Publications by authors named "Paul J Harrison"

171 Publications

6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records.

Lancet Psychiatry 2021 Apr 1. Epub 2021 Apr 1.

Department of Psychiatry, University of Oxford, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK. Electronic address:

Background: Neurological and psychiatric sequelae of COVID-19 have been reported, but more data are needed to adequately assess the effects of COVID-19 on brain health. We aimed to provide robust estimates of incidence rates and relative risks of neurological and psychiatric diagnoses in patients in the 6 months following a COVID-19 diagnosis.

Methods: For this retrospective cohort study and time-to-event analysis, we used data obtained from the TriNetX electronic health records network (with over 81 million patients). Our primary cohort comprised patients who had a COVID-19 diagnosis; one matched control cohort included patients diagnosed with influenza, and the other matched control cohort included patients diagnosed with any respiratory tract infection including influenza in the same period. Patients with a diagnosis of COVID-19 or a positive test for SARS-CoV-2 were excluded from the control cohorts. All cohorts included patients older than 10 years who had an index event on or after Jan 20, 2020, and who were still alive on Dec 13, 2020. We estimated the incidence of 14 neurological and psychiatric outcomes in the 6 months after a confirmed diagnosis of COVID-19: intracranial haemorrhage; ischaemic stroke; parkinsonism; Guillain-Barré syndrome; nerve, nerve root, and plexus disorders; myoneural junction and muscle disease; encephalitis; dementia; psychotic, mood, and anxiety disorders (grouped and separately); substance use disorder; and insomnia. Using a Cox model, we compared incidences with those in propensity score-matched cohorts of patients with influenza or other respiratory tract infections. We investigated how these estimates were affected by COVID-19 severity, as proxied by hospitalisation, intensive therapy unit (ITU) admission, and encephalopathy (delirium and related disorders). We assessed the robustness of the differences in outcomes between cohorts by repeating the analysis in different scenarios. To provide benchmarking for the incidence and risk of neurological and psychiatric sequelae, we compared our primary cohort with four cohorts of patients diagnosed in the same period with additional index events: skin infection, urolithiasis, fracture of a large bone, and pulmonary embolism.

Findings: Among 236 379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 33·62% (95% CI 33·17-34·07), with 12·84% (12·36-13·33) receiving their first such diagnosis. For patients who had been admitted to an ITU, the estimated incidence of a diagnosis was 46·42% (44·78-48·09) and for a first diagnosis was 25·79% (23·50-28·25). Regarding individual diagnoses of the study outcomes, the whole COVID-19 cohort had estimated incidences of 0·56% (0·50-0·63) for intracranial haemorrhage, 2·10% (1·97-2·23) for ischaemic stroke, 0·11% (0·08-0·14) for parkinsonism, 0·67% (0·59-0·75) for dementia, 17·39% (17·04-17·74) for anxiety disorder, and 1·40% (1·30-1·51) for psychotic disorder, among others. In the group with ITU admission, estimated incidences were 2·66% (2·24-3·16) for intracranial haemorrhage, 6·92% (6·17-7·76) for ischaemic stroke, 0·26% (0·15-0·45) for parkinsonism, 1·74% (1·31-2·30) for dementia, 19·15% (17·90-20·48) for anxiety disorder, and 2·77% (2·31-3·33) for psychotic disorder. Most diagnostic categories were more common in patients who had COVID-19 than in those who had influenza (hazard ratio [HR] 1·44, 95% CI 1·40-1·47, for any diagnosis; 1·78, 1·68-1·89, for any first diagnosis) and those who had other respiratory tract infections (1·16, 1·14-1·17, for any diagnosis; 1·32, 1·27-1·36, for any first diagnosis). As with incidences, HRs were higher in patients who had more severe COVID-19 (eg, those admitted to ITU compared with those who were not: 1·58, 1·50-1·67, for any diagnosis; 2·87, 2·45-3·35, for any first diagnosis). Results were robust to various sensitivity analyses and benchmarking against the four additional index health events.

Interpretation: Our study provides evidence for substantial neurological and psychiatric morbidity in the 6 months after COVID-19 infection. Risks were greatest in, but not limited to, patients who had severe COVID-19. This information could help in service planning and identification of research priorities. Complementary study designs, including prospective cohorts, are needed to corroborate and explain these findings.

Funding: National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre.
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http://dx.doi.org/10.1016/S2215-0366(21)00084-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023694PMC
April 2021

Differential follow-up patterns in COVID-19 and comparison cohorts - Authors' reply.

Lancet Psychiatry 2021 Mar 10. Epub 2021 Mar 10.

Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK. Electronic address:

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http://dx.doi.org/10.1016/S2215-0366(21)00076-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946416PMC
March 2021

Disentangling the complex bidirectional associations between COVID-19 and psychiatric disorder - Authors' reply.

Lancet Psychiatry 2021 03;8(3):179

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK; Oxford Health NHS Foundation Trust, Oxford, UK. Electronic address:

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http://dx.doi.org/10.1016/S2215-0366(21)00028-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906685PMC
March 2021

Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.

EClinicalMedicine 2021 Jan 7;31:100683. Epub 2021 Jan 7.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), University of Oxford, Oxford, United Kingdom.

Background: The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood.

Methods: Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments.

Findings: At 2-3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (<0.0001 to 0.044).

Interpretation: A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness.

Funding: NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation.
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http://dx.doi.org/10.1016/j.eclinm.2020.100683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808914PMC
January 2021

Incidence of neurodegenerative and cerebrovascular diseases associated with antihypertensive drug classes.

Br J Psychiatry 2021 Jan 7:1-3. Epub 2021 Jan 7.

TriNetX Inc., Massachusetts, USA.

Antihypertensive drugs (AHTs) are associated with lowered risks of neurodegenerative diseases and stroke. However, the relative risks associated with different AHT classes are unclear. Using an electronic health record network with 34 million eligible patients, we compared rates of these disorders over a 2-year period, in propensity score-matched cohorts of people taking calcium channel blockers (CCBs) compared with those taking other AHT classes. CCBs were associated with a higher incidence of all disorders compared with renin-angiotensin system agents, and a higher incidence of dementia and cerebrovascular disease compared with diuretics. CCBs were associated with a lower incidence of movement disorders and cerebrovascular disease compared with beta-blockers. The data show that AHT classes confer differential risks of neurodegenerative and cerebrovascular diagnoses.
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http://dx.doi.org/10.1192/bjp.2020.249DOI Listing
January 2021

Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA.

Lancet Psychiatry 2021 02 9;8(2):130-140. Epub 2020 Nov 9.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK; Oxford Health NHS Foundation Trust, Oxford, UK. Electronic address:

Background: Adverse mental health consequences of COVID-19, including anxiety and depression, have been widely predicted but not yet accurately measured. There are a range of physical health risk factors for COVID-19, but it is not known if there are also psychiatric risk factors. In this electronic health record network cohort study using data from 69 million individuals, 62 354 of whom had a diagnosis of COVID-19, we assessed whether a diagnosis of COVID-19 (compared with other health events) was associated with increased rates of subsequent psychiatric diagnoses, and whether patients with a history of psychiatric illness are at a higher risk of being diagnosed with COVID-19.

Methods: We used the TriNetX Analytics Network, a global federated network that captures anonymised data from electronic health records in 54 health-care organisations in the USA, totalling 69·8 million patients. TriNetX included 62 354 patients diagnosed with COVID-19 between Jan 20, and Aug 1, 2020. We created cohorts of patients who had been diagnosed with COVID-19 or a range of other health events. We used propensity score matching to control for confounding by risk factors for COVID-19 and for severity of illness. We measured the incidence of and hazard ratios (HRs) for psychiatric disorders, dementia, and insomnia, during the first 14 to 90 days after a diagnosis of COVID-19.

Findings: In patients with no previous psychiatric history, a diagnosis of COVID-19 was associated with increased incidence of a first psychiatric diagnosis in the following 14 to 90 days compared with six other health events (HR 2·1, 95% CI 1·8-2·5 vs influenza; 1·7, 1·5-1·9 vs other respiratory tract infections; 1·6, 1·4-1·9 vs skin infection; 1·6, 1·3-1·9 vs cholelithiasis; 2·2, 1·9-2·6 vs urolithiasis, and 2·1, 1·9-2·5 vs fracture of a large bone; all p<0·0001). The HR was greatest for anxiety disorders, insomnia, and dementia. We observed similar findings, although with smaller HRs, when relapses and new diagnoses were measured. The incidence of any psychiatric diagnosis in the 14 to 90 days after COVID-19 diagnosis was 18·1% (95% CI 17·6-18·6), including 5·8% (5·2-6·4) that were a first diagnosis. The incidence of a first diagnosis of dementia in the 14 to 90 days after COVID-19 diagnosis was 1·6% (95% CI 1·2-2·1) in people older than 65 years. A psychiatric diagnosis in the previous year was associated with a higher incidence of COVID-19 diagnosis (relative risk 1·65, 95% CI 1·59-1·71; p<0·0001). This risk was independent of known physical health risk factors for COVID-19, but we cannot exclude possible residual confounding by socioeconomic factors.

Interpretation: Survivors of COVID-19 appear to be at increased risk of psychiatric sequelae, and a psychiatric diagnosis might be an independent risk factor for COVID-19. Although preliminary, our findings have implications for clinical services, and prospective cohort studies are warranted.

Funding: National Institute for Health Research.
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http://dx.doi.org/10.1016/S2215-0366(20)30462-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820108PMC
February 2021

Incidence of Parkinson's disease, dementia, cerebrovascular disease and stroke in bipolar disorder compared to other psychiatric disorders: An electronic health records network study of 66 million people.

Bipolar Disord 2020 Oct 19. Epub 2020 Oct 19.

TriNetX Inc, Cambridge, MA, USA.

Objectives: Bipolar disorder has been associated with an increased risk for neurodegenerative diseases, but uncertainties remain. The risk relative to other psychiatric disorders is not established.

Methods: We used a federated electronic health records network of 66 million people including over 700,000 with bipolar disorder. We assessed incidence of a first diagnosis of Parkinson's disease, dementia, cerebrovascular disease and stroke, in patients at least 1 year after diagnosis of bipolar disorder. Rates were compared to propensity score matched cohorts of subjects with mixed disorders, recurrent major depressive disorder (MDD) or schizophrenia.

Results: Parkinson's disease was commoner in bipolar disorder compared to all three cohorts (odds ratios [OR] ranging from 1.26 to 2.65). Dementia incidence was greater in bipolar disorder than in mixed disorders (OR = 1.61) or MDD (OR = 1.40), but not different from schizophrenia (OR = 0.96). Cerebrovascular disease and stroke were commoner in bipolar disorder than in schizophrenia (OR = 1.35) or mixed disorders (OR = 1.20) and equivocally raised compared to MDD. Results were robust to a wide range of confounding demographic, diagnostic and medication risk factors for neurodegenerative disorders.

Conclusions: Bipolar disorder confers an elevated risk for developing neurodegenerative disorders and cerebrovascular disease compared to other major adult psychiatric disorders. The results cannot be attributed to recognised confounders. The results are consistent with neuroprogressive views of bipolar disorder. The underlying mechanisms remain to be discovered.
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http://dx.doi.org/10.1111/bdi.13022DOI Listing
October 2020

Rates of delirium associated with calcium channel blockers compared to diuretics, renin-angiotensin system agents and beta-blockers: An electronic health records network study.

J Psychopharmacol 2020 08 8;34(8):848-855. Epub 2020 Jul 8.

Department of Psychiatry, University of Oxford, Oxford, UK.

Background: Antihypertensive drugs, especially calcium channel blockers, have been associated with differential rates of a number of neuropsychiatric outcomes. Delirium is commonly attributed to medication, including antihypertensive drugs, but delirium incidence has not been compared directly between antihypertensive drug classes.

Methods: Using a federated electronic health records network of 25.5 million people aged 50 years or older, we measured rates of delirium over a two-year period in patients prescribed calcium channel blockers compared to the other main antihypertensive drug classes. Extensive propensity score matching was used to create cohorts matched for a range of demographic factors and delirium risk factors. Negative control outcomes were also measured.

Results: Cohort sizes ranged from 54,000-577,000. Delirium was more common with calcium channel blockers than with renin-angiotensin system agents (~40% higher) but less common than with beta-blockers (~20% lower). These differences remained when patients with a range of other delirium risk factors were excluded, and they were not paralleled by the negative control outcomes. Comparisons between calcium channel blockers and diuretics produced inconclusive results.

Conclusions: Calcium channel blockers are associated with higher rates of delirium than renin-angiotensin system agents, but lower rates compared to beta-blockers. The findings add to the list of factors which may be considered when choosing antihypertensive drug class.
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http://dx.doi.org/10.1177/0269881120936501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376629PMC
August 2020

Sleep disturbance and psychiatric disorders.

Lancet Psychiatry 2020 07;7(7):628-637

Department of Psychiatry, University of Oxford, Oxford, UK; Health National Health Service Foundation Trust, Oxford, UK.

Signs of mental ill health that cut across psychiatric diagnostic categories at high rates are typically viewed as non-specific occurrences, downgraded in importance and disregarded. However, problems not associated with particular diagnoses should be expected if there is shared causation across mental health conditions. If dynamic networks of interacting symptoms are the reality of mental health presentations, then particularly disruptive and highly connected problems should be especially common. The non-specific occurrence might be highly consequential. One non-specific occurrence that is often overlooked is patients' chronic difficulty in getting good sleep. In this Review, we consider whether disrupted sleep might be a contributory causal factor in the occurrence of major types of mental health disorders. It is argued that insomnia and other mental health conditions not only share common causes but also show a bidirectional relationship, with typically the strongest pathway being disrupted sleep as a causal factor in the occurrence of other psychiatric problems. Treating insomnia lessens other mental health problems. Intervening on sleep at an early stage might be a preventive strategy for the onset of clinical disorders. Our recommendations are that insomnia is assessed routinely in the occurrence of mental health disorders; that sleep disturbance is treated in services as a problem in its own right, yet also recognised as a pathway to reduce other mental health difficulties; and that access to evidence-based treatment for sleep difficulties is expanded in mental health services.
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http://dx.doi.org/10.1016/S2215-0366(20)30136-XDOI Listing
July 2020

Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder.

Mol Psychiatry 2020 May 13. Epub 2020 May 13.

Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.

Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium's effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient's circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.
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http://dx.doi.org/10.1038/s41380-020-0769-6DOI Listing
May 2020

A structural brain network of genetic vulnerability to psychiatric illness.

Mol Psychiatry 2020 May 6. Epub 2020 May 6.

Department of Psychiatry, University of Oxford, Oxford, UK.

Psychiatry is undergoing a paradigm shift from the acceptance of distinct diagnoses to a representation of psychiatric illness that crosses diagnostic boundaries. How this transition is supported by a shared neurobiology remains largely unknown. In this study, we first identify single nucleotide polymorphisms (SNPs) associated with psychiatric disorders based on 136 genome-wide association studies. We then conduct a joint analysis of these SNPs and brain structural connectomes in 678 healthy children in the PING study. We discovered a strong, robust, and transdiagnostic mode of genome-connectome covariation which is positively and specifically correlated with genetic risk for psychiatric illness at the level of individual SNPs. Similarly, this mode is also significantly positively correlated with polygenic risk scores for schizophrenia, alcohol use disorder, major depressive disorder, a combined bipolar disorder-schizophrenia phenotype, and a broader cross-disorder phenotype, and significantly negatively correlated with a polygenic risk score for educational attainment. The resulting "vulnerability network" is shown to mediate the influence of genetic risks onto behaviors related to psychiatric vulnerability (e.g., marijuana, alcohol, and caffeine misuse, perceived stress, and impulsive behavior). Its anatomy overlaps with the default-mode network, with a network of cognitive control, and with the occipital cortex. These findings suggest that the brain vulnerability network represents an endophenotype funneling genetic risks for various psychiatric illnesses through a common neurobiological root. It may form part of the neural underpinning of the well-recognized but poorly explained overlap and comorbidity between psychiatric disorders.
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http://dx.doi.org/10.1038/s41380-020-0723-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644622PMC
May 2020

The Emerging Neurobiology of Bipolar Disorder.

Focus (Am Psychiatr Publ) 2019 Jul 16;17(3):284-293. Epub 2019 Jul 16.

(Reprinted with permission from , January 2018, Vol. 41, No. 1 ).
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http://dx.doi.org/10.1176/appi.focus.17309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996057PMC
July 2019

Cellular calcium in bipolar disorder: systematic review and meta-analysis.

Mol Psychiatry 2019 Dec 4. Epub 2019 Dec 4.

Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, OX3 7JX, UK.

Calcium signalling has long been implicated in bipolar disorder, especially by reports of altered intracellular calcium ion concentrations ([Ca]). However, the evidence has not been appraised critically. We carried out a systematic review and meta-analysis of studies of cellular calcium indices in bipolar disorder. 2281 records were identified and 117 screened, of which 32 were eligible and 21 were suitable for meta-analyses. The latter each involved up to 642 patients and 404 control subjects. We found that basal free intracellular [Ca] is increased in bipolar disorder, both in platelets and in lymphocytes. The effect size is 0.55, with an estimated elevation of 29%. It is observed in medication-free patients. It is present in mania and bipolar depression, but data are equivocal for euthymia. Cells from bipolar disorder individuals also show an enhanced [Ca] response to stimulation with 5-HT or thrombin, by an estimated 25%, with an effect size of 0.63. In studies which included other diagnoses, intracellular basal [Ca] was higher in bipolar disorder than in unipolar depression, but not significantly different from schizophrenia. Functional parameters of cellular Ca (e.g. calcium transients), and neuronal [Ca], have been much less investigated, and no firm conclusions can be drawn. In summary, there is a robust, medium effect size elevation of basal and stimulated free intracellular [Ca] in bipolar disorder. The results suggest altered calcium functioning in the disorder, and encourage further investigations into the underlying mechanisms, and the implications for pathophysiology and therapeutics.
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http://dx.doi.org/10.1038/s41380-019-0622-yDOI Listing
December 2019

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain.

Mol Psychiatry 2020 01 6;25(1):37-47. Epub 2019 Nov 6.

Department of Psychiatry, University of Oxford, Oxford, UK.

RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel Ca1.2. We show that CACNA1C's transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.
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http://dx.doi.org/10.1038/s41380-019-0583-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906184PMC
January 2020

Which Dopamine Polymorphisms Are Functional? Systematic Review and Meta-analysis of COMT, DAT, DBH, DDC, DRD1-5, MAOA, MAOB, TH, VMAT1, and VMAT2.

Biol Psychiatry 2019 10 28;86(8):608-620. Epub 2019 May 28.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom; Oxford Health NHS Foundation Trust, Oxford, United Kingdom. Electronic address:

Background: Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear.

Methods: We conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in genes encoding dopaminergic enzymes (COMT, DBH, DDC, MAOA, MAOB, and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4, and DRD5), the dopamine transporter (DAT), and vesicular transporters (VMAT1 and VMAT2). We defined functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product.

Results: We screened 22,728 articles and identified 255 eligible studies. We found robust and medium to large effects for polymorphisms in 4 genes. For catechol-O-methyltransferase (COMT), the ValMet polymorphism (rs4680) markedly affected enzyme activity, protein abundance, and protein stability. Dopamine β-hydroxylase (DBH) activity was associated with rs1611115, rs2519152, and the DBH-STR polymorphism. Monoamine oxidase A (MAOA) activity was associated with a 5' VNTR polymorphism. Dopamine D receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing.

Conclusions: Some widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for other polymorphisms, evidence of such an association is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as "markers" of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.
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http://dx.doi.org/10.1016/j.biopsych.2019.05.014DOI Listing
October 2019

It feels real: physiological responses to a stressful virtual reality environment and its impact on working memory.

J Psychopharmacol 2019 10 11;33(10):1264-1273. Epub 2019 Jul 11.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.

Background: Virtual reality (VR) is increasingly used to study and treat psychiatric disorders. Its fidelity depends in part on the extent to which the VR environment provides a convincing simulation, for example whether a putatively stressful VR situation actually produces a stress response.

Methods: We studied the stress response in 28 healthy men exposed either to a stressor VR elevator (which simulated travelling up the outside of a tall building and culminated in the participant being asked to step off the elevator platform), or to a control elevator. We measured psychological and physiological (salivary cortisol and alpha-amylase, blood pressure, pulse, skin conductance) stress indices. We also measured subsequent performance on the N-back task because acute stress has been reported to impact on working memory.

Results: Compared to participants in the control elevator, those in the external elevator had increases in skin conductance, pulse and subjective stress and anxiety ratings, altered heart rate variability, and a delayed rise in cortisol. N-back performance was unaffected.

Conclusions: A putatively stressful VR elevator produces a physiological as well as a psychological stress response, supporting its use in the investigation and treatment of stress-related disorders, and its potential value as an experimental laboratory stressor.
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http://dx.doi.org/10.1177/0269881119860156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764008PMC
October 2019

Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal.

Br J Psychiatry 2020 05;216(5):250-253

Professor, Neuroscience and Mental Health Research Unit, Cardiff University, UK.

We reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes. Third, research shows there is an opportunity for brain-selective CCBs, which are better suited to psychiatric indications.
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http://dx.doi.org/10.1192/bjp.2019.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557861PMC
May 2020

The genomic basis of mood instability: identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function.

Mol Psychiatry 2020 11 5;25(11):3091-3099. Epub 2019 Jun 5.

Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues and gene sets contributing to mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health.
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http://dx.doi.org/10.1038/s41380-019-0439-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116257PMC
November 2020

Cognitive Behavioural Therapy for Nightmares for Patients with Persecutory Delusions (Nites): An Assessor-Blind, Pilot Randomized Controlled Trial.

Can J Psychiatry 2019 10 26;64(10):686-696. Epub 2019 May 26.

Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.

Objective: Nightmares are relatively common in patients experiencing psychosis but rarely assessed or treated. Nightmares may maintain persecutory delusions by portraying fears in sensory-rich detail. We tested the potential benefits of imagery-focused cognitive behavioural therapy (CBT) for nightmares on nightmare severity and persecutory delusions.

Method: This assessor-blind parallel-group pilot trial randomized 24 participants with nightmares and persecutory delusions to receive CBT for nightmares delivered over 4 weeks in addition to treatment as usual (TAU) or TAU alone. Assessments were at 0, 4 (end of treatment), and 8 weeks (follow-up). Feasibility outcomes assessed therapy uptake, techniques used, satisfaction, and attrition. The primary efficacy outcome assessed nightmare severity at week 4. Analyses were intention to treat, estimating treatment effect with 95% confidence intervals (CIs).

Results: All participants offered CBT completed therapy (mean [SD], 4.8 [0.6] sessions) with high satisfaction, and 20 (83%) participants completed all assessments. Compared with TAU, CBT led to large improvements in nightmares (adjusted mean difference = -7.0; 95% CI, -12.6 to -1.3; = -1.1) and insomnia (6.3; 95% CI, 2.6 to 10.0; = 1.4) at week 4. Gains were maintained at follow-up. Suicidal ideation was not exacerbated by CBT but remained stable to follow-up, compared with TAU, which reduced at follow-up (6.8; 95% CI, 0.3 to 3.3; = 0.7). CBT led to reductions in paranoia (-20.8; 95% CI, -43.2 to 1.7; = -0.6), although CIs were wide. Three serious adverse events were deemed unrelated to participation (CBT = 2, TAU = 1).

Conclusions: CBT for nightmares is feasible and may be efficacious for treating nightmares and comorbid insomnia for patients with persecutory delusions. It shows promise on paranoia but potentially not on suicidal ideation.
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http://dx.doi.org/10.1177/0706743719847422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783669PMC
October 2019

The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data.

Lancet Psychiatry 2019 03 11;6(3):235-246. Epub 2019 Feb 11.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom; Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Electronic address:

Background: Early immunotherapy administration improves outcomes in patients with N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis. As most patients with NMDAR-antibody encephalitis present to psychiatrists, the psychopathology of NMDAR-antibody encephalitis needs to be clearly defined to encourage accurate clinical identification and prompt treatment.

Methods: For this systematic review, we searched PubMed for all studies published in English between Jan 1, 2005, and Oct 7, 2017, to identify individually reported adult patients (≥18 years) who satisfied consensus criteria for definite NMDAR-antibody encephalitis. After generating a list of 50 fine-grained, lower-level features, we extracted psychopathological data in addition to demographic and aetiological data. The lower-level features were later ordered within higher-level categories. As a means of quality control, we filtered the data according to proxy markers of psychiatric involvement in their description. Subsequently, we compared lower-level features from individual patient data with operationalised psychiatric syndromes using a constrained combination approach and principal component analysis, and did a network analysis to explore the inter-relationships between multiple lower-level features. The review protocol was prospectively registered with PROSPERO, number CRD42017068981.

Findings: Of 1096 records identified in PubMed, 333 satisfied inclusion criteria and described 1100 patients in total with NMDAR-antibody encephalitis. The psychopathology of 505 (46%) patients with reported psychiatric symptoms was described in more detailed terms than only psychiatric or behavioural. 464 (91%) of the 505 patients were from papers in which patient data were reported individually. The remainder of the analyses focused exclusively on these 464 patients. Median age was 27 years (IQR 22-34), 368 (79%) of 464 patients were female and in 147 (32%), NMDAR-antibody encephalitis was associated with ovarian teratoma. The five higher-level categories into which the 464 patients most frequently grouped were behaviour (316 [68%]), psychosis (310 [67%]), mood (219 [47%]), catatonia (137 [30%]), and sleep disturbance (97 [21%]). The overall pattern of lower-level features was statistically stable across subgroups classified by age, sex, pregnancy association, presence of ovarian teratoma, prior herpes simplex virus encephalitis, and isolated psychiatric presentations (two-way ANOVA p=0·6-0·9). Constrained combination and principal component analyses found that mixtures of mood and psychosis syndromes fit each patient better than any single diagnosis alone, particularly for the patients in the psychiatric-described subgroup (mean ΔAkaike information criterion -0·04 in non-psychiatric-described subgroup vs 0·61 in psychiatric-described subgroup). The overlapping nature of the higher-level features was also enriched upon analysis of the psychiatric-described data (221 [67%] of 329 overlaps in non-psychiatric-described subgroup vs 96 [81%] of 118 overlaps in psychiatric-described subgroup, p=0·0052). Network analysis confirmed that the features were closely related and consistent between individual patients; the psychiatric-described subgroup had a markedly high and narrow range of closeness centralities (92% above 0·93 in psychiatric-described subgroup vs 51% above 0·93 in the non-psychiatric group).

Interpretation: The distinctive aspect of NMDAR-antibody encephalitis psychopathology is complexity; core aspects of mood and psychotic disorders consistently coexist within individual patients. Alongside the predominant young female demographic, these psychopathological features could help psychiatrists identify patients who would benefit from cerebrospinal fluid testing and immunotherapies. Well-controlled prospective studies with bespoke inventories are needed to advance this clinically grounded approach.

Funding: Wellcome Trust, NIHR Oxford Biomedical Research Centre, NIHR Oxford Health Biomedical Research Centre, British Medical Association Foundation for Medical Research.
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http://dx.doi.org/10.1016/S2215-0366(19)30001-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384244PMC
March 2019

The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS): study protocol for a randomised controlled, experimental medicine study.

Trials 2019 Feb 12;20(1):120. Epub 2019 Feb 12.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, UK.

Background: The discovery that voltage-gated calcium channel genes such as CACNA1C are part of the aetiology of psychiatric disorders has rekindled interest in the therapeutic potential of L-type calcium channel (LTCC) antagonists. These drugs, licensed to treat hypertension and angina, have previously been used in bipolar disorder, but without clear results. Neither is much known about the broader effects of these drugs on the brain and behaviour.

Methods: The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS) is a high-intensity randomised, double-blind, placebo-controlled experimental medicine study on the effect of the LTCC antagonist nicardipine in healthy young adults with mood instability. An array of cognitive, psychiatric, circadian, physiological, biochemical and neuroimaging (functional magnetic resonance imaging and magnetoencephalography) parameters are measured during a 4-week period, with randomisation to drug or placebo on day 14. We are interested in whether nicardipine affects the stability of these measures, as well as its overall effects. Participants are genotyped for the CACNA1C risk polymorphism rs1006737.

Discussion: The results will clarify the potential of LTCC antagonists for repurposing or modification for use in psychiatric disorders in which cognition, mood and sleep are affected.

Trial Registration: ISRCTN, ISRCTN33631053 . Retrospectively registered on 8 June 2018 (applied 17 May 2018).
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http://dx.doi.org/10.1186/s13063-019-3175-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373140PMC
February 2019

Large-scale roll out of electronic longitudinal mood-monitoring for research in affective disorders: Report from the UK bipolar disorder research network.

J Affect Disord 2019 03 25;246:789-793. Epub 2018 Dec 25.

Psychological Medicine, University of Worcester, Henwick Grove, Worcester, WR2 6AJ, UK. Electronic address:

Background: Electronic longitudinal mood monitoring has been shown to be acceptable to patients with affective disorders within clinical settings, but its use in large-scale research has not yet been established.

Methods: Using both postal and email invitations, we invited 4080 past research participants with affective disorders who were recruited into the Bipolar Disorder Research Network (BDRN) over a 10 year period to participate in online weekly mood monitoring. In addition, since January 2015 we have invited all newly recruited BDRN research participants to participate in mood monitoring at the point they were recruited into BDRN.

Results: Online mood monitoring uptake among past participants was 20%, and among new participants to date was 46% with participants recruited over the last year most likely to register (61%). More than 90% mood monitoring participants engaged for at least one month, with mean engagement period greater than one year (58 weeks) and maximum engagement for longer than three years (165 weeks). There were no significant differences in the proportion of past and new BDRN participants providing data for at least 4 weeks (91%, 92% respectively), 3 months (78%, 82%), 6 months (65%, 54%) or one year (51%, 44%).

Limitations: Our experiences with recruiting participants for electronic prospective mood monitoring may not necessarily generalise fully to research situations that are very different from those we describe.

Conclusions: Large-scale electronic longitudinal mood monitoring in affective disorders for research purposes is feasible with uptake highest among newly recruited participants.
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http://dx.doi.org/10.1016/j.jad.2018.12.099DOI Listing
March 2019

Altered hippocampal gene expression and structure in transgenic mice overexpressing neuregulin 1 (Nrg1) type I.

Transl Psychiatry 2018 10 22;8(1):229. Epub 2018 Oct 22.

Department of Psychiatry, University of Oxford, Oxford, UK.

Transgenic mice overexpressing the type I isoform of neuregulin 1 (Nrg1; NRG1) have alterations in hippocampal gamma oscillations and an age-emergent deficit in hippocampus-dependent spatial working memory. Here, we examined the molecular and morphological correlates of these findings. Microarrays showed over 100 hippocampal transcripts differentially expressed in Nrg1 mice, with enrichment of genes related to neuromodulation and, in older mice, of genes involved in inflammation and immunity. Nrg1 mice had an enlarged hippocampus with a widened dentate gyrus. The results show that Nrg1 type I impacts on hippocampal gene expression and structure in a multifaceted and partly age-related way, complementing the evidence implicating Nrg1 signaling in aspects of hippocampal function. The findings are also relevant to the possible role of NRG1 signaling in the pathophysiology of schizophrenia or other disorders affecting this brain region.
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http://dx.doi.org/10.1038/s41398-018-0288-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197224PMC
October 2018

Genetics of self-reported risk-taking behaviour, trans-ethnic consistency and relevance to brain gene expression.

Transl Psychiatry 2018 09 4;8(1):178. Epub 2018 Sep 4.

Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.

Risk-taking behaviour is an important component of several psychiatric disorders, including attention-deficit hyperactivity disorder, schizophrenia and bipolar disorder. Previously, two genetic loci have been associated with self-reported risk taking and significant genetic overlap with psychiatric disorders was identified within a subsample of UK Biobank. Using the white British participants of the full UK Biobank cohort (n = 83,677 risk takers versus 244,662 controls) for our primary analysis, we conducted a genome-wide association study of self-reported risk-taking behaviour. In secondary analyses, we assessed sex-specific effects, trans-ethnic heterogeneity and genetic overlap with psychiatric traits. We also investigated the impact of risk-taking-associated SNPs on both gene expression and structural brain imaging. We identified 10 independent loci for risk-taking behaviour, of which eight were novel and two replicated previous findings. In addition, we found two further sex-specific risk-taking loci. There were strong positive genetic correlations between risk-taking and attention-deficit hyperactivity disorder, bipolar disorder and schizophrenia. Index genetic variants demonstrated effects generally consistent with the discovery analysis in individuals of non-British White, South Asian, African-Caribbean or mixed ethnicity. Polygenic risk scores comprising alleles associated with increased risk taking were associated with lower white matter integrity. Genotype-specific expression pattern analyses highlighted DPYSL5, CGREF1 and C15orf59 as plausible candidate genes. Overall, our findings substantially advance our understanding of the biology of risk-taking behaviour, including the possibility of sex-specific contributions, and reveal consistency across ethnicities. We further highlight several putative novel candidate genes, which may mediate these genetic effects.
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http://dx.doi.org/10.1038/s41398-018-0236-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123450PMC
September 2018

D-Amino Acid Oxidase Inhibition: A New Glutamate Twist for Clozapine Augmentation in Schizophrenia?

Authors:
Paul J Harrison

Biol Psychiatry 2018 09;84(6):396-398

Department of Psychiatry, University of Oxford, and Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2018.06.001DOI Listing
September 2018

Host-parasite interaction associated with major mental illness.

Mol Psychiatry 2020 01 20;25(1):194-205. Epub 2018 Aug 20.

Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21205, USA.

Clinical studies frequently report that patients with major mental illness such as schizophrenia and bipolar disorder have co-morbid physical conditions, suggesting that systemic alterations affecting both brain and peripheral tissues might underlie the disorders. Numerous studies have reported elevated levels of anti-Toxoplasma gondii (T. gondii) antibodies in patients with major mental illnesses, but the underlying mechanism was unclear. Using multidisciplinary epidemiological, cell biological, and gene expression profiling approaches, we report here multiple lines of evidence suggesting that a major mental illness-related susceptibility factor, Disrupted in schizophrenia (DISC1), is involved in host immune responses against T. gondii infection. Specifically, our cell biology and gene expression studies have revealed that DISC1 Leu607Phe variation, which changes DISC1 interaction with activating transcription factor 4 (ATF4), modifies gene expression patterns upon T. gondii infection. Our epidemiological data have also shown that DISC1 607 Phe/Phe genotype was associated with higher T. gondii antibody levels in sera. Although further studies are required, our study provides mechanistic insight into one of the few well-replicated serological observations in major mental illness.
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http://dx.doi.org/10.1038/s41380-018-0217-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382596PMC
January 2020

The neuropathology of bipolar disorder: systematic review and meta-analysis.

Mol Psychiatry 2020 08 20;25(8):1787-1808. Epub 2018 Aug 20.

Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.

Various neuropathological findings have been reported in bipolar disorder (BD). However, it is unclear which findings are well established. To address this gap, we carried out a systematic review of the literature. We searched over 5000 publications, identifying 103 data papers, of which 81 were eligible for inclusion. Our main findings can be summarised as follows. First, most studies have relied on a limited number of brain collections, and have used relatively small sample sizes (averaging 12 BD cases and 15 controls). Second, surprisingly few studies have attempted to replicate closely a previous one, precluding substantial meta-analyses, such that the latter were all limited to two studies each, and comprising 16-36 BD cases and 16-74 controls. As such, no neuropathological findings can be considered to have been established beyond reasonable doubt. Nevertheless, there are several replicated positive findings in BD, including decreased cortical thickness and glial density in subgenual anterior cingulate cortex, reduced neuronal density in some amygdalar nuclei, and decreased calbindin-positive neuron density in prefrontal cortex. Many other positive findings have also been reported, but with limited or contradictory evidence. As an important negative result, it can be concluded that gliosis is not a feature of BD; neither is there neuropathological evidence for an inflammatory process.
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http://dx.doi.org/10.1038/s41380-018-0213-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292507PMC
August 2020

Absent sleep EEG spindle activity in GluA1 (Gria1) knockout mice: relevance to neuropsychiatric disorders.

Transl Psychiatry 2018 08 14;8(1):154. Epub 2018 Aug 14.

Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.

Sleep EEG spindles have been implicated in attention, sensory processing, synaptic plasticity and memory consolidation. In humans, deficits in sleep spindles have been reported in a wide range of neurological and psychiatric disorders, including schizophrenia. Genome-wide association studies have suggested a link between schizophrenia and genes associated with synaptic plasticity, including the Gria1 gene which codes for the GluA1 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Gria1 mice exhibit a phenotype relevant for neuropsychiatric disorders, including reduced synaptic plasticity and, at the behavioural level, attentional deficits leading to aberrant salience. In this study we report a striking reduction of EEG power density including the spindle-frequency range (10-15 Hz) during sleep in Gria1 mice. The reduction of spindle-activity in Gria1 mice was accompanied by longer REM sleep episodes, increased EEG slow-wave activity in the occipital derivation during baseline sleep, and a reduced rate of decline of EEG slow wave activity (0.5-4 Hz) during NREM sleep after sleep deprivation. These data provide a novel link between glutamatergic dysfunction and sleep abnormalities in a schizophrenia-relevant mouse model.
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http://dx.doi.org/10.1038/s41398-018-0199-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092338PMC
August 2018

Neuregulin 1 Type I Overexpression Is Associated with Reduced NMDA Receptor-Mediated Synaptic Signaling in Hippocampal Interneurons Expressing PV or CCK.

eNeuro 2018 Mar-Apr;5(2). Epub 2018 May 8.

Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK.

Hypofunction of -methyl-d-aspartate receptors (NMDARs) in inhibitory GABAergic interneurons is implicated in the pathophysiology of schizophrenia (SZ), a heritable disorder with many susceptibility genes. However, it is still unclear how SZ risk genes interfere with NMDAR-mediated synaptic transmission in diverse inhibitory interneuron populations. One putative risk gene is neuregulin 1 (), which signals via the receptor tyrosine kinase ErbB4, itself a schizophrenia risk gene. The type I isoform of shows increased expression in the brain of SZ patients, and ErbB4 is enriched in GABAergic interneurons expressing parvalbumin (PV) or cholecystokinin (CCK). Here, we investigated ErbB4 expression and synaptic transmission in interneuronal populations of the hippocampus of transgenic mice overexpressing NRG1 type I (NRG1 mice). Immunohistochemical analyses confirmed that ErbB4 was coexpressed with either PV or CCK in hippocampal interneurons, but we observed a reduced number of ErbB4-immunopositive interneurons in the NRG1 mice. NMDAR-mediated currents in interneurons expressing PV (including PV basket cells) or CCK were reduced in NRG1 mice compared to their littermate controls. We found no difference in AMPA receptor-mediated currents. Optogenetic activation (5 pulses at 20 Hz) of local glutamatergic fibers revealed a decreased NMDAR-mediated contribution to disynaptic GABAergic inhibition of pyramidal cells in the NRG1 mice. GABAergic synaptic transmission from either PV or CCK interneurons, and glutamatergic transmission onto pyramidal cells, did not significantly differ between genotypes. The results indicate that synaptic NMDAR-mediated signaling in hippocampal interneurons is sensitive to chronically elevated NGR1 type I levels. This may contribute to the pathophysiological consequences of increased expression in SZ.
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http://dx.doi.org/10.1523/ENEURO.0418-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938717PMC
January 2019