George Schwartz

Circadian rhythms of melatonin and cortisol in aging

The relationship of age to the circadian rhythms of melatonin and cortisol was investigated in 44 men and 27 women (age range 19-89 years). Subjects were physically and psychiatrically normal. Four hourly serial blood samples were drawn from 8:00 AM until 8:00 AM the next day, with additional samples at 10:00 PM and 2:00 AM. The indoor illumination was restricted to 300 lux during day and 50 lux during the night. Plasma melatonin and cortisol were estimated by radioimmunoassay. Results show that the means of melatonin and cortisol values decreased significantly with age when the subjects were divided into three age groups, i.e., 19-25 years, 42-65 years, and 66-89 years. They also showed a significant negative correlation with age. The acrophases of the two hormonal rhythms, however, showed different relationships to age. The acrophase of melatonin rhythm showed a positive correlation with age (r = 0.38, p less than 0.001), and cortisol showed a negative correlation with age (r = -0.56, p greater than 0.001). It is suggested that this may indicate a weakened responsiveness of the circadian system in the elderly to the day-night cycle and an altered relationship between the pacemakers driving melatonin and cortisol circadian rhythms. This may thus represent a biomarker for the intrinsic process of the aging of the brain.

Longitudinal study of basal cortisol levels in healthy elderly subjects : evidence for subgroups

A group of 51 healthy elderly volunteer subjects participated in a 3- to 6-year longitudinal study of basal cortisol levels. Once per year basal cortisol levels were examined using hourly sampling over a 24-h period. Analyses of three cortisol measures (last measure obtained, mean cortisol levels across years, and the cortisol slope) revealed that the slope of the regression line measuring cortisol levels at each year was the most predictive measure of cortisol secretion over the years in this elderly population. Cortisol levels were shown to increase with years in one subgroup, to decrease in another, and to remain stable in a third. The age of the subjects was not related to either cortisol levels or to the pattern of change in cortisol secretion over years. Free and total cortisol levels were highly correlated and the groups did not differ with regard to plasma corticosteroid binding globulin. No group differences were observed for weight, height, body mass index, pulse, blood pressure and glucose. However, significant group differences were reported for plasma triglycerides levels as well as high density lipoproteins levels. Positive correlations were reported between the obsession/compulsion subscale of the SCL-90 questionnaire and the cortisol slope of subjects. Finally, previously reported group differences in neuropsychological performance are summarized. Thus, there exists considerable variation in hypothalamo-pituitary-adrenal function amongst aged humans. These results are consistent with recent animal studies showing the existence of subpopulations of aged rats which differ in hypothalamo-pituitary-adrenal activity and cognitive efficiency.

Neurobiological correlates of diagnosis and underlying traits in patients with borderline personality disorder compared with normal controls

The purpose of the study was to test the hypothesis that borderline personality disorder (BPD) and its underlying traits are associated with abnormalities in neurotransmitter systems. Subjects were 30 women with BPD and 22 normal controls, assessed using the Diagnostic Interview for Borderlines, revised, the Hamilton Depression Scale (HAM-A) and the Hamilton Anxiety Scale (HAM-A), the Diagnostic Assessment of Personality Pathology, the Buss-Durkee Guilt-Hostility Inventory, the Barratt Impulsivity Scale (BIS), and challenge tests to measure serotonergic, cholinergic and noradrenergic activity. Borderline subjects with high HAM-A and HAM-D scores showed a faster time to peak in prolactin response to meta-chlorphenylpiperazine (m-CPP) challenge. Borderline subjects with high BIS scores showed prolactin blunting. There were no differences in cortisol response to m-CPP, or on the cholinergic and noradrenergic challenges. The results suggest that impulsive traits in borderline patients are associated with abnormalities in serotonergic systems.

Lack of association between [3H]imipramine binding sites and uptake of serotonin in control, depressed and schizophrenic patients

Uptake of serotonin and [3H]imipramine binding were studied in parallel in the platelets of control, depressed and schizophrenic patients. In the depressed patient group, uptake of serotonin was consistently reduced while [3H]imipramine binding was only decreased in a number of these patients. In the schizophrenic group, uptake of serotonin was reduced to 62% of control with no changes in [3H]imipramine binding being observed. These data demonstrate a clear dissociation between uptake of serotonin and [3H]imipramine binding sites in human platelets. The possible functional role of these [3H]imipramine binding sites remains to be determined.

Dopamine transporter 3'-UTR VNTR genotype and ADHD : A pharmaco-behavioural genetic study with methylphenidate

We sought to test the hypothesis that the variable number of tandem repeat (VNTR) polymorphism in the 3′-untranslated region (3′-UTR) of the SLC6A3 gene modulates behavior in children with ADHD and/or behavioral response to methylphenidate (MPH). One hundred and fifty-nine children with AHDH (6–12 years) were assessed with regard to the Conners’ Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) and the response of these behaviors to MPH (0.5 mg/kg/day) using a 2-week prospective within-subject (crossover) trial. Based on CGI-Parents, the profile of behavioral response to MPH as compared to placebo was not parallel in the three groups of children separated according to their genotype in the 3′-UTR VNTR polymorphism of SLC6A3, as indicated by a significant (p=0.017) genotype by treatment two-way interaction. Individuals having the 9/10 and 10/10 genotypes displayed a significant positive response to MPH as opposed to those homozygous for the 9-repeat allele. No genotype or genotype by treatment interaction was observed for CGI-Teachers. These findings support a role for the DAT gene 3′-UTR VNTR polymorphism in modulating the response of some behavioral dimensions to MPH in children with ADHD. They also suggest the presence of genetic heterogeneity that could be indexed by the quality of behavioral response to MPH.

Tardive dyskinesia and the primary psychiatric diagnosis.

Abstract Over 300 patients were assessed for the presence of tardive dyskinesia in relation to the primary psychiatric diagnosis. Patients with organic mental syndrome or bipolar disorder showed a significantly (P

Effect of domperidone on apomorphine-induced growth hormone secretion in normal men

Domperidone, a peripheral dopamine (DA) receptor blocker which poorly crosses the blood-brain barrier and which is inactive towards dop-amine-sensitive adenylate cyclase, in a dose (100μg/kg) sufficient to increase serum prolactin levels at least 5-fold, decreased the growth hormone (GH) response to the DA receptor agonist, apomorphine HC1 (Apo) (0.5 mg s.c.) in each of six normal men examined. The mean GH increment at 30,45, 60 and 75 min following Apo injection, the mean individual peak increment and the mean individual GH secretion (ng min) was significantly decreased by domperidone pretreatment (p<0.05–p<0.02). These results indicate that in man Apo stimulates GH secretion by an effect on DA receptors which are not linked to adenylate cyclase and which are situated at a locus in the hypothalamic-pituitary axis that lies outside the blood-brain barrier.

Tardive dyskinesia: a two-year follow-up study.

Abstract Eighty patients whose tardive dyskinesia (TD) had been assessed two years previously were reevaluated. The majority (66%) showed no change in their TD. An almost equal number improved (18%) and worsened (16%). Patients whose TD improved were younger (P

Platelet 3H-imipramine binding: A state-dependent marker in depression

Reduced density of 3H-imipramine binding sites (Bmax) to platelets has been reported in depressed patients during an episode of illness. In the present study we assessed the usefulness of decreased Bmax of platelet 3H-imipramine binding as an indicator of the depressed state. We also investigated the effect of long-term treatment with imipramine on platelet 3H-imipramine binding. A comparison of platelet 3H-imipramine binding in 10 drug-free depressed patients and 8 normal volunteers revealed significantly lower mean Bmax values in depressed patients, whereas the affinity (Kd) of 3H-imipramine binding was identical in both groups. A longitudinal study of platelet 3H-imipramine binding in 10 depressed patients during and after imipramine treatment (125-200 mg/day) revealed consistently low Bmax values despite clinically meaningful improvement. However, Bmax values increased significantly following complete remission and remained elevated even after imipramine had been discontinued for 4 weeks. These findings suggest that decrease in the sensity of platelet 3H-imipramine binding sites in depressed patients is not likely to be a direct drug effect and that normalization of this variable may follow clinical remission.

COMT Val108/158Met polymorphism and the modulation of task-oriented behavior in children with ADHD.

It has been suggested that the symptoms of attention-deficit/hyperactivity disorder (ADHD), including inattention and/or hyperactivity/impulsivity, translate into deficits in task-oriented behavior or problem-focused activity. The frontosubcortical dopamine pathway has been implicated in ADHD. One of the key modulators of extracellular dopamine levels in the prefrontal cortex is catechol-O-methyltransferase (COMT). The objective of this study was to examine the association of the COMT Val108/158Met polymorphism with (1) task-oriented behavior in children with ADHD, and (2) response of this behavior given methylphenidate (MPH) treatment. Children of Caucasian ethnicity, having ADHD (n=188), were assessed using the Restricted Academic Situation Scale (RASS). The RASS uses a simulated academic environment within the research clinic, to assess the childs ability for independent, sustained orientation to an assignment of math problems. Each child was administered placebo and MPH (0.5 mg/kg in a divided b.i.d. dose), each for a 1-week period, in a randomized, double-blind, crossover trial. On day 3 of the respective treatment week, the child was administered placebo/MPH in the clinic, and the acute change in behavior (before and 1 h after treatment) was evaluated on the RASS. Analysis was carried out using mixed model analysis of variance. Significant main effects of COMT genotype (F2,184=5.12, p=0.007) and treatment (F1,184=44.26, p<0.001) on task-oriented behavior were observed. However, no genotype by treatment interaction was observed. These results suggest that the COMT Val108/158Met polymorphism modulates task-oriented behavior, but it does not modulate the response of this behavior with MPH treatment.