What is the role of lamotrigine (anticonvulsant medication) in the treatment of depressive disorders?

From the Guidelines

Lamotrigine is an effective medication for treating bipolar depression and may be useful for treatment-resistant unipolar depression, though it is not FDA-approved for the latter indication. For bipolar depression, lamotrigine is typically started at 25mg daily for two weeks, then increased to 50mg daily for two weeks, followed by 100mg daily for one week, and finally to a target dose of 200mg daily (range 100-400mg daily) 1. When used for treatment-resistant unipolar depression, it's generally prescribed as an augmentation strategy alongside antidepressants rather than as monotherapy. The medication works by inhibiting voltage-sensitive sodium channels and reducing glutamate release, which helps stabilize mood.

Key Considerations

• Lamotrigine has a favorable side effect profile compared to many mood stabilizers, with minimal weight gain, cognitive effects, or sexual dysfunction.
• Patients must be monitored for serious rash, particularly Stevens-Johnson syndrome, which is rare but potentially life-threatening.
• This risk is minimized by following the slow titration schedule.
• Blood level monitoring is not routinely required, and lamotrigine has few drug interactions except with valproate (which increases lamotrigine levels) and carbamazepine (which decreases levels) 2.
• Lamotrigine is particularly valuable for patients with bipolar disorder who experience more depressive than manic episodes.

Treatment Approach

• The American College of Physicians recommends selecting between either cognitive behavioral therapy or second-generation antidepressants to treat patients with major depressive disorder after discussing treatment effects, adverse effect profiles, cost, accessibility, and preferences with the patient (Grade: strong recommendation, moderate-quality evidence) 3, 1, 4.
• Lamotrigine may be considered as an alternative treatment for patients with treatment-resistant unipolar depression or bipolar depression.

Monitoring and Follow-up

• Regular monitoring for side effects, particularly serious rash, is essential when prescribing lamotrigine.
• Patients should be educated on the importance of adhering to the slow titration schedule to minimize the risk of serious rash.
• Follow-up appointments should be scheduled to assess treatment response and adjust the dose as needed.

From the Research

Role of Lamotrigine in Depressive Disorders

• Lamotrigine has been shown to be effective in the prevention of mood episodes in adult patients with bipolar I disorder, particularly in delaying time to intervention for depressive episodes 5, 6, 7, 8.
• The mechanism of action of lamotrigine in patients with bipolar disorder may be related to the inhibition of sodium and calcium channels in presynaptic neurons and subsequent stabilisation of the neuronal membrane 5, 7.
• Lamotrigine has been found to be more effective than placebo in the treatment of patients with treatment-refractory bipolar disorder or those with bipolar depression 5, 6.
• The efficacy of lamotrigine in the acute treatment of bipolar depression is still a topic of debate, with some studies showing a small effect 9 and others showing significant superiority to placebo 5, 6.
• Lamotrigine is generally well tolerated, with common adverse events including headache, nausea, infection, and insomnia, and has a preferable side-effect profile compared to standard agents for bipolar affective disorder such as lithium or carbamazepine 5, 6.

Indications and Contraindications

• Lamotrigine is approved for the maintenance treatment of adults with bipolar disorder and is also used off-label in the treatment of acute bipolar depression 7.
• Strict contraindications to the use of lamotrigine include sensitivity reactions accompanied by systemic symptoms, and phenotype testing can enable screening of patients predisposed to serious hypersensitivity reactions 7.
• Lamotrigine can cause rare, life-threatening adverse effects such as Stevens-Johnson syndrome, hemophagocytic lymphohistiocytosis, and drug reaction with eosinophilia and systemic symptoms syndrome, which require urgent intervention 7.

Dosage and Administration

• The dosage of lamotrigine is typically titrated over a 6-week period to 200 mg/day to minimize the incidence of serious rash 5.
• Adjustments to the initial and target dosages are required if coadministered with valproate semisodium or carbamazepine 5.
• The general range of doses found effective in affective disorders is from 50 to 300 mg daily, with clinical use involving a titration of dose upwards over several weeks until the desired effect is obtained 6.