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. 2021 Sep 15;9(9):CD013575.
doi: 10.1002/14651858.CD013575.pub2.

Lamotrigine in the maintenance treatment of bipolar disorder

Yasuhiko Hashimoto  1 , Kazumasa Kotake  2 , Norio Watanabe  3 , Takashi Fujiwara  4 , Shinji Sakamoto  5
Affiliations

Lamotrigine in the maintenance treatment of bipolar disorder

Yasuhiko Hashimoto et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

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

Search methods: 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).

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.

Trial registration: ClinicalTrials.gov NCT00274677 NCT00056277 NCT00550407 NCT00226135 NCT01588457.

PubMed Disclaimer

Conflict of interest statement

YH: none. KK: none. NW: none. TF: none. SS: none.

Figures

1
1
PRISMA flow diagram.
2
2
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.
3
3
Figure 3. Risk of bias table
1.1
1.1. Analysis
Comparison 1: Lamotrigine versus placebo, Outcome 1: Recurrence of any episodes at one year (Young Mania Rating Scale total score ≥15 for manic episode)
1.2
1.2. Analysis
Comparison 1: Lamotrigine versus placebo, Outcome 2: Recurrence of any episodes at one year (Montgomery‐Asberg Depression Rating Scale total score ≥15 for depressive episode; Hamilton Depression Rating Scale total score ≥14 for depressive episode)
1.3
1.3. Analysis
Comparison 1: Lamotrigine versus placebo, Outcome 3: Recurrence of any episodes at one year for clinical worsening with additional psychotropics (mood stabilizers, antidepressants, antipsychotics or benzodiazepines)
1.4
1.4. Analysis
Comparison 1: Lamotrigine versus placebo, Outcome 4: Withdrawal from treatment due to any reason, up to 12 weeks after intervention commencement (short‐term)
1.5
1.5. Analysis
Comparison 1: Lamotrigine versus placebo, Outcome 5: Withdrawal from treatment due to any reason, 6‐12 months after intervention initiation (long‐term)
1.6
1.6. Analysis
Comparison 1: Lamotrigine versus placebo, Outcome 6: Adverse effects up to 12 weeks after starting treatment (short‐term)
1.7
1.7. Analysis
Comparison 1: Lamotrigine versus placebo, Outcome 7: Adverse effects 6‐12 months after initiating the intervention (long‐term)
1.8
1.8. Analysis
Comparison 1: Lamotrigine versus placebo, Outcome 8: Recurrence of manic episode at one year
1.9
1.9. Analysis
Comparison 1: Lamotrigine versus placebo, Outcome 9: Recurrence of depressive episode at one year
2.1
2.1. Analysis
Comparison 2: Lamotrigine versus lithium, Outcome 1: Recurrence of any episodes at one year (Young Mania Rating Scale total score ≥15 for manic episode)
2.2
2.2. Analysis
Comparison 2: Lamotrigine versus lithium, Outcome 2: Recurrence of any episodes at one year (Montgomery‐Asberg Depression Rating Scale total score ≥15 for depressive episode; Hamilton Depression Rating Scale total score ≥14 for depressive episode)
2.3
2.3. Analysis
Comparison 2: Lamotrigine versus lithium, Outcome 3: Recurrence of any episodes at one year for clinical worsening with additional psychotropics (mood stabilizers, antidepressants, antipsychotics or benzodiazepines)
2.4
2.4. Analysis
Comparison 2: Lamotrigine versus lithium, Outcome 4: Recurrence of any episodes at one year (active suicidal behavior)
2.5
2.5. Analysis
Comparison 2: Lamotrigine versus lithium, Outcome 5: Withdrawal from treatment due to any reason, 6‐12 months after intervention initiation (long‐term)
2.6
2.6. Analysis
Comparison 2: Lamotrigine versus lithium, Outcome 6: Adverse effects 6‐12 months after initiating the intervention (long‐term)
2.7
2.7. Analysis
Comparison 2: Lamotrigine versus lithium, Outcome 7: Recurrence of manic episode at one year
2.8
2.8. Analysis
Comparison 2: Lamotrigine versus lithium, Outcome 8: Recurrence of depressive episode at one year
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