Can lamotrigine be used as monotherapy for an adult patient with unipolar depression (major depressive disorder) without psychotic features?

Lamotrigine Should Not Be Used as Monotherapy for Unipolar Depression

Lamotrigine is not approved or recommended as monotherapy for unipolar major depressive disorder and should not be used in this manner. The available evidence and guidelines do not support its use as a standalone treatment for unipolar depression.

Why Lamotrigine Is Not Appropriate for Unipolar Depression Monotherapy

Lack of FDA Approval and Guideline Support

• Lamotrigine is FDA-approved only for maintenance therapy in bipolar disorder, not for unipolar depression 1
• The American College of Physicians guidelines for major depressive disorder treatment (2016) do not include lamotrigine among recommended first-line or second-line monotherapy options 1
• Standard first-line treatments for unipolar depression include second-generation antidepressants (SSRIs, SNRIs) or cognitive behavioral therapy 1

Evidence Base Is Limited to Augmentation, Not Monotherapy

• The research evidence for lamotrigine in unipolar depression exclusively examines its use as an augmentation agent added to existing antidepressants, not as monotherapy 2, 3, 4
• A 2019 meta-analysis of 677 patients found lamotrigine augmentation effective when added to SSRIs or SNRIs in treatment-resistant depression, but this does not translate to monotherapy efficacy 2
• Retrospective studies showing 40-76% response rates all involved lamotrigine added to ongoing antidepressant therapy 3, 4

Bipolar vs. Unipolar Depression: A Critical Distinction

• The only controlled monotherapy trial showing lamotrigine efficacy was in bipolar I depression, not unipolar depression 5
• Even in bipolar depression, lamotrigine monotherapy showed modest effects (51% response rate at 200mg/day vs. 26% placebo) 5
• Bipolar depression and unipolar depression have different pathophysiology and treatment responses, making extrapolation inappropriate

What Should Be Done Instead

For Initial Treatment of Unipolar Depression

• Start with either a second-generation antidepressant (SSRI or SNRI) or cognitive behavioral therapy 1
• Moderate-quality evidence shows CBT and SGAs have similar effectiveness with potentially fewer adverse effects for CBT 1
• Common first-line antidepressants include fluoxetine, sertraline, escitalopram, or citalopram 1

For Treatment-Resistant Unipolar Depression

• If inadequate response occurs after 6-8 weeks of adequate antidepressant trial, consider switching to another antidepressant or augmentation strategies 1
• Lamotrigine may be considered as an augmentation agent (added to an existing antidepressant) in treatment-resistant cases 2, 3, 4
• When used for augmentation, typical dosing is 100-200 mg/day, with slow titration to minimize rash risk 2, 3
• Evidence suggests lamotrigine augmentation works better in patients with shorter illness duration and fewer failed antidepressant trials 3

For Depression with Psychotic Features

• If psychotic features are present, the preferred treatment is an SSRI combined with an atypical antipsychotic, not lamotrigine 6

Common Pitfall to Avoid

Do not confuse bipolar depression with unipolar depression. Lamotrigine has established efficacy in bipolar disorder maintenance and bipolar depression 1, 5, but this does not extend to unipolar major depressive disorder. Always confirm the diagnosis before considering lamotrigine, as using it as monotherapy for unipolar depression represents off-label use without supporting evidence.