Robert L. Dufresne

Attention tasks and EEG power spectra

The authors attempted to observe differences in alpha and beta hemispheric asymmetry during a task in which attention was directed toward input from the environment (intake task) as opposed to tasks that required that environmental events be excluded from the focus of attention (rejection tasks). In comparison to resting, both attention tasks caused a shift in alpha asymmetry ratios toward increased power on the right, with the greatest effect at temporal leads. The only significant difference between attention tasks was a finding of higher alpha power during intake than during rejection. Some characteristics of the EEG during attention indicate potential clinical utility.

Diazepam in Tardive Dyskinesia

Tardive dyskinesia, a syndrome of involuntary motor movements, can be a permanent consequence of the long-term use of antipsychotic drugs. While there is no well-established drug treatment, case reports and the results of a few clinical studies suggest that drugs that facilitate the GABA-ergic system may decrease the abnormal movements. One such class of drugs is the benzodiazepines. We administered diazepam to 13 subjects in a 24-week, crossover design study. Tardive dyskinesia and psychopathology were assessed by blind raters using the Abnormal Involuntary Movement Scale and the Brief Psychiatric Rating Scale (BPRS). The means of all movement measurements improved from the baseline, with orofacial, subtotal, symptom severity, and total reaching significance. However, we were unable to demonstrate a drug effect; the patients improved to a similar degree whether or not they received diazepam. Their psychiatric disorders did not worsen with diazepam administration and, in fact, improved slightly; the activation factor of the BPRS was significantly improved over baseline. Our results suggest that diazepam is not effective in managing the movements of tardive dyskinesia and that behavior modification strategies be investigated to help patients control symptoms.

Association between regulator of G protein signaling 9-2 and body weight.

Regulator of G protein signaling 9–2 (RGS9–2) is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI) of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9–2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc) and observed a reduction in body weight after overexpression of RGS9–2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9–2 as a factor in regulating body weight.

Chronic DMI reduces thresholds for brain stimulation reward in the rat.

The authors sought a demonstration of the validity of brain stimulation reward (BSR) models of depression. It was predicted that chronic, but not acute antidepressant treatment would enhance BSR responding. Rats with medial forebrain bundle electrodes were separated into 4 groups that received either saline or desmethylimipramine at 5, 10, or 20 mg/kg daily. A rate-free, threshold measure that has not previously been employed in studies of BSR and antidepressants was used. BSR thresholds were monitored every 3rd day over a 9-day baseline period and an 18-day drug treatment period, and after 12 days of drug withdrawal. Groups did not differ from one another till the 15th and 18th day of drug treatment. The greatest effects were seen in the 10 and 20 mg groups. The 20 mg group returned to baseline after drug withdrawal, but the 10 mg group did not. The absolute size of the effect was considered to be small, leading the authors to speculate that antidepressants act on homeostatic mechanisms that stabilize BSR substrates, only indirectly enhancing transmission of the reward signal.

Health Correlates of Exercise Behavior and Stage Change in a Community-Based Exercise Intervention for the Elderly: A Pilot Study

The effects of a community-based physical activity intervention grounded in the Transtheoretical Model were investigated in a sample of older adults. The residents (n = 48, mean age = 78.24 ± 6.69, 90% female) of an independent living complex completed pre-and postintervention assessments, including physical, mental, and general health; nutrition; bodily pain; and stages of exercise behavior change. The intervention included posters with stage-based pamphlets (for inactive stages) and in-house exercise sessions (for active participants). The intervention resulted in high exercise maintenance and more progression than regression in exercise stage. More maintainers and progressers improved on the measured variables compared to relapsers. The stage model is a promising framework on which to base and evaluate interventions for this population. The overall impact of the intervention was positive, whether by providing the actual opportunity to exercise or by motivating other physical activity. These results also support the potential quality-of-life impact for this type of intervention in older adults.

Weighing In: Emergent Diabetes Mellitus and Second-Generation Antipsychotics

Of all the metabolic effects of some of the atypical second-generation antipsychotics, their potential to induce glucose dysregulation has induced a storm of controversy over the past several years. The numerous published epidemiologic studies are difficult to interpret due to the high background rate of type 2 diabetes mellitus in this population, the inherent problems with analysis of observational data, and the short duration of the available studies. A plan to monitor for weight gain, hypertriglyceridemia, glucose dysregulation, and other potential adverse metabolic effects resulting from antipsychotic treatment is critical.

Book Review: Brain Drug Targeting: The Future of Brain Drug Development

This innovative text advocates for and describes in depth a body of work dedicated to gaining otherwise unsuitable molecules’ access to the brain. According to the author, many potentially useful therapeutic agents have not been developed because there have been insufficient means to gain central nervous system (CNS) penetration for the more than 98% of all drugs that do not cross the blood–brain barrier. He mentions how many agents tested for brain diseases often had a limited chance for efficacy due to their poor CNS penetration and that there is often a failure to even consider whether drugs could gain access to the CNS prior to their initial screening process. He states that, despite the obvious need, no large pharmaceutical firm in the world has a blood–brain barrier-targeting program. In light of recent and potential advances in genomics and other areas in which gaining access to the brain for larger molecules would be beneficial, an excellent argument is made for the importance of this work. The lack of efficacy for established drugs that achieve poor CNS concentrations, such as azidothymidine, which is subject to active efflux from the brain, is another example this book discusses to stress the need for better brain drug delivery systems. Just as the author does an excellent job arguing for the need for more work in this area, he also goes in depth describing all the inherent pitfalls as well as possible solutions necessary to develop large-molecule pharmaceuticals for brain diseases. He discusses the shortcomings of invasive brain drug delivery as well as the potential for incorporating structure–transport relationship (STR) research along with structure–activity relationship (SAR) research early in drug development. The STR strategy would increase the efficiency of the psychoactive drug screening process. He details the intricacies of lipid-mediated transport, carrier mediated influx and efflux, plasma protein–mediated transport, and receptormediated transcytosis. He explores such important topics as the use of genetically engineered “Trojan horses” for brain drug delivery and dedicates additional chapters to linker strategies, protein neurotherapeutics, antisense neurotherapeutics, gene therapy of the brain, and blood–brain barrier genomics. This is a definitive treatise on a topic that will continue to increase in importance as applied neuroscience research and genomics point the way to curative rather than palliative treatment for brain disorders such as schizophrenia, Parkinson disease, and various dementias. It is a critiNEW PUBLICATIONS

Kappa opioid receptor antagonism: Are opioids the answer for treatment resistant depression?

Introduction: Past trials of buprenorphine (BUP) in the treatment of major depressive disorder (MDD) have displayed favorable results, although its clinical utility was limited by the risk of abuse or physical dependence. By combining BUP with samidorphan (SAM), the euphoric high is negated by an opposing mechanism, which theoretically reduces addictive-like properties while allowing the antidepressant properties to remain. As such, the objective of this article is to analyze the results of BUP/SAM premarketing clinical trials as adjunctive treatment for treatment-resistant MDD. Methods: A comprehensive PubMed/MEDLINE search was conducted through November 9, 2017, using the following search terms: depression, samidorphan, buprenorphine, ALKS-5461. Additional data were obtained from Clinicaltrials.gov and resources included in the present study. All English-language clinical trials evaluating the combination of BUP/SAM in the treatment of MDD were included. Results: A few premarketing studies have evaluated the efficacy and safety of BUP/SAM combination as adjunctive treatment in patients with treatment-resistant MDD. The FORWARD-1 through FORWARD-5 trials concluded (1) the most effective dosing ratio of BUP/SAM to reduce abuse potential was 1:1; (2) statistically significant changes in scores from baseline on the Montgomery-Asberg Depression Rating Scale were noted for the 2 mg/2 mg dose compared with placebo; and (3) the most commonly reported adverse effects were nausea, dizziness, and fatigue. Discussion: Buprenorphine/samidorphan has shown favorable results for efficacy and tolerability in premarketing studies evaluating its use as adjunctive therapy for treatment-resistant MDD. Its novel mechanism targeting the opioid pathway may serve as a promising antidepressant devoid of abuse potential.

Perceptual changes with bupropion, a novel antidepressant

The authors assessed perceptual changes in 12 depressed patients treated wih bupropion, 12 patients given other antidepressants, and 12 drug-free controls. Bupropion was associated with vivid dreaming and changes in attention, memory, and perception. which may have contributed to its therapeutic effectiveness.