Psychoneuroendocrinology,VoL 17, No. 2/3, pp. 215-221,
1992
0306-4530/92 $5.00+0.00 ©1992 Pergamon Press Ltd.
Printed in Great Britain
MAJOR DEPRESSION AND SUBCLINICAL (GRADE 2) HYPOTHYROIDISM RUSSELL T. JOFFE and ANTHONY J. LEVITt Mood Disorders Program, Clarke Institute of Psychiatry, and the University of Toronto, Toronto, Canada (Received 26 March 1991; in finalform 5 August 1991)
SUMMARY Subclinical hypothyroidism (SCH) has been reported to occur in patients with a variety of affecfive syndromes. However, the clinical correlates of SCH in patients with major depression have received limited attention. We therefore examined demographic, clinical and treatment response variables in a cohort of patients with unipolar, nonpsychotic major depression with and without SCH. Of 139 subjects, 19 had SCH defined as an elevated basal TSH with normal circulating levels of T3 and T4. Major depression with SCH differed from that without SCH by the presence of a concurrent panic disorder and a poorer antidepressant response. INTRODUCTION ALTHOUGHCLINICALHYPOTHYROIDISMis a rare disorder, milder forms of hypothyroidism which more commonly occur have been identified (Cooper, 1987; Haggerty et al., 1990). The grades of hypothyroidism have been previously defined (Evered et al., 1973; Wenzel et al., 1974). Many of the studies which have examined medical aspects of subclinical hypothyroidism refer to grade 2 hypothyroidism (Gordin & Lamberg, 1981; Cooper et al., 1984; Bell et al., 1985; Althaus et aL, 1988; Drinka & Nolten, 1988; Nystrom et al., 1988) although grade 3 hypothyroidism has received more attention in the psychiatric literature (Gold et al., 1981a; 1981b; 1982; Targum et al., 1984; Haggerty et al., 1990). Subclinical, or grade 2, hypothyroidism (SCH) is defined as an elevated basal TSH with normal circulating levels of T 3 and T 4. Its prevalence is approximately 5% of the general population, although older, postmenopausal women may have a prevalence as high as 15% (Tunbridge et al., 1977; Cooper, 1987). Despite its c o m m o n occurrence, the clinical significance of SCH remains uncertain (Cooper, 1987). Subclinical hypothyroidism has been associated with alterations in serum lipids, which has been suggested to increase the risk for coronary heart disease (Althaus et al., 1988). Myocardial contractility is altered in patients with SCH, and this may be reversed by L-thyroxine replacement therapy (Cooper et al., 1984). Despite these initial studies suggesting increased medical morbidity associated with SCH, the clinical significance of these observations remains to be clarified. The significance of SCH for psychiatric disorders, particularly affective illness, is also unclear. Although some studies suggest that it may be more common in patients with affecfive Address correspondence and reprint requests to: Dr. Russell T. Joffe, Clarke Institute of Psychiatry, 250 College Street, Toronto, Ontario M5T 1R8, CANADA. 215
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illness (Gold et al., 1981a; Haggerty et al., 1987), definite conclusions await studies adequately controlled for age and sex. Nonetheless, some cognitive and behavioural effects o f S C H have been demonstrated in both psychiatric (Haggerty et al., 1986; Reus et al., 1986) and nonpsychiattic (Nystrom et al., 1988) populations. With regard to affective illness, S C H has been particularly related to rapid cycling in bipolar affective disorder in some ( C o w d r y et al., 1983; Bauer & Whybrow, 1990), but not all (Joffe et al., 1986; Wehr et al., 1988), studies. With regard to depression, G o l d et al. (1981a) reported that 8 o f 100 patients who presented with depression and anergia had evidence o f grade 2 or 3 hypothyroidism. Furthermore, there are s o m e preliminary data that depressed patients with S C H m a y respond less well to antidepressant treatment (Targum et al., 1984; Haggerty et al., 1990). Despite a p o s s i b l e relationship b e t w e e n S C H and d e p r e s s i o n and the g e n e r a l l y accepted importance o f the role o f thyroid hormones in the p a t h o p h y s i o l o g y o f m o o d disorders (Joffe, 1990), there are limited data on the clinical and treatment correlates o f S C H in patients diagnosed with m a j o r depression. We therefore carried out a systematic evaluation o f the clinical and treatment correlates o f S C H in a cohort of patients with m a j o r depressive disorder. SUBJECTS AND METHODS One hundred thirty-nine subjects, 48 men and 91 women, mean age 41.3 + 13.0 yr, consented to participate in this study, which was approved by the Human Ethics Committee at the University of Toronto. They were consecutive outpatient referrals to the Mood Disorders Program at the University of Toronto. All subjects fulfilled Research Diagnostic Criteria for unipolar nonpsychotic major depressive disorder as determined by a structured interview (Schedule for Affective Disorders and Schizophrenia- Lifetime Version; SADS-L). Subjects were excluded if they had a history of medical illness which would affect thyroid function tests or if they had a history of alcohol or drug abuse in the previous 6 mo. At the time of evaluation, the subjects had been medication-free for a minimum of 2 wk and had not received lithium treatment for at least 3 mo. During the evaluation, each of the symptoms for major depression and the presence or absence of melancholia, as determined by Research Diagnostic Criteria from the SADS-L, was recorded. Concurrent anxiety disorder diagnoses also were recorded, and the usual hierarchy in which major depression precludes the diagnosis of an anxiety disorder was suspended. All patients in the Mood Disorders Program are treated by a standard clinical treatment algorithm. Subjects receive desipramine in open clinical fashion in doses of 2.5-3.0 mg/kg body weight/day to achieve therapeutic plasma levels as determined by our clinical laboratories. The mean desipramine dose was 181.6 mg/day (range 150-250 mg) for the SCH-positive group and 170.0 rag/day (range 100-250 mg) for the SCH-negative group. Response to treatment was evaluated in two ways: First, by a score of 2 or 3 on a clinical global scale ( 0 - no change, 1 - minimal improvement, 2 - marked improvement, 3 - complete remission), and by a 50% or more reduction in the 17-item Hamilton Rating Scale for Depression (HAM-D) (Hamilton, 1960) to a score
1992
0306-4530/92 $5.00+0.00 ©1992 Pergamon Press Ltd.
Printed in Great Britain
MAJOR DEPRESSION AND SUBCLINICAL (GRADE 2) HYPOTHYROIDISM RUSSELL T. JOFFE and ANTHONY J. LEVITt Mood Disorders Program, Clarke Institute of Psychiatry, and the University of Toronto, Toronto, Canada (Received 26 March 1991; in finalform 5 August 1991)
SUMMARY Subclinical hypothyroidism (SCH) has been reported to occur in patients with a variety of affecfive syndromes. However, the clinical correlates of SCH in patients with major depression have received limited attention. We therefore examined demographic, clinical and treatment response variables in a cohort of patients with unipolar, nonpsychotic major depression with and without SCH. Of 139 subjects, 19 had SCH defined as an elevated basal TSH with normal circulating levels of T3 and T4. Major depression with SCH differed from that without SCH by the presence of a concurrent panic disorder and a poorer antidepressant response. INTRODUCTION ALTHOUGHCLINICALHYPOTHYROIDISMis a rare disorder, milder forms of hypothyroidism which more commonly occur have been identified (Cooper, 1987; Haggerty et al., 1990). The grades of hypothyroidism have been previously defined (Evered et al., 1973; Wenzel et al., 1974). Many of the studies which have examined medical aspects of subclinical hypothyroidism refer to grade 2 hypothyroidism (Gordin & Lamberg, 1981; Cooper et al., 1984; Bell et al., 1985; Althaus et aL, 1988; Drinka & Nolten, 1988; Nystrom et al., 1988) although grade 3 hypothyroidism has received more attention in the psychiatric literature (Gold et al., 1981a; 1981b; 1982; Targum et al., 1984; Haggerty et al., 1990). Subclinical, or grade 2, hypothyroidism (SCH) is defined as an elevated basal TSH with normal circulating levels of T 3 and T 4. Its prevalence is approximately 5% of the general population, although older, postmenopausal women may have a prevalence as high as 15% (Tunbridge et al., 1977; Cooper, 1987). Despite its c o m m o n occurrence, the clinical significance of SCH remains uncertain (Cooper, 1987). Subclinical hypothyroidism has been associated with alterations in serum lipids, which has been suggested to increase the risk for coronary heart disease (Althaus et al., 1988). Myocardial contractility is altered in patients with SCH, and this may be reversed by L-thyroxine replacement therapy (Cooper et al., 1984). Despite these initial studies suggesting increased medical morbidity associated with SCH, the clinical significance of these observations remains to be clarified. The significance of SCH for psychiatric disorders, particularly affective illness, is also unclear. Although some studies suggest that it may be more common in patients with affecfive Address correspondence and reprint requests to: Dr. Russell T. Joffe, Clarke Institute of Psychiatry, 250 College Street, Toronto, Ontario M5T 1R8, CANADA. 215
216
R.T. JOFFEand A. J. LEVITT
illness (Gold et al., 1981a; Haggerty et al., 1987), definite conclusions await studies adequately controlled for age and sex. Nonetheless, some cognitive and behavioural effects o f S C H have been demonstrated in both psychiatric (Haggerty et al., 1986; Reus et al., 1986) and nonpsychiattic (Nystrom et al., 1988) populations. With regard to affective illness, S C H has been particularly related to rapid cycling in bipolar affective disorder in some ( C o w d r y et al., 1983; Bauer & Whybrow, 1990), but not all (Joffe et al., 1986; Wehr et al., 1988), studies. With regard to depression, G o l d et al. (1981a) reported that 8 o f 100 patients who presented with depression and anergia had evidence o f grade 2 or 3 hypothyroidism. Furthermore, there are s o m e preliminary data that depressed patients with S C H m a y respond less well to antidepressant treatment (Targum et al., 1984; Haggerty et al., 1990). Despite a p o s s i b l e relationship b e t w e e n S C H and d e p r e s s i o n and the g e n e r a l l y accepted importance o f the role o f thyroid hormones in the p a t h o p h y s i o l o g y o f m o o d disorders (Joffe, 1990), there are limited data on the clinical and treatment correlates o f S C H in patients diagnosed with m a j o r depression. We therefore carried out a systematic evaluation o f the clinical and treatment correlates o f S C H in a cohort of patients with m a j o r depressive disorder. SUBJECTS AND METHODS One hundred thirty-nine subjects, 48 men and 91 women, mean age 41.3 + 13.0 yr, consented to participate in this study, which was approved by the Human Ethics Committee at the University of Toronto. They were consecutive outpatient referrals to the Mood Disorders Program at the University of Toronto. All subjects fulfilled Research Diagnostic Criteria for unipolar nonpsychotic major depressive disorder as determined by a structured interview (Schedule for Affective Disorders and Schizophrenia- Lifetime Version; SADS-L). Subjects were excluded if they had a history of medical illness which would affect thyroid function tests or if they had a history of alcohol or drug abuse in the previous 6 mo. At the time of evaluation, the subjects had been medication-free for a minimum of 2 wk and had not received lithium treatment for at least 3 mo. During the evaluation, each of the symptoms for major depression and the presence or absence of melancholia, as determined by Research Diagnostic Criteria from the SADS-L, was recorded. Concurrent anxiety disorder diagnoses also were recorded, and the usual hierarchy in which major depression precludes the diagnosis of an anxiety disorder was suspended. All patients in the Mood Disorders Program are treated by a standard clinical treatment algorithm. Subjects receive desipramine in open clinical fashion in doses of 2.5-3.0 mg/kg body weight/day to achieve therapeutic plasma levels as determined by our clinical laboratories. The mean desipramine dose was 181.6 mg/day (range 150-250 mg) for the SCH-positive group and 170.0 rag/day (range 100-250 mg) for the SCH-negative group. Response to treatment was evaluated in two ways: First, by a score of 2 or 3 on a clinical global scale ( 0 - no change, 1 - minimal improvement, 2 - marked improvement, 3 - complete remission), and by a 50% or more reduction in the 17-item Hamilton Rating Scale for Depression (HAM-D) (Hamilton, 1960) to a score
