Efficacy and acceptability of pharmacological,psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: an umbrella review

Top‐tier evidence on the safety/tolerability of 80 medications in children/adolescents with mental disorders has recently been reviewed in this jour­nal. To guide clinical practice, such data must be combined with evidence on efficacy and acceptability. Besides medications, psychosocial inter­ventions and brain stimulation techniques are treatment options for children/adolescents with mental disorders. For this umbrella review, we systematically searched network meta‐analyses (NMAs) and meta‐analyses (MAs) of randomized controlled trials (RCTs) evaluating 48 medications, 20 psychosocial interventions, and four brain stimulation techniques in children/adolescents with 52 different mental disorders or groups of mental disorders, reporting on 20 different efficacy/acceptability outcomes. Co‐primary outcomes were disease‐specific symptom reduction and all‐cause discontinuation (“acceptability”). We included 14 NMAs and 90 MAs, reporting on 15 mental disorders or groups of mental disorders. Overall, 21 medications outperformed placebo regarding the co‐primary outcomes, and three psychosocial interventions did so (while seven outperformed waiting list/no treatment). Based on the meta‐analytic evidence, the most convincing efficacy profile emerged for amphetamines, methylphenidate and, to a smaller extent, behavioral therapy in attention‐deficit/hyperactivity disorder; aripiprazole, risperidone and several psychosocial interventions in autism; risperidone and behavioral interventions in disruptive behavior disorders; several antipsychotics in schizophrenia spectrum disorders; fluoxetine, the combination of fluoxetine and cognitive behavioral therapy (CBT), and interpersonal therapy in depression; aripiprazole in mania; fluoxetine and group CBT in anxiety disorders; fluoxetine/selective serotonin reuptake inhibitors, CBT, and behavioral therapy with exposure and response prevention in obsessive‐compulsive disorder; CBT in post‐traumatic stress disorder; imipramine and alarm behavioral intervention in enuresis; behavioral therapy in encopresis; and family therapy in anorexia nervosa. Results from this umbrella review of interventions for mental disorders in children/adolescents provide evidence‐based information for clinical decision making.     

Mortality in people with schizophrenia: a systematic review and meta‐analysis of relative risk and aggravating or attenuating factors

People with schizophrenia die 15‐20 years prematurely. Understanding mortality risk and aggravating/attenuating factors is essential to reduce this gap. We conducted a systematic review and random‐effects meta‐analysis of prospective and retrospective, nationwide and targeted cohort studies assessing mortality risk in people with schizophrenia versus the general population or groups matched for physical comorbidities or groups with different psychiatric disorders, also assessing moderators. Primary outcome was all‐cause mortality risk ratio (RR); key secondary outcomes were mortality due to suicide and natural causes. Other secondary outcomes included any other specific‐cause mortality. Publication bias, subgroup and meta‐regression analyses, and quality assessment (Newcastle‐Ottawa Scale) were conducted. Across 135 studies spanning from 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), all‐cause mortality was increased in people with schizophrenia versus any non‐schizophrenia control group (RR=2.52, 95% CI: 2.38‐2.68, n=79), with the largest risk in first‐episode (RR=7.43, 95% CI: 4.02‐13.75, n=2) and incident (i.e., earlier‐phase) schizophrenia (RR=3.52, 95% CI: 3.09‐4.00, n=7) versus the general population. Specific‐cause mortality was highest for suicide or injury‐poisoning or undetermined non‐natural cause (RR=9.76‐8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79‐7.23), decreasing through infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4), to alcohol or gastrointestinal or renal or nervous system or cardio‐cerebrovascular or all natural causes (RR=2 to 3), and liver or cerebrovascular, or breast or colon or pancreas or any cancer causes (RR=1.33 to 1.96). All‐cause mortality increased slightly but significantly with median study year (beta=0.0009, 95% CI: 0.001‐0.02, p=0.02). Individuals with schizophrenia <40 years of age had increased all‐cause and suicide‐related mortality compared to those ≥40 years old, and a higher percentage of females increased suicide‐related mortality risk in incident schizophrenia samples. All‐cause mortality was higher in incident than prevalent schizophrenia (RR=3.52 vs. 2.86, p=0.009). Comorbid substance use disorder increased all‐cause mortality (RR=1.62, 95% CI: 1.47‐1.80, n=3). Antipsychotics were protective against all‐cause mortality versus no antipsychotic use (RR=0.71, 95% CI: 0.59‐0.84, n=11), with largest effects for second‐generation long‐acting injectable anti­psychotics (SGA‐LAIs) (RR=0.39, 95% CI: 0.27‐0.56, n=3), clozapine (RR=0.43, 95% CI: 0.34‐0.55, n=3), any LAI (RR=0.47, 95% CI: 0.39‐0.58, n=2), and any SGA (RR=0.53, 95% CI: 0.44‐0.63, n=4). Antipsychotics were also protective against natural cause‐related mortality, yet first‐generation antipsychotics (FGAs) were associated with increased mortality due to suicide and natural cause in incident schizophrenia. Higher study quality and number of variables used to adjust the analyses moderated larger natural‐cause mortality risk, and more recent study year moderated larger protective effects of antipsychotics. These results indicate that the excess mortality in schizophrenia is associated with several modifiable factors. Targeting comorbid substance abuse, long‐term maintenance antipsychotic treatment and appropriate/earlier use of SGA‐LAIs and clozapine could reduce this mortality gap.     

Impact of air pollution and climate change on mental health outcomes: an umbrella review of global evidence

The impact of air pollution and climate change on mental health has recently raised strong concerns. However, a comprehensive overview analyzing the existing evidence while addressing relevant biases is lacking. This umbrella review systematically searched the PubMed/Medline, Scopus and PsycINFO databases (up to June 26, 2023) for any systematic review with meta-analysis investigating the association of air pollution or climate change with mental health outcomes. We used the R metaumbrella package to calculate and stratify the credibility of the evidence according to criteria (i.e., convincing, highly suggestive, suggestive, or weak) that address several biases, complemented by sensitivity analyses. We included 32 systematic reviews with meta-analysis that examined 284 individual studies and 237 associations of exposures to air pollution or climate change hazards and mental health outcomes. Most associations (n=195, 82.3%) involved air pollution, while the rest (n=42, 17.7%) regarded climate change hazards (mostly focusing on temperature: n=35, 14.8%). Mental health outcomes in most associations (n=185, 78.1%) involved mental disorders, followed by suicidal behavior (n=29, 12.4%), access to mental health care services (n=9, 3.7%), mental disorders-related symptomatology (n=8, 3.3%), and multiple categories together (n=6, 2.5%). Twelve associations (5.0%) achieved convincing (class I) or highly suggestive (class II) evidence. Regarding exposures to air pollution, there was convincing (class I) evidence for the association between long-term exposure to solvents and a higher incidence of dementia or cognitive impairment (odds ratio, OR=1.139), and highly suggestive (class II) evidence for the association between long-term exposure to some pollutants and higher risk for cognitive disorders (higher incidence of dementia with high vs. low levels of carbon monoxide, CO: OR=1.587; higher incidence of vascular dementia per 1 μg/m³ increase of nitrogen oxides, NO_x: hazard ratio, HR=1.004). There was also highly suggestive (class II) evidence for the association between exposure to airborne particulate matter with diameter ≤10 μm (PM₁₀) during the second trimester of pregnancy and the incidence of post-partum depression (OR=1.023 per 1 μg/m³ increase); and for the association between short-term exposure to sulfur dioxide (SO₂) and schizophrenia relapse (risk ratio, RR=1.005 and 1.004 per 1 μg/m³ increase, respectively 5 and 7 days after exposure). Regarding climate change hazards, there was highly suggestive (class II) evidence for the association between short-term exposure to increased temperature and suicide- or mental disorders-related mortality (RR=1.024), suicidal behavior (RR=1.012), and hospital access (i.e., hospitalization or emergency department visits) due to suicidal behavior or mental disorders (RR=1.011) or mental disorders only (RR=1.009) (RR values per 1°C increase). There was also highly suggestive (class II) evidence for the association between short-term exposure to increased apparent temperature (i.e., the temperature equivalent perceived by humans) and suicidal behavior (RR=1.01 per 1°C increase). Finally, there was highly suggestive (class II) evidence for the association between the temporal proximity of cyclone exposure and severity of symptoms of post-traumatic stress disorder (r=0.275). Although most of the above associations were small in magnitude, they extend to the entire world population, and are therefore likely to have a substantial impact. This umbrella review classifies and quantifies for the first time the global negative impacts that air pollution and climate change can exert on mental health, identifying evidence-based targets that can inform future research and population health actions.     

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.     

Potential for prediction of psychosis and bipolar disorder in Child and Adolescent Mental Health Services: a longitudinal register study of all people born in Finland in 1987

Current strategies to predict psychosis identify only a small proportion of individuals at risk. Additional strategies are needed to increase capacity for pre­diction and prevention of serious mental illness, ideally during childhood and adolescence. One possible approach would be to investigate systems in which psychosis risk factors are concentrated during childhood. One notable such system is represented by Child and Adolescent Mental Health Services (CAMHS). Although psychotic disorders are uncommon in CAMHS, many risk factors for psychosis are highly prevalent in young people who enter this system. We hypothesized, therefore, that youth attending CAMHS would be a high‐risk group for psychosis if followed into adulthood and, furthermore, that CAMHS systems would capture a substantial proportion of future psychosis cases. We constructed a total population cohort study of all Finns born in 1987 (N=55,875), linking together extensive register data on health care contacts from birth through age 28 years. We identified all individuals diagnosed with a psychotic or bipolar disorder by age 28 (N=1,785). The risk of psychosis/bipolar disorder by age 28 years was 1.8% for individuals who had not attended CAMHS during childhood or adolescence, whereas it was 12.8% for those with a history of any outpatient CAMHS contact (odds ratio, OR=7.9, 95% CI: 7.2‐8.7). Furthermore, the risk of psychosis/bipolar disorder by age 28 years was 2.3% for individuals without a history of inpatient CAMHS admission, whereas it was 24.0% for those with a history of inpatient CAMHS admission (OR=13.3, 95% CI: 11.9‐14.9), and 36.5% for those with a history of inpatient CAMHS admission in adolescence (age 13‐17 years) (OR=24.2, 95% CI: 21.2‐27.6). Individuals who attended CAMHS but received no mental disorder diagnosis had an equally high risk of subsequently developing a psychosis/bipolar disorder as individuals who did receive a diagnosis (OR=0.9, 99.5% CI: 0.7‐1.1). Compared to other CAMHS attendees, individuals who developed psychosis or bipolar disorder were more likely to have had an initial CAMHS diagnosis of depressive or other mood disorder (OR=2.3, 99.5% CI: 1.6‐3.0) and disruptive behaviour disorder (OR=1.7, 99.5% CI: 1.2‐2.5). Of all psychosis/bipolar diagnoses by age 28 years, 50.2% occurred in individuals who had, at some point in childhood or adolescence, attended CAMHS, indicating that CAMHS represent not only a high‐risk but also a high‐capacity system for prediction of psychosis/bipolar disorder. These findings suggest an enormous, untapped potential for large‐scale psychosis/bipolar disorder prediction and prevention research within existing specialist CAMHS.     

Effectiveness of a WHO self‐help psychological intervention for preventing mental disorders among Syrian refugees in Turkey: a randomized controlled trial

Refugees are at high risk of developing mental disorders. There is no evidence from randomized controlled trials (RCTs) that psychological interventions can prevent the onset of mental disorders in this group. We assessed the effectiveness of a self‐help psychological intervention developed by the World Health Organization, called Self‐Help Plus, in preventing the development of mental disorders among Syrian refugees experiencing psychological distress in Turkey. A two‐arm, assessor‐masked RCT was conducted in two Turkish areas. Eligible participants were adult Syrian refugees experiencing psychological distress (General Health Questionnaire ≥3), but without a diagnosis of mental disorder. They were randomly assigned either to the Self‐Help Plus arm (consisting of Self‐Help Plus combined with Enhanced Care as Usual, ECAU) or to ECAU only in a 1:1 ratio. Self‐Help Plus was delivered in a group format by two facilitators over five sessions. The primary outcome measure was the presence of any mental disorder assessed by the Mini International Neuropsychiatric Interview at six‐month follow‐up. Secondary outcome measures were the presence of mental disorders at post‐intervention, and psychological distress, symptoms of post‐traumatic stress disorder and depression, personally identified psychological outcomes, functional impairment, subjective well‐being, and quality of life at post‐intervention and six‐month follow‐up. Between October 1, 2018 and November 30, 2019, 1,186 refugees were assessed for inclusion. Five hundred forty‐four people were ineligible, and 642 participants were enrolled and randomly assigned to either Self‐Help Plus (N=322) or ECAU (N=320). Self‐Help Plus participants were significantly less likely to have any mental disorders at six‐month follow‐up compared to the ECAU group (21.69% vs. 40.73%; Cramer''s V = 0.205, p<0.001, risk ratio: 0.533, 95% CI: 0.408‐0.696). Analysis of secondary outcomes suggested that Self‐Help Plus was not effective immediately post‐intervention, but was associated with beneficial effects at six‐month follow‐up in terms of symptoms of depression, personally identified psychological outcomes, and quality of life. This is the first prevention RCT ever conducted among refugees experiencing psychological distress but without a mental disorder. Self‐Help Plus was found to be an effective strategy for preventing the onset of mental disorders. Based on these findings, this low‐intensity self‐help psychological intervention could be scaled up as a public health strategy to prevent mental disorders in refugee populations exposed to ongoing adversities.     

Impact of mental disorders on clinical outcomes of physical diseases: an umbrella review assessing population attributable fraction and generalized impact fraction

Empirical evidence indicates a significant bidirectional association between mental disorders and physical diseases, but the prospective impact of men­tal disorders on clinical outcomes of physical diseases has not been comprehensively outlined. In this PRISMA- and COSMOS-E-compliant umbrella review, we searched PubMed, PsycINFO, Embase, and Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports, up to March 15, 2022, to identify systematic reviews with meta-analysis that examined the prospective association between any mental disorder and clinical outcomes of physical diseases. Primary outcomes were disease-specific mortality and all-cause mortality. Secondary outcomes were disease-specific incidence, functioning and/or disability, symptom severity, quality of life, recurrence or progression, major cardiac events, and treatment-related outcomes. Additional inclusion criteria were further applied to primary studies. Random effect models were employed, along with I² statistic, 95% prediction intervals, small-study effects test, excess significance bias test, and risk of bias (ROBIS) assessment. Associations were classified into five credibility classes of evidence (I to IV and non-significant) according to established criteria, complemented by sensitivity and subgroup analyses to examine the robustness of the main analysis. Statistical analysis was performed using a new package for conducting umbrella reviews ( https://metaumbrella.org ). Population attributable fraction (PAF) and generalized impact fraction (GIF) were then calculated for class I-III associations. Forty-seven systematic reviews with meta-analysis, encompassing 251 non-overlapping primary studies and reporting 74 associations, were included (68% were at low risk of bias at the ROBIS assessment). Altogether, 43 primary outcomes (disease-specific mortality: n=17; all-cause mortality: n=26) and 31 secondary outcomes were investigated. Although 72% of associations were statistically significant (p<0.05), only two showed convincing (class I) evidence: that between depressive disorders and all-cause mortality in patients with heart failure (hazard ratio, HR=1.44, 95% CI: 1.26-1.65), and that between schizophrenia and cardiovascular mortality in patients with cardiovascular diseases (risk ratio, RR=1.54, 95% CI: 1.36-1.75). Six associations showed highly suggestive (class II) evidence: those between depressive disorders and all-cause mortality in patients with diabetes mellitus (HR=2.84, 95% CI: 2.00-4.03) and with kidney failure (HR=1.41, 95% CI: 1.31-1.51); that between depressive disorders and major cardiac events in patients with myocardial infarction (odds ratio, OR=1.52, 95% CI: 1.36-1.70); that between depressive disorders and dementia in patients with diabetes mellitus (HR=2.11, 95% CI: 1.77-2.52); that between alcohol use disorder and decompensated liver cirrhosis in patients with hepatitis C (RR=3.15, 95% CI: 2.87-3.46); and that between schizophrenia and cancer mortality in patients with cancer (standardized mean ratio, SMR=1.74, 95% CI: 1.41-2.15). Sensitivity/subgroup analyses confirmed these results. The largest PAFs were 30.56% (95% CI: 27.67-33.49) for alcohol use disorder and decompensated liver cirrhosis in patients with hepatitis C, 26.81% (95% CI: 16.61-37.67) for depressive disorders and all-cause mortality in patients with diabetes mellitus, 13.68% (95% CI: 9.87-17.58) for depressive disorders and major cardiac events in patients with myocardial infarction, 11.99% (95% CI: 8.29-15.84) for schizophrenia and cardiovascular mortality in patients with cardiovascular diseases, and 11.59% (95% CI: 9.09-14.14) for depressive disorders and all-cause mortality in patients with kidney failure. The GIFs confirmed the preventive capacity of these associations. This umbrella review demonstrates that mental disorders increase the risk of a poor clinical outcome in several physical diseases. Prevention targeting mental disorders – particularly alcohol use disorders, depressive disorders, and schizophrenia – can reduce the incidence of adverse clinical outcomes in people with physical diseases. These findings can inform clinical practice and trans-speciality preventive approaches cutting across psychiatric and somatic medicine.     

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.     

Preventive psychiatry: a blueprint for improving the mental health of young people

Preventive approaches have latterly gained traction for improving mental health in young people. In this paper, we first appraise the conceptual foundations of preventive psychiatry, encompassing the public health, Gordon''s, US Institute of Medicine, World Health Organization, and good mental health frameworks, and neurodevelopmentally‐sensitive clinical staging models. We then review the evidence supporting primary prevention of psychotic, bipolar and common mental disorders and promotion of good mental health as potential transformative strategies to reduce the incidence of these disorders in young people. Within indicated approaches, the clinical high‐risk for psychosis paradigm has received the most empirical validation, while clinical high‐risk states for bipolar and common mental disorders are increasingly becoming a focus of attention. Selective approaches have mostly targeted familial vulnerability and non‐genetic risk exposures. Selective screening and psychological/psychoeducational interventions in vulnerable subgroups may improve anxiety/depressive symptoms, but their efficacy in reducing the incidence of psychotic/bipolar/common mental disorders is unproven. Selective physical exercise may reduce the incidence of anxiety disorders. Universal psychological/psychoeducational interventions may improve anxiety symptoms but not prevent depressive/anxiety disorders, while universal physical exercise may reduce the incidence of anxiety disorders. Universal public health approaches targeting school climate or social determinants (demographic, economic, neighbourhood, environmental, social/cultural) of mental disorders hold the greatest potential for reducing the risk profile of the population as a whole. The approach to promotion of good mental health is currently fragmented. We leverage the knowledge gained from the review to develop a blueprint for future research and practice of preventive psychiatry in young people: integrating universal and targeted frameworks; advancing multivariable, transdiagnostic, multi‐endpoint epidemiological knowledge; synergically preventing common and infrequent mental disorders; preventing physical and mental health burden together; implementing stratified/personalized prognosis; establishing evidence‐based preventive interventions; developing an ethical framework, improving prevention through education/training; consolidating the cost‐effectiveness of preventive psychiatry; and decreasing inequalities. These goals can only be achieved through an urgent individual, societal, and global level response, which promotes a vigorous collaboration across scientific, health care, societal and governmental sectors for implementing preventive psychiatry, as much is at stake for young people with or at risk for emerging mental disorders.     

What causes psychosis? An umbrella review of risk and protective factors

Psychosis is a heterogeneous psychiatric condition for which a multitude of risk and protective factors have been suggested. This umbrella review aimed to classify the strength of evidence for the associations between each factor and psychotic disorders whilst controlling for several biases. The Web of Knowledge database was searched to identify systematic reviews and meta‐analyses of observational studies which examined associations between socio‐demographic, parental, perinatal, later factors or antecedents and psychotic disorders, and which included a comparison group of healthy controls, published from 1965 to January 31, 2017. The literature search and data extraction followed PRISMA and MOOSE guidelines. The association between each factor and ICD or DSM diagnoses of non‐organic psychotic disorders was graded into convincing, highly suggestive, suggestive, weak, or non‐significant according to a standardized classification based on: number of psychotic cases, random‐effects p value, largest study 95% confidence interval, heterogeneity between studies, 95% prediction interval, small study effect, and excess significance bias. In order to assess evidence for temporality of association, we also conducted sensitivity analyses restricted to data from prospective studies. Fifty‐five meta‐analyses or systematic reviews were included in the umbrella review, corresponding to 683 individual studies and 170 putative risk or protective factors for psychotic disorders. Only the ultra‐high‐risk state for psychosis (odds ratio, OR=9.32, 95% CI: 4.91‐17.72) and Black‐Caribbean ethnicity in England (OR=4.87, 95% CI: 3.96‐6.00) showed convincing evidence of association. Six factors were highly suggestive (ethnic minority in low ethnic density area, second generation immigrants, trait anhedonia, premorbid IQ, minor physical anomalies, and olfactory identification ability), and nine were suggestive (urbanicity, ethnic minority in high ethnic density area, first generation immigrants, North‐African immigrants in Europe, winter/spring season of birth in Northern hemisphere, childhood social withdrawal, childhood trauma, Toxoplasma gondii IgG, and non‐right handedness). When only prospective studies were considered, the evidence was convincing for ultra‐high‐risk state and suggestive for urbanicity only. In summary, this umbrella review found several factors to be associated with psychotic disorders with different levels of evidence. These risk or protective factors represent a starting point for further etiopathological research and for the improvement of the prediction of psychosis.     

Efficacy and safety of combination PD‐1/PD‐L1 checkpoint inhibitors for malignant solid tumours: A systematic review

Treatment of multiple malignant solid tumours with programmed death (PD)‐1/PD ligand (PD‐L) 1 inhibitors has been reported. However, the efficacy and immune adverse effects of combination therapies are controversial. This meta‐analysis was performed with PubMed, Web of Science, Medline, EMBASE and Cochrane Library from their inception until January 2020. Random‐effect model was adopted because of relatively high heterogeneity. We also calculated hazard ratio (HR) of progression‐free survival (PFS), overall survival (OS) and risk ratio (RR) of adverse events (AEs), the incidence of grade 3‐5 AEs by tumour subgroup, therapeutic schedules and therapy lines. Nineteen articles were selected using the search strategy for meta‐analysis. Combined PD‐1/PD‐L1 inhibitors prolonged OS and PFS (HR 0.72, P < 0.001) and (HR 0.66, P < 0.001). In addition, incidence of all‐grade and grade 3‐5 AEs was not significant in the two subgroup analyses (HR 1.01, P = 0.31) and (HR 1.10, P = 0.07), respectively. Our meta‐analysis indicated that combination therapy with PD‐1/PD‐L1 inhibitors had greater clinical benefits and adverse events were not increased significantly.     

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.     

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.     

Adverse childhood experiences and mental health problems in a nationally representative study of heterosexual,homosexual and bisexual Danes

Non‐heterosexual persons more often report adverse childhood experiences (ACEs) than heterosexuals, and they generally bear a greater burden of mental health challenges. However, population‐based data on this topic are scarce. In a nationally representative study within the Project SEXUS, one of the world''s largest cohort studies on sexual health, we used data from 57,479 individuals in Denmark to explore the interplay between ACEs and mental health problems among self‐identified heterosexual, homosexual and bisexual persons, and among self‐identified heterosexuals with or without same‐sex sexual experience. Compared to heterosexuals, non‐heterosexual persons were more likely to report most of the studied ACEs, with odds ratios (ORs) for the ACE category “abuse” ranging from 1.38 to 1.75 for homosexual women, from 1.76 to 2.65 for homosexual men, from 2.52 to 3.64 for bisexual women, and from 1.58 to 6.07 for bisexual men. Furthermore, non‐heterosexual persons had consistently and statistically significantly higher odds for mental health problems (ORs: 1.50 to 4.63). Combinations of ACEs with a non‐heterosexual identity resulted in markedly elevated odds for mental health problems, particularly among bisexual individuals. This included high odds for suicidal thoughts/attempts among bisexual persons with a history of “neglect” (women: OR=12.82; men: OR=35.24) and “abuse” (women: OR=11.81; men: OR=11.65). Among self‐identified heterosexuals, combinations of ACEs with same‐sex sexual experience were associated with consistently elevated odds for mental health problems (ORs: 2.22 to 12.04). The greater burden of ACEs among self‐identified homosexuals and, most notably, bisexuals may account for part of their excess risk of mental health problems. These findings emphasize the public health importance of preventive measures to minimize the burden of ACEs and avert their harmful long‐term effects. Moreover, they highlight the need to safeguard the welfare of children and adolescents with non‐conforming expressions of sexuality.     

Attention‐deficit/hyperactivity disorder as a risk factor for cardiovascular diseases: a nationwide population‐based cohort study

Accumulating evidence suggests a higher risk for cardiovascular diseases among individuals with mental disorders, but very little is known about the risk for overall and specific groups of cardiovascular diseases in people with attention‐deficit/hyperactivity disorder (ADHD). To fill this knowledge gap, we investigated the prospective associations between ADHD and a wide range of cardiovascular diseases in adults. In a nationwide population‐based cohort study, we identified 5,389,519 adults born between 1941 and 1983, without pre‐existing cardiovascular diseases, from Swedish registers. The study period was from January 1, 2001 to December 31, 2013. Incident cardiovascular disease events were identified according to ICD codes. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards regression model, with ADHD as a time‐varying exposure. After an average 11.80 years of follow‐up, 38.05% of individuals with ADHD versus 23.57% of those without ADHD had at least one diagnosis of cardiovascular disease (p<0.0001). ADHD was significantly associated with increased risk of any cardiovascular disease (HR=2.05, 95% CI: 1.98‐2.13) after adjusting for sex and year of birth. Further adjustments for education level, birth country, type 2 diabetes mellitus, obesity, dyslipidemia, sleep problems and heavy smoking attenuated the association, which however remained significant (HR=1.84, 95% CI: 1.77‐1.91). Further adjustment for psychiatric comorbidities attenuated but could not fully explain the association (HR=1.65, 95% CI: 1.59‐1.71). The strongest associations were found for cardiac arrest (HR=2.28, 95% CI: 1.81‐2.87), hemorrhagic stroke (HR=2.16, 95% CI: 1.68‐2.77), and peripheral vascular disease/arteriosclerosis (HR=2.05, 95% CI: 1.76‐2.38). Stronger associations were observed in males and younger adults, while comparable associations were found among individuals with or without psychotropic medications and family history of cardiovascular diseases. These data suggest that ADHD is an independent risk factor for a wide range of cardiovascular diseases. They highlight the importance of carefully monitoring cardiovascular health and developing age‐appropriate and individualized strategies to reduce the cardiovascular risk in individuals with ADHD.     

Mental health care for older adults: recent advances and new directions in clinical practice and research

The world''s population is aging, bringing about an ever‐greater burden of mental disorders in older adults. Given multimorbidities, the mental health care of these people and their family caregivers is labor‐intensive. At the same time, ageism is a big problem for older people, with and without mental disorders. Positive elements of aging, such as resilience, wisdom and prosocial behaviors, need to be highlighted and promoted, both to combat stigma and to help protect and improve mental health in older adults. The positive psychiatry of aging is not an oxymoron, but a scientific construct strongly informed by research evidence. We champion a broader concept of geriatric psychiatry – one that encompasses health as well as illness. In the present paper, we address these issues in the context of four disorders that are the greatest source of years lived with disability: neurocognitive disorders, major depression, schizophrenia, and substance use disorders. We emphasize the need for implementation of multidisciplinary team care, with comprehensive assessment, clinical management, intensive outreach, and coordination of mental, physical and social health services. We also underscore the need for further research into moderators and mediators of treatment response variability. Because optimal care of older adults with mental disorders is both patient‐focused and family‐centered, we call for further research into enhancing the well‐being of family caregivers. To optimize both the safety and efficacy of pharmacotherapy, further attention to metabolic, cardiovascular and neurological tolerability is much needed, together with further development and testing of medications that reduce the risk for suicide. At the same time, we also address positive aging and normal cognitive aging, both as an antidote to ageism and as a catalyst for change in the way we think about aging per se and late‐life mental disorders more specifically. It is in this context that we provide directions for future clinical care and research.     

Transdiagnostic risk of mental disorders in offspring of affected parents: a meta-analysis of family high-risk and registry studies

The offspring of parents with mental disorders are at increased risk for developing mental disorders themselves. The risk to offspring may extend transdiagnostically to disorders other than those present in the parents. The literature on this topic is vast but mixed. To inform targeted prevention and genetic counseling, we performed a comprehensive, PRISMA 2020-compliant meta-analysis. We systematically searched the literature published up to September 2022 to retrieve original family high-risk and registry studies reporting on the risk of mental disorders in offspring of parents with any type of mental disorder. We performed random-effects meta-analyses of the relative risk (risk ratio, RR) and absolute risk (lifetime, up to the age at assessment) of mental disorders, defined according to the ICD or DSM. Cumulative incidence by offspring age was determined using meta-analytic Kaplan-Meier curves. We measured heterogeneity with the I² statistic, and risk of bias with the Quality In Prognosis Studies (QUIPS) tool. Sensitivity analyses addressed the impact of study design (family high-risk vs. registry) and specific vs. transdiagnostic risks. Transdiagnosticity was appraised with the TRANSD criteria. We identified 211 independent studies that reported data on 3,172,115 offspring of parents with psychotic, bipolar, depressive, disruptive, attention-deficit/hyperactivity, anxiety, substance use, eating, obsessive-compulsive, and borderline personality disorders, and 20,428,575 control offspring. The RR and lifetime risk of developing any mental disorder were 3.0 and 55% in offspring of parents with anxiety disorders; 2.6 and 17% in offspring of those with psychosis; 2.1 and 55% in offspring of those with bipolar disorder; 1.9 and 51% in offspring of those with depressive disorders; and 1.5 and 38% in offspring of those with substance use disorders. The offspring's RR and lifetime risk of developing the same mental disorder diagnosed in their parent were 8.4 and 32% for attention-deficit/hyperactivity disorder; 5.8 and 8% for psychosis; 5.1 and 5% for bipolar disorder; 2.8 and 9% for substance use disorders; 2.3 and 14% for depressive disorders; 2.3 and 1% for eating disorders; and 2.2 and 31% for anxiety disorders. There were 37 significant transdiagnostic associations between parental mental disorders and the RR of developing a different mental disorder in the offspring. In offspring of parents with psychosis, bipolar and depressive disorder, the risk of the same disorder onset emerged at 16, 5 and 6 years, and cumulated to 3%, 19% and 24% by age 18; and to 8%, 36% and 46% by age 28. Heterogeneity ranged from 0 to 0.98, and 96% of studies were at high risk of bias. Sensitivity analyses restricted to prospective family high-risk studies confirmed the pattern of findings with similar RR, but with greater absolute risks compared to analyses of all study types. This study demonstrates at a global, meta-analytic level that offspring of affected parents have strongly elevated RR and lifetime risk of developing any mental disorder as well as the same mental disorder diagnosed in the parent. The transdiagnostic risks suggest that offspring of parents with a range of mental disorders should be considered as candidates for targeted primary prevention.     

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.     

Dopamine and glutamate in individuals at high risk for psychosis: a meta‐analysis of in vivo imaging findings and their variability compared to controls

Dopaminergic and glutamatergic dysfunction is believed to play a central role in the pathophysiology of schizophrenia. However, it is unclear if abnormalities predate the onset of schizophrenia in individuals at high clinical or genetic risk for the disorder. We systematically reviewed and meta‐analyzed studies that have used neuroimaging to investigate dopamine and glutamate function in individuals at increased clinical or genetic risk for psychosis. EMBASE, PsycINFO and Medline were searched form January 1, 1960 to November 26, 2020. Inclusion criteria were molecular imaging measures of striatal presynaptic dopaminergic function, striatal dopamine receptor availability, or glutamate function. Separate meta‐analyses were conducted for genetic high‐risk and clinical high‐risk individuals. We calculated standardized mean differences between high‐risk individuals and controls, and investigated whether the variability of these measures differed between the two groups. Forty‐eight eligible studies were identified, including 1,288 high‐risk individuals and 1,187 controls. Genetic high‐risk individuals showed evidence of increased thalamic glutamate + glutamine (Glx) concentrations (Hedges’ g=0.36, 95% CI: 0.12‐0.61, p=0.003). There were no significant differences between high‐risk individuals and controls in striatal presynaptic dopaminergic function, striatal D2/D3 receptor availability, prefrontal cortex glutamate or Glx, hippocampal glutamate or Glx, or basal ganglia Glx. In the meta‐analysis of variability, genetic high‐risk individuals showed reduced variability of striatal D2/D3 receptor availability compared to controls (log coefficient of variation ratio, CVR=–0.24, 95% CI: –0.46 to –0.02, p=0.03). Meta‐regressions of publication year against effect size demonstrated that the magnitude of differences between clinical high‐risk individuals and controls in presynaptic dopaminergic function has decreased over time (estimate=–0.06, 95% CI: –0.11 to –0.007, p=0.025). Thus, other than thalamic glutamate concentrations, no neurochemical measures were significantly different between individuals at risk for psychosis and controls. There was also no evidence of increased variability of dopamine or glutamate measures in high‐risk individuals compared to controls. Significant heterogeneity, however, exists between studies, which does not allow to rule out the existence of clinically meaningful differences.     

Pre-Pregnancy BMI,Gestational Weight Gain,and the Risk of Hypertensive Disorders of Pregnancy: A Cohort Study in Wuhan,China

Background

Hypertensive disorders of pregnancy (HDP) are major causes of maternal death worldwide and the risk factors are not fully understood. Few studies have investigated the risk factors for HDP among Chinese women. A cohort study involving 84,656 women was conducted to investigate pre-pregnancy BMI, total gestational weight gain (GWG), and GWG during early pregnancy as risk factors for HDP among Chinese women.

Methods

The study was conducted between 2011–2013 in Wuhan, China, utilizing data from the Maternal and Children Healthcare Information Tracking System of Wuhan. A total of 84,656 women with a live singleton pregnancy were included. Multiple unconditional logistic regression was conducted to evaluate associations between putative risk factors and HDP.

Results

Women who were overweight or obese before pregnancy had an elevated risk of developing HDP (overweight: OR = 2.66, 95% CI = 2.32–3.05; obese: OR = 5.53, 95% CI = 4.28–7.13) compared to their normal weight counterparts. Women with total GWG above the Institute of Medicine (IOM) recommendation had an adjusted OR of 1.72 (95% CI = 1.54–1.93) for HDP compared to women who had GWG within the IOM recommendation. Women with gestational BMI gain >10 kg/m² during pregnancy had an adjusted OR of 3.35 (95% CI = 2.89–3.89) for HDP, compared to women with a gestational BMI gain <5 kg/m². The increased risk of HDP was also observed among women with higher early pregnancy (up to 18 weeks of pregnancy) GWG (>600g/wk: adjusted OR = 1.48, 95% CI = 1.19–1.84).

Conclusion

The results from this study show that maternal pre-pregnancy BMI, early GWG, and total GWG are positively associated with the risk of HDP. Weight control efforts before and during pregnancy may help to reduce the risk of HDP.