- Email: [email protected]
Peripheral thyroid hormone levels in treatment resistant depression
Peripheral Thyroid Hormone Levels in Treatment Resistant Depression Russell T. Joffe Background: Various abnormalities of thyroid function have been inconsistently reported in major depression. The inconsistency between studies may be due to several factors including the stage of treatment resistance. Methods: One hundred and one patients with major depressive disorder receiving their first antidepressant for their current major depressant episode had baseline thyroid function test performed. On completion of treatment, their stage of antidepressant resistance was determined. Results: Severity of depression but not any peripheral thyroid hormone level was associated with stage of antidepressant treatment resistance. Conclusions: Stage of treatment resistance does not appear to be a factor in the variability in peripheral thyroid hormone levels in unipolar major depression. Biol Psychiatry 1999;45:1053–1055 © 1999 Society of Biological Psychiatry Key Words: Depression, antidepressant treatment resistance, thyroid hormone
Introduction
V
arious abnormalities of thyroid hormone levels have been reported in major depression. These have included relative increases in thyroxine (T4) levels, decreased circulating triiodothyronine (T3) levels, varying degrees of subclinical hypothyroidism, and a blunted thyrotropin (TSH) response to thyrotropin releasing hormone (TRH) (Joffe and Levitt 1992; Sullivan et al 1997). These studies, have generally yielded inconsistent findings, which are likely explained by the heterogeneity of major depressive illness as well as several other demographic and clinical variables. Amongst these variables, the relationship between stages of treatment resistance and peripheral thyroid hormone levels have been examined. Some (Joffe and Levitt 1992) but not other studies (Vandoolaegag et al 1997) have suggested that treatment
From the Regional Mood Disorders Programme and Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada. Address reprint requests to Russell T. Joffe, MD, McMaster University, 1200 Main Street West, Room 2E1, Hamilton, ON, L8N 3Z5, Canada. Received May 12, 1998; revised October 5, 1998; accepted October 9, 1998.
© 1999 Society of Biological Psychiatry
resistance may be related to the presence of subclinical hypothyroidism, whereas other studies have found a relationship between T4 levels and subsequent treatment response (Sullivan et al 1997). In a recent study, Vandoolaegag and collaborators (1997) examined the relationship between varying stages of treatment resistance and measures of thyroid function. In a relatively small sample, they could not detect robust differences in thyroid function tests and stages of treatment resistance. As there has certainly been a suggestion that a link between stages of treatment resistance and levels of thyroid hormones may be relevant, we examined this in a larger cohort of patients with major depressive disorder.
Methods and Materials Subjects were 101 consecutive patients referred to the author for treatment of major depression and who consented to participate in the study. All fulfilled criteria for primary unipolar nonpsychotic major depressive disorder determined by a structured interview using the Schedule for Affective Disorders and Schizophrenia, Lifetime Version (Spitzer et al 1978). All subjects were free of any medical disorder which required concurrent treatment or which would affect the measure of thyroid hormone levels, and were included only if euthyroid, which was defined as an absence of clinical symptoms of thyroid disease and all thyroid hormone levels, including TSH, within normal limits. Blood was drawn prior to the antidepressant trial for measurement of thyroid hormone levels using standard radioimmunoassays for T4, T3, T3 resin uptake (T3RU), and TSH. The three thyroxine index (FTI) was calculated as the product of T4 and T3RU. At the time that blood samples were taken, the severity of depression was measured with the 17-item Hamilton Rating Scale for Depression (HAMD) (Hamilton 1960). Patients were classified into stages of treatment resistance using the classification of Thase and Rush (1995): stage one, nonresponse to one adequate antidepressant trial; stage two, nonresponse to two adequate trials with antidepressants from different classes; stage three, stage two plus failure to respond to a tricyclic antidepressant; stage four, stage three plus failure to respond to a monoamine oxidase inhibitor (MAOI); stage five, stage four plus nonresponse to bilateral electroconvulsive therapy. This staging was performed blind to the thyroid hormone measures at the completion of treatment. An adequate trial of antidepressant was defined as an adequate dose (for tricyclics at 0006-3223/99/$19.00 PII S0006-3223(98)00340-0
1054
R.T. Joffe
BIOL PSYCHIATRY 1999;45:1053–1055
Table 1. Peripheral Thyroid Hormone Levels in Stages of Treatment Resistant Depression (n 5 101) Stages of Treatment Resistance
Thyroxine (T4) (N 5 50 –142 nmol/l) Triiodothyronine (T3) (N 5 1.1–3.2 nmol/L) T3 resin uptake (T3RU) (N 5 0.25– 0.35) Free thyroxine index (FTI) (N 5 13–50) Thyrotropin (TSH) (N 5 0.4 – 4.5 mU/mL) HAMD a
a
Responders (n 5 20)
1 (n 5 20)
2 (n 5 19)
3 (n 5 17)
4 (n 5 18)
5 (n 5 7)
114.5 (17.1) 2.2 (.3) 0.27 (.04) 31.6 (4.9) 2.8 (1.1) 21.0 (1.6)
126.4 (14.1) 2.4 (.5) 0.26 (.03) 33.0 (4.1) 2.7 (1.3) 22.1 (2.5)
113.6 (20.7) 2.1 (.3) 0.28 (.03) 32.0 (5.2) 2.7 (1.0) 22.2 (2.5)
123.4 (16.5) 2.1 (.5) 0.27 (.03) 33.5 (4.3) 2.6 (1.1) 22.1 (2.3)
104.6 (23.7) 1.9 (.3) 0.29 (.3) 30.8 (7.2) 2.7 (1.5) 23.9 (2.8)
115.9 (25.3) 1.9 (.2) 0.26 (.03) 30.1 (5.7) 4.2 (3.1) 25.1 (2.6)
Values equal mean (SD).
least 2.5 mg/kg body weight per day; for MAOIs, 1 mg/kg body weight per day; and for SSRI’s, at least 20 mg/day of fluoxetine or paroxetine, 50 mg/day of fluvoxamine, or 100 mg/day of sertraline) for a minimum of 5 weeks. Response to a trial was determined by a global clinical outcome measure with moderate or marked response considered a responder and no or minimal response considered a nonresponder. Statistical analysis was by multivariate analysis of covariance (MANCOVA) examining group means for all the thyroid hormone measures. A comparison of means was also evaluated by analysis of variance for HAMD measures as well as student t tests.
Results The sample was made up of 37 men and 64 women with a mean age 41.0 (12.9) years. There were no gender differences in severity of depression or any of the thyroid measures. There was no significant correlation between age and any thyroid hormone measure. There was a significant difference in HAND scores across the treatment resistant groups (F 5 2.84, df 5 1, 100, p 5 .0197) (see Table 1). As thyroid hormone levels have been previously shown to be related to severity of depression in major depressive disorder (Joffe et al 1992), HAMD scores were used as a covariate in the overall analysis. MANCOVA was were used to evaluate differences in mean thyroid hormone levels across the treatment resistant groups. The overall MANCOVA was not significant (F 5 1.31, df 5 5, 94, p 5 .14) (see Table 1). To directly compare our findings to previous studies (Vandoolaegag et al 1997), patients were classified into nonresistant (responders and stage 1) and treatment-resistant (stages 2 to 5). There was no significant difference between nonresistant and treatment-resistant groups in mean levels of T4 [(120.4 (16.6) vs 113.6 (21.6)], T3 [(2.3 (.4) vs 2.0 (.4)], T3 RU [(.27 (.04) vs .28 (.03)], FTI [(32.3 (4.5) vs 31.2 (5.7)], or TSH [(2.8 (1.2) vs 2.9 (1.6)].
Discussion In our study, we could find no relationship between mean peripheral thyroid hormone levels and stages of antide-
pressant treatment resistance in a cohort of patients with unipolar major depression. In this respect, our study agrees with the findings of Vandoolaegag et al (1997), who also found no differences in thyroid function tests between resistant and nonresistant depressed patients. It extends the findings of this prior study as it involves a larger sample thereby allowing a more detailed evaluation of thyroid hormone levels in various stages of treatment resistance. In a previous study (Joffe and Levitt 1992), we suggested that patients with subclinical hypothyroidism (elevated TSH and normal T4 levels) may be less likely to respond to antidepressant treatment. The results of this current study are not inconsistent with our previous report (Joffe and Levitt 1992), as this current cohort was selected to include only those subjects with normal thyroid function tests (see “Materials and Methods”). As we did not perform a TRH test in the current study, we cannot exclude the possibility of subtle degrees of subclinical hypothyroidism with normal basal T4 and TSH levels but an exaggerated TSH response to TRH. The findings of our study are limited by the fact that patients were treated in a clinical manner and, therefore, objective criteria of treatment response such as rating scales were not employed. However, the global clinical assessment of outcome in our clinic is very thorough and our experience coincides well with objective evaluations of treatment outcome. We have previously suggested that major depression is associated with relative increases in circulating T4 (Joffe et al 1984). The failure to find a relationship between T4 levels and treatment resistance may appear to be at odds with this. However, our measure of T4 was taken at the time of assessment rather than at the onset of treatment. There is a considerable variability in peripheral thyroid hormone measures in depressed subjects (Joffe and Levitt 1992; Joffe et al 1992; Sullivan et al 1997; Vandoolaegag et al 1997). This variability may be attributed to numerous demographic and clinical factors, which are yet to be determined. Our current study would suggest that degree of treatment resistance is not a major factor in the variability in the peripheral measures of thyroid hormone levels in depressed subjects.
Thyroid and Refractory Depression
References Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56 – 61. Joffe RT, Bagby RM, Levitt AJ (1992): The thyroid and melancholia. Psychiatry Res 42:73– 80. Joffe RT, Levitt AJ (1992): Major depression and subclinical (grade two) hypothyroidism. Psychoneuroendocrinology 17: 215–221. Joffe RT, Post RM, Ray-Byrne PP, Uhde TW (1984): The thyroid and affective illness: A reappraisal. Biol Psychiatry 19:1685–1691.
BIOL PSYCHIATRY 1999;45:1053–1055
1055
Spitzer R, Williams J (1978): The Schedule for Affective Disorders and Schizophrenia Lifetime Version. New York: New York State Psychiatric Institute. Sullivan PF, Wilson DA, Mulder RT, Joyce PR (1997): The hypothalamic-pituitary thyroid axis in major depression. Acta Psychiatr Scand 95:370 –378. Thase ME, Rush HA (1995): Treatment-resistant depression. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology, the 4th Generation of Progress. New York: Raven, pp. 1081–1098. Vandoolaegag E, Maes M, Vandevyvere J, Neels H (1997): Hypothalamic-pituitary-thyroid-axis function in treatmentresistant depression. J Affect Disord. 43:143–150.
Introduction
V
arious abnormalities of thyroid hormone levels have been reported in major depression. These have included relative increases in thyroxine (T4) levels, decreased circulating triiodothyronine (T3) levels, varying degrees of subclinical hypothyroidism, and a blunted thyrotropin (TSH) response to thyrotropin releasing hormone (TRH) (Joffe and Levitt 1992; Sullivan et al 1997). These studies, have generally yielded inconsistent findings, which are likely explained by the heterogeneity of major depressive illness as well as several other demographic and clinical variables. Amongst these variables, the relationship between stages of treatment resistance and peripheral thyroid hormone levels have been examined. Some (Joffe and Levitt 1992) but not other studies (Vandoolaegag et al 1997) have suggested that treatment
From the Regional Mood Disorders Programme and Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada. Address reprint requests to Russell T. Joffe, MD, McMaster University, 1200 Main Street West, Room 2E1, Hamilton, ON, L8N 3Z5, Canada. Received May 12, 1998; revised October 5, 1998; accepted October 9, 1998.
© 1999 Society of Biological Psychiatry
resistance may be related to the presence of subclinical hypothyroidism, whereas other studies have found a relationship between T4 levels and subsequent treatment response (Sullivan et al 1997). In a recent study, Vandoolaegag and collaborators (1997) examined the relationship between varying stages of treatment resistance and measures of thyroid function. In a relatively small sample, they could not detect robust differences in thyroid function tests and stages of treatment resistance. As there has certainly been a suggestion that a link between stages of treatment resistance and levels of thyroid hormones may be relevant, we examined this in a larger cohort of patients with major depressive disorder.
Methods and Materials Subjects were 101 consecutive patients referred to the author for treatment of major depression and who consented to participate in the study. All fulfilled criteria for primary unipolar nonpsychotic major depressive disorder determined by a structured interview using the Schedule for Affective Disorders and Schizophrenia, Lifetime Version (Spitzer et al 1978). All subjects were free of any medical disorder which required concurrent treatment or which would affect the measure of thyroid hormone levels, and were included only if euthyroid, which was defined as an absence of clinical symptoms of thyroid disease and all thyroid hormone levels, including TSH, within normal limits. Blood was drawn prior to the antidepressant trial for measurement of thyroid hormone levels using standard radioimmunoassays for T4, T3, T3 resin uptake (T3RU), and TSH. The three thyroxine index (FTI) was calculated as the product of T4 and T3RU. At the time that blood samples were taken, the severity of depression was measured with the 17-item Hamilton Rating Scale for Depression (HAMD) (Hamilton 1960). Patients were classified into stages of treatment resistance using the classification of Thase and Rush (1995): stage one, nonresponse to one adequate antidepressant trial; stage two, nonresponse to two adequate trials with antidepressants from different classes; stage three, stage two plus failure to respond to a tricyclic antidepressant; stage four, stage three plus failure to respond to a monoamine oxidase inhibitor (MAOI); stage five, stage four plus nonresponse to bilateral electroconvulsive therapy. This staging was performed blind to the thyroid hormone measures at the completion of treatment. An adequate trial of antidepressant was defined as an adequate dose (for tricyclics at 0006-3223/99/$19.00 PII S0006-3223(98)00340-0
1054
R.T. Joffe
BIOL PSYCHIATRY 1999;45:1053–1055
Table 1. Peripheral Thyroid Hormone Levels in Stages of Treatment Resistant Depression (n 5 101) Stages of Treatment Resistance
Thyroxine (T4) (N 5 50 –142 nmol/l) Triiodothyronine (T3) (N 5 1.1–3.2 nmol/L) T3 resin uptake (T3RU) (N 5 0.25– 0.35) Free thyroxine index (FTI) (N 5 13–50) Thyrotropin (TSH) (N 5 0.4 – 4.5 mU/mL) HAMD a
a
Responders (n 5 20)
1 (n 5 20)
2 (n 5 19)
3 (n 5 17)
4 (n 5 18)
5 (n 5 7)
114.5 (17.1) 2.2 (.3) 0.27 (.04) 31.6 (4.9) 2.8 (1.1) 21.0 (1.6)
126.4 (14.1) 2.4 (.5) 0.26 (.03) 33.0 (4.1) 2.7 (1.3) 22.1 (2.5)
113.6 (20.7) 2.1 (.3) 0.28 (.03) 32.0 (5.2) 2.7 (1.0) 22.2 (2.5)
123.4 (16.5) 2.1 (.5) 0.27 (.03) 33.5 (4.3) 2.6 (1.1) 22.1 (2.3)
104.6 (23.7) 1.9 (.3) 0.29 (.3) 30.8 (7.2) 2.7 (1.5) 23.9 (2.8)
115.9 (25.3) 1.9 (.2) 0.26 (.03) 30.1 (5.7) 4.2 (3.1) 25.1 (2.6)
Values equal mean (SD).
least 2.5 mg/kg body weight per day; for MAOIs, 1 mg/kg body weight per day; and for SSRI’s, at least 20 mg/day of fluoxetine or paroxetine, 50 mg/day of fluvoxamine, or 100 mg/day of sertraline) for a minimum of 5 weeks. Response to a trial was determined by a global clinical outcome measure with moderate or marked response considered a responder and no or minimal response considered a nonresponder. Statistical analysis was by multivariate analysis of covariance (MANCOVA) examining group means for all the thyroid hormone measures. A comparison of means was also evaluated by analysis of variance for HAMD measures as well as student t tests.
Results The sample was made up of 37 men and 64 women with a mean age 41.0 (12.9) years. There were no gender differences in severity of depression or any of the thyroid measures. There was no significant correlation between age and any thyroid hormone measure. There was a significant difference in HAND scores across the treatment resistant groups (F 5 2.84, df 5 1, 100, p 5 .0197) (see Table 1). As thyroid hormone levels have been previously shown to be related to severity of depression in major depressive disorder (Joffe et al 1992), HAMD scores were used as a covariate in the overall analysis. MANCOVA was were used to evaluate differences in mean thyroid hormone levels across the treatment resistant groups. The overall MANCOVA was not significant (F 5 1.31, df 5 5, 94, p 5 .14) (see Table 1). To directly compare our findings to previous studies (Vandoolaegag et al 1997), patients were classified into nonresistant (responders and stage 1) and treatment-resistant (stages 2 to 5). There was no significant difference between nonresistant and treatment-resistant groups in mean levels of T4 [(120.4 (16.6) vs 113.6 (21.6)], T3 [(2.3 (.4) vs 2.0 (.4)], T3 RU [(.27 (.04) vs .28 (.03)], FTI [(32.3 (4.5) vs 31.2 (5.7)], or TSH [(2.8 (1.2) vs 2.9 (1.6)].
Discussion In our study, we could find no relationship between mean peripheral thyroid hormone levels and stages of antide-
pressant treatment resistance in a cohort of patients with unipolar major depression. In this respect, our study agrees with the findings of Vandoolaegag et al (1997), who also found no differences in thyroid function tests between resistant and nonresistant depressed patients. It extends the findings of this prior study as it involves a larger sample thereby allowing a more detailed evaluation of thyroid hormone levels in various stages of treatment resistance. In a previous study (Joffe and Levitt 1992), we suggested that patients with subclinical hypothyroidism (elevated TSH and normal T4 levels) may be less likely to respond to antidepressant treatment. The results of this current study are not inconsistent with our previous report (Joffe and Levitt 1992), as this current cohort was selected to include only those subjects with normal thyroid function tests (see “Materials and Methods”). As we did not perform a TRH test in the current study, we cannot exclude the possibility of subtle degrees of subclinical hypothyroidism with normal basal T4 and TSH levels but an exaggerated TSH response to TRH. The findings of our study are limited by the fact that patients were treated in a clinical manner and, therefore, objective criteria of treatment response such as rating scales were not employed. However, the global clinical assessment of outcome in our clinic is very thorough and our experience coincides well with objective evaluations of treatment outcome. We have previously suggested that major depression is associated with relative increases in circulating T4 (Joffe et al 1984). The failure to find a relationship between T4 levels and treatment resistance may appear to be at odds with this. However, our measure of T4 was taken at the time of assessment rather than at the onset of treatment. There is a considerable variability in peripheral thyroid hormone measures in depressed subjects (Joffe and Levitt 1992; Joffe et al 1992; Sullivan et al 1997; Vandoolaegag et al 1997). This variability may be attributed to numerous demographic and clinical factors, which are yet to be determined. Our current study would suggest that degree of treatment resistance is not a major factor in the variability in the peripheral measures of thyroid hormone levels in depressed subjects.
Thyroid and Refractory Depression
References Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56 – 61. Joffe RT, Bagby RM, Levitt AJ (1992): The thyroid and melancholia. Psychiatry Res 42:73– 80. Joffe RT, Levitt AJ (1992): Major depression and subclinical (grade two) hypothyroidism. Psychoneuroendocrinology 17: 215–221. Joffe RT, Post RM, Ray-Byrne PP, Uhde TW (1984): The thyroid and affective illness: A reappraisal. Biol Psychiatry 19:1685–1691.
BIOL PSYCHIATRY 1999;45:1053–1055
1055
Spitzer R, Williams J (1978): The Schedule for Affective Disorders and Schizophrenia Lifetime Version. New York: New York State Psychiatric Institute. Sullivan PF, Wilson DA, Mulder RT, Joyce PR (1997): The hypothalamic-pituitary thyroid axis in major depression. Acta Psychiatr Scand 95:370 –378. Thase ME, Rush HA (1995): Treatment-resistant depression. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology, the 4th Generation of Progress. New York: Raven, pp. 1081–1098. Vandoolaegag E, Maes M, Vandevyvere J, Neels H (1997): Hypothalamic-pituitary-thyroid-axis function in treatmentresistant depression. J Affect Disord. 43:143–150.