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Therapeutic Application

Capturing the different health conditions that PAP may adress

Combining Ketamine, Brain Stimulation (rTMS) and Mindfulness Therapy (TIMBER) for Opioid Addiction

February 6, 2022 / Anxiety Disorders / PTSD, Ketamine, Papers, Substance Use Disorder / Leave a Comment / By / ,

Abstract

Opioid addiction in the United States currently presents a national crisis despite availability of different treatments. Prior findings suggest that both repetitive transcranial magnetic stimulation (rTMS) and subanesthetic dose of ketamine are efficacious in patients with opioid use disorders (OUD) when administered in isolation. However, their therapeutic value may be undermined by varying clinical responses that tend to dissipate with treatment cessation. There has been no study to date that has used a combination of both for OUD, and there are still many unanswered questions with respect to both. TIMBER (Trauma Interventions using Mindfulness Based Extinction and Reconsolidation of memories) therapy attempts to alter the expression of emotionally charged memories such as traumatic memories, and has been successfully tried in chronic post-traumatic stress disorder (PTSD) and in combination with memory-altering pharmacotherapy like ketamine infusion. By a combination of extinction and reconsolidation of memory approaches, TIMBER works to not over-flood and/or retraumatize as is seen in other treatment approaches. TIMBER involves a balanced combination of both the memory extinction and memory reconsolidation approaches (rather than extinction-only approaches) which explains its superior efficacy in PTSD and benefit in substance use disorders.

Pradhan, B., & Rossi, G. (2020). Combining Ketamine, Brain Stimulation (rTMS) and Mindfulness Therapy (TIMBER) for Opioid Addiction. Cureus, 12(11), e11798. https://doi.org/10.7759/cureus.11798

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Is ketamine an appropriate alternative to ECT for patients with treatment resistant depression? A systematic review

January 21, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , ,

Abstract

Objective: Ketamine has repeatedly shown to have rapid and robust antidepressant effects in patients with treatment resistant depression (TRD). An important question is whether ketamine is as effective and safe as the current gold standard electroconvulsive therapy (ECT).

Methods: The literature was searched for trials comparing ketamine treatment with ECT for depression in the Pubmed/MEDLINE database and Cochrane Trials Library.

Results: A total of 137 manuscripts were identified, 6 articles were included in this review. Overall quality of the included studies was diverse with relevant risk of bias for some of the studies. Results suggest that ketamine treatment might give faster but perhaps less durable antidepressant effects. Side effects differed from ECT, in particular less cognitive impairment was apparent in ketamine treatment.

Limitations: The included studies have limited sample sizes, use different treatment protocols and in most trials, longer term follow up is lacking. Furthermore, allocation bias appears likely in the non-randomized trials.

Conclusions: Current available literature does not yet provide convincing evidence to consider ketamine as an equally effective treatment alternative to ECT in patients with TRD. There are indications for a more favourable short term cognitive side effect profile after ketamine treatment. Methodologically well-designed studies with larger sample sizes and longer follow up duration are warranted.

Veraart, J., Smith-Apeldoorn, S. Y., Spaans, H. P., Kamphuis, J., & Schoevers, R. A. (2021). Is ketamine an appropriate alternative to ECT for patients with treatment resistant depression? A systematic review. Journal of affective disorders, 281, 82–89. https://doi.org/10.1016/j.jad.2020.11.123

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Corticosterone as a Potential Confounding Factor in Delineating Mechanisms Underlying Ketamine’s Rapid Antidepressant Actions

January 27, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By / , , , , , ,

Abstract

Recent research into the rapid antidepressant effect of subanesthetic doses of ketamine have identified a series of relevant protein cascades activated within hours of administration. Prior to, or concurrent with, these activation cascades, ketamine treatment generates dissociative and psychotomimetic side effects along with an increase in circulating glucocorticoids. In rats, we observed an over 3-fold increase in corticosterone levels in both serum and brain tissue, within an hour of administration of low dose ketamine (10 mg/kg), but not with (2R, 6R)-hydroxynorketamine (HNK) (10 mg/kg), a ketamine metabolite shown to produce antidepressant-like action in rodents without inducing immediate side-effects. Hippocampal tissue from ketamine, but not HNK, injected animals displayed a significant increase in the expression of sgk1, a downstream effector of glucocorticoid receptor signaling. To examine the role conscious sensation of ketamine’s side effects plays in the release of corticosterone, we assessed serum corticosterone levels after ketamine administration while under isoflurane anesthesia. Under anesthesia, ketamine failed to increase circulating corticosterone levels relative to saline controls. Concurrent with its antidepressant effects, ketamine generates a release of glucocorticoids potentially linked to disturbing cognitive side effects and the activation of distinct molecular pathways which should be considered when attempting to delineate the molecular mechanisms of its antidepressant function.

Wegman-Points, L., Pope, B., Zobel-Mask, A., Winter, L., Wauson, E., Duric, V., & Yuan, L. L. (2020). Corticosterone as a Potential Confounding Factor in Delineating Mechanisms Underlying Ketamine’s Rapid Antidepressant Actions. Frontiers in pharmacology, 11, 590221. https://doi.org/10.3389/fphar.2020.590221

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Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review

January 6, 2022 / Papers, Substance Use Disorder / Leave a Comment / By / ,

Abstract

Classical psychedelics are a group of drugs characterized by their activation of the serotonin-2A (5-hydroxytryptamine-2A; 5-HT2A) receptor and the unique hallucinogenic and mystical-type experiences that result. After a substantial period of restrictions limiting investigations into the therapeutic potential of psychedelics, a relatively recent recommencement of interest has sparked the burgeoning possibility for these drugs to play a part in the treatment of a wide array of psychopathologies. One of the most promising is in the study of addiction. Evidence has emerged that psychedelic agents may provide a novel avenue for the clinical treatment of patients dealing with substance use disorders (SUD). These serotonergic hallucinogens have displayed remarkable and enduring positive outcomes in this area, even when administered as one or two doses. The neural targets for these psychedelics are varied and underlie a complex mechanism of action-modulating multiple neural networks. It is believed that these agents allow for the reorganization of disordered neural pathways in the default mode network and attenuate maladaptive signaling in mesolimbic reward circuitry. The aim of this review is to examine the current standing of evidence regarding psychedelic psychopharmacology and to provide an overview of the use and effectiveness of these drugs in the treatment of SUD, alcohol use disorder, and for smoking cessation.

DiVito, A. J., & Leger, R. F. (2020). Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review. Molecular biology reports, 47(12), 9791–9799. https://doi.org/10.1007/s11033-020-06009-x

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MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study

January 6, 2022 / MDMA, Palliative Care+, Papers / Leave a Comment / By / , , , , , , , , , , , ,

Abstract

The success of modern medicine creates a growing population of those suffering from life-threatening illnesses (LTI) who often experience anxiety, depression, and existential distress. We present a novel approach; investigating MDMA-assisted psychotherapy for the treatment of anxiety in people with an LTI. Participants with anxiety from an LTI were randomized in a double-blind study to receive MDMA (125 mg, n = 13) or placebo (n = 5) in combination with two 8-h psychotherapy sessions. The primary outcome was change in State-Trait Anxiety Inventory (STAI) Trait scores from baseline to one month post the second experimental session. After unblinding, participants in the MDMA group had one open-label MDMA session and placebo participants crossed over to receive three open-label MDMA sessions. Additional follow-up assessments occurred six and twelve months after a participant’s last experimental session. At the primary endpoint, the MDMA group had a greater mean (SD) reduction in STAI-Trait scores, – 23.5 (13.2), indicating less anxiety, compared to placebo group, – 8.8 (14.7); results did not reach a significant group difference (p = .056). Hedges’ g between-group effect size was 1.03 (95% CI: – 5.25, 7.31). Overall, MDMA was well-tolerated in this sample. These preliminary findings can inform development of larger clinical trials to further examine MDMA-assisted psychotherapy as a novel approach to treat individuals with LTI-related anxiety.Trial Registration: clinicaltrials.gov Identifier: NCT02427568, first registered April 28, 2015.

Wolfson, P. E., Andries, J., Feduccia, A. A., Jerome, L., Wang, J. B., Williams, E., Carlin, S. C., Sola, E., Hamilton, S., Yazar-Klosinski, B., Emerson, A., Mithoefer, M. C., & Doblin, R. (2020). MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study. Scientific reports, 10(1), 20442. https://doi.org/10.1038/s41598-020-75706-1

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The Effects of Ketamine on Cognition in Treatment-Resistant Depression: A Systematic Review and Priority Avenues for Future Research

January 6, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , , , , , , ,

Abstract

Replicated evidence has documented cognitive deficits in populations with treatment-resistant depression (TRD). Approximately 40 % of patients with MDD present with impairment of one or more cognitive domains. As such, there is an unmet need to discover treatments that have pro-cognitive effects in TRD patients. Ketamine has demonstrated efficacy as a rapid-onset intervention for the treatment of depression. The objective of the current review was to assess the effects of ketamine on cognition in TRD patients. We systematically searched PubMed, Google Scholar and PsycINFO between database inception to March 24th, 2020. We identified five studies that evaluated cognition in TRD populations following ketamine treatment. All studies included a 0.5 mg/kg subanesthetic intravenous (IV) administration of ketamine. One study found significant improvements in complex (p = .008) and simple (p = .027) working memory and one study found improvements in visual learning memory following IV ketamine infusions (p = .014). Improvements in speed of processing and verbal learning memory were observed in anxious TRD participants only. Importantly, a subanesthetic dose of IV ketamine does not worsen cognitive function.

Gill, H., Gill, B., Rodrigues, N. B., Lipsitz, O., Rosenblat, J. D., El-Halabi, S., Nasri, F., Mansur, R. B., Lee, Y., & McIntyre, R. S. (2021). The Effects of Ketamine on Cognition in Treatment-Resistant Depression: A Systematic Review and Priority Avenues for Future Research. Neuroscience and biobehavioral reviews, 120, 78–85. https://doi.org/10.1016/j.neubiorev.2020.11.020

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Discontinuation of medications classified as reuptake inhibitors affects treatment response of MDMA-assisted psychotherapy

January 6, 2022 / Anxiety Disorders / PTSD, Depressive Disorders, MDMA, Papers / Leave a Comment / By / , , ,

Abstract

Rationale: MDMA-assisted psychotherapy is under investigation as a novel treatment for posttraumatic stress disorder (PTSD). The primary mechanism of action of MDMA involves the same reuptake transporters targeted by antidepressant medications commonly prescribed for PTSD.

Objectives: Data were pooled from four phase 2 trials of MDMA-assisted psychotherapy. To explore the effect of tapering antidepressant medications, participants who had been randomized to receive active doses of MDMA (75-125 mg) were divided into two groups (taper group (n = 16) or non-taper group (n = 34)).

Methods: Between-group comparisons were made for PTSD and depression symptom severity at the baseline and the primary endpoint, and for peak vital signs across two MDMA sessions.

Results: Demographics, baseline PTSD, and depression severity were similar between the taper and non-taper groups. At the primary endpoint, the non-taper group (mean = 45.7, SD = 27.17) had a significantly (p = 0.009) lower CAPS-IV total scores compared to the taper group (mean = 70.3, SD = 33.60). More participants in the non-taper group (63.6%) no longer met PTSD criteria at the primary endpoint than those in the taper group (25.0%). The non-taper group (mean = 12.7, SD = 10.17) had lower depression symptom severity scores (p = 0.010) compared to the taper group (mean = 22.6, SD = 16.69). There were significant differences between groups in peak systolic blood pressure (p = 0.043) and diastolic blood pressure (p = 0.032).

Conclusions: Recent exposure to antidepressant drugs that target reuptake transporters may reduce treatment response to MDMA-assisted psychotherapy.

Feduccia, A. A., Jerome, L., Mithoefer, M. C., & Holland, J. (2021). Discontinuation of medications classified as reuptake inhibitors affects treatment response of MDMA-assisted psychotherapy. Psychopharmacology, 238(2), 581–588. https://doi.org/10.1007/s00213-020-05710-w

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The time course of psychotic symptom side effects of ketamine in the treatment of depressive disorders: a systematic review and meta-analysis

January 3, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , ,

Abstract

Objective: Ketamine is a potential rapid-acting treatment for depression. Studies have suggested that the side effects are minimal and temporary, but the psychotic symptom side effects have yet to be fully examined. This study investigated whether ketamine infusion in the treatment of mood disorders is associated with increases in positive symptoms and whether these symptom effects endure over time.

Methods: A systematic review and meta-analysis of studies of ketamine in the treatment of depression. Embase and Medline databases were searched for studies including (a) participants with major affective disorders, (b) 0.4 or 0.5 mg intravenously administered ketamine, (c) measurement of positive symptoms using BPRS+, and (d) a within-subject repeated-measures design with participants serving as their own baseline.

Results: Seventeen studies met the inclusion criteria, comprising 458 participants. The meta-analyses examined symptom change occurring within the first 4 h, after 1 day, and after 3 days. Results showed significant BPRS+ increases within the first 30-60 min in 72% of studies, followed by a return to baseline levels.

Conclusion: Peak symptom change occurred within the first hour post infusion. There are limited data to determine if ketamine is safe in the longer term, but there were no indications that psychotic symptoms re-occurred after the first hour and in the days following administration.

Tashakkori, M., Ford, A., Dragovic, M., Gabriel, L., & Waters, F. (2021). The time course of psychotic symptom side effects of ketamine in the treatment of depressive disorders: a systematic review and meta-analysis. Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists, 29(1), 80–87. https://doi.org/10.1177/1039856220961642

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Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine

January 3, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , ,

Abstract

Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid-acting antidepressant effects and summarize how diverse phenomena associated with ketamine’s antidepressant actions – such as cortical excitation, synaptogenesis, and involved molecular determinants – are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain.

Kohtala, S., Alitalo, O., Rosenholm, M., Rozov, S., & Rantamäki, T. (2021). Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine. Pharmacology & therapeutics, 221, 107741. https://doi.org/10.1016/j.pharmthera.2020.107741

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Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin

January 3, 2022 / Headache Pain and Neurological Disorders, Mushrooms / Psilocybin, Papers / Leave a Comment / By / , , , , , , , ,

Abstract

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT2A) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, – 1.65 (95% CI: – 2.53 to – 0.77) days/week) than after placebo (- 0.15 (- 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov : NCT03341689.

Schindler, E., Sewell, R. A., Gottschalk, C. H., Luddy, C., Flynn, L. T., Lindsey, H., Pittman, B. P., Cozzi, N. V., & D’Souza, D. C. (2021). Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 18(1), 534–543. https://doi.org/10.1007/s13311-020-00962-y

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