Cardiovascular Risk Factors May Moderate Pharmacological Treatment Effects in Major Depressive Disorder DAN V. IOSIFESCU, MD, NICOLETTA CLEMENTI-CRAVEN, MD, RENERIO FRAGUAS, MD, PHD, GEORGE I. PAPAKOSTAS, MD, TIMOTHY PETERSEN,PHD, JONATHAN E. ALPERT, MD, ANDREW A. NIERENBERG, MD, AND MAURIZIO FAVA, MD Objective: An increased association between depression and cardiovascular disease, as well as cardiovascular risk factors, led to the “vascular depression” hypothesis. This subtype of depression is postulated to have a different clinical presentation and to be more treatment-resistant. In this study, we measured the impact of cardiovascular risk factors on the outcome of antidepressant treatment in major depressive disorder (MDD). Method: We enrolled 348 MDD subjects, ages 19 to 65 years, in an 8-week treatment study with 20 mg fluoxetine per day. We recorded for each subject 6 cardiovascular risk factors: age (male 45, female 55), smoking, family history, hypertension, diabetes, hypercholesterolemia; and we defined a cardiovascular risk score (range, 0 – 6) by the number of risk factors present. Treatment outcome was measured as response (50% improvement on the 17-item Hamilton Rating Scale for Depression [Ham-D-17]) and remission (final Ham-D-177). Results: In logistic regression analyses, the cardiovascular risk score was significantly associated with treatment nonresponse and lack of remission when adjusting for age of onset of MDD and baseline severity of depression. The cardiovascular risk score remained significantly associated with treatment nonresponse when we additionally controlled for overall medical burden (measured with the Cumulative Illness Rating Scale). Among individual cardiovascular risk factors, elevated total cholesterol was a significant predictor of treatment nonresponse and lack of remission. Conclusion: Cardiovascular risk factors may have negative effects on the course of treatment in MDD. These results support the concept of “vascular depression” in younger subjects. Key words: major depressive disorder, treatment outcome, cardiovascular risk factors. MDD = major depressive disorder; Ham-D-17 = the 17-item Ham- ilton Rating Scale for Depression. INTRODUCTION R ecognition of the relationship between vascular disease and major depressive disorder has led investigators to describe “vascular depression,” a subtype of major depressive disorder (MDD) characterized by the presence of cerebrovas- cular disease (1,2). Indeed, multiple studies have shown high rates of depression associated with vascular disease, including myocardial infarction (3– 6), coronary artery disease (7), ca- rotid atherosclerosis (8), and stroke (6,9 –11). Moreover, high rates of depression have been reported in association with the total burden of vascular risk factors (12) and in relation to individual vascular risk factors such as hypertension (13,14), smoking (15,16), and diabetes (17,18). Although low cholesterol levels have been reported in MDD subjects (19,20), in several studies, hypercholesterolemia, a risk factor for cardiovascular disease, was associated with poor outcome of antidepressant treatment in MDD (21–23). In contrast, several other studies have reported no association between vascular risk factors and depression (24,25). The concept of “vascular depression” postulates that vas- cular disease predisposes, precipitates, or perpetuates a de- pressive syndrome, having a negative impact on treatment outcome (1,2). Few studies have assessed, however, the im- pact of cardiovascular risk factors on treatment outcome in MDD, and the results have been contradictory. Poor long-term outcome of depressive symptoms has been associated with cumulated vascular risk factors (26,27); low rates of remission in an 8-week treatment with citalopram were also predicted by the burden of cardiac disease (28). In contrast, Miller et al. (29) found no correlation among cerebrovascular risk score, time to remission of depressive symptoms, and risk for de- pressive recurrence during a 3-year follow up. Although most previous results have been described in geriatric populations, we have previously reported (30) in younger depressed subjects that cardiovascular risk factors were related to brain white matter lesions, which in turn were associated with treatment outcome. The current study is, to our knowledge, the first one to explore the impact of cardio- vascular risk factors on antidepressant treatment outcome in a group of younger subjects with MDD. We hypothe- sized that higher burden of cardiovascular risk factors at intake will be associated with lower rates of treatment response and remission. METHODS Three hundred forty-eight subjects between ages of 18 and 65 years (192 females, 55.2%) were recruited through advertisements and clinical referrals in the first phase of open-label fluoxetine treatment of a clinical study conducted at the Depression Clinical and Research Program at Massachusetts General Hospital between 1992 and 1999 (31). Written informed consent was obtained from all study participants. All subjects met criteria for MDD, diagnosed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised (DSM-III-R) Axis I Disorders–Patient Edition (SCID-P) (32). Subjects were required to have a score of 16 or greater on the modified 17-item Hamilton Rating Scale for Depression (Ham-D-17) (33) at the screen and baseline visits. The exclusion criteria for this study were: bipolar disorder; psychotic disorders; a history of organic mental or seizure disorder; serious or unstable medical illness; substance abuse or dependence disorders active within the past 12 months; acute suicidal risk; pregnancy; lactation; history of adverse reaction or allergy to the study medications; concomitant use of psychotropic medications; clinical or laboratory evidence of thyroid abnormalities; history From the Depression Clinical and Research Program, Massachusetts Gen- eral Hospital, Harvard Medical School, Boston, Massachusetts. Address correspondence and reprint requests to Dan V. Iosifescu, MD, Massachusetts General Hospital, 50 Staniford Street, suite 401, Boston, MA 02114. E-mail: diosifescu@partners.org Received for publication November 20, 2004; revision received March 21, 2005. This study was supported by NIMH grants R01-MH48483 (Dr. Fava) and K23 MH 067111 (Dr. Iosifescu). These results were presented in part at the American Psychiatric Association 156th Annual Meeting, San Francisco, California, May 2003, and at the Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting, Boca Raton, Florida, June 2003. DOI: 10.1097/01.psy.0000170338.75346.d0 703 Psychosomatic Medicine 67:703–706 (2005) 0033-3174/05/6705-0703 Copyright © 2005 by the American Psychosomatic Society