Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients.

The possibility that hypersecretion of corticotropin-releasing factor (CRF) contributes to the hyperactivity of the hypothalamo-pituitary-adrenal axis observed in patients with major depression was investigated by measuring the concentration of this peptide in cerebrospinal fluid of normal healthy volunteers and in drug-free patients with DSM-III diagnoses of major depression, schizophrenia, or dementia. When compared to the controls and the other diagnostic groups, the patients with major depression showed significantly increased cerebrospinal fluid concentrations of CRF-like immunoreactivity; in 11 of the 23 depressed patients this immunoreactivity was greater than the highest value in the normal controls. These findings are concordant with the hypothesis that CRF hypersecretion is, at least in part, responsible for the hyperactivity of the hypothalamo-pituitary-adrenal axis characteristic of major depression.

TRH (protirelin) in depressed alcoholic men. Behavioral changes and endocrine responses.

Chronic alcoholics with secondary depression were treated with protirelin in a double-blind, placebo-controlled study. Behavioral data, collected only during the acute alcohol withdrawal state, indicated a beneficial effect of protirelin three hours after injection, but not during subsequent days. Injections caused only mild and infrequent subjective side effects and no cardiovascular effects. Endocrine data were recorded in the acute withdrawal state and after clinical remission. Findings in the acute state suggested thyroid activation and increased central dopaminergic activity, as evidenced by elevated baseline levels of growth hormone, low baseline levels of prolactin, and blunted thyroid-stimulating hormone (TSH) response to protirelin. The first two abnormalities returned to normal levels in the remission state. A blunted TSH response was observed in both the acute and the remission states. Partial persistence of this finding suggests that TSH blunting may not be solely state-dependent. In the acute withdrawal state, TSH blunting was associated with favorable behavioral responses to protirelin.

Behavioral and endocrine responses of schizophrenic patients to TRH (protirelin).

We studied the effects of intravenous protirelin (thyrotropin-releasing hormone) in 17 schizophrenic patients and 17 normal subjects. A total of 12 patients received protirelin, 0.5 mg, and, on another occasion, niacin, 2 mg, in a double-blind, crossover design. Both behavioral and endocrine data were collected. Five patients received protirelin in an open trial; only endocrine data were collected. Protirelin caused about a 50% prompt decrease in psychotic symptoms. Patients then tended slowly to experience a relapse. Side effects were about as infrequent after protirelin as after niacin. We assayed serum prolactin (PRL), growth hormone (GH), thyroid-stimulating hormone (TSH), L-triiodothyronine (T3) and thyroxine (T4). Free T4 (FT4) index was calculated. The values for PRL, GH, and TSH at baseline and after protirelin stimulation were normal. Patients showed lower T3 values at baseline, but a brisker T3 response to protirelin, than controls. Their FT4 indices were higher at baseline. Patients showed diminished T4 binding sites rather than increased total T4. The causes of these alterations in thyroid dynamics are unidentified.

Serum thyrotropin concentrations and bioactivity during sleep deprivation in depression.

BACKGROUND: One night of sleep deprivation induces a brief remission in about half of depressed patients. Subclinical hypothyroidism may be associated with depression, and changes in hypothalamic-pituitary-thyroid function may affect the mood response to sleep deprivation. We wished to define precisely the status of the hypothalamic-pituitary-thyroid axis of depressed patients during sleep deprivation and the possible relationship of hypothalamic-pituitary-thyroid function to the mood response. METHODS: We studied 18 patients with major depressive disorder and 10 normal volunteers. We assessed mood before and after sleep. We measured serum thyrotropin every 15 minutes during the night of sleep deprivation, thyrotropin bioactivity, the thyrotropin response to protirelin the next afternoon, and other indexes of hypothalamic-pituitary-thyroid function. To determine if the changes were limited to the hypothalamic-pituitary-thyroid axis, we measured serum cortisol, which also has a circadian secretory pattern. RESULTS: Nocturnal serum thyrotropin concentrations were consistently higher in responders, entirely because of elevated levels in the women reponders. Responders had exaggerated responses to protirelin the next afternoon. The bioactivity of thyrotropin in nonresponders was significantly greater than in responders (F(1,8. 99) = 7.52; P =.02). Other thyroid indexes and serum cortisol concentrations were similar among groups. CONCLUSIONS: Depressed patients have mild compensated thyroid resistance to thyrotropin action, not subclinical autoimmune primary hypothyroidism. Sleep deprivation responders compensate by secreting more thyrotropin with normal bioactivity; nonresponders compensate by secreting thyrotropin with increased bioactivity.

Two patients with Cushing's disease in a kindred with multiple endocrine neoplasia type I.

Cushing's disease (pituitary ACTH-dependent Cushing's syndrome) has been described in association with the syndrome of multiple endocrine neoplasia type I (MEN-I). Cushing's disease is uncommon in MEN-I and has not been reported in more than one member of a kindred. Here we describe a mother and her daughter with Cushing's disease and major depressive disorder. The mother, her other daughter, and two other relatives also had primary hyperparathyroidism. We believe this to be the first reported instance of hereditary Cushing's disease as a manifestation of MEN-I.

Serial cerebrospinal fluid corticotropin-releasing hormone concentrations in healthy and depressed humans.

CRH, a hypothalamic peptide that is the most potent ACTH secretagogue known, also appears to be produced in the cerebral cortex and spinal cord. Depressed patients have blunted responses to exogenous CRH and normal to high concentrations of CRH immunoreactivity in single morning samples of lumbar cerebrospinal fluid (CSF). Although these data suggest that depression may be associated with hypersecretion of CRH, it has also been postulated that central nervous system insufficiency of CRH might have a pathophysiological role in certain depressive syndromes. We continuously sampled lumbar CSF via indwelling subarachnoid catheters from 1100-1700 h and measured CRH at 10-min intervals in depressed patients and normal subjects. A standardized mixed liquid meal was administered at 1300 h. CSF CRH was strikingly reduced in depressed patients compared to normal subjects [4.2 +/- 1.1 pmol/L vs. 13 +/- 2.1 pmol/L (mean +/- SEM), respectively, P less than 0.01 by Wilcoxon test]. CSF CRH concentrations rose progressively during the experiment in both groups, suggesting a diurnal rhythm and, possibly, response to a test meal. CRH had a very brief half-life in CSF (less than 10 min), suggesting that the spinal cord is the origin of CRH in lumbar CSF. The rapid transients in CSF CRH concentration demonstrate that single samples provide very limited information. There were no intraindividual correlations between CSF CRH concentrations and those of either plasma ACTH or cortisol, both of which rose in response to eating. The present data show that impaired central nervous system secretion of CRH can exist during states of severe depression.

The effects of antidepressants on the thyroid axis in depression.

Thirty-nine patients with major depression were studied to determine the differential effects of desipramine (DMI) and fluoxetine (FLU) on thyroid hormones. Twenty-six percent showed some abnormality in baseline thyroid hormone levels. There were no demonstrable differences for any of the thyroid indices from baseline to the 3- or 6-week samples for the total group or for either drug by repeated measures analysis of variance. There was a significant group by time interaction for total thyroxine (TT4) between the drug treatment groups, which was caused by a small but significant increase in TT4 in the DMI sample. Correlations were performed between the change in hormones over the 6 week period and treatment response. There was a significant association between a decline in triiodothyronine (T3) levels and response to FLU but not DMI. The implications of these findings for the pathophysiology of depression and antidepressant drug mechanisms are discussed.

Low cerebrospinal fluid corticotropin-releasing hormone concentrations in eucortisolemic depression.

Hypersecretion of corticotropin-releasing hormone (CRH) and resulting hypercortisolism have been implicated in the pathogenesis of major depression. To test this CRH hypersecretion hypothesis, cerebrospinal fluid (CSF) was continuously withdrawn from 11:00 AM to 5:00 PM via an indwelling subarachnoid catheter (placed at 8:00 AM), and immunoreactive CRH concentrations were determined at 10-min intervals in 10 depressed patients, the majority of whom exhibited at least one "atypical" symptom, and in 15 normal volunteers. CSF CRH was low, plasma adrenocorticotropin (ACTH) tended to be low, and plasma cortisol was normal in the depressed patients. Also, tobacco smokers had lower CSF CRH than nonsmokers. CRH increased acutely in response to lumbar puncture, had a brief half-life, showed rapid variability in concentration over time, and displayed a diurnal concentration rhythm that was preserved in fasting individuals and in most depressed patients. CSF CRH did not correlate with plasma ACTH or cortisol; this and its rapidly fluctuating levels suggest a primarily extrahypothalamic origin of lumbar CSF CRH.

Is there paradoxical growth hormone response to thyrotropin-releasing hormone in depression?

Several investigators have reported a paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) in depressed patients, but other studies have failed to confirm this. In the present study, the GH response to TRH was studied in depressed patients and normal subjects. The rate of paradoxical GH response to TRH in depression was no different than that observed in control subjects. This was the case whether the data was examined using mean values or using frequency of abnormal responses. Patients with blunted thyrotropin (TSH) responses did not differ in GH release from patients with normal TSH response. A variety of factors may have contributed to the earlier reports of a positive GH response to TRH, including the definition of paradoxical GH release and the fact that depressed patients exhibit more frequent spontaneous diurnal GH release than do normal subjects.

Is carbamazepine helpful in paroxysmal behavior disorders?

Carbamazepine was used to treat two patients with paroxysmal behavioral episodes and preexisting psychiatric disease. Carbamazepine abolished the paroxysmal episodes. Its effects on the preexisting disease were less clear. These data suggest carbamazepine treatment for paroxysmal behavior.

Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: a review.

In 1972 it was reported that in some euthyroid depressed patients the serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) was deficient. Since then, 41 reports describing 917 depressed patients have confirmed this finding. Although it is useful to report differences between mean response values of patient populations, it is necessary to identify those individuals in whom the fault occurs so that sensitivity, specificity, state-trait distribution, and clinical correlates can be determined. Present data allow some tentative conclusions: 1) the fault usually reflects a defect in central regulation of the pituitary-thyroid axis, 2) in some patients the fault may be a trait marker, and 3) it may represent a biological bridge between some depressed patients and some patients with other mental disorders.

TRH-induced TSH response in healthy volunteers: relationship to psychiatric history.

The authors measured thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone in 32 healthy volunteers who had never sought or received psychiatric treatment. Nine (28%) had a family or personal history of depression or alcoholism. Five of these nine subjects and one of 22 subjects without such a history showed TSH blunting (TSH data were not available for one subject). This difference was statistically highly significant. Although there were sex differences in TSH response, TSH blunting occurred most frequently in men with a family or personal history of depression or alcoholism. The fault may have utility as a marker of past episodes or as a true marker of trait.

Use of TSH response to TRH as an independent variable.

The thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) was assessed in 35 consecutive male admissions. Patients with TSH blunting were identified; they were compared with patients without blunting and with normal subjects. Patients without TSH blunting were normal as regards all endocrine variables. Patients with TSH blunting showed reduced TSH (but normal prolactin) levels before and after TRH administration, although their thyroid hormone levels and cortisol levels were normal. Height, weight, and body surface were unrelated to TSH blunting. The test-retest reliability of a blunted TSH response was acceptable.

Effects on behavior of modulation of gonadal function in men with gonadotropin-releasing hormone antagonists.

The effects of acute gonadal suppression on sexual function and behavior were studied in eight normal men. Administration of a newly developed, potent gonadotropin-releasing hormone antagonist induced azoospermia and reduced levels of serum testosterone, luteinizing hormone, and follicle-stimulating hormone. These effects coincided with a reduction in outward-directed aggression in all men. Self-reported measures of anxiety and sexual desire revealed less consistent change over time. Measures of anger control, inward-directed anger, and affective state were unaffected.

Long-term predictors of outcome in abstinent alcoholic men.

Twenty-nine alcoholic men who had been abstinent for more than 2 years were evaluated behaviorally and neuroendocrinologically and then followed for 2 years. Mean length of abstinence at intake was shorter in the eight patients with histories of depression (3.3 years) than in the patients without such histories (6.8 years). Six patients relapsed during follow-up, all of whom had been sober less than 5 years. None of the neuroendocrine variables studied was predictive of outcome. In summary, abstinence of less than 5 years and comorbidity with depression were most predictive of poor outcome.

Thyrotropin-releasing hormone (TRH) in abstinent alcoholic men.

Chronic alcoholics who had been abstinent from alcohol for more than 2 years were evaluated with the thyrotropin-releasing hormone (TRH) test. The findings suggest the following profound disturbances in the hypothalamic-pituitary-thyroid axis: 1) a "euthyroid sick syndrome," evidenced by low levels of triiodothyronine (T3), high levels of reverse T3, and normal levels of thyroxine (T4) (this syndrome implies a decreased 5'-deiodination of T4 to T3 and of reverse T3 to its lesser iodinated metabolites), 2) an increased binding capacity for thyroid hormones, evidenced by a decreased T3-uptake value and an increased level of T4-binding globulin, and 3) thyroid-stimulating hormone (TSH) blunting in 31% of patients. Paradoxically, there was a positive correlation between basal T4 and delta max TSH in subjects with blunted TSH, but baseline TSH levels were reduced in subjects with and without blunted TSH.

Thyroid and adrenal dysfunction in abstinent alcoholic men: locus of disturbance.

Certain neuroendocrine abnormalities (e.g., blunted plasma adrenocorticotropic hormone [ACTH] response to corticotropin-releasing hormone [CRH] administration and blunted serum TSH response to thyrotropin-releasing hormone [TRH] administration) are common in alcoholic patients. It was the objective of this study to evaluate whether they are centrally mediated: that is, whether they are secondary to increased activity of CRH and/or TRH neurons. We evaluated the nocturnal secretion (2200 hours to 1000 hours, q 15 min) of plasma ACTH, serum cortisol, and serum TSH, and their responses to the combined administration of CRH and TRH, in 28 acutely abstinent alcoholic (age range: 32 to 57 years; mean: 42.4 years) and 19 normal men (age range: 21 to 52 years; mean: 32.1 years). To assess the validity of administering CRH and TRH simultaneously, we gave 10 additional abstinent alcoholic men (age range: 36 to 53 years; mean: 45.8 years), in random order and at least 4 days apart, either CRH, TRH, placebo, or CRH plus TRH. Nocturnal ACTH, cortisol, and TSH secretion, as well as cortisol and TSH responses after CRH plus TRH administration, were similar in alcoholic and normal men. However, ACTH peak responses to CRH plus TRH were reduced in the alcoholic men (p < 0.05). The ACTH, but not cortisol, response was greater after combined CRH plus TRH administration than after CRH alone (p < .002). The blunted ACTH response does not appear to be the result of increased endogenous CRH activity, because all parameters of nocturnal ACTH pulsatility were normal in the alcoholics. It rather appears to be secondary to an intrinsic defect in the CRH responsiveness of the pituitary corticotroph, possibly due to genetic vulnerability or to the toxic effects of prolonged alcohol abuse.

Thyroid function in affective disorders and alcoholism.

The psychoneuroendocrinology of mood disorders and alcoholism is reviewed here. For reasons of both space and clarity, the article focuses on the clinical data and largely omits the basic science data.

Effects of thyroid hormones on central nervous system in aging.

Support for the many relationships between thyroid hormones and brain function comes from both laboratory and clinical studies. Studies in laboratory animals provide convincing evidence for a neuroregulatory role of thyroid hormones in the brain, suggesting that they may affect behavior. This notion is supported by human studies which have revealed that the effects of thyroid hormones on brain function are most important during the development and maturation of the brain; thereafter, age does not seem to critically affect brain-thyroid hormone relationships.

The TRH-induced TSH response in psychiatric patients: a possible neuroendocrine marker.

The finding of a diminished TSH response to exogenously administered TRH in a significant proportion of depressed patients has now been established as one of the most reproducible findings in biological psychiatry. More than 50 reports, in which more than 1000 patients have been studied, reveal that the TSH response is blunted in approximately 25% of patients with major depression. TSH blunting is clearly not specific for depression, because it also has been observed in mania, alcoholism, and borderline personality disorder. It is doubtful that TSH blunting represents a non-specific response to mental stress: it was found only rarely in schizophrenic patients, and the TSH response to in vivo flooding therapy in phobic patients was normal. In both depression and alcoholism, TSH blunting has been reported to be sometimes a state marker and sometimes a trait marker, i.e. the fault was found to persist into remission in more than half the patients. In both conditions, TSH blunting was unrelated to the patients' age, body weight, height, body surface, thyroid status, and serum cortisol concentrations. It also is unlikely that TSH blunting was due to increased dopaminergic inhibition of thyrotroph cells: serum prolactin concentrations in TSH blunters were found to be normal, and pretreatment with haloperidol had no effect on either basal TSH levels or TSH blunting. In depression, TSH blunting was not associated with previous drug intake, dexamethasone suppression test abnormalities, or variables of biogenic amine metabolism, nor did it usefully segregate between primary and secondary depression or between unipolar and bipolar subgroups. Preliminary evidence suggests that TSH blunting in depression may be related to duration of illness, history of violent suicide attempts, and a reduced 24 h TSH secretion. In alcoholism, TSH blunting was unrelated to family or personal history of depression and duration of abstinence. With reference to clinical utility, TSH blunting may aid in assessing the response to antidepressant treatment, predicting outcome to such treatment, assessing the risk for violent suicide attempts, and describing relationships between different psychiatric populations (e.g. depression and alcoholism).