-
Psychological Medicine Jul 2023Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use as monotherapy and adjunctive therapy.
METHODS
A systematic review and a meta-analysis were conducted on randomized placebo-controlled trials (RCTs) that reported on the efficacy and safety/tolerability of antipsychotics for the treatment of adults with MDD. Data of both monotherapy and adjunctive antipsychotic use were extracted, but analyzed separately using a random-effects model. Co-primary outcomes were study-defined-treatment response and intolerability-related discontinuation. We also illustrated the risk/benefit balance of antipsychotics for MDD, using two-dimensional graphs representing the primary efficacy and safety/tolerability outcome. Secondary outcomes included psychopathology, remission, all-cause-discontinuation, inefficacy-related discontinuation, and adverse events.
RESULTS
Forty-five RCTs with 12 724 patients were included in the analysis. In monotherapy (studies = 13, = 4375), amisulpride [1.99 (1.55-2.55)], sulpiride [1.50 (1.03-2.17)], and quetiapine [1.48 (1.23-1.78)] were significantly superior to placebo regarding treatment response. However, intolerability-related discontinuations were significantly higher compared to placebo with amisulpride and quetiapine. In adjunctive therapy (studies = 32, = 8349), ziprasidone [1.80 (1.07-3.04)], risperidone [1.59 (1.19-2.14)], aripiprazole [1.54 (1.35-1.76)], brexpiprazole [1.41 (1.21-1.66)], cariprazine [1.27 (1.07-1.52)], and quetiapine [1.23 (1.08-1.41)] were significantly superior to placebo regarding treatment response. However, of these antipsychotics that were superior to placebo, only risperidone was equivalent to placebo regarding discontinuation due to intolerability, while the other antipsychotics were inferior.
CONCLUSION
Results suggest that there are significant differences regarding the risk/benefit ratio among antipsychotics for MDD, which should inform clinical care.
Topics: Adult; Humans; Antipsychotic Agents; Quetiapine Fumarate; Risperidone; Depressive Disorder, Major; Amisulpride; Olanzapine; Benzodiazepines; Dibenzothiazepines
PubMed: 35510505
DOI: 10.1017/S0033291722000745 -
Neuroscience and Biobehavioral Reviews Jun 2023We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and... (Review)
Review
The future of child and adolescent clinical psychopharmacology: A systematic review of phase 2, 3, or 4 randomized controlled trials of pharmacologic agents without regulatory approval or for unapproved indications.
We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010-08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes.
Topics: Humans; Child; Adolescent; Psychopharmacology; Randomized Controlled Trials as Topic; Attention Deficit Disorder with Hyperactivity; Prader-Willi Syndrome; Clinical Trials, Phase II as Topic
PubMed: 37001575
DOI: 10.1016/j.neubiorev.2023.105149 -
Revista Brasileira de Psiquiatria (Sao... 2023To determine the prevalence and correlates of treatment-resistant schizophrenia (TRS) through a systematic review and meta-analysis. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To determine the prevalence and correlates of treatment-resistant schizophrenia (TRS) through a systematic review and meta-analysis.
METHODS
Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, an electronic search was performed in PubMed and Embase through May 17, 2022. All study designs that assessed a minimum of 20 schizophrenia-spectrum patients and provided data on TRS prevalence or allowed its calculation were included. Estimates were produced using a random-effects model meta-analysis.
RESULTS
The TRS prevalence across 50 studies (n = 29,390) was 36.7% (95%CI 33.1-40.5, p < 0.0001). The prevalence ranged from 22% (95%CI 18.4-25.8) in first-episode to 39.5% (95%CI 32.2-47.0) in multiple-episode samples (Q = 18.27, p < 0.0001). Primary treatment resistance, defined as no response from the first episode, was 23.6% (95%CI 20.5-26.8) vs. 9.3% (95%CI 6.8-12.2) for later-onset/secondary (≥ 6 months after initial treatment response). Longer illness duration and recruitment from long-term hospitals or clozapine clinics were associated with higher prevalence estimates. In meta-regression analyses, older age and poor functioning predicted greater TRS. When including only studies with lower bias risk, the TRS prevalence was 28.4%.
CONCLUSION
Different study designs and recruitment strategies accounted for most of the observed heterogeneity in TRS prevalence rates. The results point to early-onset and later-onset TRS as two separate disease pathways requiring clinical attention.
Topics: Humans; Antipsychotic Agents; Clozapine; Prevalence; Schizophrenia; Drug Resistance
PubMed: 37718484
DOI: 10.47626/1516-4446-2023-3126 -
EClinicalMedicine Nov 2023Mental disorders are associated with premature mortality. There is increasing research examining life expectancy and years-of-potential-life-lost (YPLL) to quantify the...
BACKGROUND
Mental disorders are associated with premature mortality. There is increasing research examining life expectancy and years-of-potential-life-lost (YPLL) to quantify the disease impact on survival in people with mental disorders. We aimed to systematically synthesize studies to estimate life expectancy and YPLL in people with any and specific mental disorders across a broad spectrum of diagnoses.
METHODS
In this systematic review and meta-analysis, we searched Embase, MEDLINE, PsychINFO, WOS from inception to July 31, 2023, for published studies reporting life expectancy and/or YPLL for mental disorders. Criteria for study inclusion were: patients of all ages with any mental disorders; reported data on life expectancy and/or YPLL of a mental-disorder cohort relative to the general population or a comparison group without mental disorders; and cohort studies. We excluded non-cohort studies, publications containing non-peer-reviewed data or those restricted to population subgroups. Survival estimates, i.e., life expectancy and YPLL, were pooled (based on summary data extracted from the included studies) using random-effects models. Subgroup analyses and random-effects meta-regression analyses were performed to explore sources of heterogeneity. Risk-of-bias assessment was evaluated using the Newcastle-Ottawa Scale. This study is registered with PROSPERO (CRD42022321190).
FINDINGS
Of 35,865 studies identified in our research, 109 studies from 24 countries or regions including 12,171,909 patients with mental disorders were eligible for analysis (54 for life expectancy and 109 for YPLL). Pooled life expectancy for mental disorders was 63.85 years (95% CI 62.63-65.06; = 100.0%), and pooled YPLL was 14.66 years (95% CI 13.88-15.98; = 100.0%). Disorder-stratified analyses revealed that substance-use disorders had the shortest life expectancy (57.07 years [95% CI 54.47-59.67]), while neurotic disorders had the longest lifespan (69.51 years [95% CI 67.26-71.76]). Substance-use disorders exhibited the greatest YPLL (20.38 years [95% CI 18.65-22.11]), followed by eating disorders (16.64 years [95% CI 7.45-25.82]), schizophrenia-spectrum disorders (15.37 years [95% CI 14.18-16.55]), and personality disorders (15.35 years [95% CI 12.80-17.89]). YPLLs attributable to natural and unnatural deaths in mental disorders were 4.38 years (95% CI 3.15-5.61) and 8.11 years (95% CI 6.10-10.13; suicide: 8.31 years [95% CI 6.43-10.19]), respectively. Stratified analyses by study period suggested that the longevity gap persisted over time. Significant cross-study heterogeneity was observed.
INTERPRETATION
Mental disorders are associated with substantially reduced life expectancy, which is transdiagnostic in nature, encompassing a wide range of diagnoses. Implementation of comprehensive and multilevel intervention approaches is urgently needed to rectify lifespan inequalities for people with mental disorders.
FUNDING
None.
PubMed: 37965432
DOI: 10.1016/j.eclinm.2023.102294 -
The British Journal of Psychiatry : the... Jul 2023Early-onset psychosis (EOP) refers to the development of a first episode of psychosis before 18 years of age. Individuals at clinical high risk for psychosis (CHR-P)... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Early-onset psychosis (EOP) refers to the development of a first episode of psychosis before 18 years of age. Individuals at clinical high risk for psychosis (CHR-P) include adolescents and young adults, although most evidence has focused on adults. Negative symptoms are important prognostic indicators in psychosis. However, research focusing on children and adolescents is limited.
AIMS
To provide meta-analytical evidence and a comprehensive review of the status and advances in the diagnosis, prognosis and treatment of negative symptoms in children and adolescents with EOP and at CHR-P.
METHOD
PRISMA/MOOSE-compliant systematic review (PROSPERO: CRD42022360925) from inception to 18 August 2022, in any language, to identify individual studies conducted in EOP/CHR-P children and adolescents (mean age <18 years) providing findings on negative symptoms. Findings were systematically appraised. Random-effects meta-analyses were performed on the prevalence of negative symptoms, carrying out sensitivity analyses, heterogeneity analyses, publication bias assessment and quality assessment using the Newcastle-Ottawa Scale.
RESULTS
Of 3289 articles, 133 were included ( = 6776 EOP, mean age 15.3 years (s.d. = 1.6), males = 56.1%; = 2138 CHR-P, mean age 16.1 years (s.d. = 1.0), males = 48.6%). There were negative symptoms in 60.8% (95% CI 46.4%-75.2%) of the children and adolescents with EOP and 79.6% (95% CI 66.3-92.9%) of those at CHR-P. Prevalence and severity of negative symptoms were associated with poor clinical, functional and intervention outcomes in both groups. Different interventions were piloted, with variable results requiring further replication.
CONCLUSIONS
Negative symptoms are common in children and adolescents at early stages of psychosis, particularly in those at CHR-P, and are associated with poor outcomes. Future intervention research is required so that evidence-based treatments will become available.
Topics: Male; Humans; Child; Psychotic Disorders; Prognosis
PubMed: 37194556
DOI: 10.1192/bjp.2022.203 -
Journal of Psychiatric Research Nov 2022Early identification of attention-deficit/hyperactivity disorder (ADHD) is critical for mitigating the many negative functional outcomes associated with its diagnosis.... (Meta-Analysis)
Meta-Analysis Review
Early identification of attention-deficit/hyperactivity disorder (ADHD) is critical for mitigating the many negative functional outcomes associated with its diagnosis. Because of the strong genetic basis of ADHD, the use of polygenic risk scores (PRS) could potentially aid in the early identification of ADHD and associated outcomes. Therefore, a systematic search of the literature on the association between ADHD and PRS in pediatric populations was conducted. All articles were screened for a priori inclusion and exclusion criteria, and, after careful review, 33 studies were included in our systematic review and 16 studies with extractable data were included in our meta-analysis. The results of the review were categorized into three common themes: the associations between ADHD-PRS with 1) the diagnosis of ADHD and ADHD symptoms 2) comorbid psychopathology and 3) cognitive and educational outcomes. Higher ADHD-PRS were associated with increased odds of having a diagnosis (OR = 1.37; p<0.001) and more symptoms of ADHD (β = 0.06; p<0.001). While ADHD-PRS were associated with a persistent diagnostic trajectory over time in the systematic review, the meta-analysis did not confirm these findings (OR = 1.09; p = 0.62). Findings showed that ADHD-PRS were associated with increased odds for comorbid psychopathology such as anxiety/depression (OR = 1.16; p<0.001) and irritability/emotional dysregulation (OR = 1.14; p<0.001). Finally, while the systematic review showed that ADHD-PRS were associated with a variety of negative cognitive outcomes, the meta-analysis showed no significant association (β = 0.08; p = 0.07). Our review of the available literature suggests that ADHD-PRS, together with risk factors, may contribute to the early identification of children with suspected ADHD and associated disorders.
Topics: Attention Deficit Disorder with Hyperactivity; Child; Comorbidity; Humans; Longitudinal Studies; Multifactorial Inheritance; Risk Factors
PubMed: 35988304
DOI: 10.1016/j.jpsychires.2022.07.032 -
JAMA Psychiatry May 2022A substantial increase in the number of trials examining metacognitive training (MCT) for psychosis necessitates an updated examination of the outcomes associated with... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
A substantial increase in the number of trials examining metacognitive training (MCT) for psychosis necessitates an updated examination of the outcomes associated with MCT.
OBJECTIVES
To review the immediate and sustained associations of MCT with proximal (directly targeted) and distal (indirectly influenced) outcomes and assess treatment- and participant-related moderators to identify the potential factors associated with the expected heterogeneity of effect sizes.
DATA SOURCES
Eleven electronic databases were searched from 2007 to June 3, 2021 (alert until September 10, 2021). Reference lists of earlier meta-analyses and included reports were screened.
STUDY SELECTION
Reports examined MCT and included participants with schizophrenia spectrum and related psychotic disorders (1045 reports identified; 281 assessed). There were no age, sex, gender, race and ethnicity, language, or study design restrictions. Two reviewers performed the selection of studies to be analyzed.
DATA EXTRACTION AND SYNTHESIS
The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Data were extracted by 3 reviewers and pooled using random effects models. Hedges g effect sizes were computed. The Mixed-Methods Appraisal tool was used to assess study quality.
MAIN OUTCOMES AND MEASURES
Proximal outcomes were global positive symptoms, delusions, hallucinations, and cognitive biases. Distal outcomes were self-esteem, negative symptoms, quality of life, well-being, and functioning. Immediate and sustained outcomes were examined. Meta-regressions, subgroup, and sensitivity analyses assessed moderators.
RESULTS
This systematic review and meta-analysis included 43 studies (46 reports). Forty reports were synthesized in meta-analysis (N=1816 participants) and 6 reports were included in narrative review. In the studies examined, MCT was associated with positive symptoms (g = 0.50; 95% CI, 0.34-0.67), delusions (g = 0.69; 95% CI, 0.45-0.93), hallucinations (g = 0.26; 95% CI, 0.11-0.40), cognitive biases (g = 0.16; 95% CI, 0.03-0.29), self-esteem (g = 0.17; 95% CI, 0.03-0.31), negative symptoms (g = 0.23; 95% CI, 0.10-0.37), and functioning (g = 0.41; 95% CI, 0.12-0.69). These associations were maintained up to 1 year. The quality of life effect size was nonsignificant (g = 0.20; 95% CI, -0.07 to 0.47); only 1 study assessed well-being. Publication year was associated with moderated hallucinations (β = 0.04; 95% CI, 0.00-0.07). Overall, narrative review results corroborated meta-analytic findings.
CONCLUSIONS AND RELEVANCE
In this meta-analysis, MCT for psychosis was associated with benefits up to 1 year postintervention in several treatment contexts. These findings suggest that MCT may merit integration in treatment guidelines for schizophrenia.
Topics: Hallucinations; Humans; Metacognition; Psychotic Disorders; Quality of Life; Schizophrenia
PubMed: 35320347
DOI: 10.1001/jamapsychiatry.2022.0277 -
Schizophrenia Research Jun 2024Although uncommon, the risk of aggression and violence is greater in people with schizophrenia than in the general population. Clozapine is the "gold standard"... (Review)
Review
Although uncommon, the risk of aggression and violence is greater in people with schizophrenia than in the general population. Clozapine is the "gold standard" pharmacologic treatment for the management of persistent agitation and aggression in people with schizophrenia and is consistently recommended by guidelines and reviews for this purpose. Although clozapine is indicated for treatment-resistant schizophrenia based on its superior efficacy, studies have proposed that clozapine may have specific properties that ameliorate aggression and hostility that are distinct from its antipsychotic effects. A literature review was conducted on June 3, 2023, using the US National Library of Medicine's PubMed resource to identify articles focusing on clozapine for the treatment of aggression, violence, and/or hostility in patients with schizophrenia or schizoaffective disorder. The majority of evidence, including from randomized control trials, supports the utilization of clozapine as maintenance treatment for persistent aggressive behavior in patients with schizophrenia, and supports that its anti-aggressive effects may be independent from its antipsychotic properties (e.g. - treatment of hallucinations and delusions). Future randomized control studies evaluating clozapine and clozapine serum levels with aggression as the primary outcome would be of benefit.
Topics: Humans; Clozapine; Aggression; Psychotic Disorders; Schizophrenia; Violence; Antipsychotic Agents
PubMed: 38290941
DOI: 10.1016/j.schres.2023.11.008 -
Frontiers in Psychiatry 2021Co-occurring substance use disorders (SUDs) among individuals with schizophrenia are a prevalent and complex psychiatric comorbidity, which is associated with increased...
Co-occurring substance use disorders (SUDs) among individuals with schizophrenia are a prevalent and complex psychiatric comorbidity, which is associated with increased symptom severity, worsened illness trajectory and high rates of treatment non-adherence. Recent evidence suggests that the use of long-acting injectable (LAI) antipsychotics may provide an effective treatment option for individuals with this dual-diagnosis. A systematic review of the literature was conducted using the databases PubMed, PsychInfo and Google Scholar for English-language studies, investigating the use of LAIs in co-occurring schizophrenia and substance use disorders (SCZ-SUDs). Eight reports [one case study ( = 1), one case series ( = 8), three open-label retrospective studies ( = 75), and three randomized controlled trials ( = 273)] investigated the use of LAI antipsychotics in 357 participants with SCZ-SUDs [alcohol use disorder: 5 studies, = 282; cocaine use disorder: 5 studies, = 85; amphetamine use disorder: 1 study, = 1; cannabis use disorder: 3 studies, = 160; opioid use disorder: 3 studies, = 19; methylenedioxymethamphetamine (MDMA) use disorder: 2 studies, = 9; ketamine use disorder: 1 study, = 4] and were included in this systematic review. Findings indicate significant improvements in substance use related outcomes across 7 of 8 studies, while in 6 of 8 studies, significant improvements in psychopathology-related outcomes were reported. LAI antipsychotics may be an efficacious intervention option for the treatment of SCZ-SUDs. However, varying methodological rigor, generally small sample sizes and heterogeneity of samples, settings, substances of abuse, tested LAIs and comparators, as well as psychosocial cotreatments and level of reported detail across studies requires that these findings be considered preliminary and interpreted with caution. Further research is required to better understand the effects of LAIs among individuals with SCZ-SUDs.
PubMed: 34975600
DOI: 10.3389/fpsyt.2021.808002 -
Progress in Neuro-psychopharmacology &... Mar 2023Schizophrenia-spectrum disorders (SSD) represent one of the leading causes of disability worldwide and are usually underpinned by neurodevelopmental brain abnormalities... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Schizophrenia-spectrum disorders (SSD) represent one of the leading causes of disability worldwide and are usually underpinned by neurodevelopmental brain abnormalities observed on a structural and functional level. Nuclear medicine imaging studies of cerebral blood flow (CBF) have already provided insights into the pathophysiology of these disorders. Recent developments in non-invasive MRI techniques such as arterial spin labeling (ASL) have allowed broader examination of CBF across SSD prompting us to conduct an updated literature review of MRI-based perfusion studies. In addition, we conducted a focused meta-analysis of whole brain studies to provide a complete picture of the literature on the topic.
METHODS
A systematic OVID search was performed in Embase, MEDLINEOvid, and PsycINFO. Studies eligible for inclusion in the review involved: 1) individuals with SSD, first-episode psychosis or clinical-high risk for psychosis, or; 2) had healthy controls for comparison; 3) involved MRI-based perfusion imaging methods; and 4) reported CBF findings. No time span was specified for the database queries (last search: 08/2022). Information related to participants, MRI techniques, CBF analyses, and results were systematically extracted. Whole-brain studies were then selected for the meta-analysis procedure. The methodological quality of each included studies was assessed.
RESULTS
For the systematic review, the initial Ovid search yielded 648 publications of which 42 articles were included, representing 3480 SSD patients and controls. The most consistent finding was that negative symptoms were linked to cortical fronto-limbic hypoperfusion while positive symptoms seemed to be associated with hyperperfusion, notably in subcortical structures. The meta-analysis integrated results from 13 whole-brain studies, across 426 patients and 401 controls, and confirmed the robustness of the hypoperfusion in the left superior and middle frontal gyri and right middle occipital gyrus while hyperperfusion was found in the left putamen.
CONCLUSION
This updated review of the literature supports the implication of hemodynamic correlates in the pathophysiology of psychosis symptoms and disorders. A more systematic exploration of brain perfusion could complete the search of a multimodal biomarker of SSD.
Topics: Humans; Schizophrenia; Cerebrovascular Circulation; Magnetic Resonance Imaging; Psychotic Disorders; Spin Labels
PubMed: 36341843
DOI: 10.1016/j.pnpbp.2022.110669