Lamotrigine as a treatment for prevention of recurrence of bipolar disorder

Review question

To investigate the clinical effectiveness (benefits and harms) of lamotrigine for maintenance therapy of bipolar disorder in comparison with placebo, combination therapy or existing drugs (e.g. lithium, olanzapine).


Lamotrigine is approved for the maintenance treatment (treatment for prevention of recurrence) of bipolar disorder. It could be a viable and effective treatment strategy for the maintenance of bipolar disorder, where it demonstrated a lower risk of recurrence than placebo. In addition, it has been reported to be as effective as lithium. Therefore, we performed a systematic review to investigate the efficacy and safety of lamotrigine in the maintenance treatment (treatment for prevention of recurrence) of bipolar disorder.

Key findings

The evidence is current to May 2021. We included 11 studies in this review with a total 2314 participants. 1146 participants were assigned to lamotrigine, and 1168 participants were assigned to control intervention (869 received placebo and 299 received lithium).

Our review identified the following.

Lamotrigine versus placebo

Benefits: lamotrigine was found to be superior over placebo in the following outcomes.

1) Reduced the rate of recurrence of manic symptoms 

2) Suppressed depressive symptoms

3) Less need for additional therapeutic agents for the recurrence of all symptoms

4) Reduction in the withdrawal rate due to any causes six months or more after the initiating of intervention

Harms: adverse-event profile of lamotrigine was similar to that of placebo.

Lamotrigine versus lithium

Benefits: lamotrigine was as effective as lithium, except for the recurrence of manic symptoms, for which the rate was higher in people who received lamotrigine than people treated with lithium.

Harms: the rate of adverse events associated with lamotrigine was lower than that of lithium.

Certainty of the evidence

We assessed the certainty of our included evidence to be very low to moderate. This is because majority of the included trials did not describe how treatment allocation was concealed. Given that we were unable to identify high-confidence evidence the overall findings of this systematic review should be interpreted carefully.


Lamotrigine may be superior to placebo in efficacy and may be comparable in safety. And then, lamotrigine was as effective as lithium except for its recurrence rate of mania, and was superior to lithium in terms of safety. Future studies in this field with robust methods and transparent reporting are needed to confirm our results and to fully answer our pre-specified review question.

Authors' conclusions: 

Low- to moderate-certainty evidence collectively suggests that lamotrigine may be superior to placebo as a treatment modality for bipolar disorder. In comparison to lithium, people with bipolar disorder seem to tolerate lamotrigine better in the long run; however, the demonstrated efficacy in the maintenance of bipolar disorder was similar between the two groups.

Read the full abstract...

Bipolar disorder is a chronic mental disorder with repetitive mania/hypomania as well as depressive episodes, which eventually results in marked impairment in overall functioning and health-related quality of life.  A worldwide prevalence rate of 2.4% has been reported. The risk of suicide is higher in people with bipolar disorder than those with other mental disorders. Therefore, effective management of bipolar disorder in the maintenance period is warranted to minimize the risk of relapse or recurrence. Although lithium has been the standard treatment of bipolar disorder for many years, it is associated with adverse effects and teratogenicity. Lamotrigine is approved to be expected for prevention of recurrence for the maintenance treatment of bipolar disorder. In addition, lamotrigine is as effective as lithium. Therefore, we performed a systematic review to confirm the efficacy and safety of lamotrigine in the maintenance treatment of bipolar disorder.


To assess the efficacy and tolerability of lamotrigine in the maintenance treatment of bipolar disorder.

Search strategy: 

We searched Ovid MEDLINE, Embase, PsycINFO, the Cochrane Common Mental Disorders Group's Specialized Register (CCMDCTR) and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to 21 May 2021. We also searched international trial registries and contacted experts in the field.

Selection criteria: 

We included randomized controlled trials enrolling adults with bipolar disorder who were treated with lamotrigine, placebo or lithium.

Data collection and analysis: 

Two reviews authors independently checked the eligibility of studies and extracted data using a standardized form. Data extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in the term of efficacy and tolerability. Study information were then entered into RevMan web.

Main results: 

We included 11 studies with a total of 2314 participants in this review; 1146 were randomized to lamotrigine, 869 were randomized to placebo and, 299 to lithium.

We rated all studies as having an unclear risk of bias in at least one domain of Cochrane's tool for assessing risk of bias, with the most commonly observed weakness being selection bias (random sequence generation and allocation concealment). We judged five studies to be at a high risk of detection bias (blinding of outcome assessment). These potential biases pose as major threat to the validity of the included studies in this review.

Outcomes of efficacy showed a possible advantage of lamotrigine over placebo. The estimated risk ratio (RR) for recurrence of manic symptom at one year as measured by the Young Mania Rating Scale (YMRS) was 0.67, (95% confidence interval (CI) 0.51 to 0.87; 3 studies, 663 participants; low-certainty evidence) in favor of lamotrigine. The RR of clinical worsening with the need for additional psychotropic treatment (RR 0.82, 95% CI 0.70 to 0.98; 4 studies, 756 participants) based on moderate-certainty evidence. The possible benefits of lamotrigine were also seen for the outcome of treatment withdrawal due to any reason at 6-12 months after treatment (RR 0.88, 95% CI 0.78 to 0.99; 4 studies, 700 participants; moderate-certainty evidence). Regarding tolerability, our analyses showed that the incidence rates of adverse effects were similar between the lamotrigine group and the placebo group (short-term effect: RR 1.07, 95% CI 0.81 to 1.42; 5 studies, 1138 participants; very low-certainty evidence; long-term effect: RR 0.97, 95% CI 0.77 to 1.23; 4 studies, 756 participants; moderate-certainty evidence).

In the comparison between lamotrigine and lithium, efficacy was similar between groups except for recurrence of mania episode at one year. Recurrence of manic symptoms was higher in the lamotrigine group than that of the lithium group (RR 2.13, 95% CI 1.32 to 3.44; 3 studies, 602 participants; moderate-certainty evidence). Analysis of adverse effects at 6-12 months showed that a lower proportion of participants experienced at least one adverse effect when treated with lamotrigine compared to lithium (RR 0.70, 95% CI 0.51 to 0.96; 4 studies, 691 participants; moderate-certainty evidence).

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