Psychosomatics 45:419-425, October 2004
© 2004 The Academy of Psychosomatic Medicine
Comorbid Medical Illness and Relapse of Major Depressive Disorder in the Continuation Phase of Treatment
Dan V. Iosifescu, M.D.,
Andrew A. Nierenberg, M.D.,
Jonathan E. Alpert, M.D.,
George I. Papakostas, M.D.,
Roy H. Perlis, M.D.,
Shamsah Sonawalla, M.D., and
Maurizio Fava, M.D.
Received June 16, 2003; revision received Dec. 24, 2003; accepted Jan. 30, 2004. From the Depression Clinical and Research Program, Psychiatry Department, Massachusetts General Hospital and Harvard Medical School. Address reprint requests to Dr. Iosifescu, Massachusetts General Hospital, 50 Staniford St., Suite 401, Boston, MA 02114; diosifescu{at}partners.org (e-mail).
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ABSTRACT
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The authors examined the impact of comorbid medical illness on the rate of relapse of major depressive disorder during continuation therapy. Subjects (N=128) with major depressive disorder (according to DSM-III-R criteria) achieved clinical remission (a 17-item Hamilton Depression Rating Scale score  7) after 8 weeks of treatment with fluoxetine and entered the continuation phase of antidepressant treatment. They used the Cumulative Illness Rating Scale to measure the severity of comorbid medical illness. Eight patients (6.3%) relapsed during the 28-week continuation phase. With logistic regression, the total burden and the severity of comorbid medical illness significantly predicted the relapse of major depressive disorder during continuation therapy with fluoxetine. Greater medical comorbidity was also associated with higher increases in self-reported symptoms of depression, anxiety, and anger during the follow-up.
Key Words: depression • antidepressants
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INTRODUCTION
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The presence of comorbid medical illness has been associated with a higher prevalence of major depressive disorder.1–3 Other investigators found that comorbid medical illness is a risk factor for depression.4–6 Medically ill patients with major depressive disorder appear to be at greater risk for a chronic course of depression or less complete recovery.7–9
Worse depression outcomes and lower rates of response to antidepressant treatment have been reported in the acute treatment of subjects with major depressive disorder and medical comorbidity compared with subjects with major depressive disorder with no medical comorbidity.8,10–13 However, few studies have measured the long-term impact of medical comorbidity on the treatment outcome of depressed individuals, and the reported results have been contradictory.14,15
In the present study, we examined the effect of general medical illness on treatment outcome among patients who responded to an initial treatment with fluoxetine, 20 mg for 8 weeks.16 We hypothesized that subjects with medical comorbidity will experience higher rates of relapse of major depressive disorder and more severe symptoms of depression during the continuation treatment phase of major depressive disorder.
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METHOD
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Subjects (N=128) between the ages of 18 and 65 enrolled in a 28-week continuation treatment study with fluoxetine, 40 mg/day. Before entering this study, all subjects had met criteria for major depressive disorder, diagnosed by the physician-administered Structured Clinical Interview for DSM-III-R Axis I Disorders—Patient Edition (SCID-P)17 and had achieved clinical remission18 (defined as a Hamilton Rating Scale for Depression19 score 7) after an 8-week acute treatment with fluoxetine, 20 mg/day. Written informed consent was obtained from all study participants.
The exclusion criteria for this study were the following: women of childbearing potential who were not using a medically accepted means of contraception (i.e., an intrauterine device or a barrier device but not birth control pills); women who were lactating or pregnant; those at serious suicide risk; those with serious medical illness that was not stabilized, such as hospitalization for treatment of an illness that was likely within the next 2 weeks; seizure disorder; a history of organic mental disorders; substance use disorders, including alcohol, that were active within the last year; schizophrenia; delusional disorder; psychotic disorders not otherwise specified; bipolar disorder; mood congruent or incongruent psychotic features; antisocial personality disorder; history of multiple adverse drug reactions or allergy to fluoxetine; concurrent use of psychotropic drugs; hypothyroidism; and subjects who failed to respond during the current episode of major depressive disorder to at least one adequate antidepressant trial (e.g., 6 weeks or more of treatment with fluoxetine  60 mg/day, imipramine 150 mg/day, or a monoamine oxidase inhibitor 60 mg/day).
At the screening visit, the study physicians generated for each subject (meeting DSM-III-R criteria for major depression) a list of all existing and past medical illnesses, detailed by organ systems, and a list of current and past treatments. Each subject underwent physical examinations and screening laboratory tests. The results of these procedures and any subsequent medical workup were also incorporated into the list of medical illness. A trained physician (D.V.I.) reviewed the charts of all patients enrolled in the trial and was blind to treatment outcome and assigned a score on the Cumulative Illness Rating Scale (CIRS).20,21 The CIRS measures the total burden and the severity of comorbid medical illness for each patient. The CIRS classifies comorbid illnesses by 14 organ systems affected and rates them according to their severity from 0 to 4. Within each category, when two diseases are present, the disease with the highest score is counted. A score of 0 represents "no problem," 1 represents "current mild or past significant problem," 2 means "moderate disability requiring first-line treatment, 3 is "uncontrollable chronic problems or significant disability," and 4 is "end-organ failure requiring immediate treatment." For this study, we rated only 13 organ systems (mental health was excluded). We never assigned a score of 4, since the presence of severe/emergent medical conditions was an exclusion criterion. We generated for each patient four ratings, according to the instructions of the CIRS scale: total score, number of categories endorsed, severity index (total score/number of categories endorsed), and number of categories at level 3. Because we only used one rater for CIRS scoring, we did not compute interrater reliability.
Follow-up study visits occurred every 4 weeks. The 31-item Hamilton depression scale was administered during all study visits. At entry and exit from the study, we also administered the Kellner's Symptom Questionnaire.22 This is a 92-item self-rating instrument with scales for depression, anxiety, somatization, and anger, as well as contentment, friendliness, relaxation, and somatic well-being.
The clinical outcome measured was depressive relapse, defined as meeting criteria for a new episode of major depressive disorder at any continuation visit, or Hamilton depression scale score 15 at two consecutive visits. Relapse was confirmed by a follow-up visit 1 week later with another clinician. All subjects who took at least 1 week of study medication and had at least two study visits were included in the statistical analysis, with the last observation carried forward.
Logistic regression was used to assess the relationship between relapse of major depressive disorder and the four CIRS scores. The logistic regression was adjusted for age, gender, length of current episode, number of previous episodes, and baseline Hamilton depression rating scale score. The threshold for statistical significance was set at p<0.05. Odds ratios, with 95% confidence intervals, were computed by using parameter estimates from the logistic regression models.
We used simple linear regression to evaluate the relationship between the four CIRS scores and the secondary outcomes (including change in Hamilton depression scale and Kellner's Symptom Questionnaire scale and subscale scores). The linear regression was adjusted for age, gender, length of current episode, number of previous episodes, and baseline Hamilton depression scale score.
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RESULTS
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Of 128 patients, 69 (53.9%) were women. The mean age was 40.4 (SD=10.3) years old. The mean total CIRS score was 1.59 (SD=1.67). The mean number of endorsed categories of medical comorbidity (CIRS) was 1.41 (SD= 1.35). The mean CIRS severity index for this population was 0.76 (SD=0.58). Eight subjects (6.3%) relapsed with a new episode of major depressive disorder during the continuation phase of this study. The number of subjects who relapsed was low, presumably related to the higher fluoxetine dosing in the continuation phase (40 mg, after clinical response was obtained at 20 mg in the acute phase). Table 1 presents the clinical characteristics of our patient group, and the distribution of those characteristics by burden of medical illnesses (CIRS score).
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TABLE 1. Clinical Characteristics of Groups of Depressed Patients With Different Scores on the Cumulative Illness Rating Scale (CIRS)
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The relapse of depressive symptoms during the continuation phase was significantly correlated with the total burden of medical illness (Table 2) (logistic regression of total CIRS score; i.e., there was a 102% increase in the chance of depressive relapse for each additional point on the total burden of disease CIRS score). The relapse of depressive symptoms during the continuation phase was also significantly correlated with the severity of medical illness (logistic regression of CIRS severity score; i.e., there was a 400% increase in the chance of depressive relapse for each additional point on the CIRS severity score). There was also nearly statistical significance in the correlation between relapse of depressive symptoms and the number of organ systems involved by medical illness.
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TABLE 2. Logistic Regression for Prediction of Nonrelapse of Depression, Adjusted for Age, Gender, Length of Current Episode, Number of Previous Episodes, and Baseline Hamilton Depression Scale Score
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Among patients enrolled in the continuation phase, only one subject had a comorbid medical illness rated as 3, i.e., "uncontrollable chronic problems or significant disability," and that patient experienced a depressive relapse during the continuation phase. Because only one patient was present in this group, no statistical analyses are presented for "number of CIRS categories scored 3."
Relapse is a discrete event and does not capture the changes in depressive symptoms experienced by the majority of subjects, who did not relapse. Those changes can be better described with clinician-rated (Hamilton depression rating scale) and self-rated (Kellner's Symptom Questionnaire) instruments assessing depressive symptoms (Table 3 and Table 4). The final Hamilton depression rating scale score was directly correlated with the total CIRS score (linear regression: coefficient=0.45; t=2.00, df=7, p=0.04) and the mean severity of medical illness (linear regression of CIRS severity score: coefficient=1.33; t=2.22, df=7, p=0.03). The increase in Hamilton depression scale score during the continuation phase was also directly correlated with the total CIRS score (linear regression: coefficient=0.62; t=2.74, df=7, p<0.01) and the number of organ systems involved by medical illness (linear regression of number of CIRS categories: coefficient=0.59; t=2.07, df=7, p=0.04). In both linear regressions, the covariates were age, gender, length of current episode, number of previous episodes, and baseline Hamilton depression scale score.
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TABLE 3. Linear Regression for the Association of Medical Comorbidity Scores With Final Scores and Increases in 17-Item Hamilton Depression Scale Scores During the Continuation Phase of Treatmenta
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TABLE 4. Linear Regression for the Association Between Medical Comorbidity Scores and Increases in Self-Reported Symptoms in Depressed Patients
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The increase in self-reported depression (Kellner's Symptom Questionnaire, depression subscale score) during continuation treatment was directly correlated with the total CIRS score (linear regression: coefficient=1.05; t=3.13, df=7, p<0.01), the number of organ systems involved by medical illness (linear regression of number of CIRS categories: coefficient=0.925: t=2.17, df=7, p<0.04), and with the mean severity of medical illness (linear regression of CIRS severity score: coefficient=2.63: t=2.83, df=7, p<0.01). The increase in the self-reported anxiety (Kellner's Symptom Questionnaire) during continuation treatment was directly correlated with the total CIRS score (linear regression: coefficient=0.65; t=2.34, df=7, p=0.02) and with the mean severity of medical illness (linear regression of CIRS severity score: coefficient=1.79; t=2.37, df=7, p<0.02). Moreover, the increase in the self-reported anger and hostility (Kellner's Symptom Questionnaire) during continuation treatment was also correlated with the total CIRS score (linear regression: coefficient=0.61; t=2.21, df=7, p<0.03). For all linear regressions, the covariates were age, gender, length of current episode, number of previous episodes, and baseline Hamilton depression scale score.
Thirty-eight subjects (29.7%) discontinued the study for reasons other than depressive relapse. The reasons for discontinuation were treatment noncompliance (13 subjects, 10.2%), loss to follow-up (eight subjects, 6.3%), medication side effects (six subjects, 4.7%), moved out of the area (three subjects, 2.3%), time commitment and scheduling difficulties (three subjects, 2.3%), needed exclusionary treatments (two subjects, 1.6%), pregnancy (two subjects, 1.6%), paranoia (one subject, 0.8%). No statistically significant correlation was found between medical comorbidity scores and discontinuation from the study for causes other than depressive relapse (p>0.05 for all analyses).
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DISCUSSION
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In the continuation phase of antidepressant treatment, the total burden of comorbid medical illness (total CIRS score) and the severity of medical illness (CIRS severity index) were statistically significant predictors of depressive relapse. Also, higher CIRS scores were also significantly related to higher endpoint Hamilton depression scale scores, to increases in Hamilton depression scale scores, and to increases in self-reported Kellner's Symptom Questionnaire symptoms for depression, anxiety, and anger/hostility during continuation treatment. These are important results, demonstrating that comorbid medical illness can have a significant negative impact on the outcome of continuation treatment in major depressive disorder.
Our results appear robust, as objective (Hamilton depression scale) and subjective (Kellner's Symptom Questionnaire) measurements of depressive symptoms, as well as rates of depressive relapse, are independently correlated with medical comorbidity scores. An alternative hypothesis to explain our results, that medically ill subjects have more difficulty complying with a 7-month study and drop out selectively, is not supported by our data. The rates of discontinuation from our study, from causes other than depressive relapse, were not statistically correlated with medical comorbidity scores.
Our findings suggest that the total burden and severity of medical disease are predictors of depressive relapse rates in the continuation phase of treatment in major depression. This finding is consistent with other longitudinal studies in the literature reporting that medically ill patients with major depressive disorder may be at greater risk for a chronic course of depression and for depressive relapse.7–9
Koike et al.15 studied a sample of 1,356 subjects with major depression, dysthymia, and subthreshold depression. The presence of chronic medical conditions increased significantly the presence of depressive disorders at the 6-month follow-up (47% versus 30% in patients with no comorbid medical disorder; p=0.01). The same difference was observed at the 12-month follow-up (49% rates of depressive disorders in subjects with medical comorbidity versus 32% in subjects with no comorbid medical disorder; p<0.001).
However, other studies are not consistent with our findings. Alexopoulos and collaborators14 used the CIRS to assess medical comorbidity in 58 elderly subjects who responded to acute treatment with nortryptyline (mean CIRS score=4.7). In their study, the burden of medical illness did not correlate with the rates of depressive relapse in the continuation phase. The smaller sample size (N=57 in the study by Alexopoulos et al.,14 N=128 in our study) may explain the lack of statistical association between the burden of medical illness and depressive relapse. Since the study by Alexopoulos et al.14 included elderly subjects with cognitive dysfunction and cognitive dysfunction (primarily in executive functions) was associated with depressive relapse, it is also possible that the effect of medical comorbidity was masked by the patients' cognitive deficits.
For the present study, we used fluoxetine, a selective serotonin reuptake inhibitor with reported efficacy in preventing depressive relapse.23 Our study design also involved increasing the dose of fluoxetine in the continuation phase from 20 mg (on which subjects had achieved response in the acute phase) to 40 mg/day. We may have minimized the rates of depressive relapse in our study group related to inadequate dosing, thus emphasizing the role of other factors with impact on relapse, such as comorbid medical illness.
There are several hypotheses attempting to explain the mechanism by which medical illness affects clinical response in major depressive disorder and depressive relapse. Ciechanowski et al.24 postulated that the relationship between medical illness and depressive symptoms may be mediated by factors such as self-care, nutrition, and adherence to treatment. Comorbid medical illness or concurrent medications may induce changes in pharmacokinetic or pharmacodynamic properties of antidepressants.25 This hypothesis may not be significant in our study, where the severity of medical illness and the rates of concomitant medications were small.
Another hypothesis involves the direct role of medical illness on brain structures involved in mood regulation. Most chronic medical illnesses result in activation of the immune system and significant increases in levels of cytokines, nonantibody proteins released by cells on contact with antigens. The administration of cytokines, such as interleukin 2, tumor necrosis factor, or interferon alpha, may induce depressive symptoms.26 Also, antidepressants have been shown to reduce the immune response and suppress cytokine production.27 However, there is as yet no proven association between immune response, cytokine production, and major depressive disorder relapse.
A limitation of our study is the low burden of comorbid medical illness (total CIRS score, 1.59 [SD=1.67]) and the mild to moderate severity of medical illness (CIRS severity, 0.76 [SD=0.58]) in our study population. Only one subject had a medical illness of severity 3 (i.e., "uncontrollable chronic problems or significant disability"). Our results cannot be directly generalized to populations of severely medically ill subjects. However, more severe medical comorbid illness will likely have an increased impact on depressive symptoms. Therefore, our results, found in a population with lower severity of medical illness, are likely to remain valid in the presence of more severe medical disease.
Another limitation of our study may be related to the use of CIRS. CIRS has been largely used in clinical series to rate medical comorbidity, and it has a good interrater and very good test-retest reliability.28 CIRS has also been used previously14,29 to measure the burden of medical illness in depressed subjects. However, we do not know if all comorbid diseases have given equal impact on depressive symptoms (as in the CIRS) or if certain diseases should be given more weight in calculating the burden of medical disease on depressive symptoms.
In conclusion, the total burden and the severity of comorbid medical illness significantly predict depressive relapse and are associated with higher increases of depressive, anxiety, and anger/hostility symptoms during continuation therapy with fluoxetine in major depressive disorder. Further studies will be needed to elucidate the complex relationship between comorbid medical illness and the outcome of treatment in major depressive disorder.
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ACKNOWLEDGMENTS
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Presented in part at the 155th annual meeting of the American Psychiatric Association, Philadelphia, May 18–23, 2002.
Supported by NIMH grant R01-MH48483 (to Dr. Fava) and by the Clinical Investigator Training Program from Harvard/MIT Division of Health Sciences and Technology, in collaboration with Pfizer, Inc. (Dr. Iosifescu).
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ABSTRACT
INTRODUCTION
