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 Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses.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.

Vaccination and clozapine use: a systematic review and an analysis of the VAERS database.

In the context of COVID-19 concerns related to the potential interactions between clozapine and vaccination arose. With the ultimate goal of deriving recommendations for clinical practice, we systematically reviewed the current evidence regarding altered vaccine effectiveness in clozapine-treated patients and safety aspects of vaccination, such as haematological changes and the impact of vaccines on clozapine blood levels, in clozapine-treated patients. A systematic PRISMA-conform literature search of four databases (PubMed, PsycINFO, EMBASE and Cochrane Library) complemented by a case-by-case analysis of the Vaccine Adverse Event Reporting System (VAERS) database was performed. We then systematically appraised the joint evidence and tried to derive recommendations for clinical practice. 14 records were included in this analysis. These records consisted of 5 original articles and 9 case reports. Among the original articles, two studies provided data on the association between clozapine use and antibody responses to vaccination, both indicating that clozapine use in schizophrenia may be associated with reduced levels of immunoglobulins. Additionally, three studies examined vaccine safety in clozapine-treated patients, with no clinically significant adverse effects directly attributable to the interplay between vaccinations and clozapine. VAERS Analysis encompassed 137 reports and showed no consistent evidence of an increased risk for clozapine blood level increases or adverse events. We found no evidence indicating that clozapine impairs the effectiveness of vaccines. Moreover, no serious safety concerns seem to apply when patients on clozapine are receiving vaccines. However, it is crucial to acknowledge that data on the interaction between clozapine and vaccines remain limited.

Polygenetic risk scores and phenotypic constellations of obsessive-compulsive disorder in clozapine-treated schizophrenia.

Obsessive-compulsive symptoms (OCS) are frequently observed in individuals with schizophrenia (SCZ) treated with clozapine (CLZ). This study aimed to analyze prevalence of OCS and obsessive-compulsive disorder (OCD) in this subgroup and find possible correlations with different phenotypes. Additionally, this is the first study to examine polygenetic risk scores (PRS) in individuals with SCZ and OCS. A multicenter cohort of 91 individuals with SCZ who were treated with CLZ was recruited and clinically and genetically assessed. Symptom severity was examined using the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI), the Calgary Depression Scale for Schizophrenia (CDSS), Global Assessment of Functioning Scale (GAF) and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Participants were divided into subgroups based on phenotypic OCS or OCD using Y-BOCS scores. Genomic-wide data were generated, and PRS analyses were performed to evaluate the association between either phenotypic OCD or OCS severity and genotype-predicted predisposition for OCD, SCZ, cross-disorder, and CLZ/norclozapine (NorCLZ) ratio, CLZ metabolism and NorCLZ metabolism. OCS and OCD were frequent comorbidities in our sample of CLZ-treated SCZ individuals, with a prevalence of 39.6% and 27.5%, respectively. Furthermore, the Y-BOCS total score correlated positively with the duration of CLZ treatment in years (r = 0.28; p = 0.008) and the PANSS general psychopathology subscale score (r = 0.23; p = 0.028). A significant correlation was found between OCD occurrence and PRS for CLZ metabolism. We found no correlation between OCS severity and PRS for CLZ metabolism. We found no correlation for either OCD or OCS and PRS for OCD, cross-disorder, SCZ, CLZ/NorCLZ ratio or NorCLZ metabolism. Our study was able to replicate previous findings on clinical characteristics of CLZ-treated SCZ individuals. OCS is a frequent comorbidity in this cohort and is correlated with CLZ treatment duration in years and PANSS general psychopathology subscale score. We found a correlation between OCD and PRS for CLZ metabolism, which should be interpreted as incidental for now. Future research is necessary to replicate significant findings and to assess possible genetic predisposition of CLZ-treated individuals with SCZ to OCS/OCD. Limitations attributed to the small sample size or the inclusion of subjects on co-medication must be considered. If the association between OCD and PRS for CLZ metabolism can be replicated, it should be further evaluated if CYP1A2 alteration, respectively lower CLZ plasma level, is relevant for OCD development.

Association of Four Medication Classes and Non-suicidal Self-injury in Adolescents with Affective Disorders - A Retrospective Chart Review.

BACKGROUND: Non-suicidal self-injury (NSSI) behaviour is frequently observed in children and adolescents with psychiatric conditions. Affected individuals are regularly treated with psychotropic drugs, although the impact of these agents on NSSI behaviour remains elusive. METHODS: We performed a retrospective chart review from clinical routine data in a large cohort (N=1140) of adolescent inpatients with primary affective and non-affective psychiatric disorders according to ICD-10 (mean age=15.3±1.3 years; 72.6% female). Four separate mixed regression models compared the frequency of NSSI between treatment periods without any medication and four medication categories (benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), high- and low-potency antipsychotics). RESULTS: In those individuals with affective disorders as the primary diagnosis, periods without medication were associated with significantly lower NSSI/day compared to all four other medication conditions (benzodiazepines p<10-8, antidepressants/SSRIs p=0.0004, high-potency antipsychotics p=0.0009, low-potency antipsychotics p<10 -4). In individuals with a primary diagnosis other than an affective disorder, NSSI was significantly lower during the period without medication compared to the treatment periods with benzodiazepines (p=0.005) and antidepressants/SSRIs (p=0.01). However, NSSI rates in the no-medication condition were comparable to NSSI rates under high-potency (p=0.89) and low-potency antipsychotics (p=0.53). CONCLUSIONS: The occurrence of NSSI correlates with the treatment with a psychotropic drug in children and adolescents with psychiatric disorders. Due to the retrospective design, it remains elusive to what extent psychotropic drugs might alter the frequency of NSSI in adolescents or if NSSI might indicate a transdiagnostic feature of more pronounced disease severity.

[Management of treatment resistance-Treatment-resistant schizophrenia]. / Management von Therapieresistenzen ­ therapieresistente Schizophrenie.

Despite a very high prevalence and substantial impairments among affected individuals, treatment-resistant schizophrenia (TRS) has not been sufficiently researched in clinical research in the field of psychiatric disorders and the pathophysiology is still poorly understood. A better clinical and pathophysiological understanding of this heterogeneous and severely affected population of people with persistent symptoms in different domains is necessary in order not only to be able to intervene early but also to develop novel therapeutic strategies or individualized treatment approaches. This review article presents the state of the art criteria of the pharmacological TRS, neurobiological disease models and predictive factors for TRS as well as the phenomenon of pseudo-treatment resistance and the clinical management of TRS. In the future, not only the use of operationalized criteria and definitions of TRS in longitudinal studies and randomized-controlled trials (RCTs) are paramount, but also the observation of trajectories with the integration of multimodal longitudinal phenotyping and the longitudinal collection of clinical routine data in academic research, which will be possible in the newly created German Center for Mental Health (DZPG).

[Deprescribing in DGPPN S3 guidelines-a systematic analysis]. / "Deprescribing" in DGPPN-S3-Leitlinien ­ eine systematische Analyse.

BACKGROUND: Deprescribing of medication or psychotherapy represents a critical phase in treatment. The aim of the work is to systematically analyze recommendations for deprescribing medication and discontinuation of psychotherapy in the evidence- and consensus-based S3 guidelines of the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) to identify potential research gaps. METHODS: A systematic analysis of the DGPPN S3 guidelines to investigate and compare information and recommendations on deprescribing. RESULTS: Regarding deprescribing of medication, our analysis showed that eight of the 20 included S3 guidelines contain information both in the form of recommendations and background information. Regarding psychotherapy, only two guidelines provided information on deprescribing. CONCLUSION: Our results highlight the need to expand guidelines to include evidence-based recommendations for deprescribing medication or discontinuation of psychotherapy. Future research should focus on the development of specific, generic, and evidence-based guidelines that support both medical staff and patients during these critical phases of therapy.

[Inpatient Treatment of Mentally Ill Prisoners in General Psychiatric Departments and Hospitals]. / Status der stationären Behandlung psychisch erkrankter Strafgefangener in allgemeinpsychiatrischen Abteilungen und Kliniken.

BACKGROUND: Inpatient psychiatric treatment of prisoners is organized differently in Germany, depending on the structural conditions of the federal state and prison. There are very few findings on the different possibilities of treatment and the view of the hospitals on this issue. OBJECTIVES: Our aim was to gain an up-to-date picture of inpatient treatment of prisoners in general psychiatric departments and hospitals and the challenges these institutions face. METHODS: We conducted an anonymous online survey of the frequency, extent, and challenges of inpatient treatment of prisoners. Approximately 460 chief physicians of German general psychiatric departments and hospitals were invited to participate in this survey. In addition to descriptive statistics, we calculated group differences by type of hospital and by subjective responsibility for inpatient care of prisoners. RESULTS: A total of 74 chief physicians surveyed participated; 51.4% of the surveyed hospitals provided psychiatric inpatient treatment to prisoners in 2020. Group differences between the different types of hospitals were found only for the presence of anticipated anxiety among regular inpatients. Various differences were found between responsible and non-responsible hospitals, especially with regard to organizational aspects. DISCUSSION: For the treatment of mentally ill prisoners, various organizational challenges as well as fears of hospital staff and fellow patients were mentioned by the participants. The type of hospital appears to play a subordinate role here, whereas the responsibility of the hospital for the inpatient treatment of mentally ill prisoners might be more decisive for anticipated concerns and barriers.

Higher Subjective Burden in Psychiatric Compared to Somatic Healthcare Workers in Germany During the first wave of the COVID-19 Pandemic.

The COVID-19 pandemic has posed unprecedented challenges for health care workers (HCWs) worldwide. While the adverse effects of the pandemic on the well-being of HCWs in general have now been established, little is known about the impact on HCWs of psychiatric hospitals (PHCWs). PHCWs are of special interest, given that they faced both an increase in infection rates among psychiatric patients as well as in mental strain of the general public due to consequences of the pandemic. The aim of the present study was to investigate how the pandemic affected PHCWs as well as possible differences between PHCWs and other health care workers (OHCWs) in Germany during the first wave of the pandemic. We conducted a country-wide anonymous online survey early during the first pandemic wave between April 15th and May 1st, 2020, to assess different aspects of subjective burden and perceived stress using 5-point Likert-scale questions. We analysed data of 1530 PHCWs and 2114 OHCWs and showed that PHCWs reported higher subjective burden and stress compared to OHCWs (p<0.001). Overall, nurses from both groups of HCWs showed higher ratings in subjective burden and stress than physicians. These higher ratings for subjective burden were even more pronounced for nurses working in psychiatric hospitals. Future research is needed to investigate the causes for PHCWs' increased stress and subjective burden, especially when taking into account the long-term effects of the pandemic, which may lead to further challenges and an ever-increasing workload, especially for PHCWs.

Effects of add-on Celecoxib treatment on patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame): study design and methodology of a multicentre randomized, placebo-controlled trial.

Neuroinflammation has been proposed to impact symptomatology in patients with schizophrenia spectrum disorders. While previous studies have shown equivocal effects of treatments with add-on anti-inflammatory drugs such as Aspirin, N-acetylcysteine and Celecoxib, none have used a subset of prospectively recruited patients exhibiting an inflammatory profile. The aim of the study is to evaluate the efficacy and safety as well as the cost-effectiveness of a treatment with 400 mg Celecoxib added to an ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. The "Add-on Celecoxib treatment in patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame)" is a multicentre randomized, placebo-controlled phase III investigator-initiated clinical trial with the following two arms: patients exhibiting an inflammatory profile receiving either add-on Celecoxib 400 mg/day or add-on placebo. A total of 199 patients will be assessed for eligibility by measuring blood levels of three pro-inflammatory cytokines, and 109 patients with an inflammatory profile, i.e. inflamed, will be randomized, treated for 8 weeks and followed-up for additional four months. The primary endpoint will be changes in symptom severity as assessed by total Positive and Negative Syndrome Scale (PANSS) score changes from baseline to week 8. Secondary endpoints include various other measures of psychopathology and safety. Additional health economic analyses will be performed. TargetFlame is the first study aimed at evaluating the efficacy, safety and cost-effectiveness of the antiphlogistic agent Celecoxib in a subset of patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. With TargetFlame, we intended to investigate a novel precision medicine approach towards anti-inflammatory antipsychotic treatment augmentation using drug repurposing. Clinical trial registration: http://www.drks.de/DRKS00029044 and https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00029044.

Blood-brain barrier dysfunction and folate and vitamin B12 levels in first-episode schizophrenia-spectrum psychosis: a retrospective chart review.

Vitamin deficiency syndromes and blood-brain barrier (BBB) dysfunction are frequent phenomena in psychiatric conditions. We analysed the largest available first-episode schizophrenia-spectrum psychosis (FEP) cohort to date regarding routine cerebrospinal fluid (CSF) and blood parameters to investigate the association between vitamin deficiencies (vitamin B12 and folate) and BBB impairments in FEP. We report a retrospective analysis of clinical data from all inpatients that were admitted to our tertiary care hospital with an ICD-10 diagnosis of a first-episode F2x (schizophrenia-spectrum) between January 1, 2008 and August 1, 2018 and underwent a lumbar puncture, blood-based vitamin status diagnostics and neuroimaging within the clinical routine. 222 FEP patients were included in our analyses. We report an increased CSF/serum albumin quotient (Qalb) as a sign of BBB dysfunction in 17.1% (38/222) of patients. White matter lesions (WML) were present in 29.3% of patients (62/212). 17.6% of patients (39/222) showed either decreased vitamin B12 levels or decreased folate levels. No statistically significant association was found between vitamin deficiencies and altered Qalb. This retrospective analysis contributes to the discussion on the impact of vitamin deficiency syndromes in FEP. Although decreased vitamin B12 or folate levels were found in approximately 17% of our cohort, we found no evidence for significant associations between BBB dysfunction and vitamin deficiencies. To strengthen the evidence regarding the clinical implications of vitamin deficiencies in FEP, prospective studies with standardized measurements of vitamin levels together with follow-up measurements and assessment of symptom severity in addition to CSF diagnostics are needed.

Guideline for schizophrenia: implementation status and attitude toward an upcoming living guideline.

The implementation status of clinical guidelines is, despite their important role in connecting research with practice, frequently not satisfactory. This study aims to investigate the implementation status of the current German guideline for schizophrenia. Moreover, the attitude toward a living guideline has been explored for the first time by presenting screenshots of the German schizophrenia guideline transferred to a digital living guideline format called MAGICapp. A cross-sectional online survey was performed under the participation of 17 hospitals for psychiatry and psychosomatic medicine in Southern Germany and one professional association for German neurologists and psychiatrists. 439 participants supplied sufficient data for analysis. 309 provided complete data sets. Regarding the current guideline for schizophrenia and key recommendations, a large awareness-to-adherence gap was found. Group comparisons between different professions (caregivers, medical doctors, psychologists/psychotherapists, psychosocial therapists) detected differences in the implementation status showing higher awareness and agreement with the schizophrenia guideline and its key recommendations among medical doctors compared to psychosocial therapists and caregivers. Moreover, we detected differences in the implementation status of the guideline as a whole and its key recommendations between specialist and assistant doctors. The attitude toward an upcoming living guideline was mostly positive, especially among younger healthcare professionals. Our findings confirm an awareness-to-adherence gap, not only for the current schizophrenia guideline in general but also for its key recommendations with apparent differences between professions. Overall, our results show promising positive attitudes toward the living guideline for schizophrenia among healthcare providers, suggesting that a living guideline may be a supportive tool in everyday clinical practice.

Conventional and living guideline for schizophrenia: barriers and facilitating factors in guideline implementation.

This study aims to investigate the barriers and facilitators to guideline adherence for the print format of the German schizophrenia guideline as well as for the concept of a digital living guideline for the first time. For this purpose, the schizophrenia guideline was transferred to a digital guideline format within the web-based tool MAGICapp. An online survey was performed under participation of mental healthcare professionals (medical doctors, psychologists/psychotherapists, psychosocial therapists, caregivers) in 17 hospitals for psychiatry in Southern Germany and a professional association for German neurologists and psychiatrists. 524 participants opened the survey, 439 completed the demographic questions and commenced the content-related survey and 309 provided complete data sets. Results indicate a higher occurrence of knowledge-related barriers for the living guideline. The print version is associated with more attitude-related and external barriers. Older professionals reported more attitude-related barriers to a living guideline compared to younger professionals. Differences between professions regarding barriers were found for both formats. Various barriers exist for both guideline formats and a need for facilitators was expressed across professions. Many of the mentioned obstacles and facilitators can be more easily addressed with living guidelines. However, also living guidelines face barriers. Thus, the introduction of these new formats alone cannot lead to sustainable behavior change regarding guideline adherence. Yet, living guidelines seem to be a cornerstone to improved and tailored guideline implementation as they facilitate to keep recommendations up to date and to address the need of individual professional groups.

Optical coherence tomography reveals retinal thinning in schizophrenia spectrum disorders.

BACKGROUND: Schizophrenia spectrum disorders (SSDs) are presumed to be associated with retinal thinning. However, evidence is lacking as to whether these retinal alterations reflect a disease-specific process or are rather a consequence of comorbid diseases or concomitant microvascular impairment. METHODS: The study included 126 eyes of 65 patients with SSDs and 143 eyes of 72 healthy controls. We examined macula and optic disc measures by optical coherence tomography (OCT) and OCT angiography (OCT-A). Additive mixed models were used to assess the impact of SSDs on retinal thickness and perfusion and to explore the association of retinal and clinical disease-related parameters by controlling for several ocular and systemic covariates (age, sex, spherical equivalent, intraocular pressure, body mass index, diabetes, hypertension, smoking status, and OCT signal strength). RESULTS: OCT revealed significantly lower parafoveal macular, macular ganglion cell-inner plexiform layer (GCIPL), and macular retinal nerve fiber layer (RNFL) thickness and thinner mean and superior peripapillary RNFL in SSDs. In contrast, the applied OCT-A investigations, which included macular and peripapillary perfusion density, macular vessel density, and size of the foveal avascular zone, did not reveal any significant between-group differences. Finally, a longer duration of illness and higher chlorpromazine equivalent doses were associated with lower parafoveal macular and macular RNFL thickness. CONCLUSIONS: This study strengthens the evidence for disease-related retinal thinning in SSDs.

Effects of Early Clozapine Treatment on Remission Rates in Acute Schizophrenia (The EARLY Trial): Protocol of a Randomized-Controlled Multicentric Trial.

BACKGROUND: Quick symptomatic remission after the onset of psychotic symptoms is critical in schizophrenia treatment, determining the subsequent disease course and recovery. In this context, only every second patient with acute schizophrenia achieves symptomatic remission within three months of initiating antipsychotic treatment. The potential indication extension of clozapine-the most effective antipsychotic-to be introduced at an earlier stage (before treatment-resistance) is supported by several lines of evidence, but respective clinical trials are lacking. METHODS: Two hundred-twenty patients with acute non-treatment-resistant schizophrenia will be randomized in this double-blind, 8-week parallel-group multicentric trial to either clozapine or olanzapine. The primary endpoint is the number of patients in symptomatic remission at the end of week 8 according to international consensus criteria ('Andreasen criteria'). Secondary endpoints and other assessments comprise a comprehensive safety assessment (i. e., myocarditis screening), changes in psychopathology, global functioning, cognition, affective symptoms and quality of life, and patients' and relatives' views on treatment. DISCUSSION: This multicentre trial aims to examine whether clozapine is more effective than a highly effective second-generation antipsychotics (SGAs), olanzapine, in acute schizophrenia patients who do not meet the criteria for treatment-naïve or treatment-resistant schizophrenia. Increasing the likelihood to achieve symptomatic remission in acute schizophrenia can improve the overall outcome, reduce disease-associated burden and potentially prevent mid- and long-term disease chronicity.

Pathogenese der Schizophrenie(n).

Schizophrenia is a mental disorder characterized by marked heterogeneity at both the phenomenological and neurobiological levels. Its diagnostic disentanglement would lead to more precise treatment and improved prognosis in people with schizophrenia. For this, a deeper understanding of the pathophysiological mechanisms of schizophrenia is needed.

60 Years of Combining Tranylcypromine: A Systematic Review of Available Evidence.

BACKGROUND: Tranylcypromine is the only irreversible monoamine oxidase inhibitor that is approved in the United States and in Europe for the management of treatment-resistant major depressive disorder. Comprehensive data in the literature regarding the efficacy and tolerability of tranylcypromine (TCP) combination strategies have not been systematically investigated yet. METHODS: We conducted a systematic review of available literature based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Study types considered eligible for inclusion were studies that reported information on efficacy and/or tolerability/adverse effects of pharmacological TCP add-on or coadministration strategies among people with psychiatric disorders. RESULTS: Ninety-six articles were included in qualitative analyses. A relevant body of evidence shows that TCP combined with first- and second-generation antipsychotics seems relatively safe and might have beneficial effects in some patients with depressive disorders, although caution is needed with some second-generation antipsychotics that have proserotonergic activity. Although evidence is not entirely consistent, amitriptyline as add-on agent might be efficacious and associated with a low rate of severe adverse events. Although available data from case reports are scarce, certain other agents, such as trazodone, but also lithium, seem to have a good risk-benefit profile with regard to TCP that should be further investigated in the context of high-quality studies. CONCLUSIONS: Any combination of a psychotropic with TCP should be preceded by an evaluation of drug-to-drug interaction and an informed consent process and followed by close monitoring. Before any combination strategy, doctors should reevaluate factors of pseudo-treatment resistance, such as rapid-metabolizing status, noncompliance, trauma, alternative diagnosis, or drug abuse.

Psychotropic drugs for the treatment of non-suicidal self-injury in children and adolescents: a systematic review and meta-analysis.

Non-suicidal self-injury (NSSI) in children and adolescents is a frequent phenomenon. NSSI at any time is a significant predictor of future NSSI but also, and more importantly, for suicide attempts. Less evidence is available for the impact, or more specifically, the therapeutic effect of psychotropic drugs on the emergence of NSSI in this population. The phenomenon is clinically highly relevant since adolescent psychiatric inpatients are often affected by NSSI and most of them are treated with psychotropic drugs. While previous reviews on NSSI comprised suicidal self-injury (SSI), this review aims at elucidating the potential impact of psychotropic drugs on the emergence of specifically NSSI in children and adolescents. Systematic searches of articles indexed electronically in PubMed, Embase and PsycInfo were conducted (PROSPERO CRD42020209505). Studies included in the quantitative synthesis were evaluated using the SIGN level of evidence rating. Meta-analyses were performed using RevMan (Version 5.4). 2227 records were identified through database searches. Two additional records were identified manually. In total, seven studies were included in qualitative and four studies in quantitative analyses. In a meta-analysis, selective serotonin reuptake inhibitors (SSRIs) were compared vs. control medication (placebo or serotonin-norepinephrine reuptake inhibitor) and here, no statistically significant difference between the groups could be observed regarding the frequency of NSSI events (Risk Ratio (RR) = 1.07, 95% confidence interval (CI) 0.60-1.91, p = 0.82, I2 = 12%). Evidence regarding the association of SSRI use and NSSI among children and adolescents is sparse and the impact of psychotropic drugs in general on NSSI rates in this population should be addressed in future clinical and observational studies.

Cognitive and functional deficits are associated with white matter abnormalities in two independent cohorts of patients with schizophrenia.

BACKGROUND: Significant evidence links white matter (WM) microstructural abnormalities to cognitive impairment in schizophrenia (SZ), but the relationship of these abnormalities with functional outcome remains unclear. METHODS: In two independent cohorts (C1, C2), patients with SZ were divided into two subgroups: patients with higher cognitive performance (SZ-HCP-C1, n = 25; SZ-HCP-C2, n = 24) and patients with lower cognitive performance (SZ-LCP-C1, n = 25; SZ-LCP-C2, n = 24). Healthy controls (HC) were included in both cohorts (HC-C1, n = 52; HC-C2, n = 27). We compared fractional anisotropy (FA) of the whole-brain WM skeleton between the three groups (SZ-LCP, SZ-HCP, HC) by a whole-brain exploratory approach and an atlas-defined WM regions-of-interest approach via tract-based spatial statistics. In addition, we explored whether FA values were associated with Global Assessment of Functioning (GAF) scores in the SZ groups. RESULTS: In both cohorts, mean FA values of whole-brain WM skeleton were significantly lower in the SCZ-LCP group than in the SCZ-HCP group. Whereas in C1 the FA of the frontal part of the left inferior fronto-occipital fasciculus (IFOF) was positively correlated with GAF score, in C2 the FA of the temporal part of the left IFOF was positively correlated with GAF score. CONCLUSIONS: We provide robust evidence for WM microstructural abnormalities in SZ. These abnormalities are more prominent in patients with low cognitive performance and are associated with the level of functioning.

Association between aerobic fitness and the functional connectome in patients with schizophrenia.

BACKGROUND: Schizophrenia is accompanied by widespread alterations in static functional connectivity associated with symptom severity and cognitive deficits. Improvements in aerobic fitness have been demonstrated to ameliorate symptomatology and cognition in people with schizophrenia, but the intermediary role of macroscale connectivity patterns remains unknown. OBJECTIVE: Therefore, we aim to explore the relation between aerobic fitness and the functional connectome in individuals with schizophrenia. Further, we investigate clinical and cognitive relevance of the identified fitness-connectivity links. METHODS: Patients diagnosed with schizophrenia were included in this cross-sectional resting-state fMRI analysis. Multilevel Bayesian partial correlations between aerobic fitness and functional connections across the whole brain as well as between static functional connectivity patterns and clinical and cognitive outcome were performed. Preliminary causal inferences were enabled based on mediation analyses. RESULTS: Static functional connectivity between the subcortical nuclei and the cerebellum as well as between temporal seeds mediated the attenuating relation between aerobic fitness and total symptom severity. Functional connections between cerebellar seeds affected the positive link between aerobic fitness and global cognition, while the functional interplay between central and limbic seeds drove the beneficial association between aerobic fitness and emotion recognition. CONCLUSION: The current study provides first insights into the interactions between aerobic fitness, the functional connectome and clinical and cognitive outcome in people with schizophrenia, but causal interpretations are preliminary. Further interventional aerobic exercise studies are needed to replicate the current findings and to enable conclusive causal inferences. TRIAL REGISTRATION: The study which the manuscript is based on is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804).

Clozapine levels as a predictor for therapeutic response: A systematic review and meta-analysis.

OBJECTIVES: Clozapine levels may be a more useful predictor of therapeutic response than the dose, given the variability in clozapine metabolism between individuals. We therefore systematically reviewed and meta-analysed the impact of clozapine levels on response and/or relapse to provide guidance on optimal clozapine levels. METHODS: We systematically searched PubMed, PsycInfo and Embase for studies exploring clozapine levels and response and/or relapse. Our primary meta-analysis was rates of response above and below clozapine level thresholds of 350 ng/ml and 600 ng/ml. Secondary analyses were undertaken of mean clozapine levels, dose and concentration/dose (C/D) ratio and response and/or relapse. A meta-regression by study duration was conducted. RESULTS: Twenty studies met inclusion criteria. Clozapine levels above 350 ng/ml were associated with statistically significantly higher rates of response (OR 2.27 95% CI 1.40-3.67, p < 0.001), but not above 600 ng/ml (OR 1.40 95% CI 0.85-2.31, p = 0.19). Higher mean clozapine levels were associated with better rates of response (SMD 0.24, 95% CI 0.00-0.49, p = 0.05), and lower rates of relapse (SMD -0.72, 95% CI -1.26 to -0.19, p = 0.008). By contrast, neither clozapine dose nor C/D ratio was associated with differing rates of response. Similarly, study duration did not affect outcome. CONCLUSIONS: Our findings are in keeping with current guidelines that recommend targeting clozapine levels above 350 ng/ml before augmentation is considered. As some clozapine associated ADRs are dose dependent, levels above 600 ng/ml may have an unfavourable risk-benefit ratio.