Association between antipsychotic/antidepressant drug treatments and hospital admissions in schizophrenia assessed using a mental health case register.

BACKGROUND: The impact of psychotropic drug choice upon admissions for schizophrenia is not well understood. AIMS: To examine the association between antipsychotic/antidepressant use and time in hospital for patients with schizophrenia. METHODS: We conducted an observational study, using 8 years' admission records and electronically generated drug histories from an institution providing secondary mental health care in Cambridgeshire, UK, covering the period 2005-2012 inclusive. Patients with a coded ICD-10 diagnosis of schizophrenia were selected. The primary outcome measure was the time spent as an inpatient in a psychiatric unit. Antipsychotic and antidepressant drugs used by at least 5% of patients overall were examined for associations with admissions. Periods before and after drug commencement were compared for patients having pre-drug admissions, in mirror-image analyses correcting for overall admission rates. Drug use in one 6-month calendar period was used to predict admissions in the next period, across all patients, in a regression analysis accounting for the effects of all other drugs studied and for time. RESULTS: In mirror-image analyses, sulpiride, aripiprazole, clozapine, and olanzapine were associated with fewer subsequent admission days. In regression analyses, sulpiride, mirtazapine, venlafaxine, and clozapine-aripiprazole and clozapine-amisulpride combinations were associated with fewer subsequent admission days. CONCLUSIONS: Use of these drugs was associated with fewer days in hospital. Causation is not implied and these findings require confirmation by randomized controlled trials.RNC was supported by the Wellcome Trust. EFE was supported by a NARSAD Young Investigator Award. The CPFT Research Database was supported by the UK National Institute of Health Research Cambridge Biomedical Research Centre. The work was conducted within the Behavioural and Clinical Neuroscience Institute, supported by the Wellcome Trust and the UK Medical Research Council.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/npjschz.2015.3

Tryptophan Depletion Promotes Habitual over Goal-Directed Control of Appetitive Responding in Humans.

BACKGROUND: Optimal behavioral performance results from a balance between goal-directed and habitual systems of behavioral control, which are modulated by ascending monoaminergic projections. While the role of the dopaminergic system in behavioral control has been recently addressed, the extent to which changes in global serotonin neurotransmission could influence these 2 systems is still poorly understood. METHODS: We employed the dietary acute tryptophan depletion procedure to reduce serotonin neurotransmission in 18 healthy volunteers and 18 matched controls. We used a 3-stage instrumental learning paradigm that includes an initial instrumental learning stage, a subsequent outcome-devaluation test, and a slip-of-action stage, which directly tests the balance between hypothetical goal-directed and habitual systems. We also employed a separate response inhibition control test to assess the behavioral specificity of the results. RESULTS: Acute tryptophan depletion produced a shift of behavioral performance towards habitual responding as indexed by performance on the slip-of-action test. Moreover, greater habitual responding in the acute tryptophan depletion group was predicted by a steeper decline in plasma tryptophan levels. In contrast, acute tryptophan depletion left intact the ability to use discriminative stimuli to guide instrumental choice as indexed by the instrumental learning stage and did not impair inhibitory response control. CONCLUSIONS: The major implication of this study is that serotonin modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. Our findings thus imply that diminished serotonin neurotransmission shifts behavioral control towards habitual responding.This work was supported by a Wellcome Trust programme grant to T.W.R. (089589/z/09/z). The Behavioral and Clinical Neuroscience Institute is jointly funded by the MRC and the Wellcome Trust (G00001354).This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/ijnp/pyv01

Neuropsychological performance in young adults with cannabis use disorder.

Funder: NIHR MedTechFunder: in vitro diagnostic Co-operativeFunder: nihr cambridge biomedical research centreFunder: Wallitt Foundation and Eton CollegeFunder: Wellcome Trust Collaborative AwardBACKGROUND AND AIMS: Cannabis is a commonly used recreational drug in young adults. The worldwide prevalence in 18- to 25-year-olds is approximately 35%. Significant differences in cognitive performance have been reported previously for groups of cannabis users. However, the groups are often heterogeneous in terms of cannabis use. Here, we study daily cannabis users with a confirmed diagnosis of cannabis use disorder (CUD) to examine cognitive performance on measures of memory, executive function and risky decision-making. METHODS: Forty young adult daily cannabis users with diagnosed CUD and 20 healthy controls matched for sex and premorbid intelligence quotient (IQ) were included. The neuropsychological battery implemented was designed to measure multiple modes of memory (visual, episodic and working memory), risky decision-making and other domains of executive function using subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: Our results showed that young adult daily cannabis users with CUD perform significantly poorer on tasks of visual and episodic memory compared with healthy controls. In addition, executive functioning was associated with the age of onset. CONCLUSIONS: Further research is required to determine whether worse performance in cognition results in cannabis use or is a consequence of cannabis use. Chronic heavy cannabis use during a critical period of brain development may have a particularly negative impact on cognition. Research into the persistence of cognitive differences and how they relate to functional outcomes such as academic/career performance is required

Impairments in reinforcement learning do not explain enhanced habit formation in cocaine use disorder

Rationale Drug addiction has been suggested to develop through drug-induced changes in learning and memory processes. Whilst the initiation of drug use is typically goal-directed and hedonically motivated, over time, drug-taking may develop into a stimulus-driven habit, characterised by persistent use of the drug irrespective of the consequences. Converging lines of evidence suggest that stimulant drugs facilitate the transition of goal-directed into habitual drug-taking, but their contribution to goal-directed learning is less clear. Computational modelling may provide an elegant means for elucidating changes during instrumental learning that may explain enhanced habit formation. Objectives We used formal reinforcement learning algorithms to deconstruct the process of appetitive instrumental learning and to explore potential associations between goal-directed and habitual actions in patients with cocaine use disorder (CUD). Methods We re-analysed appetitive instrumental learning data in 55 healthy control volunteers and 70 CUD patients by applying a reinforcement learning model within a hierarchical Bayesian framework. We used a regression model to determine the influence of learning parameters and variations in brain structure on subsequent habit formation. Results Poor instrumental learning performance in CUD patients was largely determined by difficulties with learning from feedback, as reflected by a significantly reduced learning rate. Subsequent formation of habitual response patterns was partly explained by group status and individual variation in reinforcement sensitivity. White matter integrity within goal-directed networks was only associated with performance parameters in controls but not in CUD patients. Conclusions Our data indicate that impairments in reinforcement learning are insufficient to account for enhanced habitual responding in CUD

Peak Width of Skeletonized Mean Diffusivity as a Marker of Diffuse Cerebrovascular Damage.

The peak width of skeletonized mean diffusivity (PSMD) has been proposed as a fully automated imaging marker of relevance to cerebral small vessel disease (SVD). We assessed PSMD in relation to conventional SVD markers, global measures of neurodegeneration, and cognition. 145 participants underwent 3T brain MRI and cognitive assessment. 112 were patients with mild cognitive impairment, Alzheimer's disease, progressive supranuclear palsy, dementia with Lewy bodies, or frontotemporal dementia. PSMD, SVD burden [white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds, lacunes], average mean diffusivity (MD), gray matter (GM), white matter (WM), and total intracranial volume were quantified. Robust linear regression was conducted to examine associations between variables. Dominance analysis assessed the relative importance of markers in predicting various outcomes. Regional analyses examined spatial overlap between PSMD and WMH. PSMD was associated with global and regional SVD measures, especially WMH and microbleeds. Dominance analysis demonstrated that among SVD markers, WMH was the strongest predictor of PSMD. Furthermore, PSMD was more closely associated to WMH than with GM and WM volumes. PSMD was associated with WMH across all regions, and correlations were not significantly stronger in corresponding regions (e.g., frontal PSMD and frontal WMH) compared to non-corresponding regions. PSMD outperformed all four conventional SVD markers and MD in predicting cognition, but was comparable to GM and WM volumes. PSMD was robustly associated with established SVD markers. This new measure appears to be a marker of diffuse brain injury, largely due to vascular pathology, and may be a useful and convenient metric of overall cerebrovascular burden

Molecular pathology and synaptic loss in primary tauopathies: A [18F]AV-1451 and [11C]UCB-J PET study

The relationship between in vivo synaptic density and tau burden in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology, in the primary tauopathies of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), as a function of disease severity. Twenty three patients with PSP, and twelve patients with Corticobasal Syndrome (CBS) were recruited from a tertiary referral centre. Nineteen education, sex and gender-matched control participants were recruited from the National Institute for Health Research ‘Join Dementia Research’ platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands [11C]UCB-J and [18F]AV-1451, respectively. Patients with CBS also underwent amyloid PET imaging with [11C]PiB to exclude those with likely Alzheimer’s pathology – we refer to the amyloid negative cohort as having CBD although acknowledge other pathologies exist. Disease severity was assessed with the PSP rating scale; regional non-displaceable binding potentials (BPND) of [11C]UCB-J and [18F]AV-1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for [18F]AV-1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions, and synaptic density in subcortical areas. Across brain regions, there was a positive correlation between [11C]UCB-J and [18F]AV-1451 BPND (ß = 0.4, t = 3.6, p = 0.001), independent of age or time between PET scans. However, this correlation became less positive as a function of disease severity in patients (ß = - 0.02, t = -2.9, p = 0.007, R = -0.41). Between regions, cortical [18F]AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen). Brain regions with higher synaptic density are associated with a higher [18F]AV-1451 binding in PSP/CBD, but this association diminishes with disease severity. Moreover, higher cortical [18F]AV-1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and molecular pathology with synapse rich regions vulnerable to accrual of pathological aggregates, followed by a loss of synapses in response to pathology. Given the importance of synaptic function for cognition, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.Cambridge Centre for Parkinson-Plus (RG95450); the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014); the PSP Association (“MAPT-PSP” study), and the Association of British Neurologists, Patrick Berthoud Charitable Trust (RG99368)

The effect of shunt surgery on neuropsychological performance in normal pressure hydrocephalus: a systematic review and meta-analysis.

We conducted a systematic review of the literature and used meta-analytic techniques to evaluate the impact of shunt surgery on neuropsychological performance in patients with normal pressure hydrocephalus (NPH). Twenty-three studies with 1059 patients were identified for review using PubMed, Web of Science, Google scholar and manual searching. Inclusion criteria were prospective, within-subject investigations of cognitive outcome using neuropsychological assessment before and after shunt surgery in patients with NPH. There were statistically significant effects of shunt surgery on cognition (Mini-Mental State Examination; MMSE), learning and memory (Rey Auditory Verbal Learning Test; RAVLT, total and delayed subtests), executive function (backwards digit span, phonemic verbal fluency, trail making test B) and psychomotor speed (trail making test A) all in the direction of improvement following shunt surgery, but with considerable heterogeneity across all measures. A more detailed examination of the data suggested robust evidence for improved MMSE, RAVLT total, RAVLT delayed, phonemic verbal fluency and trail making test A only. Meta-regressions revealed no statistically significant effect of age, sex or follow-up interval on improvement in the MMSE. Our results suggest that shunt surgery is most sensitive for improving global cognition, learning and memory and psychomotor speed in patients with NPH.The research was supported by the National Institute for Health Research (NIHR) Brain Injury Healthcare Technology Co-operative based at Cambridge University Hospitals NHS Foundation Trust and University of Cambridge. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Katie Peterson is funded by a grant awarded to John D. Pickard from the NIHR Biomedical Research Centre. Dan Jackson is supported by the Medical Research Council Unit Programme number U105260558. George Savulich and Clare Killikelly were supported by grants awarded to Barbara J. Sahakian from Janssen/J&J. John D. Pickard reports grants from the NIHR Senior Investigator Award, the NIHR Cambridge Brain Injury Healthcare Technology Co-operative and Van Geest Grant for hydrocephalus research. Barbara J. Sahakian receives funding from the Wellcome Trust (grant 089589/Z/09/Z), the MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute (joint award G00001354), the Human Brain Project and the NIHR Cambridge Brain Injury Healthcare Technology Co-operative.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Springer

The impact of neuroscience on society: cognitive enhancement in neuropsychiatric disorders and in healthy people.

In addition to causing distress and disability to the individual, neuropsychiatric disorders are also extremely expensive to society and governments. These disorders are both common and debilitating and impact on cognition, functionality and wellbeing. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used to treat cognitive dysfunction in Alzheimer's disease and attention deficit hyperactivity disorder, respectively. Other cognitive enhancers include specific computerized cognitive training and devices. An example of a novel form of cognitive enhancement using the technological advancement of a game on an iPad that also acts to increase motivation is presented. Cognitive enhancing drugs, such as methylphenidate and modafinil, which were developed as treatments, are increasingly being used by healthy people. Modafinil not only affects 'cold' cognition, but also improves 'hot' cognition, such as emotion recognition and task-related motivation. The lifestyle use of 'smart drugs' raises both safety concerns as well as ethical issues, including coercion and increasing disparity in society. As a society, we need to consider which forms of cognitive enhancement (e.g. pharmacological, exercise, lifelong learning) are acceptable and for which groups (e.g. military, doctors) under what conditions (e.g. war, shift work) and by what methods we would wish to improve and flourish.All cited psychopharmacological work from Professor Sahakian laboratory was funded by a Wellcome Trust Grant (089589/Z/09/Z) awarded to T.W. Robbins, B.J. Everitt, A.C. Roberts, J.W. Dalley, and B.J. Sahakian, and it was conducted at the Behavioural and Clinical Neuroscience Institute, which is supported by a joint award from the Medical Research Council and Wellcome Trust (G00001354). B.J. Sahakian receives funding from the Human Brain Project. We thank Janssen/J&J for funding the study on cognitive training in schizophrenia.This is the final version of the article. It first appeared from RSC via http://dx.doi.org/10.1098/rstb.2014.021

Obstetric Phenotypes in the Heterogeneity of Schizophrenia.

Schizophrenia is a complex mental disorder with genetic and environmental components. Obstetric complications (OCs) are one of the most common environmental risk factors described. However, despite being different in timing and outcome, OCs are usually described as a homogeneous entity. In the present study, we evaluate the presence of different patterns of OCs evaluated with the Lewis-Murray Scale in chronic schizophrenia patients (n = 101) and their association with a crude marker of the intrauterine environment such as weight at birth.OCs related with abnormal fetal growth (p < 0.001) and OCs during gestation (p = 0.003) were associated with lower birth weight. However, difficulties in delivery, complications in pregnancy, and OCs all together (as a set) were not associated with weight at birth.Our results infer that OCs cannot be taken as a homogeneous group. Different patterns of OCs result in different birth weights, which is associated with specific metabolic, cognitive, and brain structure outcomes.This work was supported by the Government of Catalonia, Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement (2014SGR441), with the grants FI-DGR-2013 Contract of the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) (2015 FI_B2 00100) and from Fundació Bosch Gimpera (FBG) within the RETOS COLABORACIÓN 2015, funded by the Spanish Ministry of Economic Affairs and Competitiveness (RTC-2015-3440-1) to G. Mezquida. Dr. Bernardo has been supported by research funding from the Spanish Ministry of Health, the Spanish Ministry of Science and Education, the Spanish Ministry of Economic Affairs and Competitiveness, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), by Secretaria d'Universitat i Recerca del Departament d'Economia I Coneixement (2014SGR441), Foundation European Group for Research In Schizophrenia (EGRIS), and the 7th Framework Program of the European Union. Dr. Garcia-Rizo is supported by the PI14/00753 project, integrated into the State Plan of Scientific and Technical Research and Innovation 2013–2016 and co-financed by the ISCIII-General Evaluation Branch and the European Regional Development Fund (ERDF). Dr. Bobes is supported by the Spanish Ministry of Health, the Spanish Ministry of Science and Education, the Spanish Ministry of Economic Affairs and Competitiveness and CIBERSAM. Dr. Paz-Portilla has been also supported by the European Commission, ISCIII-General Evaluation Branch and CIBERSAM. Dr. Savulich is funded by a grant from Eton College and theWallitt Foundation. Dr. Fernanez-Egea is supported, in part, by the NIRH-Biomedical Research Center, Cambridge

In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer’s disease

Introduction: Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging. Methods: Forty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer’s disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [11C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [11C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [11C]PK11195. Results: Global [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (β=0.63, F(1,35)=35.24, p<0.001), deep WMH (β=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (β=0.66–0.76, t=3.90–5.58, FDR-corrected p (pFDR)=<0.001–0.002) and orbitofrontal cortex (β=0.51–0.57, t=3.53–4.30, pFDR=0.001–0.004). Conclusion: Microglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD