Combining Ketamine Infusions and Written Exposure Therapy for Chronic PTSD: An Open-Label Trial

Abstract

Objective:

This open-label clinical trial examined the preliminary efficacy of combining a course of 6 ketamine infusions with a brief, evidence-based exposure-based psychotherapy—written exposure therapy (WET)—in patients with chronic posttraumatic stress disorder (PTSD).

Methods:

The trial was conducted between June 2021 and October 2023. Patients with chronic PTSD and high-moderate to severe symptom levels received 6 intravenous ketamine infusions (0.5 mg/kg), 3 times a week for 2 consecutive weeks, plus 5 WET sessions over 2 weeks, beginning after the first 4 infusions and administered on different days than infusion days. The primary outcome was change in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) scores from baseline (before the first infusion) to 12 weeks from start of WET (“Week 12”).

Results:

Fourteen eligible patients began treatment, and 13 completed all infusions and WET. The combined treatment was associated with large-magnitude improvement in PTSD symptom severity from baseline (mean CAPS-5 = 41.6 [SD = 6.2]) to Week 12 (CAPS-5 = 20.8 [14.8], Cohen d [95% CI] = 1.9 [1.0–2.8], P < .001). Nine (69%) patients were treatment responders (≥30% improvement on the CAPS-5). Response was rapid and also durable in 8 (61.5%) patients, assessed up to 6 months from baseline.

Conclusions:

Preliminary findings from this open-label clinical trial suggest that the combined treatment may yield large-magnitude and durable reductions in PTSD symptoms for patients with more severe chronic PTSD. Large-scale randomized controlled trials are needed to determine the efficacy and potential synergistic effect of this promising combined treatment in this patient population.

Trial Registration:

ClinicalTrials.gov identifier: NCT04889664

Randomized controlled trials (RCTs) of single and repeated intravenous ketamine infusions have shown rapid and robust improvements in posttraumatic stress disorder (PTSD) symptoms in predominantly civilian samples of patients with chronic PTSD,^1–3 a potentially promising intervention in the context of limited efficacy of currently available pharmacotherapies for this disorder.^4,5 After completion of infusions, however, response to ketamine is usually lost over a few weeks.² Among all currently available PTSD treatments, trauma-focused, exposure-based psychotherapies have the highest evidence base, with overall higher efficacy than pharmacotherapies. While they are considered the gold-standard intervention, they are still associated with high rates of nonresponse or limited response.^6,7 Chronic PTSD is characterized by abnormalities in fear extinction learning,^8–10 which can negatively affect response to exposure-based psychotherapies, thought to rely on adequate fear extinction learning.¹¹

Chronic PTSD is increasingly recognized as a disorder of “synaptic disconnection.”⁸ Ketamine, also found to enhance fear extinction,^12–14 rapidly enhances neuroplasticity in the short term, a potent effect thought to persist for weeks after repeated administration.^{12,13,15–17} This suggests that administering ketamine several times a week prior to initiating exposure-based psychotherapy may help enhance this type of psychotherapy. In turn, exposure-based psychotherapy might help maintain response to repeated ketamine infusions for PTSD, as most ketamine responders experience symptom relapse following cessation of infusions.² To date, 2 published pilot trials have combined ketamine with manualized exposure-based psychotherapy for PTSD.^18,19 These trials administered only 1 ketamine infusion before starting modified prolonged exposure (PE)^18,19 or a total of 3 weekly infusions (before the first 3 of 10 weekly PE sessions),¹⁹ respectively.

In recent years, written exposure therapy (WET) has emerged as a brief, efficacious, and scalable exposure-based psychotherapy for PTSD, shown to be noninferior to PE and cognitive processing therapy and potentially more tolerable, with lower drop-out rates.^20–25 The current open-label clinical trial aimed to examine the feasibility and preliminary efficacy of combining a course of 6 ketamine infusions—administered over 2 consecutive weeks—with WET in patients with high-moderate to severe chronic PTSD. We selected this frequency and total number of infusions based on the demonstrated efficacy of this protocol for individuals with chronic PTSD in our previous RCT of repeated ketamine administration.² Further, we chose to start WET after several ketamine infusions in order to “prime the brain” first, aiming to maximize ketamine’s potential effect on neuroplasticity prior to initiating psychotherapy.

METHODS

Participants and Procedure

An open-label clinical trial was conducted between June 2021 and October 2023 at the Icahn School of Medicine at Mount Sinai (ISMMS). Eligible participants, recruited through advertising or clinician referrals, were aged 18–70 years, with a current primary diagnosis of chronic PTSD, defined as meeting DSM-5 PTSD criteria on the Structured Clinical Interview for DSM-5,²⁶ of at least 3 months’ duration, and a total score ≥30 on the past-month Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).²⁷ Participants completed a medical history and physical examination conducted by a nurse practitioner, as well as laboratory testing and an electrocardiogram, followed by a review of all results by a study psychiatrist. Exclusion criteria included serious unstable medical illness, moderate/severe brain injury, alcohol/substance use disorder within the prior 3 months, active suicidal ideation, and bipolar or psychotic disorder. Concomitant medications at stable doses for at least 3 months were permitted, except for opioids and long-acting or daytime short-acting benzodiazepines. Concomitant evidence-based psychotherapy for PTSD (eg, PE, eye movement desensitization and reprocessing) was exclusionary. The study protocol was approved by the ISMMS institutional review board and registered on ClinicalTrials.gov (NCT04889664). All participants signed informed consent. They were compensated for each infusion day and each assessment, but not for WET sessions.

Six ketamine infusions (0.5 mg/kg over 40 minutes) were administered 3 times a week for 2 consecutive weeks.² The first WET session took place the day after the fourth infusion; the first 2 WET sessions were interleaved with the last 2 ketamine infusions—each on a different day—and the last 3 WET sessions were delivered the following week, schedule permitting, with a combined treatment duration of approximately 3 weeks (Figure 1).^2,17

Figure 1. Study Flowchart^a.

^a Graphical representation of the combined treatment and assessment time points. Participants with chronic PTSD received a course of 6 ketamine infusions and written exposure therapy (WET, 5 sessions). The first ketamine infusion started following the baseline assessment, and the first WET session began after completing the first 4 ketamine infusions (following the Week 0 assessment). The full combined treatment lasted approximately 3 weeks. The primary outcome was change in PTSD symptom severity, assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 12 weeks from start of WET (Week 12). Only treatment responders at Week 12, defined as at least 30% improvement on the CAPS-5 total score from baseline, were additionally assessed, monthly, for up to 24 weeks from start of WET (Week 24).

WET is a brief, evidence-based, exposure-based psychotherapy for PTSD comprising 5 total sessions with no between-session assignments. Fundamental WET components include a treatment rationale, psychoeducation, and directing individuals to write repeatedly about the details of a specific traumatic stressor linked to their symptoms, with particular attention to felt emotions and the meaning of the traumatic event, for 30 minutes per session.²⁰ The minimal therapist-patient contact, nominal time needed to train therapists, and brevity of treatment address challenges with implementing other exposure-based psychotherapies.²⁸ Several RCTs have demonstrated the efficacy and noninferiority of WET for PTSD compared to gold-standard and longer-duration exposure-based psychotherapies, with significantly lower treatment dropout rates.^23–25 In this study, WET was administered to participants via a HIPAA-compliant video telehealth platform, by licensed therapists trained and closely supervised by D.M.S., co-developer of WET.

The primary outcome was change in PTSD symptom severity, assessed with the CAPS-5, from baseline (before the first infusion) to 12 weeks following the start of WET (“Week 12”). Since prior trials of standalone WET showed continued gradual improvement up to 12 weeks from baseline, we selected this primary outcome time point to enable preliminary effect size comparisons between the combined intervention in this trial and WET alone from prior trials. The CAPS-5 was administered by trained, supervised study staff, weekly up to Week 12; CAPS-5 raters were not blinded to study time point. Treatment response was defined as ≥30% improvement^2,29–31 in the total CAPS-5 score from baseline to Week 12. Exploratory outcomes included PTSD symptom severity at 3 weeks from start of WET (ie, 1 week after completion of the combined treatment) in order to evaluate rapid response, as well as the 4 DSM-5 PTSD symptom clusters (CAPS-5 subscale scores), depressive symptoms, clinical global impression, and self-reported functional impairment.^32–34 Treatment responders at Week 12 were subsequently administered the CAPS-5 monthly up to 24 weeks from start of WET (“Week 24”), 6 months from baseline, to explore durability of the combined intervention.

Linear mixed-effects models were conducted to examine changes in primary and exploratory measures from baseline to Week 12. These models included time (baseline, Week 12) as a fixed effect, participant as a random effect, and scores on primary and exploratory measures as dependent variables. Cohen d with 95% CIs were computed to estimate the magnitude of changes in measures over time.

RESULTS

Fourteen eligible patients began study treatment (Supplementary Figure 1, CONSORT Diagram). Thirteen patients (100% female, mean [SD] age = 38.3 [7.5] years) who completed the full course of ketamine infusions and WET sessions were included in data analyses (Table 1). One patient was withdrawn by the study team after 3 infusions because of inappropriate behavior with study staff unrelated to the infusions.

Table 1.

Demographic and Clinical Characteristics of Study Participants

Characteristic
Continuous variables	Mean	SD
Age, y	38.3	7.5
BMI	27.3	7
Duration of PTSD, y	18.1	14.0
CAPS-5 score (past month)	40.5	3.9
MADRS score (past week)	31.4	6.5
Categorical variables	N	%
Female, sex	13	100
Race
Black	0	0
Asian	1	7.7
White	9	69.2
American Indian or Alaskan Native	1	7.7
More than 1 race	1	7.7
Unknown or do not wish to disclose	1	7.7
Hispanic ethnicity	4	30.8
Education
≤ High school	0	0
High school graduate	0	0
Some college or trade school	2	15.4
Graduated 4 years of college	4	30.8
Some graduate/professional degree	1	7.7
Completed graduate/professional degree	6	46.2
Unemployed	2	15.4
Married or cohabiting	2	15.4
Primary trauma
Sexual assault or molestation during childhood and/or adolescence	4	30.8
Sexual assault during adulthood	4	30.8
Physical assault or abuse during childhood and adolescence	2	15.4
Survivor of serious accident	1	7.7
Witness of violent assault	1	7.7
Survivor of 9/11 terrorist attacks	1	7.7
Current comorbid diagnoses
Major depressive disorder	10	76.9
Persistent depressive disorder	6	46.2
Generalized anxiety disorder	10	76.9
Social anxiety disorder	5	38.5
Specific phobia	1	7.7
Binge eating disorder	1	7.7
Concomitant treatment with psychotherapy	7	53.8
Concomitant treatment with psychotropic medication at stable doses	6	46.2
Marijuana use during treatment phase a	1	7.7
Marijuana use during follow-up phase b	2	15.4

^aOne participant smoked marijuana and/or used edibles on weekends.

^bDuring the follow-up phase, the same participant continued to smoke marijuana and/or used edibles on weekends; another participant used an edible for a migraine headache once on week 5.

Abbreviations: BMI = body mass index, CAPS-5 = Clinician-Administered PTSD Scale for DSM-5, MADRS = Montgomery-Asberg Depression Rating Scale, PTSD = posttraumatic stress disorder.

Among the 13 patients included in data analyses, 8 (62%) presented with sexual assault/molestation during childhood and/or adulthood as their primary trauma, and the remaining 5 (39%) with other primary traumas, with mean PTSD duration of 18 years (Table 1). Six (46%) patients were on stable doses of psychotropic medications, and 7 (53.8%) were receiving concomitant non–evidence-based psychotherapy (Supplementary Table 1).

Combined treatment with ketamine infusions and WET was associated with large-magnitude improvement in PTSD symptom severity (total CAPS-5 score) from baseline to Week 12, the primary outcome (Table 2, Figure 2). At Week 12, 9 (69%) patients were treatment responders, and 7 (54%) no longer met DSM-5 PTSD diagnostic criteria (Figure 3).

Table 2.

Pre- and Posttreatment Scores on Primary and Secondary (Exploratory) Measures

	Pretreatment Mean (SD)	Posttreatment Mean (SD)	F	P	d (95% CI)
CAPS-5 total	41.6 (6.2)	20.8 (14.8)	22.00	<.001	1.9 (1.0–2.8)
Intrusions	9.2 (2.1)	5.8 (4.1)	6.98	.014	1.1 (0.3–1.9)
Avoidance	5.3 (1.3)	1.7 (2.1)	26.99	<.001	2.1 (1.2–3.1)
NACM	16.7 (2.9)	8.0 (6.6)	18.75	<.001	1.8 (0.9–2.7)
AAR	10.4 (2.6)	5.2 (3.6)	17.17	<.001	1.7 (0.8–2.6)
MADRS	31.4 (6.5)	19.1 (13.2)	8.96	.006	1.2 (0.4–2.1)
CGI-S	4.9 (0.6)	3.2 (1.2)	19.23	<.001	1.8 (0.9–2.7)
CGI-I	NA	2.0 (0.9)	–	–	–
		77% ≥ 2
SDS work a	4.1 (3.2)	3.4 (3.1)	0.25	0.63	0.2 (−0.6 to 1.0)
SDS social	6.1 (2.5)	3.1 (3.6)	6.02	0.022	1.0 (0.2–1.8)
SDS family/home	5.7 (2.9)	2.4 (2.4)	10.17	0.004	1.3 (0.5–2.1)

^aSDS work scores were assessed in 10 participants who reported current employment.

Abbreviations: AAR = alterations in arousal and reactivity, CAPS-5 = Clinician-Administered PTSD Scale for DSM-5,²⁷ CGI-S = Clinical Global Impressions-Severity, CGI-I = Clinical Global Impressions-Improvement,³³ d = Cohen d, MADRS = Montgomery-Asberg Depression Rating Scale,³² NA = not applicable, NACM = negative alterations in cognition and mood, SDS = Sheehan Disability Scale.³⁴

Figure 2. Improvement in PTSD Symptom Severity (Overall and Symptom Clusters), from Baseline to Week 12^a.

^aThe graphs show the change in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total and subscale scores, at each assessment time point from baseline (before the first infusion) to 12 weeks from start of written exposure therapy, WET (Week 12). Values reflect least-square means; error bars indicate standard error of the mean. The timing of the first and last infusions is marked in blue, and the timing of the first and last WET sessions in purple.

Figure 3. Treatment Response and Loss of DSM-5 PTSD Diagnosis, from Baseline to Week 12, and up to Week 24 in Treatment Responders^a.

^aThe graph shows the percentage of treatment responders (at least 30% improvement from baseline on the Clinician-Administered PTSD Scale for DSM-5 [CAPS-5] total score) and percentage of patients who no longer met DSM-5 diagnostic criteria for PTSD, including the primary and exploratory assessment time points. Patients were assessed weekly from baseline to Week 12, and treatment responders monthly thereafter up to 24 weeks from start of written exposure therapy, WET (Week 24). The timing of the first and last infusions is marked in blue, and the timing of the first and last WET sessions in purple.

The combined treatment was also associated with large-magnitude improvements in the 4 DSM-5 PTSD symptom clusters, with greatest improvement in avoidance symptoms (Table 2, Figure 2), and large-magnitude improvements in depressive symptoms, clinical global impression scores, and social and family/home functioning; 10 (77%) participants were assessed to be clinically “much improved” or higher (Table 2).

Rapid Response

One week after completion of the combined treatment (3 weeks from start of WET, “Week 3”), 10 (77%) patients were treatment responders, and 8 (62%) did not meet DSM-5 PTSD diagnostic criteria (Figure 3). Only 1 of the treatment responders at Week 3 was no longer a responder by Week 12.

Maintenance of Response

Eight (61.5%) patients showed a durable response, including 7 who completed the Week-24 follow-up (6 months postbaseline) and an additional patient who was last available for follow-up at Week 20, all of whom did not meet DSM-5 PTSD diagnostic criteria at this last follow-up (Figure 3, Supplementary Figure 2).

Safety and Side Effects

As in prior trials, any dissociative symptoms emerging during ketamine infusions were transient, resolving after infusion end; no significant psychotic or manic symptoms were observed (Supplementary Table 2). General side effects are reported in Supplementary Table 3.

DISCUSSION

This open-label clinical trial provides the first known preliminary evidence of large-magnitude PTSD symptom improvement, assessed 3 months from pretreatment baseline, in patients with high-moderate to severe chronic PTSD, following a combination of repeated ketamine infusions with WET, an evidence-based, brief exposure-based psychotherapy. With the exception of 1 patient who was exited early for a non–treatment-related reason, no patients dropped out before completing treatment. Over two-thirds (N = 9, 69%) of the combined treatment sample were treatment responders 3 months from baseline. All responders improved early in treatment, based on their assessment 1 week postcompletion of the combined treatment, and most of them maintained clinical response at the 6-month follow-up.

Preliminary findings suggest that combining WET with a course of 6 ketamine infusions might maintain PTSD symptom improvement for several months in many treatment responders, potentially avoiding or reducing the need for maintenance ketamine infusions, which commonly arises when administering ketamine as a standalone treatment.² In our previous RCT, after receiving 6 ketamine infusions over 2 consecutive weeks, median time to loss of response was approximately 6 weeks from baseline.² Of note, while patients with PTSD can receive ketamine infusions at ketamine clinical practices,³⁵ intravenous ketamine is presently off-label as it is not FDA-approved for the treatment of any psychiatric disorders. Only the enantiomer esketamine, administered intranasally, is FDA-approved as an adjunct intervention for patients with treatment-resistant depression or with depression accompanied by suicidal ideation, but not for PTSD.

Preliminary findings also suggest that compared to WET as a standalone treatment,^23–25 the combined treatment is associated with a more rapid response, as early as 1–2 weeks from baseline. Additionally, the mean effect size reduction in PTSD symptoms observed in the current study (d = 1.9) is numerically larger than the moderate-to-large-magnitude within-subject reductions in PTSD symptom severity observed at 10–12-week assessments following standalone WET,^23–25,36 but comparable to the large-magnitude reduction in these symptoms observed 2 weeks following ketamine administration.² While these findings suggest that ketamine might enhance the efficacy of WET, no definitive conclusion can be reached without conducting an RCT directly comparing the combined intervention with standalone WET (with placebo infusions).

Interest in potential synergistic effects between ketamine and exposure-based psychotherapies for PTSD stems from findings that ketamine opens a window of increased neuroplasticity,^15,37 particularly in brain regions subserving emotion processing and regulation, which also underlie threat processing and fear extinction learning, putative mechanisms behind exposure-based psychotherapies including WET.^11,38–40 Different ways of combining ketamine with evidence-based psychotherapies for PTSD are being examined.^41,42 In the current trial, we administered several infusions prior to starting psychotherapy and additionally administered the full course of psychotherapy within the estimated window of ketamine-related increased neuroplasticity, aiming to maximize the potential synergistic effect of these 2 interventions. Initial findings from neuroimaging studies of exposure-based psychotherapies for chronic PTSD suggest that patients least likely to respond to exposure-based psychotherapies are those with poorer PFC inhibition of amygdala activation at pretreatment baseline.^43,44 Conversely, in our preliminary neuroimaging study of repeated ketamine for chronic PTSD, patients with lower top-down amygdala inhibition at pretreatment baseline were actually more likely to respond to ketamine.¹⁷ While much further research is needed, combined findings across studies suggest the potential benefit of “priming the brain” with repeated ketamine infusions prior to initiating exposure-based psychotherapy in patients with chronic PTSD.

Results of the present open-label clinical trial support the feasibility and preliminary safety and efficacy of combining a course of repeated ketamine infusions with a brief exposure-based psychotherapy for individuals with high-moderate to severe chronic PTSD. The time commitment required for this combined intervention was substantial but time-limited, and no participant dropped out. The study is limited by its small sample size and the absence of a control group. Large-scale RCTs are needed to determine whether the combined therapies might have a synergistic effect, namely, whether repeated ketamine infusions might enhance the efficacy of WET and, in turn, whether adding WET can help maintain therapeutic effects of a course of ketamine infusions over time in patients with this disabling condition.

Supplementary Material

Supplementary Material: Available at Psychiatrist.com.

Clinical Points.

• Among currently available treatments for chronic posttraumatic stress disorder, exposure-based psychotherapies have the highest evidence base but are limited by insufficient efficacy.

• Potential synergistic effects between ketamine and exposure-based psychotherapies might enhance treatment outcomes.

• The present open-label clinical trial aimed to examine the feasibility and preliminary efficacy of combining a course of 6 ketamine infusions with a brief exposure-based psychotherapy.