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Use of SPRAVATO in Patients with Comorbid Post-Traumatic Stress Disorder (PTSD)

Last Updated: 01/13/2023


  • 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 2 retrospective analyses describing the effect of SPRAVATO administration in patients with comorbid TRD and PTSD have been reported and summarized below.2, 3


Artin et al (2022)2 conducted a retrospective analysis to evaluate clinical outcomes in patients 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 Patient Health Questionnaire scores (PHQ-9; >15) and Patient Check List scores (PCL5; >33) at baseline. Patients 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, patients 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%) patients 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%) patients 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)3 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 (GAF) 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 19 December 2022.


1 Data on File. Esketamine. Email Communication.
2 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.
3 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.