Concomitant Use of SPRAVATO with Cognitive Behavioral Therapy or Psychotherapy

Summary

• Across the SPRAVATO phase 3 studies in treatment-resistant depression (TRD), patients receiving psychotherapy before entering the trials (including cognitive behavioral therapy [CBT]) could continue receiving psychotherapy during the trials.¹
  • CBT must have been ongoing for the last 3 months prior to the screening/prospective, observational phase. Except for new CBT, which was prohibited, new psychotherapy was allowed during these studies.¹
  • During the phase 3 program, one study removed the restriction related to CBT and allowed for all previous forms of psychotherapy to be continued or newly initiated during the study.²
• The clinical trial program in major depressive disorder (MDD) with suicidal ideation (SI) and intent provided all patients with standard-of-care (SOC) treatment, which may have included psychotherapy.³
  • In the ASPIRE-II trial, 5.3% (6/115) of patients in the SPRAVATO+SOC group and 4.4% (5/115) of patients in the placebo+SOC group received psychotherapy during the double-blind treatment phase.
• A randomized feasibility trial in patients with MDD and SI found that SPRAVATO+CBT was associated with greater improvements in certain SI and depressive symptom severity scales than SPRAVATO+treatment-as-usual (TAU; other types of psychotherapy).⁴
  • Improvements from baseline through week 18 favored the SPRAVATO+CBT group over the SPRAVATO+TAU group for Beck Scale for Suicidal Ideation (BSSI) scores (least-squares mean difference [LSMD]: -6.01 vs -4.10; P=0.025), Clinician Global Improvement Scale for Suicide Severity scores (-0.81 vs -0.49; P=0.011), and composite MADRS scores (-11.29 vs -7.52; P=0.009).
  • No difference between groups was observed in the Columbia-Suicide Severity Rating Scale (C-SSRS), Montgomery-Åsberg Depression Rating Scale (MADRS) suicide ideation (item 10) score, or the time to suicide-related events.
• In a retrospective pilot study of 6 patients with TRD and comorbid post-traumatic stress disorder (PTSD), SPRAVATO was administered in conjunction with psychotherapy (supportive therapy, eye movement desensitization and reprocessing [EMDR], or hypnosis therapy). Psychotherapy was conducted during and after SPRAVATO administration, including during the period of peak drug effects. Depressive symptoms improved in 5 of 6 patients, with a mean reduction of 12.6 points in MADRS score over 24 weeks. Mean PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders Edition 5 (DSM-5/PCL-5) score decreased by 25.1 points.⁵
• A retrospective, observational, multicentric study in patients with TRD in a compassionate use program in Spain found that CBT was significantly associated with lower MADRS scores after 90 days (13.1 vs 16.1; P=0.021) and 180 days of treatment (12.3 vs 16.1; P=0.021) compared with those who did not receive CBT.⁶
• In a phase 2b study of adolescents with MDD at imminent risk for suicide, all patients received comprehensive SOC including evidence-based psychotherapy, in conjunction with SPRAVATO or psychoactive placebo (midazolam). Additional information on this study can be found in the following scientific response: Use of SPRAVATO in Pediatrics.⁷

CLINICAL DATA

• Wilkinson et al (2026)^4,8 conducted a randomized feasibility trial to evaluate CBT following SPRAVATO treatment in patients with MDD and SI. The primary outcome was feasibility defined as achieving 80% of the target enrollment and 70% retention of enrolled subjects through week 18. Secondary objectives included assessing between-group differences in SI and depressive symptoms.

Methods

• The trial consisted of 3 phases: patients received 4 weeks of SPRAVATO during phase 1. Patients were randomized to receive CBT for 16 weeks or TAU in phase 2, with a 2-week overlap between phase 1 and 2. Phase 3 was an 8-week treatment-free follow-up period.
• CBT consisted of 16-20 face-to-face sessions and 9 computerized lessons utilizing Good Days Ahead. TAU consisted of other types of psychotherapy, which were not specified.

Results

• Overall, 93 patients were randomized to receive SPRAVATO+CBT (n=47) and SPRAVATO+TAU (n=46) groups.
• Of the 93 patients, 84 were retained through week 3 and comprised the modified intent-to-treat group (women, 64.3%; mean age, 38.0 years).
• Feasibility was achieved, with retention rates of 90.3% through week 4 (completion of SPRAVATO induction phase), 77.4% through week 18 (completion of CBT among randomized subjects), and 74.2% through week 26 (end of study).
• Improvements from baseline through week 18 favored the SPRAVATO+CBT group over the SPRAVATO+TAU group for BSSI scores (LSMD: -6.01 vs -4.10; P=0.025), Clinician Global Improvement Scale for Suicide Severity scores (-0.81 vs -0.49; P=0.011), and composite MADRS scores (-11.29 vs -7.52; P=0.009).
• The following did not show a significant difference between both treatment groups: MADRS SI item (LSMD: -1.37 vs -0.98; P=0.088), C-SSRS ([ideation only]; -0.80 vs     -0.93; P=0.623), time to suicide-related events (ie, events requiring hospitalization, SI requiring emergency department visit, suicide attempts or deaths, 75% increase from baseline in BSSI score; P=0.790).
• Common adverse events (AEs) reported in the SPRAVATO+CBT and SPRAVATO+TAU groups included headache (18 vs 17 patients), nausea (12 vs 14 patients), respiratory symptoms/infections (10 vs 15 patients), and musculoskeletal pain (11 vs 10 patients).
  • Two deaths (1 suicide, 1 unintentional motor vehicle accident) and 24 serious AEs were reported.

Krivosova et al (2026)⁹ conducted a real-world retrospective exploratory study to evaluate factors associated with response to intranasal SPRAVATO in patients with TRD or treatment-resistant bipolar depression.

• Overall, 32 patients (women, 59.4%; mean age, 57.6 years) received intranasal SPRAVATO over 2 months (12 administrations); 25% (8/32) of patients received adjunctive psychotherapy.
• SPRAVATO treatment was associated with improvements in depressive symptoms, with remission (MADRS score ≤10) achieved in 43.8% (14/32) of patients and response (≥50% reduction in MADRS) achieved in 46.9% (15/32) of patients after 12 administrations.
• Adjunctive psychotherapy was the only factor significantly associated with remission (P=0.0002).
• Adverse effects related to SPRAVATO treatment were noted in 25% of patients.
  • Commonly reported adverse effects included nausea (9.4%), increased blood pressure (9.4%), urinary incontinence (9.4%), and dissociation (3.1%).
• The study did not report safety outcomes according to psychotherapy status.
• The results of this study are considered preliminary and should be interpreted with caution. There were no corrections for multiple comparisons.

Gutiérrez-Rojas et al (2025)⁶conducted a retrospective, observational, multicentric study to assess the effectiveness and tolerability of SPRAVATO in patients with TRD in a compassionate use program in Spain. Efficacy of treatment was assessed with the MADRS at four time points: baseline, 28, 90, and 180 days of treatment.

• 71 patients (women, 70%; mean age, 54.6) were enrolled with a mean baseline MADRS score of 38.3 ± 5.9.
• Concomitant antidepressant medications included SSRIs (38%), SNRIs (63.4%), TCAs and MAOIs (57.7%), mood stabilizers (32.4%), and atypical antipsychotics (46.5%).
• 46.5% of the patients also received cognitive behavioral therapy (not SPRAVATO-assisted CBT).
• Clinical response to SPRAVATO was observed by a significant reduction in MADRS total score (P≤0.0001 at all timepoints) from baseline (38.3 ± 5.9) at 28 days (23.4 ± 12.9), 90 days (16.9 ± 11.2), and 180 days (14.1 ± 11.5).
• CBT was significantly associated with lower MADRS scores after 90 days (13.1 vs 16.1; P=0.021) and 180 days of treatment (12.3 vs 16.1; P=0.021) compared with those who did not receive CBT.
• Overall, ≥95% of patients experienced an AE, with the most frequently reported being dissociation (56.3%), dizziness (36.6%), sedation (31.0%), drowsiness (28.2%), and paresthesia (28.2%). AEs were not analyzed for the SPRAVATO + CBT cohort.

Roullet et al (2025)⁵ conducted a retrospective pilot study to evaluate SPRAVATO administered in conjunction with psychotherapy in patients with TRD and comorbid PTSD.

• Overall, 6 patients completed a 24-week treatment program consisting of intranasal SPRAVATO (initial dose, 28-56 mg; followed by 56 or 84 mg twice weekly for 4 weeks and then 56 or 84 mg once weekly during a 20-week optimization/maintenance phase). Five patients were taking concomitant antidepressants and/or anxiolytics.
• All patients received concomitant psychotherapy, including supportive therapy, EMDR, or hypnosis therapy, integrated with SPRAVATO administration.
  • EMDR treatment phases began before SPRAVATO administration and continued during the period of peak SPRAVATO effects.
  • Supportive and hypnosis therapy sessions were also conducted during SPRAVATO administration and continued as its effects diminished.
• 5 of 6 patients demonstrated improvement in depressive symptoms. By week 23/24, the mean MADRS score decreased by 12.6 points from a baseline mean of 29, and 5 patients experienced reductions of >10 points.
• By week 23/24, the mean PCL-5 score decreased by 25.1 points from an average of 54.3 at baseline.  
• Rotharmel et al (2025)¹⁰ conducted a retrospective observational study in 22 patients with TRD and comorbid PTSD to primarily describe trauma re-experiencing episodes during SPRAVATO sessions. However, the study also explored response (≥50% improvement in MADRS) and remission (MADRS <10) as well as the association between CBT/EDMR and response. The results below are focused on this relationship.
• 54.5% of patients received SPRAVATO as well as CBT or EMDR.
• After ~6 months of treatment, response and remission rates on the MADRS were 45.5% and 22.7%, respectively.
  • PTSD symptom improvement and remission rates (according to investigators’ clinical judgment) were 45.5% and 18.2%, respectively.
• Neither CBT nor EMDR was associated with depressive response (Fisher’s exact test; P=1.00) or PTSD improvement (Fisher’s exact test; P=0.675).  

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 13 July 2026.