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.

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.

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.

Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations.

Selegiline is an irreversible, selective type-B monoamine oxidase inhibitor (MAOI) approved for Parkison's disease-oral and major depressive disorder-transdermal formulation) resulting in non-selective MAOI activity at oral doses≥20 mg/day. The present systematic review and meta-analysis appraises the evidence of different formulations/dosages of selegiline across different psychiatric conditions. We inquired PubMed/MEDLINE/Cochrane-Central/WHO-ICTRP/Clarivate-WebOfScience and the Chinese-Electronic-Journal Database from inception to 10/26/2022 for selegiline trials involving psychiatric patients. Random-effects meta-analyses assessed heterogeneity, publication/risk biases, and confidence in the evidence, followed by sensitivity, subgroup, and meta-regression analyses. Co-primary outcomes were: changes in symptom score (standardized mean difference=SMD) and author-defined response (risk ratios=RRs). RRs of adverse events and all-cause discontinuation were secondary and acceptability outcomes, respectively. Systematic-review included 42 studies; meta-analysis, 23. Selegiline outperformed placebo in depressive symptom reduction (SMD=-0.96, 95%C.I.=-1.78, -0.14, k = 10, n = 1,308), depression (RR=1.61, 95%C.I.=1.20, 2.15, k = 9, n = 1,238) and atypical-depression response (RR=2.23, 95%C.I.=1.35, 3.68, k = 3, n = 136). Selegiline failed to outperform the placebo in negative (k = 4) or positive symptoms of schizophrenia (k = 4), attention-deficit-hyperactivity disorder (ADHD) symptoms reduction (k = 2), and smoking abstinence rate (k = 4). Selegiline did not differ from methylphenidate and ADHD scores (k = 2). No significant difference emerged in acceptability, incident diarrhea, headache, dizziness, and nausea RRs, in contrast to xerostomia (RR=1.58, 95%C.I. =1.03, 2.43, k = 6, n = 1,134), insomnia (RR=1.61, 95%C.I.=1.19, 2.17, k = 10, n = 1,768), and application-site reaction for transdermal formulation (RR=1.81, 95%C.I.=1.40, 2.33, k = 6, n = 1,662). Confidence in findings was low/very-low for most outcomes; moderate for depressive symptoms reduction (transdermal). Selegiline proved effective, safe, and well-tolerated for depressive disorders, yet further evidence is warranted about specific psychiatric disorders.