Fornaro Michele, Caiazza Claudio, Billeci Martina, Berk Michael, Marx Wolfgang, Balanzá-Martinez Vicent, De Prisco Michele, Pezone Rosanna, De Simone Giuseppe, Solini Niccolò, Iasevoli Felice, Berna Fabrice, Fond Guillaume, Boyer Laurent, Carvalho Andre Fèrrer, Dragioti Elena, Fiedorowicz Jess G, de Bartolomeis Andrea, Correll Christoph U, Solmi Marco
Department of Neuroscience, Reproductive Sciences, and Dentistry, Section of Psychiatry, University School of Medicine Federico II, Naples, Italy.
Deakin University, IMPACT, the Institute for Mental and Physical Health and Clinical Translation Strategic Research Centre, School of Medicine, Geelong, VIC, Australia.
Mol Psychiatry. 2025 Jan;30(1):168-187. doi: 10.1038/s41380-024-02645-y. Epub 2024 Jul 18.
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 = 0.10, I = 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.
精神分裂症患者治疗反应欠佳的情况屡见不鲜，因此在常规治疗（TAU）基础上需要增加强化治疗策略。我们通过网状Meta分析评估了营养保健品/植物药的强化治疗策略。通过以下数据库检索了精神分裂症/分裂情感性障碍的随机对照试验：PubMed、MEDLINE、EMBASE、Scopus、PsycINFO、CENTRAL和ClinicalTrials.gov。总症状变化（标准化均数差=SMD）和可接受性（风险比=RR）为共同主要结局。次要结局包括阳性、阴性、认知和抑郁症状变化、一般精神病理学、耐受性和缓解率。我们按疾病阶段进行了亚组分析，并按偏倚风险进行了敏感性分析，评估了整体/局部不一致性、发表偏倚、偏倚风险和证据可信度。系统评价纳入了49条记录，这些记录涵盖50项研究（n=2384）、22种干预措施。胞磷胆碱（SMD=-1.05，95%CI=-1.85；-0.24）、L-赖氨酸（SMD=-1.04，95%CI=-1.84；-0.25）、N-乙酰半胱氨酸（SMD=-0.87，95%CI=-1.27；-0.47）和肌氨酸（SMD=-0.5，95%CI=-0.87 - 0.13）在改善总症状方面优于安慰剂。存在高度异质性（tau=0.10，I=55.9%）和整体不一致性（Q=40.79，df=18，p=0.002），但无发表偏倚（Egger检验，p=0.42）。肌氨酸改善了阴性症状（SMD=-0.65，95%CI=-1.10；-0.19）。N-乙酰半胱氨酸改善了阴性症状（SMD=-0.90，95%CI=-1.42；-0.39）/一般精神病理学（SMD=-0.76，95%CI=-1.39；-0.13）。在急性期研究（k=7，n=422）中，没有一种化合物能改善总症状。在临床稳定的参与者中，肌氨酸（SMD=-1.26，95%CI=-1.91；-0.60）、胞磷胆碱（SMD=-1.05
