Accuracy in recognising happy facial expressions is associated with antidepressant response to a NOP receptor antagonist but not placebo treatment.

BACKGROUND: Clinical trials with putative antidepressants can be difficult to execute as it can take up to 8 weeks before differences emerge between drug and placebo, and long expensive trials often fail. Implementation of early response biomarkers could aid this process significantly with potential to identify new treatments. AIMS: In a secondary analysis, we examined the association of early effects on emotional processing with later clinical outcome following treatment with the novel NOP antagonist LY2940094 versus placebo. We hypothesised that early induction of positive bias would be associated with reduced severity of depression after 8 weeks of treatment. METHODS: This was a multicentre, randomised, double-blind, parallel-group, fixed-dose, placebo-controlled, 8 week study to assess sensitivity of the facial emotional recognition task (FERT) to early changes in emotional bias induced by LY2940094. Patients who met diagnostic criteria for major depression were randomised to receive LY2940094 (N = 70) or placebo (N = 66). At week 1 and 6, the FERT was completed by 33 patients in the LY2940094 group and 34 in the placebo group. RESULTS: Patients identified happy faces with higher accuracy (Wald χ2(1,33) = 14.25, p < 0.001) after 1 week treatment with LY290094 compared to placebo (Wald χ2(1,32) = 0.83, p = 0.36) and this correlated with eventual treatment response measured by the Hamilton Depression Rating Scale 7 weeks later. CONCLUSION: These data suggest that emotional processing biomarkers may be sensitive to early effects of antidepressant treatment indicative of later clinical response. Further studies in this area may be useful in developing new treatments and clinical trial designs for predicting antidepressant response.

Assessment of the Wearability of Facemasks against Air Pollution in Primary School-Aged Children in London.

Air pollution is a major health problem and children are particularly vulnerable to the adverse effects. Facemasks are one form of protection but, to be effective, they need to filter out airborne pollutants, fit the face well and be wearable. In this pilot study, we assess the perceived wearability of three facemasks (Vogmask, TuHao and ReSpimask) marketed in the UK as being designed to protect children against exposure to air pollution. Twenty-four primary school children wore each facemask during a standardised walking and running activity. After each activity, the children were asked to rate facemask wearability in terms of parameters, such as perceived comfort, hotness, breathability and fit. At the end of the trial, the children compared and identified their preferred facemask. The main complaint about the facemasks was the children's faces being too hot. The ReSpimask was most frequently reported as being perceived to be the hardest to breathe through. The TuHao facemask was the only adjustable strap mask assessed but was reported to be difficult to adjust. Facemasks with a nose clip were frequently rated highest for fit (TuHao and Vogmask). The patterned, cloth fabric Vogmask had significantly higher ratings for appearance and perceived fit. The results show children's perceptions of facemasks are highly affected by the facemask's design, hotness and perceived breathability. By making children's facemasks more appealing, breathable, cooler and improving their fit, wearability may be improved.

Proof-of-Concept Study to Assess the Nociceptin Receptor Antagonist LY2940094 as a New Treatment for Alcohol Dependence.

BACKGROUND: This was a proof-of-concept study to evaluate the efficacy of LY2940094, a nociceptin/orphanin FQ peptide receptor antagonist, in reducing alcohol consumption in actively alcohol-drinking patients with alcohol dependence. METHODS: Eighty-eight patients, 21 to 66 years of age, diagnosed with alcohol dependence, reporting 3 to 6 heavy drinking days per week, were randomized (1:1) to 8 weeks of treatment with once-daily oral placebo (N = 44) or 40 mg/d of LY2940094 (N = 44). The primary efficacy analysis was the change from baseline in number of drinks per day (NDD) utilizing mixed-model repeated measures comparing LY2940094 and placebo in Month 2 of the 8-week double-blind treatment period. The probability that the difference relative to placebo in NDD was ≤0 at endpoint was calculated, and a probability ≥80% was considered to be evidence that LY2940094 was associated with the reduction in NDD. RESULTS: After 8 weeks of treatment, reduction in mean NDD did not differ between LY2940094 versus placebo (-1.4 vs. -1.5, respectively, 44% probability of greater reduction relative to placebo), but there was a greater reduction in the mean percentage of heavy drinking days in a month with LY2940094 versus placebo (-24.5 vs. -15.7%, respectively, 93% probability of a greater reduction relative to placebo), and an increase in the mean percentage of abstinent days in a month compared to placebo (9.1 vs. 1.9%, respectively, 91% probability of a greater increase relative to placebo). Patients who were treated with LY2940094 showed decreased plasma levels of gamma-glutamyl transferase with probabilities ≥98% for greater reduction compared with placebo at Weeks 1, 4, 6, and 8. Treatment-emergent adverse events in ≥5% of patients treated with LY2940094 included insomnia, vomiting, and anxiety. There were no serious adverse events or significant changes in laboratory assessments or vital signs with LY2940094. CONCLUSIONS: Although not reducing the NDD, LY2940094, compared to placebo, did reduce heavy drinking days and increased abstinence days in patients with alcohol dependence.

A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies.

Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) receptor, which is a G protein-coupled receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double-blind, placebo-controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID-Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of LY2940094 being better than placebo⩾88%) was not met (82.9%). LY2940094 also had an early effect on the processing of emotional stimuli at Week 1 as shown by an increased recognition of positive relative to negative facial expressions in an emotional test battery. LY2940094 was safe and well tolerated. Overall, these are the first human data providing evidence that the blockade of NOP receptor signaling represents a promising strategy for the treatment of MDD.

Erratum: A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies.

[This corrects the article DOI: 10.1038/npp.2015.348.].

Efficient assessment of efficacy in post-traumatic peripheral neuropathic pain patients: pregabalin in a randomized, placebo-controlled, crossover study.

BACKGROUND: Detecting the efficacy of novel analgesic agents in neuropathic pain is challenging. There is a critical need for study designs with the desirable characteristics of assay sensitivity, low placebo response, reliable pain recordings, low cost, short duration of exposure to test drug and placebo, and relevant and recruitable population. METHODS: We designed a proof-of-concept, double-blind, randomized, placebo-controlled, crossover study in patients with post-traumatic peripheral neuropathic pain (PTNP) to evaluate whether such a study design had the potential to detect efficacious agents. Pregabalin, known to be efficacious in neuropathic pain, was used as the active analgesic. We also assessed physical activity throughout the study. RESULTS: Twenty-five adults (20-70 years of age) with PTNP for ≥3 months entered a screening week and were then randomized to one of the two following treatment sequences: (1) pregabalin followed by placebo or (2) placebo followed by pregabalin. These 2-week treatment periods were separated by a 2-week washout period. Patients on pregabalin treatment received escalating doses to a final dosage of 300 mg/day (days 5-15). In an attempt to minimize placebo response, patients received placebo treatment during the screening week and the 2-week washout period. Average daily pain scores (primary endpoint) were significantly reduced for pregabalin versus placebo, with a mean treatment difference of -0.81 (95% confidence interval: -1.45 to -0.17; P = 0.015). CONCLUSION: The efficacy of pregabalin was similar to that identified in a large, parallel group trial in PTNP. Therefore, this efficient crossover study design has potential utility for future proof-of-concept studies in neuropathic pain.

An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee.

The effect of PF-04457845, a potent and selective fatty acid amide hydrolase-1 (FAAH1) inhibitor, on pain due to osteoarthritis of the knee was investigated in a randomised placebo and active-controlled clinical trial. The trial involved 2 periods (separated by a 2-week washout) consisting of a 1-week wash-in phase followed by 2weeks double-blind treatment. Patients received single-blind placebo throughout the wash-in and washout periods. Patients were randomised to receive either 4mg q.d. PF-04457845 followed by placebo (or vice versa), or 500mg b.i.d. naproxen followed by placebo (or vice versa). The primary end point was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. The trial had predefined decision rules based on likelihood that PF-04457845 was better or worse than the standard of care (considered to be a 1.8 reduction in WOMAC pain score compared to placebo). A total of 74 patients were randomised to 1 of 4 treatment sequences. The mean differences (80% confidence intervals) from placebo in WOMAC pain score were 0.04 (-0.63 to 0.71) for PF-04457845 and -1.13 (-1.79 to -0.47) for naproxen, indicating that whilst naproxen seemed efficacious, PF-04457845 was not differentiated from placebo. The study was stopped at the interim analysis for futility. PF-04457845 decreased FAAH activity by >96% and substantially increased 4 endogenous substrates (fatty acid amides). PF-04457845 was well tolerated in osteoarthritis patients, and there was no evidence of cannabinoid-type adverse events. The lack of analgesic effect of FAAH1 inhibition in humans is in contrast to data from animal models. This apparent disconnect between species needs further study.

A translational study of the effects of ketamine and pregabalin on temporal summation of experimental pain.

BACKGROUND AND OBJECTIVES: Central sensitization is often seen in chronic pain. A relevant and potent mechanism of central sensitization is the central integration of nociceptive impulses. Temporal summation in humans and the wind-up process in animals share common features of central integration. This preclinical and clinical translational study investigated the effect of ketamine and pregabalin on temporal summation (TS) and wind-up of wide dynamic range (WDR) neurons of nociceptive electrical stimuli in healthy volunteers and rats. METHODS: This 3-way crossover study included healthy male volunteers (n = 18) receiving 3 doses of 300 mg pregabalin (orally) over 2 days, ketamine (intravenous loading dose 0.5 mg/kg followed by 9 µg/kg per minute for 20 mins) on the first day, or placebo. The pain detection thresholds to repetitive electrical cutaneous and suprathreshold responses stimulation were assessed.In male Sprague-Dawley rats (n = 30), WDR neuron recordings after electrical stimulation were obtained before and after 15 minutes of intravenous infusion pregabalin (0.127, 0.42, and 1.27 mg/kg per minute) and ketamine (0.006, 0.02, 0.06, and 0.2 mg/kg per minute). RESULTS: In the human study, ketamine compared with placebo significantly increased the TS pain detection threshold (P < 0.001) and significantly reduced suprathreshold pain responses (P < 0.001). In rats, the highest dose of ketamine significantly inhibited the wind-up response of the WDR neurons (P = 0.014). Pregabalin affected neither of the parameters in TS and WDR responses. CONCLUSIONS: It was shown that TS shares common features with wind-up of WDR neurons and that pregabalin does not affect this component of central sensitization.

Regions of interest analysis in pharmacological fMRI: how do the definition criteria influence the inferred result?

Prior hypotheses in functional brain imaging are often formulated by constraining the data analysis to regions of interest (ROIs). In this context, this approach yields higher sensitivity than whole brain analyses, which could be particularly important in drug development studies and clinical decision making. Here we systematically examine the effects of different ROI definition criteria on the results inferred from a hypothesis-driven pharmacological fMRI experiment, with the aim of maximising sensitivity and providing a recommended procedure for similar studies. In order to achieve this, we compared different criteria for selecting both anatomical and functional ROIs. Anatomical ROIs were defined (i) specifically for each subject, (ii) at group level, and (iii) using a Talairach-like atlas, in order to assess the effects of inter-subject anatomical variability. Functional ROIs (fROIs) were defined, both for each subject and at group level, by (i) selecting the voxels with the highest Z-score from each study session, and (ii) selecting an inclusive union of significantly active voxels across all sessions. A single value was used to summarise the response within each ROI. For anatomical ROIs we used the mean of the parameter estimates (beta values) of either all voxels or the top 20% active voxels. For fROIs we used the mean beta value of all voxels constituting the ROI. The results were assessed in terms of the achieved sensitivity in detecting the experimental effect. The use of single-subject anatomical ROIs combined with a summary value calculated from the top 20% fraction of active voxels was the most reliable and sensitive approach for detecting the experimental effect. The use of fROIs from individual sessions introduced unacceptable biases in the results, while the use of union fROIs yielded a lower sensitivity than anatomical ROIs. For these reasons, fROIs should be employed with caution when it is not possible to make clear anatomical prior hypotheses.

Effects of gabapentin on experimental somatic pain and temporal summation.

BACKGROUND AND OBJECTIVES: Gabapentin is used for treatment of neuropathic pain, but its effect on different somatic pain modalities and integrative mechanisms are not completely understood. The aim of this double-blind, placebo-controlled experimental pain study, conducted on 20 healthy volunteers, was to examine the effect of a single dose of 1200 mg gabapentin on multi-modal experimental cutaneous and muscle pain models. METHODS: The following pain models were applied: (1) pain thresholds to single and repeated cutaneous and intramuscular electrical stimulation (temporal summation to 5 stimuli delivered at 2 Hz); (2) stimulus-response function relating pain intensity scores (visual analog scale, VAS) to increasing current intensities for electrical skin and muscle stimuli (single and repeated, determined at baseline); and (3) the pain intensity (VAS) and pain areas after intramuscular injection of hypertonic saline. Pain assessments were performed prior to, and at 4, 6, and 8 hours after medication. RESULTS: When responses were averaged across the post-dose times, gabapentin: (1) significantly increased the temporal summation pain threshold in skin compared with placebo (P = .03); (2) significantly reduced the area under the pain intensity curve to hypertonic saline injections in the muscle (P = .02); and (3) significantly reduced the area of pain evoked by hypertonic saline (P = .03). CONCLUSIONS: Gabapentin reduces temporal summation of skin stimuli at pain threshold intensities; this may have potential as a biomarker for drugs with efficacy on neurogenic pain. The data also suggest that tonic muscle pain is responsive to gabapentin treatment and suggest further clinical studies.

Intra- and interstudy reproducibility of coronary artery diameter measurements in magnetic resonance coronary angiography.

PURPOSE: To determine the intra- and interstudy reproducibility of right coronary artery diameter assessment using serial magnetic resonance (MR) coronary angiography. MATERIALS AND METHODS: Two-dimensional (2D) navigator-gated segmented fast low angle shot (FLASH) images of the proximal right coronary artery were acquired three times in 11 healthy volunteers, the first two times in the same study session and the third time after repositioning the subject in the scanner. Coronary artery diameters were determined using automated segmentation software and intra- and interstudy reproducibility calculated as the standard deviation (SD) of the signed differences between measurements within and between study sessions, respectively. The reproducibility of the segmentation software was determined by repeated analysis of each individual scan. RESULTS: One subject was excluded from the study due to poor-quality images. In the remaining 10 subjects, the mean (+/- SD) intrastudy difference in coronary artery diameters was -0.05 +/- 0.12 mm, a value that is very similar to between-frame (same-film) differences reported in quantitative coronary angiography (QCA). The mean (+/- SD) interstudy difference in coronary artery diameters was 0.16 +/- 0.43 mm, although this was greatly skewed by one subject with poor image plane repositioning. Excluding that subject resulted in a mean (+/- SD) interstudy difference of 0.04 +/- 0.20 mm. The reproducibility of the segmentation software was excellent, with the mean difference between repeat analyses of the images being 0.00 +/- 0.03 mm. CONCLUSION: The intrastudy variability of coronary artery diameter measurements is low, potentially allowing MR coronary angiography to be used as a tool for the noninvasive assessment of serial changes following pharmacological intervention. A major contributing factor to this is the high reproducibility of the segmentation software. Interstudy variability is approximately three times the intrastudy variability.