N. M. K. Ng Ying Kin

The modulatory effects of corticosteroids on cognition: studies in young human populations

In the present article, we report on two studies performed in young human populations which tested the cognitive impact of glucocorticoids (GC) in situations of decreased or increased ratio of mineralocorticoid (MR) and glucocorticoid (GR) receptor occupation. In the first study, we used a hormone replacement protocol in which we pharmacologically decreased cortisol levels by administration of metyrapone and then restored baseline cortisol levels by a subsequent hydrocortisone replacement treatment. Memory function was tested after each pharmacological manipulation. We observed that metyrapone treatment significantly impaired delayed recall, while hydrocortisone replacement restored performance at placebo level. In the second study, we took advantage of the circadian variation of circulating levels in cortisol and tested the impact of a bolus injection of 35 mg of hydrocortisone in the late afternoon, at a time of very low cortisol concentrations. In a previous study with young normal controls, we injected a similar dose of hydrocortisone in the morning, at the time of the circadian peak, and reported detrimental effects of GC on cognitive function. Here, when we injected a similar dose of hydrocortisone in the afternoon, at the time of the circadian trough, we observed positive effects of GC on memory function. The results of these two studies provide evidence that GC are necessary for learning and memory in human populations.

Nicotine and Behavioral Markers of Risk for Schizophrenia: A Double-Blind, Placebo- Controlled, Cross-Over Study

We investigated the effect of nicotine on three behavioral markers of risk for schizophrenia: sustained attention (using the Continuous Performance Task (CPT)), antisaccade performance, and smooth pursuit. Smooth pursuit was investigated in two conditions, one in which attention was enhanced (monitoring target changes) and one in which attention was not enhanced (no monitoring). Patients with schizophrenia (n = 15) and controls (n = 14) were given a 14-mg nicotine patch in a double-blind, placebo-controlled, crossover design and plasma nicotine concentrations were monitored. Nicotine concentrations were similar in both groups. A Group × Drug interaction (p < .02) on CPT hits indicated that nicotine improved sustained attention in patients but not in controls. Nicotine significantly decreased antisaccade errors (p < .01) in both groups. A Drug × Monitoring condition interaction (p < .01) on pursuit gain indicated that nicotine significantly increased pursuit gain in the no-monitoring condition in patients and controls equally, but did not improve pursuit in the monitoring condition. Thus, improvement in pursuit may have been mediated via an effect on attention rather than by an effect on oculomotor function per se. In patients, the magnitude of improvement in attention on nicotine was correlated with the improvement on eye movement tasks. Thus, nicotine improves performance on both attention and oculomotor markers of risk for schizophrenia, possibly via common mechanisms.

Comparative effects of the antipsychotics sulpiride or risperidone in rats: I: Bodyweight, food intake, body composition, hormones and glucose tolerance

Obesity and related metabolic disorders are important side effects of some antipsychotic drugs (APs). The currently available animal model of AP-induced bodyweight gain (BWG) in rats is based on administration of sulpiride (SUL). However, this model has important limitations. For example, SUL is a pure dopamine antagonist, whereas most APs in current clinical use interact with multiple neurotransmitter receptors involved in food intake (FI) and metabolism regulation. Therefore, we evaluated the effects of risperidone (RIS, 0.125, 0.25 or 0.5 mg/kg during 16 days) on BWG and FI in male and female rats. Comparison between RIS (0.5 mg/kg), SUL (20 mg/kg) and vehicle (VEH) during 12 days was also conducted in females. In male rats, RIS did not significantly affect BWG, FI, glucose tolerance or leptin levels, even though prolactin and corticosterone were significantly elevated. In females, both APs significantly increased BWG and FI, but the effect was stronger with SUL. The BWG was significantly associated with an increase in body fat. Serum leptin levels were increased only in SUL-treated rats. The area under the curve for glucose (AUGC) was significantly lower in the SUL group, but it was similar for insulin in all treatment groups. The area under the curve for insulin (AUIC) and BWG positively correlated only in the RIS group. Prolactin and corticosterone were significantly increased by both APs. Serum estradiol levels were significantly increased by RIS but not by SUL, but progesterone levels were similar in both groups. The observed positive correlation between BWG and the AUIC during RIS administration suggests that this agent may represent a better model of AP administration in humans. The animal model of RIS-induced obesity in rats might be improved by testing other doses, route of administration and type of diet.

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.

Self-destructiveness and serotonin function in bulimia nervosa.

Studies have linked bulimia nervosa (BN) to alterations in brain serotonin (5-hydroxytryptamine: 5-HT) activity and to heightened propensity for parasuicidality and self-injuriousness. The coincidence of self-destructiveness and 5-HT abnormality in BN is of interest, given documentation (in various populations) of an inverse association between 5-HT activity and potential for self-harm. The present study examined the connection between 5-HT status and self-destructiveness in BN. Structured interviews and self-report questionnaires were used to assess 40 bulimic and 21 normal-eater women for: (a) history of parasuicidal or self-injurious acts; and (b) mood and impulse-regulation problems. We then applied tests, presumed to reflect 5-HT function, of serial prolactin (PRL) and cortisol (CORT) responses after oral administration of the partial 5-HT agonist, meta-chlorophenylpiperazine (m-CPP). Relative to non-bulimic women, bulimic women (on average) showed blunting of PRL and CORT following m-CPP. The blunting of neuroendocrine responses was, however, most remarkable in bulimic women with a history of self-destructiveness. These findings suggest that some serotonergic anomalies reported in BN sufferers (i.e. reduced neuroendocrine response after m-CPP) may be most characteristic of individuals in the population showing clear-cut self-destructive potential.

Moclobemide and nortriptyline in elderly depressed patients. A randomized, multicentre trial against placebo

Moclobemide and nortriptyline were compared with placebo in a double-blind randomized multinational (Canada, Denmark and UK) trial comprising 109 patients of > 60 years of age with major depression (DSM-III-R). Patients were randomized to 7 weeks of treatment with doses of 400 mg/day moclobemide, 75 mg/day nortriptyline or placebo. It was necessary to adjust nortriptyline dosage in < 20% of patients to maintain serum levels within the postulated therapeutic window of 50-170 ng/ml. At end of treatment, the remission rates were 23% for moclobemide, 33% for nortriptyline and 11% for placebo. Anticholinergic and orthostatic events occurred more often with patients on nortriptyline than either moclobemide or placebo.

Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection

Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm(3)/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p = 0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model.

Brief Motivational Interviewing for DWI Recidivists Who Abuse Alcohol and Are Not Participating in DWI Intervention: A Randomized Controlled Trial

BACKGROUND Driving while impaired (DWI) recidivists with unresolved alcohol use problems pose an ongoing risk for traffic safety. Following conviction, many do not participate in mandated alcohol evaluation and intervention programs, or continue to drink problematically after being relicensed. This study investigated if, in DWI recidivists with alcohol problems and not currently involved in DWI intervention, Brief Motivational Interviewing (BMI) produced greater reductions in risky drinking at 6- and 12-month follow-up compared to an information-advice control condition. Additional analyses explored whether BMI was associated with greater readiness to change, subsequent substance abuse treatment service utilization, and satisfaction compared to the control condition. METHODS Male and female recidivists with drinking problems and not currently engaged in DWI intervention were recruited, evaluated, and then randomly assigned to receive 1 of 2 manualized interventions: 30-minute BMI session or information-advice. Participants, interviewers, researchers, and statisticians were blind to assignment. Outcomes were changed in: percent of risky drinking days (i.e., > or =3 standard drinks/d for males; > or =2 for females) in the previous 6 months derived from the Timeline Followback, biomarkers of alcohol abuse (GGT, AST, ALT, MCV) by blood assay, and alcohol abuse-related behaviors using the MMPI-Mac scale. Data from the Readiness to Change Questionnaire, a substance abuse service utilization questionnaire, and the Client Satisfaction Scale were also collected. RESULTS Analyses revealed significant declines in risky drinking with both interventions. BMI (n = 92) resulted in a 25% reduction in risky drinking days at 12-month follow-up, which compared to the control intervention (n = 92) represented a significant decline from 6-month levels. Exposure to BMI also produced significantly greater improvement at 6-month follow-up in a biomarker of alcohol abuse and a behavioral measure related to recidivism risk. Exploration of readiness to change, substance abuse service utilization, and satisfaction with intervention indicated a perception of BMI being more useful in coping with problems. CONCLUSIONS Brief MI approaches warrant further implementation and effectiveness research as an opportunistic DWI intervention strategy to reduce risks associated with alcohol use outside of clinical and DWI relicensing settings.

Association of the promoter polymorphism -1438G/A of the 5-HT2A receptor gene with behavioral impulsiveness and serotonin function in women with bulimia nervosa

Separate lines of research suggest that the functional alterations in the serotonin (5‐HT) 2A receptor are associated with 5‐HT tone, behavioral impulsiveness, and bulimia nervosa (BN). We explored the effect of allelic variations within the 5‐HT2A receptor gene promoter polymorphism −1438G/A on trait impulsiveness and serotonin function in women with BN. Participants included women with BN having the A allele (i.e., AA homozygotes and AG heterozygotes, BNA+, N = 21); women with BN but without the A allele (i.e., GG homozygotes, BNGG, N = 12), and normal eater control women having the A allele (NEA+, N = 19) or without the A allele (NEGG; N = 9). The women were assessed for psychopathological tendencies and eating disorder symptoms, and provided blood samples for measurement of serial prolactin responses following oral administration of the post‐synaptic partial 5‐HT agonist meta‐chlorophenylpiperazine (m‐CPP). The BNGG group had higher scores than the other groups on self‐report measures of non‐planning and overall impulsiveness and had blunted prolactin response following m‐CPP. The bulimic groups did not differ from each other on current eating symptoms or on frequencies of other Axis I mental disorders. Findings indicate that women with BN who are GG homozygotes on the −1438G/A promoter polymorphism are characterized by increased impulsiveness and lower sensitivity to post‐synaptic serotonin activation. These findings implicate the GG genotype in the co‐aggregation of impulsive behaviors and alterations of post‐synaptic 5‐HT functioning in women with BN.

Presence of Abnormal Amounts of Dolichols in the Urinary Sediment of Batten Disease Patients

Summary: Polyisoprenols of the dolichol class have been identified in urinary sediment for the first time and quantified by a high performance liquid chromatographic method. In the late infantile and juvenile forms of Neuronal Ceroid Lipofuscinosis (Batten disease), greatly increased amounts of dolichols of C-90 to C-105 were found in the urinary sediment compared with a variety of other neurologic disorders and age-matched normal subjects. Dolichols purified from the urinary sediment of a late infantile Batten disease patient were shown to have spectroscopic and chemical properties identical to standard preparations of liver and brain dolichols.Speculation: Measurement of dolichols in the urinary sediment could be of value in diagnosis and screening of siblings of Batten disease. The discovery that dolichols are present in the storage cytosomes, are increased in both the brain and dehisced renal tubular cells in the urine suggests that the basic biochemical defect in these inherited disorders lies on pathways involved in the utilization of dolichols for glycoprotein synthesis.