Heterogeneity among depressed outpatients considered to be in remission

Comprehensive Psychiatry 48 (2007) 113 – 117 www.elsevier.com/locate/comppsych

Heterogeneity among depressed outpatients considered to be in remission Mark Zimmerman4, Michael A. Posternak, Iwona Chelminski Department of Psychiatry and Human Behavior, Brown University School of Medicine, Rhode Island Hospital, Providence, RI 02905, USA

Abstract More than a decade ago, a consensus panel recommended that remission be defined on the 17-item version of the Hamilton Rating Scale for Depression (HAM-D) as a cutoff of less than 7. Recently, some investigators have suggested that this threshold to define remission may be too high. If true, this means that heterogeneity exists within the group of treatment remitters accounting for variance in psychosocial function and relapse risk. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we examined whether there is heterogeneity within the group of patients that are typically classified as remitters. Three hundred three depressed psychiatric outpatients were rated on the Standardized Clinical Outcome Rating for Depression, an index of Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition remission status, and the 17-item HAM-D. Approximately half of the patients completed a measure of psychosocial impairment. Treatment responders were divided into 2 groups, remitters (HAM-D V 7) and nonremitters (HAM-D z8). The treatment remitters were further subdivided into 2 groups, remitters with and without mild residual symptoms (HAM-D 3-7 vs 0-2). We refer to these 3 nonoverlapping groups as responders, partial remitters (ie, remitters with mild residual symptoms), and full remitters (remitters without residual symptoms). Responders scored statistically significantly higher, indicating greater psychosocial impairment, than the entire group of remitters, and the partial remitters scored significantly higher than the full remitters. Among the responders, the correlation between remission status and functioning was .49 ( P b .01). Among the remitters, the correlation between residual symptom status and functioning was nearly as high ( .42, P b .05). These results suggest that there is as much heterogeneity among patients who are typically considered to be in remission as there is among responders. This supports recommendations to lower the cutoff on the HAM-D to define remission. D 2007 Elsevier Inc. All rights reserved.

Increasingly, experts in the treatment of depression have emphasized the importance of achieving remission [1-7]. This recommendation is based on studies that have consistently demonstrated that depressed patients who have responded to treatment but failed to achieve remission continue to experience more psychosocial impairment and have a higher likelihood of recurrence of a full depressive syndrome [8-11]. These studies thus indicate that the definition of treatment response, usually a 50% reduction in scores on a clinicianrated measure such as the Hamilton Rating Scale for Depression (HAM-D) [12], identifies a group that is heterogeneous in clinical status, and that there exists significant variation in psychosocial function and relapse risk within this group. Subdividing treatment responders into remitters and nonremitters reduces this heterogeneity. Through the years, many cutoff scores have been used on the HAM-D to define remission [13]. Since the publication 4 Corresponding author. Bayside Medical Center, Providence, RI 02905, USA. E-mail address: [email protected] (M. Zimmerman). 0010-440X/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.comppsych.2006.10.005

of the recommendations of Frank et al [14], a relative consensus emerged to define remission on the HAM-D as a score of 7 or less. This recommendation came from proceedings of a consensus conference and was accompanied by a call to empirically validate the definition. Little research, however, has been conducted in this area. Recently, questions have been raised about the threshold used to define remission. Judd et al [15], examining data from the longitudinal Collaborative Depression Study, found that patients in remission with residual symptoms of depression (ie, 1 or 2 depressive symptoms at a mild level of severity) were at greater risk for relapse, relapsed more quickly, and had greater psychosocial impairment, than patients in remission with no residual symptoms. Although these investigators did not study the HAM-D per se, they suggested that the commonly used threshold to define remission on this scale may be too high [15]. Although it can be argued that there are conceptual limitations with defining remission according to a cutoff score on a symptom severity measure [16], this is the

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approach that is typically used in acute treatment studies of depression. A valid definition of remission should identify a homogeneous group of patients with no to minimal association between symptom scores and external validators such as relapse rates or levels of psychosocial impairment. If, within the group of patients who are defined as remitters, there are predictable differences between high- and lowscale scorers in the same way that within the group of treatment responders there are predictable differences between nonremitters and remitters, then this suggests that the cutoff score to define remission is too high. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we examined whether there is as much heterogeneity within the group of patients classified as remitters as there is within a group of patients classified as responders to treatment. 1. Methods Participants were 303 psychiatric outpatients who were being treated for a Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV) major depressive episode in the Rhode Island Hospital Department of Psychiatry outpatient practice. This private practice group predominantly treats individuals with medical insurance on a fee-for-service basis, and it is distinct from the hospital’s outpatient residency training clinic that predominantly serves lower-income, uninsured, and medical assistance patients. The sample included 114 men (37.6%) and 189 women (62.4%), who ranged in age from 18 to 79 years (mean, 42.9; SD, 12.7). Almost half of the subjects were married (47.9%, n = 145); the remainder were single (23.4%, n = 71), divorced (19.8%, n = 60), separated (5.6%, n = 17), widowed (2.0%, n = 6), or living with someone as if in a marital relationship (1.3%, n = 4). The racial composition of the sample was 86.8% (n = 263) white, 2.6% (n = 8) black, 4.3% (n = 13) Hispanic, 0.7% (n = 2) Asian, and 5.6% (n = 17) others. The Rhode Island Hospital institutional review committee approved the research protocol, and all patients provided informed, written consent. Diagnoses were based on the Structured Clinical Interview for DSM-IV [17]. The patients were rated by the first 2 authors on the 17-item HAM-D and the Standardized Clinical Outcome Rating Scale for Depression (SCOR-D)

(described below). Interrater reliability on the HAM-D was obtained in 16 patients, with one of the authors interviewing the patient while the other observed and made independent ratings. The intraclass correlation coefficient of reliability was .97. After the recommendation of Frank et al [14], patients rated 7 or lower on the 17-item HAM-D were considered treatment remitters. The j coefficient for determining remission status was 1.0. As part of the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we modified and expanded upon the Psychiatric Status Ratings used in the Longitudinal Interval Follow-up Evaluation [18]. SCORs have been developed for the most common DSMIV disorders presenting for treatment in outpatient practice. The SCOR-D is a reliable and valid 6-point rating scale based on the number of DSM-IV criterion symptoms for a major depressive episode and level of psychosocial impairment present during the past week (Table 1) [19]. Patients rated 3 or lower on the SCOR-D were considered treatment responders. In the 16 patients who participated in the reliability evaluation, the j coefficient for determining responder status was .74. Approximately one half of the patients completed a questionnaire that included a question regarding functional impairment due to depression (bOverall, how much have symptoms of depression interfered with or caused difficulties in your life during the past week? 0 = not at all; 1 = a little bit; 2 = a moderate amount; 3 = quite a bit; 4 = extremelyQ). Only half of the patients completed the questionnaire because it was introduced midway through the study. Treatment responders were divided into 2 groups— remitters and nonremitters, based on their HAM-D score (ie, remission was defined as a score of V 7). The treatment remitters were further subdivided into 2 groups, remitters with and without mild residual symptoms. In a separate report from our group, we found that a cutoff of less than 2 on the HAM-D maximized agreement with a strict interpretation of the DSM-IV definition of remission; therefore, we used this cutoff to dichotomize remitters into those with and without residual symptoms [20]. The goal of the analysis was to determine whether there was variability amongst patients typically considered to be treatment remitters according to the most widely used definition of remission and to compare the amount of

Table 1 Ratings on the SCOR-D SCOR-D rating Definition 6 5 4 3 2 1

Meets DSM-IV criteria for major depressive disorder (MDD), and either prominent psychotic symptoms or extreme impairment in functioning Meets DSM-IV criteria for MDD, but no prominent psychotic symptoms and no extreme impairment in functioning Does not meet DSM-IV criteria, but has major symptoms or impairment from this disorder (eg, depressive episode with only 4 symptoms but still unable to work) Considerably less psychopathology than full criteria with no more than moderate impairment in functioning, but still has obvious evidence of MDD (eg, a depressive episode with only two or three symptoms of a moderate degree, 1 or 2 symptoms of a severe degree) Either patient claims not to be completely back to busual self,Q or rater notes the presence of one or more symptoms of MDD of no more than a mild degree (eg, only mild insomnia from the original episode) Full remission with no symptoms of MDD. Significant symptom from another disorder may be present (and is coded for that disorder)

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Table 2 Distribution of psychosocial impairment scores in the responders and remitters Responder/remission status (n) Responders, not remitters (n = 15) Responders, remitters (n = 35) Remitters, residual symptoms (n = 15) Remitters, asymptomatic (n = 20)

Psychosocial impairment rating (%) 0 (none)

1 (a little bit)

2 (moderate)

3 (quite a bit)

4 (extremely)

6.7 57.1 33.3 75.0

53.3 31.4 46.7 20.0

33.3 11.4 20.0 5.0

6.7 0.0 0.0 0.0

0.0 0.0 0.0 0.0

variability among remitters with the amount among treatment responders. Responders were dichotomized as remitted (HAM-D b 7) versus not remitted. Remitters were dichotomized according to the presence or absence of residual symptoms (HAM-D b2) (ie, partial vs full remission). Correlation coefficients were computed between each of these 2 dichotomous variables and the measure of psychosocial impairment. A 3-group analysis of variance compared the psychosocial impairment scores in responders, partial remitters, and full remitters. Two-group follow-up tests were conducted using the Tukey procedure. 2. Results The mean score on the 17-item HAM-D for the entire sample of 303 patients was 11.4 (SD, 8.4). Slightly more than one half of the sample were treatment responders (SCOR-D rating of V 3) (n = 154, 50.8%), and more than one third were in remission (HAM-D V 7) (n = 118, 38.9%). Psychosocial functioning was assessed in 144 (47.5%) patients. There were no demographic differences between patients who did and did not provide this information. In the 50 patients who responded to treatment and completed the psychosocial functioning rating, the correlation between remission status and functioning was .49 ( P b .01). In the 35 patients who were in remission and completed the functioning rating, the correlation between residual symptom status and functioning was nearly as high ( .42, P b .05). The distribution of the impairment ratings in responders, partial remitters (with residual symptoms), and full remitters is presented in Table 2. An analysis of variance on the functioning item comparing these 3 groups was significant (F2,47 = 11.4, P b .001). Tukey follow-up tests found that responders scored significantly higher, indicating greater psychosocial impairment, than the entire group of remitters (1.4 F 0.7 vs 0.5 F 0.7, P b .001). The partial remitters scored significantly higher than full remitters (0.9 F 0.7 vs 0.3 F 0.6, P b .05). The responders scored higher than partial remitters; however, the difference was not statistically significant (1.4 F 0.7 vs 0.9 F 0.7). 3. Discussion Keller [16] recently noted that a measurable, identifiable end point for the treatment of depression is as

important to establish as it has been for the treatment of other chronic conditions such as diabetes, hypertension, and hypercholesterolemia. Improvement in the symptoms of depression has long been the goal of treatment, and the development of instruments such as the HAM-D and Beck Depression Inventory more than 40 years ago enabled the tracking of treatment response by repeated measurement of symptom severity. During the 1970s and 1980s, different terms were used to describe the course of depression, and even the same terms were used differently by investigators. To bring order to the confusion, a consensus conference was held in order to standardize the definitions of terms such as remission and relapse. Full remission was defined as a period during which the individual is asymptomatic. Asymptomatic was not defined as a complete absence of symptoms but, instead, was defined as no more than minimal symptoms. On the 17-item HAM-D, asymptomatic was defined as a score of 7 and below. The threshold used to define remission should identify a relatively homogeneous group of patients with regard to current and future morbidity. This was the conceptual basis for subdividing treatment responders into remitted and nonremitted patients. That is, it was recognized that treatment responders were a heterogeneous group, and subdividing them according to cutoff scores on symptom rating scales identified groups who differed in their risk of relapse and levels of current psychosocial impairment. If heterogeneity remains among patients who are currently defined as remitted, such that patients with higher scores on the HAM-D demonstrate greater morbidity than lower scoring remitters, then this argues for lowering the threshold to define remission. The results of the current study indicate that there is as much heterogeneity amongst remitters as there is amongst responders. Responders reported significantly more impairment than remitters, and partial remitters (who had mild residual symptoms) significantly more impairment than full remitters. Moreover, examination of the distribution of impairment scores in the responders and remitters shows that there was a 4-fold difference in the frequency of mild-moderate impairment between responders and remitters (40.0% vs 11.4%) as well as between remitters with and without mild residual symptoms (20% vs 5%). Thus, the clinical significance of the distinction between remission with and without mild residual symptoms is comparable to the distinction between response and remission.

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Some limitations of the study should be noted. First, we examined only the 17-item version of the HAM-D. We focused on the 17-item HAM-D because it is the most commonly used measure in antidepressant efficacy trials, the cutoff used to define remission has been generally accepted, and it is the version of the scale discussed by Frank et al [14] in their seminal article on the definition of treatment response in depression. We would anticipate that our findings would be similar in studies of longer versions of the HAM-D as well as other depression severity scales such as the MontgomeryAsberg Depression Rating Scale. Second, the sample was drawn from a single large general adult outpatient private practice setting in which most patients were white, female, and in their 30s and 40s. Generalizability to samples with different demographic characteristics needs to be demonstrated. Third, only a subset of patients answered the psychosocial impairment question, although this group was not selected based on particular characteristics, and there were no demographic differences between patients who did and did not complete the rating. Fourth, the assessment of psychosocial impairment was based on a single, global, selfreport rating, although this approach toward assessing psychosocial functioning has been shown to be reliable and valid [21]. A more comprehensive assessment of functioning would be preferable to determine which aspects of functioning are most closely associated with the distinction between response and remission and between remission with and without residual symptoms. However, the lack of such an assessment does not undermine the principal conclusion of the present study, which is that there is heterogeneity within the group that is typically considered as remitted. Fifth, the focus of this article has been on a narrow perspective of defining remission—according to scores on a symptom measure that assesses symptom levels over the week before the evaluation. Defining remission should probably also consider the persistence of symptom resolution, as well as ratings of psychosocial functioning, quality of life, ability to cope with stress, and emotional control [22]. Sixth, we used an atypical definition of treatment response—a value of 3 or less on the SCOR-D. It is possible that some patients would not have demonstrated a 50% improvement in HAM-D scores, had we collected baseline HAM-D ratings. However, this does not undermine our findings that within the group of individuals who score 7 and less on the HAM-D, there exists significant heterogeneity with regard to level of psychosocial impairment. Seventh, we did not systematically record the treatments received by patients. Patients received different medications, and a subset of patients were receiving psychotherapy, thereby increasing the generalizability of the findings to routine clinical practice. And finally, we did not conduct a prospective follow-up study in order to examine validity from the perspective of prediction of relapse and future morbidity. Although this does not represent a methodological flaw with the present study of the multiple approaches toward examining the validity of the broadness of the definition of remission, prognostic significance is the

most clinically important. Judd et al [15], using ratings from the Longitudinal Interval Follow-up Evaluation, found that compared to asymptomatic patients, patients with minimal levels of residual symptoms were at greater risk for relapse. Future studies should examine whether heterogeneity regarding prognosis exists among patients scoring less than 7 on the HAM-D, the most commonly used definition of remission on the most commonly used rating scale in treatment studies of major depression.

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