Publications
1392 results found
Mirzaei N, Tang S, Ashworth S, et al., 2016, In vivo Imaging of microglial activation by positron emission tomography with [11C]PBR28 in the 5XFAD model of Alzheimer’s disease, GLIA, ISSN: 0894-1491
Microglial activation has been linked with deficits in neuronal function and synaptic plasticity inAlzheimer’s disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulatedin reactive microglia. Accurate visualization and quantification of microglial density by PET imagingusing the TSPO tracer [11C]-R-PK11195 has been challenging due to the limitations of the ligand. Inthis study, we aimed to evaluate the new TSPO tracer [11C]PBR28 as a marker for microglialactivation in the 5XFAD transgenic mouse model of AD. Dynamic PET scans were acquired followingintravenous administration of [11C]PBR28 in 6 month old 5XFAD mice and in wild-type controls.Autoradiography with [3H]PBR28 was carried out in the same brains to further confirm thedistribution of the radioligand. In addition, immunohistochemistry was performed on adjacent brainsections of the same mice to evaluate the co-localization of TSPO with microglia. PET imagingrevealed that brain uptake of [11C]PBR28 in 5XFAD mice was increased compared with control mice.Moreover, binding of [3H]PBR28, measured by autoradiography, was enriched in cortical andhippocampal brain regions, coinciding with the positive staining of the microglial marker Iba-1 andamyloid deposits in the same areas. Furthermore, double-staining using antibodies against TSPOdemonstrated co-localization of TSPO with microglia and not with astrocytes in 5XFAD mice andhuman post-mortem AD brains. Our data provide support of the suitability of [11C]PBR28 as a tool forin vivo monitoring of microglial activation and assessment of treatment response in future studiesusing animal models of AD.
Carhart-Harris RL, Kaelen M, Bolstridge M, et al., 2016, The paradoxical psychological effects of lysergic acid diethylamide (LSD), Psychological Medicine, Vol: 46, Pages: 1379-1390, ISSN: 1469-8978
BACKGROUND: Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or psychedelic that modulates consciousness in a marked and novel way. This study sought to examine the acute and mid-term psychological effects of LSD in a controlled study. METHOD: A total of 20 healthy volunteers participated in this within-subjects study. Participants received LSD (75 µg, intravenously) on one occasion and placebo (saline, intravenously) on another, in a balanced order, with at least 2 weeks separating sessions. Acute subjective effects were measured using the Altered States of Consciousness questionnaire and the Psychotomimetic States Inventory (PSI). A measure of optimism (the Revised Life Orientation Test), the Revised NEO Personality Inventory, and the Peter's Delusions Inventory were issued at baseline and 2 weeks after each session. RESULTS: LSD produced robust psychological effects; including heightened mood but also high scores on the PSI, an index of psychosis-like symptoms. Increased optimism and trait openness were observed 2 weeks after LSD (and not placebo) and there were no changes in delusional thinking. CONCLUSIONS: The present findings reinforce the view that psychedelics elicit psychosis-like symptoms acutely yet improve psychological wellbeing in the mid to long term. It is proposed that acute alterations in mood are secondary to a more fundamental modulation in the quality of cognition, and that increased cognitive flexibility subsequent to serotonin 2A receptor (5-HT2AR) stimulation promotes emotional lability during intoxication and leaves a residue of 'loosened cognition' in the mid to long term that is conducive to improved psychological wellbeing.
Maron E, Wall M, Norbury R, et al., 2015, Effect of short-term escitalopram treatment on neural activation during emotional processing, Journal of Psychopharmacology, Vol: 30, Pages: 33-39, ISSN: 1461-7285
Recent functional magnetic resonance (fMRI) imaging studies have revealed that subchronic medication with escitalopram leads to significantreduction in both amygdala and medial frontal gyrus reactivity during processing of emotional faces, suggesting that escitalopram may have adistinguishable modulatory effect on neural activation as compared with other serotonin-selective antidepressants. In this fMRI study we aimed toexplore whether short-term medication with escitalopram in healthy volunteers is associated with reduced neural response to emotional processing,and whether this effect is predicted by drug plasma concentration. The neural response to fearful and happy faces was measured before and on day7 of treatment with escitalopram (10mg) in 15 healthy volunteers and compared with those in a control unmedicated group (n=14). Significantlyreduced activation to fearful, but not to happy facial expressions was observed in the bilateral amygdala, cingulate and right medial frontal gyrusfollowing escitalopram medication. This effect was not correlated with plasma drug concentration. In accordance with previous data, we showed thatescitalopram exerts its rapid direct effect on emotional processing via attenuation of neural activation in pathways involving medial frontal gyrus andamygdala, an effect that seems to be distinguishable from that of other SSRIs.
Zohar J, Stahl S, Moller H-J, et al., 2015, A review of the current nomenclature for psychotropic agents and an introduction to the Neuroscience-based Nomenclature, EUROPEAN NEUROPSYCHOPHARMACOLOGY, Vol: 25, Pages: 2318-2325, ISSN: 0924-977X
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- Citations: 113
van Amsterdam J, Phillips L, Henderson G, et al., 2015, Ranking the harm of non-medically used prescription opioids in the UK, REGULATORY TOXICOLOGY AND PHARMACOLOGY, Vol: 73, Pages: 999-1004, ISSN: 0273-2300
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- Citations: 16
Vaz TF, Lucena F, Pé-Leve J, et al., 2015, Assessment of the quality of brain regions and neuroimaging metrics as biomarkers of Alzheimer's Disease., EJNMMI Phys, Vol: 2, ISSN: 2197-7364
Rabiner E, Searle G, Passchier J, et al., 2015, Evaluation of 5-HT2C Receptor in the Human Brain in Vivo: A [<SUP>11</SUP>C] Cimbi-36 PET Study, 54th Annual Meeting of the American-College-of-Neuropsychopharmacology (ACNP), Publisher: NATURE PUBLISHING GROUP, Pages: S191-S192, ISSN: 0893-133X
Carhart-Harris RL, Murphy K, Leech R, et al., 2015, The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level-Dependent Resting State Functional Connectivity, Biological Psychiatry, Vol: 78, Pages: 554-562, ISSN: 1873-2402
BackgroundThe compound 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine releaser that produces an acute euphoria in most individuals.MethodsIn a double-blind, placebo-controlled, balanced-order study, MDMA was orally administered to 25 physically and mentally healthy individuals. Arterial spin labeling and seed-based resting state functional connectivity (RSFC) were used to produce spatial maps displaying changes in cerebral blood flow (CBF) and RSFC after MDMA administration. Participants underwent two arterial spin labeling and two blood oxygen level–dependent scans in a 90-minute scan session; MDMA and placebo study days were separated by 1 week.ResultsMarked increases in positive mood were produced by MDMA. Decreased CBF only was observed after MDMA, and this was localized to the right medial temporal lobe (MTL), thalamus, inferior visual cortex, and the somatosensory cortex. Decreased CBF in the right amygdala and hippocampus correlated with ratings of the intensity of global subjective effects of MDMA. The RSFC results complemented the CBF results, with decreases in RSFC between midline cortical regions, the medial prefrontal cortex, and MTL regions, and increases between the amygdala and hippocampus. There were trend-level correlations between these effects and ratings of intense and positive subjective effects.ConclusionsThe MTLs appear to be specifically implicated in the mechanism of action of MDMA, but further work is required to elucidate how the drug’s characteristic subjective effects arise from its modulation of spontaneous brain activity.
Lingford-Hughes AR, Mick I, Myers J, et al., 2015, Blunted endogenous opioid release following an oral amphetamine challenge in pathological gamblers, Neuropsychopharmacology, Vol: 41, Pages: 1742-1750, ISSN: 1740-634X
Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [¹¹C]carfentanil PET with an oral amphetamine challenge. 14 PG and 15 healthy volunteers (HV) underwent two [¹¹C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [¹¹C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [¹¹C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may play an important role in the pathophysiology of addictions.
Tyacke RJ, Nutt DJ, 2015, Optimising PET approaches to measuring 5-HT release in human brain, SYNAPSE, Vol: 69, Pages: 505-511, ISSN: 0887-4476
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- Citations: 14
Lucena F, Vaz TF, Pe-Leve J, et al., 2015, Evaluation of the quality of neuroimaging features as Alzheimer's Disease biomarkers, 28th Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S828-S828, ISSN: 1619-7070
Korpi ER, den Hollander B, Farooq U, et al., 2015, Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse, PHARMACOLOGICAL REVIEWS, Vol: 67, Pages: 872-1004, ISSN: 0031-6997
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- Citations: 94
Nabavi B, Mitchell AJ, Nutt D, 2015, A Lifetime Prevalence of Comorbidity Between Bipolar Affective Disorder and Anxiety Disorders: A Meta-analysis of 52 Interview-based Studies of Psychiatric Population, EBIOMEDICINE, Vol: 2, Pages: 1405-1419, ISSN: 2352-3964
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- Citations: 64
Maron E, Nutt D, 2015, Biological predictors of pharmacological therapy in anxiety disorders, Dialogues in Clinical Neuroscience, Vol: 17, Pages: 305-317, ISSN: 1958-5969
At least one third of patients with anxiety disorders do not adequately respond to available pharmacological treatment. The reason that some patients with anxiety disorders respond well, but others not, to the same classes of medication is not yet fully understood. It is suggested that several biological factors may influence treatment mechanisms in anxiety and therefore could be identified as possible biomarkers predicting treatment response. In this review, we look at current evidence exploring different types of treatment predictors, including neuroimaging, genetic factors, and blood-related measures, which could open up novel perspectives in clinical management of patients with anxiety disorders.
Lingford-Hughes A, McGonigle J, Mick I, et al., 2015, An fMRI study of nalmefene on alcohol effects in reward anticipation in alcohol dependence, 28th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S602-S603, ISSN: 0924-977X
Curran HV, Carhart-Harris R, Nutt D, et al., 2015, Effects of MDMA on self-referent encoding and personal memories: implications for its use in PTSD, 28th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S147-S147, ISSN: 0924-977X
Nutt D, 2015, CAN WE USE NEUROIMAGING TO DEVELOP NEW TREATMENTS FOR DEVELOPMENTAL DISORDERS?, JOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Vol: 59, Pages: 801-802, ISSN: 0964-2633
Nutt D, 2015, How to rescue CNS active drugs which fail in one indication: experience from the ECNP Medicines Chest Initiative, 28th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S141-S142, ISSN: 0924-977X
Kaelen M, Barrett FS, Roseman L, et al., 2015, LSD enhances the emotional response to music., Psychopharmacology, Vol: 232, Pages: 3607-3614, ISSN: 1432-2072
RATIONALE: There is renewed interest in the therapeutic potential of psychedelic drugs such as lysergic acid diethylamide (LSD). LSD was used extensively in the 1950s and 1960s as an adjunct in psychotherapy, reportedly enhancing emotionality. Music is an effective tool to evoke and study emotion and is considered an important element in psychedelic-assisted psychotherapy; however, the hypothesis that psychedelics enhance the emotional response to music has yet to be investigated in a modern placebo-controlled study. OBJECTIVES: The present study sought to test the hypothesis that music-evoked emotions are enhanced under LSD. METHODS: Ten healthy volunteers listened to five different tracks of instrumental music during each of two study days, a placebo day followed by an LSD day, separated by 5-7 days. Subjective ratings were completed after each music track and included a visual analogue scale (VAS) and the nine-item Geneva Emotional Music Scale (GEMS-9). RESULTS: Results demonstrated that the emotional response to music is enhanced by LSD, especially the emotions "wonder", "transcendence", "power" and "tenderness". CONCLUSIONS: These findings reinforce the long-held assumption that psychedelics enhance music-evoked emotion, and provide tentative and indirect support for the notion that this effect can be harnessed in the context of psychedelic-assisted psychotherapy. Further research is required to test this link directly.
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.
Paterson LM, Flechais RSA, Murphy A, et al., 2015, The Imperial College Cambridge Manchester (ICCAM) platform study: an experimental medicine platform for evaluating new drugs for relapse prevention in addiction. Part A: study description, Journal of Psychopharmacology, Vol: 29, Pages: 943-960, ISSN: 1461-7285
Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and an evocative images task, using selective antagonists for µ-opioid, dopamine D3 receptor (DRD3) and neurokinin 1 (NK1) receptors (naltrexone, GSK598809, vofopitant/aprepitant), in a placebo-controlled, randomised, crossover design. In two years, 609 scans were performed, with 155 individuals scanned at baseline. Attrition was low and the majority of individuals were sufficiently motivated to complete all five sessions (n=87). We describe herein the study design, main aims, recruitment numbers, sample characteristics, and explain the test hypotheses and anticipated study outputs.
Stuart SA, Butler P, Munafo MR, et al., 2015, Distinct Neuropsychological Mechanisms May Explain Delayed- <i>Versus</i> Rapid-Onset Antidepressant Efficacy, NEUROPSYCHOPHARMACOLOGY, Vol: 40, Pages: 2165-2174, ISSN: 0893-133X
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- Citations: 38
Corchs F, Nutt DJ, Hince DA, et al., 2015, Evidence for serotonin function as a neurochemical difference between fear and anxiety disorders in humans?, Journal of Psychopharmacology, Vol: 29, Pages: 1061-1069, ISSN: 1461-7285
The relationships between serotonin and fear and anxiety disorders have been much studied yet many important questions remain, despite selective serotonin reuptake inhibitors having been the primary treatments for these disorders for some time. In order to explore this issue we performed a pooled analysis of six of our studies in remitted patients with a fear/anxiety disorder who were exposed to syndrome-specific aversive stimulation under acute tryptophan depletion. We based our analysis on the hypothesis that the inconsistencies observed in the studies could be predicted by Deakin and Graeff's theory about the dual role of serotonin in responses to threats, whereby serotonin is critical to prevent fear (panic) but not anxiety. In accordance with this view, our results give support to a dissociation of the disorders traditionally grouped under fear and anxiety-related disorders in terms of different roles of serotonin in modulation of responses to aversive stimulation. Implications for future studies and psychiatric nosology are discussed.
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
Nutt D, 2015, Grim repercussions: UK's legal highs ban is unscientific and will lead to more harm, New Scientist, Vol: 226, Pages: 24-25, ISSN: 1364-8500
van Amsterdam J, Nutt D, Phillips L, et al., 2015, European rating of drug harms, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 29, Pages: 655-660, ISSN: 0269-8811
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- Citations: 98
Shimshoni JA, Britzi M, Sobol E, et al., 2015, 3-Methyl-methcathinone: Pharmacokinetic profile evaluation in pigs in relation to pharmacodynamics, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 29, Pages: 734-743, ISSN: 0269-8811
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- Citations: 18
Nutt D, 2015, BMJ CONFIDENTIAL David Nutt: Champions off-licence prescribing, BMJ-BRITISH MEDICAL JOURNAL, Vol: 350, ISSN: 0959-535X
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- Citations: 1
Lebedev AV, Lövdén M, Rosenthal G, et al., 2015, Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin., Human Brain Mapping, ISSN: 1097-0193
Ego-disturbances have been a topic in schizophrenia research since the earliest clinical descriptions of the disorder. Manifesting as a feeling that one's "self," "ego," or "I" is disintegrating or that the border between one's self and the external world is dissolving, "ego-disintegration" or "dissolution" is also an important feature of the psychedelic experience, such as is produced by psilocybin (a compound found in "magic mushrooms"). Fifteen healthy subjects took part in this placebo-controlled study. Twelve-minute functional MRI scans were acquired on two occasions: subjects received an intravenous infusion of saline on one occasion (placebo) and 2 mg psilocybin on the other. Twenty-two visual analogue scale ratings were completed soon after scanning and the first principal component of these, dominated by items referring to "ego-dissolution", was used as a primary measure of interest in subsequent analyses. Employing methods of connectivity analysis and graph theory, an association was found between psilocybin-induced ego-dissolution and decreased functional connectivity between the medial temporal lobe and high-level cortical regions. Ego-dissolution was also associated with a "disintegration" of the salience network and reduced interhemispheric communication. Addressing baseline brain dynamics as a predictor of drug-response, individuals with lower diversity of executive network nodes were more likely to experience ego-dissolution under psilocybin. These results implicate MTL-cortical decoupling, decreased salience network integrity, and reduced inter-hemispheric communication in psilocybin-induced ego disturbance and suggest that the maintenance of "self"or "ego," as a perceptual phenomenon, may rest on the normal functioning of these systems. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
Savulich G, Ersche KD, Deakin B, et al., 2015, The modulatory effects of naltrexone on the underlying neural network in alcohol and drug dependence: an FMRI study, 38th Annual Scientific Meeting of the Research-Society-on-Alcoholism, Publisher: Wiley, Pages: 253A-253A, ISSN: 0145-6008
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