Neuroendocrine
Aspects of
Primary Endogenous Depression XI. Serum Melatonin Measures in Patients and Matched Control Robert T. Rubin, MD, PhD; E. Kevin Heist; Scott S.
McGeoy; Koichi Hanada, MD\s=d\;Ira
Subjects
M Lesser, MD
ascertain the extent of dysregulation of melatonin secretion in endogenous depression, we measured nocturnal and diurnal serum melatonin concentrations in 38 depressed patients (23 women and 15 men) who had primary, definite endogenous depression according to the Research Diagnostic Criteria and in 38 individually matched normal control subjects. Previous reports have suggested that such patients may have reduced nocturnal melatonin secretion, often in conjunction with increased hypothalamicpituitary-adrenal cortical axis activity. This has been considered as a possible reflection of reduced noradrenergic activity in depression. Compared with their matched controls, the depressed patients showed a trend toward a significantly elevated average nocturnal melatonin concentration that was accounted for primarily by the 14 premenopausal women\p=m-\thepostmenopausal female and male depressive patients did not differ significantly from their respective controls. The average diurnal melatonin
concentration also showed a trend toward being higher in both the female and male depressed patients. The melatonin measures were not consistently related to any of the previously reported hypothalamic-pituitary-adrenal cortical axis measures in these subjects. Our findings thus failed to confirm a "low melatonin syndrome" or an inverse relationship between nocturnal melatonin and nocturnal cortisol concentrations in depression. This discrepancy may be related to methodologic differences among studies; our data are in accord with those findings of the one other reported study in which normal controls were individually matched to patients on variables that were known to influence melatonin secretion. Most of the studies, including ours, have been cross-sectional. However, the few longitudinal studies to date have not found consistent differences in melatonin profiles in the same patients when they were depressed and when they were euthymic or manic.
abnormalities of anterior pituitary and target endocrine gland hormone secretion patterns have been reported in patients with the endogenous subtype of major depression.1"4 The most prominent and well stud¬ ied of these abnormalities involves hyperactivity of the hypothalamic-pituitary-adrenal cortical ( ) axis that has been reported to occur in 30% to 50% of patients with endogenous depression.5"9 Reduced melatonin secretion by the pineal gland also has been noted in patients with major depression compared with that in control subjects.10"15 In some studies, this has occurred in con¬ axis activity.1619 Because the junction with increased nocturnal synthesis and secretion of melatonin is con-
trolled
\s=b\ To
Several
Accepted for publication December 9, 1991. From the Department of Psychiatry, Harbor\p=m-\UCLAMedical Cen-
ter, Torrance, Calif (Drs Rubin, Hanada, and Lesser and Messrs Heist and McGeoy), the Department of Pharmacology, Stanford (Calif) University School of Medicine (Mr Heist), and the Department of Psychiatry, Shiga University of Medical Science, Otsu, Japan (Dr Hanada). Dr Rubin is now with the Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh, Pa. \s=d\DrHanada passed away on December 26, 1991. Reprint requests to the Allegheny-Singer Research Institute, Allegheny General Hospital, 320E North Ave, Pittsburgh, PA 15212 (Dr
Rubin).
(Arch Gen
Psychiatry. 1992;49:558-567)
primarily by increased noradrenergic neurotrans¬ mission to the pineal gland at night, the reduced melato¬ nin secretion in depression has been considered as a pos¬
sible reflection of a functional norepinephrine deficiency underlying the disorder.1M6·18'20·21 However, no difference in circulating melatonin concentrations between de¬ pressed patients and normal control subjects individually matched to the patients also has been reported20; indeed, in this study, there was a trend toward higher nocturnal melatonin secretion in the patients. Thus, the nature and extent of the disruption of melatonin secretion in depres¬ sion remain unclear. To document the severity and pervasiveness of neu¬ roendocrine dysfunction in endogenous depression, we measured basal circulating concentrations of multiple pi¬ tuitary and target endocrine gland hormones, and their responses to several endocrine perturbation tests, in 40 unmedicated patients with endogenous major depres¬ sion whose conditions were carefully diagnosed and in 40 normal control subjects who were individually matched to the patients on age, sex, race, and menstrual axis, status for the women. Reports on the
hypothalamic-pituitary-thyroid axis, hypothalamicpituitary-gonadal axis,, prolactin, and growth hormone (GH) have been published.2227 Serum melatonin concen-
Downloaded From: http://archpsyc.jamanetwork.com/ by a Chinese University of Hong Kong User on 05/09/2016
trations also were determined in these subjects. Their melatonin secretion profiles and the relationship of the melatonin measures to the other hormones that were studied and the demographic and clinical characteristics of the patients are the of this report.
subject
SUBJECTS AND METHODS
Subjects
Forty depressed patients (age range, 22 to 71 years) were studied in the General Clinical Research Center of the HarborUCLA Medical Center. Forty normal control subjects, individu¬ ally matched to each patient by age, sex, race, and menstrual status for the women, also were studied. Of these, 38 patientcontrol pairs had sufficient serum available for melatonin anal¬ ysis. The patients were referred from the emergency and crisis clinics of our psychiatry service and from community psychiat¬ ric facilities and psychiatrists in private practice. The control subjects were recruited from hospital employees and their fam¬ ilies and friends. The patients and control subjects were recruited for study during all seasons of the year, throughout several years. Given the several variables on which the controls had to be matched to the patients, it was not always possible to study each control at the same time of year at which his or her matching patient was studied. Each patient and control received an initial clinical interview by a project psychiatrist or the research nurse. If the subject was suitable for study, the experimental protocol was explained in detail, and written informed consent was obtained. On the ba¬ sis of a structured interview, the Schedule for Affective Disor¬ ders and Schizophrenia,28 which was conducted by two psychi¬ atrists or by one psychiatrist and the research nurse, each patient was classified according to the Research Diagnostic Criteria,29'30 the DSM-III,31 and the Newcastle endogenous index.3234 The Hamilton Depression Rating Scale35 and Beck Depression In¬ ventory36-37 also were completed on each subject. Only patients with primary, definite endogenous depression, according to the Research Diagnostic Criteria, with a Hamilton Depression Rat¬ ing Scale total score of 17 or greater (21-item version) were included. The controls had no past or present psychiatric illness. A physical examination, urinalysis, M-300 blood chemistry chest x-ray film, and electrocardiogram (for the subjects panel, older than 40 years) then were obtained on each subject. Any¬ one with a history of concomitant psychiatric illness (eg, schizo¬ phrenia, alcohol abuse, or drug abuse), with a history of major medical illness (eg, hypertension, diabetes, or other endocrinopathy), or with abnormal physical or laboratory findings, or anyone who was taking any medication that might interfere with the endocrine testing was excluded. Most of the patients had received little or no psychotropic medication in the weeks before the study. Those patients who had been treated underwent a 2- to 3-week drug washout period, under close clinical supervision, before neuroendocrine testing. For these patients, the depression rating scales were completed again, just before testing; these scores were used to meet the in¬ clusion criteria specified above and as the baseline values. Neuroendocrine Protocol Each subject was admitted to the General Clinical Research Center at 6 PM, at which time an indwelling catheter was inserted into an arm vein. All subjects were ambulatory, except when in bed between 11 PM and 7 AM. Standard hospital meals were served at 8 AM, noon, and 5 PM, and a light snack was served at 8 PM. Blood sampling, 7 mL every 30 minutes, was begun at 9 PM and continued for 26 hours. During the night from 11 PM to 7 AM, the samples were taken from an adjoining room through a long polyethylene tubing.38-39 At the latitude at which this study was performed (34° North), sunset and sunrise at the winter sol¬ stice occur at 4:48 PM and 6:55 AM, respectively, and at the sum¬ mer solstice at 8:07 PM and 5:42 AM, respectively. During a sum-
with the drapes open, the average light intensity 1200 lux. From late afternoon until 11 PM, the drapes were closed, and the room was illuminated by overhead fluorescent lights (average intensity 200 lux). From 11 PM until 7 AM, only a night-light was on (average intensity,
Aspects of
Primary Endogenous Depression XI. Serum Melatonin Measures in Patients and Matched Control Robert T. Rubin, MD, PhD; E. Kevin Heist; Scott S.
McGeoy; Koichi Hanada, MD\s=d\;Ira
Subjects
M Lesser, MD
ascertain the extent of dysregulation of melatonin secretion in endogenous depression, we measured nocturnal and diurnal serum melatonin concentrations in 38 depressed patients (23 women and 15 men) who had primary, definite endogenous depression according to the Research Diagnostic Criteria and in 38 individually matched normal control subjects. Previous reports have suggested that such patients may have reduced nocturnal melatonin secretion, often in conjunction with increased hypothalamicpituitary-adrenal cortical axis activity. This has been considered as a possible reflection of reduced noradrenergic activity in depression. Compared with their matched controls, the depressed patients showed a trend toward a significantly elevated average nocturnal melatonin concentration that was accounted for primarily by the 14 premenopausal women\p=m-\thepostmenopausal female and male depressive patients did not differ significantly from their respective controls. The average diurnal melatonin
concentration also showed a trend toward being higher in both the female and male depressed patients. The melatonin measures were not consistently related to any of the previously reported hypothalamic-pituitary-adrenal cortical axis measures in these subjects. Our findings thus failed to confirm a "low melatonin syndrome" or an inverse relationship between nocturnal melatonin and nocturnal cortisol concentrations in depression. This discrepancy may be related to methodologic differences among studies; our data are in accord with those findings of the one other reported study in which normal controls were individually matched to patients on variables that were known to influence melatonin secretion. Most of the studies, including ours, have been cross-sectional. However, the few longitudinal studies to date have not found consistent differences in melatonin profiles in the same patients when they were depressed and when they were euthymic or manic.
abnormalities of anterior pituitary and target endocrine gland hormone secretion patterns have been reported in patients with the endogenous subtype of major depression.1"4 The most prominent and well stud¬ ied of these abnormalities involves hyperactivity of the hypothalamic-pituitary-adrenal cortical ( ) axis that has been reported to occur in 30% to 50% of patients with endogenous depression.5"9 Reduced melatonin secretion by the pineal gland also has been noted in patients with major depression compared with that in control subjects.10"15 In some studies, this has occurred in con¬ axis activity.1619 Because the junction with increased nocturnal synthesis and secretion of melatonin is con-
trolled
\s=b\ To
Several
Accepted for publication December 9, 1991. From the Department of Psychiatry, Harbor\p=m-\UCLAMedical Cen-
ter, Torrance, Calif (Drs Rubin, Hanada, and Lesser and Messrs Heist and McGeoy), the Department of Pharmacology, Stanford (Calif) University School of Medicine (Mr Heist), and the Department of Psychiatry, Shiga University of Medical Science, Otsu, Japan (Dr Hanada). Dr Rubin is now with the Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh, Pa. \s=d\DrHanada passed away on December 26, 1991. Reprint requests to the Allegheny-Singer Research Institute, Allegheny General Hospital, 320E North Ave, Pittsburgh, PA 15212 (Dr
Rubin).
(Arch Gen
Psychiatry. 1992;49:558-567)
primarily by increased noradrenergic neurotrans¬ mission to the pineal gland at night, the reduced melato¬ nin secretion in depression has been considered as a pos¬
sible reflection of a functional norepinephrine deficiency underlying the disorder.1M6·18'20·21 However, no difference in circulating melatonin concentrations between de¬ pressed patients and normal control subjects individually matched to the patients also has been reported20; indeed, in this study, there was a trend toward higher nocturnal melatonin secretion in the patients. Thus, the nature and extent of the disruption of melatonin secretion in depres¬ sion remain unclear. To document the severity and pervasiveness of neu¬ roendocrine dysfunction in endogenous depression, we measured basal circulating concentrations of multiple pi¬ tuitary and target endocrine gland hormones, and their responses to several endocrine perturbation tests, in 40 unmedicated patients with endogenous major depres¬ sion whose conditions were carefully diagnosed and in 40 normal control subjects who were individually matched to the patients on age, sex, race, and menstrual axis, status for the women. Reports on the
hypothalamic-pituitary-thyroid axis, hypothalamicpituitary-gonadal axis,, prolactin, and growth hormone (GH) have been published.2227 Serum melatonin concen-
Downloaded From: http://archpsyc.jamanetwork.com/ by a Chinese University of Hong Kong User on 05/09/2016
trations also were determined in these subjects. Their melatonin secretion profiles and the relationship of the melatonin measures to the other hormones that were studied and the demographic and clinical characteristics of the patients are the of this report.
subject
SUBJECTS AND METHODS
Subjects
Forty depressed patients (age range, 22 to 71 years) were studied in the General Clinical Research Center of the HarborUCLA Medical Center. Forty normal control subjects, individu¬ ally matched to each patient by age, sex, race, and menstrual status for the women, also were studied. Of these, 38 patientcontrol pairs had sufficient serum available for melatonin anal¬ ysis. The patients were referred from the emergency and crisis clinics of our psychiatry service and from community psychiat¬ ric facilities and psychiatrists in private practice. The control subjects were recruited from hospital employees and their fam¬ ilies and friends. The patients and control subjects were recruited for study during all seasons of the year, throughout several years. Given the several variables on which the controls had to be matched to the patients, it was not always possible to study each control at the same time of year at which his or her matching patient was studied. Each patient and control received an initial clinical interview by a project psychiatrist or the research nurse. If the subject was suitable for study, the experimental protocol was explained in detail, and written informed consent was obtained. On the ba¬ sis of a structured interview, the Schedule for Affective Disor¬ ders and Schizophrenia,28 which was conducted by two psychi¬ atrists or by one psychiatrist and the research nurse, each patient was classified according to the Research Diagnostic Criteria,29'30 the DSM-III,31 and the Newcastle endogenous index.3234 The Hamilton Depression Rating Scale35 and Beck Depression In¬ ventory36-37 also were completed on each subject. Only patients with primary, definite endogenous depression, according to the Research Diagnostic Criteria, with a Hamilton Depression Rat¬ ing Scale total score of 17 or greater (21-item version) were included. The controls had no past or present psychiatric illness. A physical examination, urinalysis, M-300 blood chemistry chest x-ray film, and electrocardiogram (for the subjects panel, older than 40 years) then were obtained on each subject. Any¬ one with a history of concomitant psychiatric illness (eg, schizo¬ phrenia, alcohol abuse, or drug abuse), with a history of major medical illness (eg, hypertension, diabetes, or other endocrinopathy), or with abnormal physical or laboratory findings, or anyone who was taking any medication that might interfere with the endocrine testing was excluded. Most of the patients had received little or no psychotropic medication in the weeks before the study. Those patients who had been treated underwent a 2- to 3-week drug washout period, under close clinical supervision, before neuroendocrine testing. For these patients, the depression rating scales were completed again, just before testing; these scores were used to meet the in¬ clusion criteria specified above and as the baseline values. Neuroendocrine Protocol Each subject was admitted to the General Clinical Research Center at 6 PM, at which time an indwelling catheter was inserted into an arm vein. All subjects were ambulatory, except when in bed between 11 PM and 7 AM. Standard hospital meals were served at 8 AM, noon, and 5 PM, and a light snack was served at 8 PM. Blood sampling, 7 mL every 30 minutes, was begun at 9 PM and continued for 26 hours. During the night from 11 PM to 7 AM, the samples were taken from an adjoining room through a long polyethylene tubing.38-39 At the latitude at which this study was performed (34° North), sunset and sunrise at the winter sol¬ stice occur at 4:48 PM and 6:55 AM, respectively, and at the sum¬ mer solstice at 8:07 PM and 5:42 AM, respectively. During a sum-
with the drapes open, the average light intensity 1200 lux. From late afternoon until 11 PM, the drapes were closed, and the room was illuminated by overhead fluorescent lights (average intensity 200 lux). From 11 PM until 7 AM, only a night-light was on (average intensity,
