SUMMARY

• SPRAVATO has not been formally evaluated in patients with treatment-resistant depression (TRD) and posttraumatic stress disorder (PTSD), though patients with comorbid PTSD were included in the phase 3 TRD studies.
• Across the phase 3 trial program in TRD, 12/1601 patients (0.7%) treated with SPRAVATO had PTSD upon enrollment based on the Mini International Neuropsychiatric Interview.¹
• Results from 5 retrospective analyses describing the effect of SPRAVATO administration in patients with comorbid TRD and PTSD have been reported and are summarized below. Overall, improvements in depressive and PTSD symptoms were observed following treatment with SPRAVATO.^2-6

CLINICAL DATA

Zhang et al (2025)² conducted a retrospective analysis of 119 United States veterans (aged 27 to 77 years) with TRD at the VA San Diego Medical Center, 88 (73.9%) of whom had been diagnosed with comorbid PTSD. Ninety-nine veterans received SPRAVATO and 20 received intravenous racemic ketamine. SPRAVATO was administered at a typical dose of 56 mg initially, with most patients (75%) undergoing dose titration to 84 mg in subsequent sessions. All participants completed at least 8 SPRAVATO or ketamine treatment sessions between January 2020 and June 2022. Depression symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9) and PTSD symptoms were assessed using the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5). An analysis was also performed to evaluate how a history of comorbid traumatic brain injury (TBI; n=38) and obstructive sleep apnea (OSA; n=61) affected response to treatment when compared to cohorts without TBI/OSA.

• After 8 sessions, both treatments led to a significant reduction in the PHQ-9 score (mean change, 3.43±0.79; P=0.001) and in the PCL-5 score (mean change, 10.56±14.84; P=0.012).
• PTSD symptom change over the course of treatment did not differ significantly between those with and without TBI. OSA severity, assessed using the apnea-hypopnea index (AHI), did not significantly affect PTSD symptom trajectories (P=0.095), and no interaction was found between AHI and the ketamine session (P=0.151).
• There was no significant effect of TBI history (P= 0.697) or OSA (AHI; P=0.658) on PHQ-9. Mixed-effects modeling showed that treatment type did not significantly influence PCL-5 (P=0.436) or PHQ-9 (P=0.855).
• Only patients (n=3) with both comorbid TBI and severe OSA were found to have worsening depression symptoms.

Titone et al (2023)³ conducted a retrospective analysis to evaluate the efficacy of SPRAVATO and the possible interference of OSA on treatment efficacy in Veterans with TRD and PTSD who were receiving SPRAVATO between January 2020 and April 2021 (N=60) and had valid PCL-5 questionnaire data collected before and/or during treatment. Veterans received SPRAVATO twice weekly for the first 4 weeks, followed by a once-weekly or less dosing schedule for those who continued with the treatment. The starting dose of SPRAVATO was 56 mg for the first treatment, which was up-titrated (84 mg) or down-titrated (28 mg) based on clinical response. The study was restricted to 13 weeks of treatment (17 doses of SPRAVATO).

• There was a negative association between PTSD symptoms, as assessed by the PCL-5 scores, and treatment session number (bivariate Pearson correlation [b]=-0.95, t-tests [t](474.29)=-10.40, P<0.001), indicating that PTSD symptoms decreased over time with SPRAVATO treatment. Similar results were obtained for depressive symptoms as assessed by the Patient Health Questionnaire-9 (PHQ-9) scores (b=-0.22, t[46.00]=-4.60, P<0.001).
• There was a significant interaction between apneas and hypopneas per hour (AHI) and treatment session number predicting PCL-5 scores (b=0.40, t[182.54]=2.45, P=0.015), indicating a significant interference of OSA on the efficacy of SPRAVATO for PTSD symptoms. There was no significant interaction between AHI and treatment session number predicting PHQ-9 scores (b=0.06, t[20.09]=0.69, P=0.496), indicating that depression response to SPRAVATO was not affected by OSA severity.

Artin et al (2022)⁴ conducted a retrospective analysis to evaluate clinical outcomes in Veterans with comorbid TRD and PTSD who had received at least 2 doses of SPRAVATO between January 2020 and March 2021 (N=35) and had elevated PHQ-9 (>15) and PCL5 scores (>33) at baseline. Veterans with prior ketamine exposure were excluded. During the induction phase, treatment with SPRAVATO 56 mg was initiated followed by flexible dosing twice weekly for 4 weeks (a total of 8 treatments). During the maintenance phase, Veterans who chose to continue treatment after induction received SPRAVATO once weekly for an additional 8 treatments (n=19). The primary outcome was a change in the PHQ-9 and PCL-5 scores across the treatment-induction phase.

• In the induction phase, PHQ-9 scores changed from 19.8 (standard error of mean [SEM]=0.7) at treatment 1 (T1) to 14.7 (SEM=0.8) at T8 (week 4) with a mean reduction of 5.1 (SEM=0.7). At T8, 5 (14%) Veterans had a 50% reduction in the PHQ-9 score, 2 achieved remission (PHQ-9<5), and 18 (51%) had a reduction of >6 in the PHQ-9 score. In the maintenance phase, PHQ-9 scores changed from a mean of 15 (SEM=1.1) at T9 to a mean of 14.2 (SEM=1.2) at T16.
• In the induction phase, PCL-5 scores changed from 54.8 (SEM=2) at T1 to 39.3 (SEM=2.9) at T8 with a mean reduction of 15.5 (SEM=2.4). At T8, 16 (46%) Veterans had a meaningful clinical response (≥30% reduction in the PCL-5 score), and 5 (15%) had remission (PCL-5 dropped below the diagnostic cutoff score of ≤33). In the maintenance phase, PCL-5 scores changed from a mean of 39.3 (SEM=3.2) to a mean of 33.2 (SEM=2.9).
• Among all subdomains of PTSD, there was a mean reduction of 3.6 points in cluster B (intrusion/re-experiencing symptoms), 1.6 points in cluster C (avoidance symptoms), 6.5 points in cluster D (mood and cognition symptoms), and 5 points in cluster E (arousal symptoms).
• A significant positive correlation was noted between changes in the PHQ-9 and PCL-5 scores (r=0.47, P=0.005).

Rothärmel et al (2022)⁵ conducted an open-label, single-arm, retrospective pilot study that evaluated the efficacy and safety of SPRAVATO in adult patients with comorbid TRD and chronic PTSD who received treatment between February 2020 and November 2021 (N=11). SPRAVATO was administered at 56 or 84 mg twice weekly during weeks 1-4, 56 or 84 mg once weekly during weeks 5-8, and 56 or 84 mg once every 1 or 2 weeks from week 9 onwards. All patients received SPRAVATO coadministered with a newly initiated oral antidepressant, and voluntary patients received trauma focused psychotherapy (once every 1 or 2 weeks) within 1 week of SPRAVATO administration. The primary outcome was changes in the MADRS score between treatment initiation at baseline and 6 months of treatment.

• The mean (SD) MADRS score changed significantly from 38.6 (6.4) at baseline to 18.2 (10.0) at 6 months of SPRAVATO administration (P<0.001).
• Overall, 1 (9.1%), 5 (45.5%), and 7 (63.6%) patients achieved response (≥50% reduction in the MADRS total score) after 1, 3, and 6 months, respectively. At 3 and 6 months, 3 (27.3%) patients achieved remission (MADRS total score ≤12), including 1 (9.1%) patient who achieved remission after 1 month of treatment initiation.
• There was a significant decrease in the PHQ-9 scores (P=0.012) and a significant increase in the Global Assessment of Functioning scores (P=0.001) over the treatment period.
• The percentage of patients who were moderately to severely suicidal reduced from 63.6% at baseline to 27.3% after 1 month and to 20% after 3 months.
• PTSD symptoms were assessed through the PCL-5 scores before and after psychotherapy (n=7) with a mean interval of 5.6 months. The mean (SD) score changed from 58.6 (3.9) before treatment to 32.7 (16.0) after treatment; the mean (SD) relative improvement was 45.3% (25.5).
• A total of 3 patients discontinued SPRAVATO before 6 months (remission, n=1; travel difficulties, n=1; lack of efficacy, n=1).
• The most frequent adverse events (AEs) included dissociation (n=7), somnolence (n=4), nausea (n=4), sedation (n=3), dizziness (n=3), anxiety (n=2), and increased blood pressure or hypertension (n=1). No discontinuation due to AEs was reported. No serious AEs or safety issues due to repeated SPRAVATO administration were reported throughout the study.

Rothärmel et al (2024)⁶ extended their earlier pilot study by analyzing data from 22 adult patients (aged 21-62 years) with TRD and comorbid PTSD who had received SPRAVATO between February 2020 and March 2023 across 11 psychiatric centers. Approximately 73% of patients had unipolar depression and 27% had bipolar depression. All patients experienced at least 1 trauma-related flashback during the SPRAVATO sessions. The objective of the study was to evaluate how flashbacks impacted the trajectories of these patients. Majority of the patients (86%) had complex PTSD.

• Benzodiazepines were prescribed to 77.3% of patients. Antipsychotics were coprescribed in 54.5% of patients (n=12), and psychotherapy (cognitive behavioral therapy/eye movement desensitization and reprocessing) was ongoing in 54.5% of patients.
• Flashbacks typically emerged between the 4^th and 5^th session (SD, 5.1), with 77.3% occurring within the first 5 sessions.
• Overall, 72.7% of patients saw flashbacks resolve over time, whereas 27.3% of patients discontinued treatment due to persistent flashbacks.
• For depression and PTSD, respectively, the clinical response rate was 45.5% and 45.5% and the remission rate was 22.7% and 18.2% at approximately 6 months.
• Flashback impact was significantly associated with PTSD response: response was noted in 91.7% vs 30% of patients with light to mild vs severe, respectively (P=0.006).
• Neither antipsychotic use nor psychotherapy showed a significant association with PTSD or depression treatment outcomes.
• There were feelings of cartharsis following SPRAVATO-induced flashbacks in 12 cases but these feelings were not significantly associated with PTSD response.
• Adverse effects included depersonalization/derealization (without flashbacks; 59.1%), nausea/vomiting (27.3%), sensory hypersensitivity (27.3%), headache (22.7%), sedation (13.6%), and hypertension (4.6%).

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 21 August 2025.

This response excludes case reports and case series.