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The thyroid, sleep, and depression
BRIEF REPORTS
The Thyroid, Sleep, and Depression Russell T. Joffe, Martin P. Szuba, Stephen T.H. Sokolov, and Anthony J. Levitt Key Words:
Depression, thyroid, thyroxine, sleep
Introduction Thyroid hormones are implicated in the biology of depressive disorder, although their exact role remains to be clarified. Many but not all studies (reviewed in Bauer and Whybrow 1988; Joffe and Levitt 1993) find that depressed subjects have higher levels of thyroxine (T4) as compared with controls. Further, longitudinal studies indicate that there are substantial decreases in measures of T4 with antidepressant treatment (Bauer and Whybrow 1988; Joffe and Levitt 1993). Various explanationshave been offered for these findings, including: I) that depression is a state ofT4 excess with decreases in T4 being required for antidepressant response (Joffe et al 1984), or 2) that the higher levels of T4 observed are a compensatory mobilization of thyroid hormone in response to the depressed state to facilitate an antidepressant effect (Bauer and Whybrow 1988). While these two main, competing hypotheses remain to be tested, another possibility is that the increases in T4 are an epiphenomenon resulting from particular symptoms of the depressed state. Several studies have shown that full or partial sleep deprivation in patients with depressive disorder is associated with significant increases, in T4, triiodothyronine (T3) and thyrotropin (TSH) (Baumgartner et al 1990a,b). This effect has also been observed in healthy female volunteers (Baumgarmer et al 1993). As sleep disruption is a common manifestation of major depressive disorder, it is possible that the elevations of T4 observed may be a consequence of insomnia rather than a core component of the biology of depression as previously hypothesized (Bauer and Whybrow 1988; Joffe et al 1984). We therefore investigated the relationship between sleep alteration and thyroid hor-
Fromthe MoodDisordersProgram,ClarkeInstituteofPsychiatryandtheUniversity ofToronto,Ontario,Canada(RTJ,STHS,AJL)andthe DepartmentofPsychialay,UniversityofPennsylvania,Philadelphia,PA(MPS). Address reprintto RussellT. Joffe, M.D., Departmentof Psychiatry.McMaster University,1200MainStreetWest,Room3G-56,Hamilton,OntarioL8N 3Z5, Canada. ReceivedJune29, 1994;revisedSeptember7,1994. © 1995SocietyofBiologicalPsychiatry
mone levels in a cohort of patients with primary major depressive disorder.
Methods Subjects comprised 159 outpatients from a database with a primary major depressive disorder by Research Diagnostic Criteria as determined by a structured interview using the Schedule for Affective Disorders and Schizophrenia-LifetimeVersion (SADSLV). All subjects scored at least 16 on the 17-item Hamilton Rating Scale for Depression (HAMD). All subjects had been medication free a minimum of 2 weeks and had not taken any medication that could affect thyroid function tests for a minimum of 6 weeks. All subjects gave informed consent to participate in the study. Subjects were excluded if they had any medical disorder that would affect measurement of thyroid hormone levels. At the time the SADS-LV was administered, a blood sample was taken for measurement of thyroid hormone levels by standard radioimmunoassays for T4 (International Diagnostic Services, Orland Park, IL), T3 (InternationalDiagnostic Services), T3 resin uptake, T3RU, (International Diagnostic Services) and an ultrasensitive immunoradiometric assay for TSH (Serono Diagnostics Chavannes-de-Borgis, Switzerland). The free thyroxin index, FFI, was calculated as the product of the T4 and T3RU. The sleep symptomatology of each patient was ascertained from the SADS-LV from the questions concerning sleep in the section on major depression. Patients were retrospectively classified as having hypersomnia, insomnia, or no sleep disturbance. The assessment of sleep difficulties was made without knowledge of the results of the thyroid function tests. For each thyroid hormone, a one way analysis of variance (ANOVA) was performed across the three groups (hypersomnia vs. insomnia vs. no problem). StudentNeuman-Keuls correction for multiple statistical tests was applied. 0006-3223/95/$09.50 SSDI 0006-3223(94)00255-2
Brief Reports
BIOL PSYCHIATRY 1995 ;37:196-- 197
Table 1. Summary of Results
Male:Female Mean age (yr) Thyroxine (n = 51-142 nmol/1) T3 Resin uptake (n = 0.25--0.35) Free thyroxine index (n = 13-50) Triiodothyronine (n = 1.1-3.2 nmoVl) Thyrotropin (n = 0.4--4.5 mlU/l)
Insomnia (n = 118)
Hypersomnia (n = 22)
No Sleep Disturbance (n = 19)
40:78 37.5 --- 9.8 120.8 _+25.3
7:15 34.5 _ 9.3 129.3± 28.2
6:13 41.2 ± 8.5 114.5± 16.9
0.28 ± 0.03
0.27 -+ 0.03
0.29 + 0.03
33.9 _ 6.2
33.7 ± 5.3
32.7 _+ 5.8
2.4 _ 0.5
2.6 ± 0.4
2.2 ± 0.4
2.0 ± 1.3
2.0 ± 1.3
1.9 ± 1.2
Results In Table 1, the gender distribution and mean age of each of the groups are shown. There were no significant differences in T4, T3RU, FI?I, or TSH levels across the three groups. By ANOVA, there was a significant difference in T3 levels across the three groups (F = 5.09, df = 2, p < .05). By Student-Newman-Keuls procedure, mean T3 levels were significantly higher in the hypersomnia vs. no sleep disturbance problem group. There were no
197
significant differences between the insomnia and the other two groups with respect to T3.
Discussion Our preliminary study suggests that insomnia, unlike full or partial sleep deprivation, is not associated with elevations of T4 or FTI levels in major depression. This suggests that the relative increases in T4 observed in major depression cannot be explained by the symptom of insomnia. We did observe an increase in T3 levels in the hypersomnia compared to the no sleep disturbance group, but no significant difference was observed between the insomnia group and the other two groups. The potential importance of this observation is uncertain, as consistent alterations of T3 in major depression have not been observed (Joffe and Levitt 1993). Furthermore, there may have been insufficient statistical power to detect a difference between the insomnia and no sleep disturbance group. Before it can be definitely concluded that T4 elevations in depression are not related to sleep disruption, our study would have to be replicated using more direct evaluations of sleep such as polysomnography. Nonetheless, although our study involved evaluation of sleep symptomatology by a relatively crude retrospective measure derived from the SADS-LV interview, our preliminary findings suggest that sleep disturbance is unlikely to explain the alteration of T4 observed in depression.
References Bauer MS, Whybrow PC (1988): Thyroid hormones and the central nervous system in affective illness: interactions that may have clinical significance. Integrative Psychiatry 6:75-100. Baumgartner A, Graf K-J, Kurten I, Meinhold H, Scholz P (1990a): Neuroendocrinological investigations during sleep deprivation and depression. I. Early morning levels of thyrotropin, TH, Corfisol, Prolactin, LH, FSH, estradiol and testosterone. Biol Psychiatry 28:556-568. Baumgartner A, Graf K-J, Kurten I, Meinhold H (1990b): Thyrotropin (TSH) and thyroid hormone concentrations during partial sleep deprivation in patients with major depressive disorder. J Psychiatr Res 24: 281-292.
Baumgartner A, Dietzel M, Saletu B, et al (1993): Influence of partial sleep deprivation on the secretion of thyrotropin, thyroid hormones, growth hormone, prolactin, luteinizing hormone, follicle stimulating and estradiol in healthy young women. Psychiatry Res 48:153-178. Joffe RT, Roy-Byrne PP, Uhdetw Post RM (1984) Thyroid function and affective illness: A reappraisal. Biol Psychiatry 19:1685-1691. Joffe RT, Levitt AJ (1993): The thyroid and depression. In Joffe RT, Levitt AJ (eds), The thyroid axis and psychiatric illness. Washington DC: American Psychiatric Press, pp 195-254.
The Thyroid, Sleep, and Depression Russell T. Joffe, Martin P. Szuba, Stephen T.H. Sokolov, and Anthony J. Levitt Key Words:
Depression, thyroid, thyroxine, sleep
Introduction Thyroid hormones are implicated in the biology of depressive disorder, although their exact role remains to be clarified. Many but not all studies (reviewed in Bauer and Whybrow 1988; Joffe and Levitt 1993) find that depressed subjects have higher levels of thyroxine (T4) as compared with controls. Further, longitudinal studies indicate that there are substantial decreases in measures of T4 with antidepressant treatment (Bauer and Whybrow 1988; Joffe and Levitt 1993). Various explanationshave been offered for these findings, including: I) that depression is a state ofT4 excess with decreases in T4 being required for antidepressant response (Joffe et al 1984), or 2) that the higher levels of T4 observed are a compensatory mobilization of thyroid hormone in response to the depressed state to facilitate an antidepressant effect (Bauer and Whybrow 1988). While these two main, competing hypotheses remain to be tested, another possibility is that the increases in T4 are an epiphenomenon resulting from particular symptoms of the depressed state. Several studies have shown that full or partial sleep deprivation in patients with depressive disorder is associated with significant increases, in T4, triiodothyronine (T3) and thyrotropin (TSH) (Baumgartner et al 1990a,b). This effect has also been observed in healthy female volunteers (Baumgarmer et al 1993). As sleep disruption is a common manifestation of major depressive disorder, it is possible that the elevations of T4 observed may be a consequence of insomnia rather than a core component of the biology of depression as previously hypothesized (Bauer and Whybrow 1988; Joffe et al 1984). We therefore investigated the relationship between sleep alteration and thyroid hor-
Fromthe MoodDisordersProgram,ClarkeInstituteofPsychiatryandtheUniversity ofToronto,Ontario,Canada(RTJ,STHS,AJL)andthe DepartmentofPsychialay,UniversityofPennsylvania,Philadelphia,PA(MPS). Address reprintto RussellT. Joffe, M.D., Departmentof Psychiatry.McMaster University,1200MainStreetWest,Room3G-56,Hamilton,OntarioL8N 3Z5, Canada. ReceivedJune29, 1994;revisedSeptember7,1994. © 1995SocietyofBiologicalPsychiatry
mone levels in a cohort of patients with primary major depressive disorder.
Methods Subjects comprised 159 outpatients from a database with a primary major depressive disorder by Research Diagnostic Criteria as determined by a structured interview using the Schedule for Affective Disorders and Schizophrenia-LifetimeVersion (SADSLV). All subjects scored at least 16 on the 17-item Hamilton Rating Scale for Depression (HAMD). All subjects had been medication free a minimum of 2 weeks and had not taken any medication that could affect thyroid function tests for a minimum of 6 weeks. All subjects gave informed consent to participate in the study. Subjects were excluded if they had any medical disorder that would affect measurement of thyroid hormone levels. At the time the SADS-LV was administered, a blood sample was taken for measurement of thyroid hormone levels by standard radioimmunoassays for T4 (International Diagnostic Services, Orland Park, IL), T3 (InternationalDiagnostic Services), T3 resin uptake, T3RU, (International Diagnostic Services) and an ultrasensitive immunoradiometric assay for TSH (Serono Diagnostics Chavannes-de-Borgis, Switzerland). The free thyroxin index, FFI, was calculated as the product of the T4 and T3RU. The sleep symptomatology of each patient was ascertained from the SADS-LV from the questions concerning sleep in the section on major depression. Patients were retrospectively classified as having hypersomnia, insomnia, or no sleep disturbance. The assessment of sleep difficulties was made without knowledge of the results of the thyroid function tests. For each thyroid hormone, a one way analysis of variance (ANOVA) was performed across the three groups (hypersomnia vs. insomnia vs. no problem). StudentNeuman-Keuls correction for multiple statistical tests was applied. 0006-3223/95/$09.50 SSDI 0006-3223(94)00255-2
Brief Reports
BIOL PSYCHIATRY 1995 ;37:196-- 197
Table 1. Summary of Results
Male:Female Mean age (yr) Thyroxine (n = 51-142 nmol/1) T3 Resin uptake (n = 0.25--0.35) Free thyroxine index (n = 13-50) Triiodothyronine (n = 1.1-3.2 nmoVl) Thyrotropin (n = 0.4--4.5 mlU/l)
Insomnia (n = 118)
Hypersomnia (n = 22)
No Sleep Disturbance (n = 19)
40:78 37.5 --- 9.8 120.8 _+25.3
7:15 34.5 _ 9.3 129.3± 28.2
6:13 41.2 ± 8.5 114.5± 16.9
0.28 ± 0.03
0.27 -+ 0.03
0.29 + 0.03
33.9 _ 6.2
33.7 ± 5.3
32.7 _+ 5.8
2.4 _ 0.5
2.6 ± 0.4
2.2 ± 0.4
2.0 ± 1.3
2.0 ± 1.3
1.9 ± 1.2
Results In Table 1, the gender distribution and mean age of each of the groups are shown. There were no significant differences in T4, T3RU, FI?I, or TSH levels across the three groups. By ANOVA, there was a significant difference in T3 levels across the three groups (F = 5.09, df = 2, p < .05). By Student-Newman-Keuls procedure, mean T3 levels were significantly higher in the hypersomnia vs. no sleep disturbance problem group. There were no
197
significant differences between the insomnia and the other two groups with respect to T3.
Discussion Our preliminary study suggests that insomnia, unlike full or partial sleep deprivation, is not associated with elevations of T4 or FTI levels in major depression. This suggests that the relative increases in T4 observed in major depression cannot be explained by the symptom of insomnia. We did observe an increase in T3 levels in the hypersomnia compared to the no sleep disturbance group, but no significant difference was observed between the insomnia group and the other two groups. The potential importance of this observation is uncertain, as consistent alterations of T3 in major depression have not been observed (Joffe and Levitt 1993). Furthermore, there may have been insufficient statistical power to detect a difference between the insomnia and no sleep disturbance group. Before it can be definitely concluded that T4 elevations in depression are not related to sleep disruption, our study would have to be replicated using more direct evaluations of sleep such as polysomnography. Nonetheless, although our study involved evaluation of sleep symptomatology by a relatively crude retrospective measure derived from the SADS-LV interview, our preliminary findings suggest that sleep disturbance is unlikely to explain the alteration of T4 observed in depression.
References Bauer MS, Whybrow PC (1988): Thyroid hormones and the central nervous system in affective illness: interactions that may have clinical significance. Integrative Psychiatry 6:75-100. Baumgartner A, Graf K-J, Kurten I, Meinhold H, Scholz P (1990a): Neuroendocrinological investigations during sleep deprivation and depression. I. Early morning levels of thyrotropin, TH, Corfisol, Prolactin, LH, FSH, estradiol and testosterone. Biol Psychiatry 28:556-568. Baumgartner A, Graf K-J, Kurten I, Meinhold H (1990b): Thyrotropin (TSH) and thyroid hormone concentrations during partial sleep deprivation in patients with major depressive disorder. J Psychiatr Res 24: 281-292.
Baumgartner A, Dietzel M, Saletu B, et al (1993): Influence of partial sleep deprivation on the secretion of thyrotropin, thyroid hormones, growth hormone, prolactin, luteinizing hormone, follicle stimulating and estradiol in healthy young women. Psychiatry Res 48:153-178. Joffe RT, Roy-Byrne PP, Uhdetw Post RM (1984) Thyroid function and affective illness: A reappraisal. Biol Psychiatry 19:1685-1691. Joffe RT, Levitt AJ (1993): The thyroid and depression. In Joffe RT, Levitt AJ (eds), The thyroid axis and psychiatric illness. Washington DC: American Psychiatric Press, pp 195-254.