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Several large-scale electronic health records studies have reported increased diagnostic rates for neuropsychiatric disorders following Coronavirus disease 2019 [COVID-19 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 infection)], but many questions remain. To highlight the issues, we selectively review this literature, focusing on mood disorder, anxiety disorder, psychotic disorder, and cognitive impairment (‘brain fog’). Eight key questions are addressed, comprising: (i) the nature and magnitude of the risks; (ii) their association with severity of infection; (iii) their duration; (iv) whether the risks differ between adults and children, or between men and women; (v) whether prior vaccination protects against them; (vi) the risk profile associated with different SARS-CoV-2 strains; (vii) what the underlying mechanisms might be; and (viii) whether the sequelae can be predicted. We consider the major unknowns, the limitations of electronic health records for research in this area, and the use of additional approaches to help characterize and understand the neuropsychiatric burden of COVID-19.

A role for voltage-gated calcium channels (VGCCs) in psychiatric disorders has long been postulated as part of a broader involvement of intracellular calcium signalling. However, the data were inconclusive and hard to interpret. We review three areas of research that have markedly advanced the field. First, there is now robust genomic evidence that common variants in VGCC subunit genes, notably CACNA1C which encodes the L-type calcium channel (LTCC) CaV1.2 subunit, are trans-diagnostically associated with psychiatric disorders including schizophrenia and bipolar disorder. Rare variants in these genes also contribute to the risk. Second, pharmacoepidemiological evidence supports the possibility that calcium channel blockers, which target LTCCs, might have beneficial effects on the onset or course of these disorders. This is especially true for calcium channel blockers that are brain penetrant. Third, long-range sequencing is revealing the repertoire of full-length LTCC transcript isoforms. Many novel and abundant CACNA1C isoforms have been identified in human and mouse brain, including some which are enriched compared to heart or aorta, and predicted to encode channels with differing functional and pharmacological properties. These isoforms may contribute to the molecular mechanisms of genetic association to psychiatric disorders. They may also enable development of therapeutic agents that can preferentially target brain LTCC isoforms and be of potential value for psychiatric indications.

SummaryAn antiviral effect of lithium has been proposed, but never investigated for coronavirus disease 2019 (COVID-19). Using electronic health records of 26 554 patients with documented serum lithium levels during the pandemic, we show that the 6-month COVID-19 infection incidence was lower among matched patients with ‘therapeutic’ (0.50–1.00) versus ‘subtherapeutic’ (0.05–0.50) lithium levels (hazard ratio (HR) = 0.82, 95% CI 0.69–0.97, P = 0.017) and among patients with ‘therapeutic’ lithium levels versus matched patients using valproate (HR = 0.79, 95% CI 0.67–0.92, P = 0.0023). Lower rates of infection were observed for both new COVID-19 diagnoses and positive polymerase chain reaction tests, regardless of underlying psychiatric diagnosis and vaccination status.

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an “end-on” manner. uSTA-guided modeling and a high-resolution cryo–electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis.

Background COVID-19 is associated with increased risks of neurological and psychiatric sequelae in the weeks and months thereafter. How long these risks remain, whether they affect children and adults similarly, and whether SARS-CoV-2 variants differ in their risk profiles remains unclear. Methods In this analysis of 2-year retrospective cohort studies, we extracted data from the TriNetX electronic health records network, an international network of de-identified data from health-care records of approximately 89 million patients collected from hospital, primary care, and specialist providers (mostly from the USA, but also from Australia, the UK, Spain, Bulgaria, India, Malaysia, and Taiwan). A cohort of patients of any age with COVID-19 diagnosed between Jan 20, 2020, and April 13, 2022, was identified and propensity-score matched (1:1) to a contemporaneous cohort of patients with any other respiratory infection. Matching was done on the basis of demographic factors, risk factors for COVID-19 and severe COVID-19 illness, and vaccination status. Analyses were stratified by age group (age Findings We identified 1 487 712 patients with a recorded diagnosis of COVID-19 during the study period, of whom 1 284 437 (185 748 children, 856 588 adults, and 242 101 older adults; overall mean age 42·5 years [SD 21·9]; 741 806 [57·8%] were female and 542 192 [42·2%] were male) were adequately matched with an equal number of patients with another respiratory infection. The risk trajectories of outcomes after SARS-CoV-2 infection in the whole cohort differed substantially. While most outcomes had HRs significantly greater than 1 after 6 months (with the exception of encephalitis; Guillain-Barré syndrome; nerve, nerve root, and plexus disorder; and parkinsonism), their risk horizons and time to equal incidence varied greatly. Risks of the common psychiatric disorders returned to baseline after 1–2 months (mood disorders at 43 days, anxiety disorders at 58 days) and subsequently reached an equal overall incidence to the matched comparison group (mood disorders at 457 days, anxiety disorders at 417 days). By contrast, risks of cognitive deficit (known as brain fog), dementia, psychotic disorders, and epilepsy or seizures were still increased at the end of the 2-year follow-up period. Post-COVID-19 risk trajectories differed in children compared with adults: in the 6 months after SARS-CoV-2 infection, children were not at an increased risk of mood (HR 1·02 [95% CI 0·94–1·10) or anxiety (1·00 [0·94–1·06]) disorders, but did have an increased risk of cognitive deficit, insomnia, intracranial haemorrhage, ischaemic stroke, nerve, nerve root, and plexus disorders, psychotic disorders, and epilepsy or seizures (HRs ranging from 1·20 [1·09–1·33] to 2·16 [1·46–3·19]). Unlike adults, cognitive deficit in children had a finite risk horizon (75 days) and a finite time to equal incidence (491 days). A sizeable proportion of older adults who received a neurological or psychiatric diagnosis, in either cohort, subsequently died, especially those diagnosed with dementia or epilepsy or seizures. Risk profiles were similar just before versus just after the emergence of the alpha variant (n=47 675 in each cohort). Just after (vs just before) the emergence of the delta variant (n=44 835 in each cohort), increased risks of ischaemic stroke, epilepsy or seizures, cognitive deficit, insomnia, and anxiety disorders were observed, compounded by an increased death rate. With omicron (n=39 845 in each cohort), there was a lower death rate than just before emergence of the variant, but the risks of neurological and psychiatric outcomes remained similar. Interpretation This analysis of 2-year retrospective cohort studies of individuals diagnosed with COVID-19 showed that the increased incidence of mood and anxiety disorders was transient, with no overall excess of these diagnoses compared with other respiratory infections. In contrast, the increased risk of psychotic disorder, cognitive deficit, dementia, and epilepsy or seizures persisted throughout. The differing trajectories suggest a different pathogenesis for these outcomes. Children have a more benign overall profile of psychiatric risk than do adults and older adults, but their sustained higher risk of some diagnoses is of concern. The fact that neurological and psychiatric outcomes were similar during the delta and omicron waves indicates that the burden on the health-care system might continue even with variants that are less severe in other respects. Our findings are relevant to understanding individual-level and population-level risks of neurological and psychiatric disorders after SARS-CoV-2 infection and can help inform our responses to them. Funding National Institute for Health and Care Research Oxford Health Biomedical Research Centre, The Wolfson Foundation, and MQ Mental Health Research.

Post-COVID cognitive deficits (often referred to as ‘brain fog’) are common and have large impacts on patients’ level of functioning. No specific intervention exists to mitigate this burden. This study tested the hypothesis, inspired by recent experimental research, that post-COVID cognitive deficits can be prevented by inhibiting receptor-interacting protein kinase. Using electronic health record data, we compared the cognitive outcomes of propensity score-matched cohorts of patients with epilepsy taking phenytoin (a commonly used receptor-interacting protein kinase inhibitor) versus valproate or levetiracetam at the time of COVID-19 diagnosis. Patients taking phenytoin at the time of COVID-19 were at a significantly lower risk of cognitive deficits in the 6 months after COVID-19 infection than a matched cohort of patients receiving levetiracetam (hazard ratio 0.78, 95% confidence interval 0.63–0.97, P = 0.024) or valproate (hazard ratio 0.73, 95% confidence interval 0.58–0.93, P = 0.011). In secondary analyses, results were robust when controlling for subtype of epilepsy, and showed specificity to cognitive deficits in that similar associations were not seen with other ‘long-COVID’ outcomes such as persistent breathlessness or pain. These findings provide pharmacoepidemiological support for the hypothesis that receptor-interacting protein kinase signaling is involved in post-COVID cognitive deficits. These results should prompt empirical investigations of receptor-interacting protein kinase inhibitors in the prevention of post-COVID cognitive deficits.

Calcium channel blockers (CCBs) differ in their ability to penetrate into the brain. Pharmacoepidemiological studies suggest that CCBs as a class may have beneficial effects on the risks and outcomes of some psychiatric and neurological disorders. It is plausible but unknown whether this effect relates to their brain penetrance. To address this, we used the TriNetX electronic health records network to identify people prescribed a brain-penetrant CCB (BP-CCB), or those given amlodipine, a CCB with low brain penetrability. We created cohorts of patients who, prior to first CCB exposure, either had to have, or could not have had, a recorded ICD-10 diagnosis in any of the following categories: psychotic disorder; affective disorder (including bipolar disorder and major depressive disorder); anxiety disorder; substance use disorder; sleep disorder; delirium; dementia, or movement disorder. Cohort pairs were propensity score matched for age, sex, race, blood pressure, body mass index, and a range of other variables. The outcomes were the incidence of these disorders measured over a two-year exposure period. Matched cohort sizes ranged from 17,896 to 49,987. In people with no prior history of psychiatric or neurodegenerative disorder, there was a significantly lower incidence of most disorders with BP-CCBs compared to amlodipine, with risk ratios ranging from 0.64 to 0.88 and an overall risk ratio of 0.88, i.e. a risk reduction of 12%. In people who did have a prior psychiatric or neurodegenerative diagnosis, differences were much smaller, but again showed lower risks for several disorders with BP-CCBs compared to amlodipine. The differences were somewhat more marked in women and in people less than 60 years old. Results were similar when comparing BP-CCBs with verapamil and diltiazem. We also compared BP-CCBs with angiotensin receptor blockers, and found an overall risk ratio of 0.94 in favour of BP-CCBs, but with differential effects across disorders including a higher risk of psychotic disorder and dementia, but a lower risk for anxiety and sleep disorders. In some analyses, there was evidence of residual confounding even after the extensive matching, in that negative control outcomes showed a reduced incidence with BP-CCBs relative to the comparator cohort. In summary, CCBs that readily penetrate the brain are associated with a lower incidence of neuropsychiatric disorders, especially first diagnoses, compared to CCBs which do not. This may reflect their blockade of neuronal voltage-gated calcium channels. The findings encourage repurposing trials using existing BP-CCBs, and suggest that novel BP-CCBs with enhanced and more selective central actions might have greater therapeutic potential for psychiatric and neurodegenerative disorders.

Funder: National Institute for Health and Care Research, Vaccination has proven effective against infection with SARS-CoV-2, as well as death and hospitalisation following COVID-19 illness. However, little is known about the effect of vaccination on other acute and post-acute outcomes of COVID-19. Data were obtained from the TriNetX electronic health records network (over 81 million patients mostly in the USA). Using a retrospective cohort study and time-to-event analysis, we compared the incidences of COVID-19 outcomes between individuals who received a COVID-19 vaccine (approved for use in the USA) at least 2 weeks before SARS-CoV-2 infection and propensity score-matched individuals unvaccinated for COVID-19 but who had received an influenza vaccine. Outcomes were ICD-10 codes representing documented COVID-19 sequelae in the 6 months after a confirmed SARS-CoV-2 infection (recorded between January 1 and August 31, 2021, i.e. before the emergence of the Omicron variant). Associations with the number of vaccine doses (1 vs. 2) and age (

After a period of withdrawal, pharmaceutical companies have begun to reinvest in neuropsychiatric disorders, due to improvements in our understanding of these disorders, stimulated in part by genomic studies. However, translating this information into disease insights and ultimately into tractable therapeutic targets is a major challenge. Here we consider how different sources of information might be integrated to guide this process. We review how an understanding of neurobiology has been used to advance therapeutic candidates identified in the pre-genomic era, using catechol-O-methyltransferase (COMT) as an exemplar. We then contrast with ZNF804A, the first genome-wide significant schizophrenia gene, and draw on some of the lessons that these and other examples provide. We highlight that, at least in the short term, the translation of potential targets for which there is orthogonal neurobiological support is likely to be more straightforward and productive than that those relying solely on genomic information. Although we focus here on information from genomic studies of schizophrenia, the points are broadly applicable across major psychiatric disorders and their symptoms.

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.

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.

Hippocampal theta-band oscillations are thought to facilitate the co-ordination of brain activity across distributed networks, including between the hippocampus and prefrontal cortex (PFC). Impairments in hippocampus-PFC functional connectivity are implicated in schizophrenia and are associated with a polymorphism within the ZNF804A gene that shows a genome-wide significant association with schizophrenia. However, the mechanisms by which ZNF804A affects hippocampus-PFC connectivity are unknown. We used a multimodal imaging approach to investigate the impact of the ZNF804A polymorphism on hippocampal theta and hippocampal network coactivity. Healthy volunteers homozygous for the ZNF804A rs1344706 (A[risk]/C[nonrisk]) polymorphism were imaged at rest using both magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). A dual-regression approach was used to investigate coactivations between the hippocampal network and other brain regions for both modalities, focusing on the theta band in the case of MEG. We found a significant decrease in intrahippocampal theta (using MEG) and greater coactivation of the superior frontal gyrus with the hippocampal network (using fMRI) in risk versus nonrisk homozygotes. Furthermore, these measures showed a significant negative correlation. Our demonstration of an inverse relationship between hippocampal theta and hippocampus-PFC coactivation supports a role for hippocampal theta in coordinating hippocampal-prefrontal activity. The ZNF804A-related differences that we find in hippocampus-PFC coactivation are consistent with previously reported associations with functional connectivity and with these changes lying downstream of altered hippocampal theta. Changes in hippocampal-PFC co-ordination, driven by differences in oscillatory activity, may be one mechanism by which ZNF804A impacts on brain function and risk for psychosis. Hum Brain Mapp 36:2387–2395, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Group II metabotropic glutamate receptors (mGlu2 and mGlu3, encoded by GRM2 and GRM3) have been implicated in both cognitive and emotional processes, although their precise role remains to be established. Studies with knockout (KO) mice provide an important approach for investigating the role of specific receptor genes in behaviour. In the present series of experiments we extended our prior characterisation of GRM2/3(-/-) double KO mice and, in complementary experiments, investigated the behavioural phenotype of single GRM2(-/-) and GRM3(-/-) mice. We found no consistent effect on anxiety in either the double or single KO mice. The lack of an anxiety phenotype in any of the lines contrasts with the clear anxiolytic effects of mGlu2/3 ligands. Motor co-ordination was impaired in GRM2/3(-/-) mice, but spared in single GRM2(-/-) and GRM3(-/-) mice. Spatial working memory (rewarded alternation) testing on the elevated T-maze revealed a deficit in GRM2(-/-) mice throughout testing, whereas GRM3(-/-) mice exhibited a biphasic effect (initially impaired, but performing better than controls by the end of training). A biphasic effect on activity levels was seen for the GRM2(-/-) mice. Overall, the phenotype in both GRM2(-/-) and GRM3(-/-) mice was less pronounced - if present at all - compared to GRM2/3(-/-) mice, across the range of task domains. This is consistent with possible redundancy of function and/or compensation in the single KO lines. Results are discussed with reference to a possible role for group II metabotropic glutamate receptors at the interface between arousal and behavioural performance, according to an inverted U-shaped function.

Introduction. Gabapentin has been extensively prescribed off-label for psychiatric indications, with little established evidence of efficacy. Both gabapentin and pregabalin, a very similar drug with the same mechanism of action, bind to a subunit of voltage dependent calcium channels, which are implicated in the aetiopathogenesis of bipolar disorder, anxiety and insomnia. This systematic review and meta-analysis aims to collect and critically appraise all the available evidence about efficacy and tolerability of gabapentin and pregabalin in the treatment of bipolar disorder, insomnia and anxiety. Methods and analysis. We will include all randomized controlled trials reported as double-blind and comparing gabapentin or pregabalin with placebo or any other active pharmacological treatment (any preparation, dose, frequency, route of delivery or setting) in patients with bipolar disorder, anxiety or insomnia. For consideration of adverse effects (tolerability), single blind or open label RCTs and non-randomised evidence will also be summarised. The main outcomes will be efficacy (measured both as dichotomous and continuous outcome) and acceptability (proportion of patients who dropped out of the allocated treatment). Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least two independent reviewers. We will conduct a random-effects meta-analysis to synthesize all evidence for each outcome. Heterogeneity between studies will be investigated by the I2 statistic. Data from included studies will be entered into a funnel plot for investigation of small-study effects. No subgroup analysis will be undertaken, but we will carry out sensitivity analyses about combination treatment, psychiatric comorbidity, use of rescue medications and fixed versus random-effects model.

Schizophrenia is one of the most complex and disabling diseases to affect mankind. Relatively little is known about its nature and its origins, and available treatments are inadequate for most patients. As a result, there are inevitable controversies about what causes it, how to diagnose it, and how best to treat it. However, in the past decade, there has been an explosion of new research, with dramatic discoveries involving genetic etiology and epidemiological risk factors. There has also been a catalog of new drugs coming to market, and controversy about the relative advantages and disadvantages of newer compared with older therapies. In addition, developing technologies in genomics, molecular biology and neuroimaging provide streams of new information. This book represents a definitive, essential, and up-to-date reference text on schizophrenia. It extensively and critically digests and clarifies recent advances and places them within a clinical context. The Editors (one American and one British), highly respected clinical psychiatrists and researchers and acknowledged experts on schizophrenia, have again assembled an outstanding group of contributors from the USA, UK, Europe and Australia, It will be of value to practising psychiatrists and to trainees, as well as to clinical and neuroscience researchers interested in keeping up with this field or coming into it. The book consists of four sections: Descriptive aspects, biological aspects, physical treatments, and psychological and social aspects. It reviews the theoretical controversies over symptomatology, classification and aetiology (particularly pertinent as DSM-V is being developed), the relationship of schizophrenia to the other psychoses, the significance of positive and negative symptoms and pre-morbid personality. It describes a variety of approaches to integrating the vast research data about schizophrenia, including neurodevelopmental, genetic, pharmacological, brain imaging and psychological findings. The biological treatment section reviews the comparative efficacy of various drugs, the management of drug-resistant patients and both neurological and metabolic complications. The final section looks at psychological therapies, social outcomes, and the economics of schizophrenia. Highly Commended in the Psychiatry section of the 2012 BMA Book Awards. © 2011 Blackwell Publishing Ltd.

The classification procedure of streaming data usually requires various ad hoc methods or particular heuristic models. We explore a novel non-parametric and systematic approach to analysis of heterogeneous sequential data. We demonstrate an application of this method to classification of the delays in responding to the prompts, from subjects with bipolar disorder collected during a clinical trial, using both synthetic and real examples. We show how this method can provide a natural and systematic way to extract characteristic features from sequential data., 16 pages, 7 figures

Disruption of the serotonergic system is suggested to be involved in suicidal behaviour and depression. Results from polymorphism studies have been equivocal in their appraisal of a genetic contribution to this involvement. In the current investigation, the frequencies of the 5-HT2A receptor (T102C) and 5-HT2C receptor (Cys23Ser) polymorphisms were examined in a well-characterised sample of deliberate self-harm (DSH) patients and in healthy controls. DSH patients (n= 144) were recruited from the general hospital in Oxford (UK) as part of the WHO/EURO multicentre study on parasuicide. Interviews were conducted using the European Parasuicide Interview Schedule. Additional psychiatric and personality assessments were carried out using structured interview schedules. Controls (currently n = 265; matched for age, gender and ethnicity) were recruited from local blood donation clinics. Genotyping was performed using PCR-based methods (Marshall et al., 1999. Am J Med Genet. 88; 621-7). Allele frequencies were in Hardy-Weinberg equilibrium. Preliminary Chi-squared (cs) analysis of the 5-HT2A (T102 vs. C102: cs = 0.0) and 5-HT2C (Cys23 vs. Ser23: males-cs = 0.38; females-cs = 0.64) revealed no association between allele frequencies and DSH. Within the DSH group there was no association of allele frequencies with either history of major depression or with a composite score for high suicide risk. These results indicate a lack of association between these polymorphisms and suicidal behaviour.

L-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of ”brain-selective” LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes.

Schizophrenia is a severe mental disorder striking mainly young adults and leading to life-long disability in a substantial portion of the sufferers. On the other hand, substantial knowledge about its etiology and pathogenesis is still lacking. Therefore the European Science Foundation (ESF) sponsored a meeting of a panel of European experts on schizophrenia research to discuss the state of art and future perspectives of key topics in this area. The fields covered genetics, epidemiology, animal models, molecular neuropathology and imaging. This was a first step to establish a network of European groups dedicated to Schizophrenia research. The coming calls of the frame work program will be used to strengthen this network in order to achieve substantial progress in understanding and treating this devastating illness.

The N-methyl-D-aspartate receptor co-agonist d-serine is synthesized by serine racemase and degraded by D-amino acid oxidase. Both D-serine and its metabolizing enzymes are implicated in N-methyl-D-aspartate receptor hypofunction thought to occur in schizophrenia. We studied D-amino acid oxidase and serine racemase immunohistochemically in several brain regions and compared their immunoreactivity and their mRNA levels in the cerebellum and dorsolateral prefrontal cortex in schizophrenia. D-Amino acid oxidase immunoreactivity was abundant in glia, especially Bergmann glia, of the cerebellum, whereas in prefrontal cortex, hippocampus and substantia nigra, it was predominantly neuronal. Serine racemase was principally glial in all regions examined and demonstrated prominent white matter staining. In schizophrenia, D-amino acid oxidase mRNA was increased in the cerebellum, and as a trend for protein. Serine racemase was increased in schizophrenia in the dorsolateral prefrontal cortex but not in cerebellum, while serine racemase mRNA was unchanged in both regions. Administration of haloperidol to rats did not significantly affect serine racemase or D-amino acid oxidase levels. These findings establish the major cell types wherein serine racemase and D-amino acid oxidase are expressed in human brain and provide some support for aberrant D-serine metabolism in schizophrenia. However, they raise further questions as to the roles of D-amino acid oxidase and serine racemase in both physiological and pathophysiological processes in the brain.

Schizophrenia risk gene ZNF804A does not influence macroscopic brain structure: an MRI study in 892 volunteers