Relapse in clinically stable adult patients with schizophrenia or schizoaffective disorder: evidence-based criteria derived by equipercentile linking and diagnostic test accuracy meta-analysis.

BACKGROUND: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder. METHODS: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation. FINDINGS: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented. INTERPRETATION: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores. FUNDING: German Research Foundation (grant number: 428509362).

Predicting psychotic relapse following randomised discontinuation of paliperidone in individuals with schizophrenia or schizoaffective disorder: an individual participant data analysis.

BACKGROUND: Predicting relapse for individuals with psychotic disorders is not well established, especially after discontinuation of antipsychotic treatment. We aimed to identify general prognostic factors of relapse for all participants (irrespective of treatment continuation or discontinuation) and specific predictors of relapse for treatment discontinuation, using machine learning. METHODS: For this individual participant data analysis, we searched the Yale University Open Data Access Project's database for placebo-controlled, randomised antipsychotic discontinuation trials with participants with schizophrenia or schizoaffective disorder (aged ≥18 years). We included studies in which participants were treated with any antipsychotic study drug and randomly assigned to continue the same antipsychotic drug or to discontinue it and receive placebo. We assessed 36 prespecified baseline variables at randomisation to predict time to relapse, using univariate and multivariate proportional hazard regression models (including multivariate treatment group by variable interactions) with machine learning to categorise the variables as general prognostic factors of relapse, specific predictors of relapse, or both. FINDINGS: We identified 414 trials, of which five trials with 700 participants (304 [43%] women and 396 [57%] men) were eligible for the continuation group and 692 participants (292 [42%] women and 400 [58%] men) were eligible for the discontinuation group (median age 37 [IQR 28-47] years for continuation group and 38 [28-47] years for discontinuation group). Out of the 36 baseline variables, general prognostic factors of increased risk of relapse for all participants were drug-positive urine; paranoid, disorganised, and undifferentiated types of schizophrenia (lower risk for schizoaffective disorder); psychiatric and neurological adverse events; higher severity of akathisia (ie, difficulty or inability to sit still); antipsychotic discontinuation; lower social performance; younger age; lower glomerular filtration rate; benzodiazepine comedication (lower risk for anti-epileptic comedication). Out of the 36 baseline variables, predictors of increased risk specifically after antipsychotic discontinuation were increased prolactin concentration, higher number of hospitalisations, and smoking. Both prognostic factors and predictors with increased risk after discontinuation were oral antipsychotic treatment (lower risk for long-acting injectables), higher last dosage of the antipsychotic study drug, shorter duration of antipsychotic treatment, and higher score on the Clinical Global Impression (CGI) severity scale The predictive performance (concordance index) for participants who were not used to train the model was 0·707 (chance level is 0·5). INTERPRETATION: Routinely available general prognostic factors of psychotic relapse and predictors specific for treatment discontinuation could be used to support personalised treatment. Abrupt discontinuation of higher dosages of oral antipsychotics, especially for individuals with recurring hospitalisations, higher scores on the CGI severity scale, and increased prolactin concentrations, should be avoided to reduce the risk of relapse. FUNDING: German Research Foundation and Berlin Institute of Health.

The effects of social isolation stress and discrimination on mental health.

Social isolation and discrimination are growing public health concerns associated with poor physical and mental health. They are risk factors for increased morbidity and mortality and reduced quality of life. Despite their detrimental effects on health, there is a lack of knowledge regarding translation across the domains of experimental research, clinical studies, and real-life applications. Here, we review and synthesize evidence from basic research in animals and humans to clinical translation and interventions. Animal models indicate that social separation stress, particularly in early life, activates the hypothalamic-pituitary-adrenal axis and interacts with monoaminergic, glutamatergic, and GABAergic neurotransmitter systems, inducing long-lasting reductions in serotonin turnover and alterations in dopamine receptor sensitivity. These findings are of particular importance for human social isolation stress, as effects of social isolation stress on the same neurotransmitter systems have been implicated in addictive, psychotic, and affective disorders. Children may be particularly vulnerable due to lasting effects of social isolation and discrimination stress on the developing brain. The effects of social isolation and loneliness are pronounced in the context of social exclusion due to discrimination and racism, during widespread infectious disease related containment strategies such as quarantine, and in older persons due to sociodemographic changes. This highlights the importance of new strategies for social inclusion and outreach, including gender, culture, and socially sensitive telemedicine and digital interventions for mental health care.

Stimulus data and experimental design for a self-paced reading study on emoji-word substitutions.

This data paper presents the experimental design and stimuli from an online self-paced reading study on the processing of emojis substituting lexically ambiguous nouns. We recorded reading times for the target ambiguous nouns and for emojis depicting either the intended target referent or a contextually inappropriate homophonous noun. Furthermore, we recorded comprehension accuracy, demographics and a self-assessment of the participants' emoji usage frequency. The data includes all stimuli used, the raw data, the full JavaScript code for the online experiment, as well as Python and R code for the data analysis. We believe that our dataset may give important insights related to the comprehension mechanisms involved in the cognitive processing of emojis. For interpretation and discussion of the experiment, please see the original article entitled "The processing of emoji-word substitutions: A self-paced-reading study".

Adverse events after antipsychotic discontinuation: an individual participant data meta-analysis.

BACKGROUND: Adverse events can occur after antipsychotic discontinuation but evidence from antipsychotic drug trials is scarce. We aimed to estimate the occurrence of adverse events after discontinuing antipsychotics. METHODS: For this two-stage individual participant data meta-analysis, we searched the Yale University Open Data Access Project's database for randomised controlled trials of antipsychotics from database inception until May 6, 2021. We included placebo-controlled antipsychotic randomised controlled trials with individual participant data of participants (aged ≥ 18 years, of any sex and ethnicity) with schizophrenia, schizoaffective disorder, or bipolar disorder. Studies were excluded if treatment with antidepressants, lithium, or antiepileptic drugs was initiated as additive therapy at the start of the placebo phase. Starting from the screening or washout phase, we divided participants who were randomised to placebo into two groups: the discontinuation group (participants who discontinued prestudy antipsychotics at the start of the screening or washout phase) and control group (participants who did not take prestudy antipsychotics for at least 4 weeks before the start of the screening or washout phase). Participants were excluded from the discontinuation and control groups if they discontinued prestudy treatment with antidepressants, lithium, or antiepileptic drugs up to 4 weeks before baseline, received an antipsychotic as a tolerability test, or received a long-acting injection of an antipsychotic within 12 weeks before baseline. In the discontinuation group, individuals were excluded if they discontinued prestudy antipsychotic treatment more than 3 days before, or any day after, the start of screening or washout phase. The prespecified primary outcome was occurrence of at least one new somatic adverse event with an onset within 4 weeks after the start of the screening or washout phase. We implemented a generalised linear model that accounted for potential confounders, to estimate the effect of antipsychotic discontinuation. This study is registered with PROSPERO (CRD42021224350). FINDINGS: We identified 409 records of which 18 were eligible and included in the analysis. From these 18 studies, 692 individuals (242 [35·0%] women and 450 [65·0%] men) were eligible for the discontinuation group and 935 individuals (339 [36·3%] women and 596 [63·7%] men) were eligible for the control group (median age in both groups: 39 years [IQR 30-47]). New somatic adverse events occurred in 295 (43%) individuals in the discontinuation group and 293 (31%) individuals in the control group (OR 1·74; 95% CI 1·27-2·39; τ2=0·15; moderate strength of evidence). New psychiatric adverse events were also more frequent in the discontinuation group than the control group (OR 2·01; 95% CI 1·38-2·94). Longer duration of treatment before discontinuation (OR for doubling the duration of treatment: 1·08; 95% CI 1·01-1·14) was associated with a higher probability of new somatic adverse events after antipsychotic discontinuation, and tapered discontinuation (compared with abrupt discontinuation: 0·54; 0·32-0·91) and no history of somatic illness (compared with history of somatic illness: 0·63; 0·43-0·91) were associated with lower probabilities of new somatic adverse events after antipsychotic discontinuation. The risk of bias was moderate in 13 (72·2%) studies and serious in five (27·8%) studies. INTERPRETATION: We detected moderate evidence of emerging somatic adverse events after discontinuation of first-generation and second-generation antipsychotics, particularly after discontinuation of longer durations of treatment. Tapered discontinuation can mitigate the risk of emerging somatic adverse events after antipsychotic discontinuation. These findings have implications for the safety of treatment discontinuation and could be used for tailored treatment planning. FUNDING: German Research Foundation.

The effect of second-generation antipsychotic withdrawal on the occurrence of vacuous chewing movements in animal models: A review.

INTRODUCTION: Abrupt discontinuation of antipsychotics is associated with an increased risk of adverse events such as extrapyramidal symptoms in humans. In animal models, vacuous chewing movements may occur after antipsychotic discontinuation. We aim to assess vacuous chewing movements after the discontinuation of second-generation antipsychotics in animal models. METHODS: PubMed, EMBASE, and Web of Science databases were searched for studies since inception until January 2, 2021. In addition, we manually searched references from included and relevant studies. Studies were included if a behavioral assessment of vacuous chewing movements (VCMs) in animal models was performed after discontinuation of a second-generation antipsychotic (SGA). Findings will be reviewed qualitatively and discussed with regard to clinical implications. RESULTS: 5607 studies were screened and five studies were considered eligible for the qualitative analysis. The five studies reported results of behavioral assessments of VCMs after discontinuation of clozapine, olanzapine, and risperidone. VCMs were not reported to be increased after discontinuation of clozapine and olanzapine. However, VCMs were reported to be increased after discontinuation of higher but not lower dosages of risperidone. DISCUSSION: These findings, based on a limited series of studies, suggest differences in the occurrence of extrapyramidal symptoms between second-generation antipsychotics. More research is needed to determine the magnitude of differences between antipsychotics and implications for clinical practice in humans.

Anxiety-related Symptoms following the Sporadic Use of Ecstasy - A Case Study.

3,4-methylenedioxymethamphetamine (MDMA/"ecstasy") is widespread in the electronic club scene, but MDMA has also been suggested for the treatment of anxiety spectrum disorders like posttraumatic stress disorder (PTSD) and social anxiety in autistic adults. Here, we report a case of a high functioning 24-old student with a sporadic recreational use of ecstasy, and a history of a single episode of obsessive-compulsive disorder (OCD). A few days after using ecstasy during a period of stressful life events, he developed a complex depersonalization/derealization syndrome (DDS) including intermittent distortions of time and very short intermittent episodes of misidentification of persons. Furthermore, obsessive thoughts reappeared and he suffered a panic attack for the first time in his life. Under combined pharmacological treatment and psychotherapy, symptoms gradually subsided until full remission after 14 months. Some months after discontinuation of escitalopram, however, panic attacks recurred, evolving into a regular pattern. Even if MDMA is a promising tool for the treatment of some anxiety spectrum disorders in the framework of substance-assisted psychotherapy, the use of ecstasy might be also harmful for some patients with a history of anxiety or dissociative symptoms, when used recreationally or as a self-medication outside of a controlled clinical setting.

Cannabis use during the early COVID-19 pandemic: Use patterns, predictors, and subjective experiences.

Background: Even in the early stages, global crises such as the COVID-19 pandemic lead to serious dislocations of social life, secondary adjustment reactions to external restrictions and individual concerns. Coping mechanisms may also include dysfunctional strategies like an increase of drug use. Considering the wide-spread use of cannabis, the aim of this study was to elucidate the interplay of social restrictions, psychopathology, concerns related to the pandemic in addition to the users' experiences, motivations and consumption quantities during the early COVID-19 pandemic. It was presumed that cannabis intake would increase during the early phase of the crisis and that consumption quantities would be related to corona-related restrictions, concerns as well as subjective substance effects and psychopathology. Materials and methods: As part of an international, cross-sectional, internet-based survey (N = 5,049) available in five languages, consumption quantities and patterns of cannabis use in the early phase of the pandemic from April to August 2020 were examined. Participants retrospectively rated restrictions and concerns related to the pandemic, motives of cannabis use prior to and during 1 month the pandemic, and subjective consumption effects. Results: Cannabis use behavior showed no significant differences when consumption quantities prior and during 1 month after the COVID-19 outbreak were compared. Higher quantities of cannabis intake prior and during 1 month of the pandemic as well as more corona-related concern were associated with an increased perception of positive effects of cannabis during the pandemic. Predictors of its use during 1 month of pandemic were higher pre-pandemic consumption quantity, older age, quarantinization, a lesser degree of being affected by negative effects of the pandemic and a stronger subjective experience of corona-related positive effects of cannabis. Comparisons of the motives for cannabis intake in the pre-pandemic versus the pandemic period showed that all rationales for consumption were reported less frequently, except boredom. Conclusion: Frequencies of cannabis intake remained relatively stable in the early pandemic phase. Risk factors for increased use seem related to habitual consumption patterns that become more prominent under quarantinization. The use of cannabis as a dysfunctional coping strategy might not be amenable via self-report and should therefore receive special attention in clinical contexts.

Predictors of Alcohol Consumption Among Younger Adults During the First Phase of the COVID-19 Pandemic.

Background: The COVID-19 pandemic may lead to negative mental health effects but the effect on alcohol consumption among younger adults is unclear. We assess predictors of change in alcohol consumption during the first phase of the COVID-19 pandemic among younger adults. Methods: This cross-sectional internet-based survey was part of an overarching project, the Corona Drug Survey, which was conducted from April 30 to August 4, 2020. Participants of any sex and ≥18 years old were included. The primary outcome measure was change in alcohol consumption during the early COVID-19 pandemic. We implemented an ordinal logistic regression to assess the effect (odds ratio [OR] and 95% confidence interval [CI]) of the following predictors: quarantine restrictions on leaving the residence, number of individuals in the household, problematic alcohol consumption before the pandemic (CAGE [cutting down, annoyance by criticism, guilty feeling, and eye-opener] score), personal concern regarding the pandemic, age, and sex. Results: 3,321 participants with a mean age of 32 (SD: 13) years were included in this study. 70.4% of participants reported less or unchanged alcohol consumption in the recent 4 weeks of the pandemic compared to before the pandemic. A higher number of individuals in the household was associated with a reduced alcohol consumption (OR = 0.869; 95% CI = 0.815-0.927). No quarantine restrictions on leaving the residence (OR = 1.593; 95% CI = 1.397-1.817), a higher age (1.006; 1.001-1.011), and female sex (compared to males: 1.206; 1.062-1.371) were associated with an increase in alcohol consumption. The CAGE score before the pandemic (OR = 0.983; 95% CI = 0.931-1.037) and the pandemic concern (0.927; 0.857-1.003) were not associated with a significant change in alcohol consumption. Celebrations were no longer frequent drinking occasions during the pandemic compared to before the pandemic. The majority of participants (60.9%) did not use alcohol drinking as a coping mechanism to mitigate negative effects of the pandemic. Interpretation: In this cohort of younger adults with fewer celebratory drinking occasions, restrictions on leaving the residence and the number of persons in the household were the strongest predictors of reduced alcohol consumption during the early phase of the pandemic.

Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity.

Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.

Mental health effects of infection containment strategies: quarantine and isolation-a systematic review and meta-analysis.

Due to the ongoing COVID-19 pandemic, an unprecedented number of people worldwide is currently affected by quarantine or isolation. These measures have been suggested to negatively impact on mental health. We conducted the first systematic literature review and meta-analysis assessing the psychological effects in both quarantined and isolated persons compared to non-quarantined and non-isolated persons. PubMed, PsycINFO, and Embase databases were searched for studies until April 22, 2020 (Prospero Registration-No.: CRD42020180043). We followed PRISMA and MOOSE guidelines for data extraction and synthesis and the Newcastle-Ottawa Scale for assessing risk of bias of included studies. A random-effects model was implemented to pool effect sizes of included studies. The primary outcomes were depression, anxiety, and stress-related disorders. All other psychological parameters, such as anger, were reported as secondary outcomes. Out of 6807 screened articles, 25 studies were included in our analyses. Compared to controls, individuals experiencing isolation or quarantine were at increased risk for adverse mental health outcomes, particularly after containment duration of 1 week or longer. Effect sizes were summarized for depressive disorders (odds ratio 2.795; 95% CI 1.467-5.324), anxiety disorders (odds ratio 2.0; 95% CI 0.883-4.527), and stress-related disorders (odds ratio 2.742; 95% CI 1.496-5.027). Among secondary outcomes, elevated levels of anger were reported most consistently. There is compelling evidence for adverse mental health effects of isolation and quarantine, in particular depression, anxiety, stress-related disorders, and anger. Reported determinants can help identify populations at risk and our findings may serve as an evidence-base for prevention and management strategies.

Antipsychotic Withdrawal Symptoms: A Systematic Review and Meta-Analysis.

OBJECTIVE: Avoiding withdrawal symptoms following antipsychotic discontinuation is an important factor when planning a safe therapy. We performed a systematic review and meta-analysis concerning occurrence of withdrawal symptoms after discontinuation of antipsychotics. DATA SOURCES: We searched the databases CENTRAL, Pubmed, and EMBASE with no restriction to the beginning of the searched time period and until October 1, 2019 (PROSPERO registration no. CRD42019119148). STUDY SELECTION: Of the 18,043 screened studies, controlled and cohort trials that assessed withdrawal symptoms after discontinuation of oral antipsychotics were included in the random-effects model. Studies that did not implement placebo substitution were excluded from analyses. The primary outcome was the proportion of individuals with withdrawal symptoms after antipsychotic discontinuation. We compared a control group with continued antipsychotic treatment in the assessment of odds ratio and number needed to harm (NNH). DATA EXTRACTION: We followed guidelines by the Cochrane Collaboration, PRISMA, and MOOSE. RESULTS: Five studies with a total of 261 individuals were included. The primary outcome, proportion of individuals with withdrawal symptoms after antipsychotic discontinuation, was 0.53 (95% CI, 0.37-0.70; I2 = 82.98%, P < 0.01). An odds ratio of 7.97 (95% CI, 2.39-26.58; I2 = 82.7%, P = 0.003) and NNH of 3 was calculated for the occurrence of withdrawal symptoms after antipsychotic discontinuation. CONCLUSION: Withdrawal symptoms appear to occur frequently after abrupt discontinuation of an oral antipsychotic. The lack of randomized controlled trials with low risk of bias on antipsychotic withdrawal symptoms highlights the need for further research.

Denser brain capillary network with preserved pericytes in Alzheimer's disease.

Pericytes are vascular mural cells that surround capillaries of the central nervous system (CNS). They are crucial for brain development and contribute to CNS homeostasis by regulating blood-brain barrier function and cerebral blood flow. It has been suggested that pericytes are lost in Alzheimer's disease (AD), implicating this cell type in disease pathology. Here, we have employed state-of-the-art stereological morphometry techniques as well as tissue clearing and two-photon imaging to assess the distribution of pericytes in two independent cohorts of AD (n = 16 and 13) and non-demented controls (n = 16 and 4). Stereological quantification revealed increased capillary density with a normal pericyte population in the frontal cortex of AD brains, a region with early amyloid ß deposition. Two-photon analysis of cleared frontal cortex tissue confirmed the preservation of pericytes in AD cases. These results suggest that pericyte demise is not a general hallmark of AD pathology.

Correction to: Migration and schizophrenia: meta-analysis and explanatory framework.

In the original article, the reference number #36 is listed with the wrong list of authors. The first author was unfortunately omitted. The correct reference #36 should read: Lasalvia A, Bonetto C, Tosato S, Cristofalo D, Salazzari D et al (2014) First-contact incidence of psychosis in north-eastern Italy: influence of age, gender, immigration and socioeconomic deprivation. Br J Psychiatry 205:127-134. https://doi.org/10.1192/bjp.bp.113.134445 .Additionally, this reference is cited in Table 1 and Fig. 2 as "Bonetto (2015)" and the correct citation is "Lasalvia (2014)".

Migration and schizophrenia: meta-analysis and explanatory framework.

Systematic reviews and meta-analyses suggest that there are increased rates of schizophrenia and related psychoses in first- and second-generation migrants and refugees. Here, we present a meta-analysis on the incidence of non-affective psychotic disorders among first- and second-generation migrants. We found substantial evidence for an increased relative risk of incidence among first- and second-generation migrants compared to the native population. As heterogeneity of included studies was high, effect estimates should be interpreted with caution and as guiding values rather than exact risk estimates. We interpret our findings in the context of social exclusion and isolation stress, and provide an explanatory framework that links cultural differences in verbal communication and experienced discrimination with the emergence of psychotic experiences and their neurobiological correlates. In this context, we discuss studies observing stress-dependent alterations of dopamine neurotransmission in studies among migrants versus non-migrants as well as in subjects with psychotic disorders. We suggest that social stress effects can impair contextualization of the meaning of verbal messages, which can be accounted for in Bayesian terms by a reduced precision of prior beliefs relative to sensory data, causing increased prediction errors and resulting in a shift towards the literal or "concrete" meaning of words. Compensatory alterations in higher-level beliefs, e.g., in the form of generalized interpretations of ambiguous interactions as hostile behavior, may contribute to psychotic experiences in migrants. We thus suggest that experienced discrimination and social exclusion is at the core of increased rates of psychotic experiences in subjects with a migration background.

Risk of Psychosis Among Refugees: A Systematic Review and Meta-analysis.

Importance: This systematic review and meta-analysis is, to date, the first and most comprehensive to focus on the incidence of nonaffective psychoses among refugees. Objective: To assess the relative risk (RR) of incidence of nonaffective psychosis in refugees compared with the RR in the native population and nonrefugee migrants. Data Sources: PubMed, PsycINFO, and Embase databases were searched for studies from January 1, 1977, to March 8, 2018, with no language restrictions (PROSPERO registration No. CRD42018106740). Study Selection: Studies conducted in Denmark, Sweden, Norway, and Canada were selected by multiple independent reviewers. Inclusion criteria were (1) observation of refugee history in participants, (2) assessment of effect size and spread, (3) adjustment for sex, (4) definition of nonaffective psychosis according to standardized operationalized criteria, and (5) comparators were either nonrefugee migrants or the native population. Studies observing ethnic background only, with no explicit definition of refugee status, were excluded. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and assessing data quality and validity as well as risk of bias of included studies. A random-effects model was created to pool the effect sizes of included studies. Main Outcomes and Measures: The primary outcome, formulated before data collection, was the pooled RR in refugees compared with the nonrefugee population. Results: Of the 4358 screened articles, 9 studies (0.2%) involving 540 000 refugees in Denmark, Sweden, Norway, and Canada were included in the analyses. The RR for nonaffective psychoses in refugees was 1.43 (95% CI, 1.00-2.05; I2 = 96.3%) compared with nonrefugee migrants. Analyses that were restricted to studies with low risk of bias had an RR of 1.39 (95% CI, 1.23-1.58; I2 = 0.0%) for refugees compared with nonrefugee migrants, 2.41 (95% CI, 1.51-3.85; I2 = 96.3%) for refugees compared with the native population, and 1.92 (95% CI, 1.02-3.62; I2 = 97.0%) for nonrefugee migrants compared with the native group. Exclusion of studies that defined refugee status not individually but only by country of origin resulted in an RR of 2.24 (95% CI, 1.12-4.49; I2 = 96.8%) for refugees compared with nonrefugee migrants and an RR of 3.26 (95% CI, 1.87-5.70; I2 = 97.6%) for refugees compared with the native group. In general, the RR of nonaffective psychosis was increased in refugees and nonrefugee migrants compared with the native population. Conclusions and Relevance: Refugee experience appeared to be an independent risk factor in developing nonaffective psychosis among refugees in Denmark, Sweden, Norway, and Canada. These findings suggest that applying the conclusions to non-Scandinavian countries should include a consideration of the characteristics of the native society and its specific interaction with the refugee population.

Antidepressant Withdrawal and Rebound Phenomena.

BACKGROUND: Antidepressants are among the most commonly prescribed drugs worldwide. They are often discontinued, frequently without the knowledge of the prescribing physician. It is, therefore, important for physicians to be aware of the withdrawal and rebound phenomena that may arise, in order to prevent these phenomena, treat them when necessary, and counsel patients appropriately. METHODS: This review is based on a comprehensive, structured literature search on antidepressant withdrawal phenomena that we carried out in the CENTRAL, PubMed (Medline), and Embase databases. We classified the relevant publications and reports by their methodological quality. RESULTS: Out of a total of 2287 hits, there were 40 controlled trials, 38 cohort studies and retrospective analyses, and 271 case reports that met the inclusion criteria. Withdrawal manifestations are usually mild and self-limiting; common ones include dizziness, headache, sleep disturbances, and mood swings. More serious or pro- longed manifestations rarely arise. There is an increased risk with MAO inhibitors, tricyclic antidepressants, venlafaxine, and paroxetine; on the other hand, for agome- latine and fluoxetine, abrupt discontinuation seems to be unproblematic. There is also some evidence of rebound phenomena, i.e., of higher relapse rates or especially severe relapses of depression after the discontinuation of an anti- depressant. CONCLUSION: A robust evidence base now indicates that there can be acute with- drawal phenomena when antidepressants are discontinued. Putative rebound phenomena have not been adequately studied to date. It is recommended that antidepressants should be tapered off over a period of more than four weeks.