Dose-response studies with thyrotropin-releasing hormone: evidence for differential pituitary responses in men with major depression, alcoholism, or no psychopathology.

A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) has been reported in both alcoholic and depressed men. To discern whether the pathophysiological basis of a reduced TSH response is similar in these two disorders, the present study compares the dose-response patterns of TSH and prolactin (PRL) to TRH in depressed, alcoholic, and control men. Four doses of TRH (25, 100, 500, and 800 micrograms) were given at several day intervals to 6 men with major depression, 8 men with alcohol dependence, and 7 control men. Examination of the pattern of TRH-induced TSH and PRL response revealed differences for each paired group comparison: depressed versus control, depressed versus alcoholic, and alcoholic versus control. Compared with controls, depressed men had low TSH and low PRL responses to TRH, whereas alcoholic men had low TSH responses and normal PRL responses. Levels of neither thyroid hormones, cortisol, or sex steroids, nor age or body size, explained these differences. These findings suggest that the pathophysiological basis of a reduced TSH response to TRH is different in alcoholism, compared with depression.

Dose-response studies with protirelin.

BACKGROUND: A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (protirelin [TRH]) has been found consistently in a portion of patients with major depression. One hypothesis to explain this observation is that pituitary TRH receptors are down-regulated in major depression. One prediction stemming from this hypothesis is that prolactin (PRL) as well as TSH responses to TRH should be attenuated. To adequately test the pattern of protirelin-induced TSH and PRL responses with a protirelin dose-response design is necessary. METHODS: Four doses of protirelin (25, 100, 500, and 800 micrograms) were infused in an ascending schedule at intervals of 3 to 7 days in patients with major depression and in control subjects. Seven women and six men with major depression were compared with age- and gender-matched controls (five women and seven men). The TSH and PRL responses were measured at regular intervals following each dose of protirelin. RESULTS: No significant group differences in baseline levels of thyroid hormones or cortisol were present. Depressed men exhibited significant reductions in both TSH and PRL responses to protirelin across all doses compared with control men. Depressed women exhibited significant reductions in TSH responses but not in PRL responses compared with control women. CONCLUSIONS: The findings that men with major depression exhibit reductions in both protirelin-induced TSH and PRL responses support the hypothesis that TRH receptors are downregulated in depression. The findings in women are less clear and may represent the greater variance in the protirelin-induced PRL responses found in women.

Dose-response studies with thyrotropin-releasing hormone (TRH) in abstinent male alcoholics: evidence for selective thyrotroph dysfunction?

A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) has been reported in subjects with a history of alcoholism whereas prolactin (PRL) responses have generally been normal. One hypothesis proposed to explain the reduced TSH response is down-regulation of pituitary TRH receptors. If this is correct, PRL response should also be diminished. To account for the different dose-response characteristics of TSH/PRL we have given four dosages of TRH (25, 100, 500 and 800 micrograms) to eight noncirrhotic, male alcoholics abstinent from ethanol a minimum of 28 days and to seven male control subjects. Across the TRH dose range the alcoholic subjects exhibited reduced basal TSH (p = .01) and a reduced TSH response (p = .0023) but no differences in basal and stimulated PRL levels. Alcoholic subjects had higher basal T4, T3 and FT4I values than did control subjects but covarying for T4, T3 and FT4I did not change the significance of either TSH or PRL findings. No significant differences in estradiol, estrone, testosterone, cortisol or glucose were noted between groups. The present study confirms the observation of a lower TSH response to TRH in abstinent alcoholics and indicates that the lower response cannot be overcome by increasing TRH dosage. The similar PRL response between groups suggests normal lactotroph function in noncirrhotic abstinent alcoholics and argues against the pituitary TRH receptor down-regulation hypothesis.

Differential psychopharmacology of methylphenidate and the neuropsychology of childhood hyperactivity.

The principle of rate-dependency has been proposed to explain the therapeutic effects of stimulant drugs in hyperactive children (HAC). This paper is a critical discussion of the salience of rate-dependency to childhood hyperactivity, on mathematical, theoretical and clinical levels. The results of a stimulant drug trial in 55 HAC are presented; the data are analyzed using analysis of variance to describe main drug effects, and these are compared to results derived from a traditional rate dependency analysis. The latter are found to have little salience to the actual clinical effects of stimulant drugs on a wide variety of behavioral, physiological and laboratory measures. The weakness of the rate dependency hypothesis, however, is not necessarily fatal to the idea that the state of the organism prior to drug administration influences the response profile of the drug. The heterogeneity of stimulant effects, and the relationship between stimulant effects and the predrug state of the organism, especially in electrophysiological paradigms, are clear. A hypothesis is presented to suggest that HAC may be characterized by a trait of excessive variability. Homeostatic stimulant effects in reducing response variability may be central to the therapeutic action of the drug. A neural substrate for the abnormal oscillations which characterize HAC, the correction of which is germane to therapeutic stimulant effects, is presented in terms of the regulatory functions of the frontal lobe. A neuroanatomic locus of childhood hyperactivity is proposed in terms of disorder or dysmaturation of frontal striatal systems.

Lack of acute d-amphetamine effects on thyrotropin release.

Case reports have suggested that amphetamine abuse causes excessive secretion of thyrotropin (TSH) and thyroxine (T4). Such an amphetamine-induced effect might be noradrenergic-mediated in the hypothalamus. The current controlled study examined oral d-amphetamine effects on the hypothalamic-pituitary-thyroid axis in normal humans. No acute effects were seen on TSH, T3 or T4 levels. d-Amphetamine elevated cortisol levels at 180 min, as previously reported.

Lithium potentiation of tricyclic antidepressants following lack of T3 potentiation.

Four patients whose depressions were failing to respond to administration of tricyclic antidepressants were given separate trials of T3 and lithium. In all four cases, T3 failed to potentiate the antidepressant, whereas the lithium did.

ABO incompatibility and parity effects on perinatal mortality.

PIP: The perinatal mortality rate increases with parity. Maternal-fetal ABO incompatibility also increases fetal wastage. Using data on 14,732 pregnancies from the British Perinatal Study, the authors compare the perinatal mortality rate to ABO blood type and parity. Within each maternal blood group, the perinatal mortality rate increases with parity. The slope of the mortality and parity regression line is substantially steeper for O mothers than for A, B, or AB mothers. Parity effects on perinatal mortality are most strongly felt by O mothers, who are also most prone to develop an immune reaction to fetal blood group antigens. Data on fetal ABO status was unavailable.^ieng

Long-term psychotherapy of Munchausen syndrome.

In this paper we describe the long-term outpatient psychotherapy of a patient with Munchausen syndrome. We present detailed observations on the role of current object relations in the evolution of factitious symptoms, and discuss the communicative aspects of this behavior.

Influence of sex of antecedent siblings on the human sex ratio.

Analysis of family configurations in a population of 649,366 American secondary school students confirmed that sex of later-born children is influenced by the sex of antecedent siblings. Antecedent brothers decrease the probability of subsequent male births. This observation, a confirmation of an earlier report in a substantially smaller sample, is consistent with an immunologic influence on human sex determination.

A developmental study of temporal duration judgments.

First, third, fifth, and seventh graders and college students (18 per grade) made four serial reproductions of each of three time intervals, 8, 13, and 32 sec. The results paralleled those of other studies using only adults since both the psychophysical function and the Weber fraction were typical, and magnitude of judgments was an increasing, negatively accelerated function of trials. None of these effects was a function of age nor were there any age effects in an analysis of variable errors. Analysis of first-degree sequential dependency of judgments (using lag correlations) revealed a slight negative recency which was also invariant with age of Ss.

Tardive dyskinesia and other clinical consequences of neuroleptic treatment in children and adolescents.

Of 41 children, adolescents, and young adults who were withdrawn from chronic neuroleptic treatment, 18 developed tardive dyskinesia, withdrawal dyskinesia, nondyskinetic withdrawal symptoms, or transient behavior deterioration. Development of neuroleptic-related problems seemed to be associated with cumulative neuroleptic dose and possibly with the sex of the subject. Only 12 of the 41 subjects required resumption of neuroleptic treatment after a prolonged trial withdrawal period.

The persistence of stimulant effects in chronically treated children: further evidence of an inverse relationship between drug effects and placebo levels of response.

Seventeen hyperactive children who had been treated for 1-5 years with methylphenidate were studied in a double-blind placebo-controlled crossover study. Specific measures of stimulant response were found to be inversely related to the subject's level of response in the placebo condition. This inverse relationship was previously found to characterize the clinical effects of hyperactive children in an acute-treatment paradigm. It is equally valid in a chronic-treatment study. "State-contingency" is not, therefore, simply a function of the "novelty" of initial drug treatment.

Cannabis, atropine, and temporal information processing.

In experiment 1, subjects judged time by duration production under no-counting instructions. The productions were made following intravenous injection of atropine sulfate or saline, and after smoking cigarettes with and without (-)-delta 9-tetrahydrocannabinol (THC). THC increased the subjective time rate (STR); i.e., the rate at which subjective time passes relative to clock time, whereas atropine had no effect on STR. Thus, reduction in central acetylcholine activity is not a sufficient explanation of THC's effect on STR. Experiment 2 replicated the THC effect on STR when subjects were counting subjective seconds. This result indicates that THC affects the experience of time as it is passing, and not solely the memory for duration experience after a time period.

Diet and hyperkinesis--an update.

Ten years ago, Dr. Feingold proposed that hyperactivity and learning disabilities in children are commonly caused by the ingestion of food additives and claimed that elimination of foods with additives from the diet resulted in major improvements in three-quarters of hyperactive children. In the last five years, controlled double-blind studies have been conducted by many investigators to test this hypothesis. The results, which are mainly negative, are summarized. The authors conclude that 2% (contrasted with Feingold's claims of 75%) of hyperactive children respond adversely to dye additives. Even the 2% are questionable. There is no need for high-priority research or for changes in public policy regarding the use and labeling of foods containing additives. Hyperkinesis has multiple etiologies, which require other types of biological and psychological research.

Effects of response language and stimulus context upon judgments of visual and temporal extent.

College-student subjects judged duration (Experiment 1) or line length (Experiment 2) using conventional measurement units (sec and in.) and cross-modality matching. In each experiment, three stimulus contexts were created varying in average stimulus value. Judgmental contrast was observed in the cross-modality judgments, but not in the conventional-units judgments. It was inferred that the context effects were operating on response-translation processes.