The relationship between cognitive functioning and psychopathology in patients with psychiatric disorders: a transdiagnostic network analysis.

BACKGROUND: Patients with psychiatric disorders often experience cognitive dysfunction, but the precise relationship between cognitive deficits and psychopathology remains unclear. We investigated the relationships between domains of cognitive functioning and psychopathology in a transdiagnostic sample using a data-driven approach. METHODS: Cross-sectional network analyses were conducted to investigate the relationships between domains of psychopathology and cognitive functioning and detect clusters in the network. This naturalistic transdiagnostic sample consists of 1016 psychiatric patients who have a variety of psychiatric diagnoses, such as depressive disorders, anxiety disorders, obsessive-compulsive and related disorders, and schizophrenia spectrum and other psychotic disorders. Psychopathology symptoms were assessed using various questionnaires. Core cognitive domains were assessed with a battery of automated tests. RESULTS: Network analysis detected three clusters that we labelled: general psychopathology, substance use, and cognition. Depressive and anxiety symptoms, verbal memory, and visual attention were the most central nodes in the network. Most associations between cognitive functioning and symptoms were negative, i.e. increased symptom severity was associated with worse cognitive functioning. Cannabis use, (subclinical) psychotic experiences, and anhedonia had the strongest total negative relationships with cognitive variables. CONCLUSIONS: Cognitive functioning and psychopathology are independent but related dimensions, which interact in a transdiagnostic manner. Depression, anxiety, verbal memory, and visual attention are especially relevant in this network and can be considered independent transdiagnostic targets for research and treatment in psychiatry. Moreover, future research on cognitive functioning in psychopathology should take a transdiagnostic approach, focusing on symptom-specific interactions with cognitive domains rather than investigating cognitive functioning within diagnostic categories.

Changes in peripheral blood compounds following psychopharmacological treatment in drug-naïve first-episode patients with either schizophrenia or major depressive disorder: a meta-analysis.

BACKGROUND: This meta-analysis on peripheral blood compounds in drug-naïve first-episode patients with either schizophrenia or major depressive disorder (MDD) examined which compounds change following psychopharmacological treatment. METHODS: The Embase, PubMed and PsycINFO databases were systematically searched for longitudinal studies reporting measurements of blood compounds in drug-naïve first-episode schizophrenia or MDD. RESULTS: For this random-effects meta-analysis, we retrieved a total of 31 studies comprising 1818 schizophrenia patients, and 14 studies comprising 469 MDD patients. Brain-derived neurotrophic factor (BDNF) increased following treatment in schizophrenia (Hedges' g (g): 0.55; 95% confidence interval (CI) 0.39-0.70; p < 0.001) and MDD (g: 0.51; CI 0.06-0.96; p = 0.027). Interleukin (IL)-6 levels decreased in schizophrenia (g: -0.48; CI -0.85 to -0.11; p = 0.011), and for MDD a trend of decreased IL-6 levels was observed (g: -0.39; CI -0.87 to 0.09; p = 0.115). Tumor necrosis factor alpha (TNFα) also decreased in schizophrenia (g: -0.34; CI -0.68 to -0.01; p = 0.047) and in MDD (g: -1.02; CI -1.79 to -0.25; p = 0.009). Fasting glucose levels increased only in schizophrenia (g: 0.26; CI 0.07-0.44; p = 0.007), but not in MDD. No changes were found for C-reactive protein, IL-1ß, IL-2 and IL-4. CONCLUSIONS: Psychopharmacological treatment has modulating effects on BDNF and TNFα in drug-naïve first-episode patients with either schizophrenia or MDD. These findings support efforts for further research into transdiagnostic preventive strategies and augmentation therapy for those with immune dysfunctions.

Altered peripheral blood compounds in drug-naïve first-episode patients with either schizophrenia or major depressive disorder: a meta-analysis.

IMPORTANCE: Schizophrenia and major depressive disorder (MDD) are associated with increased risks of immunologic disease and metabolic syndrome. It is unclear to what extent growth, immune or glucose dysregulations are similarly present in these disorders without the influence of treatment or chronicity. OBJECTIVE: To conduct a meta-analysis investigating whether there are altered peripheral growth, immune or glucose metabolism compounds in drug-naïve first-episode patients with schizophrenia or MDD compared with controls. DATA SOURCES AND STUDY SELECTION: Case-control studies reporting compound measures in drug-naïve first-episode patients with schizophrenia or MDD compared with controls in the Embase, PubMed and PsycINFO databases. DATA EXTRACTION AND SYNTHESIS: Two independent authors extracted data for a random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Peripheral growth, immune or glucose metabolism compounds in schizophrenia or MDD compared with controls. Standardized mean differences were quantified with Hedges' g (g). RESULTS: 74 studies were retrieved comprising 3453 drug-naïve first-episode schizophrenia patients and 4152 controls, and 29 studies were retrieved comprising 1095 drug-naïve first-episode MDD patients and 1399 controls. Growth factors: brain-derived neurotrophic factor (BDNF) (g = -0.77, P < .001) and nerve growth factor (NGF) (g = -2.51, P = .03) were decreased in schizophrenia. For MDD, we observed a trend toward decreased BDNF (g = -0.47, P = .19) and NGF (g = -0.33, P = .08) levels, and elevated vascular endothelial growth factor levels (g = 0.40, P = .03). Immune factors: interleukin (IL)-6 (g = 0.95, P < .001), IL-8 (g = 0.59, P = .001) and tumor necrosis factor alpha (TNFα) (g = 0.48, P = .002) were elevated in schizophrenia. For C-reactive protein (CRP) (g = 0.57, P = .09), IL-4 (g = 0.44, P = .10) and interferon gamma (g = 0.33, P = .11) we observed a trend toward elevated levels in schizophrenia. In MDD, IL-6 (g = 0.62, P = .007), TNFα (g = 1.21, P < .001), CRP (g = 0.53, P < .001), IL-1ß (g = 1.52, P = .009) and IL-2 (g = 4.41, P = .04) were elevated, whereas IL-8 (g = -0.84, P = .01) was decreased. The fasting glucose metabolism factors glucose (g = 0.24, P = .003) and insulin (g = 0.38, P = .003) were elevated in schizophrenia. CONCLUSIONS AND RELEVANCE: Both schizophrenia and MDD show alterations in growth and immune factors from disease onset. An altered glucose metabolism seems to be present from onset in schizophrenia. These findings support efforts for further research into transdiagnostic preventive strategies and augmentation therapy for those with immune or metabolic dysfunctions.

Protocol Across study: longitudinal transdiagnostic cognitive functioning, psychiatric symptoms, and biological parameters in patients with a psychiatric disorder.

BACKGROUND: Patients with psychiatric disorders, such as major depressive disorder, schizophrenia or obsessive-compulsive disorder, often suffer from cognitive dysfunction. The nature of these dysfunctions and their relation with clinical symptoms and biological parameters is not yet clear. Traditionally, cognitive dysfunction is studied in patients with specific psychiatric disorders, disregarding the fact that cognitive deficits are shared across disorders. The Across study aims to investigate cognitive functioning and its relation with psychiatric symptoms and biological parameters transdiagnostically and longitudinally. METHODS: The study recruits patients diagnosed with a variety of psychiatric disorders and has a longitudinal cohort design with an assessment at baseline and at one-year follow-up. The primary outcome measure is cognitive functioning. The secondary outcome measures include clinical symptoms, electroencephalographic, genetic and blood markers (e.g., fatty acids), and hair cortisol concentration levels. DISCUSSION: The Across study provides an opportunity for a transdiagnostic, bottom-up, data-driven approach of investigating cognition in relation to symptoms and biological parameters longitudinally in patients with psychiatric disorders. The study may help to find new clusters of symptoms, biological markers, and cognitive dysfunctions that have better prognostic value than the current diagnostic categories. Furthermore, increased insight into the relationship among cognitive deficits, biological parameters, and psychiatric symptoms can lead to new treatment possibilities. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NL8170.

Driving us mad: the association of Toxoplasma gondii with suicide attempts and traffic accidents - a systematic review and meta-analysis.

Unnatural causes of death due to traffic accidents (TA) and suicide attempts (SA) constitute a major burden on global health, which remained stable in the last decade despite widespread efforts of prevention. Recently, latent infection with Toxoplasma gondii (T. gondii) has been suggested to be a biological risk factor for both TA and SA. Therefore, a systematic search concerning the relationship of T. gondii infection with TA and/or SA according to PRISMA guidelines in Medline, Pubmed and PsychInfo was conducted collecting papers up to 11 February 2019 (PROSPERO #CRD42018090206). The random-effect model was applied and sensitivity analyses were subsequently performed. Lastly, the population attributable fraction (PAF) was calculated. We found a significant association for antibodies against T. gondii with TA [odds ratio (OR) = 1.69; 95% confidence interval (CI) 1.20-2.38, p = 0.003] and SA (OR = 1.39; 95% CI 1.10-1.76, p = 0006). Indication of publication bias was found for TA, but statistical adjustment for this bias did not change the OR. Heterogeneity between studies on SA was partly explained by type of control population used (ORhealthy controls = 1.9, p < 0.001 v. ORpsychiatric controls = 1.06, p = 0.87) and whether subjects with schizophrenia only were analysed (ORschizophrenia = 0.87, p = 0.62 v. ORvarious = 1.8, p < 0.001). The association was significantly stronger with higher antibody titres in TA and in studies that did not focus on schizophrenia subjects concerning SA. PAF of a T. gondii infection was 17% for TA and 10% for SA. This indicates that preventing T. gondii infection may play a role in the prevention of TA or SA, although uncertainty remains whether infection and outcome are truly causally related.

Incidence rates and risk factors of bipolar disorder in the general population: a population-based cohort study.

OBJECTIVE: To estimate the incidence rates (IRs) of bipolar I and bipolar II disorders in the general population according to sociodemographic population characteristics. METHODS: A cohort study (during the years 1996-2007) was conducted in a general practitioners research database with a longitudinal electronic record of 800000 patients throughout the Netherlands [the Integrated Primary Care Information (IPCI) database]. Cases of bipolar disorder were identified and classified by systematic review of medical records. Age- and gender-specific IRs were calculated per calendar year, degree of urbanization, and degree of deprivation. RESULTS: The overall IR of bipolar disorder was 0.70/10000 person-years (PY) [95% confidence interval (CI): 0.57-0.83]; the IR of bipolar I disorder was 0.43/10000 PY (95% CI: 0.34-0.55) and the IR of bipolar II disorder was 0.19/10000 PY (95% CI: 0.13-0.27). Two peaks in the age at onset of the disorder were noticed: one in early adulthood (15-24 years; 0.68/10000 PY) and a larger peak in later life (45-54 years; 1.2/10000 PY). In bipolar II disorder, only one peak, in the 45-54 year age category (IR 0.42/10000 PY), was found. The IRs of bipolar disorder were significantly higher in deprived areas. Similar rates were found for men compared to women and in urban compared to rural areas. No association was found between the onset of first (hypo)manic episode and month or season of birth. CONCLUSIONS: We found two peaks in the age at onset of bipolar disorder, one in early adulthood and one in later life, the former consisting mainly of bipolar I disorder subjects. The incidence of bipolar disorder is higher in deprived areas. The onset of bipolar disorder is not associated with gender, urbanization, or month or season of birth.

Annual incidence rate of schizophrenia and schizophrenia spectrum disorders in a longitudinal population-based cohort study.

BACKGROUND: Longitudinal incidence studies of schizophrenia spectrum disorders (SSD) performed in mental health service organizations are prone to confounding factors not found in research performed in the general population. OBJECTIVES: To estimate the incidence rates (IRs) over a 10-year period of SSD (broadly defined) and schizophrenia (narrowly defined) in the general population and to analyze associated risk factors. METHODS: A cohort study (1996-2006) in a large general practitioners research database was conducted with longitudinal medical records of 350,524 patients throughout the Netherlands. Cases of SSD were identified and classified by systematic review of medical records. Age- and gender-specific IRs were calculated per calendar year, date of birth, degree of urbanicity and deprivation. RESULTS: Overall IR of SSD in this population was 22/100,000 person years (PY) (95% CI 19-24). IR of schizophrenia was 12/100,000 PY (95% CI 10-14). Period prevalence was 3.5 per 1,000 PY. IRs were higher in men compared to women, had a peak at age 15-25 years, decreasing rapidly after 25 years by 40% per 10 years. IRs of SSD were significantly higher in urban areas, irrespective of deprivation. No association was found between IRs of SSD and living in deprived areas or month of birth. There was no significant time trend of the IR during the period under study. CONCLUSIONS: IRs of SSD are higher in urban areas, independent of social deprivation. Age- and gender-specific differences in IR were found. The magnitude of these differences was larger in narrowly defined schizophrenia than in SSD.

The interplay between psychopathological symptoms: transdiagnostic cross-lagged panel network model.

BACKGROUND: Recent paradigm shifts suggest that psychopathology manifests through dynamic interactions between individual symptoms. AIMS: To investigate the longitudinal relationships between symptoms in a transdiagnostic sample of patients with psychiatric disorders. METHOD: A two-wave, cross-lagged panel network model of 15 nodes representing symptoms of depression, (social) anxiety and attenuated psychotic symptoms was estimated, using baseline and 1-year follow-up data of 222 individuals with psychiatric disorders. Centrality indices were calculated to determine important predictors and outcomes. RESULTS: Our results demonstrated that the strongest relationships in the network were between (a) more suicidal ideation predicting more negative self-view, and (b) autoregressive relationships of social anxiety symptoms positively reinforcing themselves. Negative self-view was the most predictable node in the network as it had the highest 'in-expected influence' centrality, and may be an important transdiagnostic outcome symptom. CONCLUSIONS: The results give insight into longitudinal interactions between symptoms, which interact in ways that do not adhere to broader diagnostic categories. Our results suggest that self-view can also be a transdiagnostic outcome of psychopathology rather than just a predictor, as is normally posited, and may especially have an important relationship with suicidal ideation. Overall, our study demonstrates the dynamic complexity of psychopathology, and further supports the importance of investigating symptom interactions of different psychopathological dimensions over time and across disorders.

Association of Toxoplasma gondii Seropositivity With Cognitive Function in Healthy People: A Systematic Review and Meta-analysis.

Importance: The parasite Toxoplasma gondii has been associated with behavioral alterations and psychiatric disorders. Studies investigating neurocognition in people with T gondii infection have reported varying results. To systematically analyze these findings, a meta-analysis evaluating cognitive function in healthy people with and without T gondii seropositivity is needed. Objective: To assess whether and to what extent T gondii seropositivity is associated with cognitive function in otherwise healthy people. Data Sources: A systematic search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. A systematic search of PubMed, MEDLINE, Web of Science, PsycInfo, and Embase was performed to identify studies from database inception to June 7, 2019, that analyzed cognitive function among healthy participants with available data on T gondii seropositivity. Search terms included toxoplasmosis, neurotoxoplasmosis, Toxoplasma gondii, cognition disorder, neuropsychological, and psychomotor performance. Study Selection: Studies that performed cognitive assessment and analyzed T gondii seroprevalence among otherwise healthy participants were included. Data Extraction and Synthesis: Two researchers independently extracted data from published articles; if needed, authors were contacted to provide additional data. Quantitative syntheses were performed in predefined cognitive domains when 4 independent data sets per domain were available. Study quality, heterogeneity, and publication bias were assessed. Main Outcomes and Measures: Performance on neuropsychological tests measuring cognitive function. Results: The systematic search yielded 1954 records. After removal of 533 duplicates, an additional 1363 records were excluded based on a review of titles and abstracts. A total of 58 full-text articles were assessed for eligibility (including reference list screening); 45 articles were excluded because they lacked important data or did not meet study inclusion or reference list criteria. The remaining 13 studies comprising 13 289 healthy participants (mean [SD] age, 46.7 [16.0] years; 6586 men [49.6%]) with and without T gondii seropositivity were included in the meta-analysis. Participants without T gondii seropositivity had favorable functioning in 4 cognitive domains: processing speed (standardized mean difference [SMD], 0.12; 95% CI, 0.05-0.19; P = .001), working memory (SMD, 0.16; 95% CI, 0.06-0.26; P = .002), short-term verbal memory (SMD, 0.18; 95% CI, 0.09-0.27; P < .001), and executive functioning (SMD, 0.15; 95% CI, 0.01-0.28; P = .03). A meta-regression analysis found a significant association between older age and executive functioning (Q = 6.17; P = .01). Little suggestion of publication bias was detected. Conclusions and Relevance: The study's findings suggested that T gondii seropositivity was associated with mild cognitive impairment in several cognitive domains. Although effect sizes were small, given the ubiquitous prevalence of this infection globally, the association with cognitive impairment could imply a considerable adverse effect at the population level. Further research is warranted to investigate the underlying mechanisms of this association.

Resting-state brain oscillations predict cognitive function in psychiatric disorders: A transdiagnostic machine learning approach.

BACKGROUND: Cognitive dysfunction is widespread in psychiatric disorders and can significantly impact quality of life. Deficits cut across traditional diagnostic boundaries, necessitating new approaches to understand how cognitive function relates to large-scale brain activity and psychiatric symptoms across the diagnostic spectrum. OBJECTIVE: Using random forest regression, we aimed to identify transdiagnostic patterns linking cognitive function to resting-state EEG oscillations. METHODS: 216 participants recruited through an outpatient psychiatric clinic completed the Cambridge Neuropsychological Test Automated Battery and underwent a 5-minute eyes-closed resting state EEG recording. We built random forest regression models to predict performance on each cognitive test using the resting-state EEG power spectrum as input, and we compared model performance to a sampling distribution constructed with random permutations. For models that performed significantly better than chance, we used feature importance estimates to identify features of the EEG power spectrum that are predictive of cognitive functioning. RESULTS: Random forest models successfully predicted performance on measures of episodic memory and associative learning (Paired Associates Learning, PAL), information processing speed (Choice Reaction Time, CRT), and attentional set-shifting and executive function (Intra-Extra Dimensional Set Shift, IED). Oscillatory power in the upper alpha range was associated with better performance on PAL and CRT, while low alpha power was associated with worse CRT performance. Beta power predicted poor performance on all three tests. Theta power was associated with good performance on PAL, and delta and theta oscillations were identified as predictors of good performance on IED. No differences in cognitive performance were found between diagnostic categories. CONCLUSION: Resting oscillations are predictive of certain dimensions of cognitive function across various psychiatric disorders. These findings may inform treatment development to improve cognition.

Skin autofluorescence of advanced glycation end products and mortality in affective disorders in the lifelines cohort study: A mediation analysis.

OBJECTIVE: Life expectancy in patients suffering from affective disorders is considerably diminished. We investigated whether skin autofluorescence (SAF), indicating concentration of advanced glycation end products in the skin and oxidative stress, mediates the association between affective disorders and excess mortality. METHODS: Included were 81,041 participants of the Lifelines cohort study. Presence of major depressive disorder, dysthymia, generalised anxiety disorder, panic disorder or social phobia was assessed with the Mini-International Neuropsychiatric Interview. SAF was assessed as mediator in Cox proportional hazards models for all-cause or natural-cause mortality. RESULTS: Mortality was increased in cases with major depression compared to controls (36.4 vs. 22.5 per 100,000 person years). Partial mediation by SAF of the association between affective disorders and mortality was shown (9.0-10.5%, P<.001-.002), although attenuated by cardiometabolic parameters and history of physical illness. For major depressive disorder, partial mediation by 5.5-10.3% was shown (crude model: P<.001; fully adjusted model: P=.03). LIMITATIONS: The relatively short duration of follow-up and the relatively young cohort resulted in a lack of power to detect an association between mortality and dysthymia, social phobia and two or more comorbid disorders. CONCLUSION: Evidence of partial mediation by SAF of the association between affective disorders and all-cause and natural-cause mortality was demonstrated, although attenuated by health factors. For major depression, mediation by SAF was largest and remained significant after adjustment for sociodemographic and health factors, identifying oxidative stress as possible determinant of premature death.

Ethnic discrimination and depressed mood: The role of autonomic regulation.

Perceived ethnic discrimination (PED) is thought to underlie increased prevalence of depressed mood in ethnic minorities. Depression is associated with increased sympathetic and decreased parasympathetic activity. We investigated a biopsychosocial model linking PED, disrupted sympathovagal balance and depressed mood. Baseline data of HELIUS, a cohort study on health among a multi-ethnic population, was used. Heart rate variability (HRV), baroreflex sensitivity (BRS), PED (evaluated with the Everyday Discrimination Scale) and presence of depressed mood (evaluated with the Patient Health Questionnaire-9) were assessed. Associations of PED, HRV/BRS and depressed mood were analyzed with linear and logistic regression analyses. Mediation of the association of PED and depressed mood by HRV/BRS was assessed in a potential outcomes model and four steps mediation analysis. Of 9492 included participants, 14.7% fulfilled criteria for depressed mood. Higher PED was associated with depressed mood (P < .001). Lower autonomic regulation indexes were associated with depressed mood (deltaR2 = 0.4-1.1%, P < .001) and at most weakly with PED (deltaR2 = 0.2-0.3%, P < .001). A very modest mediating effect by HRV/BRS in the association between PED and depressed mood was attenuated after adjustment for socioeconomic status. To conclude, we found no support for the hypothesis that autonomic regulation relevantly mediates the association between PED and depression.

Accumulation rate of advanced glycation end products in recent onset psychosis: A longitudinal study.

Schizophrenia is associated with excessive oxidative stress. Production of advanced glycation end products (AGEs) in the skin is strongly associated with oxidative stress. Increased skin AGE-levels have been demonstrated at cross-sectional level in recent onset psychosis and chronic schizophrenia, indicating increased cardiovascular risk. We aimed to investigate factors underlying AGE-accumulation and accumulation rate of AGEs in recent onset psychosis. From December 2016 through May 2017, 66 patients and 160 (highly educated) healthy controls from a previous case-control study of AGE-levels were assessed for a follow-up measurement 12-24 months after baseline. Possible determinants of AGE-accumulation were analyzed. AGE-accumulation rates in patients and controls were compared adjusted for relevant confounders. In healthy controls, a significant association of AGE-accumulation with ethnicity and tobacco exposure was found. An indication of a markedly higher AGE-accumulation rate was found in patients suffering from recent onset psychosis compared to healthy controls, independent of ethnicity and tobacco smoking, but not independent of cannabis use (more prevalent in patients than controls), although results were not significant.

Association between skin autofluorescence of advanced glycation end products and affective disorders in the lifelines cohort study.

BACKGROUND: Oxidative stress may be a mechanistic link between affective disorders (depressive and anxiety disorders) and somatic disease. Advanced glycation end products are produced under the influence of oxidative stress and in the skin (measured by skin autofluorescence [SAF]) serve as marker for cumulative oxidative stress. Aim of study was to determine whether SAF is associated with presence of affective disorders. METHODS: Participants in the Lifelines cohort study who had completed the Mini-International Neuropsychiatric Interview for affective disorders and a SAF-measurement were included. Cross-sectional associations between SAF and presence of the following psychiatric disorders were investigated through logistic regression analyses adjusted for sociodemographic factors, cardiometabolic parameters, and somatic morbidities: major depressive disorder, dysthymia, generalised anxiety disorder, panic disorder or social phobia. RESULTS: Of 81,041 included participants (41.7% male, aged 18-91 years), 6676 (8.2%) were cases with an affective disorder. SAF was associated with presence of affective disorders (OR=1.09 [95%CI 1.07-1.12], P<.001 adjusted for sociodemographic factors). Association with major depressive disorder was strongest and significant after adjustment for all confounders (OR=1.31 [95%CI 1.25-1.36], P<.001 in the crude model; OR=1.12 [95%CI 1.07-1.17], P<.001 in the fully adjusted model). For other disorders, associations lost significance after adjustment for cardiometabolic parameters and somatic morbidities. LIMITATIONS: Persons of non-Western descent and severely (mentally or physically) ill individuals were underrepresented. CONCLUSIONS: SAF was associated with presence of affective disorders, suggesting a link between these disorders and cumulative oxidative stress. For major depressive disorder, this association was strongest and independent of sociodemographic, cardiometabolic factors, and somatic morbidities.

Skin autofluorescence of advanced glycation end products and course of affective disorders in the lifelines cohort study, a prospective investigation.

BACKGROUND: Skin autofluorescence (SAF), indicating concentration of advanced glycation end products in the skin and oxidative stress, is cross-sectionally associated with affective disorders. Prospective studies of oxidative stress markers will help to clarify the pathophysiological role of oxidative stress. METHODS: Data of a population-based cohort study were used. Presence of major depressive disorder, dysthymia, generalised anxiety disorder, panic disorder or social phobia was assessed at baseline and at 5-year follow-up with the Mini-International Neuropsychiatric Interview. Associations between SAF at baseline and incidence and persistence/recurrence of affective disorders were assessed with logistic regression. RESULTS: Of 43,267 participants with no disorder at baseline, 2885 (6.7%) developed an incident disorder during follow-up. In 1360 of 3648 participants (37.3%) with an affective disorder at baseline, a persisting/recurrent disorder was present at follow-up. A modest association existed between SAF and incident affective disorders (OR=1.07 [95%CI 1.03-1.12], P<.001), specifically major depressive disorder (OR=1.11 [95%CI 1.04-1.19], P=.003); this association lost statistical significance after adjustment for sociodemographic factors. Associations between SAF and persistence/recurrence were not significant. LIMITATIONS: Many confounders might also act as intermediate: extensive adjustment for confounders caused overfitting and possibly masked effects of SAF on course of affective disorders. Relatively small sample sizes for analyses of SAF and persistence/recurrence of affective disorders resulted in a low power. CONCLUSIONS: Increased SAF modestly raises the odds of incident affective disorders, particularly major depressive disorder, providing evidence that oxidative stress plays a role in subsequent occurrence of affective disorders. However, significance of effects faded after adjustment for socioeconomic status.

Increased prevalence of ECG suspicious for Brugada Syndrome in recent onset schizophrenia spectrum disorders.

BACKGROUND: Schizophrenia is associated with an increased risk of sudden cardiac death, traditionally attributed to prolonged QTc interval and increased prevalence of cardiovascular risk factors. However, defective ion channels implicated in both schizophrenia and Brugada Syndrome (BrS) may be associated with an increased risk of cardiac arrhythmias. Moreover, these cardiac arrhythmias can be provoked by various drugs, including psychotropic drugs. OBJECTIVE: To assess the prevalence of the occurrence of ECG suspicious for BrS (suspect BrS-ECG) and the prevalence of BrS in patients with recent onset schizophrenia spectrum disorders (SSD). METHODS: In this case-control study, ECGs of 388 patients with recent onset SSD admitted between 2006 and 2015 and 844 healthy controls were made. All persons who had a suspect BrS-ECG were offered an ajmaline provocation test to diagnose or exclude BrS. Data on possible confounders were ascertained. Patients with and without suspect BrS-ECG were compared regarding clinical and ECG variables. RESULTS: Suspect BrS-ECG was found in 33 patients (8.5%) and 13 healthy controls (1.5%), with an adjusted Odds Ratio of 3.5 (p < 0.0001). This finding was not explained by potential confounders such as gender, age, ethnicity, cannabis use, cardiovascular risk factors, medication use or serum electrolytes. BrS was confirmed in three patients and one control. CONCLUSION: A considerable subset of patients with recent onset SSD have suspect BrS-ECG, extending earlier findings in patients with chronic schizophrenia. Screening for BrS in schizophrenia could be relevant both to prevent sudden cardiac death and to identify a subgroup of patients with possible ion-channel dysfunctioning.

The association between antibodies to neurotropic pathogens and bipolar disorder : A study in the Dutch Bipolar (DB) Cohort and meta-analysis.

Exposure to neurotropic pathogens has been hypothesized to be a risk factor for the development of bipolar disorder (BD). However, evidence so far is inconsistent. We, therefore, analyzed the seroprevalence and titer levels of IgG antibodies against several herpesviruses and Toxoplasma gondii (T. gondii) in plasma of 760 patients with a bipolar disorder, 144 first-degree matched relatives and 132 controls of the Dutch Bipolar (DB) Cohort using ELISA. In addition, we performed a literature-based meta-analysis on the seroprevalence of IgG antibodies against these pathogens (n = 14). Our results in the DB Cohort and subsequent meta-analysis (n = 2364 BD patients, n = 5101 controls) show no association between exposure to herpesviruses and bipolar disorder (HSV-1 [adjusted OR 0.842, 95% CI 0.567-1.230], HSV-2 [adjusted OR 0.877, 95% CI 0.437-1.761], CMV [adjusted OR 0.884 95% CI 0.603-1.295], EBV [adjusted OR 0.968 95% CI 0.658-1.423]). In the DB Cohort, we did not find an association between bipolar disorder and T. gondii titer or seroprevalence either [adjusted OR 1.018, 95% CI 0.672-1.542]. The overall OR was not significant for T. gondii [OR: 1.4, 95% CI 0.95-1.90, p = 0.09), but subgroup analyses in age groups below 40 years showed a significantly increased seroprevalence of T. gondii IgGs in BD [OR: 1.8 (95% CI 1.10-2.89, p = 0.021]. Our meta-analysis indicates that T. gondii exposure may be a risk factor for BD in certain subpopulations.

Clozapine and Long-Term Mortality Risk in Patients With Schizophrenia: A Systematic Review and Meta-analysis of Studies Lasting 1.1-12.5 Years.

INTRODUCTION: Patients with schizophrenia have an elevated mortality risk compared to the general population, with cardiovascular-related deaths being the leading cause. The role of clozapine use in the long-term mortality risk is unclear. While clozapine treatment may increase the risk for cardiovascular mortality, it may have protective effects regarding suicidal behavior. METHODS: We systematically searched EMBASE, MEDLINE, and PsycINFO and reviewed studies that used a long-term follow-up (ie, >52 weeks) and reported on mortality in adults diagnosed with schizophrenia-spectrum disorders who had received clozapine treatment. RESULTS: Altogether, 24 studies reported on 1327 deaths from any causes during 217691 patient years in patients treated with clozapine. The unadjusted mortality rate in 22 unique samples during a follow-up of 1.1-12.5 (median = 5.4) years was 6.7 (95% confidence interval [CI] = 5.4-7.9) per 1000 patient years. Long-term, crude mortality rate ratios were not significantly lower in patients ever treated with clozapine during follow-up, but significantly lower in patients continuously treated with clozapine compared to patients with other antipsychotics (mortality rate ratio = 0.56, 95% CI = 0.36-0.85, P-value = .007). Few studies reported on rates of long-term cause-specific mortality (suicide and ischemic heart disease), which showed no significant difference in patients using clozapine compared to patients using other antipsychotics. Statistical heterogeneity was high in all analyses. DISCUSSION: Continuous clozapine treatment in schizophrenia patients was associated with a significantly lower long-term all-cause mortality rate compared to other antipsychotic use. These findings, combined with the known efficacy of clozapine, give reason to re-evaluate the hesitancy to prescribe clozapine in regular care settings. TRIAL REGISTRATION: PROSPERO CRD42017069390.

Plasma dopa decarboxylase activity in treatment-resistant recent-onset psychosis patients.

Treatment resistance (TR) in psychosis is a major clinical problem. A biomarker predicting TR against conventional antipsychotic drugs would be relevant, potentially reducing unnecessary delay to adequate treatment with clozapine. Dopa decarboxylase (DDC) activity in the striatum, measured with positron emission tomography, is elevated in responders, but not in treatment-resistant patients. Plasma DDC activity could be a surrogate marker for DDC brain activity, and thus a potential biomarker that could be used in daily clinical practice. Therefore, we determined plasma DDC activity in 40 male patients with recent-onset psychosis, of whom the majority had started treatment, whereby 21 turned out to be treatment responders and 19 treatment resistant during follow up. We observed no significant group differences. Furthermore, symptom severity was not associated with plasma DCC activity. We did observe a trend level difference in the distribution of plasma DDC activity across categories of medication, with subsequent post hoc analysis showing lower DDC activity in risperidone-using patients. This may suggest that risperidone could influence plasma DDC activity. Based on these results, plasma DDC activity does not appear to be a promising biomarker for TR in recent-onset psychosis patients who are already receiving antipsychotic treatment.