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Psychosomatic Medicine 67:703-706 (2005)
© 2005 American Psychosomatic Society

ORIGINAL ARTICLES

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

From the Depression Clinical and Research Program, Massachusetts General 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{at}partners.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
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

Abbreviations: MDD = major depressive disorder; Ham-D-17 = the 17-item Hamilton Rating Scale for Depression.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Recognition 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 cerebrovascular 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), carotid 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 vascular disease predisposes, precipitates, or perpetuates a depressive syndrome, having a negative impact on treatment outcome (1,2). Few studies have assessed, however, the impact 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 depressive 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 cardiovascular risk factors on antidepressant treatment outcome in a group of younger subjects with MDD. We hypothesized that higher burden of cardiovascular risk factors at intake will be associated with lower rates of treatment response and remission.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
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 of treatment resistance to fluoxetine, desipramine, and lithium; and subjects who failed to respond during the current episode of MDD to at least 1 adequate antidepressant trial.

We assessed for each subject 6 cardiovascular risk factors, following the National Institutes of Health NIH ATP III guidelines (34,35): 1) age: male >45 years old, female >55 years old; 2) active smoking status (defined as regular use during the previous 12 months), smokers in our study used on average 20.0 (standard deviation [SD] 13.9) cigarettes per day and had a 17.9 (SD 11.6)-year smoking history; 3) family history of premature vascular disease (e.g., myocardial infarction, stroke) in male first-degree relatives <55 years old and in female first-degree relatives <65 years old; 4) arterial hypertension (blood pressure >140/90 mm Hg or on antihypertensive medications); 5) diabetes mellitus; and 6) hypercholesterolemia: total cholesterol >200 mg/dL. We calculated a cardiovascular risk score (range, 0–6) by assigning a point for each of the 6 cardiovascular risk factors. We also used the Cumulative Illness Rating Scale (36,37) to rate the overall burden of comorbid medical illness for all subjects.

The Ham-D-17 was administered 6 times during the study (at screen, baseline, then every other week). We measured clinical outcome as response to treatment (defined as ≥50% reduction of Ham-D-17 scores from baseline to end of trial) and remission (defined as Ham-D-17 score ≤7 at the end of the trial).

We performed all analyses on subjects completing the 8-week treatment (completer analyses). We also report secondary analyses using the last observation carried forward (LOCF) method, in which we included all subjects who took at least 1 week of study medication and had at least 1 postbaseline efficacy assessment. We performed 2 logistic regression analyses for each of the outcome measures (response and remission). For the first logistic regression, dependent variables were response (then remission) and the covariates were the cardiovascular risk score (range, 0–6), age of onset of MDD, and baseline severity of depression (Ham-D-17 score). For the second logistic regression, dependent variables were response (then remission) and the covariates were the 6 cardiovascular risk factors (age and gender, hypertension, family history, smoking, diabetes, hypercholesterolemia), age of onset of MDD, and baseline severity of depression (Ham-D-17 score). Odds ratios, with 95% confidence intervals, were computed using parameter estimates from the logistic regression models.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Of 348 patients, 192 (55.2%) were female. The mean age was 39.8 years (SD 10.6). Ninety-nine subjects (28.4%) had no cardiovascular risk factors. The mean cardiovascular risk score (sum of cardiovascular risk factors; range, 0–6) was 1.49 (SD 1.34). Two hundred eighty-eight subjects (82.8%) completed 8 weeks of treatment with fluoxetine. Table 1 presents the clinical characteristics of our patient sample and the distribution of those characteristics by cardiovascular risk score.


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  		TABLE 1. Demographic and Clinical Characteristics of Patients With Different Cardiovascular Risk Scores

 

In logistic regression analyses, the cardiovascular risk score was significantly correlated with lack of treatment response (logistic regression, coefficient = 0.24, {chi}2 = 5.39, df = 3, p = .02) and with lack of remission (logistic regression, coefficient = 0.23, {chi}2 = 4.88, df = 3, p < .03) when adjusting for age of onset of MDD and baseline severity of depression (see Table 2). For predicting lack of response, the odds ratio was 1.32 (95% confidence interval [CI], 1.06–1.64); and for lack of remission, the odds ratio was 1.24 (95% CI, 1.01–1.53). When we additionally controlled for the burden of medical illness (the Cumulative Illness Rating Scale score), the cardiovascular risk score remained associated with lack of treatment response (logistic regression, coefficient = 0.24, {chi}2 = 5.05, df = 4, p < .03) and with lack of remission (logistic regression, coefficient = 0.23, {chi}2 = 4.65, df = 4, p < .04).


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  		TABLE 2. Correlations Between Treatment Outcome (Response and Remission) and Cardiovascular Risk Factors

 

Hypercholesterolemia was associated with decreased treatment response (logistic regression, coefficient = 0.46, {chi}2 = 7.84, df = 8, p < .01) and with decreased remission (logistic regression, coefficient = 0.47, {chi}2 = 8.15, df = 8, p < .01), in a logistic regression model controlling for all other cardiovascular risk factors, age of onset of MDD, and baseline severity of depression. None of the other cardiovascular risk factors (age, smoking, family history, hypertension, diabetes) were significantly associated with treatment outcome (p > .05 for all analyses, see Table 2).

We obtained similar results when analyzing the data with LOCF (i.e., we included all subjects who took at least 1 week of study medication and had at least 1 postbaseline efficacy assessment). The cardiovascular risk score was significantly correlated with lack of treatment response (logistic regression, coefficient = 0.204, {chi}2 = 4.29, df = 3, p < .04) and with lack of remission (logistic regression, coefficient = 0.35, {chi}2 = 7.30, df = 3, p < .01) when adjusting for age of onset of MDD and baseline severity of depression. In the multivariate logistic regression, which included all cardiovascular risk factors, lack of treatment response correlated with hypercholesterolemia (logistic regression, coefficient = 0.38, {chi}2 = 6.42, df = 8, p < .02), and lack of remission correlated with hypercholesterolemia (logistic regression, coefficient = 0.36, {chi}2 = 5.58, df = 8, p < .02) and with smoking (logistic regression, coefficient = 0.55, {chi}2 = 4.63, df = 8, p < .04).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
Based on our data, the cardiovascular risk score (which sums the number of cardiovascular risk factors) is significantly associated with lack of response to fluoxetine treatment and to lack of remission. This is, to our knowledge, the first study to demonstrate an impact of vascular risk factors on the outcome of acute antidepressant treatment in MDD. As suggested by the "vascular depression" model, the effect of vascular risk factors on depressive symptoms is possibly related to early vascular brain pathology (2,30).

Our data are consistent with the study of Alexopoulos and coworkers (28), in which low rates of remission in an 8-week treatment with citalopram were predicted by the burden of cardiac disease (measured with CIRS). Our results are also in agreement with Lyness et al. (26), who reported that cumulated vascular risk factors were predictive of persistent depression at 1-year follow up. However, in our study, the association between depression outcome and cerebrovascular risk factors remained statistically significant when controlling for the overall burden of medical illness (CIRS scores), contrary to the results of Lyness et al. (26). Our results are not consistent with the study of Miller and coworkers (29), in which cerebrovascular risk factors did not predict time to depressive remission in the acute treatment or risk of MDD recurrence during a 3-year follow up. Compared with Miller et al. (29), we studied a larger group of MDD subjects (N = 348 versus N = 156), which may give our study greater statistical power to demonstrate a difference.

Although in our study the cardiovascular risk score was significantly associated with treatment nonresponse and lack of remission, this association appears to account for only 8% to 10% of the variance. Moreover, our Table 1 suggests that the impact of vascular factors on depression treatment applies primarily to a subset of depressed subjects with high levels of vascular risk (scores 5 and 6 on our scale). This may also explain the inconsistent findings in the literature reviewed here, because studies that did not include subjects with high levels of vascular risk may not have been able to detect an association with treatment outcome.

We found hypercholesterolemia was associated with lack of antidepressant response and remission. Although low cholesterol levels have been reported in MDD subjects (19,20), several previous studies in our group have shown hypercholesterolemia to be associated with poor treatment outcome in MDD with different classes of antidepressants: selective serotonin reuptake inhibitors (21,23) and nortriptyline (22). Our current results are consistent with these previous reports (21–23).

Our current results support the concept of "vascular depression" in younger MDD subjects. However, hypercholesterolemia may also decrease the fluidity of cell membranes and membrane permeability (38), with changes in second messenger systems and in neurotransmission (39) which may explain the associations with lack of antidepressant response in MDD.

Several limitations in the current study should be recognized. First, although we used cardiovascular risk factors defined by the National Institutes of Health NIH ATP III guidelines (34,35), our cumulated cardiovascular risk score (the number of risk factors present) has not been used as such in the literature. We do not know if each cardiovascular risk factor should be given equal weight (like in our score) or if certain cardiovascular risk factors should be given more weight in calculating the impact on treatment outcome in MDD. Second, only 10% of MDD subjects in our study had 4 or more cardiovascular risk factors; our data represents primarily subjects with lower levels of cardiovascular risk. Third, because we measured only total cholesterol (and not fractions of cholesterol), it is possible our results do not reflect the full impact of this cardiovascular risk factor. Other cardiovascular risk factors, not measured in this study (e.g., C-reactive protein), may also play a role in the outcome of antidepressant treatment in MDD. Lastly, because our results compare response rates on a fixed dose of fluoxetine (20 mg), we cannot exclude that subjects with cardiovascular risk factors would experience increased response rates at higher doses of fluoxetine.

Despite these limitations, this study demonstrates a significant association between cardiovascular risk factors and poor outcome of antidepressant treatment in nongeriatric MDD subjects. Our results support the concept of "vascular depression" in younger subjects with MDD and have clear clinical implications: MDD subjects with greater vascular burden appear to be a more vulnerable group, prone to higher rates of treatment resistance and requiring closer clinical monitoring and more intensive antidepressant treatment.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 

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


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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