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ANNALS OF CLINICAL PSYCHIATRY 2019;31(4):271-276
Introduction
Combat veterans are at high risk for the development of posttraumatic stress disorder (PTSD) and substance use disorders. Ketamine has been shown to be an effective treatment for numerous mental health disorders, although research on its efficacy in combat-related PTSD in veterans is very limited.
Combat veterans are at high risk for the development of posttraumatic stress disorder (PTSD) as well as comorbid mental health and substance use disorders that can lead to significant functional impairment and morbidity. The estimated prevalence of PTSD ranges from 27% to 37% in Vietnam armed forces veterans, 10.1% for Gulf War veterans, 11.5% for veterans deployed to Afghanistan, and 18% for those deployed to Iraq. It is estimated that less than half of returning veterans receive mental health treatment, and of those who do seek treatment, only half receive quality care. Ketamine, a widely used anesthetic, recently has been found to effectively treat mental health disorders, including treatment-refractory major depressive disorder, bipolar depression, suicidality, and PTSD. This study sought to better characterize the role that ketamine could play in the treatment of PTSD.
Methods
The study population consisted of 30 US military veterans with combat-related PTSD. Participants underwent a standard induction series of six 1-hour ketamine infusions with the goal of obtaining a transpersonal dissociative experience. Participants were given a series of self-report questionnaires to assess for changes in symptoms of depression, PTSD, and substance use prior to the first and sixth infusions.
The study population consisted of 30 US military veterans. Inclusion criteria included participants who previously served in a designated combat zone and who had been diagnosed with combat-related PTSD by clinicians at the Department of Veterans Affairs. Participants were men and women aged 18 to 75 who passed medical screening, were not receiving lamotrigine or any monoamine oxidase inhibitors and did not have psychosis. The Institutional Review Board at IntegReview (Austin, Texas) approved the study (Protocol KRP001), and written informed consent was obtained from all study participants. Procedures Eligible participants were identified by the clinical staff.
After consenting to participate in the study, each participant underwent a psychosocial evaluation by a trained mental health professional. Medical records from the Department of Veterans Affairs were reviewed. Military service records from the Department of Defense were also reviewed to ensure that the participants had served in a combat zone. Participants underwent a standard induction series of six 1-hour ketamine infusions. The first infusion began with a dose of 1 mg/kg of the participant’s body weight, with a maximum of 60 mg on the first 1-hour infusion.
There were no boluses given. After the first infusion, the dose was adjusted up or down, with the goal of attaining what the investigators referred to as the psychotropic therapeutic response (PTR). The treatment center defined the PTR as the dose at which the patient experiences the optimum transpersonal and transformative experience. The major assumption that underlies this treatment strategy is that the experiential (or “psychedelic”) aspect of ketamine infusion therapy is not a “side effect” to be eliminated, but rather an essential component of the treatment. The PTR is an individualized dose specific to each patient. For each infusion, the patient sat in a recliner in a private room with one staff member in attendance for the entire 1-hour infusion and for at least 30 minutes afterward. The 6 infusions were performed over a 2- to 3-week period depending on each patient’s availability. Patients had IV access established and were monitored using continuous pulse oximetry and 3-lead cardiac monitoring.
Blood pressure was recorded prior to infusion and at regular intervals during and after each infusion. Most patients watched videos of nature scenes with a relaxing soundtrack. Some patients chose to listen to their own music with or without the video playing. Each infusion room was decorated to create a relaxing ambiance. Although historically used as an anesthetic agent, the use of ketamine in this context would be more appropriately referred to as ketamine for non-anesthetic indications (KNAI). Study design and outcome measures This was an observational case series of US veterans who received ketamine infusion therapy for the treatment of PTSD. Each participant was given a series of self-report questionnaires prior to the first and sixth ketamine infusions.
The PTSD Checklist for DSM-5 (PCL-5), a 20-item self-report measure, was administered to monitor changes in PTSD symptoms.18 The Patient Health Questionnaire (PHQ-9) was used to screen for symptoms of depression.19 Alcohol consumption, behaviors associated with alcohol consumption, and alcohol-related problems were screened for using the Alcohol Use Disorders Identification Test (AUDIT).20 The Drug Abuse Screen Test (DAST-10) was administered to screen for drug abuse and the negative consequences of drug use.21 In addition, participants were asked about current marijuana use and history of recreational ketamine use. Participants were also asked to describe their experience regarding the dissociative and psychomimetic effect of the ketamine and their perceptions of the value of PTR as part of their therapy.
Results
Symptoms of depression as measured by the change in score on the Patient Health Questionnaire decreased significantly from an average of 18.9 to 9.5 (P < .001). Similarly, symptoms of PTSD as measured by the change in score on the PSTD Checklist for DSM-5 dropped significantly from an average of 56.2 to 31.3 (P < .001). Self-reported levels of substance use did not significantly decrease during the study period, although the level of
use trended down.
Although the ketamine doses administered in this study were generally higher than those in previously reported research, the participants were responsive to verbal stimuli at all times during the infusion. The doses were gradually increased on each infusion based on a given participant’s response during the previous infusion. Ketamine dose calculations and final doses are presented in TABLE 1. Other than some occasional nausea, none of the participants experienced any significant adverse events or significant vital sign abnormalities. Comparisons of self-report questionnaires pre- and post-infusion are demonstrated in TABLE 2. Individual responses on the PHQ-9 and PCL-5 for pre-and-post infusions are outlined in TABLE 3. No participants endorsed increased symptoms on the PHQ-9, and 2 participants (7%) reported no change in symptoms.
On the PCL-5, 3 participants (10%) endorsed increased symptoms. On measures of substance abuse (DAST-10 and AUDIT), 6 and 7 participants had missing data, respectively. While self-reported levels of substance abuse did not significantly decrease during the study period, it appeared that ketamine infusion did not predispose patients to increased substance use, and the level of use trended down. Anecdotally, some participants reported a decreased desire to drink alcohol after receiving the ketamine infusions. On a measure of depression (PHQ-9), symptoms of depression dropped significantly, from an average score of 18.9 to 9.5, a 50% reduction, with a Cohen’s d effect size of 1.38 (F = 90.0, P < .001). Finally, symptoms of PTSD as measured by PCL-5 also dropped significantly, from an average score of 56.2 to 31.3, a 44% reduction, with a Cohen’s d effect size of 1.42 (F = 55.6, P < .001).
Discussion
This observational study suggests that ketamine infusion therapy could be a valuable tool in the treatment of combat-related PTSD. Case reports have indicated that ketamine or ketamine analogs may be an effective treatment for veterans with PTSD.22 McGhee et al23 reported the somewhat serendipitous finding that PTSD in Operation Iraqi Freedom/Operation Enduring Freedom veterans who received ketamine during surgeries was 27% compared with 46% in those who did not receive ketamine. In a recent study by Albott et al,24 veterans with comorbid treatment-resistant depression (TRD) and PTSD were administered 6 ketamine infusions of 0.5 mg/kg over a 12-day period. The researchers found a significant decrease and remission of both symptoms of depression and PTSD over the study period, with a median length of symptom relapse of 20 days for depression and 41 days for PTSD.24 As such, ketamine infusions appear to be a promising treatment for veterans with TRD and/or PTSD, and further research is needed to understand ketamine’s safety and efficacy in this population.
To our knowledge, this is the first study to investigate the efficacy of high-dose ketamine infusion treatment of PTSD in combat veterans. There is a rapidly growing body of literature showing that ketamine is a safe, effective, and novel therapy for TRD.8,13-16,24 Given the alarming number of veteran suicides in the United States, a more effective means for treating PTSD and TRD is urgently needed. Many of the current theories of how ketamine works to treat TRD center around its action at the N-methyl-d-aspartate receptor and the alpha-amino-3-hydroxy-5-methyl- 4-isoxazole propionic acid receptor.6 Anecdotally, many of the patients treated at our center report that the ability to achieve a change in their cognitive paradigms and the ability to “reset” their thought patterns helps them to radically alter the way in which they contextualize their traumatic experiences. As our results show, this can lead to a significant decrease in symptomatology in this population. While this study was not designed to elucidate the exact role of the experiential component, it does demonstrate successful outcomes with ketamine doses that are higher than the traditional 0.5 mg/kg, which is the dose administered in many previous studies. Some authors have suggested that ketamine therapy may increase the symptoms of PTSD.25 In our study, 3 of 30 participants endorsed increased symptoms; however, the 2 previous studies that showed an increase in symptoms looked at the administration of ketamine shortly after a traumatic injury, which is a very different context than the patients we were treated in this study.25,26 It is not entirely clear why 3 veterans endorsed an increase in their PTSD symptoms, especially in light of the fact that 2 of the 3 had a decline in their depressive symptoms.
Additionally, none of the participants reported subjectively that the experience worsened their symptoms. We have found that the appropriate “set and setting” makes an enormous difference in how the ketamine experience is perceived. The staff member in attendance plays a very proactive role in helping to guide and ground the patient through his/her ketamine journey. In this regard, our treatment strategy diverges from a more traditional “infusion center” model in that it incorporates elements of shamanistic healing that have historically been absent
from Western medicine. Further studies are needed to better characterize the role of the experiential component of ketamine and PTSD symptomatology, as well as if any individuals experience increased PTSD symptomatology from ketamine infusions.
Limitations
There are several limitations to this study. This was an observational study and did not have a placebo arm. Also, because the final set of survey instruments was administered before the sixth infusion, the data demonstrate the effect of ketamine after 5 infusions. We suspect that the effect size would have been greater if the instruments could have been administered several days after the sixth infusion. In our clinical experience, however, we have found that compliance with questionnaires and psychological screening instruments in the veteran population can be quite challenging to obtain after they have finished their induction series of infusions. We felt that it would be better to have a complete data set after 5 infusions rather than to risk losing patients to follow-up after they completed their full series of 6.
Another limitation was the ability to assess the effect of ketamine on veterans’ use of alcohol and illicit drugs. A few of the veterans in this study did not fill out the AUDIT and the DAST-10; thus, there was an incomplete data set with regard to those instruments. Several veterans also admitted that they initially underreported their use of alcohol and illicit substances because they had not yet built a sense of trust with the treatment team. Nonetheless, there was a trend toward a decrease in alcohol use. Anecdotally, several participants reported a significantly decreased desire to drink alcohol. This element of ketamine therapy deserves further study. Finally, this study did not look at long-term outcomes but rather the change in PTSD symptomatology over the course of the 2- to 3-week induction series. In our clinical experience, patients will need a “booster” infusion at regular intervals in order to maintain the improvement in symptomatology.
Conclusion
We feel that this study provides valuable evidence of the role that ketamine can play in the treatment of combat-related PTSD. Specifically, the success we had with significantly higher doses than those used in other studies suggests that the experiential or psychedelic effect of ketamine may be a critical element of how it works therapeutically, rather than an adverse effect to be eliminated. Further study is clearly needed to better elucidate ketamine’s mechanism of action with regard to the treatment of PTSD.
Disclosures
Dr. Bonnett is the medical director and owner of Klarisana, the ketamine infusion center where this study was conducted. To preserve objectivity, outcome measures and statistical analyses were verified by Cassie Ross, PsyD, who has no financial relationship with Klarisana. Dr. Jain has received research support from or served as a consultant to, speaker for, or on the advisory board of Addrenex, Alkermes, Allergan, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Osmotica, Otsuka, Pamlab, Pfizer, Shire, Sunovion, Supernus, Takeda, Teva, and Tris Pharmaceuticals. Drs. Ross and Wolfson have no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.
