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Serial dexamethasone suppression tests by measuring urinary cortisol among rapidly cycling patients
Serial Dexamethasone Suppression Tests by Measuring Urinary Cortisol among Rapidly Cycling Patients Shin-ichiro Tomitaka, Kaoru Sakamoto, Itaru Kojima, and Hiroko Fujita K e y W o r d s : Rapid cycling affective disorder, urinary cortisol, dexamethasone suppression test, hypothalamic-pituitary-adrenocortical axis, state marker
Introduction Rapid cycling affective disorder has been the subject of great theoretical and clinical interest. Since patients with this disorder display frequent alterations of mood over a short time span, they are assumed to constitute good models to study the neurochemical correlates of the switch process between distinct mood states (Gannet al 1993). Although a dominant postulate focuses on central nervous system cholinergic-aminergic transmitter imbalance and hypothalamic-pituitary-adrenocortical(HPA) dysfunction (Carroll, 1982) in relation to the pathophysiology of affective disorders, little information about serial HPA axis function in rapid cycling affective disorder is available. Endocrinologists have recently reported that spot determinations of urinary free cortisol (UFC) are more sensitive and specific than plasma cortisol in diagnosing Cushing's syndrome (Allin et al 1984; Contreras et al 1986; Fujita et al 1991) and some investigators (Carroll et al 1980; Zis et al 1987; Maes et al 1991,) have reported on the validity of UFC to assess HPA axis function in affective disorders. In addition, since the spot determinations of UFC allow patients to collect samples at home without invasive venipuncture, it is appropriate for serial assessment of HPA axis function in patients with rapid cycling. In the present study, we assessed HPA axis function in patients with depression and hypomania by measuring UFC in the From the Department of Psychiatry, Tokyo Women's Medical College (ST, KS); the Institute of Endocrinology, Gunma University (IK); and the Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo, Japan (HF). Address reprint requests to Shin-ichiro Tomitaka, M.D., Department of Cortical Function Disorder, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo 187, Japan. Received June 1, 1994; revised December 30, 1994.
© 1995 Society of Biological Psychiatry
dexamethasone suppression test (DST). We tested the hypothesis that rapid cycling patients display different HPA axis function in different mood states.
Methods We studied six rapidly cycling bipolar women (age 30-53 years; mean, 44 years). Each had been treated in the outpatient psychiatric clinic of Tokyo Women's Medical College. Rapid cycling affective disorder was defined in accordance with the criteria of Dunner and Fiere (1974) as four or more affective episodes per year, and the duration of rapid cycling in each patient was more than 2 years (Tomitaka and Sakamoto 1994). The diagnosis of each episode was made by two psychiatrists using Research Diagnostic Criteria (Spitzer et al 1977). Five of the six rapid cycling patients were diagnosed as bipolar I and one as bipolar II. The study protocol did not determine or influence treatment. The subjects were treated with psychotropics known (Carroll et al 1981) not to interfere with the DST, low-dosage neuroleptics, benzodiazepines (no more than 20 mg/day of diazepam equivalents), lithium, and, most commonly, tricyclic antidepressants. The exclusion criteria proposed by Carroll (1982) were applied. Informed consent was obtained from each patient. Serial DSTs were performed, four times between 1992 and 1993, including twice during different depressive episodes and twice during different hypomanic episodes. On the same day DST was performed the severity of clinical psychopathology was assessed using the Hamilton Rating Scale for Depression (HRSD) (Hamilton 1960) during depression and the Petterson Rating Scale (Petterson et al 1973) during hypomania. The subjects were outpatients at the time of each test. 0006-3223/95/$09.50 SSDI 0006-3223(95)00055-L
Brief Reports
BIOL PSYCHIATRY
129
1995;38:128-130
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predexamethasone 8:00
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150
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Results
The HRSD score (mean - SD) during depression was 14.5 +_ 4.1, while the Petterson Rating score during hypomania was 14.9 _+ 2.5. The HRSD results were in the mildly depressed range, as were the Petterson mania ratings. The test-retest reliability of UFC was expressed as the correlation coefficient in the hypomanic phase (r = 0.732, p < 0.001) and in the depressed phase (r = 0.755, p < 0.001). Figure 1 shows that UFC was generally higher during depression than during hypomania. The difference was significant for both predexamethasone and postdexamethasone UFC, and most significant at 11 PM on day 2. There was a significant suppressant effect of dexamethasone on UFC at 8 A M during depression (p < 0.001) and hypomania (p < 0.001) but not at 11 PM during depression and hypomania. When the distribution of UFC at each point was compared during depression and hypomania in a scattergram, pre- and postdexamethasone UFC at 8 AM had considerable overlaps and pre- and postdexamethasone UFC at 11 PM had few overlaps (Figure 2). This suggests the usefulness of UFC at 11 eM as a state marker for rapid cycling affective disorder. When the criterion value of predexamethasone UFC at 11 PM
o~
hyDomania
hypomania
depression
D
postdexamethasone 8:00
depression
postdexamethasone 23:00
UFC
UFC
375 "
-
35o -" In the urinary free cortisol DST procedure, 1 mg dexamethasone was given orally at 11 PM on day 1. Urine samples were collected at 8 AM and 11 PM on day 1, and at 8 AM, 4 PM, and 11 PM on day 2 (minor deviations of up to _+1 h from these times were permitted). Urine samples were collected after urine had been voided 1-2 h before scheduled time. UFC was measured using a radioimmunoassay kit from Baxter after extraction with methylene chloride. The inter- and intraassay coefficients of variation were 8.2 and 7.3%, respectively. UFC is expressed as micrograms per gram creatinine (Fujita et al 1991). Statistical analysis was performed using the paired t-test.
.... ~.0. ......... . e L . . o•
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Time Figure 1. Urinary free cortisol levels (means -4- S.D.) during depression and hypomania in six rapid cycling patients. Statistical significance: *p < 0.05, **p < 0.01, ***p < 0.001.
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Figure 2. Scattergrams with the pre and post dexamethasone Urinary free cortisol (UFC) values at 8:00 and 23:00 during hypomania and depression.
was set at 130 p~g/g Cr, the sensitivity, specificity, and diagnostic confidence for depression were 75%, 91%, and 68%, respectively. When the criterion value of postdexamethasone UFC at 11 PM was set at 130 Ixg/g Cr, the sensitivity, specificity, and diagnostic confidence for depression were 100%, 92%, and 92%, respectively.
Discussion
We utilized UFC as an indicator to assess HPA function in patients with rapid cycling affective disorder. There are three theoretical advantages of UFC measurement. First, urine specimens contain only free cortisol and reflect the bioactive component (Slaunwhite 1962). Free plasma cortisol (about 10% of total plasma cortisol) represents the bioactive component; however, measurement of free plasma cortisol is impractical (Robin et al 1977). Second, plasma cortisol fluctuates markedly because of episodic and circadian secretion (Hellman et al 1970) and limits the diagnostic value of isolated measurement. Third, since this
130
BIOL PSYCHIATRY 1995;38:128-130
method enables patients to collect samples without invasive venipuncture, it is easily performed without hospitalization. Our results show that UFC levels after dexamethasone administration are effective to differentiate the hypomanic state from the depressed state in patients with rapid cycling affective disorder. For the screening test for HPA axis dysfunction in patients with depression, Zis et al (1987) reported that there was no overlap of spot predexamethasone UFC at 11 PM between healthy volunteers (mean, 47 l~g/g Cr) and nonsuppressors (mean, 158 I~g/g Cr). Our results showing that the criterion value of predexamethasone UFC at 11 PM was set at 130 Ixg/g Cr is in accordance with the findings in the previous report and suggest that postdexamethasone UFC at 11 PM may give better discrimination than predexamethasone UFC at 11 PM. Maes et al (1991) have reported that total (24 h) postdexamethasone UFC is a more sensitive and specific marker for melancholia than postdexamethasone plasma cortisol. According to our results, evening UFC may be especially related to the pathophysiology of the depressive state. However, prior to the application of the spot UFC determination, additional studies will be needed.
Brief Reports
To our knowledge, little information is available on the HPA axis function of rapid cycling patients. In general, HPA axis function in mania was not disturbed exactly as in depression (Carroll 1979). Greden et al (1982) reported that DST was normal during mania and abnormal during and before shifts to depression in three rapidly cycling patients. Our results show that rapid cycling patients have lower UFC levels during hypomanic phases than during depressive phases. Godwin et al (1984) reported that DST nonsuppression was consistent across manic and depressed phases in bipolar patients who were not cycling rapidly. This contrast suggests that rapid cycling patients display more typical biological abnormalities. The present study confirmed the hypothesis HPA axis function varies with the mood states of rapid cycling patients and suggests the validity of urinary free cortisol as a state marker for the depressive state within rapid cycling patients. This study was supported in part by a grant from the Ministry of Health and Welfare of Japan and a grant from the PharmacopsychiatryResearch Foundation.
References Allin RE, McBride JH, Rodgerson DO (1984): The elucidation of adrenal-cortical status by measuring two-hour urinary-free corisol levels. Clin Chim Acta 143:17-22. Carroll BJ (1979): Neuroendocrine function in mania. In B. Shopsin (ed), Manic Illness: A Profile in Psychobiological Research. New York: Raven Press, pp 163--176. Carroll BJ, Feinberg M, Steiner M, et al (1980): Diagnostic application of the dexamethasone suppression test in depressed outpatients. Adv Biol Psychiatry 5:107-116. Carroll BJ, Feinberg M, Greden JF, et al (1981): A specific test for the diagnosis of melancholia. Arch Gen Psychiatry 38: 15-22. Carroll BJ (1982): The dexamethasone suppression test for melancholia. Br J Psychiatry 140:17-22. Contreras LN, Hane S, Tyrrell JB (1986): Urinary cortisol in the assessment of pituitary-adrenal function: Utility of 24-hour and spot determinations. J Clin Endocrinol Metab 62:965969. Dunner DL, Fieve RR (1974): Clinical factors in lithium carbonate prophylaxis failure. Arch Gen Psychiatry 30:229-233. Fujita H, Hata K, Ogata E, et al (1991): Spot determinations of urinary cortisol for the screening of Cushing's syndrome. Endocrinol Jpn 38:441-444. Gann H, Riemann D, Strauss LG, et al (1993): 48-hour rapid cycling: results of psychopathometric, polysomnographic, PET imaging and neuro-endocrine longitudinal investigations in a single case. J Affect Disord 28:133-140. Godwin CD, Greenberg LB, Shulka S (1984): Consistent dexamethasone suppression test results with mania and depression in bipolar illness. Am J Psychiatry 141:1263-1265.
Greden JF, DeVigine J, Albala AA, et al (1982): Serial dexamethasone suppression tests among rapidly cycling bipolar patients. Biol Psychiatry 17:455-462. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62. Hellman L, Nakada F, Curti J, et al (1970): Cortisol is secreted episodically by normal man. J Clin Endocrinol Metab 30: 411-422. Maes M, Vandervorst C, Suy E, et al (1991): A multivariate study of simultaneous escape from suppression by dexamethasone of urinary free cortisol, plasma cortisol, adrenocorticotropic hormone and 13-endorphin in melancholic patients. Acta Psychiatr Scand 83:480-491. Petterson V, Fyro B, Sedval G (1973): A new scale for the longitudinal rating of manic states. Acta Psychiatr Scand 49:248-256. Robin P, Predine J, Milgrom E (1977): Assay of unbound cortisol in plasma. J Clin Endoctqnol Metab 46:277-283. Slaunwhite WR (1962): Inactivity in vivo of transcortin-bound cortisol. Science 135:1062. Spitzer RL, Endicott J, Robins E (1977): Research Diagnostic Criteria (RDC). New York: Biometrics Research Division, New York State Psychiatric Institute. Tomitaka S, Sakamoto K (1994): Definition and prognosis of rapid cycling affective disorder. Am J Psychiatry 151:1524. Zis AP, Remick t/A, Kelly Grant BE, et al (1987): The evening urine cortisol excretion test in depression. Arch Gen Psychia t ~ 44:919-920.
Introduction Rapid cycling affective disorder has been the subject of great theoretical and clinical interest. Since patients with this disorder display frequent alterations of mood over a short time span, they are assumed to constitute good models to study the neurochemical correlates of the switch process between distinct mood states (Gannet al 1993). Although a dominant postulate focuses on central nervous system cholinergic-aminergic transmitter imbalance and hypothalamic-pituitary-adrenocortical(HPA) dysfunction (Carroll, 1982) in relation to the pathophysiology of affective disorders, little information about serial HPA axis function in rapid cycling affective disorder is available. Endocrinologists have recently reported that spot determinations of urinary free cortisol (UFC) are more sensitive and specific than plasma cortisol in diagnosing Cushing's syndrome (Allin et al 1984; Contreras et al 1986; Fujita et al 1991) and some investigators (Carroll et al 1980; Zis et al 1987; Maes et al 1991,) have reported on the validity of UFC to assess HPA axis function in affective disorders. In addition, since the spot determinations of UFC allow patients to collect samples at home without invasive venipuncture, it is appropriate for serial assessment of HPA axis function in patients with rapid cycling. In the present study, we assessed HPA axis function in patients with depression and hypomania by measuring UFC in the From the Department of Psychiatry, Tokyo Women's Medical College (ST, KS); the Institute of Endocrinology, Gunma University (IK); and the Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo, Japan (HF). Address reprint requests to Shin-ichiro Tomitaka, M.D., Department of Cortical Function Disorder, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo 187, Japan. Received June 1, 1994; revised December 30, 1994.
© 1995 Society of Biological Psychiatry
dexamethasone suppression test (DST). We tested the hypothesis that rapid cycling patients display different HPA axis function in different mood states.
Methods We studied six rapidly cycling bipolar women (age 30-53 years; mean, 44 years). Each had been treated in the outpatient psychiatric clinic of Tokyo Women's Medical College. Rapid cycling affective disorder was defined in accordance with the criteria of Dunner and Fiere (1974) as four or more affective episodes per year, and the duration of rapid cycling in each patient was more than 2 years (Tomitaka and Sakamoto 1994). The diagnosis of each episode was made by two psychiatrists using Research Diagnostic Criteria (Spitzer et al 1977). Five of the six rapid cycling patients were diagnosed as bipolar I and one as bipolar II. The study protocol did not determine or influence treatment. The subjects were treated with psychotropics known (Carroll et al 1981) not to interfere with the DST, low-dosage neuroleptics, benzodiazepines (no more than 20 mg/day of diazepam equivalents), lithium, and, most commonly, tricyclic antidepressants. The exclusion criteria proposed by Carroll (1982) were applied. Informed consent was obtained from each patient. Serial DSTs were performed, four times between 1992 and 1993, including twice during different depressive episodes and twice during different hypomanic episodes. On the same day DST was performed the severity of clinical psychopathology was assessed using the Hamilton Rating Scale for Depression (HRSD) (Hamilton 1960) during depression and the Petterson Rating Scale (Petterson et al 1973) during hypomania. The subjects were outpatients at the time of each test. 0006-3223/95/$09.50 SSDI 0006-3223(95)00055-L
Brief Reports
BIOL PSYCHIATRY
129
1995;38:128-130
.E ,i-,
¢o
T
300
~
o hypomania .
.
•
depression
UFC
UFC
375
375 '
350
3SO '
OO
325
325
m 250" ~
B predexamethasone 23:00
predexamethasone 8:00
A
350
-
(J
300 275 250 ' 225 200
3OO 275
v
-
250 22S
150
200
t~
150
I00"
50
8
23
8
16
23
• 00
150 125
100
100'
Results
The HRSD score (mean - SD) during depression was 14.5 +_ 4.1, while the Petterson Rating score during hypomania was 14.9 _+ 2.5. The HRSD results were in the mildly depressed range, as were the Petterson mania ratings. The test-retest reliability of UFC was expressed as the correlation coefficient in the hypomanic phase (r = 0.732, p < 0.001) and in the depressed phase (r = 0.755, p < 0.001). Figure 1 shows that UFC was generally higher during depression than during hypomania. The difference was significant for both predexamethasone and postdexamethasone UFC, and most significant at 11 PM on day 2. There was a significant suppressant effect of dexamethasone on UFC at 8 A M during depression (p < 0.001) and hypomania (p < 0.001) but not at 11 PM during depression and hypomania. When the distribution of UFC at each point was compared during depression and hypomania in a scattergram, pre- and postdexamethasone UFC at 8 AM had considerable overlaps and pre- and postdexamethasone UFC at 11 PM had few overlaps (Figure 2). This suggests the usefulness of UFC at 11 eM as a state marker for rapid cycling affective disorder. When the criterion value of predexamethasone UFC at 11 PM
o~
hyDomania
hypomania
depression
D
postdexamethasone 8:00
depression
postdexamethasone 23:00
UFC
UFC
375 "
-
35o -" In the urinary free cortisol DST procedure, 1 mg dexamethasone was given orally at 11 PM on day 1. Urine samples were collected at 8 AM and 11 PM on day 1, and at 8 AM, 4 PM, and 11 PM on day 2 (minor deviations of up to _+1 h from these times were permitted). Urine samples were collected after urine had been voided 1-2 h before scheduled time. UFC was measured using a radioimmunoassay kit from Baxter after extraction with methylene chloride. The inter- and intraassay coefficients of variation were 8.2 and 7.3%, respectively. UFC is expressed as micrograms per gram creatinine (Fujita et al 1991). Statistical analysis was performed using the paired t-test.
.... ~.0. ......... . e L . . o•
75
7S
375
0
175
oo
lZS
Time Figure 1. Urinary free cortisol levels (means -4- S.D.) during depression and hypomania in six rapid cycling patients. Statistical significance: *p < 0.05, **p < 0.01, ***p < 0.001.
•
°8o
17S
._= L-
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350
szs : 300 : zz5 -"
300 " ~" 275 " C_)
00
175 "
125 -
ns
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200 "
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•
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125 "
el
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75
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Figure 2. Scattergrams with the pre and post dexamethasone Urinary free cortisol (UFC) values at 8:00 and 23:00 during hypomania and depression.
was set at 130 p~g/g Cr, the sensitivity, specificity, and diagnostic confidence for depression were 75%, 91%, and 68%, respectively. When the criterion value of postdexamethasone UFC at 11 PM was set at 130 Ixg/g Cr, the sensitivity, specificity, and diagnostic confidence for depression were 100%, 92%, and 92%, respectively.
Discussion
We utilized UFC as an indicator to assess HPA function in patients with rapid cycling affective disorder. There are three theoretical advantages of UFC measurement. First, urine specimens contain only free cortisol and reflect the bioactive component (Slaunwhite 1962). Free plasma cortisol (about 10% of total plasma cortisol) represents the bioactive component; however, measurement of free plasma cortisol is impractical (Robin et al 1977). Second, plasma cortisol fluctuates markedly because of episodic and circadian secretion (Hellman et al 1970) and limits the diagnostic value of isolated measurement. Third, since this
130
BIOL PSYCHIATRY 1995;38:128-130
method enables patients to collect samples without invasive venipuncture, it is easily performed without hospitalization. Our results show that UFC levels after dexamethasone administration are effective to differentiate the hypomanic state from the depressed state in patients with rapid cycling affective disorder. For the screening test for HPA axis dysfunction in patients with depression, Zis et al (1987) reported that there was no overlap of spot predexamethasone UFC at 11 PM between healthy volunteers (mean, 47 l~g/g Cr) and nonsuppressors (mean, 158 I~g/g Cr). Our results showing that the criterion value of predexamethasone UFC at 11 PM was set at 130 Ixg/g Cr is in accordance with the findings in the previous report and suggest that postdexamethasone UFC at 11 PM may give better discrimination than predexamethasone UFC at 11 PM. Maes et al (1991) have reported that total (24 h) postdexamethasone UFC is a more sensitive and specific marker for melancholia than postdexamethasone plasma cortisol. According to our results, evening UFC may be especially related to the pathophysiology of the depressive state. However, prior to the application of the spot UFC determination, additional studies will be needed.
Brief Reports
To our knowledge, little information is available on the HPA axis function of rapid cycling patients. In general, HPA axis function in mania was not disturbed exactly as in depression (Carroll 1979). Greden et al (1982) reported that DST was normal during mania and abnormal during and before shifts to depression in three rapidly cycling patients. Our results show that rapid cycling patients have lower UFC levels during hypomanic phases than during depressive phases. Godwin et al (1984) reported that DST nonsuppression was consistent across manic and depressed phases in bipolar patients who were not cycling rapidly. This contrast suggests that rapid cycling patients display more typical biological abnormalities. The present study confirmed the hypothesis HPA axis function varies with the mood states of rapid cycling patients and suggests the validity of urinary free cortisol as a state marker for the depressive state within rapid cycling patients. This study was supported in part by a grant from the Ministry of Health and Welfare of Japan and a grant from the PharmacopsychiatryResearch Foundation.
References Allin RE, McBride JH, Rodgerson DO (1984): The elucidation of adrenal-cortical status by measuring two-hour urinary-free corisol levels. Clin Chim Acta 143:17-22. Carroll BJ (1979): Neuroendocrine function in mania. In B. Shopsin (ed), Manic Illness: A Profile in Psychobiological Research. New York: Raven Press, pp 163--176. Carroll BJ, Feinberg M, Steiner M, et al (1980): Diagnostic application of the dexamethasone suppression test in depressed outpatients. Adv Biol Psychiatry 5:107-116. Carroll BJ, Feinberg M, Greden JF, et al (1981): A specific test for the diagnosis of melancholia. Arch Gen Psychiatry 38: 15-22. Carroll BJ (1982): The dexamethasone suppression test for melancholia. Br J Psychiatry 140:17-22. Contreras LN, Hane S, Tyrrell JB (1986): Urinary cortisol in the assessment of pituitary-adrenal function: Utility of 24-hour and spot determinations. J Clin Endocrinol Metab 62:965969. Dunner DL, Fieve RR (1974): Clinical factors in lithium carbonate prophylaxis failure. Arch Gen Psychiatry 30:229-233. Fujita H, Hata K, Ogata E, et al (1991): Spot determinations of urinary cortisol for the screening of Cushing's syndrome. Endocrinol Jpn 38:441-444. Gann H, Riemann D, Strauss LG, et al (1993): 48-hour rapid cycling: results of psychopathometric, polysomnographic, PET imaging and neuro-endocrine longitudinal investigations in a single case. J Affect Disord 28:133-140. Godwin CD, Greenberg LB, Shulka S (1984): Consistent dexamethasone suppression test results with mania and depression in bipolar illness. Am J Psychiatry 141:1263-1265.
Greden JF, DeVigine J, Albala AA, et al (1982): Serial dexamethasone suppression tests among rapidly cycling bipolar patients. Biol Psychiatry 17:455-462. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62. Hellman L, Nakada F, Curti J, et al (1970): Cortisol is secreted episodically by normal man. J Clin Endocrinol Metab 30: 411-422. Maes M, Vandervorst C, Suy E, et al (1991): A multivariate study of simultaneous escape from suppression by dexamethasone of urinary free cortisol, plasma cortisol, adrenocorticotropic hormone and 13-endorphin in melancholic patients. Acta Psychiatr Scand 83:480-491. Petterson V, Fyro B, Sedval G (1973): A new scale for the longitudinal rating of manic states. Acta Psychiatr Scand 49:248-256. Robin P, Predine J, Milgrom E (1977): Assay of unbound cortisol in plasma. J Clin Endoctqnol Metab 46:277-283. Slaunwhite WR (1962): Inactivity in vivo of transcortin-bound cortisol. Science 135:1062. Spitzer RL, Endicott J, Robins E (1977): Research Diagnostic Criteria (RDC). New York: Biometrics Research Division, New York State Psychiatric Institute. Tomitaka S, Sakamoto K (1994): Definition and prognosis of rapid cycling affective disorder. Am J Psychiatry 151:1524. Zis AP, Remick t/A, Kelly Grant BE, et al (1987): The evening urine cortisol excretion test in depression. Arch Gen Psychia t ~ 44:919-920.