Abstract: The update search in 2012 detected two further studies that met our inclusion criteria. We did not find any further studies that met our inclusion criteria in the 2015 search. This review now includes 22 studies, with a total of 763 participants (median mean age: 35 years, range: 26 to 72 years). Most studies were small, of short duration, and incompletely reported. As we detected a high risk of bias in many studies, the overall methodological quality of the included sample was rather low. Three small studies comparing lithium with placebo as the sole treatment showed no difference in any of the outcomes we analysed. In eight studies comparing lithium with antipsychotic drugs as the sole treatment, more participants in the lithium group left the studies early (eight RCTs; n = 270, RR 1.77, 95% CI 1.01 to 3.11, low quality evidence). Thirteen studies examined whether the augmentation of antipsychotic drugs with lithium salts is more effective than antipsychotic drugs alone. More participants who received lithium augmentation had a clinically significant response (10 RCTs; n = 396, RR 1.81, 95% CI 1.10 to 2.97, low quality evidence). However, this effect became non-significant when we excluded participants with schizoaffective disorders in a sensitivity analysis (seven RCTs; n = 272, RR 1.64, 95% CI 0.95 to 2.81), when we excluded non-double-blind studies (seven RCTs; n = 224, RR 1.82, 95% CI 0.84 to 3.96), or when we excluded studies with high attrition (nine RCTs; n = 355, RR 1.67, CI 0.93 to 3.00). The overall acceptability of treatment (measured by the number of participants leaving the studies early) was not significantly different between groups (11 RCTs; n = 320, RR 1.89, CI 0.93 to 3.84, very low quality evidence). Few studies reported on side effects. There were no significant differences, but the database is too limited to make any judgement in this regard. For example, there were no data on thyroid dysfunction and kidney problems - two major and well-known side effects of lithium. The evidence base for the use of lithium in schizophrenia is limited to 22 studies of overall low methodological quality. There is no randomised trial-based evidence that lithium on its own is an effective treatment for people with schizophrenia. There is some GRADE low quality evidence that augmentation of antipsychotics with lithium is effective, but the effects are not significant when more prone-to-bias open RCTs are excluded. Nevertheless, further large and well-designed trials are justified. These should concentrate on two target groups: (1) people with no affective symptoms, so that trialists can determine whether lithium has an effect on the core symptoms of schizophrenia, and (2) people with schizoaffective disorders for whom lithium is widely used in clinical practice, although there is no evidence to support this use.

Plain-language summary: The update search in 2012 detected two further studies that met required standards, and no further studies were found in the 2015 search. This review now includes 22 randomised studies, with a total of 763 participants. The studies randomised people with schizophrenia or similar illnesses into groups that received either lithium or placebo (dummy drug), lithium or antipsychotic drugs, lithium plus antipsychotic drugs, or antipsychotic drugs alone. The findings in this review show that there is no good quality evidence that lithium on its own is effective for people with schizophrenia or schizoaffective disorder. There is some low quality evidence for the effectiveness of lithium as an add-on treatment with antipsychotic drugs, but this result is inconclusive. Few studies reported on the side effects of lithium (such as kidney and thyroid problems). Most of the studies were small, of short duration, and poorly reported. The review authors rated the quality of evidence for the main outcomes to be low or very low quality. Further large and well-designed trials are needed. Ben Gray, Senior Peer Researcher, McPin Foundation (http://mcpin.org/), wrote this plain language summary.