Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders - An individual patient data meta-analysis.

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorders(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI -0.55-0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05-0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17-0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptoms severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies.

Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis.

Reduced gut-microbial diversity ("gut dysbiosis") has been associated with an anhedonic/amotivational syndrome ("sickness behavior") that manifests across severe mental disorders and represent the key clinical feature of chronic fatigue. In this systematic review and meta-analysis, we investigated differences in proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue vs. controls and the association of these biomarkers with sickness behavior across diagnostic categories. Following PRISMA guidelines, we searched from inception to April 2020 for all the studies investigating proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue. Data were independently extracted by multiple observers, and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. Thirty-three studies were included in the systematic review; nineteen in the meta-analysis (N = 2758 patients and N = 1847 healthy controls). When compared to controls, patients showed increased levels of zonulin (four studies reporting data on bipolar disorder and depression, SMD = 0.97; 95% Cl = 0.10-1.85; P = 0.03, I2 = 86.61%), lipopolysaccharide (two studies reporting data on chronic fatigue and depression, SMD = 0.77; 95% Cl = 0.42-1.12; P < 0.01; I2 = 0%), antibodies against endotoxin (seven studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.99; 95% CI = 0.27-1.70; P < 0.01, I2 = 97.14%), sCD14 (six studies reporting data on bipolar disorder, depression, schizophrenia, and chronic fatigue, SMD = 0.54; 95% Cl 0.16-0.81; P < 0.01, I2 = 90.68%), LBP (LBP, two studies reporting data on chronic fatigue and depression, SMD = 0.87; 95% Cl = 0.25-1.48; P < 0.01; I2 = 56.80%), alpha-1-antitripsin (six studies reporting data on bipolar disorder, depression, and schizophrenia, SMD = 1.23; 95% Cl = 0.57-1.88; P < 0.01, I2: 89.25%). Elevated levels of gut dysbiosis markers positively correlated with severity of sickness behavior in patients with severe mental illness and chronic fatigue. Our findings suggest that gut dysbiosis may underlie symptoms of sickness behavior across traditional diagnostic boundaries. Future investigations should validate these findings comparing the performances of the trans-diagnostic vs. categorical approach. This will facilitate treatment breakthrough in an area of unmet clinical need.

The serum metabolomic profile of a distinct, inflammatory subtype of acute psychosis.

A range of studies suggest that a proportion of psychosis may have an autoimmune basis, but this has not translated through into clinical practice-there is no biochemical test able to accurately identify psychosis resulting from an underlying inflammatory cause. Such a test would be an important step towards identifying who might require different treatments and have the potential to improve outcomes for patients. To identify novel subgroups within patients with acute psychosis we measured the serum nuclear magnetic resonance (NMR) metabolite profiles of 75 patients who had identified antibodies (anti-glycine receptor [GlyR], voltage-gated potassium channel [VGKC], Contactin-associated protein-like 2 [CASPR2], leucine-rich glioma inactivated 1 [LGI1], N-methyl-D-aspartate receptor [NMDAR] antibody) and 70 antibody negative patients matched for age, gender, and ethnicity. Clinical symptoms were assessed using the positive and negative syndrome scale (PANSS). Unsupervised principal component analysis identified two distinct biochemical signatures within the cohort. Orthogonal partial least squared discriminatory analysis revealed that the serum metabolomes of NMDAR, LGI1, and CASPR2 antibody psychosis patients were indistinct from the antibody negative control group while VGKC and GlyR antibody patients had significantly decreased lipoprotein fatty acids and increased amino acid concentrations. Furthermore, these patients had more severe presentation with higher PANSS scores than either the antibody negative controls or the NMDAR, LGI1, and CASPR2 antibody groups. These results suggest that a proportion of patients with acute psychosis have a distinct clinical and biochemical phenotype that may indicate an inflammatory subtype.

Cervical lymph nodes and ovarian teratomas as germinal centres in NMDA receptor-antibody encephalitis.

Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P < 0.0001). Within patients, ovarian teratoma status was associated with a higher frequency of NR1-IgA positivity in serum (OR = 3.1; P < 0.0001) and CSF (OR = 3.8, P = 0.047), particularly early in disease and before ovarian teratoma resection. Consistent with this immunoglobulin class bias, ovarian teratoma samples showed intratumoral production of both NR1-IgG and NR1-IgA and, by single cell RNA sequencing, contained expanded highly-mutated IgA clones with an ovarian teratoma-restricted B cell population. Multiplex histology suggested tertiary lymphoid architectures in ovarian teratomas with dense B cell foci expressing the germinal centre marker BCL6, CD21+ follicular dendritic cells, and the NR1 subunit, alongside lymphatic vessels and high endothelial vasculature. Cultured teratoma explants and dissociated intratumoral B cells secreted NR1-IgGs in culture. Hence, ovarian teratomas showed structural and functional evidence of NR1-specific germinal centres. On exploring classical secondary lymphoid organs, B cells cultured from cervical lymph nodes of patients with NMDAR-antibody encephalitis produced NR1-IgG in 3/7 cultures, from patients with the highest serum NR1-IgG levels (P < 0.05). By contrast, NR1-IgG secretion was observed neither from cervical lymph nodes in disease controls nor in patients with adequately resected ovarian teratomas. Our multimodal evaluations provide convergent anatomical and functional evidence of NMDAR-autoantibody production from active germinal centres within both intratumoral tertiary lymphoid structures and traditional secondary lymphoid organs, the cervical lymph nodes. Furthermore, we develop a cervical lymph node sampling protocol that can be used to directly explore immune activity in health and disease at this emerging neuroimmune interface.

Time to re-evaluate the risks and benefits of valproate and a call for action.

Valproate is widely used in psychiatry and neurology, including off-label use. Here we consider its potential benefits and risks, particularly for women of childbearing potential, and the evidence that clinical guidelines are adhered to. Finally, we consider the implications for clinical practice and research into its efficacy in off-label indications.

Autoantibody-associated psychiatric syndromes: a systematic literature review resulting in 145 cases.

BACKGROUND: Autoimmune encephalitis (AE) is an important consideration during the diagnostic work-up of secondary mental disorders. Indeed, isolated psychiatric syndromes have been described in case reports of patients with underlying AE. Therefore, the authors performed a systematic literature review of published cases with AE that have predominant psychiatric/neurocognitive manifestations. The aim of this paper is to present the clinical characteristics of these patients. METHODS: The authors conducted a systematic Medline search via Ovid, looking for case reports/series of AEs with antineuronal autoantibodies (Abs) against cell surface/intracellular antigens combined with predominant psychiatric/neurocognitive syndromes. The same was done for patients with Hashimoto encephalopathy/SREAT. Only patients with signs of immunological brain involvement or tumors in their diagnostic investigations or improvement under immunomodulatory drugs were included. RESULTS: We identified 145 patients with AE mimicking predominant psychiatric/neurocognitive syndromes. Of these cases, 64% were female, and the mean age among all patients was 43.9 (±22.1) years. Most of the patients had Abs against neuronal cell surface antigens (55%), most frequently against the NMDA-receptor (N = 46). Amnestic/dementia-like (39%) and schizophreniform (34%) syndromes were the most frequently reported. Cerebrospinal fluid changes were found in 78%, electroencephalography abnormalities in 61%, and magnetic resonance imaging pathologies in 51% of the patients. Immunomodulatory treatment was performed in 87% of the cases, and 94% of the patients responded to treatment. CONCLUSIONS: Our findings indicate that AEs can mimic predominant psychiatric and neurocognitive disorders, such as schizophreniform psychoses or neurodegenerative dementia, and that affected patients can be treated successfully with immunomodulatory drugs.

Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort.

Anhedonia and amotivation are debilitating symptoms and represent unmet therapeutic needs in a range of clinical conditions. The gut-microbiome-endocannabinoid axis might represent a potential modifiable target for interventions. Based on results obtained from animal models, we tested the hypothesis that the endocannabinoid system mediates the association between gut-microbiome diversity and anhedonia/amotivation in a general population cohort. We used longitudinal data collected from 786 volunteer twins recruited as part the TwinsUK register. Our hypothesis was tested with a multilevel mediation model using family structure as random intercept. The model was set using alpha diversity (within-individual gut-microbial diversity) as predictor, serum and faecal levels of the endocannabinoid palmitoylethanolamide (PEA) as mediator, and anhedonia/amotivation as outcome. PEA is considered the endogenous equivalent of cannabidiol, with increased serum levels believed to have anti-depressive effects, while increased stool PEA levels, reflecting increased excretion, are believed to have opposite, detrimental, effects on mental health. We therefore expected that either reduced serum PEA or increased stool PEA would mediate the association between microbial diversity and anhedonia amotivation. Analyses were adjusted for obesity, diet, antidepressant use, sociodemographic and technical covariates. Data were imputed using multiple imputation by chained equations. Mean age was 65.2 ± 7.6; 93% of the sample were females. We found a direct, significant, association between alpha diversity and anhedonia/amotivation (ß = -0.37; 95%CI: -0.71 to -0.03; P = 0.03). Faecal, but not serum, levels of the endocannabinoid palmitoylethanolamide (PEA) mediated this association: the indirect effect was significant (ß = -0.13; 95%CI: -0.24 to -0.01; P = 0.03), as was the total effect (ß = -0.38; 95%CI: -0.72 to -0.04; P = 0.03), whereas the direct effect of alpha diversity on anhedonia/amotivation was attenuated fully (ß = -0.25; 95%CI: -0.60 to 0.09; P = 0.16). Our results suggest that gut-microbial diversity might contribute to anhedonia/amotivation via the endocannabinoid system. These findings shed light on the biological underpinnings of anhedonia/amotivation and suggest the gut microbiota-endocannabinoid axis as a promising therapeutic target in an area of unmet clinical need.

Mental healthcare clinician engagement with point of care testing; a qualitative study.

BACKGROUND: Point of Care Testing (POCT) is being increasingly used to augment the delivery of physical health care in a variety of settings, but their use in mental health has been limited. Research into understanding the barriers faced for successful implementation of POCT in these settings is lacking. We aimed to identify factors affecting engagement and implementation of POCT within mental health teams by exploring the attitudes to POCT, and the perceived impact POCT has on the practice of mental healthcare clinicians. METHODS: Alongside a study evaluating the impact of a point of care device in Community Mental Health Teams (CMHTs), qualitative interviews were carried out with CMHT clinicians using POCT as part of annual physical checks for patients with severe and enduring mental illness. Data were collected using semi-structured interviews and analysed using thematic analysis. RESULTS: Fifteen clinicians were interviewed across a range of professional backgrounds. Clinicians identified usability of the technology, positive impact on their patient's experience and improved self-efficacy as drivers for successful implementation of POCT into their clinical practice. Issues with device functioning and the potential for a negative effect on the therapeutic relationship with their patients were identified as barriers. Level of physical heath training was not found to be a barrier by mental health professionals to using POCT. CONCLUSIONS: Understanding barriers and drivers for engagement is important to allow co-production of POCT and guidelines to facilitate introduction of POCT into routine clinical practice.

Specialised early intervention teams (extended time) for recent-onset psychosis.

BACKGROUND: Psychosis is an illness characterised by the presence of hallucinations and delusions that can cause distress or a marked change in an individual's behaviour (e.g. social withdrawal, flat or blunted effect). A first episode of psychosis (FEP) is the first time someone experiences these symptoms that can occur at any age, but the condition is most common in late adolescence and early adulthood. This review is concerned with FEP and the early stages of a psychosis, referred to throughout this review as 'recent-onset psychosis.' Specialised early intervention (SEI) teams are community mental health teams that specifically treat people who are experiencing, or have experienced, a recent-onset psychosis. SEI teams provide a range of treatments including medication, psychotherapy, psychoeducation, educational and employment support, augmented by assertive contact with the service user and small caseloads. Treatment is time limited, usually offered for two to three years, after which service users are either discharged to primary care or transferred to a standard adult community mental health team. Evidence suggests that once SEI treatment ends, improvements may not be sustained, bringing uncertainty about the optimal duration of SEI to ensure the best long-term outcomes. Extending SEI has been proposed as a way of providing continued intensive treatment and continuity of care, of usually up to five years, in order to a) sustain the positive initial outcomes of SEI; and b) improve the long-term trajectory of the illness. OBJECTIVES: To compare extended SEI teams with treatment as usual (TAU) for people with recent-onset psychosis. To compare extended SEI teams with standard SEI teams followed by TAU (standard SEI + TAU) for people with recent-onset psychosis. SEARCH METHODS: On 3 October 2018 and 22 October 2019, we searched Cochrane Schizophrenia's study-based register of trials, including registries of clinical trials. SELECTION CRITERIA: We selected all randomised controlled trials (RCTs) comparing extended SEI with TAU for people with recent-onset psychosis and all RCTs comparing extended SEI with standard SEI + TAU for people with recent-onset psychosis. We entered trials meeting these criteria and reporting usable data as included studies. DATA COLLECTION AND ANALYSIS: We independently inspected citations, selected studies, extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous outcomes we calculated the mean difference (MD) and their 95% CIs, or if assessment measures differed for the same construct, we calculated the standardised mean difference (SMD) with 95% CIs. We assessed risk of bias for included studies and created a 'Summary of findings' table using the GRADE approach. MAIN RESULTS: We included three RCTs, with a total 780 participants, aged 16 to 35 years. All participants met the criteria for schizophrenia spectrum disorders or affective psychoses. No trials compared extended SEI with TAU. All three trials randomly allocated people approximately two years into standard SEI to either extended SEI or standard SEI + TAU. The certainty of evidence for outcomes varied from low to very low. Our primary outcomes were recovery and disengagement from mental health services. No trials reported on recovery, and we used remission as a proxy. Three trials reported on remission, with the point estimate suggesting a 13% increase in remission in favour of extended SEI, but this included wide confidence intervals (CIs) and a very uncertain estimate of no benefit (RR 1.13, 95% CI 0.97 to 1.31; 3 trials, 780 participants; very low-certainty evidence). Two trials provided data on disengagement from services with evidence that extended SEI care may result in fewer disengagements from mental health treatment (15%) in comparison to standard SEI + TAU (34%) (RR 0.45, 95% CI 0.27 to 0.75; 2 trials, 380 participants; low-certainty evidence). There may be no evidence of a difference in rates of psychiatric hospital admission (RR 1.55, 95% CI 0.68 to 3.52; 1 trial, 160 participants; low-certainty evidence), or the number of days spent in a psychiatric hospital (MD -2.70, 95% CI -8.30 to 2.90; 1 trial, 400 participants; low-certainty evidence). One trial found uncertain evidence regarding lower global psychotic symptoms in extended SEI in comparison to standard SEI + TAU (MD -1.90, 95% CI -3.28 to -0.52; 1 trial, 156 participants; very low-certainty evidence). It was uncertain whether the use of extended SEI over standard SEI + TAU resulted in fewer deaths due to all-cause mortality, as so few deaths were recorded in trials (RR 0.38, 95% CI 0.09 to 1.64; 3 trials, 780 participants; low-certainty evidence). Very uncertain evidence suggests that using extended SEI instead of standard SEI + TAU may not improve global functioning (SMD 0.23, 95% CI -0.29 to 0.76; 2 trials, 560 participants; very low-certainty evidence). There was low risk of bias in all three trials for random sequence generation, allocation concealment and other biases. All three trials had high risk of bias for blinding of participants and personnel due to the nature of the intervention. For the risk of bias for blinding of outcome assessments and incomplete outcome data there was at least one trial with high or unclear risk of bias. AUTHORS' CONCLUSIONS: There may be preliminary evidence of benefit from extending SEI team care for treating people experiencing psychosis, with fewer people disengaging from mental health services. Evidence regarding other outcomes was uncertain. The certainty of evidence for the measured outcomes was low or very low. Further, suitably powered studies that use a consistent approach to outcome selection are needed, but with only one further ongoing trial, there is unlikely to be any definitive conclusion for the effectiveness of extended SEI for at least the next few years.

Specialised early intervention teams for recent-onset psychosis.

BACKGROUND: Psychosis is an illness characterised by the presence of hallucinations and delusions that can cause distress or a marked change in an individual's behaviour (e.g. social withdrawal, flat or blunted effect). A first episode of psychosis (FEP) is the first time someone experiences these symptoms that can occur at any age, but the condition is most common in late adolescence and early adulthood. This review is concerned with first episode psychosis (FEP) and the early stages of a psychosis, referred to throughout this review as 'recent-onset psychosis.' Specialised early intervention (SEI) teams are community mental health teams that specifically treat people who are experiencing, or have experienced a recent-onset psychosis. The purpose of SEI teams is to intensively treat people with psychosis early in the course of the illness with the goal of increasing the likelihood of recovery and reducing the need for longer-term mental health treatment. SEI teams provide a range of treatments including medication, psychotherapy, psychoeducation, and occupational, educational and employment support, augmented by assertive contact with the service user and small caseloads. Treatment is time limited, usually offered for two to three years, after which service users are either discharged to primary care or transferred to a standard adult community mental health team. A previous Cochrane Review of SEI found preliminary evidence that SEI may be superior to standard community mental health care (described as 'treatment as usual (TAU)' in this review) but these recommendations were based on data from only one trial. This review updates the evidence for the use of SEI services. OBJECTIVES: To compare specialised early intervention (SEI) teams to treatment as usual (TAU) for people with recent-onset psychosis. SEARCH METHODS: On 3 October 2018 and 22 October 2019, we searched Cochrane Schizophrenia's study-based register of trials, including registries of clinical trials. SELECTION CRITERIA: We selected all randomised controlled trials (RCTs) comparing SEI with TAU for people with recent-onset psychosis. We entered trials meeting these criteria and reporting useable data as included studies. DATA COLLECTION AND ANALYSIS: We independently inspected citations, selected studies, extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous outcomes we calculated the mean difference (MD) and their 95% CIs, or if assessment measures differed for the same construct, we calculated the standardised mean difference (SMD) with 95% CIs. We assessed risk of bias for included studies and created a 'Summary of findings' table using the GRADE approach. MAIN RESULTS: We included three RCTs and one cluster-RCT with a total of 1145 participants. The mean age in the trials was between 23.1 years (RAISE) and 26.6 years (OPUS). The included participants were 405 females (35.4%) and 740 males (64.6%). All trials took place in community mental healthcare settings. Two trials reported on recovery from psychosis at the end of treatment, with evidence that SEI team care may result in more participants in recovery than TAU at the end of treatment (73% versus 52%; RR 1.41, 95% CI 1.01 to 1.97; 2 studies, 194 participants; low-certainty evidence). Three trials provided data on disengagement from services at the end of treatment, with fewer participants probably being disengaged from mental health services in SEI (8%) in comparison to TAU (15%) (RR 0.50, 95% CI 0.31 to 0.79; 3 studies, 630 participants; moderate-certainty evidence). There was low-certainty evidence that SEI may result in fewer admissions to psychiatric hospital than TAU at the end of treatment (52% versus 57%; RR 0.91, 95% CI 0.82 to 1.00; 4 studies, 1145 participants) and low-certainty evidence that SEI may result in fewer psychiatric hospital days (MD -27.00 days, 95% CI -53.68 to -0.32; 1 study, 547 participants). Two trials reported on general psychotic symptoms at the end of treatment, with no evidence of a difference between SEI and TAU, although this evidence is very uncertain (SMD -0.41, 95% CI -4.58 to 3.75; 2 studies, 304 participants; very low-certainty evidence). A different pattern was observed in assessment of general functioning with an end of trial difference that may favour SEI (SMD 0.37, 95% CI 0.07 to 0.66; 2 studies, 467 participants; low-certainty evidence). It was uncertain whether the use of SEI resulted in fewer deaths due to all-cause mortality at end of treatment (RR 0.21, 95% CI 0.04 to 1.20; 3 studies, 741 participants; low-certainty evidence). There was low risk of bias for random sequence generation and allocation concealment in three of the four included trials; the remaining trial had unclear risk of bias. Due to the nature of the intervention, we considered all trials at high risk of bias for blinding of participants and personnel. Two trials had low risk of bias and two trials had high risk of bias for blinding of outcomes assessments. Three trials had low risk of bias for incomplete outcome data, while one trial had high risk of bias. Two trials had low risk of bias, one trial had high risk of bias, and one had unclear risk of bias for selective reporting. AUTHORS' CONCLUSIONS: There is evidence that SEI may provide benefits to service users during treatment compared to TAU. These benefits probably include fewer disengagements from mental health services (moderate-certainty evidence), and may include small reductions in psychiatric hospitalisation (low-certainty evidence), and a small increase in global functioning (low-certainty evidence) and increased service satisfaction (moderate-certainty evidence). The evidence regarding the effect of SEI over TAU after treatment has ended is uncertain. Further evidence investigating the longer-term outcomes of SEI is needed. Furthermore, all the eligible trials included in this review were conducted in high-income countries, and it is unclear whether these findings would translate to low- and middle-income countries, where both the intervention and the comparison conditions may be different.

Attitudes to physical healthcare in severe mental illness; a patient and mental health clinician qualitative interview study.

BACKGROUND: People with severe mental illness experience physical health significantly worse than the general population. Physical health monitoring is shared between primary care and secondary mental healthcare services, though there is debate whether mental health teams should provide more physical healthcare. The views of mental health clinicians and patients with mental illness towards physical healthcare provision are unclear. AIMS: To explore the attitudes of Community Mental Health Team (CMHT) clinicians and patients experiencing severe mental illness towards physical healthcare and its provision. DESIGN AND SETTING: Qualitative study in a CMHT setting. METHODS: Interviews were carried out with CMHT clinicians and patients with severe mental illness. Data were collected using semi-structured interviews and analysed using thematic analysis. RESULTS: There were 14 patients and 15 clinicians recruited. Patients varied in their awareness of the association between physical and mental health, but were engaged in physical health monitoring. Clinicians were aware of the importance of physical healthcare but reported barriers to provision, including lack of training, resource constraints and uncertainty in their role. There was no consensus in either group regarding how physical healthcare should be provided, with diverse attitudes expressed for why CMHTs should and shouldn't provide more physical healthcare. CONCLUSIONS: Increasing physical healthcare provision from mental health teams requires healthcare-related barriers be addressed, but it remains unclear whether CMHT clinicians or patients believe this to be a solution.

N-methyl-D-aspartate receptor antibody production from germinal center reactions: Therapeutic implications.

INTRODUCTION: N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1-IgG production and the contribution of germinal center B cells to NR1-IgG levels are unknown. METHODS: Clinical data and longitudinal paired serum NR1-reactive IgM and IgG levels from 10 patients with NMDAR-antibody encephalitis were determined. Peripheral blood mononuclear cells from these 10 patients, and two available ovarian teratomas, were stimulated with combinations of immune factors and tested for secretion of total IgG and NR1-specific antibodies. RESULTS: In addition to disease-defining NR1-IgG, serum NR1-IgM was found in 6 of 10 patients. NR1-IgM levels were typically highest around disease onset and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+ CD27++ CD38++ antibody-secreting cells in vitro and, from 90% of patients, secreted NR1-IgM and NR1-IgG. Secreted levels of NR1-IgG correlated with serum NR1-IgG (p < 0.0001), and this was observed across the varying disease durations, suggestive of an ongoing process. Furthermore, ovarian teratoma tissue contained infiltrating lymphocytes which produced NR1-IgG in culture. INTERPRETATION: Serum NR1-IgM and NR1-IgG, alongside the consistent production of NR1-IgG from circulating B cells and from ovarian teratomas suggest that ongoing germinal center reactions may account for the peripheral cell populations which secrete NR1-IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR-antibody encephalitis. Ann Neurol 2018;83:553-561.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Review of Psychiatric Phenotypes and Management Considerations: A Report of the American Neuropsychiatric Association Committee on Research.

OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder characterized by prominent neuropsychiatric symptoms. Given the nature of its pathophysiology, psychiatrists tend to be one of the first clinicians encountering patients with the disease. METHODS: In the present review of patients described in the literature with psychiatric symptoms, the authors aimed to characterize the psychiatric symptoms of the disease and its management in adults and adolescents as well as children (≤12 years old). A total of 544 patients fulfilled the inclusion criteria. RESULTS: The authors found that 77% of patients with NMDAR encephalitis presented initially with psychiatric symptoms. These were mostly agitation (59%) and psychotic symptoms (in 54%, especially disorganized behavior and visual-auditory hallucinations), with agitation even more commonly being the presenting symptom in children (66%). Where psychotic symptoms were detailed, visual (64%) and auditory (59%) hallucinations were the most common, as well as persecutory delusions (73%). However, delusions were not clearly characterized in most cases. Catatonia was described in 42% of adult patients and 35% of children. Of the patients with documented exposure to antipsychotics, 33% were suspected to have an adverse drug reaction (notably, neuroleptic malignant syndrome in 22% of the cases). CONCLUSIONS: On the basis of these findings, it is important to consider anti-NMDAR encephalitis in the differential diagnosis of patients with an acute onset psychosis, especially in association with agitation, catatonia, or adverse response to antipsychotics. Furthermore, it is important to use antipsychotics with caution in patients with suspected or confirmed anti-NMDAR encephalitis.

Treating Sleep Problems in Young People at Ultra-High Risk of Psychosis: A Feasibility Case Series.

BACKGROUND: Our view is that sleep disturbance may be a contributory causal factor in the development and maintenance of psychotic experiences. A recent series of randomized controlled intervention studies has shown that cognitive-behavioural approaches can improve sleep in people with psychotic experiences. However, the effects of psychological intervention for improving sleep have not been evaluated in young people at ultra-high risk of psychosis. Improving sleep might prevent later transition to a mental health disorder. AIMS: To assess the feasibility and acceptability of an intervention targeting sleep disturbance in young people at ultra-high risk of psychosis. METHOD: Patients were sought from NHS mental health services. Twelve young people at ultra-high risk of psychosis with sleep problems were offered an eight-session adapted CBT intervention for sleep problems. The core treatment techniques were stimulus control, circadian realignment, and regulating day-time activity. Participants were assessed before and after treatment and at a one month follow-up. RESULTS: All eligible patients referred to the study agreed to take part. Eleven patients completed the intervention, and one patient withdrew after two sessions. Of those who completed treatment, the attendance rate was 89% and an average of 7.6 sessions (SD = 0.5) were attended. There were large effect size improvements in sleep. Post-treatment, six patients fell below the recommended cut-off for clinical insomnia. There were also improvements in negative affect and psychotic experiences. CONCLUSION: This uncontrolled feasibility study indicates that treating sleep problems in young people at ultra-high of psychosis is feasible, acceptable, and may be associated with clinical benefits.

Psychosis: an autoimmune disease?

Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B-cell markers CD19 and CD20 achieve genome-wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19+ and reduced CD3+ lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post-mortem studies have found CD3+ and CD20+ lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody-mediated (NSAb) central nervous system disease provides an antigen-specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo-controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis.

Emerging psychiatric syndromes associated with antivoltage-gated potassium channel complex antibodies.

Antibodies against the voltage-gated potassium channel (VGKC) were first recognised as having a potential pathogenic role in disorders of the central nervous system in 2001, with VGKC antibodies described in patients with limbic encephalitis, and the subsequent seminal paper describing the clinical phenotype and immunotherapy treatment responsiveness in 13 patients with VGKC antibodies and limbic encephalitis in 2004. These initial case descriptions were of a progressive neuropsychiatric syndrome with abnormalities of mood, sleep and cognition recognised alongside the neurological symptoms of seizures and autonomic instability. The clinical syndromes associated with VGKC complex (VGKCC) antibodies have broadened considerably over the last 15 years, with multiple cases of more restricted 'formes fruste' presentations associated with VGKCC antibodies being described. However, the relevance of antibodies in these cases has remained controversial. The understanding of the pathogenic nature of VGKC antibodies has further advanced since 2010 with the discovery that VGKC antibodies are not usually antibodies against the VGKC subunits themselves, but instead to proteins that are complexed with the potassium channel, in particular leucine-rich, glioma-inactivated protein 1 (LGI1) and contactin-associated protein 2 (Caspr2). Antibodies against these proteins have been associated with particular, although overlapping, clinical phenotypes, each also including neuropsychiatric features. Our aim is to critically review the association between VGKCC, LGI1 and Caspr2 antibodies with isolated psychiatric presentations-with a focus on cognitive impairment, mood disorders and psychosis. We recommend that screening for VGKCC, LGI1 and Caspr2 antibodies be considered for those with neuropsychiatric presentations.

Clinical relevance of serum antibodies to extracellular N-methyl-D-aspartate receptor epitopes.

OBJECTIVE: There are now a large number of requests for N-methyl-D-aspartate receptor autoantibody (NMDAR-Ab) tests, and it is important to assess the clinical relevance of all results, particularly when they are reported as 'Low Positive'. METHODS: The clinical data of 56 patients found Positive or Low Positive by the Oxford live cell-based assay were reviewed. An autoimmune basis for the condition was assigned as 'Definite', 'Possible' or 'Unlikely'. The number of core features (encephalopathy, psychiatric, cognitive, epileptic, extrapyramidal and inflammatory cerebrospinal fluid (CSF)) was tabulated. RESULTS: Twenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin's lymphoma), 18 (32.1%) a Possible NMDAR-Ab encephalitis and 13 (23.2%) an Unlikely autoimmune syndrome. Serum NMDAR-Ab levels were higher in patients with tumours. Positive NMDAR-Abs were found not only in patients with three or more core features and a Definite syndrome, but also in five patients classified as Possible. Conversely, Low Positive NMDAR-Abs were present in 7 Definite cases as well as in 13 Possible cases. Unlikely patients had mainly Low Positive antibodies and fewer core features. CSF NMDAR-Abs, only available in 11 pairs and at varying time points, broadly related to serum levels and were Positive in 3/3 patients with tumours but in only 2/5 Definite patients, and none of the Possible or Unlikely cases. INTERPRETATION: Using live cell-based assays, Positive and Low Positive antibodies can be of clinical significance. The number of core clinical features should help to select those patients in whom an immunotherapy intervention might be considered, irrespective of the antibody level.

What happens after early intervention? Mapping early intervention in psychosis care pathways in the 12 months after discharge.

AIM: Early intervention services are the established and evidence-based treatment option for individuals with first-episode psychosis. They are time-limited, and care pathways following discharge from these services have had little investigation. We aimed to map care pathways at the end of early intervention treatment to determine common trajectories of care. METHODS: We collected health record data for all individuals treated by early intervention teams in two NHS mental health trusts in England. We collected data on individuals' primary mental healthcare provider for 52 weeks after the end of their treatment and calculated common trajectories of care using sequence analysis. RESULTS: We identified 2224 eligible individuals. For those discharged to primary care we identified four common trajectories: Stable primary care, relapse and return to CMHT, relapse and return to EIP, and discontinuity of care. We also identified four trajectories for those transferred to alternative secondary mental healthcare: Stable secondary care, relapsing secondary care, long-term inpatient and discharged early. The long-term inpatient trajectory (1% of sample) accounted for 29% of all inpatient days in the year follow-up, with relapsing secondary care (2% of sample and 21% of inpatient days), and Relapse and return to CMHT (5% of sample, 15% of inpatient days) the second and third most frequent. CONCLUSIONS: Individuals have common care pathways at the end of early intervention in psychosis treatment. Understanding common individual and service features that lead to poor care pathways could improve care and reduce hospital use.

Approaches and challenges to assessing risk of violence in first episode psychosis: A qualitative interview study of clinicians, patients and carers.

AIM: Clinical services for early psychosis seek to improve prognosis for a range of adverse outcomes. For some individuals, perpetration of violence is an important potential outcome to reduce. How these clinical services currently assess this risk however is uncertain. This study aimed to address this gap by using qualitative methods to examine in depth current approaches, attitudes and challenges to assessing violence risk in this clinical setting, from the perspectives of multidisciplinary clinicians, patients and carers. METHODS: Participants were recruited from two UK Early Intervention in Psychosis services. Semi-structured individual interviews were undertaken using a topic guide. In addition, clinical vignettes were presented to clinician participants as a probe to prompt discussion. Data were analysed using thematic analysis, informed by the constant comparative method. RESULTS: We conducted 30 qualitative interviews, of 18 clinicians and 12 patients and carers. Themes developed from clinician interviews included key difficulties of low confidence, limited training, accessing collateral information and variation in how risk is appraised and communicated. Potential stigma and sensitivity of the topic of violence were perceived as barriers to its discussion. Patient and carer perspectives provided insight into how to address barriers, and highlighted the importance of an open approach, including with families. CONCLUSIONS: We recommend developing contextually appropriate pathways to collaboratively assess violence risk and identify modifiable needs to reduce this risk, and for practical improvements in training and information-sharing.