Is Ketamine Infusion an Effective Treatment for Post-Traumatic Stress Disorder? A Meta-Analysis

Abstract. Post-traumatic stress disorder (PTSD) affects ~ 6% of adolescents and adults in the US. Increased N-methyl-D-aspartate (NMDA) receptor activation leads to heightened intrusive memories and is associated with an increased risk of developing PTSD. Ketamine is an NMDA antagonist with ultra-rapid therapeutic action for treatment-resistant depression and suicide. In this meta-analysis, we assessed the effect of subanesthetic ketamine infusion on PTSD severity. Six databases were investigated according to PRISMA guidelines with quality assessments according to the NIH Quality Assessment tool. Eligible criteria included: 1) Randomized Control Trial (RCT) or cohort study 2) Used a single or multiple ketamine infusion(s) 3) Studies using another treatment for PTSD to which (2) is added 4) PTSD symptoms are measured at pre-infusion baseline and up to at least 40 minutes after infusion using a valid PTSD symptom measurement scale 5) Study included ≥ 5 patients. The primary outcome was the first measured value of PTSD symptoms after treatment completion. Meta-analysis using a random effects model was performed on pre-to-post changes in PTSD severity within ketamine treated patients and to compare ketamine to control outcomes. The search retrieved 526 articles. Nine articles met inclusion criteria: 5 RCTs and 4 cohort studies. Meta-analysis revealed that ketamine infusion reduced PTSD symptom severity (pre-post ketamine: standardized mean difference pre-to-post: 3.07, 95% confidence interval 1.54–4.60, P < 0.01). These results support ketamine infusions as an effective treatment modality for PTSD symptoms. Ketamine-assisted psychotherapy is shown to enhance ketamine effect and aid in prolonging remission. Further research is needed to provide effective and long-lasting PTSD treatment.

Introduction. Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder which is characterized by persistent vivid recall of past severe traumatic events [1]. It affects an estimated 6.0% of adults and 5.0% of adolescents in the United States [1, 2]. Because PTSD by definition is related to an experienced traumatic event, populations with significant exposure to traumatic events such as veterans and the victims of sexual assault/intimate partner violence have a markedly increased risk of developing PTSD [3, 4]. PTSD is associated with substantial comorbidities such as treatment resistant depression, substance abuse, suicidality, loss of quality of life and considerable societal burden through loss of productivity [5]. The limited number of pharmacological agents currently approved for treatment of PTSD lack significant efficacy, and medications as well as psychotherapy have long latency for their onset of therapeutic actions. Two selective serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, are approved by the United States Food and Drug Administration (FDA) for treatment of PTSD [6, 7]. Unfortunately, less than 60% of patients with PTSD respond to SSRIs and only 20–30% of patients achieve full remission of symptoms [6, 7]. Pharmacological response is further diminished in patients with severe PTSD, such as veterans [8]. Due to the low efficacy of SSRIs, serotonin–norepinephrine reuptake inhibitors and atypical antipsychotic drugs are commonly used off-label as first line treatments [6, 9].

In light of the limited treatment effects of existing pharmacotherapy for PTSD, trauma- and trauma non-focused psychotherapies are the first line treatment modalities. Trauma focused approaches include cognitive behavioral therapies (CBTs) such as cognitive processing therapy, prolonged exposure therapy, eye movement desensitization and reprocessing and more recently, mindfulness-based cognitive therapy such as TIMBER (trauma interventions using mindfulness-based extinction and reconsolidation of trauma memories) [10, 11]. The trauma non-focused approaches are stress inoculation training and CBT as usual. However, with high dropout and non-response rates there is limited short lived efficacy for therapy as a sustained treatment [12].

While the active pursuit by the scientific community for a rapid and effective medication for PTSD is still ongoing [13], ketamine, a glutamate (N-methyl-D-aspartate type/NMDA) receptor antagonist and well known since 1960s for its anesthetic use, has recently proven in a pivotal trial to be efficacious in treatment resistant depression that led to its 2019 approval by the US FDA in its aerosol formulation for the intranasal route of usage [14–16]. Data is emerging for Ketamine’s ultra-rapid therapeutic actions (in 40-minutes) in chronic PTSD as well [15, 17]. In PTSD, increased NMDA receptor activation leads to heightened intrusive memories and is associated with an overall increased risk of developing PTSD [18–20]. Additionally, work by one of the authors and colleagues suggest that increase in the serum concentration of D-serine, an NMDA receptor co-agonist, can serve as a biological marker of severity and clinical response to ketamine and mindfulness therapy (TIMBER) in chronic PTSD and co-morbid treatment resistant depression [11]. Thus, extending its therapeutic effects on treatment resistant depression, ketamine has garnered attention as a potential treatment for PTSD as well. This development is important because ketamine’s therapeutic effects are ultra-rapid and in preliminary studies it has shown therapeutic effects in suicidality and substance abuse (opioids, alcohol, cocaine) as well [21].

Previous narrative reviews have discussed ketamine’s potentially unique role for the treatment of PTSD based on emerging evidence from both animal and human models [18, 22]. Clinical studies on the clinical efficacy of ketamine to treat PTSD are rapidly emerging and there is a need to synthesize the current state of evidence for clinical use. We conducted a systematic literature review and meta-analysis assessing the efficacy of subanesthetic intravenous ketamine (0.5–1 mg/kg) to reduce PTSD severity.

Methods. The systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [23]. This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO, Registration number: CRD42020184237) [24].

Search Criteria: PubMed, Embase, Cochrane, Clincialtrials.gov, Web of Science, and Google Scholar databases were searched on 4/2020. No limits on date range, place of publication, or language were used. The search terms for two databases which obtained the greatest number of abstracts are presented in Table 1.

Table 1 Search Terms
PubMed	(ketamine OR ketamin* OR ketalar OR calipsol OR ketanest OR ketaset OR calypsol OR kalipsol OR “ci 581” OR “S-ketamine” OR “S ketamine” OR “(S)-ketamine” OR “S(+)-ketamine” OR esketamine OR “R-ketamine” OR “R ketamine” OR “R,S ketamine” OR “(R)-ketamine” or “(R)-(−)-ketamine” OR “R(+)-ketamine” OR arketamine) AND (posttraumatic stress disorder OR “post-traumatic stress disorder” OR ptsd).
Embase	(‘posttraumatic stress disorder’/exp OR ‘posttraumatic stress disorder’ OR (posttraumatic AND (‘stress’/exp OR stress) AND (‘disorder’/exp OR disorder)) OR ‘post-traumatic stress disorder’/exp OR ‘post-traumatic stress disorder’ OR ‘ptsd’/exp OR ptsd) AND (‘ketamine’/exp OR ketamine OR ketamin* OR ‘ketalar’/exp OR ketalar OR ‘calipsol’/exp OR calipsol OR ‘ketanest’/exp OR ketanest OR ‘ketaset’/exp OR ketaset OR ‘calypsol’/exp OR calypsol OR ‘kalipsol’/exp OR kalipsol OR ‘ci 581’/exp OR ‘ci 581’ OR ‘s-ketamine’/exp OR ‘s-ketamine’ OR ‘s ketamine’/exp OR ‘s ketamine’ OR ‘(s)-ketamine’ OR ‘s(+)-ketamine’/exp OR ‘s(+)-ketamine’ OR ‘esketamine’/exp OR esketamine OR ‘r-ketamine’ OR ‘r ketamine’ OR ‘r,s ketamine’ OR ‘(r)-ketamine’ OR ‘(r)-(−)-ketamine’ OR ‘r(+)-ketamine’ OR arketamine).

All potential studies from the 6 databases were considered for eligibility and a manual search of relevant studies from the reference section of included studies were further reviewed.

Inclusion criteria: Studies were eligible for inclusion if: 1) Randomized control trail or cohort study 2) Used a single or multiple ketamine infusion(s) as intervention 3) Studies using another treatment for PTSD, to which (2) is added 4) PTSD symptoms are measured at pre-infusion baseline and up to at least 40 minutes after infusion using a valid PTSD symptom measurement scale 5) Study included 5 or more patients. Pediatric studies were excluded.

Outcome measures: The primary outcome is PTSD symptom severity measured on a validated measurement scale (e.g., PCL-5, CAPS-5, IES-R) before and after ketamine infusion treatment. Side effects and complications of infusion treatment, including but not limited to hypertension or headaches, were additional outcomes of interest.

Study Selection: Two groups of reviewers (C.M/N.v.H and H.K/B.P) independently screened for eligible studies by assessing title and abstract. If one reviewer deemed a study potentially relevant for inclusion, the full text was assessed for eligibility. Subsequently, all full texts were assessed for inclusion.

In case of a disagreement, consensus was reached through discussion between the two reviewer groups. If consensus was not reached upon initial discussion a third reviewer (L.M) was consulted as a tiebreaker, which led to agreement in all assessments.

Data Collection: The following data was extracted 1) Location of study, 2) Year of study, 3) Type of study, 4) Number of subjects enrolled, 5) Demographics, 6) Intervention, 7) Ketamine infusion treatment details, 8) Control arm treatment details (if present), 9) Duration, 10) Type of PTSD outcome measurement, 11) Timing outcome measurement, 12) Descriptive statistics of outcome measure 13) PTSD relapse rate, 14) PTSD scale, 15) Side effects of ketamine infusion treatment.

Quality Assessment: The refined version of the National Heart, Lung, and Blood Institute quality assessment tool was used to evaluate study quality in the present review [25]. Initial assessments of all studies were made independently by 2 reviewers (N.v.H and C.M). In case of a disagreement in quality assessment, consensus was reached through discussion between the 2 reviewers.

Data Analysis Plan: Random effects modeling was used for meta-analysis. Standardized mean differences between the ketamine and control groups at baseline and post infusion in each included study are reported. The standardized mean differences were pooled by using Hedges-g, which provides a small number correction. In order to estimate the between-study variance (tau), we used a restricted maximum likelihood procedure. R was used for all analyses (R Foundation for Statistical Computing, Vienna, Austria).

Meta-Analys of Results of RCTs and Cohort Studies. We analyzed each included study for their control and test group baseline and post interventions outcome score based on their respective PTSD scale. There was no significant difference at baseline between the ketamine and control groups in the RCTs (standardized mean difference: 0.10, 95% confidence interval -0.44 – 0.65, P = 0.34) (Figure 2).

Meta-analysis of all studies revealed that ketamine infusion reduced PTSD symptom severity substantially (ketamine standardized mean difference pre-to-post: 3.07, 95% confidence interval 1.54 – 4.60, P<0.01) (Figure 3). There were significant differences between the ketamine groups vs control groups of the RCTs at the follow up period (moderate standardized mean difference: -0.58, 95% confidence interval -0.95 – -0.21, P = 0.002) (Figure 4).

There were significant differences between the pre-post control groups of the RCTs (standardized mean difference pre-to-post: 2.85, 95% confidence interval 0.50 – 5.20, P<0.01) (Figure 5). We postulate this significant difference between the pre/post control groups is due to the beneficial effects of the novel TIMBER psychotherapy.

Discussion. Principal Findings: Our study adds to the existing literature by providing a meta-analysis of the specific relationship between ketamine infusions and its effect on PTSD symptomology. In all included studies, ketamine infusions were shown to improve PTSD symptom severity [10, 11, 17, 26-31]. Ketamine assisted psychotherapy not only extended ketamine’s effectiveness but also prolonged remission from PTSD. The statistically significant associations that were reported occurred in a diverse age range of patients with varying types of past trauma.

Comparable Literature:  There have been promising results of ketamine infusion for treatment resistant major depression with its recent FDA approval in 2019 [16]. Unfortunately, the current state of PTSD therapy falls severely short of any adequate advances. Krystal et al. 2017 advocate for further PTSD therapy research as it should be a national mental health priority [13].

Glutamate dysfunctions in CNS have been the predominant neurobiological hypothesis for the perpetuation of symptoms in chronic PTSD and NMDA receptor activation plays a role in over-consolidation of intrusive traumatic memories [18]. Ketamine administration is a known receptor NMDA receptor antagonist that induces and enhances neuroplasticity and modulates glutamatergic transmission which can reverse the stress-induced neuronal changes [32].

A recent meta-analysis investigated ketamine’s effect on PTSD for military soldiers [33]. Du et al. determined ketamine had no effect in reducing PTSD incidence for soldiers on the battlefield. Interestingly, it was shown that ketamine was not only ineffective in treating early PTSD but also led to exacerbation of the PTSD [33]. However, in their longitudinal study analysis, ketamine was shown to be effective in treating chronic PTSD [33]. It is possible that there is an inadequate consolidation of traumatic memories in acute PTSD whereby ketamine cannot induce its modulatory effects on early stress induced neurons.

Our study supports Du et al.’s results [33] and builds on the importance of including psychotherapy with pharmacological treatment for PTSD. Psychotherapy is a first-line treatment for PTSD, though its effects are short-lived. Hoge et al. showed the effectiveness of mindfulness meditation and yoga in changing brain chemistry in patients with general anxiety disorder [34]. These practices were seen to reduce concentrations of GABA, adrenocorticotropic hormone and pro-inflammatory cytokines which in turn led to a reduction in mental stress [34].

The combination of ketamine-assisted psychotherapy (KAT) has shown promising results in various psychiatric conditions. Krupitsky et al. highlighted the significant abstinence effect of multiple KAT sessions for patients with heroin dependence [35]. At the end of one year, the rate of abstinence in the multiple KAT session group was twice as high as the single KAT session group [35].

Four of the included studies investigated KAT for PTSD treatment [10, 11, 29, 31]. Both of Pradhan et al KAT methodology included one infusion (ketamine or normal saline) with 12 sessions of TIMBER psychotherapy [10, 11]. Significant decreases were noted in PTSD symptoms in both study arms at the 24-hour time point suggesting that the TIMBER protocol contributed to the clinical change in both groups [10, 11]. Bolstering their results, they noted that TIMBER psychotherapy alone produced a significant reduction (~10%) in basal plasma concentrations of D-serine at the 40-minute time point [11]. D-serine was identified as a NMDA receptor co-agonist that not only induces long term potentiation and NMDA-induced neurotoxicity but also acquisition and extinction of fear memory in animals and patients with PTSD [36, 37].

Keizer et al.’s KAT methodology included an incremental increase of ketamine (until a final dose of 11 – 15 μg/kg/min was achieved) over ~96 hours with 90 minutes of psychotherapy [29]. Though patients included in the study participated in psychotherapy in the year prior, the 5 days of therapy achieved optimistic breakthroughs of patients’ internalizing of their traumatic memories. 90% of patients were more dedicated to psychotherapy post-infusion [29]. Patients were able to unmask previous trauma and enhance interpersonal relationships. For combat-specific PTSD, patients were able to configure their therapy to underlying pre-combat sexual and/or physical abuse and subsequent life experiences and consequences [29]. Shiroma et al’s KAT methodology included multiple ketamine infusions (3), which further highlighted the synergistic effect of ketamine with KAT [31].

Ketamine is utilized due to its fast-acting effects (~40 minutes) but its insufficient lasting effects of 1-2 weeks undermines its utility [15, 17]. Though only 42% (3/7) of included studies reported long-term remission data, it is an effective measure to determine which methodology obtains long-lasting relief [11, 26, 28]. Pradhan et al 2018 unique KAT protocol (single ketamine infusion) had noted a sustained response for a median PTSD symptomology relapse time that was twice as long compared to TIMBER therapy alone and 5x longer than the ketamine therapy alone [11].

Our study highlights the integral union of psychotherapy with ketamine therapy for PTSD. Psychotherapy not only enhances ketamine’s effect but also prolongs PTSD symptom remission. A single ketamine infusion with appropriate psychotherapy is shown to be at least as effective, if not better, in prolonging remission times. These promising results can help shape future research on limiting the required dosage/infusion number for PTSD therapy which in turn lowers the risk of tolerance and side effects (notably dissociative symptoms [17, 26, 28-30] and elevated blood pressure [11, 17, 26, 28]).

Limitations: All studies were limited with a small sample size. The largest [17] and smallest [29] sample size were 41 and 11 patients, respectively. Generalizability of the results were a major limitation due to the exclusion of patients with comorbid psychotic, bipolar, active suicidal or homicidal ideation on presentation current alcohol or substance use disorders in order to protect against worsening of psychotic symptoms or abuse potential [17, 26, 27]. One study did not maintain per protocol analysis since 14% of patients did not undergo a second ketamine infusion due to the sustained reduction in PTSD symptom levels 2 weeks after ketamine infusion and a modified intention to treat analysis was undertaken [17]. The design of open-label studies with no placebo group limits contextualization of results due to lack of control group results and blinding. The cohort study with the largest sample size of n = 30 did not delineate their patient demographics in detail [30]. Although Albott et al 2018 and Shiroma et al appropriately described their statistical analysis, Keizer et al and Ross et al did not describe their statistical analysis to the readers [28-31]. Since each study obtained its PTSD symptom severity through various scales (CAPS-5, PCL-5, and IES-R), standardization with the gold standard Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) should be used for future protocols. Further knowledge of how individual variables in each scale changed over the course of the ketamine infusions would give insight into which parts of the patient’s recurrent trauma is being affected.

This meta-analysis analyzes the therapeutic relationship between ketamine and chronic PTSD across nine studies. In summary, the results support ketamine infusions as an effective treatment modality in alleviating PTSD symptoms as evidenced by the standardized mean difference pre-to-post: 3.07, 95% confidence interval 1.54 – 4.60, P<0.01. Ketamine assisted psychotherapy is shown to enhance ketamine effect with the longest sustained response with only 1 ketamine infusion 33 ± 22.98 days [10] and 34.44 ± 19.12 days [11]. Limitations included small sample sizes in included studies and lack of standardization of PTSD scales. Future studies should include more longitudinal data to ascertain remission status based on number of ketamine infusions and psychotherapy sessions completed. In light of the ongoing COVID-19 pandemic and its unforeseen consequences on PTSD [38, 39], further research is urgently needed to make strides in a more effective and long-lasting PTSD treatment.

PTSD: Post-traumatic stress disorder, NMDA: N-methyl-D-aspartate, RCT: Randomized Control Trial, TIMBER: trauma interventions using mindfulness-based extinction and reconsolidation of trauma memories, CBT: Cognitive behavioral therapy, SSRI: selective serotonin reuptake inhibitors, FDA: Food and Drug Administration, KAT: ketamine-assisted psychotherapy, PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses.

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