Analysis Finds Lithium Maintenance Most Effective Monotherapy in Bipolar Disorder

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Researchers conducted the first systematic review of observational studies comparing the effectiveness of lithium monotherapy vs other mood stabilizers as maintenance treatment for bipolar disorder.

Lithium monotherapy is associated with superior outcomes in comparison with other mood stabilizers in monotherapy, according to a systematic review of nonrandomized controlled observational studies on bipolar maintenance therapy recently published in Bipolar Disorders.

Data from 9 nonrandomized controlled observational studies comparing lithium monotherapy maintenance to maintenance monotherapy using other mood stabilizers were chosen for analysis.

Eight of these 9 studies — which included a total of 14,271 patients with bipolar disorder from Sweden, Denmark, the United Kingdom, Austria, Germany, Italy, the United States, and Canada — demonstrated the superiority of lithium monotherapy compared with other mood stabilizers, including lamotrigine, olanzapine, valproate, quetiapine, carbamazepine/lamotrigine, unspecified antipsychotics, unspecified atypical antipsychotics, and unspecified anticonvulsants. In addition to the evidence of more positive outcomes with lithium maintenance monotherapy, the systematic review found that lithium treatment reduces suicide risk and may prevent the onset of dementia.

The Swedish study found no difference between maintenance monotherapy with quetiapine, olanzapine, or valproate and maintenance monotherapy with lithium. The inconsistent findings could be due to the other studies including both patients with bipolar I disorder and patients with bipolar II disorder, while the Swedish study only followed patients with bipolar type I. Another possibility is that the Swedish study’s statistical power to identify differences was diluted by including longitudinal data for the same patient multiple times (ie, 6502 index hospitalizations for 4250 individuals), thereby allowing nonresponders to medications to affect the analysis.

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The review was conducted as part of the International Society for Bipolar Disorders Task Force on Lithium Treatment, to augment evidence from randomized controlled trials (RCTs) with evidence from observational studies, which are able to include a wider range of patients in real-world settings over a longer period of time than RCTs. The external validity of the International Society for Bipolar Disorders Task Force on Lithium Treatment’s review can be seen as very high. The studies reviewed allowed for patients to be included regardless of gender, age, severity, co-prescriptions, comorbidity with substance abuse or other disorders, suicidality, socioeconomic status, and other criteria that cause many real-life patients to be excluded from RCTs.

The investigators conclude that “Given the combined evidence from RCTs and observational studies… the use of lithium is still underrepresented in clinical practice and should be incorporated more assertively into current guidelines.”


Kessing LV, Bauer M, Nolen WA, Severus E, Goodwin GM, Geddes J. Effectiveness of maintenance therapy of lithium vs other mood stabilizers in monotherapy and in combinations: a systematic review of evidence from observational studies [published online February 14, 2018]. Bipolar Disord. doi:10.1111/bdi.12623