Relationship between mood and TSH response to TRH stimulation in bipolar affective disorder

Moderate to severe depression and mania are associated with a reduced thyroid stimulating hormone (TSH) response to TSH releasing hormone (TRH). Continued reduction of this response after clinical recovery seems indicative of early relapse. The aim of the present study was to test the relationship between mild changes in mood and the TSH response to TRH stimulation in patients with bipolar affective disorder. Nineteen outpatients with bipolar affective disorder were followed prospectively for three years. Every third month, mood symptoms were rated using the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Bech-Rafaelsen Mania Scale (BRMS). A TRH test was performed in connection with each rating session (IV injection of 200 microg TRH), and serum TSH was measured at 0, 20, and 60 min. The maximum TSH response (D-max TSH) and the temporal change in D-max TSH between succeeding rating sessions (DD-max TSH) were determined. Psychometric rating and TRH data were obtained for a total of 198 examinations. The temporal change in mood symptom rating score was negatively correlated with the temporal change in D-max TSH, thus suggesting that increasing severity of mood symptoms was related to a reduced TSH response to TRH stimulation. The temporal change in TSH response to TRH stimulation correlated with the actual score on an overall index of symptom severity. In conclusion, milder fluctuations in mood in bipolar affective disorder seem to correlate with the TSH response to TRH stimulation: Increasing severity of mood symptoms seems to be associated with reduced TSH response.     

Pituitary thyrotropin response to thyrotropin-releasing hormone in affective illness: relationship to spinal fluid amine metabolites.

The authors studied pituitary thyrotropin, i.e., thyroid-stimulating hormone (TSH), response to thyrotropin-releasing hormone (TRH) in patients with primary affective disorder. There were no overall differences between either depressed or manic patients and normal controls; however, the TSH response was significantly lower in the unipolar depressed patients than in either bipolar depressed patients or normal subjects. Bipolar patients in the manic phase tended to have a lower response than bipolar depressed patients. In the unipolar group, the TSH response showed a significant negative correlation with the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the CSF. These neuroendocrine responses may constitute markers of specific monoamine dysfunction in subgroups of patients with affective illness.     

Mood-incongruent versus mood-congruent psychosis: differential antipsychotic response to lithium therapy

The authors previously reported that a subgroup of schizophrenic-like patients respond favorably to lithium (Li) therapy, as do patients with a classical manic illness. In the present study, the time course of psychotic and affective symptom remission after Li therapy was examined in these two groups of patients. Li responsive patients with a mood-incongruent psychosis (schizophrenic-like illness) demonstrated a rapid antipsychotic response to Li therapy, showing a 50% improvement during the first 7 days, while no improvement in affective symptoms was seen until week 2 or 3 of treatment. Alternatively, patients with a mood-congruent psychosis (where mania is the primary diagnosis) demonstrated no antipsychotic response to Li therapy during the first 2 weeks of treatment, while some improvement in manic symptoms occurred during treatment week 2. The present study demonstrates that Li therapy differentially affects psychotic symptoms in mood-incongruent as opposed to mood-congruent psychosis. Further, the growth hormone (GH) response to apomorphine administration differentiated these two groups of Li responsive patients. Patients with a Li responsive mood-incongruent psychosis demonstrated over a seven-fold greater GH response than mood-congruent psychotic patients. The present data suggest that mood-incongruent and mood-congruent psychoses may represent two biologically distinct psychotic processes separable by both medication response and central dopamine function.     

Thyrotrophin-releasing hormone (TRH) stimulation test in manic-depressive illness.

The thyrotrophin (TSH) response to thyrotrophin-releasing hormone (TRH 200 microgram intravenously was studied in 19 patients with unipolar depression, 12 with bipolar depression, 14 with mania, and 5 with mixed manic-depressive illness. The TSH responses were decreased in all of these affective disorders compared to those found in 10 patients with reactive depression, 5 with reactive paranoid psychosis, 14 with neurotic depression, and 60 controls. The decrease of the TSH response in manics could not be accounted for by the effects of neuroleptic drugs. The TSH response in the groups with reactive depression, reactive paranoid psychosis, and neurotic depression, respectively, did not differ significantly from that found in controls. With the exception of a decrease in serum T3 level and free T3 index in the manics, no significant differences in serum T3 level or in free T3 and T4 indexes were found between the groups. Changes found in serum T4 level were due to changes in the thyroxine-binding proteins.     

The effects of carbamazepine on the thyrotropin response to thyrotropin-releasing hormone

A thyrotropin (thyroid-stimulating hormone; TSH) stimulation test with thyroid-releasing hormone (TRH) was performed on six patients with a DSM-III diagnosis of major depressive disorder, both before and during a trial of carbamazepine. Carbamazepine, an anticonvulsant effective in the treatment of affective illness, caused a reduction in the TSH response to TRH. This finding suggests that carbamazepine may decrease thyroid function primarily at the level of the pituitary in affectively ill patients.     

Effects of age and diagnosis on thyrotropin response to thyrotropin-releasing hormone in psychiatric patients

The thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropin-releasing hormone (TRH) was studied in 64 age-matched healthy volunteers, 44 patients with endogenous depression, and 21 patients with schizophrenia. A significant negative correlation between delta TSH and age was found both in healthy subjects and in depressed patients. We based our comparison on normal ranges for delta TSH calculated from the delta TSH values in the healthy subjects related to age. It was then seen that blunted TSH response to TRH does not occur significantly more often in depression (13.6%) than in healthy controls (4.7%). Blunted TRH test results were also found in a considerable number of severely ill schizophrenic patients (19%). Application of an improved radioimmunoassay revealed a highly significant correlation between TSH values at baseline and after stimulation, and showed decreased baseline TSH levels in subjects with blunted TRH test results.     

Thyroid stimulating hormone response after thyrotropin releasing hormone in depressed, schizophrenic and normal women.

(1) Thyroid stimulating hormone (TSH) response after injection of thyrotropin releasing hormone (TRH) was studied in 23 depressed, 9 schizophrenic and 40 normal women. (2) In no group was TSH response correlated with age. (3) In the depressed patients, no relationship was found between TSH response and (i) severity of illness, (ii) clinical subtypes (unipolar/bipolar) and (iii) clinical remission. (4) There were no statistically significant differences in TSH baseline values between the groups. (5) Neither of the two patient groups showed reliable differences from controls regarding TSH response. However, depressed patients tended to show lower values than controls, while schizophrenic patients tended to show higher values than normal controls. (6) Significant differences were found between depressed and schizophrenic patients in regard to TSH response. In three depressed patients a TSH response below 5 μU/ml was found. This deficient TSH response occurred in unipolar depressed patients and was not seen in bipolar depressed patients, schizophrenic patients or normal controls. (7) These data provide evidence for a fault in hypothalamic pituitary regulation in some depressed patients but not in schizophrenic patients.     

Serial DST, TRH test, and TRH-like immunoreactivity measurements in major affective disorders

Neuroendocrine functions in depressed patients with major affective disorders were serially investigated by the Dexamethasone Suppression Test (DST), the thyrotropin-releasing hormone (TRH) stimulation test, and the plasma TRH-like immunoreactivity (TRH-LI) measurement. Prior to antidepressant therapy, the sensitivity for nonsuppression to the DST was 36.0%, whereas that for blunted thyroid-stimulating hormone (TSH) response to TRH was 28.0%. Both DST nonsuppression and TSH blunting appeared to be state-related markers for depressed patients. Specifically, a significant increase of maximum TSH response to TRH after 4 weeks of antidepressant therapy was associated with clinical improvement. Plasma TRH-LI in depressed patients was significantly lower than that of healthy controls. It is possible that the lower plasma TRH-LI level is related to the pathophysiology of some depressed patients with major affective disorders.     

Thyrotropin stimulating hormone response to thyrotropin releasing hormone in patients with panic disorder

OBJECTIVE: The aim of this study is to assess thyrotropin stimulating hormone (TSH) response to thyrotropin releasing hormone (TRH) in patients with panic disorder (PD). METHOD: The effects of TRH administration on the release of TSH were examined in 15 patients who met DSM-III-R criteria for PD and compared their test results with those of 15 normal control subjects. Blood samples were taken before TRH administration (baseline values) and at 15, 30 and 60 min. RESULTS: delta max TSH values were lower in the panic disorder patients than in the control subjects. Using the criterion of delta max TSH < or = 7 mlU/l, nine of the 15 panic disorder patients and four of the 15 control subjects had a blunted TSH response to TRH. CONCLUSIONS: These results confirm the findings from earlier reports that patients with PD show blunted TSH response to TRH which is similar to that seen in depressed patients.     

Response of thyrotropin to thyrotropin-releasing hormone as predictor of treatment outcome. Prediction of recovery and relapse in treatment with antidepressants and neuroleptics

We determined whether the response of thyrotropin (TSH) to thyrotropin-releasing hormone could predict the outcome of treatment with antidepressant and neuroleptic drugs. We studied 114 female patients diagnosed as having major and minor depressive, manic, schizoaffective, and schizophrenic disorders. A blunted TSH response (less than 5 microU/mL [less than 5 mU/L]) at admission was associated with recovery after nine weeks of inpatient treatment using clomipramine hydrochloride for depression and haloperidol for psychosis. A blunted TSH response at discharge was associated with early relapse in depressives receiving clomipramine maintenance therapy. Our findings support the notion that the thyrotropin-releasing hormone test is a "state" marker that may be of use in predicting the outcome of treatment with antidepressant and neuroleptic drugs.     

The thyrotropin response to thyrotropin-releasing hormone as a predictor of response to treatment in depressed outpatients.

We evaluated the predictive value of the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in 32 depressed outpatients completing a double-blind placebo-controlled trial of s-adenosyl-l-methionine (SAMe), which failed to show any significant difference between SAMe and placebo. Treatment response was defined as the change in Hamilton Rating Scale for Depression (HRSD-24) score between baseline and the end of the six-week trial. Subjects with TSH response outside the normal range (7-25 uU/ml) had a significantly greater response than patients with a normal response. There was also a significant correlation between absolute deviations from the mean TSH response (16 uU/ml) and changes in HRSD-24 scores.     

Deficient nocturnal surge of TSH secretion during sleep and sleep deprivation in rapid-cycling bipolar illness

Rapid-cycling bipolar patients have a high prevalence of hypothyroidism, and this disturbance in their hypothalamic-pituitary-thyroid (HPT) function may provide a model for understanding the less severe thyroid dysfunction present in other forms of affective disorder. For these reasons, we investigated HPT function in eight rapid-cycling bipolar patients and eight normal controls by measuring plasma levels of thyroid-stimulating hormone (TSH) and cortisol every 30 min during a baseline 24-h period and during an additional night of sleep deprivation. Thyrotropin-releasing hormone (TRH) (500 micrograms) challenge tests were also performed in the patients. Controls exhibited a significant circadian variation in TSH with a nocturnal rise that was augmented by sleep deprivation. In the rapid cyclers, the nocturnal rise in TSH was absent, and sleep deprivation failed to raise their TSH levels significantly compared with baseline. Low nocturnal TSH levels were associated with blunted TSH responses to TRH infusions; due to the relatively brief sampling interval used in the TRH challenge tests, however, these results do not reliably discriminate between hypothalamic and pituitary dysfunction as an etiology for low nocturnal TSH levels. Additional studies are needed to determine the precise nature of the HPT disturbance in rapid-cycling patients.     

The thyroid axis and desipramine treatment in depression

Although there has been much recent investigation of the role of thyroid function in affective illness, few studies have addressed the effects of the tricyclic antidepressants on the pituitary-thyroid axis. In the present study, thyroid functions (TFTs) and thyrotropin-releasing hormone (TRH) stimulation of thyroid-stimulating hormone (TSH) were measured before and after treatment with desipramine (DMI) in 13 men with a diagnosis of major depressive disorder. All subjects had normal TFTs and baseline TSH measured in a drug-free state at the initiation of the study. Both mean free thyroxine index and baseline TSH decreased after DMI treatment. The amount of decrease in baseline TSH correlated with increase in delta TSH. Four subjects had blunted delta TSH (delta TSH less than or equal to 5 microIU/ml); three of these subjects "normalized" with treatment (delta TSH less than or equal to 5 microIU/ml; greater than or equal to 20 microIU/ml). Two subjects had a high delta TSH, and both "normalized" during treatment. The decrease in both free T4 index and TSH suggests a down-regulation of the thyroid axis at the hypothalamic level. "Normalization" of subtle dysregulation of the thyroid axis is suggested as a mechanism of antidepressant therapy in the treatment of some depressions.     

Hormonal response to thyrotropin-releasing hormone following rest-activity reversal in normal men

The prolactin (PRL) and thyrotropin (TSH) response to an intravenous dose (400 micrograms) of thyrotropin-releasing hormone (TRH) was studied in eight healthy young men in the morning (0800 hr), in the evening (2000 hr), and after an acute 12-hr shift of the rest-activity cycle. The PRL and TSH response to TRH was significantly greater in the evening than the morning. The increased PRL and TSH responses observed in the evening were significantly reduced following rest-activity reversal. Our findings underscore the importance of temporal factors in determining response to TRH. These factors may be relevant in clarifying the mechanisms underlying abnormal hormonal responses to TRH in patients with affective disorders.     

Thyrotropin and prolactin response to thyrotropin-releasing hormone in depressed and nondepressed alcoholic men

Thyrotropin-releasing hormone (TRH) stimulation tests were performed on 81 alcoholic men after at least 3 weeks of abstinence. Subjects were given 500 micrograms of TRH intravenously, and thyroid-stimulating hormone (TSH) and prolactin (PRL) were measured at baseline, and then 15 and 30 min later. Comparisons were made among alcoholics with (n = 27) and without (n = 54) a lifetime history of depression as determined by the Diagnostic Interview Schedule. Nine nondepressed, nonalcoholic subjects served as controls. Alcoholics with or without a depression history did not differ from each other or from control in TSH or PRL response area under the curve. Blunted TSH responses were present in 10 (12%) of the alcoholics and none of the controls when blunting was defined as a delta max TSH less than 5 microU/ml. When blunting was defined as a delta max TSH less than 7 microU/ml, 18 (22%) of the alcoholics and 1 (1%) of the controls were blunted. Conversely, 2 (2.5%) of the alcoholics had a delta max TSH greater than 32 microU/ml. All subjects were clinically euthyroid. Contrary to expectation, depressed subjects were slightly less likely to show blunted responses than nondepressed subjects. No relationship was found between neuroendocrine measurements and several measurements of alcoholism or depression. Some alcoholic subjects show a blunted TSH response to TRH injection, which may be a function primarily of the alcoholism itself. The precise mechanism remains unknown.     

Panic, suicide, and agitation: independent correlates of the TSH response to TRH in depression.

We investigated the relationship between suicidality, agitation, panic attacks, and the thyrotropin-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH), and tested the hypothesis that panic would account for the association between a reduced TSH response and the other conditions. Twenty-seven euthyroid primary unipolar depressed inpatient women received a TRH test and systematic psychiatric assessment. Panic attacks were insufficient to explain the link between the TSH response and suicidal intent, lethality, and agitation; each condition was independently associated with a lower TSH response. In an additive fashion, copresence of conditions further reduced TSH response. The symptom constellation of panic, agitation, and suicidality in depression may correlate with the greatest reduction in TSH response.     

TRH stimulation test and depression

A thyrotropin-releasing hormone (TRH) stimulation test was performed in 52 male inpatients with major depressive disorder. Twenty-nine percent of the 52 subjects had a delta thyroid-stimulating hormone (delta TSH) less than 5 microU/ml. The cerebrospinal fluid (CSF) amine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA), were measured in 29 subjects, and a dexamethasone suppression test (DST) was performed in 48 subjects. Of the three CSF amine metabolites, only MHPG correlated significantly with baseline TSH and none correlated with delta TSH. The baseline TSH correlated positively with the TSH response at 30 minutes. Neither baseline TSH nor delta TSH correlated with cortisol levels before or after dexamethasone. The correlation between CSF MHPG and serum TSH suggests a relationship between central norepinephrine and baseline TSH.     

Peripheral thyroid hormones and response to selective serotonin reuptake inhibitors

OBJECTIVE: To examine the relation between baseline measurements of thyroid function and response to selective serotonin reuptake inhibitors (SSRIs) and to consider the effect of these antidepressants on thyroid hormone levels. METHODS: Nineteen subjects with major depression, but without a history of thyroid treatment or lithium treatment, were treated openly with either sertraline or fluoxetine in a university- affiliated tertiary care hospital. Hamilton Depression Rating Scale (Ham-D) scores were measured before and after treatment. Clinical Global Impressions (CGI) scores were measured at study end. Thyroid data, consisting of values for thyroid-stimulating hormone (TSH), triiodothyronine (T(3), measured by radioimmunoassay [RIA]), thyroxine (T(4), measured by RIA) and free T(4), were collected before and after treatment. Complete thyroid data were available for 17 subjects. Data were collected during 1997-1999. RESULTS: Baseline TSH correlated strongly with response to treatment as measured by change in Ham-D scores (r = 0.64, p = 0.003). Low TSH values correlated with greater improvement in depressive symptoms. Thyroid hormone levels decreased with treatment, but these decreases did not correlate with clinical improvement. CONCLUSION: Baseline thyroid function, as measured by serum TSH, may predict a patient's response to antidepressant treatment with SSRIs. Optimal thyroid function, beyond simply being within the normal laboratory values, may be necessary for an optimal response to antidepressants.     

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.     

Sex differences in the cortisol response to awakening in recent onset psychosis

A dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis has been suggested as a factor in the etiology and exacerbation of psychosis, but has not been reported consistently. Sex differences are apparent in many aspects of psychotic disorders and may explain some of the equivocation associated with the regulation of the HPA axis in the illness. The present study compared the cortisol response to awakening (CRA) in 27 patients (16 men and 11 women) with recent onset of psychosis (within the past 2 years) and 40 age and gender matched controls. Within the patient group, we also assessed the relationship between the CRA and positive and negative symptoms of psychosis, anxiety and depression. The CRA in patients was not significantly different from controls. However, within the patient group, we observed a significant sex difference, with a blunted cortisol response to awakening in men but not in women (F=7.26; p<0.002). This difference could not be explained by differences between male and female patients in awakening time, medication, or diagnosis of schizophrenia vs. affective psychosis. Cortisol levels were not related to symptom measures. Our findings demonstrate a dysregulation of the HPA axis in male patients with recent onset of psychosis. This sex specificity might be related to and explain in part the unfavorable course of the illness observed in men.