Development of Ketamine Administration as a Treatment for Chronic PTSD
Abigail B. Collins, BS; Sarah B. Rutter, MA; and Adriana Feder, MD
Psychiatric Annals, 2020, 50, (2), 68-76.
doi : 10.3928/00485713-20200109-01
Posttraumatic stress disorder (PTSD) is a highly prevalent, chronic, and dis-abling condition for which currently available pharmacotherapies are insuf-ficiently effective. Ketamine, which is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, has emerged as a promising and rapid-act-ing novel treatment intervention for this disorder. Findings from a proof-of-concept, randomized, controlled cross-over study of single-dose intravenous ketamine administration (compared to single-dose midazolam) in patients with chronic PTSD suggest that ketamine is associated with rapid improvement in core PTSD symptoms and comorbid depressive symptoms, and is generally well tolerated. Additional research is needed to confirm its efficacy and safe-ty for patients with PTSD. Results from ongoing trials of repeated intravenous administration for PTSD are expected to yield more definitive evidence. Po-tential mechanisms of action as well as future research directions are discussed.
Grants : Ketamine studies for posttraumatic stress disorder (PTSD) conducted at the Icahn School of Medicine at Mount Sinai have been funded by a grant (W81XWH-08-1-0602) from the US Army Research and Materiel Command, a National Alliance for Research on Schizophrenia & Depression Independent In-vestigator Award from the Brain and Behavior Research Foundation, technology development awards from Mount Sinai Innovation Partners, and by a generous donation from Mr. Gerald Greenwald and Mrs. Glenda Greenwald for the conduct of ketamine studies for PTSD at Icahn School of Medicine at Mount Sinai.Disclosure: Adriana Feder is a named co-inventor on a patent application in the United States, and on several issued patents outside the US, filed by the Icahn School of Medicine at Mount Sinai related to the use of ketamine for the treatment of posttraumatic stress disorder.
Posttraumatic stress disorder (PTSD) is a chronic and disabling condition that can develop after a traumatic event (eg, exposure to actual or threatened death, serious injury, or violence) and has an estimated lifetime prevalence of 7.8% in the general population.1
The disorder is characterized by four symptom clusters: (1) intrusion symptoms, (2) avoidance, (3) negative alterations in cognition and mood, and (4) altera-tions in arousal and reactivity.
Currently available pharmacotherapies for PTSD are insufficiently effective, with only two medications, the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine, approved by the US Food and Drug Administration. SSRIs and other off-label treatments (eg, venlafaxine) are frequently ineffective or only partially ef-fective, often necessitating treatment with combinations of medications with insufficient empirical guidance. Thus, there is an imperative need for novel pharma-cotherapeutic interventions for this disabling disorder.
DEVELOPMENT OF A NOVEL TREATMENT INTERVENTION FOR PTSD
Ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, had been in use as an anesthetic agent for several decades before the idea first surfaced that it might help alleviate PTSD symptoms. In the year 2000, a single intravenous (IV ) infusion of a subanesthetic dose of ketamine was first reported to rapidly reduce depressive symptoms in patients with major depression,2 and subsequent research on IV ketamine administration has shown significant promise for treatment-resistant depression (TRD).3 These initial findings led to the conduct of the first proof-of-concept, random-ized controlled trial (RCT) of IV ket-amine for PTSD, which was funded by the US Army Research and Materiel Command and led by author AF in collaboration with the principal investigator (Dennis Charney, MD, Icahn School of Medicine at Mount Sinai).4
At the time, there was concern in the field that ketamine, a dissociative anesthetic, might potentially worsen PTSD symptoms, including dissociation. Published chart review and obervational studies involving ketamine administration to patients in the aftermath of trauma exposure but not to patients with chronic PTSD had yielded mixed results. A retrospective chart review study of 56 moderately injured accident survivors found significantly higher PTSD symptoms 1 year after injury in patients who had received esketamine during ambulance transport than in those treated with racemic ketamine or opioid medica-tion.5 Acute stress symptomatology was also strongly elevated in the esketamine group but only mildly elevated in the racemic ketamine group, sug-gesting that peritraumatic ketamine administration might increase the risk of PTSD symptom development.5 The same research group subsequently con-ducted a prospective, naturalistic study of 50 moderately injured accident victims who received a single infusion of racemic ketamine, opioids, or non-opioid analgesics.6 When subsequently screened within 3 days of hospital admission, patients treated with ketamine exhibited significantly higher acute stress disorder symptoms compared to the other groups.6 Both esketamine and racemic ketamine were co-admin-istered with midazolam.
By contrast, a retrospective chart review study of a larger sample of US service members who had suffered burns during deployment, ranging in severity, yielded opposite findings. Of the 147 service members who underwent at least one surgical operation at the burn center, the group that had received intraoperative ketamine showed significantly lower prevalence of PTSD (32 of 119) than the group that had not (13 of 28) despite higher burn severity and number of surgeries in the former group.7 Although a more recent retro-spective chart review study in a larger sample of burned service members who had received intraoperative ket-amine (n = 189) or had not (n = 100) did not replicate these findings, PTSD prevalence did not differ statistically between the two groups, suggest-ing that intraoperative ketamine after trauma does not increase risk of PTSD development.8 A recent retrospec-tive matched cohort study of US ser-vice members injured in combat who received (n = 107) or did not receive (n = 1,051) ketamine for analgesia during hospitalization yielded simi-lar findings, but dosing data were not available.9
It is possible that these diverging findings might be due to differences in administered doses of ketamine (sub-anesthetic vs anesthetic) or co-admin-istered medications (eg, midazolam). Further, given the results from a da-tabase review suggesting that opioid administration during acute care after combat injury might protect against the emergence of PTSD,10 it is difficult to interpret findings from the studies by Schönenberg et al.5,6 because opioids were used as the comparison condition. After publication of studies of ket-amine administration in the after-math of trauma, several case reports of single-dose IV ketamine administered to patients with chronic PTSD ap-peared in the literature. A 23-year-old veteran with chronic treatment-resistant PTSD and major depressive disorder (MDD) experienced rapid PTSD and depressive symptom im-provement after IV ketamine adminis-tration combined with propofol, lasting for 15 days.11 A 26-year-old veteran with comorbid MDD and PTSD, who was also receiving midazolam, propo-fol, and lidocaine, experienced rapid remission of depression and anxiety, followed by relapse 14 days later.12 In another report, a 7-year-old child with PTSD and severe emotional and ag-gressive outbursts showed dramatic improvement in all symptoms, and was able to speak during psychotherapy for the first time about his past abuse history after receiving IV ketamine for two procedures (tonsillectomy and neuroimaging) separated by 3 months; symptom improvement lasted 13 and 8 days, respectively.13 Additionally, a retrospective analysis of oral ketamine augmentation in patients with TRD, and several with comorbid PTSD or severe anxiety, found a 70% reduc-tion in inpatient hospital days and a 65% reduction in hospital admissions (Table 1).14