Neuropsychiatric
Kirk
Manifestations
D. Denicoff, Jacob
T
here is a vast literature on the relationship between thyroid function and neuropsychiatnic symptoms. Clinical studies attempting to clarify this relationship have evaluated neuropsychiatnic symptoms in patients with thyroid disease (1-4), thyroid functioning in psychiatric patients (5, 6), tniiodothyronine (T3) potentiation of antidepressant efficacy (7, 8), and the effects of thyrotropin-releasing hormone (TRH) on depression (9). Psychiatric symptoms are reported to be a common clinical complication of thynoid disorders (1). In particular, hypothyroidism has frequently been described as accompanied by depressive symptoms (1). Whybrow and Ferrell (1) reported that in a group of seven hypothyroid patients the predominant affective disturbance was a marked depression of mood. Jam (2) assessed 30 consecutive patients diagnosed as hypothyroid and judged 13 patients to be clinically depressed. In addition, patients who are hypothyroid have been reported to suffer from impairment of cognitive functions, such as recent memory, concentration, and simple calculations (1, 2, 4). Conversely, it has been reported that some psychiatric patients have abnormal results on thyroid func-
Presented at the 140th meeting of the American ciation, Chicago, May 9-14, 1987. Received July Psychiatry National
NIH, logical Rockvitte
14, 1989; Branch, Institute
Bethesda, Psychiatry Pike, authors
and Susheet
94
29, 1989.
Psychiatric 1 1, 1988;
From
thank
Patit for
of TSH M.
was
performed
Christine Hoban, their contributions
Joan to this
the Biological
by Serono Todd, study.
State
M.D.,
tion tests. Gold et al. (5) reported that in 100 consecutive patients referred to a neuropsychiatnic evaluation and research unit with complaints of depression and/or anergia, nine patients had low T3 uptake, a low thyroxine (T4) level, a high basal thyrotropin (TSH) level, or a change in TSH greater than 35 pJU/ml in response to TRH stimulation. Five of these patients were diagnosed as suffering from major depression, and the other four had atypical or minor depression. Loosen (10) has reported that the TSH response to exogenously administered TRH is blunted in approximately 25% of patients with major depression. The association between depression and hypothynoidism is consistent with the hypothesis that increases in thyroid hormone levels accelerate recovery and decreases in thyroid hormone levels interfere with necovery in patients with major depression (11). However, studies have shown that most treatments which are effective in manic-depressive illness are associated with significant decreases in thyroid hormone levels (12). Responders to lithium (R.T. Joffe, unpublished data), carbamazepine (13), and possibly ECT (14) have a significantly greaten decrease in thyroid hormone levels than do nonrespondens. These observations led to Joffe et al.’s hypothesis (12) that decreases in T4, with consequent decreases in cerebral thyroid hormone concentrations, are required for successful treatment in depression. This hypothesis is based on a variety of evidence suggesting that cerebral T4 and T3 are primanly derived from plasma T4 and that, therefore, exogenous T4 and T3 would have different effects on cerebral thyroid concentrations and hence cerebral function (e.g., mood or cognition). If such differences could be identified, it could advance our understanding of the role of thyroid hormones in neuropsychiatnic, particularly affective, illness and its treatments. In this study we investigated mood and cognitive changes in thyroidectomized patients receiving T4, T3, and no thyroid hormone.
Assorevision
NIMH, and the Clinical Endocrinology Branch, of Diabetes and Digestive and Kidney Diseases, Md. Address reprint requests to Dr. Denicoff, BioBranch, NIMH, Bldg. 10, Rm. 3N238, 9000 Bethesda, MD 20892.
Radioimmunoassay The
acceptedJune
Thyroid
M.D., Russell T. Joffe, M.D., Mark C. Lakshmanan, Robbins, M.D., and David R. Rubinow, M.D.
The authors assessed the mood and cognitive effects of sequential T4, T3, and withdrawal of thyroid hormone replacement on 25 patients who had had thyroidectomies for thyroid cancer. The patients experienced increased sadness and anxiety when they were without medication, but no significant difference in mood was noted between T4 and T3. The patients who experienced increased affective symptoms when not taking medication were more likely to have histories of affective illness or mood lability. (Am J Psychiatry 1990; 147:94-99)
receivedJune
of Altered
Miaclone. Kari
Muller,
METHOD The subjects were 25 patients who had had thyroidectomies for thyroid cancer and who, in preparation for thyroid scans, received sequentially T4, T3, and no thyroid hormone replacement. They ranged in age from 21 to 62 years; 19 were female, and six were
Am
J
Psychiatry
147:1,
January
1990
DENICOFF,
male. Most of the patients were in good health except for their thyroid conditions. Two patients suffered from hypertension, one had hypoparathyroidism, one had polymyositis, and one displayed decreased strength in her extremities because of vertebral/spinal cord pathology. One patient had a current diagnosis of major depression. Nine patients had past histories of psychiatric illness: five had had major depression, and one each had had bipolar II disorder, adjustment disorder-depressed mood, organic delusional syndrome, and dysthymic disorder. The patients received maintenance T4 and were then changed to T3 for 4 weeks. The T3 was then discontinued, and the subjects received no thyroid medication for approximately two and a half weeks. When the patients were receiving maintenance T4, the dose was titrated to an amount that was sufficient to suppress the TSH to below 1.0 iJU/ml according to an ultrasensitive assay. When the patients were switched to T3, the dose was usually quartered. For example, a patient who was receiving 200 p.g/day of T4 would be given SO pjg/day of T3 (25 ig b.i.d). Both cross-sectional and longitudinal assessments were performed. Tests were administered on three occasions: just before discontinuation of T4, during the fourth week of T3 replacement, and during the third week without thyroid hormone replacement. Mood assessment included administration of the Beck Depression Inventory (15), the Spielberger State Anxiety Scale (16), and the SCL-90 (17). The Beck and the Spielberger inventories are 21- and 20-item questionnaires that provide total depression and anxiety scores, nespectively. The SCL-90 is a self-report inventory that measures different dimensions of psychopathology, including depression, anxiety, somatization, and angerhostility. The cognitive tests included a standardized mental status test called the Cognitive Capacity Screening Examination (18) and the digit-symbol subtest of the WAIS (19). The Cognitive Capacity Screening Examination is a 30-point test that examines a variety of cognitive functions, such as orientation, memory, calculations, and abstraction. The WAIS digit-symbol subtest consists of rows of blank squares, each paired with one of nine randomly assigned nonsense symbols. At the top of the page is a key that pairs each nonsense symbol with a number from one to nine. The patient is allowed 90 seconds to fill in the blank squares with the appropriate numbers. In addition, a semistructured interview of lifetime psychiatric history, the modified Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) (20), was administered at the time of the first assessment. The patients used visual analogue scales to rate themselves daily on mood, anxiety, physical comfort, mental tranquility, concentration, energy level, and global assessment. Within several days of each of the three assessments, while the patients were in a nonfasting state, venous blood samples were drawn for measurement of T4, free T4, T3, TSH, and thyroxine-binding globulin. All
AmJPsychiatry
147:1,January
1990
JOFFE,
LAKSHMANAN,
ET
AL.
blood samples were drawn between 8:00 a.m. and 5:00 p.m. The TSH was measured by means of radioimmunoassay. The lower limit of sensitivity of the assay is 0.1 p.IU/ml. The intra-assay coefficients of vanation for TSH were 5% at 1.9 iiIU/ml, 10% at 9.9 iiIU/ml, and 10% at 22.8 iIU/ml. Analysis of variance with repeated measures (ANOVA) was performed for each psychometric measure, with treatment phase as the independent variable. When the analysis of variance was significant, differences were analyzed with the Bonferroni t test to take into account multiple t tests. As the patients did not always complete the rating forms, the degrees of freedom differ slightly across the reported comparisons.
RESULTS
Mood The
Changes TSH
levels
and
rating
scale
scores
are
shown
in
table 1 During T4 replacement, four patients each had a score on the Beck Depression Inventory of at least 14, which is the cutoff score for indicating a moderate level of depression (21). Three patients had a score of at least 14 when receiving T3, and five patients had a score of at least 14 when receiving no thyroid hormone replacement; three patients had a scone of at least 14 during all three treatment phases. There was a significant effect of treatment phase on mood as measured by the Beck Depression Inventory (table 2). The patients’ mean Beck score was significantly higher after .
the thyroid medication was discontinued than when they were taking either T4 (t=3.97, df=36, pO.OS), but a significant change was observed between each medication and no medication (T4 versus no medication: t=3.04, df=40, p
Kirk
Manifestations
D. Denicoff, Jacob
T
here is a vast literature on the relationship between thyroid function and neuropsychiatnic symptoms. Clinical studies attempting to clarify this relationship have evaluated neuropsychiatnic symptoms in patients with thyroid disease (1-4), thyroid functioning in psychiatric patients (5, 6), tniiodothyronine (T3) potentiation of antidepressant efficacy (7, 8), and the effects of thyrotropin-releasing hormone (TRH) on depression (9). Psychiatric symptoms are reported to be a common clinical complication of thynoid disorders (1). In particular, hypothyroidism has frequently been described as accompanied by depressive symptoms (1). Whybrow and Ferrell (1) reported that in a group of seven hypothyroid patients the predominant affective disturbance was a marked depression of mood. Jam (2) assessed 30 consecutive patients diagnosed as hypothyroid and judged 13 patients to be clinically depressed. In addition, patients who are hypothyroid have been reported to suffer from impairment of cognitive functions, such as recent memory, concentration, and simple calculations (1, 2, 4). Conversely, it has been reported that some psychiatric patients have abnormal results on thyroid func-
Presented at the 140th meeting of the American ciation, Chicago, May 9-14, 1987. Received July Psychiatry National
NIH, logical Rockvitte
14, 1989; Branch, Institute
Bethesda, Psychiatry Pike, authors
and Susheet
94
29, 1989.
Psychiatric 1 1, 1988;
From
thank
Patit for
of TSH M.
was
performed
Christine Hoban, their contributions
Joan to this
the Biological
by Serono Todd, study.
State
M.D.,
tion tests. Gold et al. (5) reported that in 100 consecutive patients referred to a neuropsychiatnic evaluation and research unit with complaints of depression and/or anergia, nine patients had low T3 uptake, a low thyroxine (T4) level, a high basal thyrotropin (TSH) level, or a change in TSH greater than 35 pJU/ml in response to TRH stimulation. Five of these patients were diagnosed as suffering from major depression, and the other four had atypical or minor depression. Loosen (10) has reported that the TSH response to exogenously administered TRH is blunted in approximately 25% of patients with major depression. The association between depression and hypothynoidism is consistent with the hypothesis that increases in thyroid hormone levels accelerate recovery and decreases in thyroid hormone levels interfere with necovery in patients with major depression (11). However, studies have shown that most treatments which are effective in manic-depressive illness are associated with significant decreases in thyroid hormone levels (12). Responders to lithium (R.T. Joffe, unpublished data), carbamazepine (13), and possibly ECT (14) have a significantly greaten decrease in thyroid hormone levels than do nonrespondens. These observations led to Joffe et al.’s hypothesis (12) that decreases in T4, with consequent decreases in cerebral thyroid hormone concentrations, are required for successful treatment in depression. This hypothesis is based on a variety of evidence suggesting that cerebral T4 and T3 are primanly derived from plasma T4 and that, therefore, exogenous T4 and T3 would have different effects on cerebral thyroid concentrations and hence cerebral function (e.g., mood or cognition). If such differences could be identified, it could advance our understanding of the role of thyroid hormones in neuropsychiatnic, particularly affective, illness and its treatments. In this study we investigated mood and cognitive changes in thyroidectomized patients receiving T4, T3, and no thyroid hormone.
Assorevision
NIMH, and the Clinical Endocrinology Branch, of Diabetes and Digestive and Kidney Diseases, Md. Address reprint requests to Dr. Denicoff, BioBranch, NIMH, Bldg. 10, Rm. 3N238, 9000 Bethesda, MD 20892.
Radioimmunoassay The
acceptedJune
Thyroid
M.D., Russell T. Joffe, M.D., Mark C. Lakshmanan, Robbins, M.D., and David R. Rubinow, M.D.
The authors assessed the mood and cognitive effects of sequential T4, T3, and withdrawal of thyroid hormone replacement on 25 patients who had had thyroidectomies for thyroid cancer. The patients experienced increased sadness and anxiety when they were without medication, but no significant difference in mood was noted between T4 and T3. The patients who experienced increased affective symptoms when not taking medication were more likely to have histories of affective illness or mood lability. (Am J Psychiatry 1990; 147:94-99)
receivedJune
of Altered
Miaclone. Kari
Muller,
METHOD The subjects were 25 patients who had had thyroidectomies for thyroid cancer and who, in preparation for thyroid scans, received sequentially T4, T3, and no thyroid hormone replacement. They ranged in age from 21 to 62 years; 19 were female, and six were
Am
J
Psychiatry
147:1,
January
1990
DENICOFF,
male. Most of the patients were in good health except for their thyroid conditions. Two patients suffered from hypertension, one had hypoparathyroidism, one had polymyositis, and one displayed decreased strength in her extremities because of vertebral/spinal cord pathology. One patient had a current diagnosis of major depression. Nine patients had past histories of psychiatric illness: five had had major depression, and one each had had bipolar II disorder, adjustment disorder-depressed mood, organic delusional syndrome, and dysthymic disorder. The patients received maintenance T4 and were then changed to T3 for 4 weeks. The T3 was then discontinued, and the subjects received no thyroid medication for approximately two and a half weeks. When the patients were receiving maintenance T4, the dose was titrated to an amount that was sufficient to suppress the TSH to below 1.0 iJU/ml according to an ultrasensitive assay. When the patients were switched to T3, the dose was usually quartered. For example, a patient who was receiving 200 p.g/day of T4 would be given SO pjg/day of T3 (25 ig b.i.d). Both cross-sectional and longitudinal assessments were performed. Tests were administered on three occasions: just before discontinuation of T4, during the fourth week of T3 replacement, and during the third week without thyroid hormone replacement. Mood assessment included administration of the Beck Depression Inventory (15), the Spielberger State Anxiety Scale (16), and the SCL-90 (17). The Beck and the Spielberger inventories are 21- and 20-item questionnaires that provide total depression and anxiety scores, nespectively. The SCL-90 is a self-report inventory that measures different dimensions of psychopathology, including depression, anxiety, somatization, and angerhostility. The cognitive tests included a standardized mental status test called the Cognitive Capacity Screening Examination (18) and the digit-symbol subtest of the WAIS (19). The Cognitive Capacity Screening Examination is a 30-point test that examines a variety of cognitive functions, such as orientation, memory, calculations, and abstraction. The WAIS digit-symbol subtest consists of rows of blank squares, each paired with one of nine randomly assigned nonsense symbols. At the top of the page is a key that pairs each nonsense symbol with a number from one to nine. The patient is allowed 90 seconds to fill in the blank squares with the appropriate numbers. In addition, a semistructured interview of lifetime psychiatric history, the modified Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) (20), was administered at the time of the first assessment. The patients used visual analogue scales to rate themselves daily on mood, anxiety, physical comfort, mental tranquility, concentration, energy level, and global assessment. Within several days of each of the three assessments, while the patients were in a nonfasting state, venous blood samples were drawn for measurement of T4, free T4, T3, TSH, and thyroxine-binding globulin. All
AmJPsychiatry
147:1,January
1990
JOFFE,
LAKSHMANAN,
ET
AL.
blood samples were drawn between 8:00 a.m. and 5:00 p.m. The TSH was measured by means of radioimmunoassay. The lower limit of sensitivity of the assay is 0.1 p.IU/ml. The intra-assay coefficients of vanation for TSH were 5% at 1.9 iiIU/ml, 10% at 9.9 iiIU/ml, and 10% at 22.8 iIU/ml. Analysis of variance with repeated measures (ANOVA) was performed for each psychometric measure, with treatment phase as the independent variable. When the analysis of variance was significant, differences were analyzed with the Bonferroni t test to take into account multiple t tests. As the patients did not always complete the rating forms, the degrees of freedom differ slightly across the reported comparisons.
RESULTS
Mood The
Changes TSH
levels
and
rating
scale
scores
are
shown
in
table 1 During T4 replacement, four patients each had a score on the Beck Depression Inventory of at least 14, which is the cutoff score for indicating a moderate level of depression (21). Three patients had a score of at least 14 when receiving T3, and five patients had a score of at least 14 when receiving no thyroid hormone replacement; three patients had a scone of at least 14 during all three treatment phases. There was a significant effect of treatment phase on mood as measured by the Beck Depression Inventory (table 2). The patients’ mean Beck score was significantly higher after .
the thyroid medication was discontinued than when they were taking either T4 (t=3.97, df=36, pO.OS), but a significant change was observed between each medication and no medication (T4 versus no medication: t=3.04, df=40, p
