Review question
To examine whether the drug lithium alone is an effective treatment for schizophrenia and schizophrenia-like illnesses. To look at whether lithium is an effective treatment when added on as an extra treatment with antipsychotic drugs.
Background
People with schizophrenia often have two main types of symptoms with their illness, the acute symptoms of hearing voices or seeing things (hallucinations) and strange beliefs (delusions). Examples of chronic symptoms are low mood/depression, social withdrawal, and memory problems. The main treatment for schizophrenia is antipsychotic drugs. However, many people with schizophrenia do not respond fully to these drugs, and certain symptoms of the illness can remain when only an antipsychotic is given. In these cases, various add-on medications are used, among them lithium. Lithium stabilises a person's mood and is used as an add-on treatment with antipsychotics for schizophrenia. Lithium can reduce mania and depression.
Study characteristics
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.
Key results
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).
Quality of the evidence
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.
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.
Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary anti-psychotic drug treatment. In these cases, various add-on medications are used, among them lithium.
To assess whether:
1. Lithium alone is an effective treatment for schizophrenia, schizophrenia-like psychoses and schizoaffective psychoses; and
2. Lithium augmentation of antipsychotic medication is an effective treatment for the same illnesses.
In July 2012, we searched the Cochrane Schizophrenia Group’s Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. This search was updated on January 20, 2015. For the first version of the review, we also contacted pharmaceutical companies and authors of relevant studies to identify further trials and obtain original participant data.
Randomised controlled trials (RCTs) of lithium compared with antipsychotics or placebo (or no intervention), whether as sole treatment or as an adjunct to antipsychotic medication, in the treatment of schizophrenia or schizophrenia-like psychoses or both.
We extracted data independently. For dichotomous data, we calculated random-effects meta-analyses, risk ratios (RRs), and 95% confidence intervals (CI) on an intention-to-treat basis. For continuous data, we calculated mean differences (MD) and 95% confidence intervals. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to create 'Summary of findings' tables and assessed risk of bias for included studies.
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.