C. Kirkegaard

THE THYROTROPIN RESPONSE TO THYROTROPIN-RELEASING HORMONE IN ENDOGENOUS DEPRESSION

Abstract The maximal response of thyrotropin (TSH) to thyrotropin-releasing hormone (TRH) (Δ max TSH) is reduced in endogenous depression (ED). In the majority of studies Δ max TSH was reduced to the same degree in unipolar and bipolar depression, as well as in manic patients. Decreases present in anorexia nervosa and heroin addiction possibly were secondary to reduced caloric intake and administration of heroin, respectively. When the TRH test was repeated in patients with ED who were clinically cured after short-term antidepressant therapy, the patients could be divided into two groups, one with an increase of Δ max TSH > 2.0 μU/ml, and another with an increase

Increased levels of TRH in cerebrospinal fluid from patients with endogenous depression

(1) A radioimmunoassay of thyrotropin releasing hormone (TRH) in cerebrospinal fluid (CSF) has been developed. The lower detection limit was 2.0 pg/ml. (2) The concentration of TRH in lumbar fluid from 20 patients with various neurological diseases averaged 5.4 pg/ml (1.9–10.7). In 2 patients the concentration was below detection limit. (3) The TRH concentration was not related to sex or age. (4) In 15 patients with endogenous depression the concentration was elevated (p<0.01), before electroconvulsive treatment (24.2 pg/ml, range: 6.9–187) as well as after such therapy (14.4 pg/ml, range 6.0–31.0). The values before and after treatment were not significantly different. (5) The concentration of TRH was not correlated to the serum thyrotropin (TSH) response to 200 μg TRH i.v. (6) Changes in TRH concentration were also unrelated to changes in the TSH response to TRH and to the clinical outcome after 6 months of observation.

Studies on the influence of biogenic amines and psychoactive drugs on the prognostic value of the TRH stimulation test in endogenous depression.

Abstract (1) By means of the variations in the maximal thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) before and after treatment it was possible to predict early relapse in all of 14 patients, and a recovery continuing more than 6 months in five of seven patients with endogenous depression. (2) The prognostic value was not affected by small doses of phenothiazines and benzodiazepines. (3) Short-term administration of chlorpromazine resulted in a small, but significant ( p l -5-OH-tryptophan.

Parallel changes of the responses of thyrotropin, growth hormone and prolactin to thyrotropin-releasing hormone in endogenous depression

The responses of growth hormone (GH) and prolactin (Prl) to thyrotropin releasing hormone (TRH) were studied in two selected groups of patients with endogenous depression (ED). One group, ED 1, was characterized by an increased thyrotropin (TSH) response to TRH after recovery from depression and by a good prognosis, whereas the other group, ED 2, was characterized by an unaltered TSH response and relapse within six months after stopping the antidepressive treatment. (1) After treatment significantly increased responses of GH (p <0.01) and Prl (p <0.05) to TRH were found in group ED 1, whereas those in group ED 2 were unchanged. (2) Using an increase of the GH response after treatment of 0.5 mg/ml compared to that before treatment, and an increase of 8.0 ng/ml of the Prl response, a correct prediction of the prognosis was possible in 74 and 72% of the patients, respectively. Using the TSH response to TRH we have previously reported correct prediction in 91% of patients with ED. This value is significantly higher than those obtained with the GH and Prl responses (p <0.05). (3) GH and Prl responses in ED were compared to those obtained in healthy and psychiatric controls, but they were found to be of no diagnostic value.

Continuation therapy in endogenous depression controlled by changes in the TRH stimulation test

Thyrotropin response to thyrotropin-releasing hormone is impaired during endogenous depression and normalized between the depressive periods. Changes in the thyrotropin response to thyrotropin-releasing hormone were shown to be of predictive value and might be useful in the control of continuation therapy with antidepressants in patients with endogenous depression.

Circadian variation of serum thyrotropin in endogenous depression

The circadian variation of serum thyrotropin (thyroid-stimulating hormone; TSH) was studied in nine patients with endogenous depression before and after recovery. Depressed state did not appear to influence the pattern of TSH. When 2 mg of dexamethasone was administered, serum TSH was significantly reduced for 18 hours, whereafter the effect leveled off. The TSH response to thyrotropin-releasing hormone (TRH) was evaluated 25 hours after the administration of dexamethasone and the response was found to be unchanged.

Effect of amitriptyline on the thyrotropin response to thyrotropin-releasing hormone in endogenous depression

Patients with endogenous depression whose depressive episodes were clinically resolved after electroconvulsive therapy were divided into two groups: one in which patients remained well (n = 16) and another in which patients relapsed within 6 months (n = 11). Treatment with amitriptyline for 3 weeks did not affect the median thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropin-releasing hormone (TRH) in recovered patients, whereas that in relapsed patients was significantly enhanced. The data suggest that amitriptyline affects the TSH response to TRH differently in stably recovered and relapsed patients. If this effect is maintained beyond the 3-week period studied, treatment with amitriptyline will invalidate the predictive value of the TRH test.

METABOLIC CLEARANCE AND PRODUCTION RATES OF 3,3′‐DIIODOTHYRONINE, 3′,5′‐DIIODOTHYRONINE AND 3′‐MONOIODOTHYRONINE IN HYPER‐ AND HYPOTHYROIDISM

Complete turnover studies of thyroxine (T4), 3,5,3′‐triiodothyronine (T3), 3,3′,5′‐triiodothyronine (rT3), 3,3′‐diiodothyronine (3,3′‐T2), 3′,5′‐diiodothyronine (3′,5′‐T2) and 3′‐monoiodothyronine (3′‐T1) were performed in each of eight healthy subjects, eight hyperthyroid and eight hypothyroid patients, using the single injection, non‐compartmental approach. The median metabolic clearance rate (litre per day per 70 kg) in controls was, T4 1·19; T3 19·7. rT3 147; 3,3′‐T2 1073; 3′,5′‐T2 256 and 3′‐T1 518. Hyperthyroid patients had increased and hypothyroid patients reduced values. The median production rate (PR) (nmol per day per 70 kg) in controls was, T4 117, T3 39, rT3 52, 3,3′‐T2 35, 3′,5′‐T2 14 and 3′‐T1 27. The PR of all iodothyronines studied was increased in hyperthyroidism, the increase in PR of T3 being the most pronounced. Hypothyroid patients had reduced PRs, a reduction which was relatively less pronounced for T3. Assuming thyroidal secretion contributes little rT3 and 3′,5′‐T2, the conversion rates (CRs) of T4 to rT3 and further to 3′,5′‐T2 were calculated. CR of T4 to rT3 in controls was in median 34%. By comparison the CR in hyperthyroid patients was increased to 56% (P < 0·05). In contrast the CR of rT3 to 3′,5′‐T2 was similar in controls and hyperthyroid patients, 26% v. 31%.

Thyroid Hormone Metabolism in Hypermetabolic Patients with Haematological Disorders

Turnover tracer studies of T4 and T3 using the single injection, noncompartmental approach were performed in 6 hypermetabolic patients with haematological disorders (HHD) (basal metabolic rate (BMR): median 141%, range 122-166%), in 10 controls with stable, nonthyroidal illness (NTIC), and in 14 healthy controls (HC). The main finding was an increase of approximately 30% of the production rate (PR) of both T4 and T3 in patients with HHD. Median PR of T4 was 134 nmol/day x 70 kg in HHD, compared to 78 nmol/day x 70 kg in NTIC (P less than 0.05) and 98 nmol/day X 70 kg in HC (p less than 0.1), whereas median PR of T3 was 40.3 nmol/day x 70 kg in HHD, compared to 25.6 nmol/day x 70 kg in NTIC (P less than 0.01) and 31.1 nmol/day x 70 kg in HC (P less than 0.1). An increase of similar magnitude was found for the apparent distribution volume and the pool size of both T4 and T3. In contrast, the mean transit times of the hormones were similar in the 3 groups. Patients with HHD had normal levels of basal serum TSH as well as of the TSH response to TRH. Only PR of T3 correlated to the BMR (R = 1.00, P less than 0.02). The data are compatible with an increased consumption of thyroid hormones by malignant haematologic cells, and the increase of BMR seems to be dependent on the production of T3.