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Use of SPRAVATO in Patients With Comorbid Post-traumatic Stress Disorder (PTSD)

Last Updated: 12/19/2023


  • SPRAVATO has not been formally evaluated in patients with treatment-resistant depression (TRD) and post-traumatic 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 3 retrospective analyses describing the effect of SPRAVATO administration in patients with comorbid TRD and PTSD have been reported and summarized below.2-4


Titone et al (2023)2 conducted a retrospective analysis to evaluate the efficacy of SPRAVATO and the possible interference of obstructive sleep apnea (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 PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (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 (apnea-hypopnea index [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)3 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)4 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 Montgomery-Åsberg Depression Rating Scale (MADRS) score between treatment initiation at baseline and 6 months of treatment.

  • The mean (standard deviation [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.

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 02 November 2023.


1 Data on File. Esketamine. Email Communication.  
2 Titone MK, Hunt C, Bismark A, et al. The effect of obstructive sleep apnea severity on PTSD symptoms during the course of esketamine treatment: a retrospective clinical study. [published online ahead of print August 04, 2023]. J Clin Sleep Med. doi:10.5664/jcsm.10746.  
3 Artin H, Bentley S, Mehaffey E, et al. Effects of intranasal (S)-ketamine on veterans with co-morbid treatment-resistant depression and PTSD: a retrospective case series. EClinicalMedicine. 2022;48:101439.  
4 Rothärmel M, Benosman C, El-Hage W, et al. Efficacy and safety of intranasal esketamine in patients with treatment-resistant depression and comorbid chronic post-traumatic stress disorder: open-label single-arm pilot study. Front Psychiatry. 2022;13:865466.