Collaborative Care for Depression in Chronic Hepatitis C Clinics

Depression often coexists with chronic general medical illness. Up to 20% of patients with heart disease and 30% of patients with diabetes have depression (1,2). Moreover, depression often worsens outcomes and adherence to general medical care for a chronic illness (3). Compared with underlying physiological factors, depressive symptoms are also more strongly associated with patient-reported health status, including symptom burden, physical limitation, quality of life, and overall health (4).

Patients with chronic hepatitis C virus (HCV) are no exception to this pattern. They have a remarkably high rate of depression (up to 50%) (5–8). Patients with both depression and HCV are at high risk of morbidity and mortality (9–12). For decades, depression also has been the leading barrier to antiviral treatment because of the concerns that interferon (that served as the backbone for HCV treatment) may worsen underlying depression (7,13–16). Although depression may no longer be an “exclusionary criterion” for the new interferon-free treatments, it may continue to play a role in predicting success of HCV treatment through its effect on retention in care and adherence to treatment. Despite its prevalence, depression is underrecognized and undertreated among HCV patients (6,7).

Collaborative care models facilitate collaboration between primary care and mental health care providers to improve the quality of depression care and outcomes (17–20). Unlike many other common chronic conditions, HCV patients are evaluated and treated for HCV in dedicated HCV specialty clinics rather than in primary care. Compared with the usual referral-based models (16), a collaborative care model in HCV may have the advantage that patients can receive depression care in the HCV clinic, which is more accessible and may be less stigmatizing than the specialty mental health clinic. Moreover, centralizing care around an HCV clinic may increase the likelihood that patients will stay in both HCV and mental health care.

The goal of this study was to adapt an evidence-based primary care model of collaborative care for depression to HCV clinic settings in four U.S. Department of Veterans Affairs (VA) facilities and evaluate the model’s clinical effectiveness.

Methods

Design

The Hepatitis C Translating Initiatives for Depression Into Effective Solutions (HEPTIDES) study compared collaborative care with usual care for depression at four VA facilities in a randomized controlled effectiveness trial (21). The same clinics also participated in a nonrandomized implementation strategy to adopt depression screening as routine care in HCV clinics and tailor the intervention to their site. The study was approved by the VA Central Institutional Review Board.

Participants

This study recruited a continuously enrolled, longitudinal sample of patients with HCV infection (positive HCV ribonucleic acid test) who were seen in HCV clinics and who screened positive for major depression on the nine-item Patient Health Questionnaire (PHQ-9) depression-screening instrument (a score ≥10). All patients completed informed consent documents before proceeding to eligibility screening. Exclusion criteria included patients already receiving HCV treatment, no access to telephone, PHQ-9 score <10, currently in bereavement, current suicidal ideation, significant cognitive impairment (score >10 on the Blessed Orientation Memory and Concentration Test) (22), in care of court-appointed guardian, diagnosis of schizophrenia, and bipolar disorder with admission for psychiatric diagnosis in the previous 12 months.

Participants were randomly assigned to the intervention or to usual care in a 1:1 ratio according to a computer-generated random assignment sequence stratified by clinic and generated in advance. Participants were enrolled from May 2012 through September 2013.

Procedure

Depression screening and intervention adaptation by clinic.

The HCV clinic staff, including nurses, physician assistants, and HCV clinicians, conducted the depression screening, and the research team delivered the intervention. Depression screening methods were adopted at each clinic as part of routine care, and patients completed the PHQ-9 before each HCV clinic visit. HCV clinic staff members were aware of the depression screening results for all participants.

HEPTIDES intervention.

The purpose of the HEPTIDES intervention was to support HCV and mental health clinicians in delivering evidence-based depression treatment. The depression care team consisted of a nurse depression care manager (DCM), a pharmacist, and a psychiatrist. This team was located off site and convened once a week and as needed by telephone or in person. The team communicated with treating clinicians via electronic medical record progress notes. The DCM communicated with patients via telephone. The HEPTIDES depression care team made treatment suggestions. Treatment decisions were made at each site by the HCV or mental health clinicians in partnership with the patient.

The DCM delivered the following components: participant education and activation, assessment of treatment barriers and possible resolutions, depression symptom and treatment monitoring, and substance abuse monitoring. The DCM used prewritten scripts that were supported by the Web-based decision support system (23). The intervention used a stepped-care model for depression treatment. The five steps included DCM monitoring plus the following components: self-management education, depression care team treatment suggestions (counseling or pharmacotherapy, with consideration of participant preference), pharmacotherapy suggestions after review of depression treatment history by the clinical pharmacist, combination pharmacotherapy and specialty mental health counseling, and referral to specialty mental health. Specific treatment suggestions were based on the VA/Department of Defense Depression Treatment Guidelines. At any time, HCV providers could refer participants directly to specialty mental health care. The stepped-care model was used to increase treatment intensity when participants did not respond to treatment.

The DCM conducted telephone-based monitoring every two weeks during acute treatment (before patients achieved a sustained 50% decrease in PHQ-9 score) and every four weeks during continuation treatment (for two months after maintaining remission [PHQ-9 score <5] or six months after maintaining a 50% decrease in the PHQ-9 score). The decision support system identified the potential need to change treatment when one or more of the following occurred: antidepressant regimen adherence of <80% during the past 14 days, counseling adherence of <75% during the past month, participant report of severe adverse effects during two consecutive DCM encounters, participant report of a 5-point increase in depression severity from the enrollment PHQ-9 score based on two consecutive DCM encounters, and lack of participant response (<50% decrease from enrollment PHQ-9 score during two consecutive DCM encounters) during an eight-week antidepressant course or 12-week counseling trial.

Usual care.

Usual care included depression screening with the same PHQ-9 used for intervention patients. Usual care patients received “standard of care” depression treatment, which typically included referral to specialty mental health clinics or depression treatment at integrated primary care–mental health clinics where patients had access to evidence-based psychotherapy and pharmacotherapy available at each site. Usual care patients did not have interactions with the DCM or depression care team.

Data collection.

Baseline and six-month data were collected by a telephone interviewer who was blinded to treatment assignment. At baseline the Depression Outcomes Module (DOM) was administered to assess patient demographic characteristics, depression history, and co-occurring general medical problems (24,25). Mental health comorbidity was measured with the Mini-International Neuropsychiatric Interview (MINI) (26). Acceptability of antidepressant treatment was measured with an item developed for the Quality Improvement for Depression studies (20,27).

Depression Outcomes

Depression symptom severity during the past two weeks was measured with the 20-item Hopkins Symptom Checklist (SCL-20), which includes the 13-item depression scale plus seven depression-related items from the Hopkins Symptom Checklist 90–Revised (28). The items are scored from 0 to 4 and averaged to provide a mean depression severity score ranging from 0 to 4, with higher scores indicating greater severity. Depression outcomes also included response, remission, and depression-free days (DFDs). Depression treatment response at six months was defined as a 50% or greater decrease in the mean SCL-20 score compared with baseline, and remission at six months was defined as a mean SCL-20 score of <.5. DFDs were calculated as a summative measure of depression severity based on baseline and six-month SCL-20 data according to formulas originally developed by Lave and colleagues and adapted for the SCL-20 (19,29–31). For each assessment, an SCL-20 score of <.5 was considered depression free, a score of ≥2.0 was considered fully symptomatic, and scores in between were assigned a linear proportional value.

Statistical Analyses

Participants were the unit of the intent-to-treat analysis. Bivariate analyses were performed to examine associations of the depression outcomes with the study arms and baseline covariates. Chi-square tests were used for categorical variables, and t tests were used for continuous variables. Logistic and ordinary least-squares linear regression analyses were conducted to estimate the effect of the intervention on dichotomous (depression response and remission) and continuous (DFD) outcomes, respectively, with adjustment for baseline covariates that significantly predicted dependent variables at p<.20 in bivariate analyses. The only exceptions were age and race-ethnicity variables; these demographic variables were entered into the models on the basis of conceptual considerations. The results were expressed as odds ratios (ORs) for depression response and remission, beta coefficients for DFDs, and corresponding 95% confidence intervals (CIs) as appropriate.

No adjustment was made for potential nesting of participants within VA medical centers because the intraclass coefficient (–.0004) was close to zero with respect to our main outcomes, and there were no significant differences between outcomes across sites.

Results

Patient Characteristics

A total of 309 eligible patients were enrolled in the study. Of these, 292 patients completed baseline assessment interviews. Follow-up data-collection interviews were completed for 263 participants (90%) at six months. [A CONSORT diagram is available in the online supplement to this article.]

A majority of the participants were men, and the mean age of the sample was 59 years. Approximately half of our sample was African American, and 101 (38%) patients were married. The annual income was >$20,000 for only 74 (28%) of the patients. Most participants reported a history of mood disorder, and 133 (51%) reported at least one active prescription for an antidepressant medication at baseline assessment yet still scored positive for depression on the SCL-20. A total of 13 (5%) and 19 (7%) patients were taking an antipsychotic and antianxiety medication, respectively. A total of 110 (42%) patients preferred not to take an antidepressant as a treatment for depression. Half of the sample had comorbid generalized anxiety disorder, and 29 (11%) patients met the criteria for at-risk drinking (four or more standard drinks per day for men and three or more per day for women). Patients on average had five physical comorbid conditions, including bodily pain (N=199, 76%), hypertension (N=185, 70%), and arthritis (N=154, 58%). Only ten (4%) patients had a coexisting HIV infection. A total of 46 (17%) patients had progressed to advanced liver fibrosis or cirrhosis (Table 1).

At the time of baseline assessment, 18 patients who had screened positive on the PHQ-9 (≥10) reported an SCL-20 score of <.5 and thus met the criteria for being free of depression symptoms (remission). We conducted a secondary modified intention-to-treat analysis after excluding these patients. For this analysis, our sample included 245 patients (123 in the intervention and 122 in the usual care group).

Intervention Fidelity

All intervention patients were contacted by the DCM. Initial patient education, activation, and assessment for treatment barriers was completed for 126 (98%) patients, and 99% of all DCM contacts completed the PHQ-9 and the medication regimen, counseling adherence assessment, or both, depending on the current treatment. During the acute phase of treatment, a total of 255 intervention treatment trials were conducted, including 99 (39%) self-management and education, 86 (34%) pharmacotherapy, 15 (6%) counseling, and 55 (22%) combination pharmacotherapy and counseling trials. The mean number of DCM intervention telephone contacts per patient where any assessment was completed during the acute and continuation phases of treatment was 7.75 (1,000 contacts with 129 patients, range=0–14).

Depression Severity

At six months, among 129 patients in the intervention group, 24 (19%) met the criteria for treatment response, compared with 17 of the 134 patients (13%) in the usual care group (p=.12). Intervention patients were more likely than those in the usual care group to experience remission at six months (15 of 129, or 12%, versus eight of 134, or 6%). However, neither dichotomous unadjusted depression outcome reached statistical significance. The unadjusted DFDs were also not significantly different between the intervention and usual care groups at the six-month follow-up (mean 50.9 and 50.7, respectively; Table 2).

In bivariate analyses, history of depression treatment in the past six months, preference not to use antidepressants, and generalized anxiety disorder were associated with all three outcomes. General medical comorbidity and alcohol use were associated with response and DFDs; cirrhosis was associated with remission and DFDs. No recent drug use was associated with remission, whereas lower than college education and higher baseline SCL-20 score predicted fewer DFDs.

After analyses adjusted for age, race-ethnicity, and the other covariates detailed above, we found that HCV patients in the intervention group were more likely to meet the criteria for response (OR=2.02) and remission (OR=2.63), and they had more DFDs (β=7.63 days) than participants in the usual care group (Table 3); however, these differences did not reach statistical significance.

We repeated the analyses, excluding 18 patients with SCL-20 scores <.5 at baseline. The observed trends reached statistical significance for all three primary endpoints for HCV patients with depression at baseline: response (OR=2.35, CI=1.07–5.13), remission (OR=3.20, CI=1.06–9.64), and DFDs (β=9.5 days, CI=1.2–17.7).

Discussion

We found in adjusted analyses that collaborative depression care for HCV patients was associated with a trend toward higher rates of depression response and remission outcomes compared with usual care. The effect of the intervention was statistically significant among patients who did not meet criteria for remission on the baseline SCL-20 and was consistent across the four study sites and across several patient subgroups.

Although we saw a twofold improvement in depression outcomes relative to usual care, the magnitude of these improvements was smaller than that seen in other studies. A collaborative care intervention for depressed HIV patients showed a 16% improvement in the response rate among patients in the intervention group at six months (32). Similarly, the adjusted incremental six-month DFDs resulting from the HEPTIDES intervention (7.6 days) was smaller compared with 19.3 incremental DFDs during 12 months among VA HIV patients (32) and 14.6 incremental DFDs during nine months in a VA primary care sample (33). However, our results are similar to those seen in a collaborative care intervention in rural VA primary care clinics that resulted in approximately an 8% absolute improvement in the six-month depression response rate compared with usual care (34). Indeed, the HEPTIDES sample was more similar to the patients included in the rural primary care clinic study in regard to age and general medical comorbidity than to the patients in the HIV study (34).

Our study included patients with serious and multiple general medical comorbid conditions. We enrolled these participants because implementation of the collaborative care program in a clinical setting would likely include patients with complex conditions. Furthermore, half of our patients screened positive for depressive symptoms while using antidepressant medications, and 103 (39%) had a history of inpatient mental health admission—higher than rates reported in previous studies (32,34). Compared with the data from collaborative care in HIV clinics, smaller between-groups differences might have been related to the differences in the specialty care cultures for HIV and HCV in the VA. Whereas many HIV specialists act as primary care providers for patients with HIV, most HCV specialists may not take this responsibility for patients with HCV. Given these differences, it is perhaps not surprising that only 13% of HCV patients in the usual care group responded to depression treatment, compared with 18% of HIV patients (33,34).

With the advent of new direct-acting antiviral agents, depression may not affect antiviral treatment decisions to the same extent as with the previous interferon-based treatment (35,36). However, an important consideration in prescribing the new treatment is patients’ ability to comply with clinic visits. It is plausible that depression will continue to play a pivotal role in predicting antiviral treatment response of HCV patients through its effect on adherence to treatment. Therefore, collaborative care depression interventions will continue to be needed to improve depression outcomes and extend the benefits of new antiviral treatment to patients with coexisting depression.

Our findings have implications for cohorts within the VA at risk of developing HCV. Veterans have much higher prevalence of HCV compared with the general U.S. population (5% versus 1%) (37). Infection is particularly common among veterans with alcohol or substance use disorders and those who are homeless (37,38). HCV disease burden is even more pronounced among those born between 1945 and 1965 (38); more and more of these patients will be diagnosed as having HCV with the implementation of birth-cohort screening in the VA. Our study also has broader implications for the organization of health care systems. Collaborative care models in which offsite mental health specialists support primary care specialty clinics with telemedicine may improve health care and reduce costs.

The study had several limitations. We did not anticipate that the study would recruit patients with no depression or that the study might have an unbalanced distribution of these patients in the two groups. Screening instruments, such as the PHQ-9, are not diagnostic, and this could explain why some patients in our sample did not meet the SCL-20 criteria for depression. The reasons underlying unequal distribution of patients with SCL-20 scores <.5 between the two groups are less clear. We did not find any difference in the proportions of patients who recently started antidepressants or the gap between initial screening and SCL-20 administration for patients who met the criteria for remission at baseline compared with those who did not. Notwithstanding the reasons, the effect of intervention across all three outcomes was stronger and statistically significant when we limited our analysis to patients with SCL-20 scores >.5 at baseline. This was a four-site study, and the results thus may not be generalizable to all veterans with HCV. However, the geographic and clinical practice differences across the four sites allowed us to examine the impact of HEPTIDES in a variety of practice settings. There was a single team, and our results may have been specific to the team members.

Conclusions

The HEPTIDES intervention improved depression outcomes in a highly comorbid group of patients with HCV. However, this improvement was modest compared with that seen in other collaborative care studies. Longer-term follow-up studies are needed. Our planned formative evaluation will also identify ways to bolster the intervention in order to enhance its effectiveness in this challenging population. Nonetheless, if future research confirms the relationship between depression and adherence noted in other studies (39,40), HCV clinics should consider collaborative care interventions to improve outcomes for their patients.