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Cortisol, thyroid hormone, and mood in atypical depression: A longitudinal case study
BIOL PSYCHL~TRY 1992;~,~:5) 5-5.),9
515
CASE REPORT
Cortisol, Thyroid Hormone, and Mood in Atypical Depression: A Longitudinal Case Study Thomas D. Geracioti, Jr., Peter T. Loosen, Philip W. Gold, and Mitchel A. Kling
It has been hypothesized that major depression may be divisible into subtypes based, in part, on divergent alterations in the activity of stress-responsive neurohormonal systems (Gold et al 1988; Kling et al 1989; Smith et al 1989). Thus, although the classic farm of major depression, melancholia, is associated with symptoms of dysphoric hyperarousal, including psychomotor agitation, insomnia, loss of appetite, and weight loss; atypical depressive syndromes are characterized by symptoms of hypoarousal, with fatigue, lethargy, anergia, weight gain, and hypersomnia. Whereas hypercortisolemia is consistently observed in melancholic depression (Sachar et ,'tl 1970; Carroll et al 1976, 1981), perhaps re,suiting from central nervous system hypersecretion of fiae adrenocorticotropic hormone (ACTH) secretagoguc corticotropin-releasing hormont:~ (Gold et a! 1984; Nemeroff et al 1984; Gold et al 1986), fewer data are available conc~xning the activity of the hypothalamic-pituitary-adrenal axis in atypical depressions. In the present study, we sought to determ;,ae the relate,reship between mood and adrenocortical activity over a 6-month period in a patient with a depressive syndrome characterized by the atypical features of lethargy, hyperphagia, weight gain, and hypersomnia. We also evaluated pituitary-thyroid function in our patient because abnormalities therein are not uncommon in patients with depressive syndromes (Gold et al 1981; Loosen and Prange 1982) and because controlled longitudinal c~tudies regarding the behavioral effects of thyroid hormone alone are lacking (Prange et al 1984). Methods
Case History and Study Design The patient was a 43-year-old Caucasian woman with recurrent depressions, characterized by hypersomnia, hyperphagia, weight gain, leaden anergia, and intrusive suicidal ideatioa. Neither hypomania nor substance abuse had ever been present. She had three 7dor hospitalizations for depression, but the present episode was distinctly unresponsive so a
From the Clinical Neuroendocrinology Branch, National lnstipate of Mental Health, Bethesda, Maryland (TDG, PWG, MAK) and the Department of Psychiatry, Vanderbilt University School of Medicine and the Veterans Administration, Nashville, Tennessee (PTL). Address reprint requests to Dr. T.D. Geracioti, Jr., Psychiatu/Service (II6A), VA Medical Ccnter, 1310 24th Ave. So., Nashville, TN 37212-2637. Received January 7, 1991; revised August 20, 1991. © 1992 Society of Biological Psychiatry
0006-3223/92/$0:i.00
516
BIOL PSYCHIATRY 1992;31:515-519
T.D. Geracioti et al
variety of tricyclic antidepressants and monoamine oxidase inhibitors. Her family history was positive for completed suicide. The study was approved by the institutional clinical research subpanel, and written, informed consent was obtained. Upon admission to a National Institute of Mental Health (NIMH) research unit, both the patient and the nursing staff wer~ blinded to medications. In turn, the patient received 40 mg per day of fluoxetine hydrochloride, which had been started prior to her admission, 6 weeks of placebo, 50 I~g per day of tdiodothyronine (T3) alone, 20 mg per day of fluoxetine in addition to T3, and finally lithium carbonate (600 rag/day) augmentation of the T3-fluoxetine combination. Mood was rated by consensus twice daily using the 15point Bunney-Hamburg scale (Bunney and Hamburg 1963) by research nurses blind to treatment. The average of the two daily ratings was used. Serum was obtained biweekly at 7:30 ,.~M and assayed by the National Institutes of Health (NIH) Clinical Laboratory for cortisol, I"4, free T4, T3, thyroid-stimulating hormone (TSH), and thyroid-binding globulin. Intrassay variability for cortisol was 3.0% and interassay variability was 5.2%. An ultrasensitive TSH IRMA assay was used; interassay variability was 5.1%. Free cortisol concentrations in more that 50 24-hr urine specimens were measured at 3mith-Kline Beecham Laboratories by radioimmunoassay using reagents obtained from Diagnostic Products, Los Angeles.
Results Clinical Response to Treatmet~t Regimens The patient was treated with various pharmacologic combinations (Figure I A). Both T3 and fluoxetine alone appeared to significantly reduce depressive symptomatology. The combination of fluoxetine and T3 led to further symptom reduction. Lithium augmentation of the T3-fluoxetine colnbination--with lithium levels uniformly 0.6 meq/l.,--resulted in virtual euthymia, and her Bunney-Hamburg depression rating dropped to 3.2 +_ 0.8 (Figure IA). Her weight ranged from 63.8 to 68.8 kg (Figure IE), always within 10% of her ideal weight (Metropolitan Life Foundation 1983).
Associations between Hormonal Measures and Mood Mood improvement was consistently associated with increased serum and 24-hr urinary free cortisol secretion, and weight loss. Mood ratings were negatively correlated over the 6-month study period with serum cortisol concentrations (r = -0.36, p = 0.002). A negative relationship that approached statistical significance was also observed between mood and urinary free cortisol excretion (r = - 0.25, p = 0.06). Free T4 concentrations, which had ranged from 0.9 to 1.2 ng/ml, were suppressed during treatment with T3 to 0.3-0.4 ng/ml.
Discussion A patient suffering from depression with atypical symptoms including hypersomnia, hyperphagia, weight gain, psychomotor retardation, and intrusive suicidal ideation, was studied longitudinally for 175 days. Her symptoms were ameliorated with various pharmacologic treatments, but she relapsed into severe depression during the placebo period. Treatment with T3 alone was as effective as fluoxetine in improving mood, even in the
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Figure I. Longitudinal (I 75 day) double-blind, placebo-controlled study of a patient with an atypical depression. (A) Depression ratings and treatment modalities. Mood was rated with the 15 point Bunney-Hamburg scale (1963), wherein higher values reflect more severe depression. Fluoxetine was started 3 weeks prior to the study. The patient responded to all treatment modalities but relapsed during placebo administration. Addition of lithium to the T3/fluoxetine combination resulted in euthymia (Depression rating ~3). (B,C) 7:30 AM serum cortisol and 24-hr urin~'y free cortisol concentrations, respectively. (D) T3 and TSH levels over the 175 day study. (E) Body weight.
518
BIOL PSYCHIATRY 1992;31:515-519
T.D. Geracioti et al
absence of frank hypothyroidism. Augmentation of T3 with fluoxetine, and of T3/fluoxetine with lithium were associated, in turn, with further mood improvement, suggesting both that thyroid hormone can augment the antidepressant effects of fluoxetine, as it does with tricyclics (Prange et al 1984) and that lithium might act synergistically with the fluoxetine/T3 combination to enhance mood, as has been reported with fluoxetine alone (Pope et al 1988). Moreover, the present data imply that the synergistic augmentation of fluoxetine's antidepressant activity by thyroid hormone and lithium might occur via separate mechanisms. In contrast to the hypercortisolemia classically ooserved in melancholia, our patient remained eucortisolemic despite severe depression. Moreover, adrenocortical activity, as judged by serum cortisol and urinary free cortisol concentrations, was inversely correlated with mood. Our finding that glucocorticoid secretion increased in association with improvement in our patient's mood is in accord with a recent report that improved mood and cognition were associated with increased salivary cortisol concentrations in eucortisolemic depressives (Blackburn et al 1987) and with the recent observation of subtley impaired adrenal responsiveness in patients with chronic fatigue syndrome and atypical depressive symptoms (Demitrack et al 1990). Interestingly, a 24-hr period of adrenocortical activation occurred on study day 57. Just before this, the patient had a worsening of her mood and a brief period of weight loss. This data is compatible with the clinical observation that patients with recurrent depression may t'resent with different patterns of neurovegetative symptoms at different times. Thus the same patient may show pathological hyperarousal with anxiety, loss of appetite, and early morning awakening on one occasion, and show apathy, hyperphagia, and hypersomnia on another, or, more likely, an admixture of the pure syndromes. More controlled, longitudinal studies of eucortisolemic depressives using repeated testings during changing states of psychopathology may help to clarify the prevalence and physiologic significance of adrenocortical activation during clinical recovery. We are indebted to Dr. R.M. Post, and the Nursing and Research Assistant Staffs on Ward 3W of the NIH Clinical Center for their support of this study.
References Blalckburn IM, Whalley LJ, Christie JE, et al (1987): Mood, cognition, and cortisol: their temporal relationships during recovery from depressive illness. J Affective Disord 13:31~--43. Bunney WE Jr, Hamburg DA (1963): Methods for reliable longitudinal observations of emotional behavior on psychiatric wards. Arch Gen Psychiatry. 17:280--294. Carroll BJ, Curtis GC, Davies BM, Mendels J, Sugarman AA (1976): Urinary free cortisol excretion in depression. Psychol Med 6:43-50. Carroll BJ, Feinberg M, Greden JF, et al (1981): A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility. Arch Gen Psychiatry 38:15-22. Demitrack MA, Dale JK, Laue L, et al (1990): Hypothalamic-pituitary-adrenal activity in patients with chronic fatigue syndrome. Neuroendocrinol Lett 12:343 (Abstract). Gold MS, Pottash AL, Extein I, et al (1981): The TRH test in the diagnosis of major and minor depression, Psychoneuroendocrinology 6:159-169. Gold PW, Chrousos G, Kellner C, et al (1984): Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry 141:619--627. Gold PW, Loriaux DL, Roy A, et ai (1986): Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. N Engl J Meal 314:1329-1335.
Adrenal and Thyroid Function in Depression
BIOL PSYCHIATRY 1992;31:515-519
519
Gold PW, Goodwin FK, Chrousos GP (1988): Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (Part 2 of 2 parts). N Engl J Med 319:413-420. Kling MA, Perini Gl, Demitrack MA, et al (1989): Stress-responsive neurohormonal systems and the symptom complex of affective illness. Psychopharmacol Bull 25:312-18. Loosen PT, Prange AJ (1982): Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: A review. Am J P~chiatry 139:405-416. Metropolitan height and weight tables (1983): Star Bull Metrop Life Found 64:3-9. Nemeroff CB, Widerlov E, Bissette G, et al (1984): Elevated concentrations of CSF corticotropinreleasing factor-like immunoreactivity in depressed patients. Science 226:1342-1344. Pope HG, McEIroy SL, Nixon RA (1988): Possible synergism between fluoxetine and lithium in refractory depression. Awi~/ p~ ~,~,~:~.~.~~~.5: |2~£-~,294. Prange AJ Jr, Loosen PT, Wilson IC, Lipton MA (1984): The therapeutic use of hormones of the thyroid axis in depression. In Post RM (ed), Neurobiology of Mood Disorders. Baltimore: Williams and Wilkens, pp 311-322. Sachar EJ, Hellman I, Fukushima DK, Gallagher 'IF (1970): Cortisol production in depressive illness: a clinical and biochemical clarification. Arch Gen Psychiatry 23:289-298. Smith MA, Kling MA, Whitfield HJ, et al (1989): Corticotropin-releasing hormone: From endocrinology to psychobiology. Horm Res 31:66-71.
515
CASE REPORT
Cortisol, Thyroid Hormone, and Mood in Atypical Depression: A Longitudinal Case Study Thomas D. Geracioti, Jr., Peter T. Loosen, Philip W. Gold, and Mitchel A. Kling
It has been hypothesized that major depression may be divisible into subtypes based, in part, on divergent alterations in the activity of stress-responsive neurohormonal systems (Gold et al 1988; Kling et al 1989; Smith et al 1989). Thus, although the classic farm of major depression, melancholia, is associated with symptoms of dysphoric hyperarousal, including psychomotor agitation, insomnia, loss of appetite, and weight loss; atypical depressive syndromes are characterized by symptoms of hypoarousal, with fatigue, lethargy, anergia, weight gain, and hypersomnia. Whereas hypercortisolemia is consistently observed in melancholic depression (Sachar et ,'tl 1970; Carroll et al 1976, 1981), perhaps re,suiting from central nervous system hypersecretion of fiae adrenocorticotropic hormone (ACTH) secretagoguc corticotropin-releasing hormont:~ (Gold et a! 1984; Nemeroff et al 1984; Gold et al 1986), fewer data are available conc~xning the activity of the hypothalamic-pituitary-adrenal axis in atypical depressions. In the present study, we sought to determ;,ae the relate,reship between mood and adrenocortical activity over a 6-month period in a patient with a depressive syndrome characterized by the atypical features of lethargy, hyperphagia, weight gain, and hypersomnia. We also evaluated pituitary-thyroid function in our patient because abnormalities therein are not uncommon in patients with depressive syndromes (Gold et al 1981; Loosen and Prange 1982) and because controlled longitudinal c~tudies regarding the behavioral effects of thyroid hormone alone are lacking (Prange et al 1984). Methods
Case History and Study Design The patient was a 43-year-old Caucasian woman with recurrent depressions, characterized by hypersomnia, hyperphagia, weight gain, leaden anergia, and intrusive suicidal ideatioa. Neither hypomania nor substance abuse had ever been present. She had three 7dor hospitalizations for depression, but the present episode was distinctly unresponsive so a
From the Clinical Neuroendocrinology Branch, National lnstipate of Mental Health, Bethesda, Maryland (TDG, PWG, MAK) and the Department of Psychiatry, Vanderbilt University School of Medicine and the Veterans Administration, Nashville, Tennessee (PTL). Address reprint requests to Dr. T.D. Geracioti, Jr., Psychiatu/Service (II6A), VA Medical Ccnter, 1310 24th Ave. So., Nashville, TN 37212-2637. Received January 7, 1991; revised August 20, 1991. © 1992 Society of Biological Psychiatry
0006-3223/92/$0:i.00
516
BIOL PSYCHIATRY 1992;31:515-519
T.D. Geracioti et al
variety of tricyclic antidepressants and monoamine oxidase inhibitors. Her family history was positive for completed suicide. The study was approved by the institutional clinical research subpanel, and written, informed consent was obtained. Upon admission to a National Institute of Mental Health (NIMH) research unit, both the patient and the nursing staff wer~ blinded to medications. In turn, the patient received 40 mg per day of fluoxetine hydrochloride, which had been started prior to her admission, 6 weeks of placebo, 50 I~g per day of tdiodothyronine (T3) alone, 20 mg per day of fluoxetine in addition to T3, and finally lithium carbonate (600 rag/day) augmentation of the T3-fluoxetine combination. Mood was rated by consensus twice daily using the 15point Bunney-Hamburg scale (Bunney and Hamburg 1963) by research nurses blind to treatment. The average of the two daily ratings was used. Serum was obtained biweekly at 7:30 ,.~M and assayed by the National Institutes of Health (NIH) Clinical Laboratory for cortisol, I"4, free T4, T3, thyroid-stimulating hormone (TSH), and thyroid-binding globulin. Intrassay variability for cortisol was 3.0% and interassay variability was 5.2%. An ultrasensitive TSH IRMA assay was used; interassay variability was 5.1%. Free cortisol concentrations in more that 50 24-hr urine specimens were measured at 3mith-Kline Beecham Laboratories by radioimmunoassay using reagents obtained from Diagnostic Products, Los Angeles.
Results Clinical Response to Treatmet~t Regimens The patient was treated with various pharmacologic combinations (Figure I A). Both T3 and fluoxetine alone appeared to significantly reduce depressive symptomatology. The combination of fluoxetine and T3 led to further symptom reduction. Lithium augmentation of the T3-fluoxetine colnbination--with lithium levels uniformly 0.6 meq/l.,--resulted in virtual euthymia, and her Bunney-Hamburg depression rating dropped to 3.2 +_ 0.8 (Figure IA). Her weight ranged from 63.8 to 68.8 kg (Figure IE), always within 10% of her ideal weight (Metropolitan Life Foundation 1983).
Associations between Hormonal Measures and Mood Mood improvement was consistently associated with increased serum and 24-hr urinary free cortisol secretion, and weight loss. Mood ratings were negatively correlated over the 6-month study period with serum cortisol concentrations (r = -0.36, p = 0.002). A negative relationship that approached statistical significance was also observed between mood and urinary free cortisol excretion (r = - 0.25, p = 0.06). Free T4 concentrations, which had ranged from 0.9 to 1.2 ng/ml, were suppressed during treatment with T3 to 0.3-0.4 ng/ml.
Discussion A patient suffering from depression with atypical symptoms including hypersomnia, hyperphagia, weight gain, psychomotor retardation, and intrusive suicidal ideation, was studied longitudinally for 175 days. Her symptoms were ameliorated with various pharmacologic treatments, but she relapsed into severe depression during the placebo period. Treatment with T3 alone was as effective as fluoxetine in improving mood, even in the
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Figure I. Longitudinal (I 75 day) double-blind, placebo-controlled study of a patient with an atypical depression. (A) Depression ratings and treatment modalities. Mood was rated with the 15 point Bunney-Hamburg scale (1963), wherein higher values reflect more severe depression. Fluoxetine was started 3 weeks prior to the study. The patient responded to all treatment modalities but relapsed during placebo administration. Addition of lithium to the T3/fluoxetine combination resulted in euthymia (Depression rating ~3). (B,C) 7:30 AM serum cortisol and 24-hr urin~'y free cortisol concentrations, respectively. (D) T3 and TSH levels over the 175 day study. (E) Body weight.
518
BIOL PSYCHIATRY 1992;31:515-519
T.D. Geracioti et al
absence of frank hypothyroidism. Augmentation of T3 with fluoxetine, and of T3/fluoxetine with lithium were associated, in turn, with further mood improvement, suggesting both that thyroid hormone can augment the antidepressant effects of fluoxetine, as it does with tricyclics (Prange et al 1984) and that lithium might act synergistically with the fluoxetine/T3 combination to enhance mood, as has been reported with fluoxetine alone (Pope et al 1988). Moreover, the present data imply that the synergistic augmentation of fluoxetine's antidepressant activity by thyroid hormone and lithium might occur via separate mechanisms. In contrast to the hypercortisolemia classically ooserved in melancholia, our patient remained eucortisolemic despite severe depression. Moreover, adrenocortical activity, as judged by serum cortisol and urinary free cortisol concentrations, was inversely correlated with mood. Our finding that glucocorticoid secretion increased in association with improvement in our patient's mood is in accord with a recent report that improved mood and cognition were associated with increased salivary cortisol concentrations in eucortisolemic depressives (Blackburn et al 1987) and with the recent observation of subtley impaired adrenal responsiveness in patients with chronic fatigue syndrome and atypical depressive symptoms (Demitrack et al 1990). Interestingly, a 24-hr period of adrenocortical activation occurred on study day 57. Just before this, the patient had a worsening of her mood and a brief period of weight loss. This data is compatible with the clinical observation that patients with recurrent depression may t'resent with different patterns of neurovegetative symptoms at different times. Thus the same patient may show pathological hyperarousal with anxiety, loss of appetite, and early morning awakening on one occasion, and show apathy, hyperphagia, and hypersomnia on another, or, more likely, an admixture of the pure syndromes. More controlled, longitudinal studies of eucortisolemic depressives using repeated testings during changing states of psychopathology may help to clarify the prevalence and physiologic significance of adrenocortical activation during clinical recovery. We are indebted to Dr. R.M. Post, and the Nursing and Research Assistant Staffs on Ward 3W of the NIH Clinical Center for their support of this study.
References Blalckburn IM, Whalley LJ, Christie JE, et al (1987): Mood, cognition, and cortisol: their temporal relationships during recovery from depressive illness. J Affective Disord 13:31~--43. Bunney WE Jr, Hamburg DA (1963): Methods for reliable longitudinal observations of emotional behavior on psychiatric wards. Arch Gen Psychiatry. 17:280--294. Carroll BJ, Curtis GC, Davies BM, Mendels J, Sugarman AA (1976): Urinary free cortisol excretion in depression. Psychol Med 6:43-50. Carroll BJ, Feinberg M, Greden JF, et al (1981): A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and clinical utility. Arch Gen Psychiatry 38:15-22. Demitrack MA, Dale JK, Laue L, et al (1990): Hypothalamic-pituitary-adrenal activity in patients with chronic fatigue syndrome. Neuroendocrinol Lett 12:343 (Abstract). Gold MS, Pottash AL, Extein I, et al (1981): The TRH test in the diagnosis of major and minor depression, Psychoneuroendocrinology 6:159-169. Gold PW, Chrousos G, Kellner C, et al (1984): Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry 141:619--627. Gold PW, Loriaux DL, Roy A, et ai (1986): Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. N Engl J Meal 314:1329-1335.
Adrenal and Thyroid Function in Depression
BIOL PSYCHIATRY 1992;31:515-519
519
Gold PW, Goodwin FK, Chrousos GP (1988): Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (Part 2 of 2 parts). N Engl J Med 319:413-420. Kling MA, Perini Gl, Demitrack MA, et al (1989): Stress-responsive neurohormonal systems and the symptom complex of affective illness. Psychopharmacol Bull 25:312-18. Loosen PT, Prange AJ (1982): Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: A review. Am J P~chiatry 139:405-416. Metropolitan height and weight tables (1983): Star Bull Metrop Life Found 64:3-9. Nemeroff CB, Widerlov E, Bissette G, et al (1984): Elevated concentrations of CSF corticotropinreleasing factor-like immunoreactivity in depressed patients. Science 226:1342-1344. Pope HG, McEIroy SL, Nixon RA (1988): Possible synergism between fluoxetine and lithium in refractory depression. Awi~/ p~ ~,~,~:~.~.~~~.5: |2~£-~,294. Prange AJ Jr, Loosen PT, Wilson IC, Lipton MA (1984): The therapeutic use of hormones of the thyroid axis in depression. In Post RM (ed), Neurobiology of Mood Disorders. Baltimore: Williams and Wilkens, pp 311-322. Sachar EJ, Hellman I, Fukushima DK, Gallagher 'IF (1970): Cortisol production in depressive illness: a clinical and biochemical clarification. Arch Gen Psychiatry 23:289-298. Smith MA, Kling MA, Whitfield HJ, et al (1989): Corticotropin-releasing hormone: From endocrinology to psychobiology. Horm Res 31:66-71.