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Background: The introduction of natural language processing (NLP) technologies has significantly enhanced the potential of self-administered interventions for treating anxiety and depression by improving human-computer interactions. Although these advances, particularly in complex models such as generative artificial intelligence (AI), are highly promising, robust evidence validating the effectiveness of the interventions remains sparse., Objective: The aim of this study was to determine whether self-administered interventions based on NLP models can reduce depressive and anxiety symptoms., Methods: We conducted a systematic review and meta-analysis. We searched Web of Science, Scopus, MEDLINE, PsycINFO, IEEE Xplore, Embase, and Cochrane Library from inception to November 3, 2023. We included studies with participants of any age diagnosed with depression or anxiety through professional consultation or validated psychometric instruments. Interventions had to be self-administered and based on NLP models, with passive or active comparators. Outcomes measured included depressive and anxiety symptom scores. We included randomized controlled trials and quasi-experimental studies but excluded narrative, systematic, and scoping reviews. Data extraction was performed independently by pairs of authors using a predefined form. Meta-analysis was conducted using standardized mean differences (SMDs) and random effects models to account for heterogeneity., Results: In all, 21 articles were selected for review, of which 76% (16/21) were included in the meta-analysis for each outcome. Most of the studies (16/21, 76%) were recent (2020-2023), with interventions being mostly AI-based NLP models (11/21, 52%); most (19/21, 90%) delivered some form of therapy (primarily cognitive behavioral therapy: 16/19, 84%). The overall meta-analysis showed that self-administered interventions based on NLP models were significantly more effective in reducing both depressive (SMD 0.819, 95% CI 0.389-1.250; P<.001) and anxiety (SMD 0.272, 95% CI 0.116-0.428; P=.001) symptoms compared to various control conditions. Subgroup analysis indicated that AI-based NLP models were effective in reducing depressive symptoms (SMD 0.821, 95% CI 0.207-1.436; P<.001) compared to pooled control conditions. Rule-based NLP models showed effectiveness in reducing both depressive (SMD 0.854, 95% CI 0.172-1.537; P=.01) and anxiety (SMD 0.347, 95% CI 0.116-0.578; P=.003) symptoms. The meta-regression showed no significant association between participants' mean age and treatment outcomes (all P>.05). Although the findings were positive, the overall certainty of evidence was very low, mainly due to a high risk of bias, heterogeneity, and potential publication bias., Conclusions: Our findings support the effectiveness of self-administered NLP-based interventions in alleviating depressive and anxiety symptoms, highlighting their potential to increase accessibility to, and reduce costs in, mental health care. Although the results were encouraging, the certainty of evidence was low, underscoring the need for further high-quality randomized controlled trials and studies examining implementation and usability. These interventions could become valuable components of public health strategies to address mental health issues., Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42023472120; https://www.crd.york.ac.uk/prospero/display&#95;record.php?ID=CRD42023472120., (©David Villarreal-Zegarra, C Mahony Reategui-Rivera, Jackeline García-Serna, Gleni Quispe-Callo, Gabriel Lázaro-Cruz, Gianfranco Centeno-Terrazas, Ricardo Galvez-Arevalo, Stefan Escobar-Agreda, Alejandro Dominguez-Rodriguez, Joseph Finkelstein. Originally published in JMIR Mental Health (https://mental.jmir.org), 21.08.2024.)