SUMMARY  

• There are limited studies evaluating the efficacy or safety of concurrent treatment with lamotrigine and SPRAVATO.
• Concomitant use of SPRAVATO with central nervous system (CNS) depressants may increase sedation; therefore, close monitoring for sedation is recommended for concomitant use of SPRAVATO and CNS depressants.¹
  • Other side effects, such as dizziness, nausea, somnolence, vomiting, and lethargy, were also reported as adverse reactions for SPRAVATO.²
• Based on their individual hypothesized mechanisms of action, SPRAVATO may increase the presynaptic release of glutamate via binding to the N-methyl-D-aspartate (NMDA) receptor while lamotrigine may decrease the release of glutamate via inhibition of voltage-dependent sodium channels.^2-4
• SPRAVATO clinical studies (ASPIRE-I, ASPIRE-II) in adults with major depressive disorder with active suicidal ideation and intent (MDSI) excluded subjects with seizures. However, concomitant use of SPRAVATO with lamotrigine as a mood stabilizer was permitted on a case-by-case basis although the number of patients taking the combination was very low.^5,6
• A case report describes the improvement in depressive symptoms in an adult patient with treatment-resistant depression (TRD) who received SPRAVATO concomitantly with lamotrigine after the effect of lamotrigine plateaued.⁷ 
• A literature search did not identify any published reports of drug interactions between SPRAVATO and lamotrigine.
• Please contact the manufacturer of lamotrigine for more information regarding the safety and drug-drug interactions of this product.

Mechanism of ACTion

• SPRAVATO is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The mechanism by which SPRAVATO exerts its antidepressant effect is unknown. The major circulating metabolite of SPRAVATO demonstrated activity at the NMDA receptor with less affinity.² Evidence within the literature suggests that this blockade transiently enhances the activity of glutamatergic neurons, including increasing the presynaptic release of glutamate.^8-10
• Lamotrigine is a phenyltriazine. The mechanism of action is not established. In vitro studies suggest that lamotrigine inhibits voltage-dependent neuronal sodium channels resulting in stabilization of neuronal membranes and modulation of presynaptic neurotransmitter release (eg, glutamate).^3,4

Case Report

Malhi et al (2024)⁷ presented a case report of a 44-year-old female patient diagnosed with TRD, generalized anxiety disorder, obsessive-compulsive disorder, and iatrogenic benzodiazepine dependence. Following stagnant response with lamotrigine 200 mg daily, diazepam, and suvorexant, the patient was enrolled in the positioning of esketamine in the treatment of depression study and administered a twice-weekly dose of SPRAVATO for 4 weeks (56 mg in week 1 and 84 mg in weeks 2-4). Lamotrigine was continued, but the dose of diazepam was slowly reduced during SPRAVATO treatment. The patient was followed up during and for 3 weeks after SPRAVATO treatment.

During SPRAVATO treatment, the patient experienced transient increased blood pressure and mild dissociation, which resolved within 1 hour after drug administration. Following treatment with SPRAVATO, the patient reported notable improvements in motivation and capacity for exercise, along with trending improvement in cognitive functioning by the end of follow-up. Additionally, symptoms of anhedonia, anxiety, and irritability decreased with time during treatment, and passive suicidal ideation ceased from day 13 of treatment and through follow-up. After 4 weeks of treatment with SPRAVATO, the Montgomery-Asberg Depression Rating Scale score improved by 24 points (from 32 at baseline to 8 at 4 weeks), the Hamilton Depression rating scale score improved by 6 points (from 17 at baseline to 7 at 4 weeks), and the Clinical Global Impressions Scale score improved by 7 points (from 4 at baseline to 11 at 4 weeks).

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 06 December 2024.

A case series attempted to evaluate the effects of lamotrigine on both esketamine and ketamine, but the sample size was too small to draw any firm conclusions.¹¹