Klaus-Jürgen Gräf

Treatment of Refractory Depression with High-Dose Thyroxine

In an open clinical trial we investigated whether addition of supraphysiological doses of thyroxine (T4) to conventional antidepressant drugs has an antidepressant effect in therapy-resistant depressed patients. Seventeen severely ill, therapy-resistant, euthyroid patients with major depression (12 bipolar, five unipolar) were studied. The patients had been depressed for a mean of 11.5 ± 13.8 months, despite treatment with antidepressants and, in most cases, augmentation with lithium, carbamazepine, and neuroleptics. Thyroxine was added to their antidepressant medication, and the doses were increased to a mean of 482 ± 72 μg/day. The patients’ scores on the Hamilton rating Scale for Depression (HRSD) declined from 26.6 ± 4.7 prior to the addition of T4 to 11.6 ± 6.8 at the end of week 8. Eight patients fulfilled the criteria for full remission (a 50% reduction in HRSD score and a final score of ⩽9) within 8 weeks and two others fully remitted within 12 weeks. Seven patients did not remit. The 10 remitted patients were maintained on high-dose T4 and followed up for a mean of 27.2 ± 22.0 months. Seven of these 10 remitted patients had an excellent outcome, two had milder and shorter episodes during T4 augmentation treatment, and one failed to profit from T4 treatment during the follow-up period. Side effects were surprisingly mild, and no complications were observed at all. In conclusion, augmentation of conventional antidepressants with high-dose T4 proved to have excellent antidepressant effects in approximately 50% of severely therapy-resistant depressed patients.

Effects of acute psychological stress on adhesion molecules, interleukins and sex hormones: implications for coronary heart disease.

Abstract Rationale. Subjects with high levels of daily stress suffer from an increased risk of coronary heart disease. Increased concentrations of the intercellular adhesion molecule-1 (ICAM-1) contribute to atherosclerosis. Cell adhesion molecules may be activated by psychological stress exposure, depending on their interaction with the interleukin network, sex hormones and cortisol secretion. Objectives. To assess effects of acute psychological stress on the interaction between cell adhesion molecules, interleukins, sex hormones and cortisol in healthy male subjects. Methods. Cell adhesion molecules, interleukin-1 beta (IL-1β), IL-2, IL-6, sex hormones and cortisol levels of 18 healthy male physicians were measured before and after an academic oral presentation and on a control day. Results. The oral presentation was perceived as a stressful event and was accompanied by a significant increase in cortisol secretion in all volunteers. Soluble ICAM-1 and IL-1β also increased in all subjects after psychological stress exposure. The stress-associated increase in IL-2 concentrations approached statistical significance and correlated negatively with luteinizing hormone plasma levels. Estradiol concentrations correlated positively with IL-6 levels. Conclusions. Subjective ratings and the increase in cortisol plasma concentrations support the validity of the chosen stress model. Acute stress exposure was followed by an increase in IL-1β, IL-2 and soluble ICAM-1 plasma concentrations, which can contribute to coronary heart disease and immunological disorders.

Neuroendocrinological investigations during sleep deprivation in depression I. Early morning levels of thyrotropin, TH, cortisol, prolactin, LH, FSH, estradiol, and testosterone ☆

Measurements of 12 hormones were conducted in patients with major depressive disorder at 8 AM on the morning before and at 8 AM on the morning after total sleep deprivation (SD). Thyrotropin (TSH), thyroxine (T4), triiodothyronine (T3), and free T3 (fT3) were measured in 50 patients, free T4 in 39 patients, reverse T3, cortisol, prolactin, luteinizing hormone, and follicle-stimulating hormone in 21, estradiol in 20 (women), and testosterone in 14 (men). After SD, there was a significant rise in TSH, T4, T3, and fT3 concentrations and a significant fall in testosterone levels. The increases in TSH levels were significantly correlated to clinical response. Responders to SD had higher T4, fT4, rT3, and testosterone concentrations before SD. Neither age, gender, polarity, nor antidepressant medication had a clearly significant effect on the response to SD.

Psychological and endocrine abnormalities in refugees from East Germany: Part I. Prolonged stress, psychopathology, and hypothalamic-pituitary-thyroid axis activity

The influence of prolonged psychological stress on hormonal secretion was investigated in 84 East Germany refugees suffering from psychiatric disorders within 6 weeks of their arrival in West Berlin shortly before or after the fall of the Berlin Wall. Before leaving the German Democratic Republic, these patients had already experienced prolonged stress, which continued after migration. In most cases, the diagnosis was anxious-depressive syndrome with vegetative complaints and symptoms of increased arousal. Their formal DSM-III-R diagnoses (American Psychiatric Association, 1987) included adjustment disorders, depressive disorders, and anxiety disorders (the latter including posttraumatic stress disorder). Serum levels of thyroid stimulating hormone (TSH) and thyroid hormones (thyroxine, free thyroxine, triiodothyronine, and reverse triiodothyronine) were measured and compared with those of 20 healthy control subjects. TSH and all thyroid hormone concentrations were significantly reduced in the patient group. Fifty-two of the patients (62%) were in the hypothyroid range but did not show any clinical signs of hypothyroidism. These disturbances in hormonal secretion were not correlated to any psychiatric diagnosis or to the severity of acute or chronic stress. The marked abnormalities in the hypothalamic-pituitary-thyroid axis seen in these refugees differ from those reported in depression and would seem to reflect severe chronic stress rather than specific psychiatric disorders. The underlying neurochemical mechanisms remain to be investigated.

Serial dexamethasone suppression tests in psychiatric illness: Part I. A study in Schizophrenia and mania

Weekly dexamethasone suppression tests (DSTs) were performed in 15 patients with schizophrenia (n = 12) and mania (n = 3) until clinical response. At initial evaluation, 53.4% of the patients were nonsuppressors, and 93.3% showed nonsuppression at least once during the treatment period. There was a tendency for DST results to normalize coincident with clinical improvement, although single peaks of DST nonsuppression occurred in several patients irrespective of clinical course. The tests did not prove useful as predictors of recovery or relapse. DST nonsuppression occurred significantly more often in severely ill patients than in moderately ill patients or in patients after recovery, emphasizing the effects of nonspecific stress factors and/or severity of illness on the DST. The cutoff point, established on the basis of DST results in 67 healthy controls, was lower than in other studies, and nonsuppression among healthy controls was associated with low dexamethasone serum levels.

Long;-term observation of the hypgthalamic-pituitary-thyroid (HPT) axis in alcohol-dependent patients

Thyroid hormone levels and thyrotrophin (TSH) were measured in 45 alcohol‐dependent patients before detoxification and 8 days, 3 months and 6 months after detoxification, and compared to levels in healthy controls. Before detoxification, levels of thyroxine (T4) and thyroxine‐binding globulin (TBG) were significantly reduced in patients compared with healthy controls, while triiodothyronine (T3), reverse T3, and TSH levels did not differ from those in healthy controls. During the entire observation period, free T4 (fT4) and free T, (fT3) levels were slightly elevated compared with those in healthy controls. T4 and TBG levels increased significantly during the first week of abstinence. Severity of withdrawal symptoms was negatively correlated with the total T4 levels after 8 days of abstinence. Three months after detoxification, relapsers displayed significantly lower T4 and TBG levels compared with abstinent patients. The increase in T3 levels was most pronounced between 8 days and 3 months of abstinence in both relapsing and abstinent patients. Six months after detoxification, only abstinent patients could be assessed, and they displayed increased TBG and T3 levels compared to healthy controls. Our findings suggest a different time‐course for T3 and T4 levels after detoxification in alcohol‐dependent patients, and indicate that T4 levels after detoxification interact with withdrawal symptoms.

The hypothalamic-pituitary-thyroid axis in psychiatric patients and healthy subjects: Parts 1–4: Part 3: The TRH test and thyroid hormone determinations as predictors of therapeutic response and long-term outcome in major depression and schizophrenia☆

Abstract Thyrotropin-releasing hormone (TRH) test results and concentrations of triiodothyronine (T 3 ), free thyroxine (fT 4 ), free T 3 (fT 3 ) did not predict response either to antidepressant drug treatment in general or to a selective norepinephrine reuptake inhibitor (maprotiline) versus a reuptake inhibitor of both norepinephrine and serotonin (clomipramine), respectively, in 31 patients with major depressive disorder. Responders had higher thyroxine (T 4 ) levels on admission than nonresponders. The response to neuroleptic drugs was not predicted by any hormone measurement in the 15 schizophrenic patients. A blunted TRH test result did not predict therapeutic response in either depressed or schizophrenic patients. Changes in either TRH test results or thyroid hormone levels during treatment did not predict relapse in 27 depressed and 12 schizophrenic patients at 6, 12, or 18 months after discharge. The normalization of a blunted TRH test after recovery was also of no value for predicting a stable long-term outcome. Thyroid hormone concentrations on discharge did not predict relapse in depressed patients, but the patients who did not relapse had lower TRH test results on discharge than those who did.