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Efficacy of Oral Ketamine Combined with Psychotherapy for Treatment Resistant Depression

Background: Treatment resistant depression (TRD) is defined as a major depressive episode that does not improve in response to at least two trials, each of a different class, of antidepressant medication. Pharmacotherapy of TRD with low dose ketamines has been shown as relatively successful in recent studies. Effects of such pharmacotherapy can be augmented by combining ketamine with psychotherapeutic interventions such as Zdyb’s Therapeutic Reset of Internal Processes (TRIP) protocol. Method: 10 adult TRD patients (4 men, 6 women) were treated with low dose ketamines and were also receiving psychotherapeutic intervention as per TRIP protocol. All patients were administered the Patient Health Questionnaire, module 9 (PHQ9) which is a measure of a major depressive episode. The PHQ9 was administered twice: on baseline (i.e., prior to treatment) and after the treatment. Results: On average, our patients fell in the moderate range of severity with respect to symptoms of TRD at baseline (pre-TRIP) as by their mean PHQ9 score of 17.9, (SD = 5.1). Their mean PHQ9 score decreased post TRIP treatment to 9.5 (SD = 6.6): the difference is significant in a t-test, t(10) = 4.3172, p = 0002 (two-tailed). The magnitude of the decrease amounts to 46.9% of the average baseline score. Discussion and Conclusions: Our patients experienced significant reductions in symptoms of TRD in this pilot study. Research studies are now needed with control groups of TRD patients on a waiting list or also of those receiving only the ketamine pharmacotherapy

Neuroimaging correlates and predictors of response to repeated-dose intravenous ketamine in PTSD: preliminary evidence

Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N = 21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [β] = 2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction β = 0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (β = 0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (βs = −2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala→vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.

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