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Background: The possibility of atypical antipsychotics (AA) to induce manic symptoms has been raised by several articles. The objective of this study was to describe whether exposure to AA may induce mania in mood disorders., Methods: We performed a systematic review following the preferred reporting items for systematic reviews and meta-analysis guidelines. The systematic search encompassed all relevant studies published until April 4th, 2022. A meta-analysis testing whether treatment emergent mania (TEM) is more frequent with the use of AA compared with placebo was performed., Results: A total of 52 studies were included in the systematic review. We found 24 case reports or case series describing 40 manic/hypomanic episodes allegedly induced by AA. Twenty-one placebo-controlled trials were included in a meta-analysis including 4823 individuals treated with AA and 3252 individuals receiving placebo. Our meta-analysis showed that the use of AA protects against the development of TEM (OR: 0.68 [95 % CI: 0.52-0.89], p = 0.005)., Limitations: AA-induced mania/hypomania was not the primary outcome in any of the observational or interventional studies. TEM was not homogeneously defined across studies. In most case reports it was not possible to establish causality between the use of AA and the development of manic symptoms., Conclusions: TEM is more frequent with placebo than with AA, which suggests that AA exposure does not represent a relevant risk for TEM. Mania/hypomania induced by an AA seems to be rare events, since anecdotal evidence from case reports and case series were not observed in observational prospective and interventional studies., Competing Interests: Conflict of interest Dr. Kapczinski reports personal fees from Janssen - Johnson & Johnson, as well as grants from the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (#20/2551-0000250-0), the Canada Foundation for Innovation, the Social Sciences and Humanities Research Council of Canada, the Canadian Institutes of Health Research, and the Natural Sciences and Engineering Research Council of Canada, outside the submitted work. All other co-authors state no conflicts of interest. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors., (Copyright © 2023 Elsevier B.V. All rights reserved.)