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 real-world retrospective analysis found no significant differences in clinical outcomes among unipolar depression patients treated with or without lamotrigine and SPRAVATO.⁷ 
• A small preliminary study that retrospectively evaluated 13 patients who received IV ketamine or SPRAVATO concurrently with lamotrigine found no conclusive evidence that lamotrigine attenuated antidepressant response.⁸ 
• Four case reports describe improvement in depressive symptoms among patients treated concomitantly with SPRAVATO and lamotrigine.^9-11 
• 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.^12-14
• 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

CLINCAL DATA

Real-World Studies

Santucci et al (2025)⁷ conducted a retrospective analysis to assess the effects of concomitant lamotrigine use on clinical outcomes in unipolar depression patients treated with SPRAVATO or IV ketamine.

• Of the 347 patients included in the analysis, 57 (16%) were treated concomitantly with lamotrigine. The average doses of SPRAVATO, IV ketamine, and lamotrigine were 57.6 mg, 36.7 mg, and 210.1 mg, respectively. Symptom severity was measured using the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) and Montgomery-Asberg Depression Rating Scale (MADRS).
• Lamotrigine did not significantly impact the QIDS (P=0.60) or MADRS (P=0.30) over time. After 8 treatments with SPRAVATO or IV ketamine, patients who received concomitant lamotrigine saw improvement in MADRS scores (±standard deviation) from baseline (33.6±7.6 to 19.9±10.7) and QIDS scores from baseline (17.7±4.7 to 10.1±6.1). There were similar improvements in QIDS (from 17.6±4.9 to 10.8±5.7) and MADRS scores (from 32.8±7.1 to 21.8±9.5) in those who did not receive concomitant lamotrigine.  
• Covariate adjustment for concomitant antidepressants and benzodiazepines, prior exposure to ECT, age, psychiatric comorbidities and hospitalizations did not affect results. Additionally, no differences were detected between low (<100 mg) and high dose (≥100 mg) lamotrigine.
• Limitations: this was a non-randomized study in patients who came from one clinic. No results were provided for SPRAVATO specifically.

Joseph et al (2023)⁸ studied the response to serial ketamine and SPRAVATO treatment among adult patients with TRD with or without lamotrigine therapy.

Study Design/Methods

The analysis evaluated data from a historical cohort study (Phase 1) and a case series (Phase 2).

• Phase 1 consisted of a secondary analysis of a published observational study¹⁵ and included adult patients with TRD who received up to 6 intravenous (IV) ketamine infusions (0.5 mg/kg over 40–100 min or up to 8 SPRAVATO (56/84 mg) treatments with or without lamotrigine therapy. Treatment response was measured with the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), defined as a ≥50% reduction from baseline; remission was defined as a QIDS-SR score ≤5. The percent change in the QIDS-SR scores from baseline, and differences in the Clinician-Administered Dissociative States Scale (CADSS) scores between the lamotrigine/non-lamotrigine groups were also measured.
• In phase 2, electronic medical records from 25 June 2021 to 31 December 2022 were reviewed to identify additional patients who received serial ketamine or SPRAVATO treatments and continued lamotrigine therapy. These data were reported in total with patients from phase 1. Endpoints included the percent change in QIDS-SR scores from baseline based on the lamotrigine dose and the effect of the lamotrigine dose on response and remission.

Results

Phase 1

• Of the 62 patients who received IV ketamine or SPRAVATO, 8 patients were on concomitant lamotrigine.
• There were no differences in patient demographics or clinical characteristics (with exception of the mean number of concurrent psychotropic medications), response and remission rates, or safety measures (including CADSS) among lamotrigine and non-lamotrigine patients. The response and remission rates of these 8 patients were similar to the overall cohort.
• Percent change in QIDS-SR from baseline: no interaction was found between the lamotrigine groups and treatment number (P=0.70), nor the overall effect of the group P=0.38).
• CADSS score: the interaction was not statistically significant (P=0.08), and there was no overall effect on the group (P=0.36). When patients on SPRAVATO were excluded, there was a significant effect of lamotrigine on the CADSS score (P=0.45) but not on the percent change in QID-SR.

Phase 2

• 5 additional patients were identified during further chart review for a total of 13 patients from both phases (11=MDD and 2=Bipolar-II depression).
• 10 patients (77%) received IV ketamine treatments, one patient received SPRAVATO, and two patients switched from IV ketamine to SPRAVATO after the third IV ketamine infusion, due to financial reasons. Nine patients (69%) achieved response and six (46%) achieved remission during the induction phase. Four patients discontinued treatment due to insufficient response, and one patient discontinued treatment due to dissatisfaction with sustained response. Seven patients continued treatment after achieving a response in the acute phase.
• Dosing for lamotrigine ranged from 25 mg to 450 mg once daily or twice daily. The median lamotrigine daily dose among the responders and remitters was lower (100 mg daily) than non-responders/non-remitters (150 mg daily), however, the difference was not statistically significant (P>0.81). A significant difference was not observed in the percent change in QIDS-SR from baseline in patients receiving a low dose of lamotrigine (n=4) versus the standard dose of lamotrigine (n=9).

Limitations

Limitations of the study included the small sample size, with only 3 patients who were treated with SPRAVATO, of which 2 had switched to SPRAVATO after 3 IV ketamine sessions. All patients came from a single clinic and were on multiple medications. Four of the 13 patients received less than the recommended dose of lamotrigine (≤50 mg) for depression. In addition, the treatment duration was short for 4 patients, 3 who received three sessions of IV ketamine, and 1 who received 5 sessions of SPRAVATO.  

Case Series and Case Reports

Ahmad et al (2025)⁹ presented a case series of five patients with TRD who failed transcranial magnetic stimulation (TMS) and who were initiated on SPRAVATO. Of the five patients included in the series, two received lamotrigine concomitantly with SPRAVATO, in addition to other antidepressants. Treatment response (≥50% symptom reduction) was measured with Patient Health Questionnaire (PHQ‑9), Beck Depression Inventory (BDI), and Generalized Anxiety Disorder‑7 (GAD‑7) scores.

• Patient 1 was a 41-year-old female with PTSD and MDD. At baseline, her PHQ-9, BDI, and GAD-7 scores were 23, 69, and 20, respectively. After 8 SPRAVATO treatment sessions, her PHQ-9, BDI, and GAD-7 scores decreased to 8, 24, and 11, respectively. Scores continued to improve after 16 sessions to 7, 19, and 10, respectively.
• Patient 2 was a 29-year-old male with MDD, GAD, and attention deficit hyperactivity disorder (ADHD). His PHQ-9 score at baseline was 13, BDI score was 42, and GAD-7 score was 10. After 8 treatment sessions, his scores improved (PHQ-9, 7; BDI, 10; GAD‑7, 8), and continued improvement was observed after 16 sessions (PHQ-9, 4; BDI, 3; GAD‑7, 5).

Malhi et al (2024)¹⁰ 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 initiated on twice weekly SPRAVATO for 4 weeks (56 mg in week 1 and 84 mg in weeks 2-4).
• 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 MADRS 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).

Arrighi et al (2024)¹¹ presented a case report of a 31-year-old female diagnosed with treatment-resistant MDD, panic disorder, and generalized anxiety disorder.

• She was admitted to an in-patient psychiatric unit following a severe depressive episode (MADRS, 42), with suicidal ideation and sleep disorders. During her hospitalization, she was continued on lamotrigine 400 mg/day and initiated on SPRAVATO 56 mg and mirtazapine 30 mg/day. SPRAVATO was increased from 56 mg to 84 mg twice weekly.
• The patient showed clinical response at week 6 but was not sustained beyond 72 hours post-administration. She then underwent an extended induction phase totaling 20 twice-weekly administrations resulting in remission (MADRS of 4).
• There were no noticeable adverse effects reported except dissociation during the first administration.
• Maintenance treatment with SPRAVATO was continued at 84 mg once weekly, followed by 84 mg every two weeks for 6 months. While she continued cognitive behavioral therapy, SPRAVATO and all other pharmacological treatments were discontinued at the end of the maintenance phase with no reports of relapse 2 years post-discontinuation.

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 20 November 2025.