Biological and clinical validation of atypical depression

PSYCHIATRY RESEARCH ELSEVIER

Psychiatry Research 60 (1996) 191-198

Biological and clinical

of atypical depression

L a t a K. M c G i n n * , G r e g o r y M. Asnis, Eileen R u b i n s o n Department of Psychiatry, Montefiore Medical Center~Albert Einstein College of Medicine, ! ! ! E. 210 Street, Bronx, NY 10467-2490, USA

Received I I January 1995; revised 6 September 1995; accepted 17 September 1995

Abstract Depressed patients with (a) mood reactivity alone (MR group), (b) mood reactivity plus one or more associated features (atypical depression, AD group), and (c) patients with neither mood reactivity nor atypical depression (non-MR/AD group) were compared on their cortisol response to 75 mg of desif~ramine (DMI), a relatively selective norepinephrine reuptake inhibitor. AD patients exhibited a significantly higher cortisol response to DMI compared with MR and non-MR/AD patients, suggesting that atypical depression may be associated with a less impaired norepinephrine system. MR and non-MR/AD patients did not differ, suggesting that mood reactivity alone is not associated with the biological profile observed in atypical depression. Results indicate that while mood reactivity may be necessary for the diagnosis of at~i:ical depression, the additional presence of at least one associated symptom is required for a distinct biological profile. Our findings provide further biological validation of the concept of atypical depression. Keywords: Desipramine; Affective disorder; Norepinephrine; Cortisol; Sex ratio

1. Introduction

Although a number of groups have defined atypical depression, criteria developed by researchers at Columbia University have been the most widely used. Their criteria require the presence of mood reactivity during the depressive episode and at least one of four associated features: hypersomnia, h.yperphagia, leaden paralysis, and rejection sensitivity (Quitkin et al., 1988, 1991; Rabkin et al., 1996). * Corresponding author, Tel: 6I 718 920-2904; Fax: +i 718 798-1816.

Although mood reactivity is a required feature within their diagnosis and is proposed in most other definitions of atypical depression (West and Dally, 1959; Robinson et al., 1973, 1974; Ravaris et al., 1980; Davidson et ai., 1982; Liebowitz et al., 1984), Quitkin et al. (1989) have demonstrated that in contrast to atypical depression (mood reactivity plus one or more associated symptoms), mood reactivity alone is not associated with a preferential treatment response to monoamine oxidase inhibitors. These findings suggest that mood reactivity, while possibly a necessary ~'eature, may not be sufficient for the diagnosis of atypical depression.

0165-1781/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved PII: SO165-! 781(96)02781-3

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We recently demonstrated that atypical depression was characterized by a greater prevalence of females and a significantly less blunted cortisol response to i.m. desipramine (DMI) compared with findings in nonatypical depression (Asnis et al., 1995, 1996). In keeping with treatment-response findings, we hypothesized that for the same group of patients, mood reactivity alone would not be associated with the clinical dimensions and biological response observed in atypical depression. In the present study, we proposed that depressed patients with mood reactivity alone (MR group) would (a) exhibit a clinical-biological profile different from depressed patients with atypical depression (AD group) and (b) exhibit a profile similar to depressed patients with neither inood reactivity nor atypical depression (non-MR/AD group). These hypotheses "weretested on data from the original cohort of 114 patients (Asnis et al., 1995) to provide fresher clinical and biological validation of the concept of atypical depression. 2. Methods

2.1. Subjects Subjects in this study were 114 consecutive outpatients who were diagnosed with major depressive disorder (MDD, n = 99), minor depressive disorder (MID, n = 5), or intermittent depressive disorder (IDD, n = 10). Table 1 provides the sex and age breakdown for the total group of patients and for each diagnostic subgroup. 2.2. Procedure Diagnoses were based on the administration of the Schedule for Affective Disorders and Schizophrenia (SADS) by trained raters (Spitzer and Endicott, 1975) according to Research Diagnostic Criteria (RDC; Spitzer et al., 1977, 1978). Scores on the Hamilton Rating Scale for Depression (HRSD) were extracted from the SADS (Endicott et al., 1981). All patients completed the Hopkins Symptom Checklist-90 (SCL-90; Derogatis et al., 1974) and were rated by clinici,:~, using the Atypical Depressive Disorder Scale (ADDS; Rabkin et al., 1996). The ADDS assesses mood reactivity and the associated features (hyperphagia, hypersomnia, leaden paralysis, and rejection sensitivity) of atypical depression.

2.3. Biological challenge The cortisol response to i.m. DMI was examined in a subset of 72 patients. At low doses, DMI is a relatively selective norepinephrine reuptake inhibitor (Randrup and Braestrup, 1977) and reliably stimulates the release of cortisol with minimal behaviors/side effects (Asnis et al., 1985, 1986, 1993; Laakman et al., 1985). Laakman et al. (1986) demonstrated that the cortisol response to DMI is predominantly regulated by ¢radrenergic receptors; pretreatment with prazosin, an aradrenergic receptor antagonist, blunted the cortisol response to DMI. All patients were drug free for a minimum of 3 weeks before the procedure. They had normal physical and laboratory evaluations, including thyroid measures. Subjects were excluded if they had taken birth control pills or steroid medications within the last 4 months, or had abused alcohol, drugs, or both within the last 6 months. Subjects fasted from 23:00 h the night before the procedure. On the following morning, they awoke at 07:00 h and reported to the laboratory for the assessment. Subjects were not allowed to nap, snack, exercise, or smoke during the study. At 09:00 h, a butterfly needle was inserted into a forearm vein and kept patent with .heparinized saline. Baseline blood specimens for cortisol (4 ml) were assessed every 15 min for 1 h after which i.m. DMI was administered into the gluteal muscle. Thereafter, blood samples were taken every 15 rain for plasma cortisol (4 ml) and every 30 min for plasma DMI (5 ml) over a 2-hour period. All samples were centrifuged; plasma was pipetted and stored in a 80°C freezer in plastic tubes for later analyses. The DMI challenge procedure was initiated after many patients had already been evaluated with the ADDS. Therefore, only the last 72 patients were assessed with DMI. Plasma cortisol was measured by a radioimmunoassay kit purchased from Diagnostic Products Corporation (Los Angeles, CA). The interassay and intra-assay coefficients of variation were 8.2% and 5.5%, respectively. The DMI assay was determined by the method of Cooper et al. (1975), with a gas liquid chromatographic system fitted with a nitrogen detector. The coefficient of variation was 6.0%. A number of behaviors/side effects (lightheaded-

L.K. McGinn et al. / Psychiatry Research 60 (1996) 191-198

ness, nausea, physical discomfort, drowsiness, anxiety, and depression) were assessed with a 100-ram line analog scale ( 0 = n o t at all, 100 = extremely) during the procedure. Subjects were asked to mark on a line how they were feeling at that moment. Assessments were conducted at baseline just before the DMI challenge and again at 15-min intervals for the first hour, and at 30-rain intervals for the second hour.

2. 4. Data analysis On the basis of the ADDS, patients were judged to be one of the following: mood reactive only (MR, n = 29), atypical (AD; mood reactivity plus at least one of four associated features, n = 33), or neither mood reactive nor atypical (non-MR/AD; patients not meeting any of the criteria for atypical depression, n = 52). The frequency of MR, AD, and non-MR/AD for depressed patients (MDD, IDD, MID) and demographic features of depressed patients with MR, AD, and non-MR/AD were examined by Yates-corrected X2 tests and univariate analyses of variance (ANOVAs). To determine if MR, AD,

193

~nd non-MR/AD patients differed on clinical featt~res, the tI~ree groups were compared on (a) SCL90 ~llbscale T-scores (anxiety, depression, hostility, ¢bsessions/compulsions, paranoia, phobia, psychoses, somatization, and interpersonal sensitivity) with profile multivariate analyses of variance (MANOVAs) and (b) extracted HRSD scores for 'past week' with univariate ANOVAs. To investigate whether the three groups differed biologically, the cortisol response to DMI was compared for a subset of the total sample (MR: n = 19, AD: n = 17, and ~:on-MR/AD: n = 36) with repeated measures analyses of covariance (ANCOVAs), using baseline plasma cortisol, sex, age, RDC diagnosis and duration of current illness as covariates. Baseline extracted HRSD scores and cortisoi levels (i.e., before DMI injec,~ion) were comp~red among the three groups by univariate ANC'¢As. DMI blood levels and behaviors/side effects, assessed throughout the DMI challenge, were compared among the groups by re~ated measures ANOVAs and MANOVAs, respectively. A computer software package (SYSTAT, version 5.1) was used to analyze the data (Wilkinson,

Table ! Comparison of depressed patients with mood reactivity (MR), with atypical depression (AD), and without mood reactivity or atypical depression (non-MR/AD) MR (n = 29)

AD (n = 33)

Non-MR/AD (n = 52) :tatistic

Frequency Total group (n = ! 14) Major depressive disorder (n = 99) Minor depressive disorder (n = 5) Intermittent depressive disorder (n = 10)

29 24

(25.4%) (24.2%)

33 26

(28.9%) (26.3%)

52 49

(45.6%) (49.5%)

2

(40.0%)

!

(20.0%)

2

(40.0%)

3

(30.0%)

6

(60.0%)

1

(16.6%)

Demographic variables Female Male Mean (SD)age (years) Mean (SD) age at onset of 1st episode (years) Mean (SD) duration of current il~ess (weeks)

18 1i 42.9 34.17

(62.1%) (37.9%) (14.5) (14.7)

123.1 (274.9)

29 4 40.7 29.88

(87.9%) (12.1%) (12.6) (13.1)

215.9 (327.6)

32 20 41.8 34.74

(61.5%) (38.5%) (14.8) (14.9)

78.98 (122.3)

X2 = 7.41, df=4, P=0.116

X2 = 7.5, dr= 2, P = 0.023* F = 0.20, df= 2,111, P = 0.82 F = 1.24, df= 2,109, P = 0.295 F = 3.3, dr= 2,110, P = 0.04i**

Note. Follow-up analyses revealed the following: *AD patients vs. MR patients, x 2 = 5.6, df= !, P - 0.018; AD vs. non-MR/AD patients, X2 = 6.9, dr= 1, P = 0.009; MR vs. non-MR/AD patients, X2 - 0.002, dr= 1, P - 0.962. **AD vs. non-MR/AD patients, t = 2.71, df= 82, P = 0.008; AD vs. MR patients, t = 1.2, dr= 60, P = 0.235; MR vs. non-MR/AD patients, t = 0.991, dr= 78, P = 0.325.

194

L.K. McGinn et al, / Psychiatry Research 60 (1996) 191-198

1990). For each analysis, a two-tailed test with a Type I error of 0.05 was used. Where appropriate, follow-up ANOVAs and t tests were conducted. 3. Results

3.1. Clinicaldata Table 1 presents frequency data and demographic features for MR, AD, and non-MR/AD patievts. Of the total group of depressive patients, 25% had MR, 29% had AD, and 46% had neither MR nor AD (non-MR/AD). The relative frequency of MR, AD, and non-MR/AD among the RDC depressive disorders (MDD, MID, and IDD) was not significantly different (x2= 7.41, df=4, P = 0.116). AD patients were significantly more likely to be female than MR patients and nonMR/AD patients (AD patients = 87.9% vs. MR patients = 62.1% and non-MR/AD patients = 61.5°/0, with no differences in sex ratio being observed among the latter two groups. As can be seen in Table 1, the three groups did not differ on current age ( F = 0.20, df= 2,111, P = 0.820) or age of onset of first episode of illness (F = 1.24, df= 2, 109, P = 0.295). On average, AD patients had a significantly longer duration of current episode of illness than non-MR/AD patients (123.1 vs. 78.98 weeks) but did not differ from MR patients (123.1 vs. 215.9 weeks). MR patients and non-MR/AD patients did not differ significantly on duration of current episode of illness (123. I vs. 78.98 weeks) (see Table 1). Of the total group of patients, 4.39% (n = 5) patients met criteria for bipolar I disorder (MR group, n = 1; AD group, n = 1; and non-MR/AD group, n = 3) and 3.51% (n = 4) met criteria for bipolar II disorder (MR group, n = 2, AD group, n = 1, non-MR/AD group, n = 1). Of the cohort of patients with MDD, 42.98% (n = 49) met criteria for recurrent depressive episodes. However, no differences were observed among MR patients, AD patients, and non-MR/AD patients (MR group, n = 11, 45.8%; AD group, n = 14, 53.9%; non-MR/AD group, n = 24, 48.9%; X2 = -0.331, df= 2, P = 0.848). Significant differences emerged among MR patients, AD patients, and non-MR/AD patients when the groups were compared on whether they

met criteria for a primary or secondary M D D (X2 = 10.541, df= 2, P = 0.005). Follow-up analyses conducted to determine the source of significance revealed that patients with non-MR/AD were significantly more likely to meet criteria for a primary MDD (39/49, 79.6%) than were patients with MR (10/24=41.7%) (X2= 10.5, df= 1, P = 0.001). However, AD patients (16/26, 61.5%) did not differ from MR patients (x2= 1.974, df= 1, P = 0 . 1 6 0 ) or non-MR/AD patients (X2= 2.83, df= 1, P = 0.092) on whether they met criteria for a primary MDD. Patients with MR, AD, and non-MR/AD exhibited significant differences on whether they met criteria for the endogenous subtype (X2 = 29.526, df= 2, P < 0.001). Follow-up analyses revealed that patients with non-MR/AD (48/49, 98%) were significantly more likely to meet criteria for endogenous depression than were MR patients (20/24, 83.3%) (X2= 5.4, df= 1, P= 0.020) and AD patients (12/26, 46.2%) (X2= 28.493, df = 1, P < 0.001) while MR patients were significantly more likely to meet criteria for the endogenous subtype than were AD patients (X2 = 7.488, df = 1, P = 0.006). MR patients, AD patients, and non-MR/AD patients did not differ significantly on the SCL-90 (F = 0.53, df= 2,85, P = 0.593) but did show significant differences on extracted HRSD scores (MR patients: mean = 21.48, SD = 6.1; AD patients: mean = 19.49, SD = 7.48; non-MR/AD patients: mean = 23.9, SD = 6.93; F = 4.26, df= 2, 11, P = 0.017). Follow-up analyses revealed that of the three groups, only AD patients scored significantly lower than non-MR/AD patients on extracted HRSD scores (F=7.72, df= 1,83, P = 0.007). MR patients did not significantly differ from non-MR/AD patients (F = 2.47, df= 1,79, P = 0 . 1 2 0 ) or AD patients ( F = 1.31, df = 1, 60, P = 0.258).

3.2. Cortisol measures 3,2.1. Baseline measures (b~rore i.m. DMI). Initial analyses conducted on the subgroup of depressives (n = 72) who were assessed on their cortisol response to DMI revealed that MR patients (n = 19), AD patients (n = 17), and nonMR/AD patients (n = 36) did not differ on the

L.K McGinn et al. /Psychiatry Research 60 (1996) 191-198

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195

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18

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16

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.,.-.... m

~14

~

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"z~ ........ ¢~

o o

"O *=oo0

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Atypical (N = 17) O - "O Mood Reactive (N = 19) Z~I.... ~. [don Mood Reactive / Atypical (N = 36)

0

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15

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30

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45 60 75 TIME (minutes)

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90

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105

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120

Fig. 1. Cortisol levels after desipramine (75 mg, La~.)in depressed patients with mood reactivity, with atypical depression, and without mood reactivity or atypical depression.

following baseline measures: (a) extracted H R S D scores (MR patients: mean = 21.2, SD = 5.9; A D patients: mean = 19.8, SD = 7.9; n o n - M R / A D patients: mean = 23.9, SD = 6.6; F = 0.087, dr= 2,69) and (b) cortisol level (MR patients: mean = 12.72, SD = 6.02; A D patients: mean = 9.4, SD = 4.4; n o n - M R / A D patients: mean = 10.2, SD = 4.03; F = 2.57, df = 2, 69, P = 0.084). 3.2.2. Responseto i.m. DMI. Fig. 1 presents cortisol levels following the i.m. injection of 75 mg of DMI for MR patients (n = 19), A D patients (n = 17), and n o n - M P J A D patients (n = 36). With baseline cortisol level, sex, age, R D C diagnosis, and duration of current illness as covariates, re-

peated measures ANCOVAs were conducted on cortisol levels for MR patients, A D patients, and non-MR/AD patients. Only baseline cortisol level and sex were significant covariates (F values for covariates: baseline cortisol, F = 19.57, df= 1,63, P < 0.001; sex, F = 5.12, df= 1,63, P = 0 . 0 2 7 ; age, F = 0 . 2 8 , df= 1,63, P = 0 . 5 9 6 ; R D C diagnoses, F = 0.11, df= 1,63, P = 0.739; duration of illness, F = 0.18, df= 1,63, P = 0.674). tU~;t~ Nonetheless, "~" . . . . .w a s d ~tSUlt|t, : - ' : ~ . .atlt . . maln " effect for group: M R patients (Adjusted LS Mean = 13.90, SE = 1.23), A D patients (Adjusted LS Mean = 17.67, SE = 1.30), and non-MR/AD patients (Adjusted LS = 13.76, SE = 0.88) differed on cortisol

196

L.K. McGinn eta!./Psychiatry Research 60 (1996) 191-198

levels (F = 4.40, d f - 2,63, P = 0.016). There was also a significant main effect for time: an increase in cortisol over time for the depressive group as a whole (F = 8.5, df = 7,441, P < 0.001). However, the group x time interaction was not significant (F = 0.86, dr= 14,441, P = 0.608), indicating that the pattern of increase over time did not differ among the three groups. Follow-up analyses were conducted among MR patients, AD patients, and non-MR/AD patients to determine the source of significance for main effects, i.e., to see which groups differed on cortisol levels. 3.2.3. MR vs. AD patients. When MR and AD patients were examined, only baseline cortisol level and sex were significant covariates (F values for covariates: baseline cortisol, F = 19.43, df= 1,29, P < 0.001; sex, F-- 6.11, dr-- 1,29, P = 0.02; age, F = 1.69, dr= 1,29; P - 0.204; RDC diagnoses, F = 0.05, df= 1,29, P = 0.825; duration of current illness, F -- 0.007, df = 1,29, P = 0.934). Nonetheless, there was a significant effect for group, indicating that AD patients had a higher cortisol response to i.m. DMI than did MR patients (F = 7.46, df= 1,29, P = 0.011). There was also a significant main effect for time: an increase in cortisol over time for both MR and AD patients (F = 4.25, df= 7,203, P < 0.001). 3.2.4. AD vs. non-MR/AD patients. When cortisol levels were examined separately for AD patients and non-MR/AD patients, only baseline cortisol level was a significant covariate (F values for covariates: baseline cortisol, F = 5.09, df--1,45, P = 0.029; sex, F = 2.02, df= 1,45, P=0.162; age, F=0.06, df=l,45, P=0.803; RDC diagnoses, F = 0.09, df= 1,45, P = 0.772; duration of current illness, F = 1.0, df= 1,45, P - 0.322). Nonetheless, there was a significant main effect: AD patients had a significantly higher cortisol response to i.m. DMI than did non-MR/ AD patients (F = 10.54, df= 1,45, P = 0.002). There was also a significant main effect for time: an increase in cortisol over time for both AD and non-MR/AD patients ( F = 5.56, d r = 7,315, P < 0.001). 3.2.5. MR vs. non-MR/AD patients. When cortisol levels were examined separately for MR patients and non-MR/AD patients, baseline cortisol level and sex were significant covariates (F values

for

covariates:

baseline

cortisol,

F = 16.33,

df= 1,47, P < 0.001; sex, F = 5.17, df= 1,47, P = 0.028; age, F--- 0.40, df= 1,47, P = 0.528; RDC diagnoses, F - 0.23, df = 1,47, P = 0.631; duration of current illness, F = 0.02, dr= 1,47, P = 0.885). There was no significant main effect for group; MR and non-MR/AD patients did not differ on cortisol levels (F=0.009, df= 1,47, P = 0.925). There was a significant main effect for time, i.e., an increase in cortisol over time for both MR ~nd non-MR/AD patients (F = 7.93, dr= 7,329, P < 0.001).

3.3. DMI blood levels and behaviors~side effects A repeated measures ANOVA revealed that all three groups had a similar increase in DMI blood levels over the course of the procedure (group: F = 0.83, dr-- 2,69, P -- 0.439; time: F = 131.23, df= 4,276, P < 0.001; group × time: F = 0.99, dr= 8,276, P = 0.447). A repeated measures MANOVA revealed that MR, AD, and nonMR/AD patients also exhibited a similar increase in behaviors/side effects over the course of the procedure (group: F-= 0.22, dr= 2,68, P = 0.801; time: F = 16.2, dr= 5,340, P < 0.001; group x time: F = 0.58, dr= 10,340, P = 0.830). 4. Uiscussiou

Our study provides further biological and clinical validation of the concept of atypical depression. It demonstrates that atypical depression must not only include mood reactivity (a necessary item for the diagnosis), but also the presence of at least one associated symptom (hyperphagia, hypersomnia, leaden paralysis, or rejection sensitivity) to have a distinct clinical and biological profile. AD patients were found to have a significantly greater proportion of females and a significantly greater cortisol response to a noradrenergic agonist (DMI challenge) than patients with mood reactivity alone (MR patients), and patients with neither mood reactivity nor mood reactivity and at least one associated symptom (non-MR/AD patients). These findings were not due to severity of illness, sex, age, basal cortisol, RDC diagnosis, or duration of current episode of illness. In other words, significant differences in the cortisol re-

L.K. McGinn et al. /Psychiatry Research 60 (1996) 191-198

sponse to DMI were obtained between AD patients and the other two groups even when the above-listed variables were controlled for in the statistical analysis. AD patients also scored significantly lower on extracted HRSD scores than non-MR/AD patients. Of course, this finding should be interpreted with caution as no differences were observed between these groups when HRSD scores were examined only among the subset of patients who received the DMI challenge. Further, the traditional HRSD may potentially underestimate the Jevei of depression experienced by AD patients because it does not examine the presence of symptoms frequently experienced by these patients (e.g., oversleeping and overeating). Finally, AD patients were less likely to meet criteria for the endogenous subtype than were non-MR/AD patients and MR patients. This finding was anticipated since AD patients by definition have fewer nonendogenous features. As hypothesized, MR patients and non-MR/AD patients were found to be similar both clinically (sex ratio, HRSD scores) and biolo~cal!y (cortisol response to DMI). Therefore, the findings inherent to atypical depression are not due primarily to mood reactivity, per se, and indicate that while mood reactivity may or may not be a necessary feature, it is not sufficient for the diagnosis of atypical depression. In summary, consistent with treatment-response data which demonstrate that mood reactivity alone is not associated with a preferential treatment response (Quitkin et al., 1989), our data demonstrate that mood reactivity alone does not appear to have a distinct clinical or biological profile. By contrast, our findings do validate the concept of atypical depression, which is included as a subtype within the mood disorders section in DSM.IV (American Psychiatric Association, 1994). Acknowledgments This work was supported in part by a grant from the MacArthur Foundation and a grant from the National Institute of Mental Health (MH-38807).

197

Earlier versions of this report were presented at the annual meetings of the American Psychiatric Association, May, 1994, and the American College of Neuropsychopharmacology, December, 1994. References American Psychiatric Association. (1994) DSM-IV: Diagnostic and Statistical Manual of Mental Disorders. 4th edn. American Psychiatric Press, Washington, DC. Asnis, G.M., Halbreich, U., Rabinovich, H., Ryan, N.D., Sachar, E.J., Nelson, B., Puig-Antich, J. and Novacenko, H. (1985) The cortisol response to desipramine in endogenous depressives and normal controls: preliminary findings. Psychiatry Res 14, 225-233. Asnis, G.M., Lemus, C.Z. and Halbreich, U. (1986) The desipramine cortisol test -- a selective noradrenergic challenge (relationship to oth~ r cortisol tests in depressives and normals). Psychopharmacol Bull 22, 571-578. Asnis, G.M., McGinn, L.K. and Sanderson, W.C. (1995) Atypical depression: clinical aspects and noradrenergic function. Am J Psychiatry 152, 31-36. Asnis, G.M., McGinn, L.K. and Sanderson, W.C. (1996) Clinical and biological characteristics of atypical depression. In: Widiger, T.A., Frances, A.J., Pincus, H.A., First, M.B., Ross, R. and Davis, W. (Eds.), DSM-IV Sourcebook. Vol. 2. American Psychiatric Press, Washington, DC. Asnis, G.M., Sanderson, W.C. and van Praag, H.M. (1993) The cortisol response to intramuscular desipramine in patients with major depression and normal control subjects. psychiatry Res 44, 237-250. Cooper, T.D., Allen, D. and Simpson, G.M. (1975) A sensitive GLC method for the determination of imipramine and desmethyl-imipramine using a nitrogen detector. Psychopharmacology Communications 4, 445-454. Davidson, J.R.T., Miller, R.D., Turnbuli, C.D. and Sullivan, J.L. (1982) Atypical depression. Arch Gen Psychiatry 39, 527-534. Derogatis, L.R., Lipman, R.S., Rickels, K., Uhlenhuth, E.H. and Covi, L. (1974) The Hopkins Symptom Checklist (HSCL): a self-report inventory. Behav Sci 19, 1-23. Endicott, J., Cohen, J., Nee, J., Fieiss, J. and Sarantakos, S. (1981) Hamilton Depression Rating Scale: extracted form and change versions of the Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 38, 98-108. Laakman, G., Schoen, H.W., Blaschke, D. and Wittman, M. (1985) Dose-dependent growth hormone, prolactin and cortisol stimulation after i.v. administration of desipramine in human subjects. Psychoneuroendocrinology 10, 83-93. ~an, G.M., Wittman, M., Schoen, H.W., Zygan, K., Weiss, A., Meissner, O.A. and Stalla, G.K. (1986) Effects of receptor blockers (methysergide, propranoloi, phentolamine, yohimbine and prazosin) on desipramine-induced pituitary hormone stimulation in humans. II1: Hypothal-

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L.K. McGinn et ai. / Psychiatry Research 60 (1996) 191-198

amo-pituitary-adrenocortical axis. Psychoneuroendocrinology I 1, 475-489. Liebowitz, M.R., Quitkin, F.M., Stewart, J.W., McGrath, P.J., Harrison, W.M., Rabkin, J.G., Tricamo, E., Markowitz, J.S. and Klein, D.S. (1984) Phenelzine venus imipramine in atypical depression. Arch Gen Psychiatry 41, 669-677. Quitkin, F.M., Harrison, W.M., Stewart, J.W., McGrath, P.J., Tricamo, E., Ocepek-Welikson, K., Rabkin, J.G., Wager, S.G., Nunes, E. and Klein, D.F. (1991) Response to phenelzinc and imipramine in placebo responders with atypical depression. Arch Gen Psychiatry 48, 319-323. Quitkin, F.M., McGrath, P., Stewart, J.W., Harrison, W., Wager, S.G., Nunes, E., Rabkin, J.G., Tricamo, E., Markowitz, J. and Klein, D.F. (1989) Phenelzine and imipramine in raood reactive depressives: further delineation of the syndrome of atypical depression. Arch Gen Psychiatry 46, 787-793. Quitkin, F.M., Stewart, J.W., McGrath, P.J., Liebowitz, M.R., Harrison, W.M., Tricamo, E., Klein, D.F., Rabkin, J.G., Markowitz, J.S. and Wager, S.G. (1988) Phenelzine versus imipramine in the treatment of probable atypical depression: defining syndrome boundaries of selective MAOI responders. Am .l Psychiatry 145, 306-311. Rabkin, J.G., Stewart, J.W., Quitkin, F.M., McGrath, P.J., Harrison, W.M. and Klein, D.F. (1996) Should atypical depression be included as a separate entity in DSM.IV?. A review of the research evidence. In: Widiger, T.A., Frances, A.J., Pincus, H.A., First, M.B., Ross, R. and Davis, W. (Eds.), DSM-IV Sourcebook. Vol. 2. American Psychiatric Press, Washington, DC. Randrup, A. and Braestrup, P. (1977) Uptake inhibition of bio-

genic amines by newer antidepressant drugs: relevance to the dopamine hypothesis. Psychopharmacology 53, 309319. Ravaris, C.L., Robinson, D.S., Ives, J.O., Nies, A. and Bartlett, D. (! 980) Phenelzine and amitriptyline in the treatment of depression: a comparison of past and present studies. Arch Gen Psychiatry 37, 1075-1080. Robinson, D.S., Nies, A'., Ravaris, C.L., Ires, J.O. and Lambom, K.R. (1974) Treatment response to MAO inhibitors: relation to depressive typology and blood platelet MAO inhibitors. In: Stuttgart, A.J. (Ed.), Classification and Prediction of Outcome of Depression. Schattauer Verlag, Berlin, pp. 259-267. Robinson, D.S., Nies, A., Ravaris, C.L. and Lamborn, K.R. (1973) The monoamine oxidase inhibitor, phenelzine, in the treatment of depressive-anxiety states. Arch Gen Psychiatry 29, 407-413. Spi.tz.er, R.L. and Endicott, J. (1975) Schedulefor Affective Disorders and Schizophrenia: Lifetime Version. Biometrics Research Division, New York State Psychiatric Institute, New York." Spitzer, R.L., Endicott, J. and Robins, E. (1977) Research Diagnostic Criteriafor a Selected Group of Functional Disorders. 4th edn. Biometrics Division, New York State Psychiatric Institute, New York. Spitzer, R.L., Endicott, J. and Robins, E. (1978) Research Diagnostic Criteria. Arch Gen Psychiatry 35, 777-782. West, E.D. and Dally, P.J. (1959) Effects of iproniazid in depressive syndromes. Br Med J 1, 1491-1494. Wilkinson, L. (1990) S YSTA T: The System for Statistics for the PC. SYSTAT, Inc., Evanston, IL.