131 results found
Wilson S, Anderson K, Baldwin D, et al., 2019, British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders: An update, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 33, Pages: 923-947, ISSN: 0269-8811
Lingford-Hughes A, Durant C, Paterson L, et al., 2018, Using baclofen to explore GABA-B receptor function in alcohol dependence: insights from pharmacokinetic and pharmacodynamic measures, Frontiers in Psychiatry, Vol: 9, ISSN: 1664-0640
Background: The role of GABA-B neurotransmission in addiction has recently received increased attention, with clinical trials indicating that baclofen, a GABA-B receptor agonist, may reduce alcohol consumption, craving and promote abstinence. However, the optimal dose to treat alcohol dependence is unclear with patients requesting and tolerating much higher doses of baclofen, compared with other clinical uses. We assessed the pharmacokinetics and pharmacodynamics (PK/PD) of baclofen to provide insight into GABA-B sensitivity in this patient group, relative to controls.Methods: Male healthy volunteers (controls, n = 12) and abstinent alcohol dependent individuals (AD, n = 8) received single oral doses of baclofen or placebo in a 3-way crossover design. Controls received placebo/10 mg/60 mg baclofen in a randomized, double-blind design, AD received placebo/60 mg/90 mg baclofen in a single-blind design. PK/PD measures were recorded at baseline and multiple time-points up to 6 h post-dosing, including plasma baclofen, plasma growth hormone (GH), Subjective High Assessment Scale (SHAS) and biphasic alcohol effects scale (BAES). Repeated measures ANOVA analysis explored “change from baseline” dose, time, group, and interaction effects, t-tests compared peak effects.Results: Dose-dependent effects of baclofen on PK and PD measures were observed in both control and AD groups. Whilst there were no significant group differences in any baclofen PK parameters (t1/2, tmax, Cmax, AUC), marked differences in PD effects were clearly evident. In controls, 60 mg baclofen significantly increased total SHAS and BAES scores, and significantly increased plasma GH levels compared with placebo, with peak effects at 60–120 min, in line with its PK profile. In AD, 60 mg baclofen had limited effects on these parameters; SHAS scores, BAES scores and plasma GH levels were significantly blunted compared with controls (significant group*time interactions P = 0.0014, 0.0015 and P
Nutt D, Stahl S, Blier P, et al., 2016, Inverse agonists - what do they mean for psychiatry?, European Neuropsychopharmacology, Vol: 27, Pages: 87-90, ISSN: 1873-7862
The nomenclature of drugs is a critical aspect of science, since it can direct research and optimize treatment choices. Traditionally drugs acting on CNS receptors have been classified as either agonists or antagonists. Recently a new class of ligand, the inverse agonist, has been identified in some receptor systems. Inverse agonists have opposite actions to those of agonists but the effects of both of these can be blocked by antagonists. Pimavanserin is a new 5-HT2A receptor acting drug that has been given market authorization for psychosis in Parkinson׳s disease. The FDA have termed it an inverse agonist, but this conclusion is based on in-vitro data. In this paper we discuss the evidence for such a claim being made for pimavanserin in the human brain and conclude that this is not currently sufficient. It is therefore premature to conclude that the actions of pimavanserin in humans are due to inverse agonism, and we are of the opinion that it should be called a 5-HT2A antagonist until better evidence emerges.
Magazzini L, Muthukumaraswamy SD, Campbell AE, et al., 2016, Significant reductions in human visual gamma frequency by the gaba reuptake inhibitor tiagabine revealed by robust peak frequency estimation, Human Brain Mapping, Vol: 37, Pages: 3882-3896, ISSN: 1097-0193
The frequency of visual gamma oscillations is determined by both the neuronal excitation-inhibition balance and the time constants of GABAergic processes. The gamma peak frequency has been linked to sensory processing, cognitive function, cortical structure, and may have a genetic contribution. To disentangle the intricate relationship among these factors, accurate and reliable estimates of peak frequency are required. Here, a bootstrapping approach that provides estimates of peak frequency reliability, thereby increasing the robustness of the inferences made on this parameter was developed. The method using both simulated data and real data from two previous pharmacological MEG studies of visual gamma with alcohol and tiagabine was validated. In particular, the study by Muthukumaraswamy et al.  (Neuropsychopharmacology 38(6):1105-1112), in which GABAergic enhancement by tiagabine had previously demonstrated a null effect on visual gamma oscillations, contrasting with strong evidence from both animal models and very recent human studies was re-evaluated. After improved peak frequency estimation and additional exclusion of unreliably measured data, it was found that the GABA reuptake inhibitor tiagabine did produce, as predicted, a marked decrease in visual gamma oscillation frequency. This result demonstrates the potential impact of objective approaches to data quality control, and provides additional translational evidence for the mechanisms of GABAergic transmission generating gamma oscillations in humans. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
Harrison L, Wilson S, Munafo MR, 2016, Pain-related and Psychological Symptoms in Adolescents With Musculoskeletal and Sleep Problems, CLINICAL JOURNAL OF PAIN, Vol: 32, Pages: 246-253, ISSN: 0749-8047
Nahar LK, Cordero R, Nutt D, et al., 2016, Validated method for the quantification of baclofen in human plasma using solid-phase extraction and liquid chromatography–tandem mass spectrometry, Journal of Analytical Toxicology, Vol: 40, Pages: 117-123, ISSN: 0146-4760
A highly sensitive and fully validated method was developed for the quantification of baclofen in human plasma. After adjusting the pH of the plasma samples using a phosphate buffer solution (pH 4), baclofen was purified using mixed mode (C8/cation exchange) solid-phase extraction (SPE) cartridges. Endogenous water-soluble compounds and lipids were removed from the cartridges before the samples were eluted and concentrated. The samples were analyzed using triple-quadrupoleliquid chromatography–tandem mass spectrometry (LC–MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous quantification and confirmation. The assay was linear from 25 to 1,000 ng/mL (r2 > 0.999; n = 6). Intraday (n = 6) and interday (n = 15) imprecisions (% relative standard deviation) were <5%, and the average recovery was 30%. The limit of detection of the method was 5 ng/mL, and the limit of quantification was 25 ng/mL. Plasma samples from healthymale volunteers (n = 9, median age: 22) given two single oral doses of baclofen (10 and 60 mg) on nonconsecutive days were analyzed to demonstrate method applicability.
Harrison L, Wilson S, Heron J, et al., 2016, Exploring the associations shared by mood, pain-related attention and pain outcomes related to sleep disturbance in a chronic pain sample, Psychology & Health, Pages: 1-13, ISSN: 1476-8321
OBJECTIVE: Sleep disturbance in chronic pain is common, occurring in two-thirds of patients. There is a complex relationship between chronic pain and sleep; pain can disrupt sleep and poor sleep can exaggerate pain intensity. This may have an impact on both depressive symptoms and attention to pain. This study aims to evaluate the relationship between chronic pain and sleep, and the role of mood and attention. METHODS: Chronic pain patients, recruited from a secondary care outpatient clinic, completed self-report measures of pain, sleep, depressive symptoms and attention to pain. Hierarchical regression and structural equation modelling were used to explore the relationships between these measures. Participants (n = 221) were aged between 20 and 84 (mean = 52) years. RESULTS: The majority of participants were found to be 'poor sleepers' (86%) with increased pain severity, depressive symptoms and attention to pain. Both analytical approaches indicated that sleep disturbance is indirectly associated with increased pain severity Instead the relationship shared by sleep disturbance and pain severity was further associated with depressive symptoms and attention to pain. CONCLUSIONS: Our results indicate that sleep disturbance may contribute to clinical pain severity indirectly though changes in mood and attention. Prospective studies exploring lagged associations between these constructs could have critical information relevant to the treatment of chronic pain.
Wilson S, Hojer A-M, Buchberg J, et al., 2015, Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 1, a pharmacokinetic/pharmacodynamic comparison with paroxetine in healthy men, Journal of Psychopharmacology, Vol: 29, Pages: 1085-1091, ISSN: 1461-7285
We compared the effect of vortioxetine, paroxetine and placebo after three days of dosing on sleep architecture. This was a randomised, double-blind, four-way crossover, placebo-controlled, multiple-dose study in 24 healthy young men. Subjects received 20mg vortioxetine, 40mg vortioxetine, 20mg paroxetine or placebo for three consecutive days in four different periods with at least three weeks between them. Polysomnography and blood sampling for pharmacokinetic analysis were performed on the pre-dose night and nights 1 and 3 of dosing in each period. Plasma concentrations of vortioxetine and paroxetine during the polysomnography measurement were used to estimate SERT occupancies using published relationships in healthy subjects.All three active treatments significantly increased REM onset latency and decreased time spent in REM sleep. In the pharmacokinetic/pharmacodynamics analysis significant relationships were found between REM onset latency and time spent in REM sleep and vortioxetine/paroxetine exposure. The relation between REM suppression parameters and SERT occupancy was significantly different between vortioxetine and paroxetine, despite the same SERT occupancy. This indicates that vortioxetine has a different clinical pharmacological profile from paroxetine, which may explain the differences in adverse effect profile of the two drugs, for instance the lower incidence of nausea, weight gain and sexual dysfunction with vortioxetine.
Turton S, Durant C, Wilson S, et al., 2015, GABA-B receptor function in healthy volunteers, a pharmacokinetic and pharmacodynamic study of two doses of baclofen compared to placebo
AIMS AND HYPOTHESISTo assess the subjective and objective effects of baclofen on brain function in healthy volunteers. BACKGROUNDRecent evidence suggests baclofen, a γ-aminobutyric acid type B (GABA-B) receptor agonist, reduces alcohol consumption and craving and promotes abstinence in alcoholics. However, characterisation of the GABA-B receptor system in clinical addiction is limited, and it is unclear why some patients require, or tolerate, higher doses to treat alcoholism. This study assesses the effects of baclofen on brain function in healthy volunteers to inform future studies investigating the sensitivity of GABA-B receptors in alcohol addiction. METHODSEight healthy male volunteers completed a double blind randomised 3-way cross over study, receiving oral placebo (vitamin C 100mg), 10mg and 60mg baclofen. Subjective and objective measurements were taken at baseline (before medication) and at +30mins, 1, 2, 3, 4 and 6 hours after dosing. Objective measures included blood plasma samples, heart rate and blood pressure. Subjective measures included; the Subjective High Assessment Questionnaire (SHAS), visual analogue scales for sleepy, relaxed, tense and alert and a motor coordination task (zig-zag task). Pharmacokinetic data was obtained using liquid chromatography mass-spectrometry (LC-MS) to measure plasma baclofen concentrations.RESULTS60mg Baclofen showed changes in subjective measures peaking at 2 hours post dosing compared with placebo, including a significant increase (p<0.05) in total SHAS scores with individual items, including feeling ‘drunk or intoxicated’, effects of alcohol and ‘muddled or confused’ particular affected.. Systolic blood pressure was significantly increased (p<0.05) at the 2 hours post 60mg dose. For both 10mg and 60mg baclofen, peak plasma concentration was achieved 60 minutes post dose. Pharmacokinetic data will be presented. There were no significant changes in these measures between 10mg Baclof
Harrison L, Durant C, Wilson S, et al., 2015, The effects of sleep disruption on central pain modulation: A polysomnographic study in healthy volunteers, ECNP Workshop for Junior Scientists in Europe, Publisher: ELSEVIER SCIENCE BV, Pages: S89-S89, ISSN: 0924-977X
Nutt D, Wilson S, Lingford-Hughes A, et al., 2015, Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: A study in healthy volunteers, NEUROPHARMACOLOGY, Vol: 88, Pages: 155-163, ISSN: 0028-3908
Watson BJ, Taylor LG, Reid AG, et al., 2014, Investigating expectation and reward in human opioid addiction with [C-11]raclopride PET, ADDICTION BIOLOGY, Vol: 19, Pages: 1032-1040, ISSN: 1355-6215
Stokes PRA, Myers JF, Kalk NJ, et al., 2014, Acute increases in synaptic GABA detectable in the living human brain: A [C-11]Ro15-4513 PET study, NEUROIMAGE, Vol: 99, Pages: 158-165, ISSN: 1053-8119
Harrison L, Wilson S, Munafo MR, 2014, Exploring the associations between sleep problems and chronic musculoskeletal pain in adolescents: A prospective cohort study, PAIN RESEARCH & MANAGEMENT, Vol: 19, Pages: E139-E145, ISSN: 1203-6765
Diaper A, Rich AS, Wilson SJ, et al., 2013, Changes in cardiovascular function after venlafaxine but not pregabalin in healthy volunteers: a double-blind, placebo-controlled study of orthostatic challenge, blood pressure and heart rate, HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL, Vol: 28, Pages: 562-575, ISSN: 0885-6222
Harrison L, Wilson S, Munafo MR, 2013, Sleep disturbance and pain severity: the influence of affective and attentional state, Publisher: ELSEVIER SCIENCE BV, Pages: S623-S624, ISSN: 0924-977X
Muthukumaraswamy SD, Myers JFM, Wilson SJ, et al., 2013, Elevating Endogenous GABA Levels with GAT-1 Blockade Modulates Evoked but Not Induced Responses in Human Visual Cortex, NEUROPSYCHOPHARMACOLOGY, Vol: 38, Pages: 1105-1112, ISSN: 0893-133X
Muthukumaraswamy SD, Myers JFM, Wilson SJ, et al., 2013, The effects of elevated endogenous GABA levels on movement-related network oscillations, NEUROIMAGE, Vol: 66, Pages: 36-41, ISSN: 1053-8119
Lingford-Hughes A, Myers JF, Watson B, et al., 2012, Imaging GABA-benzodiazepine receptor subtypes in addiction, 25th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S133-S133, ISSN: 0924-977X
Durant CF, Wilson SJ, Lightman S, et al., 2012, Sleep and the HPA axis; the effect on sleep of two doses of hydrocortisone administered as a bolus during the day in healthy volunteers, 21st Congress of the European-Sleep-Research-Society, Publisher: WILEY-BLACKWELL, Pages: 24-24, ISSN: 0962-1105
Bonaventure P, Dugovic C, Kramer M, et al., 2012, Translational Evaluation of JNJ-18038683, a 5-Hydroxytryptamine Type 7 Receptor Antagonist, on Rapid Eye Movement Sleep and in Major Depressive Disorder, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, Vol: 342, Pages: 429-440, ISSN: 0022-3565
Wilson S, Argyropoulos S, 2012, Sleep in schizophrenia: time for closer attention, BRITISH JOURNAL OF PSYCHIATRY, Vol: 200, Pages: 273-274, ISSN: 0007-1250
Watson BJ, Taylor LG, Reid A, et al., 2011, Investigating the effect of expectation on striatal dopamine release in heroin addicts: an C-11-raclopride PET study, 24th Congress of the European-College-of-Neuropsychopharmacology, Publisher: ELSEVIER SCIENCE BV, Pages: S320-S320, ISSN: 0924-977X
Paterson LM, Nutt DJ, Wilson SJ, 2011, Sleep and its disorders in translational medicine, J.Psychopharmacol., Vol: 25, Pages: 1226-1234
The study of sleep is a useful approach to studying the brain in psychiatric disorders and in investigating the effects of psychotropic drugs. Sleep physiology lends itself well to pharmacological and physiological manipulation, as it has the advantage of a functional output, the electroencephalograph, which is common to all mammals, and can be measured in freely moving (or naturally sleeping) animals under controlled laboratory conditions or in a naturalistic home environment. The complexity of sleep architecture varies between species but all share features which are comparable. In addition, sleep architecture is sensitive to changes in brain neurotransmitters such as serotonin, so cross-species sleep measurement can be combined with pharmacological manipulation to investigate the receptor mechanisms controlling sleep-wake regulation and sleep architecture in response to known and novel agents. Translational approaches such as these have improved our understanding of sleep circuitry and facilitated the development of new treatments for sleep disorders, particularly insomnia. This review provides examples of how research findings within the sleep field have been translated between animal models, healthy volunteers and patient populations with particular focus on the serotonergic system
Durant CF, Wilson SJ, Lightman S, et al., 2011, DOSE RELATED SLEEP CHANGES IN HEALTHY VOLUNTEERS AFTER TWO DOSES OF HYDROCORTISONE: A DOUBLE BLIND PLACEBO CONTROLLED STUDY, Summer Meeting of the British-Association-for-Psychopharmacology, Publisher: SAGE PUBLICATIONS LTD, Pages: A56-A56, ISSN: 0269-8811
Wilson SJ, Paterson LM, Durant CF, et al., 2011, ACUTE EFFECTS OF HIGH DOSE HYDROCORTISONE ON SLEEP IN PATIENTS WITH TREATMENT RESISTANT DEPRESSION: A DOUBLE BLIND PLACEBO CONTROLLED STUDY, Summer Meeting of the British-Association-for-Psychopharmacology, Publisher: SAGE PUBLICATIONS LTD, Pages: A23-A23, ISSN: 0269-8811
Watson BJ, Wilson S, Griffin L, et al., 2011, A pilot study of the effectiveness of D-cycloserine during cue-exposure therapy in abstinent alcohol-dependent subjects, PSYCHOPHARMACOLOGY, Vol: 216, Pages: 121-129, ISSN: 0033-3158
Watson BJ, Wilson S, Griffin L, et al., 2011, A pilot study of the effectiveness of D-cycloserine during cue-exposure therapy in abstinent alcohol-dependent subjects, Pages: 121-129
RATIONALE: Cue-exposure therapy (CET) has been advocated as a potentially effective treatment of addictive behaviours. Strategies that enhance learning may improve the outcome of CET. D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist, has been shown to facilitate extinction of learned fear in rats and augment exposure-based treatment in some anxiety disorders in man. OBJECTIVE: This double-blind placebo-controlled pilot study used a cue-exposure paradigm, salient for an individual's alcohol drinking, to see if DCS would reduce cue-reactivity compared with placebo. METHODS: Sixteen abstinent, alcohol-dependent individuals were randomised to receive either a single-dose (250 mg) DCS or placebo before CET sessions, separated by at least 1 week. Subjective responses were assessed using the Alcohol Urge Questionnaire (AUQ) and visual analogue scales. Cardiovascular responses were assessed using Finapres(c). RESULTS: The cue-exposure paradigm significantly increased craving assessed with the AUQ during the first session. In subsequent sessions, the degree of craving was reduced. However, no significant difference was seen between the DCS and placebo groups in any outcome measure. The variability of responses between individuals was great with more than half the groups reporting no or very small changes in AUQ scores. CONCLUSION: This is the first human study to our knowledge to assess the efficacy of DCS in facilitating CET in alcohol dependence. The high proportion of subjects with little or no response to cue-exposure would make any effect of DCS very difficult to detect. It is important that future studies carefully consider the criteria for inclusion
Seddon K, Morris K, Bailey J, et al., 2011, Effects of 7.5% CO2 challenge in generalized anxiety disorder, J.Psychopharmacol., Vol: 25, Pages: 43-51
We have previously developed a putative model of generalized anxiety disorder in healthy volunteers using a 20-minute 7.5% carbon dioxide (CO(2)) inhalation challenge. The aim of this study was to validate the 7.5% CO(2) paradigm by assessing its effects in patients with generalized anxiety disorder in a test-retest design. Twelve medication-free generalized anxiety disorder patients attended our lab for two study days. On each study day placebo (compressed air) and 7.5% CO(2) mixture were randomly administered over 20 min, at least 30 min apart, in a single blind, randomized, placebo-controlled cross-over design. Subjective ratings, cardiovascular measures and cortisol levels were collected throughout. CO(2) challenge significantly increased ratings for anxiety and other subjective symptoms associated with generalized anxiety disorder, compared with air. It also significantly increased systolic blood pressure on day 2, indicating increased autonomic arousal. There was no change between the two test days in mean anxiety rating scores, and there also appeared to be a correlation for individual scores on a number of the subjective measures. In conclusion, 20 min of 7.5% CO(2) gas inhalation increases anxiety responses in patients with generalized anxiety disorder, and this is reliable over time
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