 1.39 to 4.86, P = 0.003). At 6 months rates of remission (mean SCL-20 item score below 0.5) measured 22% in the intervention group and 11.9% in the standard-care group, also yielding more than twice higher odds of success in the HITIDES group (aOR 2.40, 95% CI 1.10 to 5.22, P = 0.03). At 12 months, as in the SLAM DUNC study,22 these betweengroup differences dwindled to nonsignificance.

But veterans in the HITIDES group reported significantly fewer depression-free days through 12 months (β = 19.3 days, P < 0.001)), and veterans in the intervention group had significantly lower HIV symptom severity at 6 months (β = -2.6, P < 0.001) and at 12 months (β = -0.82, P = 0.03).

In both the SLAM DUNC22 and HITIDES24 studies, the intervention improved depression faster than usual care (through 6 months) but the usual-care arms caught up with the intervention arms in some measures of depression (through 12 months). VA researchers24 suggest two reasons for delayed response in the control arms that could apply to both trials: First, all participants were receiving care in the context of a clinical trial in which providers and patients accepted the need for improved depression care. Second, as the trials proceeded, clinicians in the control arm became more practiced in prescribing antidepressants and monitoring responses because of their involvement in the trials. If these speculations are true, they suggest that providers who begin paying more attention to depression care in routine practice will improve the mental health of their depressed patients.

A small randomized trial involving young adults with HIV found that 24 weeks of combined "measurementguided psychotherapy and medication management" tailored for this age group yielded significantly higher depression remission rates at 24 and 48 weeks in the intervention group than in a standard-care contingent.25 More psychotherapy in the measurement-guided group probably contributed to better outcomes in this arm.

The trial recruited 18- to 24-year-olds in care at one of four US Adolescent Trials Network (ATN) sites. Participants had a diagnosis of nonpsychotic depression with significant symptoms defined as a Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) score of 7 or higher. Enrollees could not have psychosis, bipolar disorder, or a diagnosis of alcohol or substance dependence in the last 6 months.

Researchers randomized two ATN sites to use the combination psychotherapy and medication management (COMB) plan and two to treat patients according to standard practice. Clinicians in the COMB arm implemented and adjusted antidepressant therapy (starting with an SSRI) according to an algorithm online). As in the SLAM DUNC trial,22 this algorithm uses depression response as the primary driver of treatment decisions. The trial offered all COMB participants cognitive behavioral therapy conducted by a site psychotherapist. Psychotherapists and prescribing clinicians in the COMB arm received 2 or 1 day of training respectively. Therapy continued for 24 weeks, and participants in both arms completed QIDS-SR at 6, 12, 24, 36, and 48 weeks.

Both study groups averaged 21.5 years in age and included similar proportions of blacks (83% overall) and Hispanics (21% overall). The intervention group had a significantly higher proportion of men than the control group (96% versus 40%, P < 0.001). The study arms had similar QIDS-SR scores when entering the trial. After 24 weeks this measure showed significantly fewer depressive symptoms in the intervention COMB group than in controls (mean 4.3 versus 11.1, P < 0.001) and that advantage persisted through 48 weeks (mean 4.1 versus 10.2, P < 0.001). Response rates (at least 50% drop in QIDS-SR) proved significantly greater in the COMB group at week 24 (85% versus 20%, P < 0.001) and week 48 (88% versus 33%, P < 0.001) (Figure 3). Remission rates (QIDS-SR below 5) were also better with COMB than standard care at weeks 24 (65% versus 10%) and 48 (71% versus 7%).

Combined Depression Therapy Versus Usual Care for Young Adults With HIV
Combined Depression Therapy Versus Usual Care for Young Adults With HIV Figure 3. A trial of measurement-guided psychotherapy and medication management for young adults with HIV and depression found significantly greater depression response and remission rates in the combination (COMB) intervention arm than the usual-care arm through 24 weeks of treatment and for an additional 24 weeks after the interventions ended.25
Teresa B. Southwell/The Center for AIDS Information & Advocacy

A significantly higher proportion of young adults in the COMB group received psychotherapy (95% versus 45%, P < 0.001) and attended more psychotherapy sessions through 24 weeks (12.6 versus 5, P < 0.001). Antidepressant use did not differ significantly between the two groups. At week 24 only 35% in the COMB arm and 45% in the usual-care arm took an antidepressant. These findings suggest that cognitive behavioral therapy explained much of the improved response in the COMB arm.

This is a small feasibility study without reported statistical power calculations. The researchers caution that results may not apply to all young people with HIV because they excluded those with substance use disorders. But the impact of the intervention proved significant and sustained. And because existing staff at study sites carried out these interventions, the authors propose that this approach "is feasible in other US medical care sites."25

These three studies in distinct HIV groups with depression22,24,25 show that response-guided treatment strategies conducted by trained professionals supporting prescribing clinicians can improve depression outcomes over the course of 12 months (Table 2). The three strategies differ in their details, but all three involve treatment response plans to guide the prescribing HIV provider.

All three trials randomized participants to the study intervention or to standard care. The study in 18- to 24-year-olds25 differed from the two studies in middleaged people22,24 in finding significantly better response and remission rates at both 6 and 12 months, while the other studies recorded more depression-free days through 12 months with the intervention. The strategy for young adults also differed in aiming to combine cognitive behavioral therapy and antidepressant therapy, while the other two studies focused primarily on antidepressants. As detailed above, cognitive behavioral therapy appeared to explain the response advantage in the intervention arm of this trial in young adults,25 but the trial was small and results should be confirmed in bigger groups.

The larger trials in middle-aged adults with HIV and depression22,24 relied on gradual antidepressant dose escalation guided by test-measured responses and patient reports of tolerance. Both studies used algorithms to inform antidepressant adjustment recommendations, though the algorithm for the VA study24 is not currently available online.

All three response-guided strategies22,24,25 rely on regular patient monitoring, especially during the first months of a new antidepressant, to ensure reaching a dose that leads to symptom remission without causing side effects. But the strategies differ in the type and number of supporting professionals required. The SLAM DUNC approach is the simplest, requiring a quickly trained professional who may be a medical assistant, nurse, or clinical social worker.22 The strategy for young adults needs a trained psychotherapist.25 And the HITIDES approach creates a three-person team: nurse, clinical pharmacist, and psychiatrist.

Clinicians who see a need for support in offering patients response-guided depression care could profit by exploring the three approaches described here and picking one that seems to mesh best with that clinician's practice.

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