Psychopathological and behavioral correlates of dopaminergic sensitivity in alcohol-dependent patients.

OBJECTIVES: To explore 2 facets of dopamine receptor sensitivity in alcoholics: (1) whether reduced sensitivity of central dopamine receptors is correlated with anxiety, depression, or novelty seeking and (2) whether this reduction is associated with poor treatment outcome. METHOD: Sixty-four alcohol-dependent patients were assessed according to their clinical outcome, sensitivity of central dopamine receptors (apomorphine-induced growth hormone secretion), mood states, and personality traits before and after detoxification. RESULTS: Patients with poor treatment outcome displayed a blunted growth hormone response before, but not after, detoxification. Growth hormone response was not significantly correlated with novelty seeking. Relapsing patients tended to be less depressed than patients who remained abstinent during observation. CONCLUSION: This study did not support the hypothesis that reduced sensitivity of dopamine receptors is associated with anxiety, depressed mood, or high novelty seeking in alcoholism.

The hypothalamic-pituitary-thyroid axis in patients maintained on lithium prophylaxis for years: high triiodothyronine serum concentrations are correlated to the prophylactic efficacy.

Serum concentrations of thyrotropine (TSH), thyroxine (T4), free T4 (fT4), triiodothyronine (T3) and reverse T3 (rT3) were measured 4 x during a 12-month period in 28 patients with major depressive disorder maintained on lithium prophylaxis for 4-23 years (mean = 11.8). The course of illness was carefully monitored and documented for all patients throughout a 3.5-year period. All hormones were also measured in 41 healthy controls matched for age and gender. Patients on lithium had normal serum concentrations of TSH, T4, fT4 and T3 only the levels of rT3 were elevated. The efficacy of the lithium prophylaxis was significantly correlated to the serum concentrations of T3, i.e., the higher the patients' serum levels of T3, the shorter was the overall duration of recurrences of depression within the 3.5-year period. We conclude that: (1) thyrotropine and the thyroid hormones, which are often abnormal during the first weeks or months of lithium treatment, returned to normal when lithium prophylaxis was maintained for years; (2) a possible explanation for the higher T3-serum concentrations in responders might be that lithium interacts with thyroid hormone metabolism in the CNS, leading to enhanced T3 concentrations in the tissue and to a secondary increase in the serum concentrations of T3.

Blunted growth hormone response is associated with early relapse in alcohol-dependent patients.

Growth hormone (GH) secretion, stimulated by the dopamine D1 and D2 receptor agonist apomorphine, was assessed in 55 alcohol-dependent patients before detoxification (on the day of admittance to hospital) and after 7 days of treatment on the ward (day 8). Patients who relapsed early (i.e., within 3 months after detoxification) showed significantly blunted GH secretion before detoxification, compared with both healthy controls and patients who abstained for 6 months. Among early relapsing patients, GH secretion was blunted whether or not patients were acutely intoxicated on the day of admittance to hospital. However, for patients who abstained during observation, a blunting effect of acute ethanol consumption on GH secretion was demonstrated. On day 8, a trend toward blunted GH secretion was found in early relapsing patients only when GH response over infusion time was assessed. Therefore, GH blunting, and no other variable indicating the clinical course of the disease, was associated with early relapse in alcohol-dependent patients. These findings are evidence of reduced dopamine receptor function in a subgroup of early relapsing alcohol-dependent patients during chronic intoxication.

Hypothalamic-pituitary-gonadal axis, prolactin, and cortisol in alcoholics during withdrawal and after three weeks of abstinence: comparison with healthy control subjects.

Serum concentrations of luteinizing hormone, follicle-stimulating hormone, testosterone, androstenedione, estradiol, sex hormone-binding globulin, cortisol, and prolactin were measured in 12 male chronic alcoholics once during withdrawal and once after 21 days of abstinence. The results were compared with those of 14 healthy volunteers. During withdrawal, luteinizing hormone, estradiol, and cortisol levels were significantly enhanced. Estradiol and cortisol concentrations fell significantly during abstinence, whereas luteinizing hormone concentrations remained elevated. The results may be interpreted as follows: the well-known inhibitory effect of alcohol on the biosynthesis of testosterone may have led to a compensatory increase in luteinizing hormone secretion, so that normal serum concentrations of testosterone were maintained. On the other hand, peripheral conversion from androstenedione to estradiol via aromatase pathways seemed to be enhanced in chronic alcoholics, at least during withdrawal. Whether this marked increase in estradiol concentrations is implicated in different clinical and psychological symptoms seen in chronic alcoholics remains to be investigated.

Hypothalamic-pituitary-thyroid (HPT) axis in chronic alcoholism. I. HPT axis in chronic alcoholics during withdrawal and after 3 weeks of abstinence.

Thyroxine (T4), free T4 (fT4), triiodothyronine (T3), free T3 (fT3), reverse T3 (rT3), thyrotropin (TSH), thyroxine binding globulin (TBG), and T3 uptake were measured in 14 chronic alcoholics during withdrawal and after 21 days of abstinence. Results were compared with those of 16 healthy volunteers. During withdrawal, the fT4 and fT3 concentrations were subnormal, whereas the respective protein-bound fractions were normal. T4, T3, and TBG increased during the abstinence period, T3 and TBG being significantly higher than in normals at the second measuring time. T3 uptake values fell, but remained well within the normal range at both measuring times. During abstinence, the fT3 levels remained significantly lower than in healthy subjects. rT3 concentrations decreased, but not significantly. The TSH values were normal throughout. These results showed numerous abnormalities in the hypothalamic-pituitary-thyroid axis in alcoholics, the reasons for which are as yet unclear. The following possible interpretations are suggested: 1. The abnormally low serum fT3 and fT4 levels during withdrawal might reflect an increase in tissue uptake. 2. The increases in T4--and partly those in T3--during abstinence seem to reflect increased binding by TBG, the level of which rose markedly for reasons as yet unknown. 3. If increases in TBG during abstinence are taken into account, the decreases in rT3 concentrations may reach the level of statistical significance. These falls in rT3 concentrations may reflect an increase in rT3 metabolization (deiodination) in various tissues, including the CNS, leading to a reduction in serum rT3 bioavailability. 4. Factors such as liver disease, protein caloric malnutrition, and "psychological stress" do not fully explain all these abnormalities. A direct effect of ethanol on intracellular thyroid hormone metabolism and/or function seems conceivable.

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.

Psychological and endocrine abnormalities in refugees from East Germany: Part II. Serum levels of cortisol, prolactin, luteinizing hormone, follicle stimulating hormone, and testosterone.

We investigated afternoon serum levels of cortisol, prolactin, luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone in a group of 84 refugees who had fled from East to West Germany and suffered from psychiatric disorders within 6 weeks of their arrival in West Berlin. The mean hormone levels were compared with those of healthy control subjects. Cortisol levels were lower and LH levels were higher in the patients than in the control subjects, but only at trend levels of significance. No differences were found between the prolactin, FSH, or testosterone concentrations of the two groups. The patients with major depressive disorder (MDD) had a significantly higher mean cortisol level than the mean levels in the subgroups in whom posttraumatic stress disorder, dysthymia, and adjustment disorder were diagnosed. It can be concluded that the hypothalamic-pituitary-adrenal axis may "adapt" during severe long-term psychological stress and that long-term stress may be only one of the neurochemical mechanisms underlying the hypercortisolemia in patients with MDD.

Influence of partial sleep deprivation on the secretion of thyrotropin, thyroid hormones, growth hormone, prolactin, luteinizing hormone, follicle stimulating hormone, and estradiol in healthy young women.

The influence of partial sleep deprivation during the second half of the night on the secretion of thyroid stimulating hormone (TSH), thyroxin (T4), free T4 (fT4), triiodothyronine (T3), prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), follicle stimulating hormone (FSH), and estradiol (E2) was investigated in 10 healthy young women. Blood samples were drawn at hourly intervals over a 64-hour period (i.e., 3 consecutive days and nights). During night 2, all subjects were awakened at 1:30 a.m. During partial sleep deprivation, TSH concentrations increased significantly and remained elevated throughout the following day. Levels of T4, fT4, and T3 were enhanced during the partial sleep deprivation hours only, and changes in these hormones seemed to be independent of TSH. PRL levels decreased, LH and E2 concentrations increased, and GH and FSH secretion remained unchanged during partial sleep deprivation. This pattern of change of different endocrine axes during partial sleep deprivation resembles those seen after total sleep deprivation, suggesting that similar neurochemical changes are induced by both forms of antidepressant therapy. The late evening GH peak occurred almost exclusively before the onset of sleep. Partial sleep deprivation did not influence the chronobiological profiles of any of the hormones investigated. The chemical changes underlying these alterations are speculated to involve enhancement of central norepinephrine and dopamine activity with a concomitant increase in the activity of the sympathetic nervous system.

Type II alveolar epithelial eicosanoid metabolism: predominance of cyclooxygenase pathways and transcellular lipoxygenase metabolism in co-culture with neutrophils.

Arachidonic acid (AA) metabolism was studied in freshly isolated type II alveolar epithelial cells of rabbits. Substantial basal secretion of prostanoids with predominance of prostaglandin (PG) I2 was noted. Challenge with the calcium ionophore A23187 resulted in a time- and dose-dependent increase in the generation of all AA cyclooxygenase products to severalfold values following the rank order of 12-heptadecatrienoic acid (12-HHT) greater than PGI2 greater than PGE2 greater than or equal to thromboxane A2 greater than PGF2 alpha approximately PGD2. Even larger augmentation of prostanoid generation was evoked by challenge with free exogenous AA. Generation of the different AA cyclooxygenase products was inhibited by acetylsalicylic acid with IC50 in the range between 250 and 500 microM. In addition to the prostanoid release, ionophore-challenged type II pneumocytes liberated substantial amounts of AA lipoxygenase products with leukotriene (LT) B4 greater than 15-hydroxyeicosatetraenoic acid (HETE) greater than 12-HETE greater than 5-HETE. Generation of LTs and HETEs was markedly increased upon simultaneous disposal of free exogenous AA. No omega-oxidation of LTB4 was noted, and no evidence for secretion of intact LTA4 was obtained. The epithelial cells displayed avid uptake of exogenously offered LTA4 with subsequent enzymatic conversion to LTB4. Co-stimulation of pneumocytes with neutrophils (PMN) resulted in an amplification of LTB4 generation, paralleled by a decrease in nonenzymatic decay products of PMN-derived LTA4; both phenomena were dose dependent on the pneumocyte-PMN ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Thyrotropin (TSH) and thyroid hormone concentrations during partial sleep deprivation in patients with major depressive disorder.

Thyrotropin (TSH), thyroxine (T4), free T4, triiodothyronine (T3), and free T3 (fT3) concentrations were measured in 25 patients with major depressive disorder at 8 a.m. both before and after partial sleep deprivation (PSD) during the second half of the night. Significant increases in TSH and T3 levels and a corresponding trend in fT3 levels were seen. No convincing correlations occurred between changes in the secretion of any of the hormones and the antidepressant effect of PSD. However, this does not rule out the possibility that the two phenomena, which occur in depression at different anatomical levels with presumably different degrees of disturbance in the respective receptor systems, have common underlying neurochemical mechanisms. Comparison of the effect of the PSD on changes in hormone secretion and mood with the corresponding effects in a sample of depressed patients who underwent total sleep deprivation showed no significant differences between the effects of these two forms of sleep deprivation on either variable.

Prolactin in patients with major depressive disorder and in healthy subjects. I. Cross-sectional study of basal and post-TRH and postdexamethasone prolactin levels.

Prolactin (PRL) levels were investigated in patients with major depressive illness and in healthy subjects. Basal and postdexamethasone levels were measured in 27 patients, and levels after thyrotropin-releasing hormone (TRH) stimulation (delta PRL) were measured in 22 patients. Basal and delta PRL were also determined in 64 age- and sex-matched healthy subjects. Both basal and postdexamethasone PRL levels were normal in depressed patients, with the postdexamethasone levels in particular showing no correlation to postdexamethasone cortisol concentrations. One milligram oral dexamethasone did not influence 4:00 PM PRL levels in 15 healthy subjects. delta PRL was significantly elevated in both male and female patients. These increases were not correlated with severity of illness and are difficult to interpret owing to the complexity of the PRL regulatory system. No significant correlations were found between basal or post-TRH PRL and cortisol, thyroid-stimulating hormone (TSH), thyroid hormones, gonadotropins, or estradiol in the patients. However, surprisingly significant positive correlations between basal PRL and basal cortisol, T4 and reverse T3 occurred in healthy subjects. It is as yet unclear how this finding can be explained and what relevance it has. Women tended to have higher basal PRL concentrations than men, but the difference was not significant in either group. delta PRL was significantly higher in women than in men in both patients and controls. No significant influence of age was found.

Prolactin in patients with major depressive disorder and in healthy subjects. II. Longitudinal study of basal prolactin and post-TRH-stimulated prolactin levels.

Longitudinal investigations of basal prolactin (PRL) and prolactin concentrations following thyrotopin-releasing hormone (TRH) stimulation (delta PRL) were conducted in 17 patients with major depressive disorder and healthy subjects. The patients were being treated with either clomipramine or maprotiline. Both basal and delta PRL increased significantly after clinical response during treatment with both drugs. However, these increases in basal and delta PRL were independent of each other. Surprisingly, elevations of basal PRL were significantly greater in responders than in nonresponders, whereas those in delta PRL showed no corresponding significant difference. These results suggest that the two drugs stimulate basal and delta PRL by different mechanisms. The increases in basal prolactin levels found in responders may possibly be due to weaker inhibition of prolactin due to "down-regulated" beta adrenergic receptors and/or enhanced activity of supersensitive serotonergic receptors. Neither basal PRL nor delta PRL proved to be a predictor of therapy response. The intraindividual retest reliabilities of both basal and delta PRL in healthy subjects was so good that a single blood sample would seem to be sufficient for investigating most issues involving PRL in psychiatric patients.

Prolactin in patients with major depressive disorder and in healthy subjects. III. Investigation of basal and post-TRH prolactin during different forms of acute and chronic psychological stress.

Prolactin (PRL) levels after thyrotropin-releasing hormone (TRH) (delta PRL) were determined 4 times and basal prolactin levels 6 times in 10 healthy medical students before, during, and after a major examination in medicine. No significant differences in basal or delta PRL levels occurred during the examination period. Basal PRL was also measured in 14 doctors of medicine after delivering a paper at a clinical conference and a further 9 doctors both before and after delivering a paper. PRL was measured serially at 20-min intervals in 4 doctors on the day on which they presented the paper. No significant differences in PRL levels were found in any of the tests conducted during this kind of stress as compared with the corresponding values obtained under nonstressful conditions. Increases in PRL before delivering the paper were seen in 3 subjects, but such increases also occurred completely independently of stress. An 18-hr fast did not influence PRL secretion in 11 healthy volunteers. Both the information obtained from a review of the literature on the influence of stress on PRL secretion and our own results strongly suggest that contrary to common opinion, there is no evidence at all that psychological stress affects PRL secretion in man.

Serial dexamethasone suppression tests in psychiatric illness: Part II. A study in major depressive disorder.

Weekly dexamethasone suppression tests (DSTs) were performed in 35 patients with major depressive disorder until clinical response. At initial evaluation, 65% of the patients showed nonsuppression, and 85.7% showed nonsuppression at least once during the treatment period. Normalization of the DST results usually coincided with or occurred before clinical recovery, although isolated "peaks" of DST nonsuppression occurred in 45.7% of the patients, irrespective of the clinical course. The test was not useful as a predictor of clinical recovery or relapse. Moderately ill depressed patients had significantly higher nonsuppression rates than schizophrenic or manic patients with corresponding severity scores, indicating that different factors might be associated with nonsuppression in different diagnoses. However, many abnormal DST results could neither be related to the course of the depression nor to the severity of illness; thus other factors must also be responsible for DST nonsuppression.

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.

[Uricemia and uric acid quantities in urine under unbalanced diet (author's transl)]. / Urikämie und Harnsäuremengen im Urin unter einseitiger Ernährung.

Under exclusive intake of glucose or fat production of uric acid and growth is lowered in male rats. Just the same can be observed in adult animals. Loss in weight and impairment in production of uric acid seem to relate to each other. Growth-inhibition, i.e. weight reduction cannot be the reason for the obviously reduced synthesis of uric acid, because corresponding findings can not be ascertained in protein-fed animals in spite of weight-reduction. These findings suggest that synthesis of uric-acid depends on the intake of amino-acids. Thereby the pool of amino acids would be decisive for the synthesis-rate of nucleic acids. It might be conceivable, that the decrease of uric acid serum concentration during aging relates to the suggestion mentioned above.

The dynamics of collagen deposition in liver damaged by CCl4.

The rates of synthesis and catabolism of collagen are determined in the livers of normal rats and of rats treated with carbon tetrachloride. Several experimental conditions are applied with the intention of investigating the dynamic processes separately, in order to determine the relevant values. The deposition of collagen in liver after damage by CCl4 is a consequence of the reduction of turnover with a simultaneous increase in collagen-production. Together with the increase in synthesis, which seems to be a consequence of a numerical increase in cells, there is a reduction in catabolism of collagen: the more severe the damage, the more marked is the decrease of specific catabolism. Collagen-deposition in the liver is thus the result of accumulation. The results indicate the possibility that collagen-catabolism is effected by enzymes produced by adjacent parenchymal cells, so that their destruction enhances the accumulation of collagen material. The findings mentioned above are discussed in the context of the general criteria of scar-formation and the repair of damaged tissues.