Psychoendocrinological aspects of affective disorders.

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Psychoendocrinological Aspects of Affective Disorders John B. Murray

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Psychology Department , St. John's University , USA Published online: 06 Jul 2010.

To cite this article: John B. Murray (1991) Psychoendocrinological Aspects of Affective Disorders, The Journal of General Psychology, 118:4, 395-421, DOI: 10.1080/00221309.1991.9917800 To link to this article: http://dx.doi.org/10.1080/00221309.1991.9917800

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The Journal of General Psychology, 118(4), 395-421


Psychoendocrinological Aspects of Affective Disorders JOHN B. MURRAY Psychology Department St. John’s University

ABSTRACT. Psychoendocrinological studies have opened a new approach to understanding affective disorders. In this study, the links of affective illnesses to changes in endocrine secretions-particularly adrenal, gonadal, growth, pineal, thyroidal, and prolactin-were reviewed with the object of adding to the number of depressed whose symptoms can be relieved.

IN THE LAST FEW DECADES, neuroendocrine studies and improved biochemical measurement have expanded our knowledge of the interrelationships between hormonal changes and affective illness (Board, Persky, & Hamburg, 1956; Cookson, 1985; McNeal & Cimbolic, 1986; Winokur,Amsterdam, Caroff, Snyder, & Brunswick, 1982; Zimmerman, Coryell, & Black, 1990). Before antidepressant drugs, psychoendocrinology occupied center stage in biological psychiatry. In the 1920s the hypothalamus was shown to exert endocrine functions. Thirty-five years ago, several hypothalamic hormones were isolated and synthesized, and psychoendocrine impli‘cations of the thyroid hormone were recognized (Loosen & Range, 1982). Although altered neuroendocrine functions have been found in depressed patients, it is difficult to know whether these findings on depression represent significant changes because the relationship between hormonal and emotional factors is poorly understood and because the regulatory mechanisms that affect pituitary functions are multiple (Gold, Goodwin, & Chrousos, 1988; Lewis et al. 1987).

Requestsfor reprints should be sent to John B. Murray, Psychology Department, St. John’s University, Jamaica, NY 11439. 395


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The Journal of General Psychology

Many patients with major endocrine disorders experience significant changes in mood, and many psychiatric patients have pathological alterations in neuroendocrine functions (Akiskal, 1989; Reus, 1986). Well-documented neuroendocrine abnormalities in depression include alterations in thyroid, adrenal, gonadal, and growth hormones, and prolactin (Brown, 1989). Some patients with affective illness have manifested diminished thyrotropin responsivity to thyrotropin-releasing hormone (TRH) (Barry & Dinan, 1990). The Occurrence of hypersecretion in plasma and urinary cortisol and the lack of suppression in the dexamethasone suppression test (DST) in some patients indicate that the adrenal gland plays a role in depression (Gold et al., 1986). An increase in prolactin has been observed in both unipolar and bipolar patients (Grof, Brown, Grof, & Finkelberg, 1981). Growth hormone regulation is very complex, but a proportion of affective disorder patients have shown abnormal growth hormone response to TRH and to insulin as well as alterations in nocturnal levels of melatonin. Neurotransmitters have been implicated both in the psychobiological mechanisms of affective disorder and in the regulation of neuroendocrine functions (Amsterdam, Maislin, Skolnick, Berwish, & Winokur, 1989; Cookson, 1985; Deakin, Pennell, Upadhyaya, & Lofthouse, 1990; Ettigi & Brown, 1977; Siever & Davis, 1985). Neurotransmitters, norepinephrine, serotonin, and dopamine, and their interrelationships, operate in some of the effective antidepressant agents (Murray, 1985; Ostrow, 1985). Both the tricyclic and monoamine oxidase inhibitor (MAOI) antidepressants have a significant effect on brain biogenic amines. MAOIs block dopamine receptors and inhibit the degradation of dopamine, norepinephrine, and serotonin (Goodman & Charney, 1985). Medications that enhance dopamine neurons increase the synthesis and/or the release of dopamine and have precipitated mania, and those that inhibit dopamine synthesis or block dopamine receptors have been effective in reducing manic symptoms (Silverstone, 1985). Interaction between catecholamine activity and thyroid function may play a role in affective disorders (Whybrow & Range, 1981). However, direct attempts to provide metabolic evidence of a monoamine metabolic defect fundamental to the pathophysiology of depression in human subjects have produced equivocal results at best (Baldessarini, 1984). In addition to psychotherapy, current treatment options for affective disorders include antidepressant drugs, total and partial sleep deprivation, and light therapy for seasonal affective disorder, but neuroendocrine strategies might make effective therapy available to even more patients (Regier et al., 1988). With the object of assisting in the diagnosis and treatment of affective disorders, I focused the review of research on evidence for relationships between alterations in thyroid activity and depression, followed by investigations of changes in activity of the adrenal, gonadal, growth hormones, and prolactin in their relations to affective disorders. Definitive endocrine profiles

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of specific affective disorders were neither anticipated nor discovered, but evidence pointing to endocrine interaction with affectiveillness provides hope for the future of diagnosis and treatment.


Relationships Between Depression and Thyroid Hormones Much of the research on the involvement of endocrines in affective disorders has been focused on investigations of the hypothalamic-pituitary-thyroid (HPT) axis (Burch & Messervy, 1978; Tollefson, Valentine, Hoffman, Gamey, & ’hason, 1985; Wallace, MacCrimmon, & Goldberg, 1980). Thyroid hormone receptors were identified in the early 1970s(Evans, 1988). Diseases attributed to defects in thyroid hormone function were identified relatively early in medical history. Clinical thyroid disorders are frequently accompanied by depressive symptoms (Joffe, Roy-Byme, Uhde, & Post, 1984). Increases in thyroid hormone levels tend to accelerate the recovery of some depressed patients, and decreases in thyroid hormone levels have interfered with the recovery of some depressed patients (Denicoff, Joffe, Lakshmanan, Robbins, & Rubinow, 1990). The cloning of thyroid receptors should advance researchers’ understanding of fundamental hormonal functions. The endocrine system is controlled in part by cells in the hypothalamus that secrete hormones that are carried to the anterior pituitary gland, stimulating it to secrete its hormones (McNeal & Cimbolic, 1986). The hypothalamic hormone TRH stimulates the synthesis and release of thyroidstimulating hormone (TSH) from the anterior pituitary and has a broad spectrum of CNS activity. The thyroid gland in turn secretestwo major hormones, thyroxine 0 4 ) and triiodothyronine (T3). Thyroxine increases the metabolic rate of cells. More T4 is produced than T3,but the latter is more potent and diffuses more rapidly (Banki, Bissette, Arato, & Nemeroff, 1988). Both thyroid hormones circulate back to the hypothalamus and pituitary, exerting a negative feedback on TSH secretion. Most of the iodine in the blood is in the form of T4. Investigating the hypothesis that major depressed patients manifest increased variability of neuroendocrine responsiveness, Winokur et al. (1983) compared the effects of administering TRH to 45 major depressed patients to the effects of administering TRH to 32 healthy volunteers. The depressed patients responded to TRH with more variability in five pituitary hormones, TSH, prolactin, growth hormone, luteinizing hormone, and follicle-stimulatinghormone. The TRH test, which measures the serum TSH concentration, has become standard procedure in assessing the functional activity of the HPT axis (Extein, Pottash, & Gold, 1984; Roy, Pickar, & Paul, 1984). Injection of synthetic TRH challenges the anterior pituitary to respond and in normal subjects leads to a peak concentration within 15 to 30 min (Hershman, 1974). Depressed patients’ TSH response to TRH is typically reduced. Resting TSH


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and TRH-induced TSH response can be high or lowhormal. A high-level response suggests primary hypothyroidism, whereas lowhormal response points to pituitary or hypothalamic hypothyroidism, probably reflecting a defect in central regulation of the HPT axis or lowered sensitivity to TRH (Loosen & Prange, 1982). A blunted response to TRH means that the maximum increase in serum TSH above the baseline is less than that found in age- or sex-matched normal subjects. Since 1972,41 reports describing 917 depressed subjects have confirmed that in some euthyroid depressed patients the TSH response to TRH was deficient (Prange & Loosen, 1980). Of 10 women with primary depression to whom TRH was administered intravenously, only 2 lacked signs of thyroid disorder, as indicated by blunted TSH response. An abnormal TSH response to TRH has been noted in 25% to 30% of the endogenously depressed (Banki et al. 1988; Duval, Macher, & Mokrani, 1990; Targum et al. 1984). Under some conditions TRH also stimulates the release of prolactin and growth hormone, and it may induce mild euphoria in normal subjects. Women in the follicular phase of the menstrual cycle show a stronger response, and older men a weaker response to TRH (Sternbach, Gerner, & Gwirtsman, 1982). The neuroendocrinological mechanism of TSH-blunting in depression remains obscure. Golstein, VanCauter, Linkowski, Vanhaelset, and Mendlewicz (1980) found striking differences in TSH response patterns to TRH between unipolar and bipolar patients and found that bipolar patients’ TSH response pattern was similar to that of the control subjects. Unipolar subjects’ TSH average patterns over 24 hr were significantly lower than control subjects’ TSH mean. Blunted TSH response to TRH of 1 14 women inpatients, some of whom were depressed, was associated with recovery after 9 weeks of treatment (Langer et al. 1986). In eight studies of TRH stimulation of 129 depressed patients, 54 had blunted TSH response. However, although both unipolar and bipolar patients showed diminished TSH response, in Stembach et al.’s 1982 study, bipolar patients’ TSH was greater than that of unipolar patients. Walter and Fabs (1987) described a case in which a man developed mania during a hyperthyroid condition. The investigations of both Souetre et al. (1988) and Duval et al. (1990) indicated that the usual nocturnal surge of TSH was blunted during depression and corrected after recovery. Through their capacity to stimulate heat production, thyroid hormones may contribute to regulation of body temperature in warm-blooded animals. Exposure to cold stimulates and exposure to heat inhibits TSH secretion. Thus, an increase in body temperature at night could be responsible for the blunting nocturnal TSH secretion. Body temperature at night has been reported to be abnormally high in depressed subjects. The inverse relationship between changes in body temperature and decreased TSH response during depression suggests that thermoregulation may play a role in

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the pathophysiology of depression (Avery, Wildschiodtz, & Rafaelsen,


1982).

Some patients with endocrine disorders manifest prominent depressive symptoms (Nemeroff, 1989; Tapp, 1988). In three studies, 20% of the subjects with hyperthyroidism had psychotic symptoms (Whybrow, Prange, & Treadway, 1969). Among 144 consecutive female psychiatric patients, 27% of whom had a personal history of thyroid disorder, a history of goiter was significantly more likely in those with major depression than in those with panic/agoraphobia symptoms (Orenstein, Peskind, & Raskind, 1988). Hypothyroidism can produce symptoms and signs manifested as depression or lethargy (Gold, Pottash, Mueller, & Extein, 1981). Clinically depressed subjects with occult thyroid dysfunction are usually overweight and sluggish and experience cognitive slowing and obsessional ruminations. Occult thyroid dysfunction may be present in 25% of depressed patients. Of 101 consecutivedepressed patients, 15%were identified as hypothyroid, and 60% of these had positive thyroid microsomal antibodies. Hypothyroidism, which is not an all-or-none phenomenon, can be identified by thorough thyroid examination and measurement of TRH-induced TSH response and the thyroid hormones T3 and T4 (Evered, Ormston, Smith, Hall, & Bird, 1973; Kirkegaard, Norlem, Lauridsen, Bjorum, & Christiansen, 1975). Hypothyroidism may be a predisposing factor to rapid-cycling mania (Cowdry, Wehr, Zis, & Goodwin, 1983; Extein, Pottash, & Gold, 1982; Prange, Lipton, Nemeroff, & Wilson, 1977). In a prospective study, hypothyroid abnormalities were present in 30 rapid-cycling bipolar patients at a rate significantly greater than the base rate in unselected bipolar patients (Bauer, Whybrow, & Winokur, 1990). The incidence of psychosis associated with thyrotoxicosis has ranged from 1% to 20% (Burch & Messervy, 1978). Thyrotoxicosis can precipitate manic states, and the antidepressant lithium, which can increase thyroid size, can also induce thyrotoxicosis (Cookson, 1985; Pemld, Hegedus, Baastrup, Kayser, & Kastberg, 1990; Reus, Gold, & Post, 1979; Yassa, Saunders, Nastase, & Camille, 1988). Evidence of occult thyroid dysfunction includes abnormal response to TRH stimulation test, high titers of antimicrosomal thyroid and antithyrogobulin antibodies, and an elevated level of TSH (Haggerty et al. 1990). Nemeroff, Simon, Haggerty, and Evans (1985) investigated antithyroid antibodies in 45 hospitalized psychiatric patients who had prominent depressive symptoms. Antithyroid antibodies were detectable in 20% of the patients, a proportion that was much larger than the 5% and 10%rate expected in normal subjects. Such findings support the hypothesis that subtle thyroid dysfunction may be present in some patients who have prominent depressive symptoms. TSH blunting is not specific to depression; it has been observed in alcoholic patients and in patients with anorexia nervosa, as well as in manic subjects. The absence of TSH blunting in schizophrenics suggests that TSH


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blunting is not merely a correlate of mental disorder. Other factors have been associated with TRH-induced TSH response and must be noted in studies of older subjects, males, those experiencing chronic renal failure or acute starvation, those of whom TRH was administered many times, or those who received somatostatin, neurotension, dopamine, thyroid hormone, or glucocorticoids (Goodwin, Fairburn, Keenan, & Cowen, 1988). Administration of thyroid hormones has helped some individuals with affective disorders (Joffe, 1988; Joffe, Blank, Post, & Uhde, 1985). Five patients who received TRH in a double-blind crossover investigation experienced reduced symptoms of depression (Kastin, Schaech, Ehrensing, & Anderson, 1972). TRH caused prompt, brief improvement for 10 women with unipolar depression in another double-blind crossover study (Prange, Lara, Wilson, Alltop, & Breese, 1972). In a placebo-control study, T3 was an effective adjunct to the antidepressant imipramine for 30 depressed patients (Whybrow, Coppen, Prange, Noguera, & Bailey, 1972). Five out of 8 female refractory depressed patients responded positively to thyroxine alone or to a combination of thyroxine and antidepressants (Gewirtz et al. 1988). In 5 of 7 manic-depressive women, rapid-cycling was abolished by high doses of levothyroxine (Stander & Persad, 1982). Ten of 11 rapid-cycling patients-refractory to antidepressant-received relief from depressive symptoms when levothyroxine was added to their medication (Bauer & Whybrow, 1990).

Consistent with the results of earlier studies, which were not doubleblind, the controlled investigation of Goodwin, Prange, Post, Muscettola, and Lipton (1982) indicated that adjunctive use of thyroid hormones shortened the latency of tricyclic antidepressants. However, in three studies, adjunctive use of the thyroid hormone T3 did not reduce depressive symptoms (Schwarcz et al. 1984; Thase, Kupfer, & Jarrett, 1989; Wager & Klein, 1988). Radioactive iodine treatment improved neurotic emotional distress in 19 acutely hyperthyroid women as compared with a normal control group of 19 women (Wallace, MacCrimmon, & Goldberg, 1980). Because 20% to 30% of depressed patients do not respond to antidepressants alone, thyroid hormone alone or adjunctively may bring relief to some patients who are not helped by drugs. The literature reports no negative reactions to adjunctive use of thyroid hormones. Some evidence suggested that thyroid deficiency in hypothyroidism attentuated the effects of the catecholamines and that interaction between thyroid hormones and catecholamines may underlie the therapeutic effectiveness of combining thyroid hormones and the antidepressants(Denicoff et al. 1990; Whybrow et al. 1969). Joffe et al. (1984) proposed that decreases in T4 leading to diminished cerebral thyroid concentrations are necessary for successful treatment of depression. The antidepressant-response-potentiatingproperties of thyroid hormones appear promising enough-especially for rapid-cycling


depressive patients-to deserve careful clinical investigation (Browne, Rice, Evans, & Prange, 1990;Post, Kramlinger, Altshuler, Ketter, & Denicoff,

1990). Lithium carbonate, which is the treatment of choice for bipolar affective disorder, inhibits the release of thyroid hormone, whereas the TSH level is increased (Chamberlain, Hahn, Casson, & Reid, 1990;Pemld, Hegedus, Baastrup, Kayser, & Kastberg, 1990). Effects of carbamazepine-an alternative drug for lithium-resistant bipolar disorder-and lithium are reflected in clinical laboratory measures of thyroid indices (Cho, Bone, Dunner, Colt, & Fieve, 1979;Post, Uhde, Roy-Byme, & Joffe, 1986;Roy-Byme, Joffe, Uhde, & Post, 1984). Lithium is associated with a notable (7% to 8%) incidence of hypothyroidism in bipolar depressives (Cowdry et al. 1983;Lindstedt, Nilsson, Walinder, Skott, & Ohman, 1977;Yassa et al. 1988). Although both drugs reduce peripheral thyroid hormone levels to a similar degree, lithium treatment is associated with increases of TSH levels, but carbamazepine is not (Joffe et al. 1984;Kramlinger & Post, 1990). Tollefson et al.’s (1985)longitudinal study monitored several aspects of thyroid function in 40 recurrent major depressed patients, who upon admission had lower thyroxine and higher TSH secretion levels than control groups but were euthyroid. Five tests of thyroid function were included. Depressed patients’ scores on the Global Assessment Scale (Endicott, Spitzer, Fliess, & Cohen, 1976)indicated remission of depressive symptoms during the 2 years of the study, which was double-blind and in which lithium and placebo, imipramine and placebo, double placebo, and both drugs were employed. Higher T4 values and high TSH at admission were associated with recurrent depression. Thyroid deficiencies may coexist with or exacerbate an underlying major depressive disorder. Abnormalities of the hypothalamic-pituitary-thyroidaxis have been associated with bipolar affective disorder. Depression is present in 25% to 40% of patients with hypothyroidism. Slight changes in the thyroid state appear to promote recovery from depression, and lithium, recognized as an effective antidepressant, has been known to af€ect thyroid function. Mood changes occur when thyroid hormone replacement is stopped. Thyroid activity may act as a marker for depressed patients who could benefit from continued thyroid additives. Whether treatment with thyroid hormone alone or adjunctively with antidepressants benefits depressed patients with thyroid antibodies has not been investigated. The anterior pituitary is regulated by feedback mechanisms, and other regions of the brain may influence the secretion of TSH and TRH. The role of neurotransmitters in connection with HPT axis dysfunctions needs more study, particularly regarding the interplay of thyroid hormone and catecholamines. Interaction among many factors seems to be involved in thyroid relationships with affectiveillness, and in at least some depressive patients, thy-

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roid dysfunction exists. Perhaps a relative increase in thyroid indices, rather than absolute hormone levels achieved with treatment, is an important factor in response to treatment. Decreased thyroid function may predispose patients to depression, and the increased availability of thyroid hormones may be involved in recovery from depression; TSH response to TRH, which is common in severely depressed patients and may be attributable to down-regulation of TRH receptors, recovers with successful treatment.

Relationships Between Affective Disorders and Hyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) Axis There is a long history of investigation of the relationships between disturbed affect and adrenal function (Rubin & Mandell, 1966). Clinical association has been noted between affective disturbances and diseases of the adrenal gland, Cushing’s syndrome, and diabetes (Carroll, Curtis, & Mendels, 1976a; Gold et al. 1986; Popkin, Callies, Lentz, Colon, & Sutherland, 1988; Prange et al. 1977; Reus, 1986; Wilkinson, 1981). Hypercortisolism is one of the most consistent findings in subjects with depressive disorders, suggesting a defect at the hypothalamic level (Anton, 1987; Gold et al. 1988; Kling et al. 1989; McNeal & Cimbolic, 1986). Although HPA regulation is very complex and not completely understood, evidence of excessive activation of the HPA axis is one of the best established biological findings in depression (Schlesser, Winokur, & Sherman, 1980). Peripheral measures of cortisol activity have revealed that during depressive states the production rate of cortisol is elevated, whereas during recovery from depression, the production rate falls (Carpenter & Bunney, 1971). The corticotropin-releasing factor (CRF) in the hypothalamus is believed to induce the adrenal cortex to secrete cortisol in response to adrenocorticotropin hormone (ACTH) (Garver & Davis, 1979). Cortisol levels follow a 24-hr rhythm, with no cortisol secretion until after about 6 hr of sleep (Platman & Fieve, 1968). Plasma cortisol secretion peaks during the morning and levels off during the day. The cycles of cortisol secretion correspond to pituitary secretion of ACTH and CRF (Carroll, Curtis, & Mendels, 1976b). However, depressed patients’ plasma cortisol concentration is not suppressed during sleep, and their cortisol concentrations tend to be much higher than normal subjects’ (Kronfol, Nasrallah, Chapman, & House, 1985; Sachar, Hellman, Fukushima, & Gallagher, 1970). The DST, which is widely used for measuring plasma ACTH in depressed patients, was originally developed to clarify dysfunction of the HPA axis in endocrine diseases (APA, 1987;Hirschfeld, Koslow, & Kupfer, 1983). In the DST, 1 mg of dexamethasone, a potent, long-acting synthetic steroid, is administered at 1 1:00 p,m., a low point in the circadian rhythm of endog-


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enous corticosteroid secretion. The drug normally suppresses cortisol release into plasma by blocking the release of CRF from the hypothalamus and ACTH from the anterior pituitary. On the day after administration of dexamethasone, blood samples for determining plasma concentrations are usually drawn at 8:OO a.m., 4:OO p.m., and 11:OO p.m. Elevated plasma concentration of cortisol in any blood sample between 9 and 24 hr after the administration of dexamethasone indicates failure of normal suppression of cortisol levels and an abnormal, or positive, test result (Coryell, Pfohl, & Zm erm an, 1984). The abnormal DST returns to normal when the depressed patient recovers. A positive DST has also been associated with a favorable response to tricyclic antidepressantsand electroconvulsive therapy (McNeal & Cimbolic, 1986).

DST is generally assumed to be a test of the dysfunction of central neuronal and neuroendocrine systems associated with major depression and probably involves both the limbic system and the hypothalamus (Carrollet al. 1976b). An essential disturbance of neuroendocrine regulation in depression is traced to failure of the normal brain inhibitory influence. However, the details of the assumption remain to be clarified (Gold et al. 1988). The actions of the limbic system in controlling human HPA functions have been established, thereby providing a functional connection between emotions and anatomical sites (Carroll et al. 1976a). Researchers studying psychoendocrinology have realized the importance of examining the more subtle features of central HPA regulation, such as circadian rhythms and response to stress (Czeisler et al. 1989; Niles, Brown, & Grota,1979). Although postdexamethasone cortisol nonsuppression is associated with high plasma ACTH concentration, the DST has not indicated depression in all patients and yields abnormal results, even for healthy subjects ( M A , 1987; Berger, Pirke, Doerr, Krieg, & Von Zerssen, 1984; Brown, 1989; Brown, Keitner, Qualls, & Haier, 1985). DST may be more sensitive in unipolar than in bipolar depression (Feinberg & Carroll, 1984). Both DST and TRH differentiated endogenous from nonendogenous depressive patients in Levy and Stem’s (1987) study, but DST and growth hormone secretion tests did not indicate specificity for endogenous subtypes of depression in the investigation of Berger, Doerr, Lund, Bronisch, and Von Zerssen (1982). Nonsuppressive DST has distinguished primary unipolar depressive patients from secondary unipolar depressed psychiatric patients, but data suggest there may be distinctive patterns of HPA axis activity for different depressive illnesses (Schlesser et al. 1980). Depressed patients exhibited a blunted ACTH response to intravenously administered CRF, in comparison with the response of manic patients, recovered depressive patients, and control subjects (Gold et al. 1988). This finding may indicate an intact cortisol feedback mechanism at the pituitary that halts ACTH response to exogenous CRF because of the persistently high plasma


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cortisol concentration. Synthetic CRF is available as a new tool to study the pathophysiology of the exaggerated pituitary adrenocortical activity of depressed patients (Holsboer, Gerken, Stalla, & Muller, 1987). Although DST is used to distinguish those with and without pituitaryadrenocortical disinhibition, suppressors and nonsuppressors do not consistently differ in clinical presentation (Brown, Arato, & Shrivastava, 1986). Nonsuppressors averaged greater elevation in plasma cortisol and corticotropin levels than suppressors, whose cortisol level was almost the same as that of normal control group members but whose corticotropin was significantly higher than the normal group’s level (Pfohl, Sherman, Schlechte, & Stone, 1985). Nonsuppressors may also be more likely to relapse, to develop mania, hypomania, and/or to make serious suicide attempts (Coryell, 1990). Both age and weight may affect DST results (Casat & Powell, 1988; Goodwin et al. 1988; Puig-Antich et al. 1989; Roy, 1988; Swade, Metcalfe, Coppen, Mendlewicz, & Linkowski, 1987; Van Bemmel, van Diest, Smeets, van Dongen, & Hilgerson, 1988). Differencesduring depression occur in a number of other physiological dimensions, including sleep architecture, response to sleep deprivation, and sensory inhibition (Meller, Kathol, Jaeckle, Gambsch, &Lopez, 1988). The combination of TRH and DST yielded a sensitivity of 77% to 84% in two studies, in contrast to 40% to 50% sensitivity expected in endogenously depressed through DST alone. The combination of DST, TSH, and growth hormone (GH) challenges in 3 days of testing identified 80% of 33 major depressed subjects on at least one parameter studied, 30% on both DST nonsuppression and blunted GH (Barry & Dinan, 1990). One out of 5 depressed subjects gave normal responses on all three endocrine tests. Some overlap occurred among the abnormal results, but the reason depressed subjects showed endocrine abnormality on specific tests was not clear. The variety of response abnormality underlines the need for examining hormonal responses on several neuroendocrine axes (Winokur et al. 1983). Because not all depressed patients respond to the DST test, possibly in part because depression is a heterogeneousdisorder, or because cutoffs on the DST for cortisol secretion may differ, investigators have used other “biological marker” tests such as arginine vasopressin, which reliably stimulates cortisol secretion (Meller et al. 1988). Specific arginine vasopressin receptors have been identified in anterior pituitary corticotroph cells. Depressed subjects had a significantly greater cortisol response to arginine vasopressin than control subjects did. Relative insulin insensitivity, insulin-induced hypoglycemia, and differential ACTH response have all been associated with depression (Wright, Jacisin, Radin, & Bell, 1978). A combination of these three different tests increased the sensitivity of the tests of depression over DST or any of the tests alone, but the tests may identify different subsets of affective disorder subjects.


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Examination of the clinical responses of depressed DST suppressors and nonsuppressors to pharmacological antidepressant agents has produced inconsistent results (Brown et al. 1986). In general, nonsuppressors respond somewhat better than suppressorsto the tricyclic antidepressants desipramine and maprotiline, which are relatively potent uptake blockers of the neurotransmitter norepinephrine; nonsuppressors respond relatively poorly to clomipramine, which is a potent uptake inhibitor of the neurotransmitter serotonin. The two kinds of depressives do not differ consistently in their response to the tricyclic drugs imipramine and amitriptyline, which affect both norepinephrine and serotonin. HPA dysfunction has been associated with primary depressive illness (Carroll, 1976). About half of those patients with primary depression display elevated plasma cortisol levels. Because less than 5% of other psychiatric patients have been found to have elevated cortisol levels, cortisol level has been accepted as a biological marker for endogenous depression (Grof et al. 1981). Abnormal secretion of cortisol may result from an abnormal secretion of ACTH from the pituitary gland, triggered by abnormal activity in the brain regions associated with emotional states, namely, the limbic system, and may represent an indirect functional marker of associated limbic system disturbances. Some portion of depressed patients also seems to be relatively unresponsive to a normal feedback signal as measured in DST, so other strategies have been developed to identify depressed patients and to differentiate between subtypes of depression. The accumulating evidence of an association between the abnormal function of the HPA axis and depression has added to a picture of the involvement of brain and body malfunction in affective disorders.

Prolactin Mective disorders have been associated with several other endocrines about which research has been less extensive than research in connection with the adrenal and thyroid glands. One of these endocrines, prolactin, which has lactogenic and mammotropic actions, is stimulated by drugs that may precipitate depression and has been found in altered levels in some depressive states (De La Fuente & Rosenbaum, 1981; Fava et al. 1988; Judd et al. 1982). Secretion of prolactin from the anterior pituitary is predominantly under the inhibitory control of the hypothalamus, so that the blunted prolactin response observed in depressed patients suggests some dysfunction in the anterior pituitary or hypothalamic neurotransmitters (McNeal & Cimbolic, 1986; Meltzer, 1981). Many neuroleptics produce increased secretion of prolactin (Richelson, 1985). The hypothalamus exerts control by releasing peptides and neurotransmitters that may stimulate or inhibit the release of hormones. The neurotransmitter dopamine is the main inhibiting factor of prolactin release (Asnis, Nathan, Halbreich, Halpern, & Sachar, 1980; Cookson, 1985;


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Snyder, 1984). By antagonizing dopamine receptors, neuroleptics produce elevated serum levels of prolactin. Plasma prolactin patterns were significantly greater in subjects when they recovered from depression (Lisansky et al., 1984). However, some studies of the relationships between prolactin and depression have conflicting results, possibly because of the heterogeneity of depression and the influence of other variables, such as sleep and sex steroids; corticosteroids apparently inhibit prolactin release, and the relationship of cortisol and prolactin in depression is an important variable (Fava et al. 1988). Prolactin levels can be determined by obtaining small blood samples, frequently and over an extended period of time. Assays are reliable and inexpensive. The 24-hr rhythm of prolactin is characterized by a sharp nocturnal increase reaching a peak a few hours after the onset of sleep. Variability in prolactin levels around a 24-hr average is absent or reduced in both unipolar and bipolar patients, and nocturnal secretion increases after recovery (Linkowski et al. 1989). Prolactin level secretion does not diminish over a 24-hr period, unlike corticotropic and somatotropicaxes disturbances. Endogenous depressed males’ characteristic early timing of prolactin secretion and reduced nighttime prolactin level elevation may continue to be present during clinical remission following antidepressant treatment. The serum prolactin levels of 7 depressed subjects were significantly higher than those of 5 control subjects several hours before sleep (Halbreich, Grunhaus, & Ben-David, 1979). However, Rubin, Poland, Lesser, and Martin (1989) found no differences in basal nocturnal prolactin concentration between 40 depressed patients and 40 control subjects matched in age and sex. Because other stimuli can increase its secretion, prolactin’s association with affective disorders must be carefully evaluated. Endocrinopathologic factors, including hypoglycemia, renal failure, and liver damage, as well as sleep, exercise, stress, pregnancy, nursing, opiates, and antipsychotic drugs, may influence prolactin secretion (Extein et al., 1980; George, Copeland, & Wilson, 1980; Meltzer, 1981). The drugs reserpine (which may induce severe forms of depression) and alpha-methyldopa have been responsible for a significant incidence of depression and have been known to cause pronounced elevation of prolactin serum levels. (Fava et al., 1988). Dopamine, which is involved in some newer antidepressants, is a major regulator of pituitary prolactin secretion, and serotonin, which also appears to influence the secretion of prolactin, is contained in antidepressant medications (Coppen, Rao, Bishop, Abou-Saleh, & Wood, 1980; Deakin et al. 1990; Goodman & Charney, 1985; Lisansky et al., 1984; Volkow et al., 1990). The effect of prolactin on neuronal function and ultimately on human behavior is beginning to be known. Prolactin secretion appears to be selfregulated by a short loop mechanism. As with other hormones, its release can be increased in response to physical and emotional stress, but prolactin may be a more sensitive index than ACTH, cortisol, and growth hormone (GH).


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The interactions between pituitary-adrenal axis, GH, thyroid, and prolactin appear to be important for understanding and treating affective illness. A number of physiologic and physiopathologicalevents have been identified in which abnormalities in serum levels of prolactin occur, but all its effects on human behavior and the hypothalamic mechanism involved in control of prolactin are not fully understood. Although no evidence indicates that it plays a causative role in inducing psychiatric syndromes, changes in circulating levels of prolactin resulting from drugs that are associated with depression may be clinically useful in diagnosing or treating affective disorders.

Relations of Depression and Gonadal Hormone: Premenstrual and Postmenstrual Syndrome and Postpartum Psychosis Reports of sex and age differences in some biological markers for depression are relevant to relationships between endocrine dysfunction and affective disorders (Ballinger, 1990; Halbreich, Vital-Herve, Goldstein, & Zander, 1984; Nott, Franklin, Armitage, & Gelder, 1976). The hypothalamic-pituitarygonadal axis has provided another approach to neuroendocrine studies of endogenous depression. Menstruation, childbirth, and menopause are not only psychologically meaningful events but may also be associated with hormonal fluctuation and depression (Chamberlain et al. 1990; Ehlert, Patalla, Kirschbaum, Piedmont, & Hellhammer, 1990; Hamilton, Parry, & Blumenthal, 1988a; Harris et al. 1989; Levy, 1987; Rubinow, Roy-Byme, Hoban, Gold, & Post, 1984). Some endocrinologic data support the theory that postpartum affective disorders have a hormonal basis, but a link between postpartum psychosis and endocrine changes has not been confirmed (Fung et al. 1988; Stewart et al. 1988). Progesterone and estrogen levels drop sharply after parturition (Prange et al. 1977). Approximately 75% to 80% of hospitalized postpartum depression syndrome cases are affective in nature and during the first 3 months after delivery women are at high risk for depression (Gitlin & Pasnau, 1989). Traditionally, depression was thought to be a high risk in the menopausal period, but there are no data that support this view (Hamilton, Parry, & Blumenthal, 1988b). However, most of the biological theories of postmenstrual syndrome involved hormones. Estrogen therapy benefitted severely depressed women who had not responded to other treatments in a double-blind study that included both pre- and post-menopausal inpatients (Klaiber, Broverman, Vogel, & Kobayashi, 1979). Posttreatment Hamilton Depression Scale (Hamilton, 1960) scores were significantlyreduced during the 3 months of study. Surgically menopausal women who received estrogen and androgen injections once a month felt more composed and elated than women in control groups who had had similar operations but who had received no hormonal injections (Sherwin, 1988).


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Dramatic changes in mood and behavior in some women in relation to the menstrual cycle have been the focus of recent research. Multiple interrelated endocrinologic changes are associated with premenstrual and postpartum affective disorders. Mood disturbance is common in the 6 weeks before childbirth, but relationships between depressive symptoms and hormonal changes are weak (Susman & Katz, 1988). The neurotransmitters norepinephrine and serotonin that are involved in antidepressant medications are associated with the secretion of female hormones and may influence moods directly in the brain. Clinical studies and endocrine investigations, together with psychodynamic factors and family histories, may discover links between mood disorders and disorders of the female reproductive system and help to expand the diagnosis and treatment of depressed women.

Growth Hormone Growth hormone, which is produced in the pituitary, promotes the growth of bones and muscles. In recent research, it also appears to be a neuroendocrine abnormality in depression (Amsterdam & Maislin, 1990; Deakin et al. 1990; Siever & Davis, 1985). GH exerts direct effects on target organs and indirect effects-medicated by insulin-like growth factors-on other processes. Blunted GH response after insulin administration and diminished hypoglycemic response in depressed subjects have been demonstrated (Sachar, Frantz, Altman, & Sassin, 1973). Psychological, as well as metabolic factors, sleep, and drugs influence GH secretion (Jarrett, Miewald, & Kupfer, 1990).

An association between affective illness and alterations in glucose utilization has been recognized, and one of the earliest strategies for assessing neuroendocrine dysregulation in depression involved in the insulin tolerance test (IlT) (Amsterdam, Schweizer, & Winokur, 1987; Mueller, Heninger, & McDonald, 1969; Wright et al. 1978). The rate of glucose utilization is low in psychotically depressed patients and increases when they recover. In the I'TT, crystalline insulin is injected intravenously and blood samples drawn at 15, 30, 45, 60, 90, and 120 min after injection (Sachar, Finkelstein, & Hellman, 1971). Depressed patients, in contrast to controls, had significantly higher basal glucose levels, suggesting a functional state of insulin resistance during affective illness (Winokur, Maislin, Phillips, & Amsterdam, 1988). The GH response to insulin-induced hypoglycemia of 10 postmenopausal women who were primary unipolar depressed was significantly lower than that of 10 agematched normal postmenopausal women (Gruen, Sachar, Altman, & Sassin, 1975). Some diabetics have displayed elevated blood sugar levels during depression episodes (Popkin et al. 1988; Wilkinson, 1981). Interpretationsof the blunted response to ITT are unsure because studies have been based on


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small samples, and many lacked age- and sex-matched controls. Some evidence suggested the possibility of alteration in CNS neurotransmitter regulation. Nocturnal serum GH concentrations and GH response to TRH and DST in 40 primary endogenous depressed patients did not differ from those of 40 matched control subjects (Rubin, Poland, & Lesser, 1990). GH release is regulated in part by central norepinephrine systems because adrenergic blockers diminish insulin release (Amsterdam et al. 1989; Ansseau et al. 1988; Lesch, Laux, Schulte, Pfuller, & Beckmann, 1988). Clonidine, an agonist of norepinephrine, stimulates alpha adrenergic receptors and brings about the release of GH. Administered intravenously, clonidine may be unpleasant to take, and monoamine oxidase inhibitor antidepressants such as desipramine, which produce an increase in GH levels while blocking reuptake of norepinephrine, have been used in research instead of clonidine (Dinan & Barry, 1990). GH response to imipramine decreases in older men and women after menopause (Ryan et al. 1988). Estrogen potentiates GH response to a variety of stimuli so that the diminished estrogen secretion after menopause could account for reduced GH response. Differences in nutrition or stress also affect GH secretion. Thus, it is unclear whether deficient GH responses to hypoglycemia are characteristic of all depressed patients. Neuroendocrine mechanisms involved in GH secretion during depressive states are unclear, and GH regulation is so complex that its clinical use is limited. More subtle alterations in circadian GH secretion patterns might be detected in longitudinal studies.

Relations of Pineal Hormone-Melatonin and Depressive Illness Researchers have paid considerable attention to melatonin, a secretion of the pineal endocrine gland, in connection with seasonal affective disorder (SAD) (Murray, 1989; Niles et al. 1979; Wehr, Skwerer, Jacobsen, Sack, & Rosenthal, 1987). SAD is a subgroup of affective disorders that is characterized by recurrent fall-winter depression and spring-summer hypomania or euthymia. Studies in the United States and Europe have shown that S A D symptoms can be reversed by treatment with bright, full spectrum artificial light (phototherapy), although the mechanisms remain unsettled (Jacobsen, Wehr, Skwerer, Sack, & Rosenthal, 1987; Rosenthal et al. 1985). Melatonin production occurs during nighttime darkness mediated through the retinohypothalamic tract. The light-dark cycle synchronizes an endogenous circadian pacemaker. When humans are exposed to light during the night, melatonin production is reduced. The melatonin rhythm is expressed in the blood and cerebrospinal fluid (Reppert, Weaver, Rivkees, & Stopa, 1988). The normal nocturnal level of melatonin is reduced in some depressed patients and increased during treatment with antidepressant medi-


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cations (Brown, 1989). Melatonin output increased substantially in manic patients in contrast to depressed and euthymic patients (Kennedy, Tighe, McVey, & Brown, 1989). Some features of affective illness suggest abnormalities in biologic rhythms such as circadian cycles and sleep architecture involving the length and timing of sleep stages (Duval et al. 1990; Gold et al. 1988; Golstein, VanCauter, Linkowski, Vanhaelst, & Mendlewicz, 1980; Jarrett et al. 1990; Parker, Pekary, & Hershman, 1974; Siever & Davis, 1985; Souetre et al. 1988; Takahashi & Zatz, 1982). Early researchers of the effectiveness of phototherapy for SAD proposed an extension of the apparent length of daytime by adding exposure to light. Patients in the United States have consistently improved with exposure to bright, full spectrum light treatment. Time schedules for exposure to light varied; some studies used light in the early morning, and others used light in the evening. Some improvement in symptoms was affected by these exposure schedules, and some improvement came about when patients were exposed to dim lights (Isaacs, Stainer, Sensky, Moor, & Thompson, 1988). Other researchers have proposed that the disturbance of circadian rhythms is associated with SAD. According to this theory, circadian rhythm in SAD patients becomes phase-delayed and light pulses are able to restore the timing of the circadian rhythms (Czeisler et al. 1989; Jacobsen et al. 1987; Lewy, Sack, Miller, & Hoban, 1986; Sack et al. 1990). Mean secretion of melatonin and cortisol decreased significantly with age in a study of 44 men and 27 women (Sharma et al., 1989). These findings point to abnormality in photoperiodic regulation of pineal output of melatonin in some depressed patients. Levels of the neurotransmitterserotonin, from which melatonin is synthesized, are high during the day and low during the night, a rhythm that is the inverse of melatonin (Tamarkin, Baird, & Almeida, 1985). Melatonin by itself apparently did not contribute to SAD patients’ improvement (Isaacs et al. 1988; Rosenthal et al. 1988). Current antidepressant treatment approaches include light therapy in managing affective disorders with marked seasonal variation. Total and partial sleep deprivation and shifting the timing of sleep also have been shown to affect temporary remissions in patients with both unipolar and bipolar depression (Regier et al. 1988). Because some studies report that reduced nocturnal surge in serum melatonin and cortisol levels is typically elevated during depression, the two hormones seem to offer two approaches to understanding affective illness.

Discussion For centuries, relations between affective states and endocrines have been suspected. Neuroendocrine functions have provided a target for research on


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psychiatric illness. Progress in psychoendocrinology of depression has been made possible through the identification of hypothalamic hormones that trigger endocrine secretion and through more accurate measurement of complex substances that have hormonal function. Some 80% to 90% of major depressive patients can be treated successfully. However, only about one in three of those who suffer from a depressivedisorder ever seek treatment in the general medical or specialty mental health sector. Even when people do seek help, depression is too often poorly recognized, undertreated, or inappropriately treated by the health care system. Despite recent advances in psychoneuroendocrinology, one distinctive profile of all affective disorders has not been discovered, but it has been demonstrated that in some depressed patients an endocrine deficiency may be present, and treatment for it may reduce symptoms of depression. Research has demonstrated elevated CSF TRH concentrations in patients with major depression, and one of the most consistently observed findings in patients with major affective disorders is that a variety of antidepressants bring about a substantial decrease in thyroid function. If only endocrine data on depression were available, endocrine changes might be considered only a reflection of being depressed. Endocrine findings in depression, for example, are not in accordance with the unipolar-bipolar dichotomy. Age and sex changes influence changes in levels of hormones that may be biological markers in depression. However, depressed patients manifest altered neuroendocrine functions in plasma and urinary cortisol in responsiveness to GH and TSH, in prolactin secretion, in sensitivity to insulin, and in reduced pineal output. Several tests of endocrine functions-the DST, TSH, and insulin tolerance-can identify depression. On the other hand, no one test or combination of tests identifies all affective disorders, and no one endocrine dysfunction is always present in altered affective states. The antidepressant medications-tricyclics, MAOIs, and newer drugs-owe some of the reduction of symptoms to their impact on endocrines like prolactin through the neurotransmitter dopamine. Because thyroid hormones inhibit monoamine oxidase, which destroys serotonin and dopamine, they would in effect potentiate the neurotransmitters. However, doparnine levels in the brain decline with age, as do the enzymes involved in the breakdown of tyrosine to dopamine and norepinephrine. Depressed patients may be more vulnerable to disease, but retrospective studies have not confirmed this. Thyroid and other endocrine changes are associated with depression too often to be ignored. Adrenal steroids influence body homeostasis, control glycogen, and mediate response to stress. Some endocrine changes seem certain to belong among the causal elements that together might bring vulnerable subjects to the threshold of depression. Alterations in some endocrine functions seem to sustain depression, and slight changes in other endocrine functions appear to promote recovery from


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depression. Hence, endocrine changes seem likely to play a role both in precipitating depression and in producing therapeutic relief. Hormonal changes in affective disorders may be most clearly associated with variability in comparison with the responses of normal subjects, but the mechanism underlying the response variability is not clear. The subtle nature of neuroendocrine dysregulation in depressive illness makes it difficult to identify a consistent abnormal pattern. Perhaps a disorder of temporal ordering is involved in the psychopathology of some affective illness. Sleep latency, circadian rhythms, and neuroendocrine interactions may be operative in the early timing of endocrine secretions in some depressed individuals. The nocturnal surge of GH, the rise toward a morning peak of cortisol levels, and the early beginning of nocturnal prolactin secretion represent significant endocrine abnormalities associated with affective disorders. Studies of neuroendocrinology have clarified the pathophysiology of primary affective disorders and should continue to expand the range of those with affective disorders whose symptoms can be reduced or modified.

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Received April 12, 1991

[Dissociative disorders and affective disorders].

[Affective disorders and eating disorders].

[Affective disorders and personality disorders].

Genetics of affective disorders.

Management of affective disorders.

[Affective disorders and impulsivity].

Tryptophan and affective disorders.

Serotonin in affective disorders.

[Comorbidities and affective disorders].

The classification of affective disorders.

Neurodevelopmental aspects of bipolar affective disorder.

Affective disorders in alcoholic women.

Relative humidity and affective disorders.

Neuroendocrine factors in affective disorders.

Multiple sclerosis and affective disorders.

[Affective disorders and anxiety comorbidities].

[Affective disorders and neurological comorbidities].

Treatment of affective disorders in cardiac disease.

Biogenic amine hypotheses of affective disorders.

Linguistic analysis of speech in affective disorders.

Orthopedic aspects of collagen disorders.

Clinical aspects of mitochondrial disorders.

Aspects of intensity of affective constructs in depressed patients.

Platelet monoamine oxidase in affective disorders.