NHLBI Working Group Assessment and Treatment of Depression in Patients with Cardiovascular Disease

Assessment Panel Recommendations

The Assessment panel?s recommendations are intended to promote development of more uniform assessment of depression in CVD patients. Toward that end, the Assessment panel makes separate recommendations for different research purposes. These recommendations will be modified as needed based on comments from the clinical and research communities and a more detailed discussion of the recommendations and their rationale will be published following public comment.

These recommendations are intended to apply only to research, including clinical trials, epidemiologic studies, and studies of mechanisms. Recommendations for application to clinical use were thought to be beyond the scope of the Assessment Panel?s mandate. However, the Panel recognizes that for ultimate application in primary care at a reasonable cost, the initial screening of patients for depression should be simple enough for primary care physicians or clinical research coordinators to use with minimal training or should be self-administered by the patient. Agreement on a screening tool would also result in simpler and less expensive recruitment of CVD patients for depression treatment trials and simpler translation of trial results into practice.

The Panel strongly recommends that diagnostic instruments be administered only by well-trained individuals, with attention to implementing quality control procedures such as audiotaping of interviews for review, where warranted. A brief description of each of the measures discussed below is contained in the Appendix.

Epidemiologic Studies of CHD Patients: The widespread use of the Beck Depression Inventory (BDI-I) and its well-understood properties place it as the leading self-report instrument for use in epidemiologic studies. In the near future new psychometric data will become available on the BDI-II, at which time it will become clearer whether it should replace BDI-I. The Inventory of Depressive Symptomatology - Self-report version (IDS-SR) can also be considered. The Panel does not recommend other self-report measures at this time.

For epidemiologic research that requires diagnostic measures of depression and for which the time and resources for diagnosing depression are available, the panel recommends the Depression Interview and Structured Hamilton (DISH)4 or the Composite International Diagnostic Interview (CIDI). The CIDI is favored for epidemiologic studies primarily because (1) it was designed for use in epidemiologic studies (i.e., it is highly structured, efficient, and designed for use by lay interviewers, although training is required) and (2) it has been used in some of the largest and most important studies in the recent history of psychiatric epidemiology, both in the U.S. and internationally. The high prevalence of depression reported in the National Comorbidity Survey10 raised concerns about the CIDI. This is an important issue, but the Panel is not aware of an existing instrument that would be clearly superior at this time.

Screening Candidates for Eligibility in RCTs: The 2-item screening tool from the Patient Health Questionnaire-9 (PHQ-9) is recommended to identify currently depressed patients within a CVD population. Should one or both of the items of the PHQ be positive, all nine PHQ items should be administered. The BDI can be used as a screening instrument, provided time is available, keeping in mind that it is not a diagnostic instrument. In the ENRICHD study, the BDI was found to be an accurate screening tool for depression in post-MI patients.11 These instruments can also be used to screen and record depression history in CVD trials that do not involve depression as a primary endpoint.

Diagnostic Ascertainment of Depression for RCTs: After considerable discussion the Panel concluded that the Depression Interview and Structured Hamilton (DISH) and the Composite International Diagnostic Interview (CIDI) have substantial advantages for diagnosing depressed patients for inclusion in randomized clinical trials. Although the Structured Clinical Interview for DSM-IV (SCID) was considered as a candidate for this purpose, some limitations were noted including heavy interviewer and subject burden, unknown reliability for medically ill patients, and the need for lengthy and continuous training. A significant advantage of the DISH is that it yields a score on Williams? structured version of the17-item Hamilton Rating Scale for Depression (HAM-D) in addition to diagnoses of major and minor depression and dysthymia.

The panel noted that the outcome of the DISH and CIDI interviews are not reliable or useful without appropriate interviewer training and audio recording of interviews for quality control.

Rating Depression Severity During a RCT: The Assessment Panel recommends using observer ratings of depression as well as self-reports (not necessarily as the primary outcome measure of depression). Currently, the BDI-I is recommended as the self-report instrument of choice. However, as already noted for clinical epidemiologic studies, new data on the psychometric properties of the BDI-II may support its future use in RCTs. Despite the widely recognized limitations of the 17-item Hamilton Rating Scale for Depression, the Panel recommends using the HAM-D-17 to rate depression severity in clinical trials based on its acceptability to the FDA and its use in previous trials. The HAM-D-17 may be supplemented when possible with one of the psychometrically sophisticated measures such as the Inventory for Depressive Symptomatology ? Clinician Rating (IDS-CR). Further research is needed to determine whether the IDS-CR and the Montgomery-Asberg Depression Rating Scale (MADRS) are appropriate for stand-alone use in the CVD population. In addition to training and quality control, the Panel emphasizes that masking or blinding assessment staff to treatment condition is critical to ensure the internal validity of the trial assessments. Centralized telephone rating should be considered in multicenter trials.

Ascertainment of Treatment Success in a RCT: The Panel did not make recommendations concerning the amount of symptom reduction in the proposed measures that would constitute a ?successful? treatment response. The Panel does recommend that remission of depression (e.g. a Ham-D < 7) be pre-specified as one of the outcome measures for any clinical trial, whether of treatment efficacy for depression or for medical outcomes, and the percent remitting among randomized arms be compared. A criterion for success based on differences in depression scores between randomized arms of a trial also should be pre-specified. The Panel requests comments from the broader clinical research community on the criterion to be used to evaluate the success of depression treatments relative to a usual care/placebo control group, including discussion of the applicability to clinical trials in CVD patients of common conventions and estimates of depression treatment response that are considered clinically meaningful for non-medically ill populations.

Research Needs: Considerable discussion focused on research needed to inform future recommendations. A large validation study in which a number of assessment measures are employed simultaneously was thought to be ideal. Such a study should include a sufficient number of men, women, and minority groups, with over-sampling as needed, to ascertain differences between subgroups, as well as concurrent validity and psychometric properties. Limitations of many of the measures, including ability to differentiate between somatic and cognitive symptoms, association with other negative affective states and psychiatric co-morbidity, and validity of self-report instruments in elderly, frail medical patients require further evaluation. The timeframe used for each measure (e.g. Depressive symptoms in the last week? In the last month? Prior to the acute coronary event?) should also be considered. Comments concerning research needs and opportunities are welcome.

Treatment Panel Recommendations

The Treatment Panel noted that the observational evidence base for an association between depression and cardiovascular morbidity and mortality has become larger and more consistent during the past decade. In addition, since cardiovascular disease and depression are the two most prevalent causes of death and disability worldwide it is important to increase research efforts to develop effective interventions when these disorders occur together.

A major focus of the Treatment Panel?s discussion was on the question of effective treatment for depression in CHD patients. The Panel evaluated the efficacy of pharmacological and psychotherapeutic interventions for depression generally and their application specifically to treatment of depressive symptoms in CHD patients.

Treatment Options for Depression in Coronary Heart Disease Patients

A considerable literature demonstrates that several efficacious treatment options exist for treating clinical depression in the general population. During the past 25 years, the therapeutic targets for a DSM-IV diagnosis of major depression as well as chronic depression (dysthymia) have received considerable attention. The first generation of antidepressants (the tricyclics and monoamine oxidase inhibitors, MAOIs) was shown to benefit the majority of patients with clinical depression, but their side effect profile was not considered ideal. In addition, their safety profile for CHD patients was poor. These issues were alleviated by the introduction of the next generation of antidepressants, particularly the SSRIs, whose safety in CHD patients is superior. Safety of serotonin-norepinephrine reuptake inhibitors (SNRIs) for CHD patients remains unknown. Currently, the majority of patients with clinical depression in medical or primary care settings are treated with SSRI?s or SNRI?s.

Pharmacotherapy is not considered the only acceptable treatment for mild to moderately severe clinical depression. Psychotherapeutic interventions such as Interpersonal Psychotherapy (IPT) and Cognitive Behavior Therapy (CBT) also have been found to be effective. For chronic depression, a variant on CBT known as Cognitive Behavioral Analysis System of Psychotherapy (CBASP) has been evaluated recently in several clinical trials. While monotherapy or targeted psychotherapy have been the major components of first-line treatment, many patients do not achieve complete remission, and combined treatments are common. These have been called either augmentation or sequencing strategies and have included the combination of two medications or the combination of a pharmacologic intervention and targeted psychotherapy. Augmentation strategies have also included other classes of psychotropic drugs including lithium and, more recently, low doses of the the class of medications known as atypical antipsychotics.

The large-scale multistep clinical trial of outpatients with nonpsychotic major depressive disorder (STAR*D) is testing an algorithm involving several first-line antidepressants combined with cognitive therapy. Collaborative Case Management was a key component of the treatment algorithm for the IMPACT clinical trial for late-life depression in primary care.9 Other treatment strategies (e.g., light therapy) are commonly used for treating subsyndromal depression, a milder form of depression, and the efficacy of new treatments, such as transcranial magnetic stimulation (TMS), for severe or treatment-resistant depression is currently being explored. For RCT?s, the treatment algorithm should be pre-specified carefully so that a full range of options can be implemented systematically to assure effective treatment of treating depression in the CHD patients.

While these approaches to treatment emerged primarily from treatment trials for acute depression, recurrence is common in clinical depression, and prevention of recurrence is an important consideration. For both acute and chronic treatment strategies, functional outcome measures including quality of life should be added to the usual depressive symptom outcome measures. The Treatment Panel began with the premise that currently available algorithms for treating depression in non-CHD patients should be evaluated for treating depression in CHD patients and that assessments of medical outcomes can be added to examine the impact of the depression treatment on reduction of cardiac risk factors and cardiac events.

Subgroup analyses from the SADHART and ENRICHD trials suggest that patients with more severe depression, those with a past history of depression,2,5 and patients who receive SSRI pharmacotherapy in addition to CBT may respond better to treatment. In ENRICHD, subgroup analyses also found that patients in the treatment arm whose depression was successfully treated had lower rates of mortality and reinfarction.3 The Panel discussed these and other issues raised by the ENRICHD and SADHART trials relevant to treating CHD patient:

• Timing of the intervention: a strategy of initiating and limiting treatment of depression to the immediate post-MI period (e.g., first 6 months post-MI) may have limited potential because patients are medically less stable and their depression status in the immediate post-MI period is highly labile (it is often more severe immediately following the event) and may be a transient reaction to the MI itself. For an RCT, this situation can result in enrollment of individuals whose depression may remit spontaneously in the weeks and months following the event. These may not be the best patients in whom to test the causal hypothesis that reducing depression will reduce the risk of mortality and morbidity in patients with acute coronary syndromes. On the other hand, to the extent that treatment by pharmacotherapy may affect cardiovascular function parameters directly, rather than through improvement in depression, initiating treatment early may be preferable. Further data are needed to inform this issue.
• Duration of the intervention: The ENRICHD intervention was delivered for 6 months and included specific strategies for relapse prevention and extended treatment only via pharmacotherapy. The discontinuation of psychotherapy at 6 months most likely contributed to diminishing differences in depression status between the treatment and usual care groups over time. Longer treatments may be particularly important if the effect of depression on event-free cardiovascular survival is being explored. It is likely that treatment should be delivered longer than was the case in either the SADHART or ENRICHD trials, especially to prevent and address recurrences. (The Panel notes that several cardiovascular therapies do not result in survival differences between treatment and control groups for 6-12 months. Examples include trials of angiotensin-converting enzyme inhibitors in high-risk patients without heart failure6 and trials of ICD therapy in MI patients with reduced ejection fraction.7 )
• Responsiveness of the patient population to treatment: it was noted that in clinical trials of patients presenting with ACS rather than depression, and enrollment based on in-hospital screening for depression, patients may not appreciate the importance of their mood disorder. This raises an important motivational issue that may influence adherence to treatment. Studies of depression treatments in other medical populations (diabetes, congestive heart failure) that involve patients motivated to treat their depression and that offer patients a choice between initial treatment options have reported good results.8,9 These factors should be considered in establishing eligibility criteria and in the design of clinical trials.

Based on the data reviewed, Treatment Panel members agreed that depression treatments found to be effective in non-CHD populations (CBT, SSRIs, and combined treatments) also reduce depression in CHD patients. Given that depression can be treated safely and effectively in CHD patients, and that a large and consistent body of evidence shows that depression is associated with approximately a three-fold risk of CVD mortality and morbidity, the Treatment Panel concluded that a randomized clinical trial is needed to determine whether an SSRI, psychotherapy, or combined treatment can reduce the risk of CVD events and mortality associated with depression in CHD patients.

Research Needs: After considering various options, the Working Group recommends that a randomized clinical trial be planned in detail. The trial would involve multiple centers for recruiting a sufficient number of patients, and specify clearly defined treatment algorithms with adequate follow-up to accumulate a sufficient number of cardiac events. Depressed CHD patients should be at moderate cardiac risk (e.g., low ejection fraction) recruited from cardiology & primary care settings and assigned randomly to either a stepped-care depression treatment arm or a usual care arm in which they would receive usual cardiologic care. The intervention should be of sufficient duration and intensity to ensure a difference in depression between the randomized arms. Results of such a trial would provide important information concerning the clinical care of depressed CHD patients.

References

1. Berkman LF, Blumenthal J, Burg M, Carney RM, Catellier D, Cowan MJ, Czajkowski SM, DeBusk R, Hosking J, Jaffe A, Kaufmann PG, Mitchell P, Norman J, Powell LH, Raczynski JM, Schneiderman N; Enhancing Recovery in Coronary Heart Disease Patients Investigators (ENRICHD). Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. JAMA, 2003,289:3106-16.
2. Glassman AH, O'Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT, Jr., Krishnan KR, van Zyl LT, Swenson JR, Finkel MS, Landau C, Shapiro PA, Pepine CJ, Mardekian J, Harrison WM, Barton D, McLvor M. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA, 2002;288:701-9.
3. Carney RM, Blumenthal JA, Freedland KE, Youngblood M, Veith RC, Burg MM, Cornell C, Saab PG, Kaufmann PG, Czajkowski SM, Jaffe AS; ENRICHD Investigators. Depression and late mortality after myocardial infarction in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study. Psychosom Med. 2004,66:466-74.
4. Freedland KE, Skala JA, Carney RM, Raczynski JM, Taylor CB, Mendes de Leon CF, Ironson G, Youngblood ME, Krishnan KR, Veith RC. The Depression Interview and Structured Hamilton (DISH): rationale, development, characteristics, and clinical validity. Psychosom Med. 2002,64:897-905
5. Covey LS, Glassman AH, Stetner F, Rivelli S, Stage K. A randomized trial of sertraline as a cessation aid for smokers with a history of major depression. Am J Psychiatry. 2002;159:1731-7.
6. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000, 342:145-53.
7. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML; Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002, 346:877-83.
8. Katon WJ, Von Korff M, Lin EH, Simon G, Ludman E, Russo J, Ciechanowski P, Walker E, Bush T. The Pathways Study: a randomized trial of collaborative care in patients with diabetes and depression. Arch Gen Psychiatry. 2004;61:1042-9.
9. Unutzer J, Katon W, Callahan CM, Williams JW, Jr., Hunkeler E, Harpole L, Hoffing M, Della Penna RD, Noel PH, Lin EH, Arean PA, Hegel MT, Tang L, Belin TR, Oishi S, Langston C. Collaborative care management of late-life depression in the primary care setting: a randomized controlled trial. JAMA 2002;288:2836-45.
10. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry, 1994 Jan;51(1):8-19.
11. Unpublished data, manuscript in preparation.

Appendix - Summary of Instruments

Beck Depression Inventory (BDI)

The BDI assesses the severity of 21 symptoms of depression. Each item is rated on a 4-point scale (range: 0-3). Thirteen items address cognitive or affective symptoms such as hopelessness and guilt. Two of these 13 items assess the cardinal symptoms of depression: depressed mood and loss of interest or pleasure in usual activities. The remaining eight items assess somatic symptoms such as insomnia, fatigue, and poor appetite. In screening uses, a total score of 10 or higher is the most widely used cutoff for clinically significant depression. BDI total scores of 10-18 are consistent with mild, 19-29 with moderate, and 30 or higher with severe depression.

Beck AT, Ward CH, Mendelsohn M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561-71.

Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev 1988;8:77-100.

Composite International Diagnostic Interview (CIDI)

The CIDI is a comprehensive and fully standardized diagnostic interview designed for assessing mental disorders according to the definitions of the Diagnostic Criteria for Research of ICD-10 and DSM-III-R. The instrument contains 276 symptom questions, many of which are coupled with probe questions to evaluate symptom severity, as well as questions for assessing help-seeking behavior, psychosocial impairments, and other episode-related questions. Although primarily intended for use in epidemiologic studies of mental disorders, it is also being used extensively for clinical and other research purposes.

WHO,1997. Composite International Diagnostic Interview (CIDI). Basis versie 2.1, 12 maanden, Red. Ter Smitten MH, Smeets RMW, Van den Brink W.

Wittchen, 1994. Reliability and validity studies of the WHO-Composite International Diagnostic Interview (CIDI): A critical review. J of Psychiatric Research, 28(1), 57-84.

Robins, L.N.; Wing, J.; Wittchen, H.U.; Helzer, J.E.; Babor, T.F.; Burke, J.; Farmer, A.; Jablensky, A.; Pickens, R.; Regier, D.A.; Sartorius, N.; and Towle, L.H. The Composite International Diagnostic Interview: An epidemiologic instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch Gen Psychiatry 45:1069-1077, 1989.

Richter P, Werner J, Heerlein A, Kraus A, Sauer H. On the validity of the Beck Depression Inventory. A review. Psychopathology1998;1998;31(3):160-8.

Depression Interview and Structured Hamilton (DISH)

The DISH is a structured interview designed to diagnose major and minor depressive disorders according to the DSM-IV criteria. The17-item Hamilton Rating Scale for Depression (HAM-D-17) is also embedded within the DISH to assess severity of depression. Nine of the HAM-D items are rated on a 0-2 scale, and eight are rated on a 0-4 scale. HAM-D total scores can range from 0 to 50. Among medical patients, DISH scores between 10 and 23 are consistent with mild depression and scores of 24 or higher with relatively severe depression.

Freedland KE, Skala JA, Carney RM et al. The Depression Interview and Structured Hamilton (DISH): rationale, development, characteristics, and clinical validity. Psychosom Med 2002.

Hamilton Depression Rating Scale (HAM-D)

The Hamilton Depression Rating Scale is a 17-item scale that evaluates depressed mood, vegetative and cognitive symptoms of depression, and comorbid anxiety symptoms. The HAM-D was one of the first rating scales developed to quantify the severity of depressive symptomatology. First introduced by Max Hamilton in 1960, it has since become the most widely used and accepted outcome measure for evaluating depression severity. It provides ratings on current DSM-IV symptoms of depression, with the exceptions of hypersomnia, increased appetite, and concentration/indecision. The HAM-D was designed to be administered by a trained clinician using a semi-structured clinical interview.  The 17-items are rated on either a 5-point (0-4) or a 3-point (0-2) scale.

Williams, J.B.W., "A Structured Interview Guide for the Hamilton Depression Rating Scale," Archives of General Psychiatry, American Medical Association, August 1988, Vol. 45, Num. 8, pp. 742-747.

Inventory of Depressive Symptomatology (IDS)

The construction of the IDS-C30 and IDS-SR30 was intended to remedy deficits in the Hamilton (HAM-D) and Montgomery Asberg (MADRS) depression rating scales by, among others, including all nine symptom domains needed to diagnose a DSM-IV major depressive episode in order to assess symptom remission, improve ability to detect milder levels of symptoms than the HAM-D, and provide unconfounded and more equivalent weighting among items. There are two versions of the IDS with identical items: a clinician rating (IDS-C30) and a self-report (IDS-SR30). The self-report was developed to determine if it could be used as an alternative to the IDS-C30 in clinical or research settings, which would provide a low cost, easily used gauge of depressive symptom severity to assist patients and providers in managing the disorder.

Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C. The Inventory for Depressive Symptomatology: preliminary findings. Psychiatry Res 1986;18:65-87.

Montgomery-Asberg Depression Rating Scale (MADRS)

The Montgomery-Asberg Depression Rating Scale is a 10 item severity scale constructed to be sensitive to change with treatment. It was designed to be sensitive for individual items and is therefore useful for measuring differential profiles of action. Ratings of patients on a 65 item comprehensive psychopathology scale were used to identify the 17 most commonly occurring symptoms in primary depressive illness, and ratings on these 17 items for 64 patients participating in studies of four different antidepressant drugs were used to create a depression scale consisting of the 10 items which showed the largest changes with treatment and the highest correlation to overall change.

Kearns NP, Cruickshank CA, McGuigan KJ, Riley SA, Shaw SP, Snaith RP. A comparison of depression rating scales. Br J Psychiatry1982 Jul;141:45-9.

Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382-9.

Patient Health Questionnaire (PHQ)

The Patient Health Questionnaire (PHQ) is a self-administered version of the Primary Care Evaluation of Mental Disorders (PRIME-MD) diagnostic instrument for common mental disorders. The PHQ-9 is the depression module, which scores each of the 9 DSM-IV criteria as "0" (not at all) to "3" (nearly every day). The PHQ-2 is a two-item depression screener which uses 2 items from the PHQ that inquire about the frequency of depressed mood and anhedonia over the past 2 weeks, scoring each as 0 ("not at all") to 3 ("nearly every day").

Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001 Sep; 16(9):606-13.

Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care 2003 Nov 41(11):1284-92.

Structured Clinical Interview for DSM-IV (SCID)

The SCID is a semistructured interview for making the major Axis I DSM-IV diagnoses. It is administered by a clinician and includes an introductory overview followed by nine modules, seven of which represent the major Axis I diagnostic classes. Because of its modular construction, it can be adapted for use in studies in which only particular diagnoses (e.g., depression) are of interest. Using a decision tree approach, the SCID guides the clinician in testing diagnostic hypotheses as the interview is conducted. The output of the SCID is a record of the presence or absence of each of the disorders being considered, for current episode (past month) and for lifetime occurrence.

Spitzer RL, Williams JB, Gibbon M, First MB. The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. Arch Gen Psychiatry 1992 Aug;49(8):624-9.

Williams JB, Gibbon M, First MB, Spitzer RL, Davies M, Borus J, Howes MJ, Kane J, Pope HG Jr., Rounsaville B, et al. The Structured Clinical Interview for DSM-III-R (SCID). II. Multisite test-retest reliability. Arch Gen Psychiatry1992 Aug 49(8): 630-6.

Summary of Assessment Recommendations

Table 1 Summary of Assessment Recommendations for Epidemiologic Studies

Table 2 Summary of Assessment Recommendations for Screening for Trial Inclusion

Table 3 Summary of Assessment Recommendations for Diagnostic Ascertainment for Trial Inclusion

Table 4 Summary of Assessment Recommendations for Depression Severity Rating During a Trial