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R. Moaddel

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

August 2, 2017 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Papers, Psychology / By / , , , , , ,

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.
Pradhan, B. K., Wainer, I. W., Moaddel, R., Torjman, M. C., Goldberg, M., Sabia, M., … & Pumariega, A. J. (2017). 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. Asia Pacific Journal of Clinical Trials: Nervous System Diseases, 2(3), 80. 10.4103/2542-3932.211589
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NMDAR inhibition-independent antidepressant actions of ketamine metabolites

May 4, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.

Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., … & Dossou, K. S. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. http://dx.doi.org/10.1038/nature17998
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(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function

July 1, 2014 / Depressive Disorders, Ketamine, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

BACKGROUND: Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown.

METHODS: Rats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined.

RESULTS: The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor.

CONCLUSIONS: The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.

Paul, R. K., Singh, N. S., Khadeer, M., Moaddel, R., Sanghvi, M., Green, C. E., … & Wainer, I. W. (2014). (R, S)-Ketamine metabolites (R, S)-norketamine and (2S, 6S)-hydroxynorketamine increase the mammalian target of rapamycin function. The Journal of the American Society of Anesthesiologists, 121(1), 149-159. http://dx.doi.org/10.1097/ALN.0000000000000285
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