Efficacy and safety of long-acting injectable versus oral antipsychotics in the treatment of patients with early-phase schizophrenia-spectrum disorders: a systematic review and meta-analysis.

Background: Long-acting injectable antipsychotics (LAIs) have advantages over oral antipsychotics (OAPs) in preventing relapse and hospitalization in chronically ill patients with schizophrenia-spectrum disorders (SSDs), but evidence in patients with first-episode/recent-onset, that is, early-phase-SSDs is less clear. Objectives: To assess the relative medium- and long-term efficacy and safety of LAIs versus OAPs in the maintenance treatment of patients with early-phase SSDs. Method: We searched major electronic databases for head-to-head randomized controlled trials (RCTs) comparing LAIs and OAPs for the maintenance treatment of patients with early-phase-SSDs. Design: Pairwise, random-effects meta-analysis. Relapse/hospitalization and acceptability (all-cause discontinuation) measured at study-endpoint were co-primary outcomes, calculating risk ratios (RRs) with their 95% confidence intervals (CIs). Subgroup analyses sought to identify factors moderating differences in efficacy or acceptability between LAIs and OAPs. Results: Across 11 head-to-head RCTs (n = 2374, median age = 25.2 years, males = 68.4%, median illness duration = 45.8 weeks) lasting 13-104 (median = 78) weeks, no significant differences emerged between LAIs and OAPs for relapse/hospitalization prevention (RR = 0.79, 95%CI = 0.58-1.06, p = 0.13) and acceptability (RR = 0.92, 95%CI = 0.80-1.05, p = 0.20). The included trials were highly heterogeneous regarding methodology and patient populations. LAIs outperformed OAPs in preventing relapse/hospitalization in studies with stable patients (RR = 0.65, 95%CI = 0.45-0.92), pragmatic design (RR = 0.67, 95%CI = 0.54-0.82), and strict intent-to-treat approach (RR = 0.64, 95%CI = 0.52-0.80). Furthermore, LAIs were associated with better acceptability in studies with schizophrenia patients only (RR = 0.87, 95%CI = 0.79-0.95), longer illness duration (RR = 0.88, 95%CI = 0.80-0.97), unstable patients (RR = 0.89, 95%CI = 0.81-0.99) and allowed OAP supplementation of LAIs (RR = 0.90, 95%CI = 0.81-0.99). Conclusion: LAIs and OAPs did not differ significantly regarding relapse prevention/hospitalization and acceptability. However, in nine subgroup analyses, LAIs were superior to OAPs in patients with EP-SSDs with indicators of higher quality and/or pragmatic design regarding relapse/hospitalization prevention (four subgroup analyses) and/or reduced all-cause discontinuation (five subgroup analyses), without any instance of OAP superiority versus LAIs. More high-quality pragmatic trials comparing LAIs with OAPs in EP-SSDs are needed. Trial registration: CRD42023407120 (PROSPERO).

OBJECTIVE: We aimed to uncover whether LAIs or regular antipsychotic pills demonstrate better outcomes over the medium and long term for individuals in the early stages of schizophrenia. METHOD: We scrutinized several studies comparing LAIs to regular pills in treating early-stage schizophrenia. Employing a combined analysis, we assessed factors such as preventing relapses and hospitalizations, as well as patient treatment adherence. DESIGN: We combined different study results in one unique analysis. We delved into whether LAIs surpassed regular pills in preventing relapses and hospitalizations and in patient treatment adherence. RESULTS: In our study of 11 trials involving over 2000 participants, we observed that LAIs and regular antipsychotic pills were generally comparable regarding preventing relapses, hospitalizations, and treatment adherence. However, on closer inspection, LAIs appeared slightly more effective for specific groups in the early stages of schizophrenia. CONCLUSION: While LAIs and regular antipsychotic pills showed similar results for most individuals in the early stages of schizophrenia, our findings hint at the possibility that LAIs might have a slight edge for certain groups. Nevertheless, we emphasize the need for more high-quality studies to gain a clearer understanding. REGISTRATION: This study is registered under CRD42023407120 (PROSPERO).

Comparing long-acting injections and pills for early schizophrenia: a study review and combined analysis Background: We explored whether antipsychotics long-acting injections (LAIs) might outperform regular antipsychotics pills for people dealing with early-stage conditions like schizophrenia. While LAIs have clear benefits for those with long-term challenges, their effectiveness for those just starting to grapple with these issues is less certain.

Sleep-wake variations of electrodermal activity in bipolar disorder.

BACKGROUND: Affective states influence the sympathetic nervous system, inducing variations in electrodermal activity (EDA), however, EDA association with bipolar disorder (BD) remains uncertain in real-world settings due to confounders like physical activity and temperature. We analysed EDA separately during sleep and wakefulness due to varying confounders and potential differences in mood state discrimination capacities. METHODS: We monitored EDA from 102 participants with BD including 35 manic, 29 depressive, 38 euthymic patients, and 38 healthy controls (HC), for 48 h. Fifteen EDA features were inferred by mixed-effect models for repeated measures considering sleep state, group and covariates. RESULTS: Thirteen EDA feature models were significantly influenced by sleep state, notably including phasic peaks (p < 0.001). During wakefulness, phasic peaks showed different values for mania (M [SD] = 6.49 [5.74, 7.23]), euthymia (5.89 [4.83, 6.94]), HC (3.04 [1.65, 4.42]), and depression (3.00 [2.07, 3.92]). Four phasic features during wakefulness better discriminated between HC and mania or euthymia, and between depression and euthymia or mania, compared to sleep. Mixed symptoms, average skin temperature, and anticholinergic medication affected the models, while sex and age did not. CONCLUSION: EDA measured from awake recordings better distinguished between BD states than sleep recordings, when controlled by confounders.

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, NOx: 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.

Pharmacological treatments for psychotic depression: a systematic review and network meta-analysis.

BACKGROUND: There are no recommendations based on the efficacy of specific drugs for the treatment of psychotic depression. To address this evidence gap, we did a network meta-analysis to assess and compare the efficacy and safety of pharmacological treatments for psychotic depression. METHODS: In this systematic review and network meta-analysis, we searched ClinicalTrials.gov, CENTRAL, Embase, PsycINFO, PubMed, Scopus, and Web of Science from inception to Nov 23, 2023 for randomised controlled trials published in any language that assessed pharmacological treatments for individuals of any age with a diagnosis of a major depressive episode with psychotic features, in the context of major depressive disorder or bipolar disorder in any setting. We excluded continuation or maintenance trials. We screened the study titles and abstracts identified, and we extracted data from relevant studies after full-text review. If full data were not available, we requested data from study authors twice. We analysed treatments for individual drugs (or drug combinations) and by grouping them on the basis of mechanisms of action. The primary outcomes were response rate (ie, the proportion of participants who responded to treatment) and acceptability (ie, the proportion who discontinued treatment for any reason). We calculated risk ratios and did separate frequentist network meta-analyses by using random-effects models. The risk of bias of individual studies was assessed with the Cochrane risk-of-bias tool and the confidence in the evidence with the Confidence-In-Network-Meta-Analysis (CINeMA). This study was registered with PROSPERO, CRD42023392926. FINDINGS: Of 6313 reports identified, 16 randomised controlled trials were included in the systematic review, and 14 were included in the network meta-analyses. The 16 trials included 1161 people with psychotic depression (mean age 50·5 years [SD 11·4]). 516 (44·4%) participants were female and 422 (36·3%) were male; sex data were not available for the other 223 (19·2%). 489 (42·1%) participants were White, 47 (4·0%) were African American, and 12 (1·0%) were Asian; race or ethnicity data were not available for the other 613 (52·8%). Only the combination of fluoxetine plus olanzapine was associated with a higher proportion of participants with a treatment response compared with placebo (risk ratio 1·91 [95% CI 1·27-2·85]), with no differences in terms of safety outcomes compared with placebo. When treatments were grouped by mechanism of action, the combination of a selective serotonin reuptake inhibitor with a second-generation antipsychotic was associated with a higher proportion of treatment responses than was placebo (1·89 [1·17-3·04]), with no differences in terms of safety outcomes. In head-to-head comparisons of active treatments, a significantly higher proportion of participants had a response to amitriptyline plus perphenazine (3·61 [1·23-10·56]) and amoxapine (3·14 [1·01-9·80]) than to perphenazine, and to fluoxetine plus olanzapine compared with olanzapine alone (1·60 [1·09-2·34]). Venlafaxine, venlafaxine plus quetiapine (2·25 [1·09-4·63]), and imipramine (1·95 [1·01-3·79]) were also associated with a higher proportion of treatment responses overall. In head-to-head comparisons grouped by mechanism of action, antipsychotic plus antidepressant combinations consistently outperformed monotherapies from either drug class in terms of the proportion of participants with treatment responses. Heterogeneity was low. No high-risk instances were identified in the bias assessment for our primary outcomes. INTERPRETATION: According to the available evidence, the combination of a selective serotonin reuptake inhibitor and a second-generation antipsychotic-and particularly of fluoxetine and olanzapine-could be the optimal treatment choice for psychotic depression. These findings should be taken into account in the development of clinical practice guidelines. However, these conclusions should be interpreted cautiously in view of the low number of included studies and the limitations of these studies. FUNDING: None.

Regional differences in mortality risk and in attenuating or aggravating factors in schizophrenia: A systematic review and meta-analysis.

People with schizophrenia die prematurely, yet regional differences are unclear. PRISMA 2020-compliant systematic review/random-effects meta-analysis of cohort studies assessing mortality relative risk (RR) versus any control group, and moderators, in people with ICD/DSM-defined schizophrenia, comparing countries and continents. We conducted subgroup, meta-regression analyses, and quality assessment. The primary outcome was all-cause mortality. Secondary outcomes were suicide-, /natural-cause- and other-cause-related mortality. We included 135 studies from Europe (n = 70), North-America (n = 29), Asia (n = 33), Oceania (n = 2), Africa (n = 1). In incident plus prevalent schizophrenia, differences across continents emerged for all-cause mortality (highest in Africa, RR=5.98, 95 %C.I.=4.09-8.74, k = 1, lowest in North-America, RR=2.14, 95 %C.I.=1.92-2.38, k = 16), suicide (highest in Oceania, RR=13.5, 95 %C.I.=10.08-18.07, k = 1, lowest in North-America, RR=4.4, 95 %C.I.=4.07-4.76, k = 6), but not for natural-cause mortality. Europe had the largest association between antipsychotics and lower all-cause mortality/suicide (Asia had the smallest or no significant association, respectively), without differences for natural-cause mortality. Higher country socio-demographic index significantly moderated larger suicide-related and smaller natural-cause-related mortality risk in incident schizophrenia, with reversed associations in prevalent schizophrenia. Antipsychotics had a larger/smaller protective association in incident/prevalent schizophrenia regarding all-cause mortality, and smaller protective association for suicide-related mortality in prevalent schizophrenia. Additional regional differences emerged in incident schizophrenia, across countries, and secondary outcomes. Significant regional differences emerged for all-cause, cause-specific and suicide-related mortality. Natural-cause death was homogeneously increased globally. Moderators differed across countries. Global initiatives are needed to improve physical health in people with schizophrenia, local studies to identify actionable moderators.

Residual effects of medications for sleep disorders on driving performance: A systematic review and network meta-analysis of randomized controlled trials: NMA driving and hypnotics.

Sleep medications often carry residual effects potentially affecting driving safety, warranting network meta-analysis (NMA). PubMed/EMBASE/TRID/Clinicaltrials.gov/WHO-ICTRP/WebOfScience were inquired for randomized controlled trials of hypnotic driving studies in persons with insomnia and healthy subjects up to 05/28/2023, considering the vehicle's standard deviation of lateral position - SDLP (Standardized Mean Difference/SMD) and driving impairment rates on the first morning (co-primary outcomes) and endpoint. Risk-of-bias, global/local inconsistencies were measured, and CINeMA was used to assess the confidence in the evidence. Of 4,805 identified records, 26 cross-over RCTs were included in the systematic review, of which 22 entered the NMA, focusing on healthy subjects only. After a single administration, most molecules paralleled the placebo, outperforming zopiclone regarding SDLP. In contrast, ramelteon 8 mg, daridorexant 100 mg, zolpidem 10 mg bedtime, zolpidem middle-of-the-night 10 mg and 20 mg, mirtazapine 15-30 mg, and triazolam 0.5 mg performed significantly worse than placebo. Lemborexant 2.5-5 mg, suvorexant 15-20 mg, and zolpidem 3.5 mg middle-of-the-night associated with lower impairment than zopiclone. Repeated administration (maximum follow-up time of ten days) caused fewer residual effects than acute ones, except for flurazepam. Heterogeneity and inconsistency were negligible. Confidence in the evidence was low/very low. Sensitivity analyses confirmed the main analyses. Most FDA-approved hypnotics overlapped placebo at in-label doses, outperforming zopiclone. Repeated administration for 15 days or less reduced residual effects, warranting further research on the matter.

Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis.

Background: Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). Methods: We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference=SMD) in total symptomatology and acceptability (Risk Ratio=RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. Results: The systematic review included 49 records documenting 50 studies (n=2,384) documenting 22 interventions. Citicoline (SMD=-1.05,95%CI=-1.85; -.24), L-lysine (SMD=-1.04,95%CI=-1.84;-.25), N-acetylcysteine (SMD=-.87,95%CI=-1.27;-.47) and sarcosine (SMD=-.5,95%CI=-.87-.13) outperformed placebo for total symptomatology. High heterogeneity (tau2=.10, I2=55.9%) and global inconsistency (Q=40.79, df=18, p=.002) emerged without publication bias (Egger's test, p=.42). Sarcosine improved negative symptoms (SMD=-.65, 95%CI=-1.10; -.19). N-acetylcysteine improved negative symptoms (SMD=-.90, 95%CI=-1.42; -.39)/general psychopathology (SMD=-.76, 95%CI=-1.39; -.13). No compound improved total symptomatology within acute phase studies (k=7, n=422). Sarcosine (SMD=-1.26,95%CI=-1.91; -.60), citicoline (SMD=-1.05,95%CI=-1.65;-.44), and N-acetylcysteine (SMD=-.55,95%CI=-.92,-.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effect vs. placebo for N-acetylcysteine (SMD=-1.10,95%CI=-1.75,-.45), L-lysine (SMD=-1.05,95%CI=-1.55,-.19), omega-3 fatty acids (SMD=-.83,95%CI=-1.31,-.34) and withania somnifera (SMD=-.71,95%CI=-1.21,-.22). Citicoline (SMD=-1.05,95%CI=-1.86,-.23), L-lysine (SMD=-1.04,95%CI=-1.84,-.24), N-acetylcysteine (SMD=-.89,95%CI=-1.35,-.43) and sarcosine (SMD=-.61,95%CI=-1.02,-.21) outperformed placebo augmentation of TAU ("any phase"). Drop-out due to any cause or adverse events did not differ between nutraceutical/phytoceutical vs. placebo+TAU. Conclusions: Sarcosine, citicoline, and N-acetylcysteine are promising augmentation interventions in stable patients with schizophrenia, yet the quality of evidence is low to very low. Further high-quality trials in acute phases/specific outcomes/difficult-to-treat schizophrenia are warranted.

Exploring Clinical Subgroups of Participants with Major Depressive Disorder that may Benefit from Adjunctive Minocycline Treatment.

Objective: : To explore illness-related factors in patients with major depressive disorder (MDD) recipients of adjunctive minocycline (200 mg/day) treatment. The analysis included participants experiencing MDD from a 12-week, double blind, placebo-controlled, randomized clinical trial (RCT). Methods: : This is a sub-analysis of a RCT of all 71 participants who took part in the trial. The impact of illness chronicity (illness duration and number of depressive episodes), systemic illness (endocrine, cardiovascular and obesity), adverse effects and minocycline were evaluated as change from baseline to endpoint (12-week) using ANCOVA. Results: : There was a consistent but statistically non-significant trend on all outcomes in favour of the use of adjunctive minocycline for participants without systemic illness, less illness chronicity, and fewer adverse effects. Conclusion: : Understanding the relationship between MDD and illness chronicity, comorbid systemic illness, and adverse effects, can potentially better characterise those individuals who are more likely to respond to adjunctive anti-inflammatory medications.

Clinical features in co-occuring obsessive-compulsive disorder and bipolar disorder: A systematic review and meta-analysis.

Obsessive-compulsive disorder (OCD) frequently co-occurs with various psychiatric conditions and may impact as many as one-fifth of individuals diagnosed with bipolar disorder (BD). Despite the expanding body of literature on the coexistence of OCD and BD, there is a notable lack of comprehensive data pertaining to the distinct features of obsessive-compulsive symptoms that define this comorbidity. To bridge this knowledge gap, we conducted a systematic search of PubMed/MEDLINE, Scopus, EMBASE, and PsycINFO until August 7th, 2023. We performed random-effects meta-analyses to compare individuals with both OCD and BD to those with OCD in terms of OCD symptomatology as well as the specific categories of obsessions and compulsions. Out of the 10,393 records initially screened, 17 studies were ultimately incorporated into the qualitative assessment, with 15 of them being included in the quantitative analysis. Individuals with OCD and BD experienced fewer lifetime contamination obsessions (OR=0.71; 95 %CI=0.53, 0.95; p = 0.021) and more sexual obsessions (OR=1.77; 95 %CI=1.03, 3.04; p = 0.04) compared to individuals with OCD without BD. No significant difference was observed for other types of obsessions or compulsions or for the severity of OCD symptoms, although BD type may play a role according to meta-regression analyses. The detection of the presence of sexual or contamination obsessions through a detailed interview may be the focus of clinical attention when assessing OCD in the context of comorbid BD. Sub-phenotyping complex clinical presentation of comorbid psychiatric disorders can aid in making more informed decisions when choosing an appropriate treatment approach.

The Mixed Tendency in Bipolar Disorder: An Operational Proposal for the Integration of Mixed Episodes in Predominant Polarity.

Predominant Polarity (PP) is an established specifier of Bipolar Disorder (BD), holding significant clinical implications. Nevertheless, there exists no consensus on how to incorporate mixed states into PP, leaving patients prone to mixed recurrences that are unclassified. In a comprehensive study involving 701 euthymic BD patients, we sought to redefine PP by introducing a novel metric, the "mixed tendency", and establish a practical threshold to identify patients with a "mixed phenotype". Furthermore, we investigated potential associations between the mixed phenotype and specific PP categories. Our findings revealed that the mixed tendency correlated significantly with early BD type I, lifetime suicide attempts, self-aggressive behaviour, and lifetime number of affective episodes (>5). Using a ROC curve analysis, we determined an optimal cut-off point for the mixed tendency at 0.228, suggesting that patients with ~25% of lifetime mixed episodes relative to total affective episodes should be identified as having a mixed phenotype. Notably, the mixed phenotype was positively associated with undetermined PP and negatively with manic and depressive PP. This study introduces a promising approach to incorporating mixed episodes into the PP definition, potentially enabling tailored interventions for patients with a substantial history of mixed episodes. However, further research in large, longitudinal cohorts is essential to validate these findings.

An umbrella review of candidate predictors of response, remission, recovery, and relapse across mental disorders.

We aimed to identify diagnosis-specific/transdiagnostic/transoutcome multivariable candidate predictors (MCPs) of key outcomes in mental disorders. We conducted an umbrella review (protocol  link ), searching MEDLINE/Embase (19/07/2022), including systematic reviews of studies reporting on MCPs of response, remission, recovery, or relapse, in DSM/ICD-defined mental disorders. From published predictors, we filtered MCPs, validating MCP criteria. AMSTAR2/PROBAST measured quality/risk of bias of systematic reviews/individual studies. We included 117 systematic reviews, 403 studies, 299,888 individuals with mental disorders, testing 796 prediction models. Only 4.3%/1.2% of the systematic reviews/individual studies were at low risk of bias. The most frequently targeted outcome was remission (36.9%), the least frequent was recovery (2.5%). Studies mainly focused on depressive (39.4%), substance-use (17.9%), and schizophrenia-spectrum (11.9%) disorders. We identified numerous MCPs within disorders for response, remission and relapse, but none for recovery. Transdiagnostic MCPs of remission included lower disease-specific symptoms (disorders = 5), female sex/higher education (disorders = 3), and quality of life/functioning (disorders = 2). Transdiagnostic MCPs of relapse included higher disease-specific symptoms (disorders = 5), higher depressive symptoms (disorders = 3), and younger age/higher anxiety symptoms/global illness severity/ number of previous episodes/negative life events (disorders = 2). Finally, positive trans-outcome MCPs for depression included less negative life events/depressive symptoms (response, remission, less relapse), female sex (response, remission) and better functioning (response, less relapse); for schizophrenia, less positive symptoms/higher depressive symptoms (remission, less relapse); for substance use disorder, marital status/higher education (remission, less relapse). Male sex, younger age, more clinical symptoms and comorbid mental/physical symptoms/disorders were poor prognostic factors, while positive factors included social contacts and employment, absent negative life events, higher education, early access/intervention, lower disease-specific and comorbid mental and physical symptoms/conditions, across mental disorders. Current data limitations include high risk of bias of studies and extraction of single predictors from multivariable models. Identified MCPs can inform future development, validation or refinement of prediction models of key outcomes in mental disorders.

Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials.

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

Emotion dysregulation in bipolar disorder compared to other mental illnesses: a systematic review and meta-analysis.

People with bipolar disorder (BD) often present emotion dysregulation (ED), a pattern of emotional expression interfering with goal-directed behavior. ED is a transdiagnostic construct, and it is unclear whether it manifests itself similarly in other conditions, such as major depressive disorder (MDD) or borderline personality disorder (BPD), or has specific features in BD. The present systematic review and meta-analysis explored ED and adopted emotion regulation (ER) strategies in BD compared with other psychiatric conditions. PubMed/MEDLINE, EMBASE, Scopus, and PsycINFO databases were systematically searched from inception to April 28th, 2022. Studies implementing validated instruments assessing ED or ER strategies in BD and other psychiatric disorders were reviewed, and meta-analyses were conducted. Twenty-nine studies yielding multiple comparisons were included. BD was compared to MDD in 20 studies (n = 2451), to BPD in six studies (n = 1001), to attention deficit hyperactivity disorder in three studies (n = 232), to anxiety disorders in two studies (n = 320), to schizophrenia in one study (n = 223), and to post-traumatic stress disorder in one study (n = 31). BD patients did not differ from MDD patients in adopting most adaptive and maladaptive ER strategies. However, small-to-moderate differences in positive rumination and risk-taking behaviors were observed. In contrast, patients with BPD presented an overall higher degree of ED and more maladaptive ER strategies. There were insufficient data for a meta-analytic comparison with other psychiatric disorders. The present report further supports the idea that ED is a transdiagnostic construct spanning a continuum across different psychiatric disorders, outlining specific clinical features that could represent potential therapeutic targets.

Correlation between emotion dysregulation and mood symptoms of bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Emotion dysregulation (ED) is a transdiagnostic construct characterized by difficulties regulating intense emotions. People with bipolar disorder (BD) are more likely to show ED and use maladaptive emotion regulation strategies than adaptive ones. However, little is known about whether ED in BD is a trait or it is rather an epiphenomenon of mood symptoms. METHODS: We conducted a systematic review and meta-analysis of the evidence across major literature databases reporting correlations between measures of emotion regulation (overall ED and different emotion regulation strategies) and measures of depressive and (hypo)manic symptoms in BD from inception until April 12th, 2022. RESULTS: Fourteen studies involving 1371 individuals with BD were included in the qualitative synthesis, of which 11 reported quantitative information and were included in the meta-analysis. ED and maladaptive strategies were significantly higher during periods with more severe mood symptoms, especially depressive ones, while adaptive strategies were lower. CONCLUSION: ED significantly correlates with BD symptomatology, and it mainly occurs during mood alterations. ED may be a target for specific psychotherapeutic and pharmacological treatments, according to precision psychiatry. However, further studies are needed, including patients with mood episodes and longitudinal design, to provide more robust evidence and explore the causal direction of the associations.

Differences in facial emotion recognition between bipolar disorder and other clinical populations: A systematic review and meta-analysis.

Facial emotion (or expression) recognition (FER) is a domain of affective cognition impaired across various psychiatric conditions, including bipolar disorder (BD). We conducted a systematic review and meta-analysis searching for eligible articles published from inception to April 26, 2023, in PubMed/MEDLINE, Scopus, EMBASE, and PsycINFO to examine whether and to what extent FER would differ between people with BD and those with other mental disorders. Thirty-three studies comparing 1506 BD patients with 1973 clinical controls were included in the present systematic review, and twenty-six of them were analyzed in random-effects meta-analyses exploring the discrepancies in discriminating or identifying emotional stimuli at a general and specific level. Individuals with BD were more accurate in identifying each type of emotion during a FER task compared to individuals diagnosed with schizophrenia (SCZ) (SMD = 0.27; p-value = 0.006), with specific differences in the perception of anger (SMD = 0.46; p-value = 1.19e-06), fear (SMD = 0.38; p-value = 8.2e-04), and sadness (SMD = 0.33; p-value = 0.026). In contrast, BD patients were less accurate than individuals with major depressive disorder (MDD) in identifying each type of emotion (SMD = -0.24; p-value = 0.014), but these differences were more specific for sad emotional stimuli (SMD = -0.31; p-value = 0.009). No significant differences were observed when BD was compared with children and adolescents diagnosed with attention-deficit/hyperactivity disorder. FER emerges as a potential integrative instrument for guiding diagnosis by enabling discrimination between BD and SCZ or MDD. Enhancing the standardization of adopted tasks could further enhance the accuracy of this tool, leveraging FER potential as a therapeutic target.

The efficacy, safety, and adverse events of azapirones in anxiety disorders: A systematic review and meta-analysis of randomized controlled trials.

Azapirones have been proposed as anxiety and mood modulators. We assessed azapirones' viability in anxiety disorders via systematic review and random-effects meta-analysis, inquiring PubMed/MEDLINE/CENTRAL/WHO-ICTRP/WebOfScience/VIP up-to 05/01/2023. We conducted sensitivity, and subgroup analyses assessing heterogeneity, publication bias, risk of bias, and confidence in the evidence within the GRADE framework. Symptom reduction (mean difference/MD), study-defined response (risk ratios/RRs), and acceptability were co-primary outcomes. Adverse events and withdrawal were secondary. Seventy studies were included. In generalized anxiety disorder (GAD), azapirones largely outperformed placebo (MD=-4.91, 95%C.I.[-5.91, -3.90], Hedges'g -1.37 [-1.02, -0.73]), k = 22, n = 2,567; RR=1.64, 95%C.I.[1.45, 1.86], k = 9, n = 1,346). While azapirones overlapped benzodiazepines in symptom reduction (MD=-0.12, 95%C.I.[-0.70, 0.45], k = 34, n = 3,160), they were slightly outperformed in response rate (RR=0.94, 95%C.I.[0.90, 0.99], k = 18, n = 2,423). Azapirones overlapped SRIs (MD=0.09, 95%C.I.[-0.49, 0.67], k = 8, n = 747; RR=0.97, 95%C.I.[0.89, 1.07], k = 7, n = 737). Confidence in estimates was high/moderate vs. placebo, moderate/low vs. benzodiazepine, very-low vs. SRIs. Azapirones failed to outperform the placebo in panic and social anxiety disorders. Azapirones overlapped placebo and SRIs in drop-out rates, while they showed higher treatment discontinuation rates than benzodiazepines (RR=1.33, 95%C.I.[1.16, 1.53], k = 23, n = 2,768). Azapirones caused less sedation/fatigue/drowsiness/weakness/cognitive issues than benzodiazepines, resembling placebo. They caused more nausea and dizziness than placebo, more headache and nausea than benzodiazepines, and less nausea and xerostomia than SRIs. Azapirones proved effective and relatively well-tolerated for GAD. They should be preferred over benzodiazepines, especially in the long-term, considering their lower sedation and addiction potential, representing a potential SRI alternative. Further research is warranted to prove efficacy in panic and social anxiety.