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ScienceDirect Comprehensive Psychiatry 56 (2015) 29 – 34 www.elsevier.com/locate/comppsych
How many different ways do patients meet the diagnostic criteria for major depressive disorder? Mark Zimmerman⁎, William Ellison, Diane Young, Iwona Chelminski, Kristy Dalrymple Department of Psychiatry and Human Behavior, Brown Medical School Department of Psychiatry, Rhode Island Hospital, Providence
Abstract There are 227 possible ways to meet the symptom criteria for major depressive disorder (MDD). However, symptom occurrence is not random, and some symptoms co-occur significantly beyond chance. This raises the questions of whether all of the theoretically possible different ways of meeting the MDD criteria actually occur in patients, and whether some combinations of criteria are much more common than others. More than 1500 patients who met DSM-IV criteria for MDD at the time of the evaluation were interviewed with semi-structured interviews. The patients met the MDD symptom criteria in 170 different ways. Put another way, one-quarter (57/227) of the criteria combinations did not occur. The most frequent combination was the presence of all 9 criteria (10.1%, n = 157). Nine combinations (all 9 criteria, 3 of the 8-criterion combinations, 4 of the 7-criterion combinations, and one 6-criterion combination) were present in more than 2% of the patients, together accounting for more than 40% of the diagnoses. The polythetic definition of MDD, which requires a minimum number of criteria from a list, results in significant diagnostic heterogeneity because there are many different ways to meet criteria. While there is significant heterogeneity amongst patients meeting the MDD diagnostic criteria, a relatively small number of combinations could be considered as diagnostic prototypes as they account for more than 40% of the patients diagnosed with MDD. © 2014 Elsevier Inc. All rights reserved.
1. Introduction The era of specified inclusion and exclusion criteria to make psychiatric diagnoses began in 1972 when a group of researchers at Washington University published an article entitled “Diagnostic Criteria for Use in Psychiatric Research” [1]. Referred to as the Feighner criteria (after the lead author of the article), or the Washington University criteria (after the academic affiliation of the authors), this article delineated for the first time specific inclusion and exclusion criteria for 15 disorders that the authors considered to have been empirically validated. While this article is generally credited with ushering in the modern era of specified diagnostic criteria, in fact, this publication was not the first description of specific criteria for depression. In a 1957 report on the clinical features of manic–depressive disorder, Cassidy and colleagues [2] diagnosed depressive
Potential conflicts of interest: None. ⁎ Corresponding author at: 146 West River Street, Providence, RI 02904. E-mail address: [email protected] (M. Zimmerman). http://dx.doi.org/10.1016/j.comppsych.2014.09.007 0010-440X/© 2014 Elsevier Inc. All rights reserved.
disorder in patients who reported both low mood and 6 of a list of 10 symptoms. The ten criterion symptoms of depression listed by Cassidy et al. were slow thinking, poor appetite, constipation, insomnia, fatigue, loss of concentration, suicidal ideas, weight loss, decreased libido, and agitation. The Washington University definition of depression represented a modification of the Cassidy et al. symptom list, deleting one item (constipation) and adding others (guilt, worthlessness, indecisiveness, hypersomnia, pervasive loss of interest). Feighner et al. did not indicate the reasons for changing the criteria developed by Cassidy et al., and, to our knowledge, never published any data to empirically support their selection of particular symptoms over others. Nonetheless, the symptom inclusion criteria identified by the Washington University group have changed relatively little during the past 40 years, thus attesting to the astute observations of these clinical researchers. The symptom inclusion criteria for major depressive disorder (MDD) in the DSM-5 [3], as well as the threshold to distinguish between cases and noncases, are similar to the ones originally articulated by Feighner and colleagues. The DSM-5 symptom inclusion criteria for MDD require the presence of at least five characteristic features from a list
30
M. Zimmerman et al. / Comprehensive Psychiatry 56 (2015) 29–34
of nine, at least one of which must be low mood or anhedonia. This approach towards defining depression, based on a minimum number of features from a longer list, results in heterogeneity in patients’ clinical profile because there are many different possible combinations of criteria that qualify for a diagnosis. Altogether, there are 227 different ways to meet the symptom criteria for MDD, and it is possible for 2 patients diagnosed with MDD to have no symptoms in common. (Because some of the MDD criteria have multiple components, 2 patients can meet the same criterion in different ways. Thus, 2 patients can have no symptoms in common.) While there are numerous ways in which a patient might meet the symptom criteria for MDD, it is also recognized that the criteria “hang together” as a syndrome thereby justifying the identification of the clinical syndrome. While the sensitivity and specificity of the MDD criteria vary, all are independently associated with the diagnostic construct [4], and they co-occur significantly beyond chance [5]. This raises the questions of whether all of the theoretically possible different ways of meeting the MDD criteria actually occurs in patients, and whether some combinations of criteria are much more common than others and capture the majority of patients diagnosed with MDD. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we examined in a large cohort of depressed patients the different ways in which they met the DSM-5 symptom inclusion criteria. We hypothesized that some of the 227 possible criteria combinations would occur more frequently than other combinations.
2. Methods The Rhode Island MIDAS project represents an integration of research methodology into a community-based outpatient practice affiliated with an academic medical center [6]. A comprehensive diagnostic evaluation is conducted upon presentation for treatment. This private practice group predominantly treats individuals with medical insurance (including Medicare but not Medicaid) 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. Data on referral source were recorded for the last 1800 patients enrolled in the study. Patients were most frequently referred from primary care physicians (30.0%), psychotherapists (16.1%), and family members or friends (18.8%). The Rhode Island Hospital institutional review committee approved the research protocol, and all patients provided informed, written consent. The sample examined in the present report was derived from the 3800 psychiatric outpatients evaluated with semistructured diagnostic interviews. Patients were interviewed by a diagnostic rater who administered a modified version of the Structured Clinical Interview for DSM-IV (SCID) [7]. The focus of the present report is the 1566 patients who met
DSM-IV criteria for MDD at the time of the evaluation. The sample included 539 (34.4%) men and 1027 (65.6%) women who ranged in age from 18 to 84 years (mean = 39.9, SD = 12.6). Approximately two-fifths of the patients were married (41.9%, n = 656); the remainder were single (27.3%, n = 427), divorced (16.3%, n = 256), separated (6.3%, n = 99), widowed (2.1%, n = 33), or living with someone as if in a marital relationship (6.1%, n = 95). Approximately two-thirds of the patients attended school beyond high school (68.1%, n = 1066), though only one-quarter graduated a 4-year college (26.2%, n = 410). The racial composition of the sample was 83.9% (n = 1314) white, 5.5% (n = 86) black, 4.2% (n = 65) Hispanic, 0.8% (n = 13) Asian, and 5.6% (n = 88) from another or a combination of the above racial backgrounds. The diagnostic raters were highly trained and monitored throughout the project to minimize rater drift. The diagnostic raters included Ph.D. level psychologists and research assistants with college degrees in the social or biological sciences. Research assistants received three to four months of training during which they observed at least 20 interviews, and they were observed and supervised in their administration of more than 20 evaluations. Psychologists only observed 5 interviews, and they were observed and supervised in their administration of 15 to 20 evaluations. During the course of training the senior author (M.Z.) met with each rater to review the interpretation of every item on the SCID. Also during training, every interview was reviewed on an item-by-item basis by the senior rater who observed the evaluation and by the senior author who reviewed the case with the interviewer. At the end of the training period the raters were required to demonstrate exact, or near exact, agreement with a senior diagnostician on five consecutive evaluations. Throughout the MIDAS project, ongoing supervision of the raters consisted of weekly diagnostic case conferences involving all members of the team. In addition, every case was reviewed by the senior author (M.Z.). Reliability was examined in 65 patients. A joint-interview design was used in which one rater observed another conducting the interview, and both raters independently made their ratings. Of relevance to the present report, the reliability for MDD (k = 0.90) was good. The reliability coefficients of the symptoms of depression ranged from .54 to .94 (mean k = .80). For specific symptoms, Kappa coefficients were: depressed mood (k = .92), loss of interest or pleasure (k = .90), decreased appetite (k = .89), increased appetite (k = .63), decreased weight (k = .69), increased weight (k =.79), insomnia (k = .91), hypersomnia (k = .54), psychomotor agitation (k = .83), psychomotor retardation (k = .63), loss of energy (k = .88), feelings of worthlessness (k = .80), excessive guilt (k = .76), decreased concentration (k = .78), indecisiveness (k = .88), thoughts of death (k = .86), and suicidal ideas/plan/attempt (k = .94).
3. Results Of the 1566 patients who met criteria for MDD, the mean number of criteria met was 6.8 (S.D. = 1.3), and the modal
M. Zimmerman et al. / Comprehensive Psychiatry 56 (2015) 29–34
number of criteria met was 7 (25.2%, n = 394). One hundred fifty-seven individuals met all 9 criteria (10.0%), and 19.6% (n = 307) met the minimum number of 5 criteria. Depressed mood was the most frequent criterion (93.7%) and suicidal thoughts the least frequent (50.0%) (Table 1). The rank order of criterion frequency was similar for patients who met 5, 6, 7 or 8 MDD criteria (Table 1). If each of the 227 possible combinations of criteria was equally likely to occur, then approximately 0.4% (or 7 patients) would meet each combination. The most frequent combination was the presence of all 9 criteria (10.0%, n = 157). An additional two combinations were met by at least 5% of the depressed patients; both were combinations of 8 criteria (Table 2). There are 35 possible combinations of 7 criteria (Table 3). All combinations but two were present in at least one patient. The most frequent 7 criterion combination was present in 3.6% (n = 56) of all patients. Four combinations were present in more than 2% of all patients, and these 4 combinations accounted for 44.3% (175/395) of the patients who met 7 criteria. There are 77 possible combinations of 6 criteria. Only 1 combination was present in more than 2% of all patients (Table 4). Eighteen combinations of 6 criteria were not present in any patient. There are 105 possible combinations of 5 criteria. The most frequent 5-criterion combination was present in 1.8% (n = 29) of all patients (Table 5). Thirty-seven combinations of 5 criteria were not present in any patient. In all, 57 out of the 227 criterion combinations did not occur in any patient.
4. Discussion Polythetic definitions of psychiatric disorders, which require a minimum number of criteria from a list, potentially result in diagnostic heterogeneity because there are many different ways to meet criteria. However, the diagnostic criteria used to define a disorder are not randomly occurring signs and symptoms but instead “hang together” and cooccur at greater than chance levels, thus concerns about
31
Table 2 Frequency of DSM-IV symptom criteria combinations in 367 psychiatric outpatients with major depressive disorder who met 8 criteria. Depression Criteria Combination a
N
%b
12345678 12345679 12345689 12345789 12346789 12356789 12456789 13456789 23456789
121 5 18 17 113 21 40 28 4
33.0 1.4 4.9 4.6 30.8 5.7 10.9 7.6 1.1
a
The numbers refer to the number of the criterion as denoted in Table 1. The percentage refers to the percentage of the sample of 367 patients with 8 criteria who had the combination. b
diagnostic heterogeneity may be more theoretical than actual. To the best of our knowledge this is the first study to empirically examine the expanse of diagnostic heterogeneity of major depressive disorder. In the present study a large sample of psychiatric outpatients was administered a semistructured diagnostic interview. We found that the patients met the DSM-IV symptom criteria for major depressive disorder in 170 different ways. Put another way, one-quarter (57/227) of the criteria combinations did not occur. As predicted, some criteria combinations were much more frequent than others. Nine combinations (all 9 criteria, 3 of the 8-criterion combinations, 4 of the 7-criterion combinations, and one 6-criterion combination) were present in more than 2% of the patients, accounting for more than 40% of the diagnoses. Thus, while there is significant heterogeneity amongst patients meeting the diagnostic criteria, a relatively small number of combinations could be considered as diagnostic prototypes. Future research should examine whether the patients meeting prototypic combinations differ from the depressed patients who do not. Many medical disorders vary in presenting signs and symptoms, and while this might make diagnosis difficult, it does not necessarily indicate disease heterogeneity. However, in diagnostic classifications since DSM-III, the heterogeneity of the major depressive disorder has been acknowledged through
Table 1 Frequency of DSM-IV symptom criteria in 1566 psychiatric outpatients with major depressive disorder meeting different number criteria. Depressive Criterion
1. 2. 3. 4. 5. 6. 7. 8. 9.
Depressed Mood Loss of Interest or Pleasure Appetite/Weight Disturbance Sleep Disturbance Psychomotor Change Loss of Energy Worthlessness/Excessive Guilt Concentration/Indecision Death/Suicidal Thoughts
All Patients (n = 1566)
5 Criteria Met (N = 307)
6 Criteria Met (n = 341)
7 Criteria Me (n = 394)
8 Criteria Met (n = 367)
n
%
n
%
n
%
n
%
N
%
1467 1287 1093 1342 815 1376 1160 1365 783
93.7 82.2 69.8 85.7 52.0 87.9 74.1 87.2 50.0
265 205 139 218 63 235 141 204 65
86.3 66.8 45.3 71.0 20.5 76.5 45.9 66.4 21.2
307 247 207 282 121 290 208 272 112
90.0 72.4 60.7 82.7 35.5 85.0 61.0 79.8 32.8
375 339 263 339 220 344 305 370 203
95.2 86.0 66.8 86.0 55.8 87.3 77.4 93.9 51.5
363 339 327 346 254 350 349 362 246
98.9 92.4 89.1 94.3 69.2 95.4 95.1 98.6 67.0
32
M. Zimmerman et al. / Comprehensive Psychiatry 56 (2015) 29–34
Table 3 Frequency of DSM-IV symptom criteria combinations in 395 psychiatric outpatients with major depressive disorder who met 7 criteria.
Table 4 Frequency of DSM-IV symptom criteria combinations in 341 psychiatric outpatients with major depressive disorder who met 6 criteria.
Depression Criteria Combination a
N
%b
N
%b
%b
7 39 3 17 0 5 56 9 17 12 18 1 1 2 16 35 2 15 7 45 13 14 2 6 5 13 3 12 5 0 3 2 6 1 2
1.8 9.9 0.8 4.3 – 1.3 14.2 2.3 4.3 3.0 4.6 0.3 0.3 0.5 4.1 8.9 0.5 3.8 1.8 11.4 3.3 3.6 0.5 1.5 1.3 3.3 0.8 3.0 1.3 – 0.8 0.5 1.5 0.3 0.5
Depression Criteria Combination a
n
1234567 1234568 1234569 1234578 1234579 1234589 1234678 1234679 1234689 1234789 1235678 1235679 1235689 1235789 1236789 1245678 1245679 1245689 1245789 1246789 1256789 1345678 1345679 1345689 1345789 1346789 1356789 1456789 2345678 2345679 2345689 2345789 2346789 2356789 2456789
Depression Criteria Combination a 123456 123457 123458 123459 123467 123468 123469 123478 123479 123489 123567 123568 123569 123578 123579 123589 123678 123679 123689 123789 124567 124568 124569 124578 124579 124589 124678 124679 124689 124789 125678 125679 125689 125789 126789 134567 134568 134569 134578 134579 134589 134678 134679 134689
6 2 5 0 14 42 10 12 0 2 3 3 2 1 1 1 5 1 4 4 4 16 0 5 2 0 29 11 8 1 4 0 3 0 12 5 9 0 2 0 1 28 3 3
1.8 0.6 1.5 – 4.1 12.3 2.9 3.5 – 0.6 0.9 0.9 0.6 0.3 0.3 0.3 1.5 0.3 1.2 1.2 1.2 4.7 – 1.5 0.6 – 8.5 3.2 2.3 0.3 1.2 – 0.9 – 3.5 1.5 2.6 – 0.6 – 0.3 8.2 0.9 0.9
134789 135678 135679 135689 135789 136789 145678 145679 145689 145789 146789 156789 234567 234568 234569 234578 234579 234589 234678 234679 234689 234789 235678 235679 235689 235789 236789 245678 245679 245689 245789 246789 256789
4 4 0 2 3 1 8 3 2 3 10 3 0 10 0 1 0 0 8 1 2 1 0 0 0 0 1 3 1 2 0 3 1
1.2 1.2 – 0.6 0.9 0.3 2.3 0.9 0.6 0.9 2.9 0.9 – 2.9 – 0.3 – – 2.3 0.3 0.6 0.3 – – – – 0.3 0.9 0.3 0.6 – 0.9 0.3
a
The numbers refer to the number of the criterion as denoted in Table 1. The percentage refers to the percentage of the sample of 394 patients with 7 criteria who had the combination. b
the development of alternative methods of subtyping, though these subtyping methods themselves are often based on polythetic criteria. For example, the DSM-5 anxious distress specifier requires 2 of 5 criteria resulting in 10 possible combinations, and the mixed features specifier requires 3 of 7 criteria resulting in 35 possible combinations. Future research should examine whether the heterogeneity in meeting the criteria for major depressive disorder is reduced (or, alternatively, increased) by methods of subtyping. We speculate that such a high degree of heterogeneity has made it difficult to identify the underlying pathophysiology of depression, and, correspondingly, a biological test for depression. More than 25 years ago, when research on the dexamethasone suppression test was “hot,” one of us began a paper on the validity of the dexamethasone suppression test with the question “How does one validate a biologic marker for endogenous depression when a valid clinical definition does not exist? [8]” An analogous question can be asked in
a
The numbers refer to the number of the criterion as denoted in Table 1. The percentage refers to the percentage of the sample of 341 patients with 6 criteria who had the combination. b
the search for biomarkers for depression. Diagnostic heterogeneity not only may retard the search for etiological mechanisms, pathophysiological correlates, and biological diagnostic tests, but also may limit the effectiveness of treatment efforts. Treatments that may be very effective for subsets of the 227 combinations may appear to have more modest levels of success across the full range of diagnostic combinations. Of course, with such a large number of possible criteria combinations, the sample sizes needed to determine whether there are differential treatment effects would be prohibitively large.
M. Zimmerman et al. / Comprehensive Psychiatry 56 (2015) 29–34 Table 5 Frequency of DSM-IV symptom criteria combinations in 307 psychiatric outpatients with major depressive disorder who met 5 criteria. Depression Criteria Combination a
n
% b Depression Criteria Combination a
n
%b
12345 12346 12347 12348 12349 12356 12357 12358 12359 12367 12368 12369 12378 12379 12389 12456 12457 12458 12459 12467 12468 12469 12478 12479 12489 12567 12568 12569 12578 12579 12589 12678 12679 12689 12789 13456 13457 13458 13459 13467 13468 13469 13478 13479 13489 13567 13568 13569 13578 13579 13589 13678 13679
4 22 2 5 2 1 1 3 0 5 11 1 5 1 0 3 1 5 0 11 26 7 11 4 2 2 2 0 2 1 0 13 0 6 4 4 0 2 1 9 21 4 4 0 1 0 2 0 0 0 0 2 0
1.3 7.2 0.7 1.6 0.7 0.3 0.3 1.0 – 1.6 3.6 0.3 1.6 0.3 – 1.0 0.3 1.6 – 3.6 8.5 2.3 3.6 1.3 0.7 0.7 0.7 – 0.7 0.3 – 4.2 – 2.0 1.3 1.3 – 0.7 0.3 2.9 6.8 1.3 1.3 – 0.3 – 0.7 – – – – 0.7 –
2 1 2 2 0 1 0 0 18 6 3 1 3 1 2 1 9 1 0 1 0 3 11 0 2 0 0 1 0 0 0 0 0 3 0 0 0 1 5 1 2 0 2 4 0 0 0 2 0 0 0 1
0.7 0.3 0.7 0.7 – 0.3 – – 5.9 2.0 1.0 0.3 1.0 0.3 0.7 0.3 2.9 0.3 – 0.3 – 1.0 3.6 – 0.7 – – 0.3 – – – – – 1.0 – – – 0.3 1.6 0.3 0.7 – 0.7 1.3 – – – 0.7 – – – 0.3
13689 13789 14567 14568 14569 14578 14579 14589 14678 14679 14689 14789 15678 15679 15689 15789 16789 23456 23457 23458 23459 23467 23468 23469 23478 23479 23489 23567 23568 23569 23578 23579 23589 23678 23679 23689 23789 24567 24568 24569 24578 24579 24589 24678 24679 24689 24789 25678 25679 25689 25789 26789
a
The numbers refer to the number of the criterion as denoted in Table 1. The percentage refers to the percentage of the sample of 307 patients with 5 criteria who had the combination.
33
DSM-5 field trials [9]. A substantial number of clinicians report that they often do not adhere to the DSM criteria when diagnosing MDD [10]. If clinicians use their own idiosyncratic criteria to diagnose MDD and attend to different symptoms when making the diagnosis, then heterogeneity of presentation will make it more difficult to achieve high levels of reliability. In our analysis we focused on the DSM-IV/DSM-5 criteria as they are written. However, several of the criteria are composites of more than one symptom, only one of which needs to be present for the criterion to have been met. Psychomotor agitation and retardation constitute a single criterion, as do impaired concentration and indecisiveness, worthlessness and guilt, insomnia and hypersomnia, increased and decreased appetite (and weight), and death wishes and suicidal ideation. In each instance only 1 of the 2 symptoms must be present to judge the criterion as present. By combining symptoms into a single criterion, and examining heterogeneity at the criterion level, we have been conservative in delineating the number of possible symptom combinations. If each symptom of these compound criteria is considered separately, then there are 14,528 possible combinations of criteria. A reaction to the limited validity of the DSM diagnostic system in “carving nature at its joints” has been an increased interest in examining dimensional approaches towards understanding psychopathology [11]. In identifying and validating these dimensional representations, it is important to consider that heterogeneity may still remain. Consider, for example, that when a questionnaire is used to measure a dimension, individuals may achieve high scores on that dimension by answering different questions on the scale. If the scales are unidimensional and items measure the same latent construct, then heterogeneity is less likely a problem. However, evidence for the unidimensionality of MDD is inconsistent. There are several limitations to the present study. The subjects were patients presenting for treatment, and they may differ in their symptom presentation from depressed individuals in general. Many individuals were taking psychotropic medication which might have suppressed the expression of some symptoms and therefore influenced the frequency of some criteria combinations. Alternatively, some presumptive symptoms may have actually been medication side effects. Replication of these results in non-treatment seeking general population samples is warranted. Another potential influence on criterion frequency is the sensitivity of the particular instrument’s questions for different symptoms; assessment methods other than the SCID may produce different combinations than those obtained here. Finally, the study was conducted in a single outpatient practice in which the majority of patients were white, were female, and had health insurance. Replication of the results in samples with different demographic characteristics is warranted.
b
Such diagnostic heterogeneity might also explain the poor reliability achieved for diagnosing MDD when diagnosis is based on unstructured clinical interviews as they were in the
References [1] Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz R. Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 1972;26:57-67.
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[2] Cassidy W, Flanagan N, Spellman M, Cohen M. Clinical observations in manic-depressive disease. A quantitative study of one hundred manic–depressive patients and fifty medically sick controls. JAMA 1957;164:1535-46. [3] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, D. C.: American Psychiatric Association; 1994 [4] Zimmerman M, McGlinchey JB, Young D, Chelminski I. Diagnosing major depressive disorder I: a psychometric evaluation of the DSM-IV symptom criteria. J Nerv Ment Dis 2006;194:158-63. [5] Zimmerman M, McGlinchey JB, Young D, Chelminski I. Diagnosing major depressive disorder: II: is there justification for compound symptom criteria? J Nerv Ment Dis 2006;194:235-40. [6] Zimmerman M. Integrating the assessment methods of researchers in routine clinical practice: the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project. In: First M, editor. Standardized Evaluation in Clinical Practice. Washington, DC: American Psychiatric Publishing, Inc.; 2003. p. 29-74.
[7] First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV axis I disorders — patient edition (SCID-I/P, version 2.0). New York: Biometrics Research Department, New York State Psychiatric Institute; 1995. [8] Zimmerman M, Coryell W, Pfohl B. The validity of the dexamethasone suppression test as a marker for endogenous depression. Arch Gen Psychiatry 1986;43:347-55. [9] Regier DA, Narrow WE, Clarke DE, Kraemer HC, Kuramoto SJ, Kuhl EA, et al. DSM-5 field trials in the United States and Canada, part II: test–retest reliability of selected categorical diagnoses. Am J Psychiatry 2013;170:59-70. [10] Zimmerman M, Galione J. Psychiatrists' and nonpsychiatrist physicians' reported use of the DSM-IV criteria for major depressive disorder. J Clin Psychiatry 2010;71:235-8. [11] Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al. Research Domain Criteria (RDOC): toward a new classification framework for research on mental disorders. Am J Psychiatry 2010;167:748-51.
ScienceDirect Comprehensive Psychiatry 56 (2015) 29 – 34 www.elsevier.com/locate/comppsych
How many different ways do patients meet the diagnostic criteria for major depressive disorder? Mark Zimmerman⁎, William Ellison, Diane Young, Iwona Chelminski, Kristy Dalrymple Department of Psychiatry and Human Behavior, Brown Medical School Department of Psychiatry, Rhode Island Hospital, Providence
Abstract There are 227 possible ways to meet the symptom criteria for major depressive disorder (MDD). However, symptom occurrence is not random, and some symptoms co-occur significantly beyond chance. This raises the questions of whether all of the theoretically possible different ways of meeting the MDD criteria actually occur in patients, and whether some combinations of criteria are much more common than others. More than 1500 patients who met DSM-IV criteria for MDD at the time of the evaluation were interviewed with semi-structured interviews. The patients met the MDD symptom criteria in 170 different ways. Put another way, one-quarter (57/227) of the criteria combinations did not occur. The most frequent combination was the presence of all 9 criteria (10.1%, n = 157). Nine combinations (all 9 criteria, 3 of the 8-criterion combinations, 4 of the 7-criterion combinations, and one 6-criterion combination) were present in more than 2% of the patients, together accounting for more than 40% of the diagnoses. The polythetic definition of MDD, which requires a minimum number of criteria from a list, results in significant diagnostic heterogeneity because there are many different ways to meet criteria. While there is significant heterogeneity amongst patients meeting the MDD diagnostic criteria, a relatively small number of combinations could be considered as diagnostic prototypes as they account for more than 40% of the patients diagnosed with MDD. © 2014 Elsevier Inc. All rights reserved.
1. Introduction The era of specified inclusion and exclusion criteria to make psychiatric diagnoses began in 1972 when a group of researchers at Washington University published an article entitled “Diagnostic Criteria for Use in Psychiatric Research” [1]. Referred to as the Feighner criteria (after the lead author of the article), or the Washington University criteria (after the academic affiliation of the authors), this article delineated for the first time specific inclusion and exclusion criteria for 15 disorders that the authors considered to have been empirically validated. While this article is generally credited with ushering in the modern era of specified diagnostic criteria, in fact, this publication was not the first description of specific criteria for depression. In a 1957 report on the clinical features of manic–depressive disorder, Cassidy and colleagues [2] diagnosed depressive
Potential conflicts of interest: None. ⁎ Corresponding author at: 146 West River Street, Providence, RI 02904. E-mail address: [email protected] (M. Zimmerman). http://dx.doi.org/10.1016/j.comppsych.2014.09.007 0010-440X/© 2014 Elsevier Inc. All rights reserved.
disorder in patients who reported both low mood and 6 of a list of 10 symptoms. The ten criterion symptoms of depression listed by Cassidy et al. were slow thinking, poor appetite, constipation, insomnia, fatigue, loss of concentration, suicidal ideas, weight loss, decreased libido, and agitation. The Washington University definition of depression represented a modification of the Cassidy et al. symptom list, deleting one item (constipation) and adding others (guilt, worthlessness, indecisiveness, hypersomnia, pervasive loss of interest). Feighner et al. did not indicate the reasons for changing the criteria developed by Cassidy et al., and, to our knowledge, never published any data to empirically support their selection of particular symptoms over others. Nonetheless, the symptom inclusion criteria identified by the Washington University group have changed relatively little during the past 40 years, thus attesting to the astute observations of these clinical researchers. The symptom inclusion criteria for major depressive disorder (MDD) in the DSM-5 [3], as well as the threshold to distinguish between cases and noncases, are similar to the ones originally articulated by Feighner and colleagues. The DSM-5 symptom inclusion criteria for MDD require the presence of at least five characteristic features from a list
30
M. Zimmerman et al. / Comprehensive Psychiatry 56 (2015) 29–34
of nine, at least one of which must be low mood or anhedonia. This approach towards defining depression, based on a minimum number of features from a longer list, results in heterogeneity in patients’ clinical profile because there are many different possible combinations of criteria that qualify for a diagnosis. Altogether, there are 227 different ways to meet the symptom criteria for MDD, and it is possible for 2 patients diagnosed with MDD to have no symptoms in common. (Because some of the MDD criteria have multiple components, 2 patients can meet the same criterion in different ways. Thus, 2 patients can have no symptoms in common.) While there are numerous ways in which a patient might meet the symptom criteria for MDD, it is also recognized that the criteria “hang together” as a syndrome thereby justifying the identification of the clinical syndrome. While the sensitivity and specificity of the MDD criteria vary, all are independently associated with the diagnostic construct [4], and they co-occur significantly beyond chance [5]. This raises the questions of whether all of the theoretically possible different ways of meeting the MDD criteria actually occurs in patients, and whether some combinations of criteria are much more common than others and capture the majority of patients diagnosed with MDD. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we examined in a large cohort of depressed patients the different ways in which they met the DSM-5 symptom inclusion criteria. We hypothesized that some of the 227 possible criteria combinations would occur more frequently than other combinations.
2. Methods The Rhode Island MIDAS project represents an integration of research methodology into a community-based outpatient practice affiliated with an academic medical center [6]. A comprehensive diagnostic evaluation is conducted upon presentation for treatment. This private practice group predominantly treats individuals with medical insurance (including Medicare but not Medicaid) 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. Data on referral source were recorded for the last 1800 patients enrolled in the study. Patients were most frequently referred from primary care physicians (30.0%), psychotherapists (16.1%), and family members or friends (18.8%). The Rhode Island Hospital institutional review committee approved the research protocol, and all patients provided informed, written consent. The sample examined in the present report was derived from the 3800 psychiatric outpatients evaluated with semistructured diagnostic interviews. Patients were interviewed by a diagnostic rater who administered a modified version of the Structured Clinical Interview for DSM-IV (SCID) [7]. The focus of the present report is the 1566 patients who met
DSM-IV criteria for MDD at the time of the evaluation. The sample included 539 (34.4%) men and 1027 (65.6%) women who ranged in age from 18 to 84 years (mean = 39.9, SD = 12.6). Approximately two-fifths of the patients were married (41.9%, n = 656); the remainder were single (27.3%, n = 427), divorced (16.3%, n = 256), separated (6.3%, n = 99), widowed (2.1%, n = 33), or living with someone as if in a marital relationship (6.1%, n = 95). Approximately two-thirds of the patients attended school beyond high school (68.1%, n = 1066), though only one-quarter graduated a 4-year college (26.2%, n = 410). The racial composition of the sample was 83.9% (n = 1314) white, 5.5% (n = 86) black, 4.2% (n = 65) Hispanic, 0.8% (n = 13) Asian, and 5.6% (n = 88) from another or a combination of the above racial backgrounds. The diagnostic raters were highly trained and monitored throughout the project to minimize rater drift. The diagnostic raters included Ph.D. level psychologists and research assistants with college degrees in the social or biological sciences. Research assistants received three to four months of training during which they observed at least 20 interviews, and they were observed and supervised in their administration of more than 20 evaluations. Psychologists only observed 5 interviews, and they were observed and supervised in their administration of 15 to 20 evaluations. During the course of training the senior author (M.Z.) met with each rater to review the interpretation of every item on the SCID. Also during training, every interview was reviewed on an item-by-item basis by the senior rater who observed the evaluation and by the senior author who reviewed the case with the interviewer. At the end of the training period the raters were required to demonstrate exact, or near exact, agreement with a senior diagnostician on five consecutive evaluations. Throughout the MIDAS project, ongoing supervision of the raters consisted of weekly diagnostic case conferences involving all members of the team. In addition, every case was reviewed by the senior author (M.Z.). Reliability was examined in 65 patients. A joint-interview design was used in which one rater observed another conducting the interview, and both raters independently made their ratings. Of relevance to the present report, the reliability for MDD (k = 0.90) was good. The reliability coefficients of the symptoms of depression ranged from .54 to .94 (mean k = .80). For specific symptoms, Kappa coefficients were: depressed mood (k = .92), loss of interest or pleasure (k = .90), decreased appetite (k = .89), increased appetite (k = .63), decreased weight (k = .69), increased weight (k =.79), insomnia (k = .91), hypersomnia (k = .54), psychomotor agitation (k = .83), psychomotor retardation (k = .63), loss of energy (k = .88), feelings of worthlessness (k = .80), excessive guilt (k = .76), decreased concentration (k = .78), indecisiveness (k = .88), thoughts of death (k = .86), and suicidal ideas/plan/attempt (k = .94).
3. Results Of the 1566 patients who met criteria for MDD, the mean number of criteria met was 6.8 (S.D. = 1.3), and the modal
M. Zimmerman et al. / Comprehensive Psychiatry 56 (2015) 29–34
number of criteria met was 7 (25.2%, n = 394). One hundred fifty-seven individuals met all 9 criteria (10.0%), and 19.6% (n = 307) met the minimum number of 5 criteria. Depressed mood was the most frequent criterion (93.7%) and suicidal thoughts the least frequent (50.0%) (Table 1). The rank order of criterion frequency was similar for patients who met 5, 6, 7 or 8 MDD criteria (Table 1). If each of the 227 possible combinations of criteria was equally likely to occur, then approximately 0.4% (or 7 patients) would meet each combination. The most frequent combination was the presence of all 9 criteria (10.0%, n = 157). An additional two combinations were met by at least 5% of the depressed patients; both were combinations of 8 criteria (Table 2). There are 35 possible combinations of 7 criteria (Table 3). All combinations but two were present in at least one patient. The most frequent 7 criterion combination was present in 3.6% (n = 56) of all patients. Four combinations were present in more than 2% of all patients, and these 4 combinations accounted for 44.3% (175/395) of the patients who met 7 criteria. There are 77 possible combinations of 6 criteria. Only 1 combination was present in more than 2% of all patients (Table 4). Eighteen combinations of 6 criteria were not present in any patient. There are 105 possible combinations of 5 criteria. The most frequent 5-criterion combination was present in 1.8% (n = 29) of all patients (Table 5). Thirty-seven combinations of 5 criteria were not present in any patient. In all, 57 out of the 227 criterion combinations did not occur in any patient.
4. Discussion Polythetic definitions of psychiatric disorders, which require a minimum number of criteria from a list, potentially result in diagnostic heterogeneity because there are many different ways to meet criteria. However, the diagnostic criteria used to define a disorder are not randomly occurring signs and symptoms but instead “hang together” and cooccur at greater than chance levels, thus concerns about
31
Table 2 Frequency of DSM-IV symptom criteria combinations in 367 psychiatric outpatients with major depressive disorder who met 8 criteria. Depression Criteria Combination a
N
%b
12345678 12345679 12345689 12345789 12346789 12356789 12456789 13456789 23456789
121 5 18 17 113 21 40 28 4
33.0 1.4 4.9 4.6 30.8 5.7 10.9 7.6 1.1
a
The numbers refer to the number of the criterion as denoted in Table 1. The percentage refers to the percentage of the sample of 367 patients with 8 criteria who had the combination. b
diagnostic heterogeneity may be more theoretical than actual. To the best of our knowledge this is the first study to empirically examine the expanse of diagnostic heterogeneity of major depressive disorder. In the present study a large sample of psychiatric outpatients was administered a semistructured diagnostic interview. We found that the patients met the DSM-IV symptom criteria for major depressive disorder in 170 different ways. Put another way, one-quarter (57/227) of the criteria combinations did not occur. As predicted, some criteria combinations were much more frequent than others. Nine combinations (all 9 criteria, 3 of the 8-criterion combinations, 4 of the 7-criterion combinations, and one 6-criterion combination) were present in more than 2% of the patients, accounting for more than 40% of the diagnoses. Thus, while there is significant heterogeneity amongst patients meeting the diagnostic criteria, a relatively small number of combinations could be considered as diagnostic prototypes. Future research should examine whether the patients meeting prototypic combinations differ from the depressed patients who do not. Many medical disorders vary in presenting signs and symptoms, and while this might make diagnosis difficult, it does not necessarily indicate disease heterogeneity. However, in diagnostic classifications since DSM-III, the heterogeneity of the major depressive disorder has been acknowledged through
Table 1 Frequency of DSM-IV symptom criteria in 1566 psychiatric outpatients with major depressive disorder meeting different number criteria. Depressive Criterion
1. 2. 3. 4. 5. 6. 7. 8. 9.
Depressed Mood Loss of Interest or Pleasure Appetite/Weight Disturbance Sleep Disturbance Psychomotor Change Loss of Energy Worthlessness/Excessive Guilt Concentration/Indecision Death/Suicidal Thoughts
All Patients (n = 1566)
5 Criteria Met (N = 307)
6 Criteria Met (n = 341)
7 Criteria Me (n = 394)
8 Criteria Met (n = 367)
n
%
n
%
n
%
n
%
N
%
1467 1287 1093 1342 815 1376 1160 1365 783
93.7 82.2 69.8 85.7 52.0 87.9 74.1 87.2 50.0
265 205 139 218 63 235 141 204 65
86.3 66.8 45.3 71.0 20.5 76.5 45.9 66.4 21.2
307 247 207 282 121 290 208 272 112
90.0 72.4 60.7 82.7 35.5 85.0 61.0 79.8 32.8
375 339 263 339 220 344 305 370 203
95.2 86.0 66.8 86.0 55.8 87.3 77.4 93.9 51.5
363 339 327 346 254 350 349 362 246
98.9 92.4 89.1 94.3 69.2 95.4 95.1 98.6 67.0
32
M. Zimmerman et al. / Comprehensive Psychiatry 56 (2015) 29–34
Table 3 Frequency of DSM-IV symptom criteria combinations in 395 psychiatric outpatients with major depressive disorder who met 7 criteria.
Table 4 Frequency of DSM-IV symptom criteria combinations in 341 psychiatric outpatients with major depressive disorder who met 6 criteria.
Depression Criteria Combination a
N
%b
N
%b
%b
7 39 3 17 0 5 56 9 17 12 18 1 1 2 16 35 2 15 7 45 13 14 2 6 5 13 3 12 5 0 3 2 6 1 2
1.8 9.9 0.8 4.3 – 1.3 14.2 2.3 4.3 3.0 4.6 0.3 0.3 0.5 4.1 8.9 0.5 3.8 1.8 11.4 3.3 3.6 0.5 1.5 1.3 3.3 0.8 3.0 1.3 – 0.8 0.5 1.5 0.3 0.5
Depression Criteria Combination a
n
1234567 1234568 1234569 1234578 1234579 1234589 1234678 1234679 1234689 1234789 1235678 1235679 1235689 1235789 1236789 1245678 1245679 1245689 1245789 1246789 1256789 1345678 1345679 1345689 1345789 1346789 1356789 1456789 2345678 2345679 2345689 2345789 2346789 2356789 2456789
Depression Criteria Combination a 123456 123457 123458 123459 123467 123468 123469 123478 123479 123489 123567 123568 123569 123578 123579 123589 123678 123679 123689 123789 124567 124568 124569 124578 124579 124589 124678 124679 124689 124789 125678 125679 125689 125789 126789 134567 134568 134569 134578 134579 134589 134678 134679 134689
6 2 5 0 14 42 10 12 0 2 3 3 2 1 1 1 5 1 4 4 4 16 0 5 2 0 29 11 8 1 4 0 3 0 12 5 9 0 2 0 1 28 3 3
1.8 0.6 1.5 – 4.1 12.3 2.9 3.5 – 0.6 0.9 0.9 0.6 0.3 0.3 0.3 1.5 0.3 1.2 1.2 1.2 4.7 – 1.5 0.6 – 8.5 3.2 2.3 0.3 1.2 – 0.9 – 3.5 1.5 2.6 – 0.6 – 0.3 8.2 0.9 0.9
134789 135678 135679 135689 135789 136789 145678 145679 145689 145789 146789 156789 234567 234568 234569 234578 234579 234589 234678 234679 234689 234789 235678 235679 235689 235789 236789 245678 245679 245689 245789 246789 256789
4 4 0 2 3 1 8 3 2 3 10 3 0 10 0 1 0 0 8 1 2 1 0 0 0 0 1 3 1 2 0 3 1
1.2 1.2 – 0.6 0.9 0.3 2.3 0.9 0.6 0.9 2.9 0.9 – 2.9 – 0.3 – – 2.3 0.3 0.6 0.3 – – – – 0.3 0.9 0.3 0.6 – 0.9 0.3
a
The numbers refer to the number of the criterion as denoted in Table 1. The percentage refers to the percentage of the sample of 394 patients with 7 criteria who had the combination. b
the development of alternative methods of subtyping, though these subtyping methods themselves are often based on polythetic criteria. For example, the DSM-5 anxious distress specifier requires 2 of 5 criteria resulting in 10 possible combinations, and the mixed features specifier requires 3 of 7 criteria resulting in 35 possible combinations. Future research should examine whether the heterogeneity in meeting the criteria for major depressive disorder is reduced (or, alternatively, increased) by methods of subtyping. We speculate that such a high degree of heterogeneity has made it difficult to identify the underlying pathophysiology of depression, and, correspondingly, a biological test for depression. More than 25 years ago, when research on the dexamethasone suppression test was “hot,” one of us began a paper on the validity of the dexamethasone suppression test with the question “How does one validate a biologic marker for endogenous depression when a valid clinical definition does not exist? [8]” An analogous question can be asked in
a
The numbers refer to the number of the criterion as denoted in Table 1. The percentage refers to the percentage of the sample of 341 patients with 6 criteria who had the combination. b
the search for biomarkers for depression. Diagnostic heterogeneity not only may retard the search for etiological mechanisms, pathophysiological correlates, and biological diagnostic tests, but also may limit the effectiveness of treatment efforts. Treatments that may be very effective for subsets of the 227 combinations may appear to have more modest levels of success across the full range of diagnostic combinations. Of course, with such a large number of possible criteria combinations, the sample sizes needed to determine whether there are differential treatment effects would be prohibitively large.
M. Zimmerman et al. / Comprehensive Psychiatry 56 (2015) 29–34 Table 5 Frequency of DSM-IV symptom criteria combinations in 307 psychiatric outpatients with major depressive disorder who met 5 criteria. Depression Criteria Combination a
n
% b Depression Criteria Combination a
n
%b
12345 12346 12347 12348 12349 12356 12357 12358 12359 12367 12368 12369 12378 12379 12389 12456 12457 12458 12459 12467 12468 12469 12478 12479 12489 12567 12568 12569 12578 12579 12589 12678 12679 12689 12789 13456 13457 13458 13459 13467 13468 13469 13478 13479 13489 13567 13568 13569 13578 13579 13589 13678 13679
4 22 2 5 2 1 1 3 0 5 11 1 5 1 0 3 1 5 0 11 26 7 11 4 2 2 2 0 2 1 0 13 0 6 4 4 0 2 1 9 21 4 4 0 1 0 2 0 0 0 0 2 0
1.3 7.2 0.7 1.6 0.7 0.3 0.3 1.0 – 1.6 3.6 0.3 1.6 0.3 – 1.0 0.3 1.6 – 3.6 8.5 2.3 3.6 1.3 0.7 0.7 0.7 – 0.7 0.3 – 4.2 – 2.0 1.3 1.3 – 0.7 0.3 2.9 6.8 1.3 1.3 – 0.3 – 0.7 – – – – 0.7 –
2 1 2 2 0 1 0 0 18 6 3 1 3 1 2 1 9 1 0 1 0 3 11 0 2 0 0 1 0 0 0 0 0 3 0 0 0 1 5 1 2 0 2 4 0 0 0 2 0 0 0 1
0.7 0.3 0.7 0.7 – 0.3 – – 5.9 2.0 1.0 0.3 1.0 0.3 0.7 0.3 2.9 0.3 – 0.3 – 1.0 3.6 – 0.7 – – 0.3 – – – – – 1.0 – – – 0.3 1.6 0.3 0.7 – 0.7 1.3 – – – 0.7 – – – 0.3
13689 13789 14567 14568 14569 14578 14579 14589 14678 14679 14689 14789 15678 15679 15689 15789 16789 23456 23457 23458 23459 23467 23468 23469 23478 23479 23489 23567 23568 23569 23578 23579 23589 23678 23679 23689 23789 24567 24568 24569 24578 24579 24589 24678 24679 24689 24789 25678 25679 25689 25789 26789
a
The numbers refer to the number of the criterion as denoted in Table 1. The percentage refers to the percentage of the sample of 307 patients with 5 criteria who had the combination.
33
DSM-5 field trials [9]. A substantial number of clinicians report that they often do not adhere to the DSM criteria when diagnosing MDD [10]. If clinicians use their own idiosyncratic criteria to diagnose MDD and attend to different symptoms when making the diagnosis, then heterogeneity of presentation will make it more difficult to achieve high levels of reliability. In our analysis we focused on the DSM-IV/DSM-5 criteria as they are written. However, several of the criteria are composites of more than one symptom, only one of which needs to be present for the criterion to have been met. Psychomotor agitation and retardation constitute a single criterion, as do impaired concentration and indecisiveness, worthlessness and guilt, insomnia and hypersomnia, increased and decreased appetite (and weight), and death wishes and suicidal ideation. In each instance only 1 of the 2 symptoms must be present to judge the criterion as present. By combining symptoms into a single criterion, and examining heterogeneity at the criterion level, we have been conservative in delineating the number of possible symptom combinations. If each symptom of these compound criteria is considered separately, then there are 14,528 possible combinations of criteria. A reaction to the limited validity of the DSM diagnostic system in “carving nature at its joints” has been an increased interest in examining dimensional approaches towards understanding psychopathology [11]. In identifying and validating these dimensional representations, it is important to consider that heterogeneity may still remain. Consider, for example, that when a questionnaire is used to measure a dimension, individuals may achieve high scores on that dimension by answering different questions on the scale. If the scales are unidimensional and items measure the same latent construct, then heterogeneity is less likely a problem. However, evidence for the unidimensionality of MDD is inconsistent. There are several limitations to the present study. The subjects were patients presenting for treatment, and they may differ in their symptom presentation from depressed individuals in general. Many individuals were taking psychotropic medication which might have suppressed the expression of some symptoms and therefore influenced the frequency of some criteria combinations. Alternatively, some presumptive symptoms may have actually been medication side effects. Replication of these results in non-treatment seeking general population samples is warranted. Another potential influence on criterion frequency is the sensitivity of the particular instrument’s questions for different symptoms; assessment methods other than the SCID may produce different combinations than those obtained here. Finally, the study was conducted in a single outpatient practice in which the majority of patients were white, were female, and had health insurance. Replication of the results in samples with different demographic characteristics is warranted.
b
Such diagnostic heterogeneity might also explain the poor reliability achieved for diagnosing MDD when diagnosis is based on unstructured clinical interviews as they were in the
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[2] Cassidy W, Flanagan N, Spellman M, Cohen M. Clinical observations in manic-depressive disease. A quantitative study of one hundred manic–depressive patients and fifty medically sick controls. JAMA 1957;164:1535-46. [3] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, D. C.: American Psychiatric Association; 1994 [4] Zimmerman M, McGlinchey JB, Young D, Chelminski I. Diagnosing major depressive disorder I: a psychometric evaluation of the DSM-IV symptom criteria. J Nerv Ment Dis 2006;194:158-63. [5] Zimmerman M, McGlinchey JB, Young D, Chelminski I. Diagnosing major depressive disorder: II: is there justification for compound symptom criteria? J Nerv Ment Dis 2006;194:235-40. [6] Zimmerman M. Integrating the assessment methods of researchers in routine clinical practice: the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project. In: First M, editor. Standardized Evaluation in Clinical Practice. Washington, DC: American Psychiatric Publishing, Inc.; 2003. p. 29-74.
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