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Depression and comorbid medical illness: the National Institute of Mental Health perspective
Depression and Comorbid Medical Illness: The National Institute of Mental Health Perspective For the National Institute of Mental Health (NIMH), depression—with or without comorbid medical illness—is a major public health problem and a critical research priority. Affecting 10.3% of the U.S. adult population in any year (Kessler et al 1994), depression has become the leading cause of disability in adults (15– 44 years old) within Western Europe and North America (Murray and Lopez 1996). Depression responds to pharmacologic and behavioral treatments, both individually and in combination (National Institute of Mental Health 2002). Nonetheless, it remains stigmatized, under-recognized, and undertreated in primary care settings, where it frequently cooccurs with medical illness, and where most depressed patients are treated. A follow-up of an epidemiology survey revealed that for those with major depression, the odds of dying within a 1-year period are 2.6 times greater than for those without the disorder (Kouzis et al 1995). Some of this excess mortality is undoubtedly due to the consequences of depressive illness (suicide), but, as documented elsewhere in this issue of Biological Psychiatry, the comorbidity of depression with other illnesses accounts for a significant fraction of these deaths, because depression increases mortality and morbidity of several medical illnesses (e.g., cardiovascular disease, diabetes, stroke). Finding ways to improve detection and treatment of depression in the primary-care setting is an important NIMH research priority. It is also critical to identify the biological and behavioral links between medical illnesses and depression.
The Changing NIH Role of NIMH in Comorbidity Research The NIMH long served as the primary locus within the National Institutes of Health (NIH) for research on the behavioral and psychological aspects of all medical illness, including the study of comorbid mental and physical illness. There have been two changes at the NIH that influence funding in this area. First, in 1995, the Office of Behavioral and Social Science Research at the NIH was established to support and facilitate cross-institute efforts to broaden behavioral research. Second, restructuring of the NIH peer review process created review committees that cut across disease categories and institutes, a change © 2003 Society of Biological Psychiatry
that has strengthened the science related to health and behavior and behavioral medicine throughout the NIH. As a result, other NIH institutes have increased support of research related to comorbidity. The medical comorbidity studies NIMH supports now focus on mental illness as the dependent variable (e.g., how diabetes affects depression relapse), whereas in other NIH institutes, mental illness is studied as an independent variable affecting the diagnosis treatment, course, or outcome of specific medical illnesses of interest (e.g., how depression influences management of diabetes). Given the interdisciplinary nature of these studies, NIMH co-funds with other NIH institutes a number of comorbidity-related grants and initiatives. Overall, depression commands a substantial proportion of the NIMH research budget—17% (or $206 million) in fiscal year (FY) 2002. Whether via collaboration or through sole support, comorbidity research has increased within the NIMH extramural research budget. Between FY1999 and FY2002, funding for depression medical comorbidity research more than doubled (from $8 million to $17 million), and its share of the extramural research budget increased by 13% (NIMH data, unpublished). The National Institute of Mental Health has published a number of program announcements in this area: PAS-02–107: Basic and Translational Research on the Cognitive Sequelae of Parkinson’s Disease (http://grants.nih.gov/grants/guide/pa-files/ PAS-02–107.html); PA-02– 047: Research on Co-Morbid Mental and Other Physical Disorders (http://grants.nih. gov/grants/guide/pa-files/PA-02– 047.html); PA-00 – 109: Self-Management Strategies across Chronic Diseases (http://grants.nih.gov/grants/guide/pa-files/PA-00 – 109.html); PA-98 – 080: HIV/AIDS and the Severely Mentally Ill (http://grants.nih.gov/grants/guide/pa-files/ PA-98 – 080.html); RFA-DK-02– 009: Depression and Mental Disorders in Diabetes, Renal Disease, and Obesity/ Eating Disorders (http://grants.nih.gov/grants/guide/rfafiles/RFA-DK-02– 009.html).
Defining and Assessing Comorbidity The term “comorbidity” has many—and often confusing—meanings. It commonly refers to the co-occurrence (or dual diagnosis) of two disorders or syndromes in the same patient, regardless of whether the disorders are coincidentally or causally linked, or whether they co0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00272-5
Commentary
vary—that is, co-occur more often than expected by chance (Krishnan et al 2002; Lilienfeld et al 1994). “Comorbidity” may also refer to the epidemiologic linkage between two disorders in which one shares pathologic mechanisms with or is a risk factor for the other over time (Kraemer 1995; Krishnan et al 2002; Merikangas et al 1996). Two disorders may be “clinically comorbid” if the presence of one alters the normal course of the other (Feinstein 1967); clinical comorbidity is a common reason for excluding comorbid illness in randomized trials or stratifying based on its presence or absence (Kraemer et al 2001). The term “medical comorbidity” is used here to distinguish psychiatric–medical co-occurrence from the co-occurrence of two or more psychiatric disorders, without regard to causality.
Epidemiology Medical comorbidity research requires reliable, community-based epidemiologic data describing patterns of cooccurrence between mental disorders and medical illnesses. Also needed are longitudinal studies that identify potent and malleable risk factors that may be targets for prevention. At present, such data are scarce, and epidemiologic data on medical comorbidity are often based on relatively short-term studies of small clinical samples. To date, important insight into the adverse health consequences of mental illness has come from follow-up studies of participants in mental health epidemiology surveys (e.g., Kouzis et al 1995); however, efforts to obtain such data have been hampered by the difficulty of assessing the somatic symptoms of depression in the context of medical illness.
Pathophysiology Elucidating the links between medical illness and depression may clarify the pathophysiology of depression and suggest new approaches for its prevention and treatment. For example, it is not clear whether the excess of cardiovascular deaths in postinfarction patients with depression is due to behavioral factors (poor adherence to exercise or medication regimens), alterations in platelet function, or an increase in inflammatory factors that lead to cardiac irritability. Increasingly, we are realizing that depression is a multisystem disorder that affects immunologic, endocrine, and vascular, as well as neural, function. Given the exciting potential of research in this area, NIMH and three other NIH Institutes (National Institute of Neurologic Disease and Stroke, National Institute of Drug Abuse, National Institute of Arthritis and Musculoskeletal and Skin Diseases) issued in January 2002 the research announcement “Identifying Functional Links between the
BIOL PSYCHIATRY 2003;54:184 –186
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Immune System and Brain Function Including Behavior” to clarify how immune mediators affect brain function and behaviors related to cognition and mood (http://grants.nih. gov/grants/guide/pa-files/PA-02– 045.html). Included are studies of how immune molecules and cells affect molecular and cellular neural processes, neuronal signaling, glial–neural interactions, neural activation, and objective behavioral end points relevant to mood, cognition, and motivation.
Treatment Development Although it is clear that depression worsens the outcome of comorbid medical illnesses, we do not have evidence to date that treating depression improves medical outcome. One of the impediments in this field has been the concern that antidepressants would complicate the medical illness, precluding the use of one of our most powerful therapeutic approaches for depression. A large trial of depressed post–myocardial infarction patients who used cognitive– behavioral therapy did not find a significant impact on mortality (NHLBI Communications Office 2001). A recent study demonstrates that a selective serotonin reuptake inhibitor (SSRI) (sertraline) can be safely given to post– myocardial infarction patients (Glassman et al 2002). Similarly, preliminary data suggest the potential utility of antidepressant treatment in preventing poststroke depression (Narushima et al 2002). It will now be important to determine whether effective treatment of depression actually improves cardiovascular outcome as well as considering whether SSRIs may have beneficial effects in these populations independent of their antidpressant effects. Conversely, we need more data to determine whether the presence of a medical illness impairs the treatment of depression. Given concerns about adverse drug– drug interactions and the exacerbation of preexisting medical conditions, clinical trials of antidepressants traditionally have excluded individuals with comorbid medical illness. Recent evidence suggests that these precautions may be unnecessary. Moreover, excluding patients with comorbid medical illnesses has limited the generalizability of trial findings to practice, where medical comorbidity is frequent. To overcome these barriers and broaden their relevance, NIMH clinical trials of depression treatment in adults and children (including the Sequenced Treatment Alternatives to Relieve Depression [STAR-D] study for those with treatment-resistant depression; the Systematic Treatment Enhancement Program for Bipolar Disorder [STEP-BD] study; and the Treatment for Adolescents with Depression Study [TADS]) now enroll participants with comorbid medical illnesses and conditions, such as diabetes, epilepsy, and obesity.
186
BIOL PSYCHIATRY 2003;54:184 –186
Services Enhancement The dangerous alliance of depression with many chronic medical illnesses makes its under-recognition and undertreatment in clinical practice particularly egregious. Both descriptive and intervention studies are underway to identify barriers to appropriate recognition and care of depression in primary care and to find ways to overcome them. One study of primary care patients scoring high for depression symptoms found that less than half (44%) were recognized as psychiatrically distressed (Callahan et al 1997). A current NIMH initiative, the Prevention Of Suicide in Primary Care Elderly Collaborative Trial (PROSPECT) is a three-site study to prevent suicide in depressed elderly patients by improving the recognition of suicidal ideation and depression in primary care practice and facilitating use of a treatment algorithm based on clinical guidelines from the Agency for Healthcare Research and Quality.
Conclusions From the NIMH perspective, the interactions between depression and nonpsychiatric illness pose a formidable research challenge that is being addressed through diverse lines of basic, clinical, epidemiologic, and services research. We are, however, at an early stage in understanding how depression arises and can best be prevented or treated in the context of general medical illness. We welcome research that can advance this knowledge base, and the opportunity to collaborate with other research entities, both within and outside NIH, to bring our combined forces to bear on a critical public health problem. Ellen Stover Wayne Fenton Anne Rosenfeld Thomas R. Insel National Institute of Mental Health National Institutes of Health 6001 Executive Boulevard, Room 6217, MSC 9621 Bethesda, MD 20892-9621
References Bejjani BP, Damier P, Arnulf I, Thivard L, Bonnet AM, Dormont D, et al (1999): Transient acute depression induced by high-frequency deep brain stimulation. N Engl J Med 340:1476 –1480.
Commentary
Callahan EJ, Bertakis KD, Azari R, Helms LJ, Robbins J, Miller J (1997): Depression in primary care: Patient factors that influence recognition. Fam Med 29:172–176. Feinstein AR (1967): Clinical Judgment. Huntington, NY: Robert E. Krieger Publishing. Glassman AH, O’Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT, et al, for the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) Group (2002): Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 288:701–709. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen H-U, et al (1994): Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: Results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8 –18. Kouzis A, Eaton WW, Leaf PJ (1995): Psychopathology and mortality in the general population. Soc Psychiatry Psychiatr Epidemiol 30:165–170. Kraemer HC (1995): Statistical issues in assessing comorbidity. Stat Med 14:721–733. Kraemer HC, Stice A, Kazdin A, Kupfer D (2001): How do risk factors work together to produce an outcome? Mediators, moderators, independent, overlapping and pseudo risk factors. Am J Psychiatry 158:848 –856. Krishnan RR, Delong M, Kraemer H, Carney R, Spiegel D, Gordon C, et al (2002): Comorbidity of depression with other medical diseases in the elderly. Biol Psychiatry 52:559 –588. Lilienfeld SO, Waldman ID, Israel AC (1994): A critical examination of the use of the term and concept of comorbidity in psychopathology research. Clin Psychol Sci Pract 1:71–83. Merikangas K, Angst J, Eaton W, Canino G, Rubio-Stipec H, Wacker H, et al (1996): Comorbidity and boundaries of affective disorders with anxiety disorders and substance abuse: Results of an international task force. Br J Psychiatry 30(suppl):68 –67. Murray JL, Lopez ADL, editors (1996): The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Cambridge, MA: Harvard University Press. Narushima K, Kosier JT, Robinson RG (2002): Preventing poststroke depression: A 12-week double-blind randomized treatment trial and 21-month follow-up. J Nerv Ment Dis 190:296 –303. National Institute of Mental Health (2002): Breaking ground, breaking through: The strategic plan for mood disorders research of the National Institute of Mental Health. Biol Psychiatry 52(6) (entire issue). NHLBI Communications Office (2001): Study finds no reduction in deaths or heart attacks in heart disease patients treated for depression and low social support. Press release dated November 12, 2001. Available at: http://www.nhlbi.nih.gov/ new/press/01–11–13.htm. Accessed April 1, 2003.
The Changing NIH Role of NIMH in Comorbidity Research The NIMH long served as the primary locus within the National Institutes of Health (NIH) for research on the behavioral and psychological aspects of all medical illness, including the study of comorbid mental and physical illness. There have been two changes at the NIH that influence funding in this area. First, in 1995, the Office of Behavioral and Social Science Research at the NIH was established to support and facilitate cross-institute efforts to broaden behavioral research. Second, restructuring of the NIH peer review process created review committees that cut across disease categories and institutes, a change © 2003 Society of Biological Psychiatry
that has strengthened the science related to health and behavior and behavioral medicine throughout the NIH. As a result, other NIH institutes have increased support of research related to comorbidity. The medical comorbidity studies NIMH supports now focus on mental illness as the dependent variable (e.g., how diabetes affects depression relapse), whereas in other NIH institutes, mental illness is studied as an independent variable affecting the diagnosis treatment, course, or outcome of specific medical illnesses of interest (e.g., how depression influences management of diabetes). Given the interdisciplinary nature of these studies, NIMH co-funds with other NIH institutes a number of comorbidity-related grants and initiatives. Overall, depression commands a substantial proportion of the NIMH research budget—17% (or $206 million) in fiscal year (FY) 2002. Whether via collaboration or through sole support, comorbidity research has increased within the NIMH extramural research budget. Between FY1999 and FY2002, funding for depression medical comorbidity research more than doubled (from $8 million to $17 million), and its share of the extramural research budget increased by 13% (NIMH data, unpublished). The National Institute of Mental Health has published a number of program announcements in this area: PAS-02–107: Basic and Translational Research on the Cognitive Sequelae of Parkinson’s Disease (http://grants.nih.gov/grants/guide/pa-files/ PAS-02–107.html); PA-02– 047: Research on Co-Morbid Mental and Other Physical Disorders (http://grants.nih. gov/grants/guide/pa-files/PA-02– 047.html); PA-00 – 109: Self-Management Strategies across Chronic Diseases (http://grants.nih.gov/grants/guide/pa-files/PA-00 – 109.html); PA-98 – 080: HIV/AIDS and the Severely Mentally Ill (http://grants.nih.gov/grants/guide/pa-files/ PA-98 – 080.html); RFA-DK-02– 009: Depression and Mental Disorders in Diabetes, Renal Disease, and Obesity/ Eating Disorders (http://grants.nih.gov/grants/guide/rfafiles/RFA-DK-02– 009.html).
Defining and Assessing Comorbidity The term “comorbidity” has many—and often confusing—meanings. It commonly refers to the co-occurrence (or dual diagnosis) of two disorders or syndromes in the same patient, regardless of whether the disorders are coincidentally or causally linked, or whether they co0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00272-5
Commentary
vary—that is, co-occur more often than expected by chance (Krishnan et al 2002; Lilienfeld et al 1994). “Comorbidity” may also refer to the epidemiologic linkage between two disorders in which one shares pathologic mechanisms with or is a risk factor for the other over time (Kraemer 1995; Krishnan et al 2002; Merikangas et al 1996). Two disorders may be “clinically comorbid” if the presence of one alters the normal course of the other (Feinstein 1967); clinical comorbidity is a common reason for excluding comorbid illness in randomized trials or stratifying based on its presence or absence (Kraemer et al 2001). The term “medical comorbidity” is used here to distinguish psychiatric–medical co-occurrence from the co-occurrence of two or more psychiatric disorders, without regard to causality.
Epidemiology Medical comorbidity research requires reliable, community-based epidemiologic data describing patterns of cooccurrence between mental disorders and medical illnesses. Also needed are longitudinal studies that identify potent and malleable risk factors that may be targets for prevention. At present, such data are scarce, and epidemiologic data on medical comorbidity are often based on relatively short-term studies of small clinical samples. To date, important insight into the adverse health consequences of mental illness has come from follow-up studies of participants in mental health epidemiology surveys (e.g., Kouzis et al 1995); however, efforts to obtain such data have been hampered by the difficulty of assessing the somatic symptoms of depression in the context of medical illness.
Pathophysiology Elucidating the links between medical illness and depression may clarify the pathophysiology of depression and suggest new approaches for its prevention and treatment. For example, it is not clear whether the excess of cardiovascular deaths in postinfarction patients with depression is due to behavioral factors (poor adherence to exercise or medication regimens), alterations in platelet function, or an increase in inflammatory factors that lead to cardiac irritability. Increasingly, we are realizing that depression is a multisystem disorder that affects immunologic, endocrine, and vascular, as well as neural, function. Given the exciting potential of research in this area, NIMH and three other NIH Institutes (National Institute of Neurologic Disease and Stroke, National Institute of Drug Abuse, National Institute of Arthritis and Musculoskeletal and Skin Diseases) issued in January 2002 the research announcement “Identifying Functional Links between the
BIOL PSYCHIATRY 2003;54:184 –186
185
Immune System and Brain Function Including Behavior” to clarify how immune mediators affect brain function and behaviors related to cognition and mood (http://grants.nih. gov/grants/guide/pa-files/PA-02– 045.html). Included are studies of how immune molecules and cells affect molecular and cellular neural processes, neuronal signaling, glial–neural interactions, neural activation, and objective behavioral end points relevant to mood, cognition, and motivation.
Treatment Development Although it is clear that depression worsens the outcome of comorbid medical illnesses, we do not have evidence to date that treating depression improves medical outcome. One of the impediments in this field has been the concern that antidepressants would complicate the medical illness, precluding the use of one of our most powerful therapeutic approaches for depression. A large trial of depressed post–myocardial infarction patients who used cognitive– behavioral therapy did not find a significant impact on mortality (NHLBI Communications Office 2001). A recent study demonstrates that a selective serotonin reuptake inhibitor (SSRI) (sertraline) can be safely given to post– myocardial infarction patients (Glassman et al 2002). Similarly, preliminary data suggest the potential utility of antidepressant treatment in preventing poststroke depression (Narushima et al 2002). It will now be important to determine whether effective treatment of depression actually improves cardiovascular outcome as well as considering whether SSRIs may have beneficial effects in these populations independent of their antidpressant effects. Conversely, we need more data to determine whether the presence of a medical illness impairs the treatment of depression. Given concerns about adverse drug– drug interactions and the exacerbation of preexisting medical conditions, clinical trials of antidepressants traditionally have excluded individuals with comorbid medical illness. Recent evidence suggests that these precautions may be unnecessary. Moreover, excluding patients with comorbid medical illnesses has limited the generalizability of trial findings to practice, where medical comorbidity is frequent. To overcome these barriers and broaden their relevance, NIMH clinical trials of depression treatment in adults and children (including the Sequenced Treatment Alternatives to Relieve Depression [STAR-D] study for those with treatment-resistant depression; the Systematic Treatment Enhancement Program for Bipolar Disorder [STEP-BD] study; and the Treatment for Adolescents with Depression Study [TADS]) now enroll participants with comorbid medical illnesses and conditions, such as diabetes, epilepsy, and obesity.
186
BIOL PSYCHIATRY 2003;54:184 –186
Services Enhancement The dangerous alliance of depression with many chronic medical illnesses makes its under-recognition and undertreatment in clinical practice particularly egregious. Both descriptive and intervention studies are underway to identify barriers to appropriate recognition and care of depression in primary care and to find ways to overcome them. One study of primary care patients scoring high for depression symptoms found that less than half (44%) were recognized as psychiatrically distressed (Callahan et al 1997). A current NIMH initiative, the Prevention Of Suicide in Primary Care Elderly Collaborative Trial (PROSPECT) is a three-site study to prevent suicide in depressed elderly patients by improving the recognition of suicidal ideation and depression in primary care practice and facilitating use of a treatment algorithm based on clinical guidelines from the Agency for Healthcare Research and Quality.
Conclusions From the NIMH perspective, the interactions between depression and nonpsychiatric illness pose a formidable research challenge that is being addressed through diverse lines of basic, clinical, epidemiologic, and services research. We are, however, at an early stage in understanding how depression arises and can best be prevented or treated in the context of general medical illness. We welcome research that can advance this knowledge base, and the opportunity to collaborate with other research entities, both within and outside NIH, to bring our combined forces to bear on a critical public health problem. Ellen Stover Wayne Fenton Anne Rosenfeld Thomas R. Insel National Institute of Mental Health National Institutes of Health 6001 Executive Boulevard, Room 6217, MSC 9621 Bethesda, MD 20892-9621
References Bejjani BP, Damier P, Arnulf I, Thivard L, Bonnet AM, Dormont D, et al (1999): Transient acute depression induced by high-frequency deep brain stimulation. N Engl J Med 340:1476 –1480.
Commentary
Callahan EJ, Bertakis KD, Azari R, Helms LJ, Robbins J, Miller J (1997): Depression in primary care: Patient factors that influence recognition. Fam Med 29:172–176. Feinstein AR (1967): Clinical Judgment. Huntington, NY: Robert E. Krieger Publishing. Glassman AH, O’Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT, et al, for the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) Group (2002): Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 288:701–709. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen H-U, et al (1994): Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: Results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8 –18. Kouzis A, Eaton WW, Leaf PJ (1995): Psychopathology and mortality in the general population. Soc Psychiatry Psychiatr Epidemiol 30:165–170. Kraemer HC (1995): Statistical issues in assessing comorbidity. Stat Med 14:721–733. Kraemer HC, Stice A, Kazdin A, Kupfer D (2001): How do risk factors work together to produce an outcome? Mediators, moderators, independent, overlapping and pseudo risk factors. Am J Psychiatry 158:848 –856. Krishnan RR, Delong M, Kraemer H, Carney R, Spiegel D, Gordon C, et al (2002): Comorbidity of depression with other medical diseases in the elderly. Biol Psychiatry 52:559 –588. Lilienfeld SO, Waldman ID, Israel AC (1994): A critical examination of the use of the term and concept of comorbidity in psychopathology research. Clin Psychol Sci Pract 1:71–83. Merikangas K, Angst J, Eaton W, Canino G, Rubio-Stipec H, Wacker H, et al (1996): Comorbidity and boundaries of affective disorders with anxiety disorders and substance abuse: Results of an international task force. Br J Psychiatry 30(suppl):68 –67. Murray JL, Lopez ADL, editors (1996): The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Cambridge, MA: Harvard University Press. Narushima K, Kosier JT, Robinson RG (2002): Preventing poststroke depression: A 12-week double-blind randomized treatment trial and 21-month follow-up. J Nerv Ment Dis 190:296 –303. National Institute of Mental Health (2002): Breaking ground, breaking through: The strategic plan for mood disorders research of the National Institute of Mental Health. Biol Psychiatry 52(6) (entire issue). NHLBI Communications Office (2001): Study finds no reduction in deaths or heart attacks in heart disease patients treated for depression and low social support. Press release dated November 12, 2001. Available at: http://www.nhlbi.nih.gov/ new/press/01–11–13.htm. Accessed April 1, 2003.