Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial

The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. (“GUIDED”), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian “GAPP-MDD” RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477)

The HIM (Health for Izhevsk Men) trial protocol

BACKGROUND: Russia is one of the very few industrialised countries in the world where life expectancy has been declining. Alcohol has been implicated as a major contributor to the rapid fluctuations observed in male life expectancy since 1985 that have been particularly marked among working-age men. One approach to reducing the alcohol problem in Russia is 'brief interventions' which seek to change views of the personal acceptability of excessive drinking and to encourage self-directed behaviour change. There is limited understanding in Russia of the salience and applicability of Motivational Interviewing (MI), a well-defined brief intervention commonly used to target alcohol-related behaviour, but MI may have important potential for success within the Russian context. METHODS/DESIGN: The study will be an individually randomised two-armed parallel group exploratory trial. The primary hypothesis is that a brief adaptation of MI will be effective in reducing self-reported hazardous drinking at 3 months. The secondary hypothesis is that it will be effective in reducing self-reported past week beverage alcohol consumption, alcohol dependence and related problems at 3 months and at 12 months. MI will also be effective at 12 months in reducing self-reported hazardous drinking, alcohol dependence and related problems, proxy reported hazardous drinking, and recent alcohol use as indicated by bio-markers. Participants are drawn from the Izhevsk Family Study II, with eligibility determined based on proxy reports of hazardous drinking in the past year. All participants undergo a health check, with MI subsequently delivered to those in the intervention arm. Signed consent is obtained from those in the intervention arm at this point. Both groups are then invited for 3 and 12 month follow ups. The control group will not receive any additional intervention. TRIAL REGISTRATION: ISRCTN82405938

Chronic Allergic Inflammation Causes Vascular Remodeling and Pulmonary Hypertension in Bmpr2 Hypomorph and Wild-Type Mice

Loss-of-function mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene have been identified in patients with heritable pulmonary arterial hypertension (PAH); however, disease penetrance is low, suggesting additional factors play a role. Inflammation is associated with PAH and vascular remodeling, but whether allergic inflammation triggers vascular remodeling in individuals with BMPR2 mutations is unknown. Our goal was to determine if chronic allergic inflammation would induce more severe vascular remodeling and PAH in mice with reduced BMPR-II signaling. Groups of Bmpr2 hypomorph and wild-type (WT) Balb/c/Byj mice were exposed to house dust mite (HDM) allergen, intranasally for 7 or 20 weeks to generate a model of chronic inflammation. HDM exposure induced similar inflammatory cell counts in all groups compared to controls. Muscularization of pulmonary arterioles and arterial wall thickness were increased after 7 weeks HDM, more severe at 20 weeks, but similar in both groups. Right ventricular systolic pressure (RVSP) was measured by direct cardiac catheterization to assess PAH. RVSP was similarly increased in both HDM exposed groups after 20 weeks compared to controls, but not after 7 weeks. Airway hyperreactivity (AHR) to methacholine was also assessed and interestingly, at 20 weeks, was more severe in HDM exposed Bmpr2 hypomorph mice versus WT. We conclude that chronic allergic inflammation caused PAH and while the severity was mild and similar between WT and Bmpr2 hypomorph mice, AHR was enhanced with reduced BMPR-II signaling. These data suggest that vascular remodeling and PAH resulting from chronic allergic inflammation occurs independently of BMPR-II pathway alterations

Children's Process of Care Measure Implementation Readiness

National adult acute care outcome tracking was instituted in 2000 under the assumption that doing so, and publicly reporting the results, would lead to improvements in the healthcare industry and lives saved. The results speak for themselves. Unfortunately, the process has yet to be mandated in the care of our nation’s most valuable assets: our children. However, that is about to change. This research project explored Children’s Process of Care Measure implementation preparedness

The form of a conditioned stimulus can influence the degree to which it acquires incentive motivational properties.

There is considerable individual variation in the extent to which food- and drug-associated cues (conditioned stimuli, CSs) acquire incentive salience, as indicated by whether they elicit approach towards them, and/or act as conditioned reinforcers. Here we asked whether this variation is influenced by properties of the CS itself. In rats, we assessed both the attractiveness and conditioned reinforcing properties of two CSs: a manipulable lever CS versus an auditory (tone) CS. There was considerable individual variation in the extent to which a lever CS acquired incentive motivational properties, as indicated by whether it became attractive (evoked a sign-tracking or goal-tracking conditioned response) or acted as a conditioned reinforcer. However, with a tone CS all rats learned a goal-tracking response, and the tone CS was an equally effective conditioned reinforcer in sign-trackers and goal-trackers. Even when presented in compound (a lever-tone CS), the two elements of the compound differentially acquired motivational properties. In contrast, amphetamine and stress potentiated the conditioned reinforcing properties of both visual and auditory CSs similarly in rats that primarily sign-tracked or goal-tracked. We conclude that variation in the to the ability of CSs to acquire incentive salience, and thus their ability to act as incentive stimuli capable of motivating behavior, is determined in part by properties of the CS itself

General timeline of experimental phases.

<p>General timeline of experimental phases.</p

Pavlovian Conditioning using a tone CS.

<p>PCA Index scores were correlated with CS lever contacts during PCA (panel A) but not with CS magazine entries during the last day of tone conditioning (panel B). During tone conditioning (panel C), only goal-tracking was observed and did not differ between sign- and goal-trackers. When allowed to nose-poke for the tone in a conditioned reinforcement test (panel D), STs and GTs did not differ in the number of nose-pokes. Data are represented as mean (± SEM).</p

The lever, but not the auditory, component of a compound CS are differentially reinforcing in sign-trackers (ST), but not goal-trackers (GT).

<p>Rats nose-poked for either the lever component or the auditory component of the compound CS in separate conditioned reinforcement tests. STs, GTs, and intermediates (IN) did not differ in nose-pokes that were reinforced by the tone component of the CS (panel A), but STs made more nose-pokes for the lever component (panel B). STs approached the lever more often than GTs during the conditioned reinforcement test (Panel C). The PCA index was significantly correlated with the reinforcing efficacy of the lever component of the CS, but not the auditory component (Panels D and E). Asterisks indicate significant differences compared to goal-trackers (p<0.05). Data are represented as mean (± SEM).</p