Plasma neopterin in major depression: relationship to basal and stimulated pituitary–adrenal cortical axis function

Psychiatry Research 79 Ž1998. 21]29

Plasma neopterin in major depression: relationship to basal and stimulated pituitary]adrenal cortical axis function Susan M. O’Toolea,b , Francesco Chiappelli c , Robert T. Rubina,U a

Center for Neurosciences Research, MCP l Hahnemann School of Medicine, Allegheny Uni¨ ersity of the Health Sciences, 320 East North A¨ e., Pittsburgh, PA 15212-4772, USA b Duquesne Uni¨ ersity, Graduate School of Nursing, Pittsburgh, PA, USA c U.C.L.A. School of Dentistry, Los Angeles, CA, USA Received 14 July 1997; revised 4 February 1998; accepted 24 February 1998

Abstract We measured plasma neopterin at baseline and after oCRH and ACTH 1-24 stimulation tests in 35 unmedicated, adult major-depressive patients Žmean age s 41 " 12 years. and in 35 normal control subjects individually matched to the patients. Neopterin is released by g-interferon-stimulated macrophages; because g-interferon is secreted by activated T-lymphocytes, elevated circulating neopterin is considered to reflect activation of the cell-mediated immune system. Plasma ACTH 1-39 and cortisol also were measured as indicators of pituitary]adrenal axis activity. Baseline plasma neopterin did not differ significantly between patients and controls Žmedians s 6.25 and 6.57 m grl, respectively., but the baseline neopterin:creatinine ratio showed a trend toward lower values in the patients Ž P - 0.07.. There was no apparent plasma neopterin change from baseline Žarea under the curve-AUC. following oCRH or ACTH 1-24 administration in either group of subjects. As with baseline neopterin, there was no significant patient-control difference in neopterin AUC following either hormone challenge, but there were trends toward lower neopterin:creatinine ratios in the patients following both challenges. In the patients, neither baseline neopterin nor neopterin AUCs following hormone challenge were significantly correlated with age, duration of depressive episode, lifetime number of episodes, melancholic subtype, Hamilton Depression Scale total score, Hamilton factor scores, or the Hamilton suicidality item score. Q 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cell-mediated immunity; CRH; ACTH; Cortisol

U

Corresponding author. Tel.: q1 412 3593235; fax: q1 412 3594499; e-mail: [email protected]

0165-1781r98r$19.00 Q 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0165-1781Ž98.00019-5

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S.M. O’Toole et al. r Psychiatry Research 79 (1998) 21]29

1. Introduction Important reciprocal relationships exist between the hypothalamo]pituitary]adrenal cortical ŽHPA. axis and humoral and cellular components of the immune system. The production of HPA axis-activating cytokines in febrile illness and organ transplantation and the immunosuppressive effect of pharmacological doses of glucocorticoids are well known ŽKelso and Munck, 1984; Blalock and Smith, 1985; Dupont et al., 1985; Bateman et al., 1989; Buzzetti et al., 1989; Munck and Guyre, 1991; Chiappelli and Trignani, 1993; Kunicka et al., 1993; Marx, 1995; Tornatore et al., 1995; Meier, 1996; McEwen et al., 1997.. Specific cytokines activate specific levels of the HPA axis; e.g. the stimulation of CRH secretion by interleukin ŽIL.-1 and IL-6 and stimulation of ACTH secretion by IL-2 and IL-6 ŽBlalock and Smith, 1985; Besedovsky et al., 1986; Berkenbosch et al., 1987; Berton et al., 1987; del Rey et al., 1987; Lumpkin, 1987; Sapolsky et al., 1987; Bateman et al., 1989; Buzzetti et al., 1989; Ur et al., 1992; Tsagarakis and Grossman, 1994; Rivier, 1995.. HPA axis hyperactivity is the most prominent neuroendocrine abnormality in major depression, occurring in 30]50% of patients ŽCarroll et al., 1981; Gold et al., 1984; Arana et al., 1985; Rubin et al., 1987.. Though considerable work has been done attempting to clarify immune changes as biological markers of major depression, the results have not been consistent Žfor reviews, see Stein, 1992; Miller et al., 1993; Reichlin, 1993; Anderson, 1996.. Since most studies have focused on the cellular component of immunity in major depression, we measured plasma neopterin at baseline and after oCRH and ACTH 1-24 stimulation tests in 35 unmedicated, adult major-depressive patients and 35 normal control subjects individually matched to the patients. HPA axis measures were plasma ACTH 1-39 and cortisol. Neopterin is a reliable, easy-to-measure and well-established soluble marker of immune activation. Neopterin, a biopterin precursor, is released by macrophages and reflects activation of the cellmediated immune system ŽT-lymphocytes. ŽHuber

et al., 1984; Chiappelli, 1991.. It is a product of GTP hydrolysis by cyclohydrolase, which is stimulated by interferon-g ŽIFN-g .. IFN-g is secreted by activated T-lymphocytes; therefore, elevated plasma neopterin is considered to represent activation of T-lymphocytes, although it is secreted primarily by myeloid cells. Elevated neopterin thus reflects putative activation of the inflammatory cytokine network, including IL-1, IL-6 and tumor necrosis factor ŽTNF., which in turn act on the central nervous system ŽBesedovsky et al., 1986; Rivier, 1995.. Plasma neopterin often is elevated in states of activated cell-mediated immunity, such as autoimmune illness, organ transplantation and viral infections including the human immunodeficiency virus ŽHIV. ŽKobryn et al., 1989; Fahey et al., 1990; Neale et al., 1990.. It also is elevated in patients with anorexia nervosa, another psychiatric illness in which HPA axis activation occurs ŽChiappelli and Trignani, 1993.. In some studies neopterin results have been reported as a ratio to creatinine rather than as raw values, as reviewed below. The production of creatinine, the main metabolite of creatine, is proportional to total muscle mass and is relatively unaffected by normal physical activity, diet, or urine volume. Schafer et al. Ž1986. reported a correlation between plasma neopterin and serum creatinine of q 0.94 in 170 samples from 22 renal transplant patients with stable graft function, indicating the dependence of both substances on glomerular clearance. Plasma and urine neopterin concentrations in primary major depression have been reported in only a few studies. With reference to plasma neopterin, Dunbar et al. Ž1992. reported significantly higher plasma neopterin:creatinine ratios in 26 depressed patients compared to 63 control subjects. Maes et al. Ž1994. investigated plasma neopterin in 47 depressed subjects Ž16 minor depressives, 13 simple major depressives and 18 melancholic depressives. and in 30 normal control subjects. Plasma neopterin concentrations in all three groups of depressive patients were significantly higher than in the normal control subjects, but they did not differ significantly among themselves. Matsuda et al. Ž1994. also found significantly higher serum neopterin in 67 patients

S.M. O’Toole et al. r Psychiatry Research 79 (1998) 21]29

with major depression compared to 40 healthy volunteers. In contrast, Landmann et al. Ž1997. reported no significant difference in plasma neopterin in 22 patients with major depression compared to 22 sex- and age-matched healthy controls. Fifteen patients completed 12 weeks of antidepressant drug treatment, and plasma neopterin also was measured after weeks 4 and 12. There were no significant differences in neopterin concentration between any of the time points, and there was no significant difference between patients with a positive or negative clinical response. Urine neopterin and biopterin excretion also have been compared in depressed patients versus controls and the results have been mixed. Some studies showed significantly higher urine neopterin or urine neopterin:biopterin ratio in patients ŽDuch et al., 1984; Anderson et al., 1992; Abou-Saleh et al., 1995., whereas others found no significant difference between groups ŽGarbutt et al., 1985; Coppen et al., 1989.. The majority of these previous reports suggested higher plasma neopterin levels and urine neopterin excretion in depressed patients compared to controls. For the present study our hypotheses were as follows: Ž1. The 35 depressed patients would have significantly lower baseline plasma neopterin concentrations than their 35 individually matched controls, based on the significantly higher baseline cortisol in the patients and the suppressive action of cortisol on lymphocyte function. Ž2. The patients also would have significantly lower plasma neopterin concentrations following CRH and ACTH stimulation of the adrenals. Ž3. There would be a significant negative correlation between baseline neopterin and baseline cortisol, and significant positive correlations between plasma neopterin and severity measures of the depressive episode. 2. Methods 2.1. Subjects Thirty-five patients with major depression, ages 18]64 years, and 35 normal control subjects individually matched to each patient on age, sex, race,

23

height, weight and prerpost-menopausal status for the women were studied in the Harbor] U.C.L.A. Clinical Research Center, Torrance, CA. The patients were recruited through the hospital psychiatric emergency and crisis clinics, community psychiatric facilities, psychiatrists in private practice and public service announcements. The control subjects were recruited from hospital employees, their families and friends, and through newspaper announcements. Recruitment and study of both groups occurred during all seasons of the year. Each patient and control first received a clinical interview by the research coordinator. If the subject was suitable for study, the experimental protocol was explained in detail and written informed consent was obtained. On the basis of the Structured Clinical Interview for DSM-III-R ŽSCID. ŽSpitzer et al., 1990. conducted by a psychiatrist, each patient was classified according to the DSM-III-R ŽAmerican Psychiatric Association, 1987.. The Hamilton Depression Rating Scale ŽHamilton, 1967. also was completed on each subject; only DSM-III-R primary major depressives with a Hamilton score of 17 or greater Žfirst 21 items. were included. The controls had no past or present psychiatric illness, based on the non-patient version of the SCID, and their Hamilton scores were F 1. A physical examination, urinalysis and urine screen for common drugs of abuse, complete blood count, blood chemistry panel including creatinine, chest X-ray and electrocardiogram Žfor the subjects over 40 years old. were obtained on each subject. Exclusionary criteria were a history of concomitant psychiatric illness, such as schizophrenia, alcohol abuse, or drug abuse; a history of major medical illness, such as hypertension, diabetes, or other endocrinopathy; abnormal physical or laboratory findings; or taking of any medication that might interfere with the endocrine testing. Most of the patients had received no psychotropic medication in the weeks before the study. Those who had been treated underwent a 2- to 3-week drug-washout period, under close clinical supervision, prior to neuroendocrine testing. For these patients, the depression rating

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S.M. O’Toole et al. r Psychiatry Research 79 (1998) 21]29

scales were completed again, just prior to testing, and the scores used to meet the inclusion criteria and as the baseline values. 2.2. Neuroendocrine protocol Each subject was admitted to the Clinical Research Center at 14.00 h on 2 separate days approx. 1 week apart, and indwelling needles were inserted into a vein in each arm. All subjects were ambulatory. A standard dinner was served at 17.00 h. Blood sampling, 7 ml every 30 min, was begun at 16.00 h and continued for 3 h. At 19.00 h, either oCRH ŽFerring Laboratories, Suffern, NY., 1.0 m grkg, or synthetic ACTH 1-24 ŽCortrosynW, Organon Inc., West Orange, NJ., 0.1 m grkg, was given intravenously as a bolus. The order of testing ŽoCRH or ACTH 1-24 . was randomized across the 2 days. In normal subjects the oCRH dose used produces ACTH and cortisol responses in the high physiologic range ŽStalla et al., 1986., and the ACTH 1-24 dose used produces cortisol responses similar to those induced by strong ‘physiologic’ stresses, such as insulin hypoglycemia ŽGraybeal and Fang, 1985; Azziz et al., 1990.. Blood sampling was continued from the non-injected arm every 15 min until 20.00 h and then every 30 min until 23.00 h. Each sample was drawn into a chilled syringe, placed into chilled plastic tubes containing 100 m l 15% EDTA and 50 m l 20% sodium azide, and centrifuged at 48C for 15 min at 500 = g. Aliquots of plasma were frozen at y808C until analysis for neopterin, ACTH 1-39 and cortisol. All samples from each patient and his or her matched control were analyzed in duplicate in the same assay. Neopterin was analyzed by a doubleantibody radioimmunoassay ŽRIA. ŽDRG International, Mountainside, NJ.. Intra- and inter-assay coefficients of variation were - 12% and 15.2%, respectively, and sensitivity was 0.07 m grl. The neopterin RIA was linear over a range of 0.5]100 m grl. ACTH 1-39 was analyzed by a highly specific immunoradiometric assay ŽIRMA. ŽRaff and Findling, 1989. and cortisol was analyzed by RIA, the details of which have been given previously ŽRubin et al., 1987.. Neopterin and hor-

mone values were computed by log]logit transformation and a non-iterated, unweighted regression of the standard curve, followed by dose interpolation of the samples ŽChang et al., 1975.. The leukocyte differential was determined as part of the complete blood count, and serum creatinine was determined as part of the M-300 blood chemistry panel. 2.3. Statistical analysis Plasma neopterin, ACTH 1-39 and cortisol concentrations from the seven blood samples taken between 16.00 h and 19.00 h, prior to oCRH or ACTH 1-24 administration, were averaged across both sessions and used as the baseline measure. This was done because there were no betweensession differences in any of the measures. The area under the curve for the blood samples taken between 19.15 and 23.00 h, after oCRH or ACTH administration, was calculated by the trapezoidal rule and used as the measure of response. The neopterin measures also were calculated as a ratio to serum creatinine, since Dunbar et al. Ž1992. reported higher neopterin:creatine ratios in depressed patients compared to control subjects. The immune and hormone measures were non-Gaussian-distributed across both the depressives and the controls. Therefore, median values and first and third quartiles are presented for each group in Table 1. Because the controls were individually matched to the patients and the patient]control difference scores were Gaussiandistributed, paired t-tests were used for comparisons between the 35 patients and their controls. For product]moment correlations between neopterin and HPA axis measures and neopterin and measures of depression severity in the patients, log-transformed data were used. All reported significance levels are two-tailed; P- 0.05 is considered statistically significant, and 0.05- P - 0.10 is considered a trend. 3. Results The 35 major depressives had a mean Ž"S.D.. age of 41.4" 11.7 years and their matched con-

S.M. O’Toole et al. r Psychiatry Research 79 (1998) 21]29

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Table 1 Subject characteristics and plasma neopterin measures in 35 adult major depressives pre-treatment compared to their matched controls a

Age Žyears. Body surface area Žm2 . Hamilton Depression Scale Ž24-item. total score Plasma creatinine Žmgrdl. Baseline plasma ACTH1-39 16.00]19.00 h Žngrl. ACTH1-39 AUCc after oCRH Ž103 pmolrl= min. Baseline plasma cortisol 16.00]19.00 h Ž m grl. Cortisol AUC c after oCRH Ž103 nmolrl = min. Cortisol AUC c after ACTH1-24 Ž103 nmolrl = min. Baseline plasma neopterin 16.00]19.00 h Ž m grl. Baseline neopterin Ž16.00] 19.00 h.:creatinine ratio Neopterin AUCc after oCRH Ž103 m grl = min. Neopterin AUCc after oCRH:creatinine ratio Neopterin AUCc after ACTH1-24 Ž10 3 m grl = min. Neopterin AUCc after ACTH1-24 :creatinine ratio

Patients Ž n s 35.

Controls Ž n s 35.

Paired t-testsb Ž t; P-value.

41.4" 11.7 1.73" 0.19

40.6" 13.0 1.77" 0.20

0.76; NS y1.74; NS

27.2" 5.7 0.78" 0.20

F1 0.73" 0.26

} 1.00; NS

4.21; 2.28]7.50

7.07; 4.43]15.0

y2.40;- 0.025

0.70; 0.42]1.36

1.33; 0.87]1.76

y2.99;- 0.006

62.8; 48.9]80.6

51.6; 38.0]66.9

2.12;- 0.05

103; 66]114

94; 72]121

0.87; NS

112; 88]128

106; 88]126

0.01; NS

1.58; 1.42]1.90

1.66; 1.34]1.94

y0.95; NS

2.04; 1.72]2.44

2.31; 1.85]3.11

y1.90;- 0.07

0.35; 0.31]0.46

0.40; 0.32]0.47

y1.20; NS

0.48; 0.41]0.61

0.51; 0.44]0.81

y1.97;- 0.06

0.37; 0.32]0.42

0.38; 0.29]0.46

y0.54; NS

0.51; 0.41]0.64

0.54; 0.42]0.73

y1.80;- 0.09

a

Values are given either as mean " S.D. or as median; first and third quartiles when data for each group were not Gaussian-distributed across subjects. b Paired t-tests done on the raw difference scores, since they approximated a Gaussian distribution Žsee Sec. 2.3.. c AUCs area under the curve over the 4 h of sampling Ž19.00]23.00 h. following administration of either oCRH or ACTH1-24 .

trols had a mean age of 40.6" 13.0 years. Eight patients were men and 27 were women; 28 were Caucasian, four were black and three were Asian; three were bipolar and 32 were unipolar; nine were melancholic subtype; and none had a psychotic depression. This was the first depressive episode for 11 patients, the second for nine patients, the third for five patients and the fourth for four patients. For the other six, the episodes by history were too numerous to count reliably. Median duration of the current episode was 12 months; first and third quartiles were 4 and 24 months. At the time of study, 33 depressives were

outpatients and two were inpatients. Mean Ž"S.D.. 24-item Hamilton Depression Rating Scale total score was 27.2" 5.7. Of the 27 women, 13 were pre-menopausal, two were peri-menopausal, one was post-menopausal with no hormonal replacement therapy, four had had a panhysterectomy and were not on replacement therapy and seven either had had a panhysterectomy or were post-menopausal and were being treated with hormone-replacement therapy. This consisted of conjugated estrogens, 1.25]3.0 mg per day, and for two post-menopausal patients, medroxyprogesterone as well. One pre-meno-

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S.M. O’Toole et al. r Psychiatry Research 79 (1998) 21]29

pausal and one post-menopausal patient also were receiving low-dose thyroid replacement. The control subjects were chosen on a post-hoc basis to be matched individually to the patients on age, sex, race, height, weight and menstrual status for the women. Mean Hamilton total score for the controls was F 1. Height and weight wthe two variables used to calculate body surface area ŽBSA.x and age were not significantly different between the patients and their controls ŽRubin et al., 1996.. Regarding routine blood studies, there were no significant differences between the patients and controls for % lymphocytes, % monocytes, % granulocytes, or chemistry values. The % leukocyte subtypes also were not significantly correlated with baseline cortisol in either the patients or the controls. There was no significant effect of the first vs. second day of testing on baseline plasma neopterin, ACTH 1-39 , or cortisol concentrations in either group of subjects. The oCRH and ACTH 1-24 areas under the curve following their respective administrations were not significantly different between the depressives and their controls, indicating that both groups received quantitatively similar hormone challenges ŽRubin et al., 1996.. There was no discernible neopterin response to either oCRH or ACTH 1-24 administration in either group of subjects; post-hormone challenge values continued to be the same as the baseline values Ždata not shown.. Table 1 presents values for age, body surface area, Hamilton Depression Scale total score, serum creatinine, baseline plasma ACTH 1-39 , cortisol, neopterin and neopterin:creatinine ratio, and ACTH 1 -3 9 , cortisol, neopterin and neopterin:creatinine ratio responses to oCRH and ACTH 1-24 administration for the depressives and their matched controls. Also given in Table 1 are the results of paired t-tests of patient vs. control values. As reported previously ŽRubin et al., 1996., baseline plasma cortisol was significantly higher and baseline plasma ACTH 1-39 was significantly lower in the patients compared to their controls. The ACTH 1-39 response to oCRH was signifi-

cantly blunted in the patients, but the cortisol responses to both oCRH and ACTH 1-24 did not differ significantly between groups. Table 1 also indicates that serum creatinine and baseline plasma neopterin did not differ significantly between patients and controls, but the baseline neopterin:creatinine ratio did show a trend toward lower values in the patients. Similarly, there were no significant between-group differences in neopterin area under the curve ŽAUC. following either oCRH or ACTH 1-24 administration, but there were trends toward lower neopterin: creatinine ratios in the patients following both hormone challenges. Plasma neopterin was not significantly correlated with either plasma ACTH 1-39 or plasma cortisol. Plasma neopterin in the patients also was not significantly correlated with duration of the present depressive episode, lifetime number of episodes, melancholic subtype, Hamilton Depression Scale total score, or the Hamilton suicidality item. Factor scores of the Hamilton Scale also were calculated ŽRhoades and Overall, 1983. in order to relate specific dimensions of symptomatology to plasma neopterin. The seven factors Žsomatization, diurnal variation, sleep disturbance, weight loss, reality disturbance, mood depression, agitationranxiety . were used as independent variables in a stepwise multiple regression analysis with baseline and post-hormone challenge neopterin and neopterin:creatinine ratios as the dependent variables. None of the factors emerged as significant predictors of any of the neopterin measures. In the patients, % lymphocytes was significantly negatively correlated with the Hamilton Depression Scale total score Žy0.44; P- 0.025.. With baseline cortisol controlled for, the partial correlation increased to y 0.50 Ž P- 0.01.. 4. Discussion As reviewed above, the few previous studies of plasma neopterin appear to indicate elevated concentrations in depressed patients compared to normal controls, although the findings have been contradictory. The reasons for these discrepancies are not readily apparent, but there have been

S.M. O’Toole et al. r Psychiatry Research 79 (1998) 21]29

notable methodological differences among the studies, including sample size, degree of matching of controls to patients and methods of statistical analysis. Landmann et al. Ž1997. is the only study besides ours in which normal controls were matched to depressed patients on age and sex. These investigators included 22 subjects in each group, and we included 35 subjects in each group. Neither Landmann et al. nor we found significant differences in plasma neopterin measures between patients and controls, other than a trend toward lower neopterin:creatinine ratios in our patients. Our data indicate a slight suppression of neopterin in the depressed patients compared to their matched controls, as reflected by the trend toward a lower baseline neopterin:creatinine ratio, even though serum creatinine and baseline plasma neopterin themselves were not significantly different. This trend occurred in the context of a significantly higher baseline plasma cortisol in the patients and may have been the result of a chronic, slight suppression of T-lymphocyte activity by increased circulating cortisol. We were not able to include measures of T-lymphocyte function to elucidate this possibility. Even though both oCRH and ACTH 1-24 administration clearly increased plasma cortisol in both the patients and their controls over several hours, plasma neopterin was unaffected. This may have been too short a time to influence neopterin secretion by macrophages secondary to glucocorticoid suppression of INF-g secretion by Tlymphocytes ŽCippitelli et al., 1995.. We know of no studies that address the degree and duration of cortisol elevation required to suppress Tlymphocyte function to the point of reducing neopterin release by monocytes. A significantly lower percentage of circulating lymphocytes in depressed patients with increased HPA axis activity compared to those with normal HPA axis activity has been reported ŽReus and Miner, 1985., as has reduced lymphocyte number and functional response to stimulation in depressives compared to normal controls ŽWeisse, 1992; Miller et al., 1993; Anderson, 1996.. In several studies in which reduced lymphocyte counts and activity have been found in depressed patients compared to controls, increased HPA axis activity

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also was present in the patients ŽKronfol and House, 1984; Schleifer et al., 1984; Targum et al., 1989.. However, in our subjects there was no significant difference in lymphocyte % between patients and controls, even though the patients had significantly higher baseline cortisol, and there was no significant correlation between lymphocyte % and baseline cortisol in either group of subjects. It is of interest, however, that lymphocyte % did correlate significantly negatively with severity of depression as measured by Hamilton Depression Scale total score. Because we were unable to measure T-lymphocyte function directly, as mentioned, we cannot further infer alteration in T-lymphocytes as an explanation for our findings. In conclusion, our study indicates little change in plasma neopterin in depressed patients compared to matched normal control subjects. The lack of any significant relationships between plasma neopterin measures and clinical aspects of the depressive episode suggests that circulating neopterin is not a useful marker for such dimensions of illness as severity or duration of the present episode. Acknowledgements This study was supported by National Institute of Mental Health research grant MH28380 and Research Scientist Award MH47363 Žboth to Dr Rubin., the U.C.L.A. Program on Psychoneuroimmunology, and by a National Institutes of Health grant RR00425 to the Harbor]U.C.L.A. Clinical Research Center. Sylvia Williams, P.A., Scott McGeoy, Kenneth Czambel and Evelyn J. Ford provided valuable technical assistance. References Abou-Saleh, M.T., Anderson, D.N., Collins, J., Hughes, K., Cattell, J., Christopher, G.B., Hamon, G.B., Blair, J.A., 1995. The role of pterins in depression and the effects of antidepressive therapy. Biological Psychiatry 38, 458]463. American Psychiatric Association, 1987. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised, American Psychiatric Press, Washington, DC. Anderson, D.N., Abou-Saleh, M.T., Collins, J., Hughes, K., Cattell, R.J., Hamon, C., Blair, J.A., Dewey, M.E., 1992.

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