Glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of hypersalivation induced by clozapine (GOTHIC1): a feasibility study

Background: Clozapine-induced hypersalivation (CIH) is a common side effect of clozapine treatment and is disliked by clozapine patients, potentially threatening adherence to clozapine treatment. We proposed a trial of alternative medications, hyoscine and glycopyrrolate, for the treatment of CIH and the primary objective of the feasibility study was to assess the recruitment and retention of community clozapine patients as well as assess the metrics of the primary hypersalivation measure. Methods: This 11-month trial took place in two NHS trusts in northwest UK. Participants were community-dwelling clozapine patients aged 18-65 years who were suffering from CIH, and were recruited from community mental health clinics. They were randomised using a telephone randomisation service to receive either hyoscine (1 week at 0.6mg daily, 3 weeks at 0.9mg daily), glycopyrrolate (1 week at 2mg daily, 3 weeks at 3mg daily) or placebo. Participants and investigators were blinded to which study arm the participants had been randomised to. We collected data on salivation levels and side effects on a weekly basis and also assessed cognition at the beginning and end of the trial. We also interviewed a sample of participants after the trial to gather information on their experience of having taken part. Results: 138 potential participants agreed to being contacted by researchers about participation in the trial and of these, 29 participants were randomised. Of these, four participants exited the trial before taking any trial medication, and two participants left the study owing to concerns of side effects. Data from four participants was missing, and complete data was available for 19 participants who competed the trial. The mean recruitment rate overall was 1.3 participants per site per month, and the overall retention rate was 76%. Interview data suggested that participants’ experiences of trial participation was overwhelmingly positive. Conclusions: The feasibility study demonstrated that a trial of alternative medications in the treatment of CIH is feasible; patients were willing to be randomised to the trial and retention rate was high. Trial registration: ClinicalTrials.gov NCT02613494, registered 24 November 2015. https://clinicaltrials.gov/ct2/show/NCT0261349

Better sexual acceptability of agomelatine (25 and 50 mg) compared to escitalopram (20 mg) in healthy volunteers. A 9-week, placebo-controlled study using the PRSexDQ scale

The present double-blind, placebo-controlled study evaluates the effects of agomelatine and the selective serotonin reuptake inhibitor escitalopram on sexual dysfunction in healthy men and women

Tryptophan depletion disinhibits punishment but not reward prediction: implications for resilience

Item does not contain fulltextRATIONALE: We have previously shown that tryptophan depletion enhances punishment but not reward prediction (Cools et al. in Neuropsychopharmacology 33:2291-2299, 2008b). This provided evidence for a valence-specific role of serotonin (which declines under depleted tryptophan) in aversive processing. Recent theoretical (Dayan and Huys in PLoS Comput Biol 4:e4, 2008) and experimental (Crockett et al. in J Neurosci 29:11993-11999, 2009) approaches have, however, further specified this role by showing that serotonin is critical for punishment-induced inhibition. OBJECTIVES: We sought to examine the role of serotonin in punishment-induced inhibition. We also examined the impact of induced mood on this effect to assess whether effects of tryptophan depletion on affective inhibition are moderated by mood. METHODS: Healthy females consumed a balanced amino acid mixture with (N = 20) or without (N = 21) the serotonin precursor tryptophan. Each subject completed either negative or neutral mood induction. All subjects completed the reward and punishment reversal learning task adopted in the previous study. RESULTS: We demonstrate a punishment prediction impairment in individuals who consumed tryptophan which was absent in individuals who were depleted of tryptophan. This effect was impervious to mood state. CONCLUSIONS: Our results suggest that serotonin promotes the inhibition of responses to punishing outcomes. This may lead to reduced punishment prediction accuracy in the presence of tryptophan and may contribute to resilience to affective disorders. Reduction of serotonin via tryptophan depletion then removes this inhibition. As such, we highlight a mechanism by which reduced serotonin can contribute to disorders of impulsivity and compulsivity as well as disorders of emotion.1 januari 201

Advancing the defensive explanation for anxiety disorders: lorazepam effects on human defense are systematically modulated by personality and threat-type

Clinically effective drugs against human anxiety and fear systematically alter the innate defensive behavior of rodents, suggesting that in humans these emotions reflect defensive adaptations. Compelling experimental human evidence for this theory is yet to be obtained. We report the clearest test to date by investigating the effects of 1 and 2mg of the anti-anxiety drug lorazepam on the intensity of threat-avoidance behavior in 40 healthy adult volunteers (20 females). We found lorazepam modulated the intensity of participants’ threat-avoidance behavior in a dose-dependent manner. However, the pattern of effects depended upon two factors: type of threat-avoidance behavior and theoretically relevant measures of personality. In the case of flight behavior (one-way active avoidance), lorazepam increased intensity in low scorers on the Fear Survey Schedule tissuedamage fear but reduced it in high scorers. Conversely, in the case of risk-assessment behavior (two-way active avoidance), lorazepam reduced intensity in low scorers on the Spielberger trait anxiety but increased it in high scorers. Anti-anxiety drugs do not systematically affect rodent flight behavior; therefore, we interpret this new finding as suggesting that lorazepam has a broader effect on defense in humans than in rodents, perhaps by modulating general perceptions of threat intensity. The different patterning of lorazepam effects on the two behaviors implies that human perceptions of threat intensity are nevertheless distributed across two different neural streams, which influence effects observed on one-way or two-way active avoidance demanded by the situation

Effects of naltrexone are influenced by childhood adversity during negative emotional processing in addiction recovery

Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependence alone ($\textit{n}$=18, alcohol) and in combination with cocaine and/or opioid dependence ($\textit{n}$=21, alcohol/drugs) and healthy individuals without a history of alcohol or drug dependence ($\textit{n}$=21) were recruited. Participants were alcohol and drug abstinent before entered into this double-blind, placebo-controlled, randomized, crossover study. Functional magnetic resonance imaging was used to investigate brain response while viewing aversive and neutral images relative to baseline on 50 mg of naltrexone and placebo. We found that naltrexone modulated task-related activation in the medial prefrontal cortex and functional connectivity between the anterior cingulate cortex and the hippocampus as a function of childhood adversity (for aversive versus neutral images) in all groups. Furthermore, there was a group-by-treatment-by-condition interaction in the right amygdala, which was mainly driven by a normalization of response for aversive relative to neutral images under naltrexone in the alcohol/drugs group. We conclude that early childhood adversity is one environmental factor that influences pharmacological response to naltrexone. Pharmacotherapy with naltrexone may also have some ameliorative effects on negative emotional processing in combined alcohol and drug dependence, possibly due to alterations in endogenous opioid transmission or the kappa-opioid receptor antagonist actions of naltrexone.The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: this article presents independent research funded by the MRC as part of their addiction initiative (Grant Number G1000018). George Savulich was funded by a grant from the Wallitt Foundation