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Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). 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. The systematic review included 49 records documenting 50 studies (n = 2384) documenting 22 interventions. Citicoline (SMD =-1.05,95%CI = -1.85; -0.24), L-lysine (SMD = -1.04,95%CI = -1.84; -0.25), N-acetylcysteine (SMD = -0.87, 95%CI = -1.27; -0.47) and sarcosine (SMD = -0.5,95%CI = -0.87-0.13) outperformed placebo for total symptomatology. High heterogeneity (tau 2  = 0.10, I 2  = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger's test, p = 0.42). Sarcosine improved negative symptoms (SMD = -0.65, 95%CI = -1.10; -0.19). N-acetylcysteine improved negative symptoms (SMD = -0.90, 95%CI = -1.42; -0.39)/general psychopathology (SMD = -0.76, 95%CI = -1.39; -0.13). No compound improved total symptomatology within acute phase studies (k = 7, n = 422). Sarcosine (SMD = -1.26,95%CI = -1.91; -0.60), citicoline (SMD = -1.05,95%CI = -1.65;-0.44), and N-acetylcysteine (SMD = -0.55,95%CI = -0.92,-0.19) 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,-0.45), L-lysine (SMD = -1.05,95%CI = -1.55, -0.19), omega-3 fatty acids (SMD = -0.83,95%CI = -1.31, -0.34) and withania somnifera (SMD = -0.71,95%CI = -1.21,-0.22). Citicoline (SMD = -1.05,95%CI = -1.86,-0.23), L-lysine (SMD = -1.04,95%CI = -1.84,-0.24), N-acetylcysteine (SMD = -0.89,95%CI = -1.35,-0.43) and sarcosine (SMD = -0.61,95%CI = -1.02,-0.21) 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. 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., Competing Interests: Competing interests: MF received honoraria for his speaker activity from the American Society of Clinical Psychopharmacology (ASCP) and served as a consultant for Angelini, Otsuka, Lundbeck, Sanofi-Aventis, and Boehringer Ingelheim. WM has previously received university grants/fellowships from La Trobe University, Deakin University, University of Queensland, and Bond University. WM has received funding and/or has attended events funded by Cobram Estate Pty. Ltd and Bega Dairy and Drinks Pty Ltd. WM has received travel funding from the Nutrition Society of Australia. WM has received consultancy funding from Nutrition Research Australia and ParachuteBH. MS has received honoraria/has been a consultant for AbbVie, Angelini, Lundbeck, and Otsuka. VBM received honoraria from Angelini, unrelated to the present work. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Car dio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. All other authors declare no conflicts of interest relevant to this work., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Tardive Dyskinesia (TD) can occur in people exposed to dopamine receptor antagonists (DRAs). Its clinical management remains challenging. We conducted a systematic review/random-effects network meta-analysis (NMA) searching PubMed/MEDLINE/PsycINFO/ClinicalTrials.gov/Cochrane Central Register (22/05/2023, pre-defined protocol https://osf.io/b52ae/ ), for randomized controlled trials (RCTs) of pharmacological/brain stimulation interventions for DRA-induced TD in adults with schizophrenia or mood disorders. Primary outcomes were TD symptom change (standardized mean difference/SMD) and all-cause discontinuation (acceptability-risk ratio/RR). Sensitivity analyses were conducted. Global, local inconsistencies, risk of bias (RoB-2 tool), and confidence in evidence (CINeMA) were measured. We included 46 trials (n = 2844, age = 52.89 ± 9.94 years, males = 59.8%, schizophrenia = 84.6%, mood disorders = 15.4%), all testing pharmacological interventions versus placebo. We identified three subnetworks. In network 1, several treatments outperformed placebo on TD symptoms with large effect sizes (k = 34, n = 2269), encompassing 22 interventions versus placebo, but 18 had 1 RCTs only, and 15 had n ≤ 20. High heterogeneity (I 2  = 57.1%; tau 2  = 0.0797), and global inconsistency (Q = 32.64; df = 14; p = 0.0032) emerged. No significant differences emerged in acceptability. When restricting analyses to treatments with trials with n > 20 and >1 RCT, only valbenazine (k = 5, SMD = -0.69; 95% CI = -1.00, -0.37) and vitamin E (k = 7, SMD = -0.49; 95% CI = -0.87, -0.11) were superior to placebo. Deutetrabenazine outperformed placebo considering AIMS score and in low risk of bias trials only and with a moderate effect size for 24/36 mg (k = 2, SMD = -0.57/-0.60). Confidence in findings was low for deutetrabenazine and valbenazine, very low for all others. In network 2 (k = 2, n = 63), switch to molindone (k = 1, n = 9) versus switch to haloperidol worsened TD (SMD = 1.68; 95% CI = 0.61,2.76). In network 3 (k = 3, n = 194), antipsychotic wash-out+placebo (k = 1, n = 25) versus TAU+placebo (k = 1, n = 27) worsened TD (SMD = 1.30; 95% CI = 0.36,2.23). Despite large effect sizes for some treatments with very low quality/confidence, when considering higher quality evidence only valbenazine or deutetrabenazine are evidence-based first-line treatments for TD, and potentially vitamin E as second-line. Switching to molindone and antipsychotic washout should be avoided. More treatment options and higher-quality trials are needed., Competing Interests: Competing interests: MS received honoraria/has been a consultant for AbbVie, Angelni, Lundbeck, Otsuka. MF received honoraria from the American Society of Clinical Psychopharmacology (ASCP) for his speaker activities, and from Angelini, Lundbeck, Bristol Meyer Squibb, and Boehringer-Ingelheim. AdB has received research support from Janssen, Lundbeck, and Otsuka and lecture fees for educational meetings from Chiesi, Lundbeck, Roche, Sunovion, Viatris, Recordati, Angelini, and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Viatris. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. AC is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP-2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration and by the NIHR Oxford Health Biomedical Research Centre (grant NIHR203316). The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. The other authors have none to disclose in conjunction with the present work., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

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., Competing Interests: Declaration of Competing Interest TK has received speaker's honoraria from Sumitomo, Eisai, Janssen, Otsuka, Meiji, MSD, Viatris, and Takeda and research grants from Eisai, the Japanese Ministry of Health, Labour and Welfare (21GC1018), Grant-in-Aid for Scientific Research (C) (19K08082), and Japan Agency for Medical Research and Development (JP22dk0307107 and JP22wm0525024). MS has received honoraria/has been a consultant for Angelini, Lundbeck, and Otsuka. MF served as a rater for Massachusetts General Hospital Clinical Trials Network and Institute, Boston, MA, USA, and its subsidiaries for the following entities. MF also received honoraria from the American Society of Clinical Psychopharmacology (ASCP) for his speaker activities, and from Angelini, Lundbeck, Bristol Meyer Squibb, and Boehringer-Ingelheim. AdB has received research support from Janssen, Lundbeck, and Otsuka and lecture fees for educational meeting from Chiesi, Lundbeck, Roche, Sunovion, Vitria, Recordati, Angelini and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Vitria. All other authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

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., Competing Interests: Conflict of interest SS has served as a consultant to Acadia, AbbVie/Allergan, Alkermes, Altus, Cerevel, Clearview, Clexio, Done, Enveric Biosciences, Faber Kramer, Gedeon Richter, Genetica, Intra-Cellular Therapies, Janssen, Karuna Therapeutics, Libbs, Lipidio, Longboard, Lundbeck, Merck, Neurocrine Biosciences, Neurawell, Otsuka, Recordati, Relmada Therapeutics, Sage Therapeutics, Saniona, Sunovion, Supernus, Teva, Tonix, and Tris Pharma; he holds options in Genomind, Lipidio, Neurawell and Delix; he has served on speakers bureaus for Abbvie/Allergan, Acadia, Lundbeck, Neurocrine, Otsuka, Servier, Sunovion, and Teva; he has received research and/or grant support from Acadia, Allergan/AbbVie, Avanir, Boehringer Ingelheim Braeburn Pharmaceuticals, Daiichi Sankyo- Brazil Eisai, Eli Lilly, Harmony Biosciences, Indivior, Intra-Cellular Therapies, Ironshore, Neurocrine, Otsuka, Pear Therapeutics, Sage, Shire Sunovion, Supernus, and Torrent. VVdE receives or has received consulting fees from: PsychoTropical Research, NeuraWell Therapeutics, and Aristo Pharma GmbH; he has stock options in NeuraWell Therapeutics. HGR receives or has received: grants from ZonMW (#016.126.059 and #10140021910006), the Hersenstichting (HA2015.01.07), and the Dutch Ministry of Health; and speaking fees from Lundbeck NV and Janssen BV; he is a member of the Scientific Advisory Board of hersenonderzoek.nl; he is a member of the Executive Board of the International Society for Affective Disorders. TKB is a member of the Dutch guideline committee on the use of ECT, and the Dutch guideline committee on pharmacogenetics. KG has equity interests in, and is on the advisory board of NeuraWell Therapeutics. AdB has received research support from Janssen, Lundbeck, and Otsuka and lecture fees for educational meeting from Chiesi, Lundbeck, Roche, Sunovion, Vitria, Recordati, Angelini and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Vitria. MF served as a rater for Massachusetts General Hospital Clinical Trials Network and Institute, Boston, MA, USA, and its subsidiaries for the following entities: i) Biohaven Pharmaceuticals, Inc. (“Sponsor”) to provide services for Sponsor trial entitled “A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Troriluzole in Obsessive Compulsive Disorder,” protocol BHV4157–302; and “A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Troriluzole in Obsessive Compulsive Disorder,” protocol BHV4157–303 (“Study”), ii) ACADIA Pharmaceuticals Inc. (“Sponsor”) to provide services for Sponsor protocol ACP-103–064 entitled “A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the Negative Symptoms of Schizophrenia (ADVANCE-2)” (“Study”). MF also received honoraria from the American Society of Clinical Psychopharmacology (ASCP). All other authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)