What is the best medication to augment Lamictal (lamotrigine) for a patient with continued depression?

Augmenting Lamotrigine for Treatment-Resistant Depression

Add bupropion SR or an SSRI (citalopram, sertraline, or escitalopram) to lamotrigine for continued depression, as these augmentation strategies show equivalent efficacy with moderate-quality evidence from the STAR*D trial. 1, 2

Primary Augmentation Options

Bupropion SR (Preferred for Tolerability)

• Bupropion SR 150mg twice daily demonstrates the best tolerability profile among augmentation agents, with significantly fewer discontinuations due to adverse events (12.5%) compared to buspirone (20.6%, P < 0.001). 2, 3
• Remission rates with bupropion augmentation reach 39% in treatment-resistant depression, equivalent to other augmentation strategies but with superior side effect profile. 3
• This combination avoids serotonin syndrome risk and provides complementary mechanisms (dopamine/norepinephrine reuptake inhibition with bupropion plus glutamate modulation with lamotrigine). 2

SSRI Augmentation (Alternative First-Line)

• Add citalopram 20-40mg daily, sertraline 50-200mg daily, or escitalopram 10-20mg daily to lamotrigine if bupropion is contraindicated or not tolerated. 2
• SSRIs combined with lamotrigine show moderate-quality evidence for efficacy, with remission rates of 28-37% in treatment-resistant populations. 2, 3
• Monitor for serotonin syndrome when combining SSRIs with lamotrigine, though risk remains low. 2

Evidence Hierarchy and Reasoning

Why These Agents Are Recommended

• The 2023 American College of Physicians systematic review found no significant differences between switching antidepressants versus augmentation with buspirone or bupropion SR, allowing tolerability to guide selection. 1, 3
• The STAR*D trial provides the strongest comparative data, demonstrating that augmentation with bupropion (39% remission), buspirone (33% remission), or cognitive therapy (31% remission) produces similar efficacy. 3
• Switching strategies (sertraline 27%, bupropion-SR 26%, venlafaxine-XR 25%) show equivalent outcomes to augmentation, but augmentation preserves any partial response to lamotrigine. 3

Lamotrigine-Specific Considerations

• Lamotrigine demonstrates efficacy as augmentation in treatment-resistant unipolar depression, with significant improvements in Hamilton Depression Rating Scale scores compared to placebo. 4
• Patients with more severe illness and longer duration of illness respond more effectively to lamotrigine augmentation. 4
• The magnitude of depression improvement after lamotrigine augmentation is higher when combined with SSRIs than with SNRIs. 4
• Lamotrigine augmentation accelerates onset of antidepressant action and shows particular efficacy on depressed mood and work/interest symptoms. 5

Clinical Algorithm

1. Verify adequate lamotrigine dosing: Ensure patient is on therapeutic dose (typically 200mg/day for mood disorders) for at least 6-8 weeks before augmenting. 6, 4

2. First augmentation choice: Add bupropion SR 150mg daily, increase to 150mg twice daily after 1 week if tolerated. 2, 3

3. If bupropion contraindicated (seizure history, eating disorder, abrupt alcohol/benzodiazepine discontinuation): Add citalopram 20mg daily, titrate to 40mg daily, OR sertraline 50mg daily, titrate to 200mg daily. 2

4. Monitor response at 6 weeks: Expect 40-48% response rate with adequate augmentation trial. 3, 4

5. If inadequate response after 8 weeks: Consider switching to cognitive behavioral therapy or alternative antidepressant rather than further augmentation. 1, 3

Critical Caveats

Dosing Interactions

• If patient is on valproate, lamotrigine dose must be reduced by 50% due to pharmacokinetic interactions. 6
• If patient is on carbamazepine, lamotrigine dose must be increased due to enzyme induction. 6
• Lamotrigine does not require serum level monitoring for depression (unlike lithium), but therapeutic range is typically 3-14 mcg/mL. 6

Rash Risk

• The incidence of serious rash with lamotrigine is 0.1%, including Stevens-Johnson syndrome risk. 6
• Slow titration over 6 weeks minimizes this risk, but any new rash requires immediate evaluation and likely discontinuation. 6

Evidence Limitations

• Most augmentation evidence is low to moderate quality, and absence of statistically significant differences between strategies does not prove equivalence. 1, 2, 3
• STAR*D lacked placebo arms, making it impossible to determine how many patients would have remitted without active treatment. 3
• Limited evidence exists for augmentation with antipsychotics, lithium, or thyroid hormone specifically with lamotrigine as the base antidepressant. 1, 7

Patient Factors Predicting Response

• Shorter duration of current depressive episode and fewer failed antidepressant trials predict better response to lamotrigine augmentation. 8
• Comorbid anxiety disorders and chronic pain syndromes may show enhanced response to lamotrigine augmentation. 8
• White women who are employed with higher education/income levels show higher remission rates, though this should not exclude other patients from treatment. 3