- Email: [email protected]
The research diagnostic criteria for endogenous depression and the dexamethasone suppression test: a discriminant function analysis
Psychiatry
Research,
197
14, 197-208
Elsevier
The Research Diagnostic Criteria for Endogenous Depression and the Dexamethasone Suppression A Discriminant Function Analysis Mark
Zimmerman,
Received 1984.
Dalene
Stangl,
and William
June 12. 1984; re1aisec.i\lersion received September
Test:
Coryell 5. 1984; accepted September
17,
Abstract. Most studies examining the validity of the Research Diagnostic Criteria (RDC) for endogenous depression have been negative. RDC endogenous subtyping is not associated with short- or long-term treatment outcome. family history of affective disorder, or premorbid personality disorder. Studies examining its relationship to the dexamethasone suppression test (DST) are mixed; half report a significant association, and half do not. The RDC endogenousdiagnosis may lack validity either because the criteria do not represent, or are not specific to, the endogenous subtype, or the diagnostic algorithm is inappropriate. In the present study, we conduct a discriminant function analysis on the IO criteria for the endogenous subtype using DST results as the independent variable. We constructed a new diagnostic algorithm and cross-validated it on a second patient sample. In both samples the discriminant function classification was significantly associated with DST results, whereas the RDC algorithm was not.
Key Words. Dexamethasone Diagnostic
suppression
test, endogenous
depression,
Research
Criteria.
For the past 50 years, psychiatric nosologists have attempted to distinguish depressed patients with a presumed biological etiology from depressed patients with a presumed nonbiological (characterological. psychosocial) etiology (Gillespie, 1929; Lewis, 1934). The early advocates of this separation asserted that endogenous patients had an as yet undiscovered physical lesion, were more likely to have a positive family history of affective disorder, were less likely to respond to psychotherapy, and were more likely to require hospitalization (Gillespie, 1926; Ross, 1926; Riddoch, 1930; Strauss, 1930: Yellowlees, 1930). The goal of endogenous subtyping is to identify homogeneous groups with a common etiology and treatment response. Present-day definitions strive to identify such patients using operational and demonstrably reliable formats. If they are successful, they should identify patients who, in contrast to nonendogenous depressives, have a better response to antidepressant medications and electroconvulsive therapy (ECT), a higher morbid risk for depression in their first degree relatives. a lower frequency of premorbid personality disorder, and a higher
Mark Zimmerman. B.A., Dalene Stangl. M.A.. and William Coryell, M.D.. are at the University of Iowa College of Medicine. Department of Psychiatry. 500 Newton Rd.. Iowa City, IA 52242. USA. (Reprint
requests to M. Zimmerman.) 0165-1781 X5 SOL30 Q 1985 Elsevier Science Publishers
B.V
198 likelihood of neuroendocrine abnormality on such tests as the dexamethasone suppression test or the thyrotropin-releasing hormone stimulation test. According to the data collected so far, the Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for endogenous depression fail to attain almost all of these goals. The RDC endogenous subtyping has not predicted short-term outcome in controlled trials ofantidepressant medications (Paykel et al., 1982; Razani et al., 1983; Stewart et al., 1983) or long-term outcome in patients receiving doctor’s choice of treatment (Keller and Shapiro, 198 I; Shapiro and Keller, 198 I). Neither has it predicted short- or long-term ECT outcome (Rich et al., 1984; Zimmerman et al., 1984~). though Prusoff et al. (1980) found interpersonal psychotherapy to be more effective in nonendogenous depressed outpatients. Neither family history of depression (Leckman et al., 1984) nor premorbid personality disorder (Pfohl et al., 1984) has been significantly related to the endogenous subtype. Finally. the most extensively studied neuroendocrine correlate of depression, the dexamethasone suppression test (DST), has yielded very mixed results in its relationship to RDC subtyping. Six studies are negative (Meltzer et al., 1982; Peselow et al., 1983; Rabkin et al., 1983; Caine et al., 1984; Stokes et al.. 1984; Zimmerman et al., in press h) and five are positive (Brown and Shuey, 1980; Carroll et al., 1980; Giles and Rush, 1982; Nasr et al., 1983; Rush et al., 1983). There are at least three possible explanations for the failures of the RDC endogenous subtype. First, some investigators may be misapplying the criteria. Helzer and Coryell( 1983) cautioned that while investigators in different research centers may be using the same operational criteria, they may be applying them in substantially different ways. A second possibility is that the criteria do not represent, or are not specific to, the endogenous subtype. The RDC for endogenous depression were apparently distilled from clinical experience. The authors have never provided empirical justification for the selection of the particular symptoms included as criteria. A recent literature review found empirical support for only some of the criteria (Nelson and Charney. 1981). Finally, the criteria themselves may be appropriate, but the diagnostic algorithm may be inappropriate. RDC specifies 10 criteria that are simply scored as present or absent (Table I). Carroll (1984) argued that clinical diagnosis involves complex pattern recognition which is based on differential weighting of information. The RDC, in contrast, gives equal weight to all symptoms. Discriminant function analysis will differentially weight the importance of the symptoms and yield an algorithm that will maximize the association between diagnostic classification and an independent variable. In the present report. we conducted a discriminant function analysis on the 10 criteria for RDC endogenous depression using the DST results as the independent variable. We constructed a new diagnostic algorithm for endogenous depression and cross-validated it on a second sample of patients. Methods From August 1981 until July 1983. the investigators approached a consecutive series of depressed patients admitted to the 5%bed psychiatric inpatient unit of the University of Iowa to
depression1
(2)
even
se
If (more
retarda-
regularly
(3) is
or41
iSADS
(4)
(6) over
inallareasi.
Loss
of
interest
or
as present follow each item.
item 326 2 31
sexual
drive. ISADS
creased
I HRSD item 16 = 2 /
restlessi.
I HRSD item 6 or9 2 1 I
or
down
in or de-
year when not dieting I. usual activities
be pervasive)
(may or may
feeling of being slowed
not
pleasure
(6)
/ SADS item 326 = 6 I
several weeksor20poundsina
(HRSD item 122 1 1 a week
of inpleasure
loss
(41 or
isomeloss
terest
Pervasive
Weight loss 12 pounds
item 351 = 3
worse in the morning.
Mood
Poor appetite.
Group B
Group A
t HRSD item 5 or 6 2 1 I than mere subjective
Psychomotor tion or agitation
Early morning awaken-
(3)
ing or middle insomnia.
350=5or6\
1. The cutoffs on the SADS or HRSD that we used to count a symptom
iHRSDitem2>11
guilt.
or excessive
or inappropriate
reproach
Fee I i n g s of
(1)
ISADS
one.
a loved
item236=3or4r
happens).
the death of
following
ISADS item
when something
good
better,
temporarily,
feel
would have or has had
he
the kind of feeling
is perceived
changes
to en-
depressed,
vironmental
t once
mood
(2)
Lack of reactivity
doesn’t
i.e.,
to de-
as
mood,
quality
distinctly different from
pressed
Distinct
(1)
From Groups A and B a total of at least 4 symptoms for probable, 6 for definite, including at least 1 symptom from group A.
Table 1. RDC for endogenous
200
ask their participation in a project examining the clinical utility of the DST. Patients included in the study met the following criteria: ( 1)they were IX years of age or older, (2) they were admitted for the evaluation and oor treatment of depressive symptoms. and (3) they met the medical and pharmacological exclusion criteria described by Carroll et al. (198 I) for the DST. In addition. we excluded insulin-dependent diabetics (Cameron et al., 1983) and patients taking carbamazepine (Privitera et al., 1982). Faculty members, residents, and medical students obtained psychiatric histories before DST results were available. Two psychiatrists read these histories and independently determined whether the patients met the DSM-/I/ (American Psychiatric Association, 1980) criteria for major depressive disorder (MDD). Only those who did are described in this report. They also diagnosed the patients as psychotic or nonpsychotic and bipolar or unipolar. Disagreements were resolved by discussion. All diagnoses were made without knowledge of DST results. Two hundred and eighty-six patients with MDD consented to participate. Only 10% of the potential participants refused to participate. or, because mute and unresponsive, could not give consent. The 286 participants represent 239 patients who were in the study one time, 22 who participated twice, and one patient who participated three times. In our analyses we included only the first admission for patients in the study more than one time. The DST was completed during the first week of hospitalization (mean q 2.5 f I .6 days). The DST was carried out by administering 1mg of dexamethasone at 2300h; blood was sampled the next day at 0800h and 1600h. Serum cortisol was measured by radioimmunoassay using a specific cortisol antiserum obtained from Damon Diagnostics, Needham Heights, MA. There was no cross-reactivity with dexamethasone. progesterone, testosterone. or I I-deoxycortisol. The intra- and interassay coefficients of variation around the cutoff used to classify patients as nonsuppressors were I I. 1%~and 12.2(;& respectively. Thirty-three normal controls completed the DST based on the same procedure as the depressed patients. The test’s specificity was 97yc with a cutoff of 5 pg:dl and 91% using a cutoff of 4 pg:dl. Nonsuppression was therefore defined as a serum cortisol level > 5.0 pg. dl at either sampling. Two of the researchers (DS. MZ) completed the 24-item Hamilton Rating Scale for Depression (HRSD) (Hamilton. 1967). Beck Depression Inventory (BDI) (Beck et al., 1979). and the Global Assessment Scale (GAS) (Endicott et al.. 1976). either on the day the dexamethasone was administered or the day the blood was drawn. These measures were supplemented with questions from the Schedule for Affective Disorders and Schizophrenia (SADS) (Spitrer and Endicott, 1978) on distinct quality of mood, reactivity, diurnal variation, and anhedonia. The cutoffs that we used on the HRSD and SADS items to count the endogenous symptoms as present or absent are presented in Table 1. All clinical assessments were made without knowledge of DST results. Data Analysis. We consecutively numbered the patients with a three-digit ID upon entry into the study. The derivation group for the discriminant analysis included the even-numbered patients, whereas the odd-numbered patients formed the cross-validation group. Since our goal was to develop a discriminant function (DF) that maximally differentiated between suppressors and nonsuppressors, we used a stepwise discriminant analysis. This method selects variables based on their discriminating power. The best discriminator isentered first. followed by the next best discriminator. and then the next. until all variables that add significant information are entered. The DF did not include variables that did not significantly improve the function’s discriminating power. We simplified the DF by multiplying the standardized DF coefficients by IO and then rounding off to the nearest integer.
Results Two patients refused to answer several of the questions used to diagnose endogenous depression. and due to oversights, the DST was not completed in three other patients: thus, the final sample consists of 257 patients. The average age of the patients was
39.0 f 15.5 years. Eighty-three were male and 174 were female. At baseline the mean 17-item HRSD score was 22.5 k 6.1, the mean 24-item HRSD score was 29.3 f 8.6, the mean BDI score was 28.4 + 1I. I, and the mean GAS rating was 38.8 * 8.2. We diagnosed 174 (67.7%) patients definite endogenous depression, 47 (18.3%) probable endogenous, and 36 (14.0%) nonendogenous. Eighty-five (33.1%) patients were nonsuppressors. Nonsuppression rates were similar in the three RDC groups30.6% (1 1/ 36) of the nonendogenous, 34.0% (16/47) of the probable endogenous, and 33.3% (58/ 174) of the definite endogenous patients were nonsuppressors. Table 2 shows that pervasive or nonpervasive anhedonia, guilt or self-reproach, and middle or terminal insomnia were the most frequently mentioned endogenous symptoms. We examined whether DST nonsuppression was significantly associated with the presence or absence of any of the IO endogenous symptoms. When an alpha level of 0.005 (based on the Bonferroni correction for IO intergroup comparisons) was used, only psychomotor disturbance was significantly related to the DST results (~2 = 10.01, df’ = 1, p < 0.005). There was also a trend for a higher nonsuppression rate if the patients complained of middle or terminal insomnia (x2 = 3.44, 4’f’= I, p < 0.07) and loss of appetite (x2 4.05, 4fZ I, p < 0.05). q
Table 2. Frequency of endogenous symptoms and the univariate relationship between each symptom and the DST results (n = 257) Symptom present
Symptom absent
n
% Nonsumxession
n
% Nonsuppression
159
34.6
98
30.6
143
37.1
114
28.1
68
41 .2
189
30.2
anhedonia
125
35.2
132
31 .I
Guilt or self-reproach
216
32.4
41
36.6
Middle
214
35.5
43
20.9
Distinct
quality
of mood
Lack of reactivity Mood worse in morning Pervasive
or terminal
Psychomotor
insomnia
disturbance
175
39.4
82
19.5
Poor appetite
185
36.8
72
23.6
Weight loss
120
30.0
137
35.8
236
32.6
21
38.1
Pervasrve or nonpervasive anhedonia
Only 5 of the IO endogenous symptoms were significant contributors to the DF separating suppressors and nonsuppressors (Table 3). Four of the five symptoms were scored in the positive direction (i.e., the presence of the symptom predicts nonsuppression). and, surprisingly, one symptom (pervasive or nonpervasive anhedonia) was weighted negatively. In the derivation sample, we selected a cutoff of 8 on the DF because it maximized the relationship between DF classification and the DST results (Fig. 1). With a cutoff of 8, the overall rate of agreement between DF classification and DST results was 63.0% (SO/ 127; cells a and d in Table 4). Other cutoffs produced lower agreement rates. Table 4 shows that only 10.9% (6/ 55) of the patients scoring < 8 were nonsuppressors, whereas 43.0% (3 I/ 72) scoring > 9 were nonsuppressors (x1 = 15.61. df 1, p < 0.001). In the cross-validation group, the q
202
Table 3. Discriminant function (DF) analysis of RDC endogenous using the DST as the independent variable (n = 257)
symptoms
Standardized
Simplified
DF coefficient
weight 5
Mood worse in morning
0.47
Middle
0.57
6
0.40
4
or terminal
Psychomotor
insomnia
disturbance
Poor appetite Pervasive
or nonpervasive
Centroids
Suppressors
anhedonia
correlation
Fig. 1. Relationship (n = 127)
4 -4
= -0.25
Nonsuppressors Canonical
0.43 -0.36
= 0.61
= 0.37
between DST results and DF scores in the derivation group
30 28 26 24
Legend
22 p 5 ,=
20
’
16
g
14
5 a = 2
5
SUPPRESSORS
=
NONSUPPRESSORS
18
l2 10 8
PO I
--fv~~~sm~~~ DISCRIMINANT
FUNCTION
SCORE
203
Table 4. Relationship between discriminant function (DF) classification DST results in the derivation and cross-validation samples
and
DF classification n A. Derivation
Endogenous
Nonendogenous
127
sample
Suppressor
41 31
49
Nonsuppressor
6
B. Cross-validation
sample
130
Suppressor
47
35
Nonsuppressor
15
33
Fig. 2. Relationship group (n = 130)
between DST results and DF scores in the cross-validation
30 28 26 24
r 5 I= $ Ll_ 0 fz
m = z
22
Legend eZaSUPPRESSORS
20
W
NONSUPPRESSORS
18 16 14
l2
P
b
10 8
PO I
d
-~~~~A~~~~~~p DISCRIMINANT
FUNCTION
SCORE
204 nonsuppression rate in the patients scoring < 8 was again significantly lower than the nonsuppression rate in the patients scoring 3 9 (24.2% vs. 48.5%, ~2 = 8.25, df = 1. p < 0.01) (Fig. 2 and Table 4). Discussion In this study we used the DST as the external criterion to construct an empirical, symptom-based definition of endogenous depression. Recent studies question the DST’s specificity to affective disorders in general, and endogenous depression in particular. Coryell(l984) reviewed this literature and concluded that the DSTis rarely abnormal in healthy controls or schizophrenic patients, and that some of the results to the contrary are probably due to the lack of appropriate exclusion criteria, nonspecific assays for cortisol, and the use of overly broad definitions of schizophrenia or overly broad application of narrow definitions. Coryell also concluded that in light of family history, followup, and sleep studies, the occurrence of abnormal DST results among patients with such diagnoses as schizophreniform disorder and borderline personality is more likely to indicate diagnostic heterogeneity than DST nonspecificity. Is the DST specific to endogenous depression? This question is difficult to answer because no operational definition of endogenous depression has been proved valid. We noted that RDC subtyping is not associated with either treatment outcome or family history of depression. Similarly, DSM-III melancholic subtyping is not associated with ECT (Coryell and Zimmerman, 1984; Rich et al., 1984), tricyclic antidepressant (Razani et al., 1983), or monoamine oxidase inhibitor (Davidson et al., 1984) response, and the two studies of family history of affective disorder are negative (Price et al., 1984; Leckman et al., 1984). Without a valid clinical definition of endogenous depression, the DST’s specificity for this diagnosis cannot be evaluated. How, then, does one validate a biological marker for endogenous depression‘? Elsewhere we proposed that the validity of biological (or phenomenological) endogenous subtyping be examined in terms of its concordance with the hypotheses and predictions that reflect the theoretical construct of endogenous depression. Our results strongly supported the construct validity of the DST as an indicator of endogenous depression because DST suppressors had more premorbid personality disorder, poorer social support, more frequent marital separations or divorces, more stressful life events during the year before hospital admission, more nonserious suicide attempts during the index episode, and higher rates of antisocial personality and treated alcoholism in their first degree relatives (Zimmerman et al.. submitted). These findings justify the use of the DSTas an external criterion in empirically developing a system-based definition of endogenous depression. We diagnosed only 147~ of a consecutive series of major depressed inpatients nonendogenous according to the RDC. The Collaborative Studies on the Psychobiology of Depression, for which the RDC were developed, reported that 15.37; of I I I inpatient major depressives had nonendogenous depression (Stokes et al., 1984). In the Clinical Research Branch of the Collaborative Studies. less than 20’; of the inpatient major depressives were diagnosed nonendogenous (N. Andreasen. personal communication). Our rates are thus concordant with these two studies. Williams and Spitzer (1982) noted that the impetus for developing the DSM-III
205 melancholia criteria was to reduce the heterogeneity within the RDC endogenous subgroup. The DSM-llldefinition is based on essentially the same symptoms used to diagnose RDC endogenous depression, but the algorithm was changed (Zimmerman et al., 1984b). The new DSM-IIIalgorithm was also derived from clinical intuition and wisdom (just as the original RDC definition was created) rather than from an empirical data base. In the present study, we used the results of the DST as the independent variable and conducted a discriminant function analysis on the IO RDC endogenous symptoms in order to derive a diagnostic algorithm statistically. Our DF classification, in both the derivation and cross-validation samples. was significantly associated with DST results. In contrast, the RDC subtyping was not related to the DST. It might be added that we reported elsewhere that the DSM-III melancholia criteria were weakly. though significantly. associated to the DST results (Zimmerman et al., in press h). Moreover, in a previous study from this center, Coryell et al. (1982) found no association between DST results and melancholic status. An important methodological issue is whether symptom assessment is based upon behavioral observation or direct interview of the patient. For example, the SADS method of assessing lack of reactivity to positive environmental stimuli and loss of interest or pleasure in one’s usual activities relies heaviiy upon the patient’s report. This method may not be the most valid method of assessing these two symptoms. Nelson et al. ( 198 1) noted that some patients who report that they are unreactive to the environment are. in fact, observed to be responsive to external stimuli. Moreover, they found that observational assessments of reactivity were more predictive of drug-free improvement than were patient reports. On the other hand. we used our HRSD ratings of psychomotor agitation and retardation to determine the presence of these two symptoms. These two H RSD items are rated exlusively from behavioral observations. The SADS measurement of psychomotor disturbance is based upon both behavioral observation and patient report. How well do our results agree with the conclusions reached by Nelson and Charney’s (198 I) comprehensive literature review of the validity of the symptoms of endogenous depression? The six symptoms identified by Nelson and Charney as distinctive for endogenous depression were psychomotor disturbance, lack of reactivity to environmental changes, severe depressed mood, depressive delusions, self-reproach, and loss of interest in pleasurable activity. The RDC does not include severe depressed mood or depressive delusions as endogenous symptoms; therefore, we did not include them in our analyses. Of the remaining four symptoms identified by Nelson and Charney, only psychomotor change was included in the DF. Thus, there was only modest agreement between our results and the conclusions of their review. It should be emphasized that the present study did not attempt to derive the optimal DF distinguishing DST suppressors and nonsuppressors. Our results do not address the question of which symptoms from the universe of psychopathology should be used to diagnose endogenous depression. This important issue should only be examined when comprehensive evaluations with such instruments as the SADS are completed. In addition. we do not address the question of how severe a symptom must be in order to be counted as present. Changing the threshold for symptom inclusion might
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208
Stewart, J.W., Quitkin, F.M., Liebowitz, M., McGrath, P.J., Harrison, W.M., and Klein, D.F. Efficacy of desipramine in depressed outpatients: Response according to Research Diagnostic Criteria diagnosis and severity of illness. Archives of Genera/ Psychiatry, 40, 202 (1983). Stokes, P.E., Stall, P.M., Koslow, S.H., Maas, J.W., Davis, J.M., Swann, A.C., and Robins, E. Pretreatment DST and hypothalamic-pituitary-adrenocortical function in depressed patients and comparison groups: A multicenter study. Archives qf General Ps_vchiatry, 41,257 (1984). Strauss, E.B. Discussion on the diagnosis and treatment of the milder forms of the manicdepressive psychosis. Proceedings ofthe Royal Societ_v of Medicine, 23, 894 (1930). Criteria and DSM-III: An Williams, J.B.W., and Spitzer, R.L. Research Diagnostic annotated comparison. Archives of General Psychiatry, 39, 1283 (1982). Yellowlees, H. Discussion on the diagnosis and treatment of the milder forms of the manicdepressive psychosis. Proceedings of the Royal Societjs of Medicine, 23, 887 (1930). Zimmerman, M., Coryell, W.. and Pfohl, B.M. The importance of diagnostic thresholds in familial classification: The dexamethasone suppression test and familial subtypes ofdepression. Archives of General Psychiatry (in press a). Zimmerman, M., Coryell, W., and Pfohl, B. The validity of the dexamethasone suppression test as a marker for endogenous depression (submitted for publication). Zimmerman, M., Coryell, W., Pfohl, B., and Stangl, D. Four definitions of endogenous depression and the dexamethasone suppression test. Journalof Affective Disorders (in press h). Zimmerman, M., Coryell, W.. and Stangl. D. Five definitions of endogenous depression: Relationship to ECT response. Presented at the Annual Meeting of the Society for Biological Psychiatry, Los Angeles (1984~). Zimmerman, M.. Stangl, D.. Pfohl. B.M., and Coryell, W. Diagnosing RDC endogenous depression and DSM-III melancholia. Psychiatry Research, 12, 173 (1984b).
Research,
197
14, 197-208
Elsevier
The Research Diagnostic Criteria for Endogenous Depression and the Dexamethasone Suppression A Discriminant Function Analysis Mark
Zimmerman,
Received 1984.
Dalene
Stangl,
and William
June 12. 1984; re1aisec.i\lersion received September
Test:
Coryell 5. 1984; accepted September
17,
Abstract. Most studies examining the validity of the Research Diagnostic Criteria (RDC) for endogenous depression have been negative. RDC endogenous subtyping is not associated with short- or long-term treatment outcome. family history of affective disorder, or premorbid personality disorder. Studies examining its relationship to the dexamethasone suppression test (DST) are mixed; half report a significant association, and half do not. The RDC endogenousdiagnosis may lack validity either because the criteria do not represent, or are not specific to, the endogenous subtype, or the diagnostic algorithm is inappropriate. In the present study, we conduct a discriminant function analysis on the IO criteria for the endogenous subtype using DST results as the independent variable. We constructed a new diagnostic algorithm and cross-validated it on a second patient sample. In both samples the discriminant function classification was significantly associated with DST results, whereas the RDC algorithm was not.
Key Words. Dexamethasone Diagnostic
suppression
test, endogenous
depression,
Research
Criteria.
For the past 50 years, psychiatric nosologists have attempted to distinguish depressed patients with a presumed biological etiology from depressed patients with a presumed nonbiological (characterological. psychosocial) etiology (Gillespie, 1929; Lewis, 1934). The early advocates of this separation asserted that endogenous patients had an as yet undiscovered physical lesion, were more likely to have a positive family history of affective disorder, were less likely to respond to psychotherapy, and were more likely to require hospitalization (Gillespie, 1926; Ross, 1926; Riddoch, 1930; Strauss, 1930: Yellowlees, 1930). The goal of endogenous subtyping is to identify homogeneous groups with a common etiology and treatment response. Present-day definitions strive to identify such patients using operational and demonstrably reliable formats. If they are successful, they should identify patients who, in contrast to nonendogenous depressives, have a better response to antidepressant medications and electroconvulsive therapy (ECT), a higher morbid risk for depression in their first degree relatives. a lower frequency of premorbid personality disorder, and a higher
Mark Zimmerman. B.A., Dalene Stangl. M.A.. and William Coryell, M.D.. are at the University of Iowa College of Medicine. Department of Psychiatry. 500 Newton Rd.. Iowa City, IA 52242. USA. (Reprint
requests to M. Zimmerman.) 0165-1781 X5 SOL30 Q 1985 Elsevier Science Publishers
B.V
198 likelihood of neuroendocrine abnormality on such tests as the dexamethasone suppression test or the thyrotropin-releasing hormone stimulation test. According to the data collected so far, the Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for endogenous depression fail to attain almost all of these goals. The RDC endogenous subtyping has not predicted short-term outcome in controlled trials ofantidepressant medications (Paykel et al., 1982; Razani et al., 1983; Stewart et al., 1983) or long-term outcome in patients receiving doctor’s choice of treatment (Keller and Shapiro, 198 I; Shapiro and Keller, 198 I). Neither has it predicted short- or long-term ECT outcome (Rich et al., 1984; Zimmerman et al., 1984~). though Prusoff et al. (1980) found interpersonal psychotherapy to be more effective in nonendogenous depressed outpatients. Neither family history of depression (Leckman et al., 1984) nor premorbid personality disorder (Pfohl et al., 1984) has been significantly related to the endogenous subtype. Finally. the most extensively studied neuroendocrine correlate of depression, the dexamethasone suppression test (DST), has yielded very mixed results in its relationship to RDC subtyping. Six studies are negative (Meltzer et al., 1982; Peselow et al., 1983; Rabkin et al., 1983; Caine et al., 1984; Stokes et al.. 1984; Zimmerman et al., in press h) and five are positive (Brown and Shuey, 1980; Carroll et al., 1980; Giles and Rush, 1982; Nasr et al., 1983; Rush et al., 1983). There are at least three possible explanations for the failures of the RDC endogenous subtype. First, some investigators may be misapplying the criteria. Helzer and Coryell( 1983) cautioned that while investigators in different research centers may be using the same operational criteria, they may be applying them in substantially different ways. A second possibility is that the criteria do not represent, or are not specific to, the endogenous subtype. The RDC for endogenous depression were apparently distilled from clinical experience. The authors have never provided empirical justification for the selection of the particular symptoms included as criteria. A recent literature review found empirical support for only some of the criteria (Nelson and Charney. 1981). Finally, the criteria themselves may be appropriate, but the diagnostic algorithm may be inappropriate. RDC specifies 10 criteria that are simply scored as present or absent (Table I). Carroll (1984) argued that clinical diagnosis involves complex pattern recognition which is based on differential weighting of information. The RDC, in contrast, gives equal weight to all symptoms. Discriminant function analysis will differentially weight the importance of the symptoms and yield an algorithm that will maximize the association between diagnostic classification and an independent variable. In the present report. we conducted a discriminant function analysis on the 10 criteria for RDC endogenous depression using the DST results as the independent variable. We constructed a new diagnostic algorithm for endogenous depression and cross-validated it on a second sample of patients. Methods From August 1981 until July 1983. the investigators approached a consecutive series of depressed patients admitted to the 5%bed psychiatric inpatient unit of the University of Iowa to
depression1
(2)
even
se
If (more
retarda-
regularly
(3) is
or41
iSADS
(4)
(6) over
inallareasi.
Loss
of
interest
or
as present follow each item.
item 326 2 31
sexual
drive. ISADS
creased
I HRSD item 16 = 2 /
restlessi.
I HRSD item 6 or9 2 1 I
or
down
in or de-
year when not dieting I. usual activities
be pervasive)
(may or may
feeling of being slowed
not
pleasure
(6)
/ SADS item 326 = 6 I
several weeksor20poundsina
(HRSD item 122 1 1 a week
of inpleasure
loss
(41 or
isomeloss
terest
Pervasive
Weight loss 12 pounds
item 351 = 3
worse in the morning.
Mood
Poor appetite.
Group B
Group A
t HRSD item 5 or 6 2 1 I than mere subjective
Psychomotor tion or agitation
Early morning awaken-
(3)
ing or middle insomnia.
350=5or6\
1. The cutoffs on the SADS or HRSD that we used to count a symptom
iHRSDitem2>11
guilt.
or excessive
or inappropriate
reproach
Fee I i n g s of
(1)
ISADS
one.
a loved
item236=3or4r
happens).
the death of
following
ISADS item
when something
good
better,
temporarily,
feel
would have or has had
he
the kind of feeling
is perceived
changes
to en-
depressed,
vironmental
t once
mood
(2)
Lack of reactivity
doesn’t
i.e.,
to de-
as
mood,
quality
distinctly different from
pressed
Distinct
(1)
From Groups A and B a total of at least 4 symptoms for probable, 6 for definite, including at least 1 symptom from group A.
Table 1. RDC for endogenous
200
ask their participation in a project examining the clinical utility of the DST. Patients included in the study met the following criteria: ( 1)they were IX years of age or older, (2) they were admitted for the evaluation and oor treatment of depressive symptoms. and (3) they met the medical and pharmacological exclusion criteria described by Carroll et al. (198 I) for the DST. In addition. we excluded insulin-dependent diabetics (Cameron et al., 1983) and patients taking carbamazepine (Privitera et al., 1982). Faculty members, residents, and medical students obtained psychiatric histories before DST results were available. Two psychiatrists read these histories and independently determined whether the patients met the DSM-/I/ (American Psychiatric Association, 1980) criteria for major depressive disorder (MDD). Only those who did are described in this report. They also diagnosed the patients as psychotic or nonpsychotic and bipolar or unipolar. Disagreements were resolved by discussion. All diagnoses were made without knowledge of DST results. Two hundred and eighty-six patients with MDD consented to participate. Only 10% of the potential participants refused to participate. or, because mute and unresponsive, could not give consent. The 286 participants represent 239 patients who were in the study one time, 22 who participated twice, and one patient who participated three times. In our analyses we included only the first admission for patients in the study more than one time. The DST was completed during the first week of hospitalization (mean q 2.5 f I .6 days). The DST was carried out by administering 1mg of dexamethasone at 2300h; blood was sampled the next day at 0800h and 1600h. Serum cortisol was measured by radioimmunoassay using a specific cortisol antiserum obtained from Damon Diagnostics, Needham Heights, MA. There was no cross-reactivity with dexamethasone. progesterone, testosterone. or I I-deoxycortisol. The intra- and interassay coefficients of variation around the cutoff used to classify patients as nonsuppressors were I I. 1%~and 12.2(;& respectively. Thirty-three normal controls completed the DST based on the same procedure as the depressed patients. The test’s specificity was 97yc with a cutoff of 5 pg:dl and 91% using a cutoff of 4 pg:dl. Nonsuppression was therefore defined as a serum cortisol level > 5.0 pg. dl at either sampling. Two of the researchers (DS. MZ) completed the 24-item Hamilton Rating Scale for Depression (HRSD) (Hamilton. 1967). Beck Depression Inventory (BDI) (Beck et al., 1979). and the Global Assessment Scale (GAS) (Endicott et al.. 1976). either on the day the dexamethasone was administered or the day the blood was drawn. These measures were supplemented with questions from the Schedule for Affective Disorders and Schizophrenia (SADS) (Spitrer and Endicott, 1978) on distinct quality of mood, reactivity, diurnal variation, and anhedonia. The cutoffs that we used on the HRSD and SADS items to count the endogenous symptoms as present or absent are presented in Table 1. All clinical assessments were made without knowledge of DST results. Data Analysis. We consecutively numbered the patients with a three-digit ID upon entry into the study. The derivation group for the discriminant analysis included the even-numbered patients, whereas the odd-numbered patients formed the cross-validation group. Since our goal was to develop a discriminant function (DF) that maximally differentiated between suppressors and nonsuppressors, we used a stepwise discriminant analysis. This method selects variables based on their discriminating power. The best discriminator isentered first. followed by the next best discriminator. and then the next. until all variables that add significant information are entered. The DF did not include variables that did not significantly improve the function’s discriminating power. We simplified the DF by multiplying the standardized DF coefficients by IO and then rounding off to the nearest integer.
Results Two patients refused to answer several of the questions used to diagnose endogenous depression. and due to oversights, the DST was not completed in three other patients: thus, the final sample consists of 257 patients. The average age of the patients was
39.0 f 15.5 years. Eighty-three were male and 174 were female. At baseline the mean 17-item HRSD score was 22.5 k 6.1, the mean 24-item HRSD score was 29.3 f 8.6, the mean BDI score was 28.4 + 1I. I, and the mean GAS rating was 38.8 * 8.2. We diagnosed 174 (67.7%) patients definite endogenous depression, 47 (18.3%) probable endogenous, and 36 (14.0%) nonendogenous. Eighty-five (33.1%) patients were nonsuppressors. Nonsuppression rates were similar in the three RDC groups30.6% (1 1/ 36) of the nonendogenous, 34.0% (16/47) of the probable endogenous, and 33.3% (58/ 174) of the definite endogenous patients were nonsuppressors. Table 2 shows that pervasive or nonpervasive anhedonia, guilt or self-reproach, and middle or terminal insomnia were the most frequently mentioned endogenous symptoms. We examined whether DST nonsuppression was significantly associated with the presence or absence of any of the IO endogenous symptoms. When an alpha level of 0.005 (based on the Bonferroni correction for IO intergroup comparisons) was used, only psychomotor disturbance was significantly related to the DST results (~2 = 10.01, df’ = 1, p < 0.005). There was also a trend for a higher nonsuppression rate if the patients complained of middle or terminal insomnia (x2 = 3.44, 4’f’= I, p < 0.07) and loss of appetite (x2 4.05, 4fZ I, p < 0.05). q
Table 2. Frequency of endogenous symptoms and the univariate relationship between each symptom and the DST results (n = 257) Symptom present
Symptom absent
n
% Nonsumxession
n
% Nonsuppression
159
34.6
98
30.6
143
37.1
114
28.1
68
41 .2
189
30.2
anhedonia
125
35.2
132
31 .I
Guilt or self-reproach
216
32.4
41
36.6
Middle
214
35.5
43
20.9
Distinct
quality
of mood
Lack of reactivity Mood worse in morning Pervasive
or terminal
Psychomotor
insomnia
disturbance
175
39.4
82
19.5
Poor appetite
185
36.8
72
23.6
Weight loss
120
30.0
137
35.8
236
32.6
21
38.1
Pervasrve or nonpervasive anhedonia
Only 5 of the IO endogenous symptoms were significant contributors to the DF separating suppressors and nonsuppressors (Table 3). Four of the five symptoms were scored in the positive direction (i.e., the presence of the symptom predicts nonsuppression). and, surprisingly, one symptom (pervasive or nonpervasive anhedonia) was weighted negatively. In the derivation sample, we selected a cutoff of 8 on the DF because it maximized the relationship between DF classification and the DST results (Fig. 1). With a cutoff of 8, the overall rate of agreement between DF classification and DST results was 63.0% (SO/ 127; cells a and d in Table 4). Other cutoffs produced lower agreement rates. Table 4 shows that only 10.9% (6/ 55) of the patients scoring < 8 were nonsuppressors, whereas 43.0% (3 I/ 72) scoring > 9 were nonsuppressors (x1 = 15.61. df 1, p < 0.001). In the cross-validation group, the q
202
Table 3. Discriminant function (DF) analysis of RDC endogenous using the DST as the independent variable (n = 257)
symptoms
Standardized
Simplified
DF coefficient
weight 5
Mood worse in morning
0.47
Middle
0.57
6
0.40
4
or terminal
Psychomotor
insomnia
disturbance
Poor appetite Pervasive
or nonpervasive
Centroids
Suppressors
anhedonia
correlation
Fig. 1. Relationship (n = 127)
4 -4
= -0.25
Nonsuppressors Canonical
0.43 -0.36
= 0.61
= 0.37
between DST results and DF scores in the derivation group
30 28 26 24
Legend
22 p 5 ,=
20
’
16
g
14
5 a = 2
5
SUPPRESSORS
=
NONSUPPRESSORS
18
l2 10 8
PO I
--fv~~~sm~~~ DISCRIMINANT
FUNCTION
SCORE
203
Table 4. Relationship between discriminant function (DF) classification DST results in the derivation and cross-validation samples
and
DF classification n A. Derivation
Endogenous
Nonendogenous
127
sample
Suppressor
41 31
49
Nonsuppressor
6
B. Cross-validation
sample
130
Suppressor
47
35
Nonsuppressor
15
33
Fig. 2. Relationship group (n = 130)
between DST results and DF scores in the cross-validation
30 28 26 24
r 5 I= $ Ll_ 0 fz
m = z
22
Legend eZaSUPPRESSORS
20
W
NONSUPPRESSORS
18 16 14
l2
P
b
10 8
PO I
d
-~~~~A~~~~~~p DISCRIMINANT
FUNCTION
SCORE
204 nonsuppression rate in the patients scoring < 8 was again significantly lower than the nonsuppression rate in the patients scoring 3 9 (24.2% vs. 48.5%, ~2 = 8.25, df = 1. p < 0.01) (Fig. 2 and Table 4). Discussion In this study we used the DST as the external criterion to construct an empirical, symptom-based definition of endogenous depression. Recent studies question the DST’s specificity to affective disorders in general, and endogenous depression in particular. Coryell(l984) reviewed this literature and concluded that the DSTis rarely abnormal in healthy controls or schizophrenic patients, and that some of the results to the contrary are probably due to the lack of appropriate exclusion criteria, nonspecific assays for cortisol, and the use of overly broad definitions of schizophrenia or overly broad application of narrow definitions. Coryell also concluded that in light of family history, followup, and sleep studies, the occurrence of abnormal DST results among patients with such diagnoses as schizophreniform disorder and borderline personality is more likely to indicate diagnostic heterogeneity than DST nonspecificity. Is the DST specific to endogenous depression? This question is difficult to answer because no operational definition of endogenous depression has been proved valid. We noted that RDC subtyping is not associated with either treatment outcome or family history of depression. Similarly, DSM-III melancholic subtyping is not associated with ECT (Coryell and Zimmerman, 1984; Rich et al., 1984), tricyclic antidepressant (Razani et al., 1983), or monoamine oxidase inhibitor (Davidson et al., 1984) response, and the two studies of family history of affective disorder are negative (Price et al., 1984; Leckman et al., 1984). Without a valid clinical definition of endogenous depression, the DST’s specificity for this diagnosis cannot be evaluated. How, then, does one validate a biological marker for endogenous depression‘? Elsewhere we proposed that the validity of biological (or phenomenological) endogenous subtyping be examined in terms of its concordance with the hypotheses and predictions that reflect the theoretical construct of endogenous depression. Our results strongly supported the construct validity of the DST as an indicator of endogenous depression because DST suppressors had more premorbid personality disorder, poorer social support, more frequent marital separations or divorces, more stressful life events during the year before hospital admission, more nonserious suicide attempts during the index episode, and higher rates of antisocial personality and treated alcoholism in their first degree relatives (Zimmerman et al.. submitted). These findings justify the use of the DSTas an external criterion in empirically developing a system-based definition of endogenous depression. We diagnosed only 147~ of a consecutive series of major depressed inpatients nonendogenous according to the RDC. The Collaborative Studies on the Psychobiology of Depression, for which the RDC were developed, reported that 15.37; of I I I inpatient major depressives had nonendogenous depression (Stokes et al., 1984). In the Clinical Research Branch of the Collaborative Studies. less than 20’; of the inpatient major depressives were diagnosed nonendogenous (N. Andreasen. personal communication). Our rates are thus concordant with these two studies. Williams and Spitzer (1982) noted that the impetus for developing the DSM-III
205 melancholia criteria was to reduce the heterogeneity within the RDC endogenous subgroup. The DSM-llldefinition is based on essentially the same symptoms used to diagnose RDC endogenous depression, but the algorithm was changed (Zimmerman et al., 1984b). The new DSM-IIIalgorithm was also derived from clinical intuition and wisdom (just as the original RDC definition was created) rather than from an empirical data base. In the present study, we used the results of the DST as the independent variable and conducted a discriminant function analysis on the IO RDC endogenous symptoms in order to derive a diagnostic algorithm statistically. Our DF classification, in both the derivation and cross-validation samples. was significantly associated with DST results. In contrast, the RDC subtyping was not related to the DST. It might be added that we reported elsewhere that the DSM-III melancholia criteria were weakly. though significantly. associated to the DST results (Zimmerman et al., in press h). Moreover, in a previous study from this center, Coryell et al. (1982) found no association between DST results and melancholic status. An important methodological issue is whether symptom assessment is based upon behavioral observation or direct interview of the patient. For example, the SADS method of assessing lack of reactivity to positive environmental stimuli and loss of interest or pleasure in one’s usual activities relies heaviiy upon the patient’s report. This method may not be the most valid method of assessing these two symptoms. Nelson et al. ( 198 1) noted that some patients who report that they are unreactive to the environment are. in fact, observed to be responsive to external stimuli. Moreover, they found that observational assessments of reactivity were more predictive of drug-free improvement than were patient reports. On the other hand. we used our HRSD ratings of psychomotor agitation and retardation to determine the presence of these two symptoms. These two H RSD items are rated exlusively from behavioral observations. The SADS measurement of psychomotor disturbance is based upon both behavioral observation and patient report. How well do our results agree with the conclusions reached by Nelson and Charney’s (198 I) comprehensive literature review of the validity of the symptoms of endogenous depression? The six symptoms identified by Nelson and Charney as distinctive for endogenous depression were psychomotor disturbance, lack of reactivity to environmental changes, severe depressed mood, depressive delusions, self-reproach, and loss of interest in pleasurable activity. The RDC does not include severe depressed mood or depressive delusions as endogenous symptoms; therefore, we did not include them in our analyses. Of the remaining four symptoms identified by Nelson and Charney, only psychomotor change was included in the DF. Thus, there was only modest agreement between our results and the conclusions of their review. It should be emphasized that the present study did not attempt to derive the optimal DF distinguishing DST suppressors and nonsuppressors. Our results do not address the question of which symptoms from the universe of psychopathology should be used to diagnose endogenous depression. This important issue should only be examined when comprehensive evaluations with such instruments as the SADS are completed. In addition. we do not address the question of how severe a symptom must be in order to be counted as present. Changing the threshold for symptom inclusion might
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