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RationalePatients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function.ObjectiveIn this study we investigate potential dopaminergic dysfunction during reward processing in the context of OCD.MethodsWe studied OCD patients (n=18) and controls (n=18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of: a dopamine receptor agonist, pramipexole 0.5mg; a dopamine receptor antagonist, amisulpride 400mg, and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest.ResultsThere were no significant group, drug or interaction effects in number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p=0.089, partial ⍰2=0.1). In the imaging results, there was a significant interaction of group by drug (p=0.013, partial ⍰2=0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p=0.014, partial ⍰2=0.26, 1-β error probability=0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD.ConclusionsOur data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.

This is the first study to compare the relative systemic metabolomic and lipidomic bioactivity dose-responses for ICS. Plasma for metabolomic and lipidomic analysis was obtained from 54 subjects (GSK study 203162, NCT02991859) who received weekly escalating doses (µg/d) of FF (25,100, 200, 400, 800), FP (50, 200, 500,1000, 2000), BUD (100, 400, 800,1600, 3200) or placebo. Samples (pre & post-dose) were analysed on LC/MS/MS and polar LC-platforms and ions were matched to a library of standards for identification and quantification. Statistical analysis was by repeated measures ANOVA, cross-over model, random forest and principal component analysis using log-transformed data. Across all ICS and doses, few quantifiable metabolites (n=1971) had significant mean % changes[increases/decreases] (p 1.32 [0.41/0.91], FP 1.93 [0.41/1.52] and BUD 2.03 [0.61/1.47]. At therapeutic doses, fewer changes were also seen with FF 0.96 [0.36/0.61] versus FP 1.67 [0.46/1.22] and BUD 1.42 [0.56/0.91]. Qualitatively, dose related changes were similar including: reduced adrenal steroids (cortisone, cortisol, pregnenolone, androgens and metabolites), increased plasma amino acids, increased glycolysis, reduced fatty acid β-oxidation and branched chain amino acids. Qualitative differences included: altered secondary bile acid profiles for BUD and FF indicating changes in gut microbiome, significantly lowered neurotransmitters (dopamine metabolites) for BUD. Our findings support the safety of low/mid ICS therapeutic doses with FF 100 µg/d having least effect on most susceptible pathways involving adrenal steroid metabolites. There were few qualitative differences of note except BUD induced neurotransmitter changes.

Aims To compare the airway potency, systemic activity and therapeutic index of three inhaled corticosteroids that differ in glucocorticoid receptor binding affinity, physicochemical and pharmacokinetic properties. Methods This escalating-dose, placebo-controlled, cross-over study randomised adults with asthma to 1 or 2 treatment periods with ≥25 days washout in-between. Each treatment period comprised five 7-day dose escalations (μg/d): fluticasone furoate (FF; 25 → 100 → 200 → 400 → 800), fluticasone propionate (FP; 50 → 200 → 500 → 1000 → 2000), budesonide (BUD; 100 → 400 → 800 → 1600 → 3200) or placebo. Airway hyperresponsiveness to adenosine-5'-monophosphate (AMP PC20 ) was assessed on day 8. Plasma cortisol was assessed on day 1 (predose baseline) and from pre-PM dose on day 6 to pre-PM dose day 7 (24-h weighted mean). Results Fifty-four subjects were randomised. FF showed greater airway potency than FP and BUD (AMP PC20 dose at which 50% of the maximum effect is achieved [ED50 ] values: 48.52, 1081.27 and 1467.36 μg/d, respectively). Systemic activity (cortisol suppression) ED50 values were 899.99, 1986.05 and 1927.42 μg/d, respectively. The therapeutic index (ED50 cortisol suppression/ED50 AMP PC20 ) was wider for FF (18.55) than FP (1.84) and BUD (1.31). FF 100 μg/d and 200 μg/d were both comparable in terms of airway potency with high doses of FP (≥1000 μg twice daily [BID]) and BUD (≥1500 μg/BID). The systemic activity of FF 100 μg/d and 200 μg/d (cortisol suppression: 7.41% and 14.28%, respectively) was comparable with low doses of FP (100 μg/BID and 250 μg/BID) and BUD (100 μg/BID and 200 μg/BID). Conclusion This study provides evidence that FF can provide more protection against airway hyperresponsiveness, with less systemic activity, than FP or BUD. This suggests that all inhaled corticosteroids are not therapeutically similar and may differ in their therapeutic index. (203162; NCT02991859).

FF is an inhaled corticosteroid (ICS) with higher glucocorticoid receptor affinity, tissue permeability and lung retention than other ICS. We investigated whether these attributes improve the therapeutic index (TI), defined as systemic activity to topical efficacy ratio. In this escalating dose, randomised, incomplete-block, 2-period cross-over study (GSK study 203162, NCT02991859), 54 asthmatic subjects were randomised to one or two of four treatment periods. Each period comprised five dose escalations (µg/d) of 7-days duration: FF (25,100,200,400,800), FP (50, 200,500,1000,2000), BUD (100,400,800,1600,3200) or placebo, with a ≥25-day washout between periods. At the end of each escalation, 12h post-dose adenosine-5’-monophosphate (AMP) challenge PC20 and 24h plasma cortisol were assessed. Both endpoints showed a dose response (Figure 1). The ED50 µg/d (95% CI) values were: 49 (18,129), 1081 (448,2610), and 1467 (547,3940) for AMP PC20 and 900 (698,1102), 1986 (1575,2397) and 1927 (1699,2156) for 24h plasma cortisol and TI values (ED50 24h cortisol/ED50 AMP PC20) were 18.6, 1.84 and 1.31 for FF, FP and BUD respectively. No on treatment SAEs were reported. Within the approved dose ranges for asthma, FF gave more protection against airway hyperresponsiveness with less systemic activity compared to FP and BUD.

Introduction FF est un corticosteroide inhale (CSI) avec une affinite, une permeabilite tissulaire et une retention pulmonaire plus grande que les autres CSI. Nous avons cherche a savoir si ces proprietes ameliorent l’index therapeutique (IT), defini comme le rapport entre l’efficacite topique et l’activite systemique. Methodes Dans cette etude a doses croissantes, randomisee, a bloc incomplet, en cross-over sur 2 periodes (etude GSK 203162, NCT02991859 ), 54 sujets asthmatiques ont ete randomises pour une ou deux des quatre periodes de traitement. Chaque periode comprenait 5 augmentations de dose (μg/j) d’une duree de 7 jours : FF (25,100, 200, 400, 800), FP (50, 200, 500,1000, 2000), BUD (100, 400, 800,1600, 3200) ou un placebo, avec un wash-out ≥ 25 jours entre les periodes. A la fin de chaque augmentation, le test PC20 a l’AMP a 12 h et le cortisol plasmatique sur 24 heures ont ete evalues ( Fig. 1 ). Resultats Les valeurs d’ED50 μg/j (IC 95 %) etaient : 49 (18,129), 1081 (448,2610) et 1467 (547,3940) pour AMP PC20 et 900 (698,1102), 1986 (1575,2397) et 1927 (1699,2156) pour le cortisol plasmatique de 24 h. Les valeurs d’IT (ED50 24 h cortisol/ED50 AMP PC20) etaient 18,6 ; 1,84 et 1,31 pour FF, PF et BUD respectivement. Pas d’EIG sous traitement reporte. Conclusion FF a demontre plus de protection contre l’hyperreactivite des voies aeriennes avec moins d’activite systemique que PF ou BUD pour des dosages approuves dans l’asthme.

Objective This double-blind, randomised, placebo-controlled, two-part study assessed the impact of GSK2981710, a medium-chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults. Methods Part 1 was a four-period dose-selection study (n = 8 complete). Part 2 was a two-period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory-related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study. Results The most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma β-hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory-related neuronal activity were observed. Conclusion Over a duration of 14 days, increasing plasma BHB levels with daily administration of GSK2981710 had no effects on neuronal activity or cognitive function. This result indicates that modulating plasma ketone levels with GSK2981710 may be ineffective in improving cognitive function in healthy older adults, or the lack of observed effect could be related to several factors including study population, plasma BHB concentrations, MCT composition, or treatment duration.

BackgroundPsychotic disorders are highly heritable such that the unaffected relatives of patients may manifest characteristics, or endophenotypes, that are more closely related to risk genes than the overt clinical condition. Facial affect processing is dependent on a distributed cortico-limbic network that is disrupted in psychosis. This study assessed facial affect processing and related brain structure as a candidate endophenotype of first-episode psychosis (FEP).MethodThree samples comprising 30 FEP patients, 30 of their first-degree relatives and 31 unrelated healthy controls underwent assessment of facial affect processing and structural magnetic resonance imaging (sMRI) data. Multivariate analysis (partial least squares, PLS) was used to identify a grey matter (GM) system in which anatomical variation was associated with variation in facial affect processing speed.ResultsThe groups did not differ in their accuracy of facial affect intensity rating but differed significantly in speed of response, with controls responding faster than relatives, who responded faster than patients. Within the control group, variation in speed of affect processing was significantly associated with variation of GM density in amygdala, lateral temporal cortex, frontal cortex and cerebellum. However, this association between cortico-limbic GM density and speed of facial affect processing was absent in patients and their relatives.ConclusionsSpeed of facial affect processing presents as a candidate endophenotype of FEP. The normal association between speed of facial affect processing and cortico-limbic GM variation was disrupted in FEP patients and their relatives.

There are reasons for thinking that obsessive-compulsive disorder (OCD) and drug dependence, although conventionally distinct diagnostic categories, might share important cognitive and neurobiological substrates. We tested this hypothesis directly by comparing brain functional connectivity measures between patients with OCD, stimulant dependent individuals (SDIs; many of whom were non-dependent users of other recreational drugs) and healthy volunteers. We measured functional connectivity between each possible pair of 506 brain regional functional MRI time series representing low frequency (0.03-0.06 Hz) spontaneous brain hemodynamics in healthy volunteers (N=18), patients with OCD (N=18) and SDIs (N=18). We used permutation tests to identify i) brain regions where strength of connectivity was significantly different in both patient groups compared to healthy volunteers; and ii) brain regions and connections which had significantly different functional connectivity between patient groups. We found that functional connectivity of right inferior and superior orbitofrontal cortex (OFC) was abnormally reduced in both disorders. Whether diagnosed as OCD or SDI, patients with higher scores on measures of compulsive symptom severity showed greater reductions of right orbitofrontal connectivity. Functional connections specifically between OFC and dorsal medial pre-motor and cingulate cortex were attenuated in both patient groups. However, patients with OCD demonstrated more severe and extensive reductions of functional connectivity compared to SDIs. OCD and stimulant dependence are not identical at the level of brain functional systems but they have some important abnormalities in common compared with healthy volunteers. Orbitofrontal connectivity may serve as a human brain systems biomarker for compulsivity across diagnostic categories.

Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.

Background Compulsivity is a hallmark of drug addiction and in animal models is measured by consecutive incorrect responses to a previously rewarded stimulus during reversal learning. The aim of this study was to measure behavioral and neural markers of compulsivity in stimulant-dependent individuals and to test whether these markers could be modulated by treatment with drugs targeting the dopamine system. Methods In a randomized, double-blind, placebo-controlled, crossover design, stimulant-dependent individuals (SDIs; n = 18) and healthy volunteers ( n = 18) received single doses of dopamine D 2/3 receptor antagonist (amisulpride, 400 mg) and agonist (pramipexole, 0.5 mg) drugs. To examine compulsivity and its dopaminergic modulation more generally, patients with obsessive-compulsive disorder (OCD; n = 18) were also included in the study. Results SDIs made significantly more perseverative responses to the previously correct stimulus immediately following reversal, compared with both healthy volunteers and patients with OCD. Across all participants, the number of perseverative errors was negatively correlated with functional activation in right fronto-striato-parietal networks—in particular, the right caudate nucleus. In SDIs, perseveration-related caudate activation was abnormally reduced in the placebo condition, but the dopamine D 2/3 agonist pramipexole normalized both perseverative responding and related activation of the right caudate. Conclusions Perseveration during reversal learning was associated specifically with stimulant dependence rather than with compulsive behaviors more generally. The beneficial effects of a dopamine agonist drug challenge on both behavior and associated brain activation in SDIs may indicate new avenues for pharmacologic treatment in stimulant dependence.

Context There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges. Objective To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D 2 /D 3 receptor antagonist and agonist challenges. Design Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging. Setting Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England. Participants S timulant-dependent individuals (n = 18) and healthy volunteers (n = 18). Interventions Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions. Main Outcome Measures Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire. Results Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups. Conclusions Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation by dopaminergic challenges.

GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), which was in development as a potential treatment for Alzheimer’s disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, [18F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study. [18F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [18F]trifluoromethylation methodology. Healthy male subjects (n = 4, age range 34–42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of [18F]GSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 μg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (VT). Secondary PK and safety endpoints were also recorded. PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of [18F]GSK2647544 across all the ROIs examined. The mean whole brain VT was 0.56 (95 % CI, 0.41–0.72). Secondary PK parameters, Cmax (geometric mean) and Tmax (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20–40 % of the parent compound [18F]GSK2647544 present after 120 min. The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA2 activity. Clintrials.gov: NCT01924858.