Neuropathological Variability within a Spectrum of NMDAR-Encephalitis.

OBJECTIVE: To describe the neuropathological features of N-methyl-D-aspartate receptor (NMDAR)-encephalitis in an archival autopsy cohort. METHODS: We examined four autopsies from patients with NMDAR-encephalitis; two patients were untreated, three had comorbidities: small cell lung cancer, brain post-transplant lymphoproliferative disease (PTLD), and overlapping demyelination. RESULTS: The two untreated patients had inflammatory infiltrates predominantly composed of perivascular and parenchymal CD3+ /CD8- T cells and CD79a+ B cells/plasma cells in basal ganglia, amygdala, and hippocampus with surrounding white matter. The hippocampi showed a significant decrease of NMDAR-immunoreactivity that correlated with disease severity. The patient with NMDAR-encephalitis and immunosuppression for kidney transplantation developed a brain monomorphic PTLD. Inflammatory changes were compatible with NMDAR-encephalitis. Additionally, plasma cells accumulated in the vicinity of the necrotic tumor along with macrophages and activated microglia that strongly expressed pro-inflammatory activation markers HLA-DR, CD68, and IL18. The fourth patient developed demyelinating lesions in the setting of a relapse 4 years after NMDAR-encephalitis. These lesions exhibited the hallmarks of classic multiple sclerosis with radially expanding lesions and remyelinated shadow plaques without complement or immunoglobulin deposition, compatible with a pattern I demyelination. INTERPRETATION: The topographic distribution of inflammation in patients with NMDAR-encephalitis reflects the clinical symptoms of movement disorders, abnormal behavior, and memory dysfunction with inflammation dominantly observed in basal ganglia, amygdala, and hippocampus, and loss of NMDAR-immunoreactivity correlates with disease severity. Co-occurring pathologies influence the spatial distribution, composition, and intensity of inflammation, which may modify patients' clinical presentation and outcome. ANN NEUROL 2021;90:725-737.

The association of plasma inflammatory markers with omega-3 fatty acids and their mediating role in psychotic symptoms and functioning: An analysis of the NEURAPRO clinical trial.

BACKGROUND: There is increasing evidence that dysregulation of polyunsaturated fatty acids (FAs) mediated membrane function plays a role in the pathophysiology of schizophrenia. Even though preclinical findings have supported the anti-inflammatory properties of omega-3 FAs on brain health, their biological roles as anti-inflammatory agents and their therapeutic role on clinical symptoms of psychosis risk are not well understood. In the current study, we investigated the relationship of erythrocyte omega-3 FAs with plasma immune markers in a clinical high risk for psychosis (CHR) sample. In addition, a mediation analysis was performed to examine whether previously reported associations between omega-3 FAs and clinical outcomes were mediated via plasma immune markers. Clinical outcomes for CHR participants in the NEURAPRO clinical trial were measured using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Scale of Assessment of Negative Symptoms (SANS) and Social and Occupational Functioning Assessment Scale (SOFAS) scales. The erythrocyte omega-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] and plasma concentrations of inflammatory markers were quantified at baseline (n = 268) and 6 month follow-up (n = 146) by gas chromatography and multiplex immunoassay, respectively. In linear regression models, the baseline plasma concentrations of Interleukin (IL)-15, Intercellular adhesion molecule (ICAM)-1 and Vascular cell adhesion molecule (VCAM)-1 were negatively associated with baseline omega-3 index. In addition, 6-month change in IL-12p40 and TNF-α showed a negative association with change in omega-3 index. In longitudinal analyses, the baseline and 6 month change in omega-3 index was negatively associated with VCAM-1 and TNF-α respectively at follow-up. Mediation analyses provided little evidence for mediating effects of plasma immune markers on the relationship between omega-3 FAs and clinical outcomes (psychotic symptoms and functioning) in CHR participants. Our results indicate a predominantly anti-inflammatory relationship of omega-3 FAs on plasma inflammatory status in CHR individuals, but this did not appear to convey clinical benefits at 6 month and 12 month follow-up. Both immune and non-immune biological effects of omega-3 FAs would be resourceful in understanding the clinical benefits of omega-3 FAs in CHR papulation.

Machine learning based prediction and the influence of complement - Coagulation pathway proteins on clinical outcome: Results from the NEURAPRO trial.

BACKGROUND: Functional outcomes are important measures in the overall clinical course of psychosis and individuals at clinical high-risk (CHR), however, prediction of functional outcome remains difficult based on clinical information alone. In the first part of this study, we evaluated whether a combination of biological and clinical variables could predict future functional outcome in CHR individuals. The complement and coagulation pathways have previously been identified as being of relevance to the pathophysiology of psychosis and have been found to contribute to the prediction of clinical outcome in CHR participants. Hence, in the second part we extended the analysis to evaluate specifically the relationship of complement and coagulation proteins with psychotic symptoms and functional outcome in CHR. MATERIALS AND METHODS: We carried out plasma proteomics and measured plasma cytokine levels, and erythrocyte membrane fatty acid levels in a sub-sample (n = 158) from the NEURAPRO clinical trial at baseline and 6 months follow up. Functional outcome was measured using Social and Occupational Functional assessment Score (SOFAS) scale. Firstly, we used support vector machine learning techniques to develop predictive models for functional outcome at 12 months. Secondly, we developed linear regression models to understand the association between 6-month follow-up levels of complement and coagulation proteins with 6-month follow-up measures of positive symptoms summary (PSS) scores and functional outcome. RESULTS AND CONCLUSION: A prediction model based on clinical and biological data including the plasma proteome, erythrocyte fatty acids and cytokines, poorly predicted functional outcome at 12 months follow-up in CHR participants. In linear regression models, four complement and coagulation proteins (coagulation protein X, Complement C1r subcomponent like protein, Complement C4A & Complement C5) indicated a significant association with functional outcome; and two proteins (coagulation factor IX and complement C5) positively associated with the PSS score. Our study does not provide support for the utility of cytokines, proteomic or fatty acid data for prediction of functional outcomes in individuals at high-risk for psychosis. However, the association of complement protein levels with clinical outcome suggests a role for the complement system and the activity of its related pathway in the functional impairment and positive symptom severity of CHR patients.

The association between migrant status and transition in an ultra-high risk for psychosis population.

PURPOSE: Migrant status is one of the most replicated and robust risk factors for developing a psychotic disorder. This study aimed to determine whether migrant status in people identified as Ultra-High Risk for Psychosis (UHR) was associated with risk of transitioning to a full-threshold psychotic disorder. METHODS: Hazard ratios for the risk of transition were calculated from five large UHR cohorts (n = 2166) and were used to conduct a meta-analysis using the generic inverse-variance method using a random-effects model. RESULTS: 2166 UHR young people, with a mean age of 19.1 years (SD ± 4.5) were included, of whom 221 (10.7%) were first-generation migrants. A total of 357 young people transitioned to psychosis over a median follow-up time of 417 days (I.Q.R.147-756 days), representing 17.0% of the cohort. The risk of transition to a full-threshold disorder was not increased for first-generation migrants, (HR = 1.08, 95% CI 0.62-1.89); however, there was a high level of heterogeneity between studies The hazard ratio for second-generation migrants to transition to a full-threshold psychotic disorder compared to the remainder of the native-born population was 1.03 (95% CI 0.70-1.51). CONCLUSIONS: This meta-analysis did not find a statistically significant association between migrant status and an increased risk for transition to a full-threshold psychotic disorder; however, several methodological issues could explain this finding. Further research should focus on examining the risk of specific migrant groups and also ensuring that migrant populations are adequately represented within UHR clinics.

Do patients with different psychiatric disorders show altered social decision-making? A systematic review of ultimatum game experiments in clinical populations.

BACKGROUND: Impairments in social functioning are a common feature of psychiatric disorders. Game paradigms pose a unique way for studying how people make decisions in interpersonal contexts. In the last decade, researchers have started to use these paradigms to study social decision-making in patients with psychiatric disorders. PURPOSE: The aim of this systematic literature review is to summarise the currently available evidence on the behaviour of patients with psychiatric disorders in the commonly used Ultimatum Game (UG). METHOD: A systematic literature search including MEDLINE, PsycINFO, PSYNDEXplus Tests, PSYNDEXPLUS Literature, EBM Reviews-Cochrane Central Register of Controlled Trials, Embase and PASCAL was performed via the Ovid interface. RESULTS: We found evidence for alterations in UG behaviour for patients with frontotemporal dementia, schizophrenia, affective disorders, alcohol, cocaine, heroin and 3,4-methylenedioxymethamphetamine consumption, alcohol dependence, anxiety disorders, borderline personality disorder, autism, Tourette syndrome and oppositional defiant disorder. CONCLUSION: There is some evidence that different psychiatric disorders might go along with alterations in social decision-making. However, in general, data are currently limited and studies are hard to compare due to differences in methodologies.

Opening the Black Box of Cognitive-Behavioural Case Management in Clients with Ultra-High Risk for Psychosis.

BACKGROUND: Cognitive-behavioural therapy (CBT) is the first-choice treatment in clients with ultra-high risk (UHR) for psychosis. However, CBT is an umbrella term for a plethora of different strategies, and little is known about the association between the intensity and content of CBT and the severity of symptomatic outcome. METHODS: A sample of 268 UHR participants received 6 months of CBT with case management (CBCM) in the context of the multi-centre NEURAPRO trial with monthly assessments of attenuated psychotic symptoms (APS). Using multilevel regressions and controlling for the initial severity of APS, the associations between (1) number of CBCM sessions received and severity of APS and (2) specific CBCM components and severity of APS were investigated. RESULTS: In month 1, a higher number of sessions and more assessment of symptoms predicted an increase in APS, while in month 3, a higher number of sessions and more monitoring predicted a decrease in the level of APS. More therapeutic focus on APS predicted an overall increase in APS. CONCLUSIONS: Our findings indicate that the association between intensity/content of CBCM and severity of APS in a sample of UHR participants depends on the length of time in treatment. CBCM may positively impact the severity of APS later in the course of treatment. Therefore, it would seem important to keep UHR young people engaged in treatment beyond this initial period. Regarding the specific content of CBCM, a therapeutic focus on APS may not necessarily be beneficial in reducing the severity of APS, a possibility in need of further investigation.

Comprehension of metaphors in patients with schizophrenia-spectrum disorders.

BACKGROUND: Metaphors, mainly proverbs and idiomatic expressions of ordinary life are commonly used as a model for concretism. Previous studies have shown impaired metaphor comprehension in patients with schizophrenia-spectrum disorders compared to either psychiatric or non-psychiatric control subject. The aim of this study was to detect possible quantitative differences in figurative processing between patients with schizophrenia-spectrum disorders and healthy controls. METHODS: In order to analyse possible dissociations of different aspects of figurative speech, a range of metaphor tasks was used to distinguish between recognition of familiar metaphors, paraphrasing the meaning of the latter and generating novel metaphors: we used a standard proverb test for conventional metaphors consisting of a multiple-choice and a paraphrasing task, and the Metaphoric Triads Test for the assessment of novel metaphors. We included 40 patients with schizophrenia-spectrum disorders and 43 healthy control subjects. RESULTS: Our results showed that patients had impaired figurative speech processing regarding novel and conventional metaphors. Associations with cognitive functions were detected. Performance on the paraphrasing task was associated with the severity of negative symptoms. CONCLUSION: We conclude that patients with schizophrenia-spectrum disorders do exhibit impairments in the recognition and paraphrasing of conventional and the generation of novel metaphors and that some cognitive domains as well the extent of negative symptoms might be associated with these deficits.

Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

Development and temporal validation of a clinical prediction model of transition to psychosis in individuals at ultra-high risk in the UHR 1000+ cohort.

The concept of ultra-high risk for psychosis (UHR) has been at the forefront of psychiatric research for several decades, with the ultimate goal of preventing the onset of psychotic disorder in high-risk individuals. Orygen (Melbourne, Australia) has led a range of observational and intervention studies in this clinical population. These datasets have now been integrated into the UHR 1000+ cohort, consisting of a sample of 1,245 UHR individuals with a follow-up period ranging from 1 to 16.7 years. This paper describes the cohort, presents a clinical prediction model of transition to psychosis in this cohort, and examines how predictive performance is affected by changes in UHR samples over time. We analyzed transition to psychosis using a Cox proportional hazards model. Clinical predictors for transition to psychosis were investigated in the entire cohort using multiple imputation and Rubin's rule. To assess performance drift over time, data from 1995-2016 were used for initial model fitting, and models were subsequently validated on data from 2017-2020. Over the follow-up period, 220 cases (17.7%) developed a psychotic disorder. Pooled hazard ratio (HR) estimates showed that the Comprehensive Assessment of At-Risk Mental States (CAARMS) Disorganized Speech subscale severity score (HR=1.12, 95% CI: 1.02-1.24, p=0.024), the CAARMS Unusual Thought Content subscale severity score (HR=1.13, 95% CI: 1.03-1.24, p=0.009), the Scale for the Assessment of Negative Symptoms (SANS) total score (HR=1.02, 95% CI: 1.00-1.03, p=0.022), the Social and Occupational Functioning Assessment Scale (SOFAS) score (HR=0.98, 95% CI: 0.97-1.00, p=0.036), and time between onset of symptoms and entry to UHR service (log transformed) (HR=1.10, 95% CI: 1.02-1.19, p=0.013) were predictive of transition to psychosis. UHR individuals who met the brief limited intermittent psychotic symptoms (BLIPS) criteria had a higher probability of transitioning to psychosis than those who met the attenuated psychotic symptoms (APS) criteria (HR=0.48, 95% CI: 0.32-0.73, p=0.001) and those who met the Trait risk criteria (a first-degree relative with a psychotic disorder or a schizotypal personality disorder plus a significant decrease in functioning during the previous year) (HR=0.43, 95% CI: 0.22-0.83, p=0.013). Models based on data from 1995-2016 displayed good calibration at initial model fitting, but showed a drift of 20.2-35.4% in calibration when validated on data from 2017-2020. Large-scale longitudinal data such as those from the UHR 1000+ cohort are required to develop accurate psychosis prediction models. It is critical to assess existing and future risk calculators for temporal drift, that may reduce their utility in clinical practice over time.

Does specific psychopathology predict development of psychosis in ultra high-risk (UHR) patients?

OBJECTIVES: Studies have attempted to identify additional risk factors within the group identified as 'ultra high risk' (UHR) for developing psychotic disorders in order to characterise those at highest risk. However, these studies have often neglected clinical symptom types as additional risk factors. We aimed to investigate the relationship between baseline clinical psychotic or psychotic-like symptoms and the subsequent transition to a psychotic disorder in a UHR sample. METHOD: A retrospective 'case-control' methodology was used. We identified all individuals from a UHR clinic who had subsequently developed a psychotic disorder (cases) and compared these to a random sample of individuals from the clinic who did not become psychotic within the sampling time frame (controls). The sample consisted of 120 patients (60 cases, 60 controls). An audit tool was used to identify clinical symptoms reported at entry to the clinic (baseline) using the clinical file. Diagnosis at transition was assessed using the Operational Criteria for Psychotic Illness (OPCRIT) computer program. The relationship between transition to a psychotic disorder and baseline symptoms was explored using survival analysis. RESULTS: Presence of thought disorder, any delusions and elevated mood significantly predicted transition to a psychotic disorder. When other symptoms were adjusted for, only the presence of elevated mood significantly predicted subsequent transition (hazard ratio 2.69, p = 0.002). Thought disorder was a predictor of transition to a schizophrenia-like psychotic disorder (hazard ratio 3.69, p = 0.008). CONCLUSIONS: Few individual clinical symptoms appear to be predictive of transition to a psychotic disorder in the UHR group. Clinicians should be cautious about the use of clinical profile alone in such individuals when determining who is at highest risk.

Duration of untreated psychosis in a high-income versus a low- and middle-income region.

OBJECTIVE: Most data on duration of untreated psychosis (DUP) derives from high-income countries. An inverse relationship between DUP and income and a longer DUP in low- and middle-income (LAMI) countries has been reported. The aim of this study was to compare DUP in a high-income country with that in a LAMI country using the same methodology. METHODS: The sample consisted of in- and outpatients, aged 15-35 years for the Vienna site and 18-35 years for the Pakistani sites, with first-episode psychosis (FEP). DUP was evaluated using psychiatric interviews, medical charts and the Nottingham Onset Schedule. Differentiated reporting of duration of untreated illness (DUI) from prodrome to start of treatment, and DUP from manifest psychotic symptoms to start of treatment was ensured. Primary outcome measures, DUI and DUP, were measured at a 0.025 level of significance. RESULTS: Thirty-one FEP patients in Vienna (mean age 20.03 years, SD 4.2) and 60 FEP patients from the Pakistani sites (mean age 26.15 years, SD 5.29) participated. The mean age in Vienna was younger due to the different age range inclusion criteria. The severity of psychopathology was more pronounced in the Pakistani sample. Log DUP was significantly different between groups (i.e. longer in the Pakistani sample (p=0.001)). Log DUI showed a trend for longer duration in the Vienna sample; however, this did not reach statistical significance (p=0.036). The severity of positive psychotic symptoms was associated with length of DUI in both regions. CONCLUSION: The longer DUP in Pakistan confirms the need to provide affordable treatment for psychosis for young FEP patients in Pakistan and in other LAMI countries. The relatively long period from prodrome to treatment initiation in both regions underlines the need to further establish low-threshold early intervention strategies in order to increase detection rates and reduce factors limiting patients seeking treatment.

Clinical case report: considerable improvement of severe and difficult-to-treat obsessive-compulsive disorder with comorbid depression under treatment with esketamine and concomitant psychotherapy.

A 28-year-old man was admitted to our psychiatric ward with severe obsessive-compulsive disorder (OCD) and comorbid depression. At intake, obsessive-compulsive symptoms were present most time of the day and were related to an intense fear of causing interpersonal misunderstandings. Various treatment attempts, including cognitive-behavioural therapy (CBT) with exposure and response prevention (ERP), selective serotonin reuptake inhibitors, clomipramine, and add-on antipsychotics were either ineffective and/or were not tolerated, and the patient's condition worsened progressively. Following an in-depth multidisciplinary team discussion and a shared decision-making process, an off-label treatment trial with esketamine and concomitant psychotherapy was started. The patient received 10 esketamine + psychotherapy sessions over a period of about 2 months, followed by two maintenance sessions in about 3-week intervals. After this, he was discharged into regular outpatient care where he continued to receive maintenance esketamine treatment every 4-6 weeks and, independent of this, individual CBT. Following the establishment of esketamine with concurrent psychotherapy, the patient exhibited a remarkable clinical improvement. Obsessive-compulsive symptoms showed a clear and sustained response (Y-BOCS before treatment >35, Y-BOCS at week 8 = 23, Y-BOCS at week 26 = 14). Paralleling this, depressive symptoms also decreased (MADRS before treatment = 47, MADRS at week 9 = 12, MADRS at week 26 = 3). At a naturalistic follow-up at week 66, obsessive-compulsive symptoms were still mild (Y-BOCS = 13), and depression was still in remission (MADRS < 6). This clinical case suggests that (es)ketamine plus concomitant psychotherapy may hold promise as a therapeutic strategy for difficult-to-treat OCD and depression and its full clinical potential should be evaluated in more comprehensive future studies.

Personality functioning and self-disorders in individuals at ultra-high risk for psychosis, with first-episode psychosis and with borderline personality disorder.

BACKGROUND: Assessment of personality functioning in different stages of psychotic disorders could provide valuable information on psychopathology, course of illness and treatment planning, but empirical data are sparse. AIMS: To investigate personality functioning and sense of self in individuals at ultra-high risk (UHR) for psychosis and with first-episode psychosis (FEP) in comparison with a clinical control group of individuals with borderline personality disorder (BPD) and healthy controls. METHOD: In a cross-sectional design, we investigated personality functioning (Structured Interview of Personality Organization, STIPO; Level of Personality Functioning Scale, LPFS) and disturbances of the basic self (Examination of Anomalous Self-Experience, EASE) in 107 participants, comprising 24 individuals at UHR, 29 individuals with FEP, 27 individuals with BPD and 27 healthy controls. RESULTS: The UHR, FEP and BPD groups had moderate to severe deficits in personality organisation (STIPO) compared with the healthy control group. Self-functioning with its subdomain (facet) 'self-direction' (LPFS) was significantly worse in participants with manifest psychosis (FEP) compared with those at-risk for psychosis (UHR). The FEP group showed significantly worse overall personality functioning than the UHR group and significantly higher levels of self-disturbance (EASE) than the BPD group, with the UHR group lying between these diagnostic groups. Hierarchical cluster analysis based on the seven STIPO domains yielded three clusters differing in level of personality functioning and self-disturbances. CONCLUSIONS: Our data demonstrate that psychotic disorders are associated with impaired personality functioning and self-disturbances. Assessment of personality functioning can inform treatment planning for patients at different stages of psychotic disorder.

Psychiatric symptoms and comorbidities in patients with drug-resistant epilepsy in presurgical assessment-A prospective explorative single center study.

Introduction: People with epilepsy (PWE) have a higher prevalence of psychiatric disorders. Some individuals with drug-resistant epilepsy might benefit from surgical interventions. The aim of this study was to perform an assessment of psychiatric comorbidities with a follow-up period of 12 months in patients with drug-resistant epilepsy, comparing those who underwent surgery to those who did not. Material and methods: We assessed psychiatric comorbidities at baseline, after 4 months and after 12 months. Psychiatric symptoms and diagnoses were assessed using SCID-Interview, Hamilton Rating Scale for Depression, Beck-Depression Inventory, Hamilton Anxiety Rating Scale, Prodromal-Questionnaire and the Global Assessment of Functioning Scale. Results: Twenty-five patients were included in the study, 12 underwent surgery, 11 were esteemed as being neurologically unqualified for surgery and two refused surgery. Patients in the no-surgery group were significantly older, reported more substance use, had significantly higher levels of anxiety and were more often diagnosed with a personality disorder. Age and levels of anxiety were significant predictors of being in the surgery or the no-surgery group. The described differences between surgery and no-surgery patients did not change significantly over the follow-up period. Discussion: These data point toward a higher expression of baseline psychiatric symptoms in drug-resistant PWE without surgery. Further studies are warranted to further elucidate these findings and to clarify potential psychotropic effects of epilepsy itself, drug-resistant epilepsy and of epilepsy surgery and their impact on psychopathology. Clinically, it seems highly relevant to include psychiatrists in an interdisciplinary state-of-the-art perioperative management of drug-resistant PWE.

Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial.

BACKGROUND: Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS: To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD: Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS: The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS: We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs.

Distress Related to Attenuated Psychotic Symptoms: Static and Dynamic Association With Transition to Psychosis, Nonremission, and Transdiagnostic Symptomatology in Clinical High-Risk Patients in an International Intervention Trial.

This study examined whether distress in relation to attenuated psychotic symptoms (DAPS) is associated with clinical outcomes in an ultra-high risk (UHR) for psychosis sample. We also investigated whether DAPS is associated with cognitive style (attributional style and cognitive biases) and whether amount of psychosocial treatment provided is associated with reduction in DAPS. The study was a secondary analysis of the "Neurapro" clinical trial of omega-3 fatty acids. Three hundred and four UHR patients were recruited across 10 early intervention services. Data from baseline assessment, regular assessments over 12 months, and medium term follow-up (mean = 3.4 years) were used for analysis. Findings indicated: a positive association between DAPS assessed over time and transition to psychosis; a significant positive association between baseline and longitudinal DAPS and transdiagnostic clinical and functional outcomes; a significant positive association between baseline and longitudinal DAPS and nonremission of UHR status. There was no relationship between severity of DAPS and cognitive style. A greater amount of psychosocial treatment (cognitive-behavioral case management) was associated with an increase in DAPS scores. The study indicates that UHR patients who are more distressed by their attenuated psychotic symptoms are more likely to have a poorer clinical trajectory transdiagnostically. Assessment of DAPS may therefore function as a useful marker of risk for a range of poor outcomes. The findings underline the value of repeated assessment of variables and incorporation of dynamic change into predictive modeling. More research is required into mechanisms driving distress associated with symptoms and the possible bidirectional relationship between symptom severity and associated distress.

Twelve-Month Cognitive Trajectories in Individuals at Ultra-High Risk for Psychosis: A Latent Class Analysis.

Understanding longitudinal cognitive performance in individuals at ultra-high risk for psychosis (UHR) is important for informing theoretical models and treatment. A vital step in this endeavor is to determine whether there are UHR subgroups that have similar patterns of cognitive change over time. The aims were to: i) identify latent class trajectories of cognitive performance over 12-months in UHR individuals, ii) identify baseline demographic and clinical predictors of the resulting classes, and iii) determine whether trajectory classes were associated with transition to psychosis or functional outcomes. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) at baseline, 6- and 12-months (N = 288). Using Growth Mixture Modeling, a single unimpaired improving trajectory class was observed for motor function, speed of processing, verbal fluency, and BACS composite. A two-class solution was observed for executive function and working memory, showing one unimpaired and a second impaired class. A three-class solution was found for verbal learning and memory: unimpaired, mildly impaired, and initially extremely impaired, but improved ("caught up") to the level of the mildly impaired. IQ, omega-3 index, and premorbid adjustment were associated with class membership, whereas clinical variables (symptoms, substance use), including transition to psychosis, were not. Working memory and verbal learning and memory trajectory class membership was associated with functioning outcomes. These findings suggest there is no short-term progressive cognitive decline in help-seeking UHR individuals, including those who transition to psychosis. Screening of cognitive performance may be useful for identifying UHR individuals who may benefit from targeted cognitive interventions.

Evidence that complement and coagulation proteins are mediating the clinical response to omega-3 fatty acids: A mass spectrometry-based investigation in subjects at clinical high-risk for psychosis.

Preliminary evidence indicates beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) in early psychosis. The present study investigates the molecular mechanism of omega-3 PUFA-associated therapeutic effects in clinical high-risk (CHR) participants. Plasma samples of 126 CHR psychosis participants at baseline and 6-months follow-up were included. Plasma protein levels were quantified using mass spectrometry and erythrocyte omega-3 PUFA levels were quantified using gas chromatography. We examined the relationship between change in polyunsaturated PUFAs (between baseline and 6-month follow-up) and follow-up plasma proteins. Using mediation analysis, we investigated whether plasma proteins mediated the relationship between change in omega-3 PUFAs and clinical outcomes. A 6-months change in omega-3 PUFAs was associated with 24 plasma proteins at follow-up. Pathway analysis revealed the complement and coagulation pathway as the main biological pathway to be associated with change in omega-3 PUFAs. Moreover, complement and coagulation pathway proteins significantly mediated the relationship between change in omega-3 PUFAs and clinical outcome at follow-up. The inflammatory protein complement C5 and protein S100A9 negatively mediated the relationship between change in omega-3 PUFAs and positive symptom severity, while C5 positively mediated the relationship between change in omega-3 and functional outcome. The relationship between change in omega-3 PUFAs and cognition was positively mediated through coagulation factor V and complement protein C1QB. Our findings provide evidence for a longitudinal association of omega-3 PUFAs with complement and coagulation protein changes in the blood. Further, the results suggest that an increase in omega-3 PUFAs decreases symptom severity and improves cognition in the CHR state through modulating effects of complement and coagulation proteins.

Lithium in drinking water and suicide mortality.

BACKGROUND: There is some evidence that natural levels of lithium in drinking water may have a protective effect on suicide mortality. AIMS: To evaluate the association between local lithium levels in drinking water and suicide mortality at district level in Austria. METHOD: A nationwide sample of 6460 lithium measurements was examined for association with suicide rates per 100,000 population and suicide standardised mortality ratios across all 99 Austrian districts. Multivariate regression models were adjusted for well-known socioeconomic factors known to influence suicide mortality in Austria (population density, per capita income, proportion of Roman Catholics, as well as the availability of mental health service providers). Sensitivity analyses and weighted least squares regression were used to challenge the robustness of the results. RESULTS: The overall suicide rate (R(2) = 0.15, ß = -0.39, t = -4.14, P = 0.000073) as well as the suicide mortality ratio (R(2) = 0.17, ß = -0.41, t = -4.38, P = 0.000030) were inversely associated with lithium levels in drinking water and remained significant after sensitivity analyses and adjustment for socioeconomic factors. CONCLUSIONS: In replicating and extending previous results, this study provides strong evidence that geographic regions with higher natural lithium concentrations in drinking water are associated with lower suicide mortality rates.

Psychotic-Like Experiences: A Challenge in Definition and Assessment.

Assuming a continuum between psychotic experiences and psychotic symptoms aligned between healthy individuals and patients with non-psychotic and psychotic disorders, recent research has focused on subclinical psychotic experiences. The wide variety of definitions, assessment tools, and concepts of psychotic-like experiences (PLEs) might contribute to the mixed findings concerning prevalence and persistence rates and clinical impact. In this narrative review, we address the panoply of terminology, definitions, and assessment tools of PLEs and associated concerns with this multitude. Moreover, the ambiguous results of previous studies regarding the clinical relevance of PLEs are described. In conclusion, we address clinical implications and highly suggest conceptual clarity and consensus concerning the terminology and definition of PLEs. The development of an agreed upon use of a "gold standard" assessment tool seems essential for more comparable findings in future research.