Psychosomatics 43:36-41, February 2002
© 2002 The Academy of Psychosomatic Medicine
Clinical Outcomes Following a Trial of Sertraline in Rheumatoid Arthritis
James R. Slaughter, M.D.,
Jerry C. Parker, Ph.D.,
Matthew P. Martens, M.A.,
Karen L. Smarr, M.A., and
James E. Hewett, M.A.
Received November 2, 2000; revised October 10, 2001; accepted October 18, 2001. From the Department of Psychiatry and Neurology, University of Missouri, Columbia, Missouri. Address correspondence and reprint requests to Dr. Slaughter, Department of Psychiatry and Neurology, University of Missouri, One Hospital Dr, Columbia, Missouri 65212.
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ABSTRACT
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We report an open-label trial of sertraline in the treatment of major depression in 54 consecutive rheumatoid arthritis (RA) patients meeting DSM-IV criteria for major depressive disorder. We initially surveyed 628 RA outpatients with the Center for Epidemiologic Studies Depression Scale (CES-D) and invited those with depression to be evaluated further and treated. Eighty-four RA patients reporting depressive symptoms agreed to participate in person, and 56 met the criteria for major depressive disorder. Of these 56 patients, 54 agreed to medication treatment and were enrolled in the study. Patients were also randomized to one of three psychological treatment conditions, but for this study, conditions were collapsed because previous research on this sample indicated no significant between-group differences in depression after treatment. Patients were assessed with the CES-D and the Hamilton Rating Scale for Depression after the intervention, at 6-month follow-up, and at 15-month follow-up. At the last follow-up, 41 patients remained for assessment. In this study, sertraline was found to be a safe and efficacious treatment of depression complicating RA.
Key Words: Depression • Sertraline • Rheumatoid Arthritis
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INTRODUCTION
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Individuals with rheumatoid arthritis (RA) experience more psychological distress than healthy individuals without RA,1,2 and research indicates that RA patients are especially susceptible to depression.3–9 Although several studies have examined the effectiveness of psychological interventions in treating depression in RA,10–12 the effectiveness of pharmacologic interventions is not well established. In a 32-week, double-blind, crossover trial of amitriptyline, desipramine, trazodone, and placebo, Frank et al.13 found that treatment with amitriptyline led to significant reductions in pain measures relative to both placebo and baseline, but the authors did not report the effect of treatment on depression. However, they reported that amitriptyline led to significant improvement relative to baseline on several mood measures, including life dissatisfaction, self-esteem, down mood, social isolation, negative affect, chronic fatigue, and self-blame. Although these mood measures may be related to major depression, they do not assess depression per se. Sarzi Puttini et al.14 reported that depressed RA patients taking dothiepin (a tricyclic antidepressant available in Europe) experienced significant improvement on Hamilton Rating Scale for Depression (Ham-D)15 scores, while also improving significantly on pain scores, when compared with placebo. These two studies, however, are the only ones identified by MEDLINE that addressed pharmacologic treatment of depression in RA, and treatment was not the major focus of the research in these studies.
In a recent study, Smarr et al.16 reported on a combined psychological-pharmacologic intervention. In this study, 54 subjects diagnosed with classic or definite RA were randomly divided into three groups: a group that received both cognitive-behavioral therapy and an antidepressant medication (CB-PHARM), an attention control group that received both educational materials about RA and an antidepressant medication (AC-PHARM), and a control group that received the antidepressant medication only (CN-PHARM). The purpose of the study was to determine whether the CB-PHARM group would have better outcomes than either control group. Data were collected at baseline, after the intervention, at 6-month follow-up, and at 15-month follow-up. Results indicated no significant differences in depression scores among the three groups, but all three groups demonstrated significant differences from baseline after the intervention, at 6-month follow-up, and at 15-month follow-up. The lack of significant differences on the mean scores of various depression instruments among the groups indicates that subjects in the CB-PHARM group did not improve to a greater extent than either control group.
Although the results from Smarr et al.16 are informative regarding depression scores among RA patients, it is not known whether differences existed in terms of patients being classified as depressed with the use of screening instruments. Such a patient-by-patient classification is important because clinicians and researchers often use self-report screening instruments as a brief and easy way to assess the existence of depression. Two of the more commonly used self-report instruments are the Center for Epidemiologic Studies Depression Scale (CES-D)17 and the Ham-D,15 and these are the focus of this study. In addition, the clinical impressions of both a board-certified psychiatrist and of the patients themselves were assessed. Thus, the purpose of this study was to extend the work of Smarr et al., using the same sample, by assessing each patient for the presence or absence of depression with the use of common screening instruments. This would allow us to answer different questions regarding the nature of depression experienced by this sample. Instead of examining overall mean differences in depression scores, we would be able to assess, by  2 analyses, differences in the proportion of subjects diagnosed as depressed by self-report screening instruments. This information would help us determine the effectiveness of an antidepressant treatment program for reducing the incidence of depression as reflected by self-report measures and clinical impressions among a sample of RA patients.
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METHODS
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Subjects
The study included 54 subjects (15 male and 39 female) with a diagnosis of definite RA and a diagnosis of DSM-IV major depression by the treating psychiatrist (J.R.S.). The median age of the sample was 54.6 years. Subjects were recruited from a Department of Veterans Affairs hospital, a university medical center, and a private rheumatology practice. At the end of the study (15-month follow-up), 41 subjects remained for analysis. Exclusion criteria included a history of organic brain syndrome, presence of a psychotic disorder, other uncontrolled medical disorders, a major communication disorder, illiteracy, less than an eighth-grade education, receipt of a therapeutic dosage of an antidepressant medication, or presence of another autoimmune disease or disabling condition.
Medication
Sertraline, a selective serotonin reuptake inhibitor (SSRI), was used in this open-label trial. Sertraline is a standard treatment of depression. Before receiving sertraline, 12 participants were instructed to taper off low-dose antidepressants (e.g., amitriptyline) that were being used primarily for either sleep or pain. We attempted to titrate the dose of sertraline in all patients in the study to 100 mg within 3 weeks of entry into the open-label trial, after a 2-week placebo washout period. Dosage adjustments were made with consideration of side effects and by the clinical impression of a psychiatrist (JRS). The average sertraline dosage was 99.5 mg/day. Six individuals experienced sleep difficulties and were prescribed zolpidem. For two subjects, sertraline was deemed clinically ineffective. These subjects were then prescribed nortriptyline, with an average dosage of 75.0 mg/day.
Groups
Subjects were randomly assigned to the CB-PHARM (n = 17), AC-PHARM (n = 20), or CN-PHARM (n = 17) groups. At the 15-month follow-up, the group numbers were as follows: CB-PHARM 14, AC-PHARM 13, and CN-PHARM 14. In addition to the medication, the CB-PHARM group received 10 sessions of cognitive-behavioral therapy lasting 1.5 hours each and covering topics such as identification of stressors, management of pain, and the development of effective coping strategies. The counselor for this program was a doctoral-level psychologist with extensive training in cognitive-behavioral techniques. The same psychologist conducted the program for the AC-PHARM group, which, in addition to the medication, received 10 sessions of an educational program based on materials from the Arthritis Foundation. The CN-PHARM group received no additional intervention apart from the medication. In this study, the groups were collapsed for all data analyses.
Measures
Subjects completed a wide variety of psychosocial, health status, pain, and disease-activity measures, including the CES-D, Ham-D, Geriatric Depression Scale, Symptom Checklist–90 Revised, Coping Strategies Questionnaire, Daily Stress Inventory, Hassles Scale, State-Trait Anxiety Inventory, Arthritis Helplessness Index, Arthritis Self-Efficacy Scale, Arthritis Impact Measurement Scales-2, Multidimensional Assessment of Fatigue, Visual Analogue Scale for Pain, McGill Pain Questionnaire, and Rapid Assessment of Disease Activity in Rheumatology. All of these variables were analyzed in the previous study by Smarr et al.16 Patients also completed a self-report global impression scale (PGI), and a psychiatrist (JRS) completed a clinician's global impression scale (CGI). For this study, the measures of interest were the CES-D, Ham-D, and the two impression scales.
Center for Epidemiologic Studies Depression Scale. The CES-D is a 20-item self-report measure that assesses symptoms of depression. Each item is assessed on a 4-point response scale that addresses the frequency that each symptom is experienced (0 = none of the time; 3 = all of the time). Satisfactory reliability and validity have been established for the scale.17 Use of the CES-D by telephone has been reported previously.9 A cutoff score of 16 is commonly used on the CES-D to assess the presence of depression.17,18 Turk and Okifuji19 have recommended that the CES-D cutoff score for depression be  19 when evaluating pain patients. We evaluated both the standard 16 and 19 cutoff scores for those receiving medication.
Hamilton Rating Scale for Depression. The Ham-D is a 17-item interview-based inventory that provides a measure of depression severity and has proven to be a reliable and valid measure of depression.20,21 A cutoff score of 17 is used on the Ham-D to assess the presence of depression.15
Global Impression Scale. To provide further information about patients' improvement, we used the CGI and the PGI. The CGI ascertains the degree to which the physician (JRS) believes that the patient's total functioning has improved. The physician can rate the improvement as "very much improved," "much improved," "minimally improved," "no change," "minimally worse," "much worse," or "very much worse." The PGI ascertains a patient's perception of his or her improvement on a 7-point scale. The scale has 7 anchor points, with the lowest anchor labeled "very much better," the middle anchor labeled "same," and the highest anchor labeled "very much worse." For the purposes of this study, the two other anchors below "same" were called "much better" and "minimally better", whereas the other anchors above "same" were labeled "minimally worse" and "much worse."
Procedures
Six hundred twenty-eight patients with the diagnosis of RA established by a rheumatologist were invited to enter the screening arm of the study. All 628 patients were initially interviewed by telephone with the CES-D. Of these patients, 254 scored in the depressed range, defined using the standard CES-D cutoff score of 16. These 254 patients were invited to be interviewed in person with Ham-D and Structured Clinical Interview for DSM-IV (SCID) measures as well as psychiatric evaluation. Eighty-four subjects gave informed consent and were assessed in person. Fifty-six individuals met the SCID criteria for major depressive disorder. Two patients did not return after the initial evaluation and were never begun on study medication. They were not included in the data analyses. Patients were assessed with the CES-D at baseline, after the intervention, at 6-month follow-up, and at 15-month follow-up. Patients were compensated for travel time to complete the follow-up assessments, and assessments were completed at approximately the same time each day for every participant.
Data Analyses
Because the purpose of this study was to examine depression in RA patients from a clinical perspective, the main data analysis involved examining the percentage of patients categorized as depressed or not depressed with the CES-D and Ham-D. Because the outcome variable in this case was dichotomous, we used 2 analyses. At each time period, patients were collapsed across all three groups because previous results indicated no significant differences in mean scores across all three groups,16 and one-way 2 analyses were conducted. The purpose of these analyses was to determine whether there were significant differences in the observed proportions of depressed patients at each time period in comparison with what would be expected given the baseline results.
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RESULTS
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Dropouts
Of the 54 patients who began taking sertraline, 10 dropped out by the 6-month follow-up. Subjects dropped out for the following reasons: medical complications not related to the medication (n = 4), noncompliance with program demands (n = 5), and medication side effects (n = 1). Of the 44 patients remaining at the 6-month follow-up, 1 more had to be removed because of noncompliance. Two more patients were dropped from the study by the 15-month follow-up because of noncompliance as well.
Prevalence of Depression
The presence or absence of depression was assessed at each time period for each group by three different standards: CES-D scores with 16 as a cutoff, CES-D scores with 19 as a cutoff, and Ham-D scores with 17 as a cutoff. The percentage of depressed patients by each standard at each measurement time can be seen in Table 1. The observed proportion of depressed patients at each time period for each cutoff criterion was compared with what would be expected given the baseline proportions for each criterion. The results indicated that for each time period and each criterion, there was a significantly smaller proportion of depressed patients than would be expected given the baseline measures (see Table 2). Thus, these results indicate that sertraline was effective in reducing the prevalence of depression at all three time periods compared with baseline. Note that for the Ham-D at the 15-month follow-up, a 2 analysis could not be conducted because none of the patients scored in the depressed range.
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TABLE 1. Percentage of RA patients diagnosed with major depression scoring in the depressed range at follow-up based on CES-D and Ham-D cutoff scores
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Perceptions of Patient Improvement
Results from the CGI indicated that in the opinion of the attending physician, who was blinded to group assignment, the overall condition of most patients was improved at all follow-up periods. After collapsing across all three groups, we found that after the intervention, 24% of patients were rated as very much improved, 50% much improved, 22% minimally improved, 2% no change, and 2% minimally worse. At the 6-month follow-up, 36% of the patients were rated as very much improved, 36% much improved, 20% minimally improved, 6% no change, and 2% minimally worse. At the 15-month follow-up, all patients were rated as improved to some degree: 78% very much improved, 20% much improved, and 2% minimally improved.
Results from the PGI indicated that although most patients perceived themselves as improved from baseline, in general their perceptions of improvement were somewhat less than those of the attending physician. After the intervention, 13% of the patients rated themselves as very much better, 40% much better, 38% minimally better, 2% same, and 7% minimally worse. At the 6-month follow-up, 7% of the patients rated themselves as very much better, 18% much better, 41% minimally better, 18% same, 9% minimally worse, 5% much worse, and 2% very much worse. At the 15-month follow-up, 16% of the patients rated themselves as very much better, 29% much better, 29% minimally better, 12% same, 10% minimally worse, 2% much worse, and 2% very much worse.
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CONCLUSIONS AND CLINICAL IMPLICATIONS
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Depression is a frequent complication of RA. In our study of 628 patients, 40% of those sampled experienced significant depression as determined using CES-D cutoff scores. Further, of these patients with high CES-D scores who were willing to undergo a diagnostic interview, approximately two-thirds met the criteria for major depression. This depression leads to disability from RA over and above that of the medical disease alone.22 These large numbers of depressed RA patients would benefit substantially from identification and treatment. Our results indicate that sertraline may be an effective treatment for RA patients who experience major depression.
The results indicated that significantly fewer patients were depressed at all three follow-up times when measured by several self-report depression instruments. Further, only two patients (4%) experienced side effects requiring alternative antidepressant medication.
Our case series had certain limitations. Among those community-dwelling RA patients scoring in the depressed range on the CES-D, no attempt was made to assess those who did not present for in-person SCID and Ham-D interviews. Total numbers of treated patients remained small, and no medication placebo control was used.
Other implications from our study include the utility of the CES-D for screening RA patients. It would be reasonable, based upon our findings, to routinely screen RA patients for depression because our survey of 628 RA patients demonstrated that 40% of patients residing in the community experienced significant depressive symptoms. We recommend to those treating RA patients that they use a standardized screening instrument such as the CES-D initially upon diagnosis of RA and then at yearly intervals thereafter. We recommend that the duration of treatment extend for 1 year. These recommendations are based upon our case series and additional anecdotal experience with RA patients. In our anecdotal experience, some patients may benefit from a longer treatment period; a minority of our patients who tapered off sertraline at the end of our study returned to medication after its discontinuation and recurrence of major depression.
At present, the natural history of depression complicating RA remains to be elucidated. Our patients had experienced RA for an average of 12.6 years, and it was unclear when major depression began to manifest itself among these patients. For example, major depression may proceed along a linear pattern among RA patients, with depression worsening as the disease progresses. However, it is also possible that major depression follows a bimodal pattern, with patients becoming initially depressed upon learning of the RA diagnosis, followed by a period of relative non-depression, with depression reemerging once RA progresses to a serious state. These questions regarding the progression of depression in RA patients remain to be answered.
The type of antidepressant most efficacious in the treatment of RA depression also remains to be elucidated. In this study, we documented the effectiveness of the SSRI sertraline, but it is possible that better results would have emerged by combining sertraline in the morning with low-dose amitriptyline at night. These questions remain unanswered in the treatment of depression complicating RA. In sum, the natural history of depression, its early detection, and its treatment options await further elucidation. We hope that this report spurs further research on these and related issues in RA.
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ACKNOWLEDGMENTS
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This study was supported by the Department of Veterans Affairs, the National Institute on Disability and Rehabilitation Research of the U.S. Department of Education (grant no. H133B80075), and an unrestricted educational grant from Pfizer, Inc. The opinions in this publication are those of the grantees and do not necessarily reflect those of the Department of Veterans Affairs, the Department of Education, or Pfizer, Inc.
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ABSTRACT
INTRODUCTION
