Oral and long‐acting antipsychotics for relapse prevention in schizophrenia‐spectrum disorders: a network meta‐analysis of 92 randomized trials including 22,645 participants

According to current evidence and guidelines, continued antipsychotic treatment is key for preventing relapse in people with schizophrenia‐spectrum disorders, but evidence‐based recommendations for the choice of the individual antipsychotic for maintenance treatment are lacking. Although oral antipsychotics are often prescribed first line for practical reasons, long‐acting injectable antipsychotics (LAIs) are a valuable resource to tackle adherence issues since the earliest phase of disease. Medline, EMBASE, PsycINFO, CENTRAL and CINAHL databases and online registers were searched to identify randomized controlled trials comparing LAIs or oral antipsychotics head‐to‐head or against placebo, published until June 2021. Relative risks and standardized mean differences were pooled using random‐effects pairwise and network meta‐analysis. The primary outcomes were relapse and dropout due to adverse events. We used the Cochrane Risk of Bias tool to assess study quality, and the CINeMA approach to assess the confidence of pooled estimates. Of 100 eligible trials, 92 (N=22,645) provided usable data for meta‐analyses. Regarding relapse prevention, the vast majority of the 31 included treatments outperformed placebo. Compared to placebo, “high” confidence in the results was found for (in descending order of effect magnitude) amisulpride‐oral (OS), olanzapine‐OS, aripiprazole‐LAI, olanzapine‐LAI, aripiprazole‐OS, paliperidone‐OS, and ziprasidone‐OS. “Moderate” confidence in the results was found for paliperidone‐LAI 1‐monthly, iloperidone‐OS, fluphenazine‐OS, brexpiprazole‐OS, paliperidone‐LAI 1‐monthly, asenapine‐OS, haloperidol‐OS, quetiapine‐OS, cariprazine‐OS, and lurasidone‐OS. Regarding tolerability, none of the antipsychotics was significantly worse than placebo, but confidence was poor, with only aripiprazole (both LAI and OS) showing “moderate” confidence levels. Based on these findings, olanzapine, aripiprazole and paliperidone are the best choices for the maintenance treatment of schizophrenia‐spectrum disorders, considering that both LAI and oral formulations of these antipsychotics are among the best‐performing treatments and have the highest confidence of evidence for relapse prevention. This finding is of particular relevance for low‐ and middle‐income countries and constrained‐resource settings, where few medications may be selected. Results from this network meta‐analysis can inform clinical guidelines and national and international drug regulation policies.     

Internalizing psychopathology and all‐cause mortality: a comparison of transdiagnostic vs. diagnosis‐based risk prediction

Previous studies have documented the utility of a transdiagnostic internalizing factor in predicting important future outcomes (e.g., subsequent mental disorder diagnoses). To date, however, no study has investigated whether an internalizing factor predicts mortality risk. Also, while pre­vious studies of mortality risk have emphasized its associations with particular internalizing disorders, no study has assessed how the transdiagnostic internalizing factor vs. disorder‐specific variance differently predict that risk. The primary aims of this study were to explore: a) whether the internalizing factor predicts mortality risk, b) whether particular internalizing psychopathologies uniquely predict mortality risk over and beyond the transdiagnostic internalizing factor, and c) whether there is a significant interaction of internalizing with self‐reported health in the prediction of mortality risk. We utilized a large national sample of American adults from the Midlife in the United States (MIDUS), a longitudinal study that examined midlife development of individuals across multiple waves between 1995 and 2015. Data were analyzed for the 6,329 participants who completed the phone interview and self‐administered questionnaire in MIDUS 1 (1995‐1996) and were then followed up until October 31, 2015 or until death. To investigate the association between internalizing and mortality risk, we used the semi‐parametric proportional hazards Cox model, where survival time was regressed on a latent internalizing factor. Overall findings indicate that a transdiagnostic internalizing factor significantly predicts mortality risk over a 20‐year period (hazard ratio, HR=1.12, 95% CI: 1.05‐1.16, p<0.01) and that internalizing outperforms disorder‐specific variance (e.g., depression‐specific variance) in the prediction of that risk. Further, there was a significant interaction between transdiagnostic internalizing and self‐reported health, whereby internalizing psychopathology had a specific association with early death for individuals with excellent self‐reported health condition (HR=1.50, 95% CI: 1.17‐1.84, p<0.05). This highlights the clinical utility of using the transdiagnostic internalizing factor for prediction of an important future outcome, and supports the argument that internalizing psychopathology can be a meaningful liability to explore in public health practice.     

Diabetes mellitus in people with schizophrenia,bipolar disorder and major depressive disorder: a systematic review and large scale meta‐analysis

Type 2 diabetes mellitus (T2DM) is highly predictive of cardiovascular diseases and can have particularly deleterious health impacts in people with severe mental illness (SMI), i.e. schizophrenia, bipolar disorder or major depressive disorder. This meta‐analysis aimed: a) to describe pooled frequencies of T2DM in people with SMI; b) to analyze the influence of demographic, illness and treatment variables as well as T2DM assessment methods; and c) to describe T2DM prevalence in studies directly comparing persons with each specific SMI diagnosis to general population samples. The trim and fill adjusted pooled T2DM prevalence among 438,245 people with SMI was 11.3% (95% CI: 10.0%‐12.6%). In antipsychotic‐naïve participants, the prevalence of T2DM was 2.9% (95% CI: 1.7%‐4.8%). There were no significant diagnostic subgroup differences. A comparative meta‐analysis established that multi‐episode persons with SMI (N=133,470) were significantly more likely to have T2DM than matched controls (N=5,622,664): relative risk, RR=1.85, 95% CI: 1.45‐2.37, p<0.001. The T2DM prevalence was consistently elevated in each of the three major diagnostic subgroups compared to matched controls. Higher T2DM prevalences were observed in women with SMI compared to men (RR=1.43, 95% CI: 1.20‐1.69, p<0.001). Multi‐episode (versus first‐episode) status was the only significant predictor for T2DM in a multivariable meta‐regression analysis (r²=0.52, p<0.001). The T2DM prevalence was higher in patients prescribed antipsychotics, except for aripriprazole and amisulpride. Routine screening and multidisciplinary management of T2DM is needed. T2DM risks of individual antipsychotic medications should be considered when making treatment choices.     

Reappraising the variability of effects of antipsychotic medication in schizophrenia: a meta‐analysis

It is common experience for practising psychiatrists that individuals with schizophrenia vary markedly in their symptomatic response to antipsychotic medication. What is not clear, however, is whether this variation reflects variability of medication‐specific effects (also called “treatment effect heterogeneity”), as opposed to variability of non‐specific effects such as natural symptom fluctuation or placebo response. Previous meta‐analyses found no evidence of treatment effect heterogeneity, suggesting that a “one size fits all” approach may be appropriate and that efforts at developing personalized treatment strategies for schizophrenia are unlikely to succeed. Recent advances indicate, however, that earlier approaches may have been unable to accurately quantify treatment effect heterogeneity due to their neglect of a key parameter: the correlation between placebo response and medication‐specific effects. In the present paper, we address this shortcoming by using individual patient data and study‐level data to estimate that correlation and quantitatively characterize antipsychotic treatment effect heterogeneity in schizophrenia. Individual patient data (on 384 individuals who were administered antipsychotic treatment and 88 who received placebo) were obtained from the Yale University Open Data Access (YODA) database. Study‐level data were obtained from a meta‐analysis of 66 clinical trials including 17,202 patients. Both individual patient and study‐level analyses yielded a negative correlation between placebo response and treatment effect for the total score on the Positive and Negative Syndrome Scale (PANSS) (ρ=–0.32, p=0.002 and ρ=–0.39, p<0.001, respectively). Using the most conservative of these estimates, a meta‐analysis of treatment effect heterogeneity provided evidence of a marked variability in antipsychotic‐specific effects between individuals with schizophrenia, with the top quartile of patients experiencing beneficial treatment effects of 17.7 points or more on the PANSS total score, while the bottom quartile presented a detrimental effect of treatment relative to placebo. This evidence of clinically meaningful treatment effect heterogeneity suggests that efforts to personalize antipsychotic treatment of schizophrenia have potential for success.     

Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders,bipolar disorder and major depressive disorder: a systematic review and meta‐analysis

Metabolic syndrome (MetS) and its components are highly predictive of cardiovascular diseases. The primary aim of this systematic review and meta‐analysis was to assess the prevalence of MetS and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder, comparing subjects with different disorders and taking into account demographic variables and psychotropic medication use. The secondary aim was to compare the MetS prevalence in persons with any of the selected disorders versus matched general population controls. The pooled MetS prevalence in people with severe mental illness was 32.6% (95% CI: 30.8%‐34.4%; N = 198; n = 52,678). Relative risk meta‐analyses established that there was no significant difference in MetS prevalence in studies directly comparing schizophrenia versus bipolar disorder, and in those directly comparing bipolar disorder versus major depressive disorder. Only two studies directly compared people with schizophrenia and major depressive disorder, precluding meta‐analytic calculations. Older age and a higher body mass index were significant moderators in the final demographic regression model (z = ?3.6, p = 0.0003, r² = 0.19). People treated with all individual antipsychotic medications had a significantly (p<0.001) higher MetS risk compared to antipsychotic‐naïve participants. MetS risk was significantly higher with clozapine and olanzapine (except vs. clozapine) than other antipsychotics, and significantly lower with aripiprazole than other antipsychotics (except vs. amisulpride). Compared with matched general population controls, people with severe mental illness had a significantly increased risk for MetS (RR = 1.58; 95% CI: 1.35‐1.86; p<0.001) and all its components, except for hypertension (p = 0.07). These data suggest that the risk for MetS is similarly elevated in the diagnostic subgroups of severe mental illness. Routine screening and multidisciplinary management of medical and behavioral conditions is needed in these patients. Risks of individual antipsychotics should be considered when making treatment choices.     

Sedentary behavior and physical activity levels in people with schizophrenia,bipolar disorder and major depressive disorder: a global systematic review and meta‐analysis

People with severe mental illness (schizophrenia, bipolar disorder or major depressive disorder) die up to 15 years prematurely due to chronic somatic comorbidities. Sedentary behavior and low physical activity are independent yet modifiable risk factors for cardiovascular disease and premature mortality in these people. A comprehensive meta‐analysis exploring these risk factors is lacking in this vulnerable population. We conducted a meta‐analysis investigating sedentary behavior and physical activity levels and their correlates in people with severe mental illness. Major electronic databases were searched from inception up to April 2017 for articles measuring sedentary behavior and/or physical activity with a self‐report questionnaire or an objective measure (e.g., accelerometer). Random effects meta‐analyses and meta‐regression analyses were conducted. Sixty‐nine studies were included (N=35,682; 39.5% male; mean age 43.0 years). People with severe mental illness spent on average 476.0 min per day (95% CI: 407.3‐545.4) being sedentary during waking hours, and were significantly more sedentary than age‐ and gender‐matched healthy controls (p=0.003). Their mean amount of moderate or vigorous physical activity was 38.4 min per day (95% CI: 32.0‐44.8), being significantly lower than that of healthy controls (p=0.002 for moderate activity, p<0.001 for vigorous activity). People with severe mental illness were significantly less likely than matched healthy controls to meet physical activity guidelines (odds ratio = 1.5; 95% CI: 1.1‐2.0, p<0.001, I²=95.8). Lower physical activity levels and non‐compliance with physical activity guidelines were associated with male gender, being single, unemployment, fewer years of education, higher body mass index, longer illness duration, antidepressant and antipsychotic medication use, lower cardiorespiratory fitness and a diagnosis of schizophrenia. People with bipolar disorder were the most physically active, yet spent most time being sedentary. Geographical differences were detected, and inpatients were more active than outpatients and those living in the community. Given the established health benefits of physical activity and its low levels in people with severe mental illness, future interventions specifically targeting the prevention of physical inactivity and sedentary behavior are warranted in this population.     

The Horyzons project: a randomized controlled trial of a novel online social therapy to maintain treatment effects from specialist first‐episode psychosis services

This study aimed to determine whether, following two years of specialized support for first‐episode psychosis, the addition of a new digital intervention (Horyzons) to treatment as usual (TAU) for 18 months was more effective than 18 months of TAU alone. We conducted a single‐blind randomized controlled trial. Participants were people with first‐episode psychosis (N=170), aged 16‐27 years, in clinical remission and nearing discharge from a specialized service. They were randomly assigned (1:1) to receive Horyzons plus TAU (N=86) or TAU alone (N=84) between October 2013 and January 2017. Horyzons is a novel, comprehensive digital platform merging: peer‐to‐peer social networking; theory‐driven and evidence‐informed therapeutic interventions targeting social functioning, vocational recovery and relapse prevention; expert clinician and vocational support; and peer support and moderation. TAU involved transfer to primary or tertiary community mental health services. The primary outcome was social functioning at 18 months as measured by the Personal and Social Performance Scale (PSP). Forty‐seven participants (55.5%) in the Horyzons plus TAU group logged on for at least 6 months, and 40 (47.0%) for at least 9 months. Social functioning remained high and stable in both groups from baseline to 18‐month follow‐up, with no evidence of significant between‐group differences (PSP mean difference: –0.29, 95% CI: –4.20 to 3.63, p=0.77). Participants in the Horyzons group had a 5.5 times greater increase in their odds to find employment or enroll in education compared with those in TAU (odds ratio, OR=5.55, 95% CI: 1.09‐28.23, p=0.04), with evidence of a dose‐response effect. Moreover, participants in TAU were twice as likely to visit emergency services compared to those in the Horyzons group (39% vs. 19%; OR=0.31, 95% CI: 0.11‐0.86, p=0.03, number needed to treat, NNT=5). There was a non‐significant trend for lower hospitalizations due to psychosis in the Horyzons group vs. TAU (13% vs. 27%; OR=0.36, 95% CI: 0.11‐1.08, p=0.07, NNT=7). So, although we did not find a significant effect of Horyzons on social functioning compared with TAU, the intervention was effective in improving vocational or educational attainment, a core component of social recovery, and in reducing usage of hospital emergency services, a key aim of specialized first‐episode psychosis services. Horyzons holds significant promise as an engaging and sustainable intervention to provide effective vocational and relapse prevention support for young people with first‐episode psychosis beyond specialist services.     

The lived experience of psychosis: a bottom‐up review co‐written by experts by experience and academics

Psychosis is the most ineffable experience of mental disorder. We provide here the first co‐written bottom‐up review of the lived experience of psychosis, whereby experts by experience primarily selected the subjective themes, that were subsequently enriched by phenomenologically‐informed perspectives. First‐person accounts within and outside the medical field were screened and discussed in collaborative workshops involving numerous individuals with lived experience of psychosis as well as family members and carers, representing a global network of organizations. The material was complemented by semantic analyses and shared across all collaborators in a cloud‐based system. The early phases of psychosis (i.e., premorbid and prodromal stages) were found to be characterized by core existential themes including loss of common sense, perplexity and lack of immersion in the world with compromised vital contact with reality, heightened salience and a feeling that something important is about to happen, perturbation of the sense of self, and need to hide the tumultuous inner experiences. The first episode stage was found to be denoted by some transitory relief associated with the onset of delusions, intense self‐referentiality and permeated self‐world boundaries, tumultuous internal noise, and dissolution of the sense of self with social withdrawal. Core lived experiences of the later stages (i.e., relapsing and chronic) involved grieving personal losses, feeling split, and struggling to accept the constant inner chaos, the new self, the diagnosis and an uncertain future. The experience of receiving psychiatric treatments, such as inpatient and outpatient care, social interventions, psychological treatments and medications, included both positive and negative aspects, and was determined by the hope of achieving recovery, understood as an enduring journey of reconstructing the sense of personhood and re‐establishing the lost bonds with others towards meaningful goals. These findings can inform clinical practice, research and education. Psychosis is one of the most painful and upsetting existential experiences, so dizzyingly alien to our usual patterns of life and so unspeakably enigmatic and human.     

Thalassaemia is paradoxically associated with a reduced risk of in‐hospital complications and mortality in COVID‐19: Data from an international registry

Although numerous patient‐specific co‐factors have been shown to be associated with worse outcomes in COVID‐19, the prognostic value of thalassaemic syndromes in COVID‐19 patients remains poorly understood. We studied the outcomes of 137 COVID‐19 patients with a history of transfusion‐dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID‐19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID‐19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age‐, sex‐ and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in‐hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all‐cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in‐hospital, all‐cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all‐cause mortality. The presence of thalassaemia in COVID‐19 patients was independently associated with lower in‐hospital, all‐cause mortality and few in‐hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models.     

Initial treatment choices to achieve sustained response in major depression: a systematic review and network meta‐analysis

Major depression is often a relapsing disorder. It is therefore important to start its treatment with therapies that maximize the chance of not only getting the patients well but also keeping them well. We examined the associations between initial treatments and sustained response by conducting a network meta‐analysis of randomized controlled trials (RCTs) in which adult patients with major depression were randomized to acute treatment with a psychotherapy (PSY), a protocolized antidepressant pharmacotherapy (PHA), their combination (COM), standard treatment in primary or secondary care (STD), or pill placebo, and were then followed up through a maintenance phase. By design, acute phase treatment could be continued into the maintenance phase, switched to another treatment or followed by discretionary treatment. We included 81 RCTs, with 13,722 participants. Sustained response was defined as responding to the acute treatment and subsequently having no depressive relapse through the maintenance phase (mean duration: 42.2±16.2 weeks, range 24‐104 weeks). We extracted the data reported at the time point closest to 12 months. COM resulted in more sustained response than PHA, both when these treatments were continued into the maintenance phase (OR=2.52, 95% CI: 1.66‐3.85) and when they were followed by discretionary treatment (OR=1.80, 95% CI: 1.21‐2.67). The same applied to COM in comparison with STD (OR=2.90, 95% CI: 1.68‐5.01 when COM was continued into the maintenance phase; OR=1.97, 95% CI: 1.51‐2.58 when COM was followed by discretionary treatment). PSY also kept the patients well more often than PHA, both when these treatments were continued into the maintenance phase (OR=1.53, 95% CI: 1.00‐2.35) and when they were followed by discretionary treatment (OR=1.66, 95% CI: 1.13‐2.44). The same applied to PSY compared with STD (OR=1.76, 95% CI: 0.97‐3.21 when PSY was continued into the maintenance phase; OR=1.83, 95% CI: 1.20‐2.78 when PSY was followed by discretionary treatment). Given the average sustained response rate of 29% on STD, the advantages of PSY or COM over PHA or STD translated into risk differences ranging from 12 to 16 percentage points. We conclude that PSY and COM have more enduring effects than PHA. Clinical guidelines on the initial treatment choice for depression may need to be updated accordingly.     

Population dynamics of the glacial relict amphipods in a subarctic lake: role of density‐dependent and density‐independent factors

Relative role of intrinsic density‐dependent factors (such as inter‐ and intraspecific competition, predation) and extrinsic density‐independent factors (environmental changes) in population dynamics is a key issue in ecology. Density‐dependent mechanisms are considered as important drivers of population dynamics in many vertebrate and insect species; however, their influence on the population dynamics of freshwater invertebrates is not clearly understood. In this study, I examined interannual variations in the abundance of the glacial relict amphipod Monoporeia affinis in a small subarctic lake based on long‐term (2002–2019) monitoring data. The results suggest that the population dynamics of amphipods in the lake is influenced by the combined effects of both intrinsic and extrinsic factors. The reproductive success of amphipod cohorts was inversely related to its initial abundance, indicating it is influenced by density‐dependent factors. M. affinis recruitment was negatively correlated with population density and near‐bottom temperature but positively correlated with food availability, which is defined as the concentration of chlorophyll a. Multiple regression with chlorophyll, temperature, and abundance of parent cohort as independent factors explained about 80% of the variation in the reproductive success of amphipods. The negative correlation between amphipod recruitment and water temperature indicates that the current climate conditions adversely affect the populations of glacial relict amphipods even in cold‐water lakes of the subarctic zone. Results of this study can be useful in environmental assessments to separate population oscillations connected with density‐dependent mechanisms from human‐mediated changes.     

Community‐based social interventions for people with severe mental illness: a systematic review and narrative synthesis of recent evidence

People living with severe mental illness (SMI) are one of the most marginalized groups in society. Interventions which aim to improve their social and economic participation are of crucial importance to clinicians, policy‐makers and people with SMI themselves. We conducted a systematic review of the literature on social interventions for people with SMI published since 2016 and collated our findings through narrative synthesis. We found an encouragingly large amount of research in this field, and 72 papers met our inclusion criteria. Over half reported on the effectiveness of interventions delivered at the service level (supported accommodation, education or employment), while the remainder targeted individuals directly (community participation, family interventions, peer‐led/supported interventions, social skills training). We identified good evidence for the Housing First model of supported accommodation, for the Individual Placement and Support model of supported employment, and for family psychoeducation, with the caveat that a range of models are nonetheless required to meet the varied housing, employment and family‐related needs of individuals. Our findings also highlighted the importance of contextual factors and the need to make local adaptations when “importing” interventions from elsewhere. We found that augmentation strategies to enhance the effectiveness of social interventions (particularly supported employment and social skills training) by addressing cognitive impairments did not lead to transferable “real life” skills despite improvements in cognitive function. We also identified an emerging evidence base for peer‐led/supported interventions, recovery colleges and other interventions to support community participation. We concluded that social interventions have considerable benefits but are arguably the most complex in the mental health field, and require multi‐level stakeholder commitment and investment for successful implementation.     

Increased risk for COVID‐19 breakthrough infection in fully vaccinated patients with substance use disorders in the United States between December 2020 and August 2021

Individuals with substance use disorders (SUDs) are at increased risk for COVID‐19 infection and for adverse outcomes of the infection. Though vaccines are highly effective against COVID‐19, their effectiveness in individuals with SUDs might be curtailed by compromised immune status and a greater likelihood of exposures, added to the waning vaccine immunity and the new SARS‐CoV‐2 variants. In a population‐based cohort study, we assessed the risk, time trends, outcomes and disparities of COVID‐19 breakthrough infection in fully vaccinated SUD patients starting 14 days after completion of vaccination. The study included 579,372 individuals (30,183 with a diagnosis of SUD and 549,189 without such a diagnosis) who were fully vaccinated between December 2020 and August 2021, and had not contracted COVID‐19 infection prior to vaccination. We used the TriNetX Analytics network platform to access de‐identified electronic health records from 63 health care organizations in the US. Among SUD patients, the risk for breakthrough infection ranged from 6.8% for tobacco use disorder to 7.8% for cannabis use disorder, all significantly higher than the 3.6% in non‐SUD population (p<0.001). Breakthrough infection risk remained significantly higher after controlling for demographics (age, gender, ethnicity) and vaccine types for all SUD subtypes, except for tobacco use disorder, and was highest for cocaine and cannabis use disorders (hazard ratio, HR=2.06, 95% CI: 1.30‐3.25 for cocaine; HR=1.92, 95% CI: 1.39‐2.66 for cannabis). When we matched SUD and non‐SUD individuals for lifetime comorbidities and adverse socioeconomic determinants of health, the risk for breakthrough infection no longer differed between these populations, except for patients with cannabis use disorder, who remained at increased risk (HR=1.55, 95% CI: 1.22‐1.99). The risk for breakthrough infection was higher in SUD patients who received the Pfizer than the Moderna vaccine (HR=1.49, 95% CI: 1.31‐1.69). In the vaccinated SUD population, the risk for hospitalization was 22.5% for the breakthrough cohort and 1.6% for the non‐breakthrough cohort (risk ratio, RR=14.4, 95% CI: 10.19‐20.42), while the risk for death was 1.7% and 0.5% respectively (RR=3.5, 95% CI: 1.74‐7.05). No significant age, gender and ethnic disparities for breakthrough infection were observed in vaccinated SUD patients. These data suggest that fully vaccinated SUD individuals are at higher risk for breakthrough COVID‐19 infection, and this is largely due to their higher prevalence of comorbidities and adverse socioeconomic determinants of health compared with non‐SUD individuals. The high frequency of comorbidities in SUD patients is also likely to contribute to their high rates of hospitalization and death following breakthrough infection.     

20‐year follow‐up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20)

Antipsychotics are effective in preventing relapses of schizophrenia, but it is generally believed that their long‐term use is harmful for patients’ physical well‐being. However, there are no long‐term studies which have verified this view. This nationwide, register‐based cohort study aimed to assess the risk of hospitalization due to physical health problems, as a marker for severe physical morbidity, and the risk of all‐cause mortality, as well as of cardiovascular and suicidal death, associated with antipsychotic use in all patients treated for schizophrenia in inpatient care between 1972 and 2014 in Finland (N=62,250), with up to 20 years of follow‐up (median: 14.1 years). The use of antipsychotic drugs (i.e., use of any antipsychotic compared with non‐use) and the use of specific antipsychotics were investigated, and outcomes were somatic and cardiovascular hospitalization, and all‐cause, cardiovascular and suicide death. Hospitalization‐based outcomes were analyzed by a within‐individual design to eliminate selection bias, comparing use and non‐use periods in the same individual by stratified Cox model. Mortality outcomes were assessed by traditional between‐individual Cox multivariate models. The adjusted hazard ratios (aHRs) for any somatic hospitalization and cardiovascular hospitalization were 1.00 (95% CI: 0.98‐1.03) and 1.00 (95% CI: 0.92‐1.07) during use of any antipsychotic compared to non‐exposure periods within the same individual. The aHRs were 0.48 (95% CI: 0.46‐0.51) for all‐cause mortality, 0.62 (95% CI: 0.57‐0.67) for cardiovascular mortality, and 0.52 (95% CI: 0.43‐0.62) for suicide mortality during use vs. non‐use of any antipsychotic. The most beneficial mortality outcome was associated with use of clozapine in terms of all‐cause (aHR=0.39, 95% CI: 0.36‐0.43), cardiovascular (aHR=0.55, 95% CI: 0.47‐0.64) and suicide mortality (aHR=0.21, 95% CI: 0.15‐0.29). The cumulative mortality rates during maximum follow‐up of 20 years were 46.2% for no antipsychotic use, 25.7% for any antipsychotic use, and 15.6% for clozapine use. These data suggest that long‐term antipsychotic use does not increase severe physical morbidity leading to hospitalization, and is associated with substantially decreased mortality, especially among patients treated with clozapine.     

Patterns and correlates of patient‐reported helpfulness of treatment for common mental and substance use disorders in the WHO World Mental Health Surveys

Patient‐reported helpfulness of treatment is an important indicator of quality in patient‐centered care. We examined its pathways and predictors among respondents to household surveys who reported ever receiving treatment for major depression, generalized anxiety disorder, social phobia, specific phobia, post‐traumatic stress disorder, bipolar disorder, or alcohol use disorder. Data came from 30 community epidemiological surveys – 17 in high‐income countries (HICs) and 13 in low‐ and middle‐income countries (LMICs) – carried out as part of the World Health Organization (WHO)’s World Mental Health (WMH) Surveys. Respondents were asked whether treatment of each disorder was ever helpful and, if so, the number of professionals seen before receiving helpful treatment. Across all surveys and diagnostic categories, 26.1% of patients (N=10,035) reported being helped by the very first professional they saw. Persisting to a second professional after a first unhelpful treatment brought the cumulative probability of receiving helpful treatment to 51.2%. If patients persisted with up through eight professionals, the cumulative probability rose to 90.6%. However, only an estimated 22.8% of patients would have persisted in seeing these many professionals after repeatedly receiving treatments they considered not helpful. Although the proportion of individuals with disorders who sought treatment was higher and they were more persistent in HICs than LMICs, proportional helpfulness among treated cases was no different between HICs and LMICs. A wide range of predictors of perceived treatment helpfulness were found, some of them consistent across diagnostic categories and others unique to specific disorders. These results provide novel information about patient evaluations of treatment across diagnoses and countries varying in income level, and suggest that a critical issue in improving the quality of care for mental disorders should be fostering persistence in professional help‐seeking if earlier treatments are not helpful.     

Tardive dyskinesia risk with first‐ and second‐generation antipsychotics in comparative randomized controlled trials: a meta‐analysis

Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second‐generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first‐generation antipsychotics, FGAs). As some reports questioned this notion, we meta‐analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head‐to‐head RCTs, including 32 FGA and 86 SGA arms, were meta‐analyzed, yielding 32 FGA‐SGA pairs and 35 SGA‐SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3‐7.8%) vs. 2.6% (95% CI: 2.0‐3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39‐0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28‐0.45, p<0.0001, number‐needed‐to‐treat, NNT=20). Meta‐regression showed no FGA dose effect on FGA‐SGA comparisons (Z=?1.03, p=0.30). FGA‐SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non‐clozapine SGAs in exploratory pairwise comparisons. SGA‐SGA comparisons confirmed the olanzapine advantage vs. non‐clozapine SGAs (RaR=0.66, 95% CI: 0.49‐0.88, p=0.006, k=17, NNT=100). This meta‐analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.     

Long‐term effectiveness of oral second‐generation antipsychotics in patients with schizophrenia and related disorders: a systematic review and meta‐analysis of direct head‐to‐head comparisons

Second‐generation antipsychotics (SGAs) are recommended for maintenance treatment in schizophrenia. However, comparative long‐term effectiveness among SGAs is unclear. Here we provide a systematic review and meta‐analysis of randomized trials lasting ≥?6 months comparing SGAs head‐to‐head in schizophrenia and related disorders. The primary outcome was all‐cause discontinuation. Secondary outcomes included efficacy and tolerability, i.e., psychopathology, inefficacy‐related and intolerability‐related discontinuation, relapse, hospitalization, remission, functioning, quality of life, and adverse events. Pooled risk ratio and standardized mean difference were calculated using random‐effects models. Across 59 studies (N=45,787), lasting 47.4±32.1 weeks (range 24‐186), no consistent superiority of any SGA emerged across efficacy and tolerability outcomes. Regarding all‐cause discontinuation, clozapine, olanzapine and risperidone were significantly (p<0.05) superior to several other SGAs, while quetiapine was inferior to several other SGAs. As to psychopathology, clozapine and olanzapine were superior to several other SGAs, while quetiapine and ziprasidone were inferior to several other SGAs. Data for other efficacy outcomes were sparse. Regarding intolerability‐related discontinuation, risperidone was superior and clozapine was inferior to several other SGAs. Concerning weight gain, olanzapine was worse than all other compared non‐clozapine SGAs, and risperidone was significantly worse than several other SGAs. As to prolactin increase, risperidone and amisulpride were significantly worse than several other SGAs. Regarding parkinsonism, olanzapine was superior to risperidone, without significant differences pertaining to akathisia. Concerning sedation and somnolence, clozapine and quetiapine were significantly worse than some other SGAs. In summary, different long‐term SGA efficacy and tolerability patterns emerged. The long‐term risk‐benefit profiles of specific SGAs need to be tailored to individual patients to optimize maintenance treatment outcomes.     

The impact of pharmacological and non‐pharmacological interventions to improve physical health outcomes in people with schizophrenia: a meta‐review of meta‐analyses of randomized controlled trials

We summarized and compared meta‐analyses of pharmacological and non‐pharmacological interventions targeting physical health outcomes among people with schizophrenia spectrum disorders. Major databases were searched until June 1, 2018. Of 3,709 search engine hits, 27 meta‐analyses were included, representing 128 meta‐analyzed trials and 47,231 study participants. While meta‐analyses were generally of adequate or high quality, meta‐analyzed studies were less so. The most effective weight reduction interventions were individual lifestyle counseling (standardized mean difference, SMD=–0.98) and exercise interventions (SMD=–0.96), followed by psychoeducation (SMD=–0.77), aripiprazole augmentation (SMD=–0.73), topiramate (SMD=–0.72), d‐fenfluramine (SMD=–0.54) and metformin (SMD=–0.53). Regarding waist circumference reduction, aripiprazole augmentation (SMD=–1.10) and topiramate (SMD=–0.69) demonstrated the best evidence, followed by dietary interventions (SMD=–0.39). Dietary interventions were the only to significantly improve (diastolic) blood pressure (SMD=–0.39). Switching from olanzapine to quetiapine or aripiprazole (SMD=–0.71) and metformin (SMD=–0.65) demonstrated best efficacy for reducing glucose levels, followed by glucagon‐like peptide‐1 receptor agonists (SMD=–0.39), dietary interventions (SMD=–0.37) and aripiprazole augmentation (SMD=–0.34), whereas insulin resistance improved the most with metformin (SMD=–0.75) and rosiglitazone (SMD=–0.44). Topiramate had the greatest efficacy for triglycerides (SMD=–0.68) and low‐density lipoprotein (LDL)‐cholesterol (SMD=–0.80), whereas metformin had the greatest beneficial effects on total cholesterol (SMD=–0.51) and high‐density lipoprotein (HDL)‐cholesterol (SMD=0.45). Lifestyle interventions yielded small effects for triglycerides, total cholesterol and LDL‐cholesterol (SMD=–0.35 to –0.37). Only exercise interventions increased exercise capacity (SMD=1.81). Despite frequent physical comorbidities and premature mortality mainly due to these increased physical health risks, the current evidence for pharmacological and non‐pharmacological interventions in people with schizophrenia to prevent and treat these conditions is still limited and more larger trials are urgently needed.     

Psychopathology in 7‐year‐old children with familial high risk of developing schizophrenia spectrum psychosis or bipolar disorder – The Danish High Risk and Resilience Study ‐ VIA 7, a population‐based cohort study

This study aimed to compare the psychopathological profiles of children at familial high risk of schizophrenia spectrum psychosis (FHR‐SZ) or bipolar disorder (FHR‐BP) with population‐based controls. We used Danish nationwide registers to retrieve a cohort of 522 seven‐year‐old children of parents with schizophrenia spectrum psychosis (N=202), bipolar disorder (N=120) or none of these disorders (N=200). Psychopathology was assessed by reports from multiple informants, including children, parents and teachers. Lifetime DSM‐IV diagnoses were ascertained by blinded raters through the Schedule for Affective Disorders and Schizophrenia for School‐Age Children. The dimensional assessment of psychopathology was performed by the Child Behavior Checklist, the Teacher's Report Form, a modified version of the ADHD‐Rating Scale, the Test Observation Form, and the State‐Trait Anxiety Inventory for Children. Current level of functioning was evaluated using the Children's Global Assessment Scale (CGAS). The prevalence of lifetime psychiatric diagnoses was significantly higher in both FHR‐SZ children (38.7%, odds ratio, OR=3.5, 95% confidence interval, CI: 2.2‐5.7, p < 0.001) and FHR‐BP children (35.6%, OR=3.1, 95% CI: 1.8‐5.3, p < 0.001) compared with controls (15.2%). FHR‐SZ children displayed significantly more dimensional psychopathology on all scales and subscales compared with controls except for the Anxious subscale of the Test Observation Form. FHR‐BP children showed higher levels of dimensional psychopathology on several scales and subscales compared with controls, but lower levels compared with FHR‐SZ children. Level of functioning was lower in both FHR‐SZ children (CGAS mean score = 68.2; 95% CI: 66.3‐70.2, p < 0.0001) and FHR‐BP children (73.7; 95% CI: 71.2‐76.3, p < 0.05) compared with controls (77.9; 95% CI: 75.9‐79.9). In conclusion, already at the age of seven, FHR‐SZ and FHR‐BP children show a higher prevalence of a broad spectrum of categorical and dimensional psychopathology compared with controls. These results emphasize the need for developing early intervention strategies towards this vulnerable group of children.     

Increased risk of COVID‐19 infection and mortality in people with mental disorders: analysis from electronic health records in the United States

Concerns have been expressed that persons with a pre‐existing mental disorder may represent a population at increased risk for COVID‐19 infec­tion and with a higher likelihood of adverse outcomes of the infection, but there is no systematic research evidence in this respect. This study assessed the impact of a recent (within past year) diagnosis of a mental disorder – including attention‐deficit/hyperactivity disorder (ADHD), bipolar disorder, depression and schizophrenia – on the risk for COVID‐19 infection and related mortality and hospitalization rates. We analyzed a nation‐wide database of electronic health records of 61 million adult patients from 360 hospitals and 317,000 providers, across 50 states in the US, up to July 29, 2020. Patients with a recent diagnosis of a mental disorder had a significantly increased risk for COVID‐19 infection, an effect strongest for depression (adjusted odds ratio, AOR=7.64, 95% CI: 7.45‐7.83, p<0.001) and schizophrenia (AOR=7.34, 95% CI: 6.65‐8.10, p<0.001). Among patients with a recent diagnosis of a mental disorder, African Americans had higher odds of COVID‐19 infection than Caucasians, with the strongest ethnic disparity for depression (AOR=3.78, 95% CI: 3.58‐3.98, p<0.001). Women with mental disorders had higher odds of COVID‐19 infection than males, with the strongest gender disparity for ADHD (AOR=2.03, 95% CI: 1.73‐2.39, p<0.001). Patients with both a recent diagnosis of a mental disorder and COVID‐19 infection had a death rate of 8.5% (vs. 4.7% among COVID‐19 patients with no mental disorder, p<0.001) and a hospitalization rate of 27.4% (vs. 18.6% among COVID‐19 patients with no mental disorder, p<0.001). These findings identify individuals with a recent diagnosis of a mental disorder as being at increased risk for COVID‐19 infection, which is further exacerbated among African Americans and women, and as having a higher frequency of some adverse outcomes of the infection. This evidence highlights the need to identify and address modifiable vulnerability factors for COVID‐19 infection and to prevent delays in health care provision in this population.