Does lamotrigine (Lamictal) help treat depression, particularly unipolar major depressive disorder?

Lamotrigine for Unipolar Depression: Limited Evidence Does Not Support Routine Use

Lamotrigine (Lamictal) is not recommended as a first-line or standard treatment for unipolar major depressive disorder, as the highest-quality recent evidence shows it is not superior to placebo when unpublished trials are included in the analysis. 1

Evidence Quality and Findings

The most recent and comprehensive meta-analysis (2025) provides the clearest guidance on this question:

• When unpublished studies are included, lamotrigine shows no superiority over placebo in treating unipolar depressive episodes, either as monotherapy or as adjunctive treatment. 1
• This finding is critical because it corrects for publication bias—earlier positive impressions were likely inflated by selective reporting of favorable results. 1
• There are no maintenance studies evaluating lamotrigine for preventing recurrence of unipolar depression. 1

Contrast with Bipolar Depression

The evidence diverges sharply based on diagnosis:

• For bipolar depression, lamotrigine demonstrates clear efficacy in both acute treatment (SMD: 0.155) and prophylaxis (RR: 0.78 for preventing depressive episodes). 1
• Lamotrigine is FDA-approved for maintenance treatment of bipolar disorder to delay mood episodes, and the combination of olanzapine-fluoxetine is approved for acute bipolar depression—but lamotrigine itself has no FDA indication for acute unipolar depression. 2

Why Earlier Studies Suggested Benefit

Older reviews (2012–2013) noted inconsistent benefits in unipolar depression, with several important caveats:

• Benefits appeared primarily in treatment-resistant patients, those with comorbid anxiety, or those with borderline personality disorder. 3
• Positive signals emerged mainly in studies using higher doses and treatment durations exceeding 8 weeks—most trials were too short to detect lamotrigine's delayed onset of action. 3
• A 2013 review found "modest benefit" in subsets of severely depressed unipolar patients, but this was based on open-label and retrospective data when RCTs were unavailable. 4

Guideline-Recommended Alternatives for Unipolar Depression

Standard first-line treatments for moderate-to-severe unipolar depression include:

• Second-generation antidepressants (SSRIs or SNRIs) have a number needed to treat of 7–8 for remission and are supported by moderate-quality evidence. 2
• Cognitive-behavioral therapy (CBT) shows equivalent efficacy to antidepressants and is strongly recommended as an alternative first-line option. 2, 5
• For treatment-resistant unipolar depression (failure of ≥2 adequate antidepressant trials), adding CBT to ongoing pharmacotherapy or considering ketamine/esketamine augmentation is advised—not lamotrigine. 5

Common Pitfalls

• Do not extrapolate bipolar depression data to unipolar depression—the pathophysiology and treatment response differ substantially. 1
• Do not rely on older reviews that preceded the 2025 meta-analysis incorporating unpublished negative trials. 1
• Do not use lamotrigine as monotherapy for unipolar depression outside of clinical trials, given the lack of supporting evidence when publication bias is corrected. 1

When Lamotrigine Might Be Considered (Off-Label, Low Evidence)

If a clinician encounters a patient with treatment-resistant unipolar depression plus comorbid borderline personality disorder or prominent anxiety symptoms, lamotrigine has shown signals of benefit in small studies—but this remains off-label with weak evidence. 3 In such cases:

• Ensure at least 8–12 weeks of treatment at therapeutic doses (typically 200 mg/day) before assessing response. 3
• Use slow titration (25 mg/day for 2 weeks, then 50 mg/day for 2 weeks, then increase by 50 mg every 1–2 weeks) to minimize risk of serious rash (0.1% in adults). 6
• Adjust dosing if co-prescribed with valproate (reduce to 100 mg/day) or carbamazepine (increase up to 400 mg/day). 6

Bottom Line

Lamotrigine is an evidence-based treatment for bipolar depression but lacks robust support for unipolar depression. The 2025 meta-analysis—the single most recent and highest-quality study—definitively shows no benefit over placebo in unipolar depression when unpublished trials are included. 1 Clinicians should prioritize guideline-recommended first-line treatments (SSRIs, SNRIs, or CBT) for unipolar depression. 2, 5