Decreased Transmethylation of Biogenic Amines After In Vivo Elevation of Brain S -Adenosyl-l-Homocysteine

The ability of S -adenosyl-l-homocysteine (AdoHcy) to inhibit biologic transmethylation reactions in vitro has led us to explore the possibility of pharmacologically manipulating AdoHcy levels in vivo and examining the consequences of these alterations on the transmethylation of some biogenic amines. Swiss-Webster mice were injected intraperitoneally with different doses of adenosine (Ado) and d,l-homocysteine thiolactone (Hcy) and were killed at various times thereafter. S -Adenosyl-l-methionine (AdoMet) and AdoHcy concentrations were determined by using a modified isotope dilution-ion exchange chromatography-high pressure liquid chromatography technique sensitive to less than 10 pmol. Increasing doses of Ado + Hcy (50-1000 mg/kg of each) produced a dose-related increase in blood, liver, and brain AdoHcy levels. At a dose level of 200 mg/kg Ado + Hcy, AdoHcy levels were markedly elevated, with minimal concomitant perturbations of AdoMet. This elevation was maximal 40 min after giving Ado + Hcy, returning to control values within 6 h. Ado + Hcy treatment resulted in decreased activities of catechol- O -methyltransferase, histamine- N -methyltransferase, and AdoHcy hydrolase in vitro. The cerebral catabolism of intraventricularly administered [ 3 H]histamine (HA) was decreased in a dose-related manner by Ado + Hcy treatment as evidenced by higher amounts of nonutilized [ 3 H]HA in brain, concurrent decreases in [ 3 H]methylhistamine formation, and decreases in the transmethylation conversion index. Steady state levels of HA also showed dose-related increases after Ado + Hcy treatment. It is concluded that injections of Ado + Hcy can markedly elevate AdoHcy levels in vivo , which can, in turn, decrease the rate of transmethylation reactions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66442/1/j.1471-4159.1981.tb00426.x.pd

Characteristics of drug users who do or do not have care of their children

Aims - To compare the relative frequency of eight indicators of problem drug use and potentially adverse social circumstances in drug using parents and non-parents and to explore whether a profile based on these characteristics differs according to whether or not dependent children live with their drug-using parent. Design – The study utilises a 5-year national UK treatment monitoring system dataset. Sample – 61,425 users with, and 105,473 without dependent children accessing drug treatment services in England and Wales between January 1996 and December 2000. Measurements – Information about parenthood and children’s residence was routinely collected. Drug use and social circumstance indicators were daily heroin use, daily alcohol use, regular stimulant use, sharing of injecting equipment, living with another user, living alone, unstable accommodation, and criminal justice referral. Findings – There were clear differences between drug using parents according to where children live. Parents with children at home and non-parents showed fewer of the indicators than parents with children in care or elsewhere. Sixty-five percent of parents with none of the indicators lived with their children, compared to only 28% of those with three indicators and 9% of those with six or more indicators. Parents with children in care or living elsewhere showed the highest prevalence for each individual indicator. Conclusions – Drug using parents demonstrate a range of potentially unfavourable drug use behaviours and social circumstances but those whose children live with them use drugs less frequently and live in more favourable conditions than those whose children live elsewhere. Protective factors may operate in family situations while severe drug use and adverse social circumstances may result in a breakdown of family structures

Safety and efficacy of ABT-089 in pediatric attention-deficit/hyperactivity disorder: results from two randomized placebo-controlled clinical trials.

OBJECTIVE: To assess the safety and efficacy of ABT-089, a novel α(4)β(2) neuronal nicotinic receptor partial agonist, vs. placebo in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: Two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of children 6 through 12 years of age were conducted. Study 1 (n = 274) assessed six treatment groups over 8 weeks: 4 once-daily (QD) ABT-089 doses (0.085-0.700 mg/kg), QD atomoxetine, and placebo. Study 2 (n = 119) assessed three treatment groups over 6 weeks: 2 QD ABT-089 doses (0.7 mg/kg, 1.4 mg/kg) and placebo. The primary efficacy variable was the investigator-administered Attention-Deficit/Hyperactivity Disorder Rating Scale-IV: Home Version (ADHD-RS-IV [HV]) Total Score. Safety was assessed by adverse event (AE) monitoring, laboratory tests, vital signs, physical examinations, and electrocardiogram measures. RESULTS: There was no statistically significant difference between ABT-089 and placebo in mean change from baseline to final evaluation of ADHD-RS-IV (HV) Total Score or other outcome measures at any dose in either study. In Study 1, atomoxetine showed statistically significant improvement for the primary and most secondary endpoints. ABT-089 was generally safe and well tolerated, with no statistically significant difference between any ABT-089 dose and placebo in the overall incidence of any specific AE, and no clinically significant changes in other safety measures. CONCLUSIONS: ABT-089 did not show efficacy on the primary efficacy variable, the ADHD-RS-IV (HV) Total Score, or other measures of ADHD symptomatology in children with ADHD, and had a safety profile similar to placebo. These results contrast with published reports of efficacy of nicotinic modulators in adults with ADHD

Family-based association study of the BDNF, COMT and serotonin transporter genes and DSM-IV bipolar-I disorder in children

Background: Over the past decade pediatric bipolar disorder has gained recognition as a potentially more severe and heritable form of the disorder. In this report we test for association with genes coding brain-derived neurotrophic factor (BDNF), the serotonin transporter (SLC6A4), and catechol-O-methyltransferase (COMT). Methods: Bipolar-I affected offspring triads (N = 173) were drawn from 522 individuals with 2 parents in 332 nuclear families recruited for genetic studies of pediatric psychopathology at the Clinical and Research Program in Pediatric Psychopharmacology and Adult ADHD at Massachusetts General Hospital. Results: We failed to identify an association with the val66 allele in BDNF (OR = 1.23, p = 0.36), the COMT-l allele (OR = 1.27, p = 0.1), or the HTTLPR short allele (OR = 0.87, p = 0.38). Conclusion: Our study suggests that the markers examined thus far in COMT and SLC6A4 are not associated with pediatric bipolar disorder and that if the val66met marker in BDNF is associated with pediatric bipolar disorder the magnitude of the association is much smaller than first reported

Comorbid attention deficit hyperactivity disorder and substance use disorder complexity and chronicity in treatment-seeking adults

Introduction and Aims - Attention deficit hyperactivity disorder (ADHD) is a known risk factor for substance use disorder (SUD); however, the potential additive contribution of comorbid ADHD to drug-specific dependence in SUD populations is largely unknown. The current study aimed to assess this association between ADHD symptoms and drug-specific SUD complexity and chronicity. Design and Methods - A cross-sectional survey was administered to a convenience sample of 489 adults receiving SUD treatment at 16 Australian drug and alcohol treatment centres between September 2010 and August 2011. Participants were screened for adult ADHD symptoms using the Adult ADHD Self-Report Scale. Associations between ADHD screening status and drug-specific SUD complexity and chronicity were assessed using multivariate logistic and modified Poisson regression analysis, controlling for a range of potential confounders. Results - Overall, 215 (44%) patients screened positive for concurrent adult ADHD and SUD. After Simes' correction, a significant positive association was observed between ADHD screening status and current amphetamine SUD (odds ratio (OR) = 1.85; 95% confidence interval (CI): 1.19–2.36). Patients who screened positive for ADHD were significantly more likely to report SUD history for heavy alcohol use (OR = 2.05; 95% CI: 1.21–3.45) and amphetamine (OR = 1.96; 95% CI: 1.26–3.06) as well as significantly increased risk of moderate (3–4 years) duration for benzodiazepine and amphetamine SUDs and long (≥5 years) duration for alcohol, opiates other than heroin or methadone, and amphetamine SUDs. Discussion and Conclusions - The findings provide evidence that there is increased drug dependence complexity and chronicity in treatment-seeking SUD patients who screen positively for ADHD, specifically for amphetamine, alcohol, opiates other than heroin or methadone, and benzodiazepines

A randomized controlled trial of a novel mixed monoamine reuptake inhibitor in adults with ADHD

<p>Abstract</p> <p>Background</p> <p>NS2359 is a potent reuptake blocker of noradrenalin, dopamine, and serotonin. The aim of the study was to investigate the efficacy, safety and cognitive function of NS2359 in adults with a DSM IV diagnosis of ADHD.</p> <p>Methods</p> <p>The study was a multi-centre, double-blind, randomized placebo-controlled, parallel group design in outpatient adults (18–55 years) testing 0.5 mg NS2359 vs. placebo for 8 weeks. Multiple assessments including computerized neuropsychological evaluation were performed.</p> <p>Results</p> <p>There was no significant difference between NS2359 (n = 63) versus placebo (n = 63) on the primary outcome measure reduction in investigator rated ADHD-RS total score (7.8 versus 6.4; p < 0.45). However, in subjects with the inattentive subtype, there were significantly more responders in the NS2359 group compared to placebo (41% versus 7%; p < 0.01). For all secondary variables (ADHD-RS patient rated; The Conners Adult ADHD Scale; The Brown Adult Scale, and CGI-improvement scale) there were no significant differences between the two groups; however, in the inattentive subgroup, the response to treatment was significantly larger than to placebo. NS2359 improved composite factor scores of attention, episodic- and working memory. No serious adverse events were reported with insomnia, headaches and loss of appetite most commonly reported as side effects.</p> <p>Conclusion</p> <p>No overall effect of NS2359 was found on overall symptoms of ADHD. There was also a modest signal of improvement in the inattentive adults with ADHD and cognition warranting further exploration using differing doses.</p

Neuropsychological functioning in college students who misuse prescription stimulants

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137497/1/ajad12551.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137497/2/ajad12551_am.pd

Comparison of plasma cortisol and corticosterone in the dexamethasone suppression test for melancholia

The suppression of plasma corticosterone (B), measured by radioimmunoassay (RIA), was compared to simultaneous suppression of plasma cortisol (F), measured as total corticoids by a competitive protein binding (CPB) assay, in the overnight dexamethasone suppression test (DST). Baseline plasma B concentrations in IO control subjects were 4.04 +/- 1.07 ng/ml (X +/- S.D.) at 0800 hr and 1.51 +/- 0.68 ng/ml at 1600 hr. Post-dexamethasone 1600 hr B levels in the controls were 0.46 +/- 0.29 ng/ml. An early escape of plasma B (&gt; 1.2 ng/ml), like that of F (&gt; 5 [mu]g/dl), during the overnight 24 hr 1.0 mg dose DST was noted in patients with melancholia (endogenous depression).Half-hourly catheter samples in a normal subject stimulated to escape from dexamethasone suppression showed that in general, plasma B concentrations parallel plasma F concentrations over a 12 hr period. Repeated weekly DSTs on two patients with different psychiatric diagnoses resulted in B: F correlations of 0.74 and 0.60. Overall agreement between B- and F-DST outcomes in all categories tested at 1600 and 2300 hr was 93%; the agreement in the melancholic and non-endogenous depressed groups was 100%.Post-dexamethasone, both B and F were suppressed 55-60% below the criterion level in controls. In those patients who escaped from dexamethasone suppression, the percentage increase in plasma B above the criterion level was significantly greater (+ 55%) than the corresponding percentage change in plasma F. Most patients with borderline abnormal F-DSTs (3.5-4.9 [mu]g/dl) exhibited clearly abnormal B-DSTs (&gt; 1.2 ng/ml). We conclude that the use of dexamethasone suppression of plasma B (using 1.2 ng/ml as the abnormal criterion value) is an additional indicator of an abnormal DST in depressed patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24951/1/0000378.pd