Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy prolong the therapeutic effects of single ketamine infusion on post-traumatic stress disorder and comorbid depression: a pilot randomized, placebo-controlled, crossover clinical trial

This randomized, placebo-controlled, cross-over clinical pilot study (n=10) investigated the antidepressant efficacy of ketamine (35mg/70kg) infusion combined with Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy for patients with PTSD. Ketamine-assisted TIMBER therapy increased the duration of the sustained antidepressant response, as evidenced by improvement of depressive symptoms after switching from the placebo into ketamine condition.

Abstract

“Background and objectives: Trauma memories lay at the core in etiopathogenesis of post-traumatic stress disorder (PTSD). Using pharmacological and cognitive behavioral treatments that specifically target trauma memories can improve the outcome. Ketamine has been shown to rapidly improve symptoms in PTSD and comorbid depression, but unfortunately these effects are short-lived. Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy is a type of mindfulness based cognitive behavioral therapy that targets the trauma memories. TIMBER psychotherapy in combination with (R,S)-ketamine are increasingly used to treat PTSD and comorbid depression. This study aims to determine if the combination of (R,S)-ketamine chemotherapy and TIMBER psychotherapy would produce a positive synergistic response in patients with PTSD.

Design: This is a randomized, placebo-controlled, cross-over clinical study.

Methods: Because response to ketamine alone is short-lived, this study combined TIMBER with a single infusion of 0.5 mg/kg (R,S)-ketamine to sustain its therapeutic effects. Ten patients with chronic and refractory PTSD were randomly assigned to two groups (n = 5 each): TIMBER-K group patients received ketamine infusion in combination with 12 TIMBER sessions (3 sessions in the first week followed by 9 sessions conducted on a weekly basis) and TIMBER-P group patients received placebo (normal saline infusion) in combination with 12 TIMBER sessions. The patients in the TIMBER-P group were switched to those in the TIMBER-K group after they experienced a sustained relapse.

Outcome measures: PTSD Checklist (PCL), Clinician Administered PTSD Scale for DSM-IV (CAPS), the 17-item Hamilton Rating Scale for Depression (Ham-D-17, clinician rated), Beck Anxiety Inventory (BAI), and Montreal Cognitive Assessment (MoCA) at baseline and 8 hours after infusion were used to investigate if ketamine selectively affected trauma memories leaving the general memory intact. The mindfulness interventions in TIMBER were personalized based on subject’s scores on Assessment Scale for Mindfulness Interventions which was administered at baseline, and after 5 sessions and 9 sessions (completion) of TIMBER. In this study, scores on CAPS and PCL scales were the primary outcome measures.

Results: In the acute phase trial ( first 3 months after infusion), nine out of 10 subjects showed robust response in primary outcome measures (PCL and CAPS scores for PTSD) and in the secondary outcome measures (Ham-D-17 and Beck Anxiety Inventory for depression and anxiety respectively) with a sustained response of 31.78 ± 18.29 days. The TIMBER-K group had a more sustained response (33 ± 22.98 days) compared to the TIMBER-P group (25 ± 16.8 days, P = 0.545). After switch from TIMBER-P group to TIMBER-K, patients experienced significantly prolonged response (49 vs. 25 days, P = 0.028). There were no intolerable side effects or dropouts during the 18-month follow-up period.

Conclusion: TIMBER psychotherapy augmented with low dose (R,S)-ketamine prolongs the therapeutic effects of the later and may be a valuable treatment option for PTSD.”

Authors: Basant K. Pradhan, Irving W. Wainer, Ruin Moaddel, Marc C. Torjman, Michael Goldberg, Michael Sabia, Tapan Parikh & Andres J. Pumariega

Summary

Abstract

A combination of (R,S)-ketamine chemotherapy and Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy can improve the outcome in patients with post-traumatic stress disorder and comorbid depression.

A study was conducted on ten patients with chronic and refractory PTSD to assess the effectiveness of a single infusion of 0.5 mg/kg (R,S)- ketamine in combination with 12 TIMBER sessions.

Ketamine selectively affected trauma memories leaving the general memory intact, and the mindfulness interventions in TIMBER were personalized based on subject’s scores on Assessment Scale for Mindfulness Interventions.

Nine out of 10 subjects showed robust response in primary outcome measures and secondary outcome measures after infusion of TIMBER-K. The TIMBER-K group had a more sustained response compared to the TIMBER-P group.

This study used a specific reconsolidation window approach to determine if the combination of (R,S)-ketamine chemotherapy and TIMBER psychotherapy would produce a positive synergistic response in patients with post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a psychopathology caused by pathologically ingrained trauma memories (TMs) that are mediated by the hippocampus, amygdala, pre-frontal cortex, basal ganglia, and hypothalamus-pituitary axis.

PTSD is often chronic and refractory to treatment, and only about 60% of patients respond to frontline antidepressant (SSRI) therapy. Few studies have examined the effect of a memory specific combined pharmacological and mindfulness based psychotherapy approach on PTSD.

TIMBER (Pradhan, 2014) is a translational and TMs specific mindfulness based cognitive therapy for PTSD that integrates the mindfulness based cognitive behavioral therapy with insights gained from cutting edge research of TMs.

In this pilot study, patients received ketamine and TIMBER (12 sessions), whereas those in the TIMBER-P group received placebo and TIMBER (12 sessions). The durations of responses were determined between these two groups, and patients were followed up for 18 months.

Ethical approval

This study was approved by the Cooper University Hospital Institutional Review Board and conducted with written informed consent.

Subjects

All patients had been on treatment for at least 6 months and suffered from repeated sexual trauma, motor vehicle accidents and combat related trauma.

Ten patients with chronic and refractory PTSD were randomly assigned to two groups: TIMBER-K group received ketamine infusion in combination with 12 TIMBER sessions.

Mindfulness based graded exposure therapy (MB-GET, a type of CBT) can be used to treat PTSD and phobic situations. TIMBER uses a balanced combination of both extinction (of TMs) and reconsolidation (of calming memories) and induces a mindfulness based detachment and monitoring mental state in the patient.

TIMBER is a new treatment for PTSD that combines psychotherapy and pharmacotherapy to target the TMs. This pilot study used (R,S)-ketamine to treat patients with PTSD and found that the combination produced a positive synergistic response.

SubjectS and MethodS Study design

The combination of mini-TIMBER and ketamine causes a relaxed and dissociated mental state in the subject, which passively accepts the TMs. The arousal response is kept under control by keeping the ART-MR scale scores within 30.

The subject was admitted into the Cooper University Hospital Department of Anesthesiology’s short procedure unit at 7 a.m. and received a ketamine infusion over 40 minutes with standard telemetry monitoring. After 240 minutes, the subject was assessed for PTSD and anxiety using the PTSD Checklist and Beck Anxiety Inventory.

Follow-up assessments

All subjects were followed up every week until relapse, and then received 9 sessions of full TIMBER therapy conducted at once a week frequency and 40 – 45 minute duration/session.

Interventions and rating scale administration procedure

The TIMBER protocol has two versions: the full Timber (40 – 45 minutes) and mini-TIMBER (5 minutes), which are used for extinction of trauma memories and reconsolidation of calming memories. The mini-TIMBER protocol helps the subject to quickly deescalate the arousal response or emotional outbursts in daily life. During the peri-infusion period, controlled reactivation of traumatic memories is done by asking the subject to reflect on a personalized scripted narrative of index trauma for 1 minute. Then infusion is allowed and throughout the infusion period, extinction of traumatic memories and reconsolidation of calming memories are done by two cycles of brief and controlled arousals.

Study assessments

All subjects had a complete history and physical examination, and were administered several rating scales by the same psychiatrist. Ketamine affected only TMs, leaving the general memory intact.

TIMBER was a personalized mindfulness intervention based on subjects’ scores on the Assessment Scale for Mindfulness Interventions (ASMI), and a scripted narrative of the index trauma was prepared for each subject.

Response criteria

A subject was considered a responder if the 24-hour post-infusion scores on PCL and CAPS decreased by at least 20 points from baseline, and if the decreases were sustained for at least 7 days.

Remission of PTSD was defined as no or minimal PTSD symptoms, and remission of depression and anxiety was defined as Ham-D-17 scores of 7.

Sample size calculation

For this study, 10 subjects were recruited and divided into two groups, with a sample size of 5 subjects per group.

Statistical analysis

All study data were entered into an excel spreadsheet and analyzed using t-tests, chi-square tests, and Z-statistics. The Pearson correlation coefficient was used to evaluate the relationship between ASMI scores and duration of the sustained response.

reSultS

The average age of 10 study subjects was 43 13.3 years, with 13 2.75 years of education. There was no statistical difference between the TIMBER-K and TIMBER-P arms with respect to age, years of education, and duration of PTSD, but there was a difference on gender.

Nine out of 10 subjects with PTSD, depression and anxiety met all the response criteria and were identified as responders. The duration of response was considerably sustained (31.78 -18.29 days) as compared to usual 4 – 7 days of response seen with single infusion of (R,S)-ketamine only.

Primary outcome measures

The nine subjects who responded showed significant differences in PCL scores, PCL scores between baseline and 24 hours after infusion, and CAPS scores between baseline and 24 hours after infusion.

Secondary outcome measures

Data are expressed as the mean SD with n = 5 for each group. PTSD, depression, and anxiety were evaluated using PCL, CAPS, BAI, and Ham-D-17.

groups

All subjects were actively practicing TIMBER at home twice daily, and 3 – 5 times as needed. There was no significant difference between the TIMBER-K and TIMBER-P arms in terms of % change in mean scores from baseline in various time frames and their scores on the Z-statistics.

Results after crossover from TIMBER-P arm to TIMBER-K arm

All 5 subjects in TIMBER-P arm were switched to TIMBER-K arm after a sustained relapse, and the administration of (R,S)-ketamine significantly different time frames after initial infusion.

TIMBER-P prolonged the mean duration of response by 24 days, and no clinically significant side effects were observed, including mild nausea within 1-hour post-infusion.

dIScuSSIon

This study used a combination of (R,S)-ketamine and mindfulness based cognitive therapy to sustain the therapeutic effects of (R,S)-ketamine therapy in patients with PTSD. The combined intervention had high remission and retention rates. In this study, subjects practiced a specific reconsolidation window approach (the first 6 hours after TMs reactivation) with (R,S)-ketamine and mini-TIMBER. This combination potentiated each other’s therapeutic effects, which may explain why the therapeutic response in our sample has become so robust.

Ketamine potentiated the process of reconsolidation of calming memories, which explains why subjects in the TIMBER-K arm had a more robust response than those in the TIMBER-P arm.

The neural circuitry involved in PTSD is yet to be probed by functional neuroimaging protocols, but it is postulated that the fronto-thalamic tricircuits and the working connections between the amygdala and the prefrontal cortex are involved. This would explain how mindfulness based detached monitoring (MBDM) can alter enduring TM in PTSD patients. Combination of psychotherapy and (R,S)-ketamine administration for targeting TM may bring long-term relief and has potential for curing PTSD. Interestingly, serum D-serine level and m-TOR signaling may be biomarkers for its therapeutic effects.

We are examining the findings of this pilot study in a larger trial, and plan to use neuroimaging tools to study the effects of this protocol.

Author contributions

This study was approved by the Cooper University Hospital Institutional Review Board and performed in accordance with ethical guidelines laid out by the US National Institute of Health and the principles of the Declaration of Helsinki. Written informed consent was obtained from all subjects.

The datasets analyzed during the current study are available from the corre-sponding author on reasonable request. The article is open access and distributed under the Creative Commons Attribution-NonCommercial 3.0 License.