CRD summary

This meta-analysis assessed the efficacy of lamotrigine in patients with acute bipolar depression. The authors concluded that it could be effective for treatment and for the prevention of relapse. This conclusion reflected the evidence presented, but the potential for error and bias throughout the review means that the reliability of this conclusion is unclear.

Authors' objectives

To assess the efficacy of lamotrigine in patients with acute bipolar depression.

Searching

In addition to the initial sourcing of five trials conducted by GlaxoSmithKline, trials were sought from the following databases: MEDLINE, EMBASE, CINAHL, PsycINFO, and the Cochrane Central Register of Controlled Trials (CENTRAL).

Study selection

Randomised controlled trials (RCTs) of lamotrigine compared with placebo in patients with bipolar depression were eligible for inclusion in this review. Trials of lamotrigine monotherapy compared with placebo conducted by GlaxoSmithKline were included in the meta-analysis. Trial duration ranged from seven to 10 weeks, and the doses in the meta-analysis ranged from 100mg to 400mg. The included patients had discontinued any other psychoactive drug at least five elimination half-lives before trial entry, and had not received lamotrigine previously.

The mean age of included men and women ranged from 36 to 42 years, and the majority were white with bipolar I or bipolar II disorder, or both. Outcomes of interest were reductions of more than 50% from baseline on the Hamilton Rating Scale for Depression (HRSD) and the Montgomery and Asberg Depression Rating Scale (MADRS), and remission (defined as less than eight on HRSD, and less than 12 on MADRS). Discontinuation rates were also compared.

The authors did not state how studies were selected for the review, nor how many reviewers performed the selection.

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

Individual patient data were extracted to calculate the relative risk (RR) and 95% confidence interval (CI) of response to treatment and remission. Intention-to-treat data were used, and the number needed to treat (NNT) was estimated from the inverse of the weighted mean absolute difference in event rates. The weighted mean difference (WMD), standardised mean difference (SMD), and 95% CIs were calculated for continuous outcome measures. Separate analyses of covariance were conducted and adjusted for baseline.

The authors did not state how many reviewers performed the data extraction.

Methods of synthesis

Summary estimates and 95% CIs were pooled using the Mantel-Haenszel fixed-effect model. Subgroup analyses were conducted using meta-regression to investigate the treatment response difference between those with bipolar I and II disorder and between those with severe and moderate illnesses at randomisation. Statistical heterogeneity was assessed using the χ² test.

Results of the review

Five RCTs (n=1,072) were included in the meta-analysis.

Patients receiving lamotrigine were more likely to respond to treatment than those receiving placebo, using the HRSD (RR 1.27, 95% CI 1.09 to 1.47) and using the MADRS (RR 1.22, 95% CI 1.06 to 1.41). The NNT to achieve one more response than placebo was 11 (95% CI 7 to 25) using the HRSD and 13 (95% CI 7 to 33) using the MADRS. Remission rates for lamotrigine were significantly higher using the MADRS (RR 1.21, 95% CI 1.03 to 1.42). For continuous symptoms, there was a statistically significant difference in favour of lamotrigine using the MADRS (WMD -1.43, 95% CI -2.80 to -0.06; SMD -0.12, 95% CI -0.24 to -0.00).

There was no significant difference in discontinuation rates between lamotrigine and placebo, nor in interaction between diagnostic subgroup (bipolar I and II) and treatment effect. Lamotrigine was superior to placebo in patients with severe depressive symptoms (HRSD score more than 24) at randomisation (RR 1.47, 95% CI 1.16 to 1.87; NNT 7, 95% CI 4 to 17; SMD -0.24, 95% CI -0.42 to -0.06), and this interaction was also found using the continuous MADRS as the independent variable. The authors proposed that this interaction arose from a higher response rate in moderately ill placebo-treated patients, rather than a higher response rate from the severely ill treatment group.

Authors' conclusions

Lamotrigine could be effective for treatment of acute bipolar depression, type I or II, and for the prevention of relapse.

CRD commentary

The review question was clear, but the inclusion criteria were not sufficiently detailed to allow replication. The search strategy included some relevant databases, but the sole inclusion of five industry-sponsored trials was not fully justified. There was no apparent search for unpublished material, and publication bias was not formally assessed. No summary assessment of trial quality was reported. The review process was not reported, which means that errors and biases cannot be ruled out. The study details were adequately provided and the method of synthesis appears to have been appropriate in the absence of statistical heterogeneity (where reported). The authors declared personal links with the drug manufacturer, GlaxoSmithKline.

The authors' conclusion reflected the evidence presented, but due to the methodological uncertainties described above, the reliability of this conclusion is unclear.

Implications of the review for practice and research

Practice: The authors stated that the results of this meta-analysis were at the margins of being clinically important.

Research: The authors stated that further trials were needed to clarify the size of the treatment effect when lamotrigine was used as monotherapy or in combination.

Funding

Trials were funded by GlaxoSmithKline, no additional funding was received.

Bibliographic details

Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. British Journal of Psychiatry 2009; 194(1): 4-9. [PubMed: 19118318]

Original Paper URL

http://bjp.rcpsych.org/content/194/1/4.full

Indexing Status

Subject indexing assigned by NLM

MeSH

Adult; Aged; Bipolar Disorder /drug therapy; Calcium Channel Blockers /therapeutic use; Epidemiologic Methods; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Randomized Controlled Trials as Topic; Treatment Outcome; Triazines /therapeutic use; Young Adult

AccessionNumber

12009104222

Database entry date

20/01/2010

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.