OPEN Foundation

Depression

Plasma BDNF concentrations and the antidepressant effects of six ketamine infusions in unipolar and bipolar depression

Abstract

Objectives: Accumulating evidence has implicated that brain derived neurotrophic factor (BDNF) is thought to be involved in the pathophysiology of depression, but its correlation with ketamine’s antidepressant efficacy focusing on Chinese individuals with depression is not known. This study was aim to determine the correlation of plasma BDNF (pBDNF) concentrations and ketamine’s antidepressant efficacy.

Methods: Ninety-four individuals with depression received six intravenous infusions ketamine (0.5 mg/kg). Remission and response were defined as Montgomery-Asberg Depression Rating Scale (MADRS) scores less than 10 and a reduction of 50% or more in MADRS scores, respectively. Plasma was collected at baseline and at 24 h and 2 weeks after completing six ketamine infusions (baseline, 13 d and 26 d).

Results: A significant improvement in MADRS scores and pBDNF concentrations was found after completing six ketamine infusions compared to baseline (all ps < 0.05). Higher baseline pBDNF concentrations were found in ketamine responders/remitters (11.0 ± 6.2/10.1 ± 5.8 ng/ml) than nonresponders/nonremitters (8.0 ± 5.5/9.2 ± 6.4 ng/ml) (all ps < 0.05). Baseline pBDNF concentrations were correlated with MADRS scores at 13 d (t = – 2.011, p = 0.047) or 26 d (t = – 2.398, p = 0.019) in depressed patients (all ps < 0.05). Subgroup analyses found similar results in individuals suffering from treatment refractory depression.

Conclusion: This preliminary study suggests that baseline pBDNF concentrations appeared to be correlated with ketamine’s antidepressant efficacy in Chinese patients with depression.

Zheng, W., Zhou, Y. L., Wang, C. Y., Lan, X. F., Zhang, B., Zhou, S. M., Yan, S., & Ning, Y. P. (2021). Plasma BDNF concentrations and the antidepressant effects of six ketamine infusions in unipolar and bipolar depression. PeerJ, 9, e10989. https://doi.org/10.7717/peerj.10989

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Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes

Abstract

Mescaline is a naturally occurring psychoactive alkaloid that has been used as a sacrament by Indigenous populations in spiritual ritual and healing ceremonies for millennia. Despite promising early preliminary research and favorable anecdotal reports, there is limited research investigating mescaline’s psychotherapeutic potential. We administered an anonymous online questionnaire to adults (N = 452) reporting use of mescaline in naturalistic settings about mental health benefits attributed to mescaline. We assessed respondents’ self-reported improvements in depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol and drug use disorders (AUD and DUD). Of the respondents reporting histories of these clinical conditions, most (68-86%) reported subjective improvement following their most memorable mescaline experience. Respondents who reported an improvement in their psychiatric conditions reported significantly higher ratings of acute psychological factors including mystical-type, psychological insight, and ego dissolution effects compared to those who did not report improvements (Cohen’s d range 0.7 – 1.5). Many respondents (35-50%) rated the mescaline experience as the single or top five most spiritually significant or meaningful experience(s) of their lives. Acute experiences of psychological insight during their mescaline experience were associated with increased odds of reporting improvement in depression, anxiety, AUD and DUD. Additional research is needed to corroborate these preliminary findings and to rigorously examine the efficacy of mescaline for psychiatric treatment in controlled, longitudinal clinical trials.

Agin-Liebes, G., Haas, T. F., Lancelotta, R., Uthaug, M. V., Ramaekers, J. G., & Davis, A. K. (2021). Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes. ACS pharmacology & translational science, 4(2), 543–552. https://doi.org/10.1021/acsptsci.1c00018

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Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action

Abstract

Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.

Dos Santos, R. G., Hallak, J. E., Baker, G., & Dursun, S. (2021). Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action. Journal of psychopharmacology (Oxford, England), 35(4), 453–458. https://doi.org/10.1177/0269881120986422

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Clinical and biological predictors of psychedelic response in the treatment of psychiatric and addictive disorders: A systematic review

Abstract

Background: The use of psychedelic treatments has shown very promising results in some psychiatric and addictive disorders, but not all patients achieved a response.

Aim: The aim of this review is to explore the clinical and biological factors which could predict the response to psychedelics in psychiatric and addictive disorders.

Methods: A systematic research was performed on MEDLINE, PsycInfo, Web of science, and Scopus databases from January 1990 to May 2020. All studies investigating the predictive factors of response to psychedelics regardless of psychiatric or addictive disorders, were included.

Results: Twenty studies investigating addictive disorder, treatment-resistant depression, obsessive-compulsive disorder and depressive and anxiety symptoms in patients with life-threatening cancer were included in this review. We found that, in all indications, the main predictive factor of response to psychedelics is the intensity of the acute psychedelic experience. Indeed, we found this factor for alcohol and tobacco use disorders, treatment-resistant depression, and anxiety and depressive symptoms in patients with life-threatening cancer, but not for obsessive-compulsive disorder.

Conclusion: The intensity of the acute psychedelic experience was the main predicting factor of response. The action mechanism of this experience was not clear, but some hypotheses could be made, such as a modulation of serotoninergic system by 5-HT2A receptors agonism, a modulation of the default mode network (DMN) with an acute modular disintegration of the DMN followed by a re-integration of this network with a normal functioning, or an anti-inflammatory effect of this treatment.

Romeo, B., Hermand, M., Pétillion, A., Karila, L., & Benyamina, A. (2021). Clinical and biological predictors of psychedelic response in the treatment of psychiatric and addictive disorders: A systematic review. Journal of psychiatric research, 137, 273–282. https://doi.org/10.1016/j.jpsychires.2021.03.002

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Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property

Abstract

Long term benefits following short-term administration of high psychedelic doses of serotonergic and dissociative hallucinogens, typified by psilocybin and ketamine respectively, support their potential as treatments for psychiatric conditions such as major depressive disorder. The high psychedelic doses induce perceptual experiences which are associated with therapeutic benefit. There have also been anecdotal reports of these drugs being used at what are colloquially referred to as “micro” doses to improve mood and cognitive function, although currently there are recognized limitations to their clinical and preclinical investigation. In the present studies we have defined a low dose and plasma exposure range in rats for both ketamine (0.3-3 mg/kg [10-73 ng/ml]) and psilocybin/psilocin (0.05-0.1 mg/kg [7-12 ng/ml]), based on studies which identified these as sub-threshold for the induction of behavioral stereotypies. Tests of efficacy were focused on depression-related endophenotypes of anhedonia, amotivation and cognitive dysfunction using low performing male Long Evans rats trained in two food motivated tasks: a progressive ratio (PR) and serial 5-choice (5-CSRT) task. Both acute doses of ketamine (1-3 mg/kg IP) and psilocybin (0.05-0.1 mg/kg SC) pretreatment increased break point for food (PR task), and improved attentional accuracy and a measure of impulsive action (5-CSRT task). In each case, effect size was modest and largely restricted to test subjects characterized as “low performing”. Furthermore, both drugs showed a similar pattern of effect across both tests. The present studies provide a framework for the future study of ketamine and psilocybin at low doses and plasma exposures, and help to establish the use of these lower concentrations of serotonergic and dissociative hallucinogens both as a valid scientific construct, and as having a therapeutic utility.

Higgins, G. A., Carroll, N. K., Brown, M., MacMillan, C., Silenieks, L. B., Thevarkunnel, S., Izhakova, J., Magomedova, L., DeLannoy, I., & Sellers, E. M. (2021). Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property. Frontiers in pharmacology, 12, 640241. https://doi.org/10.3389/fphar.2021.640241

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Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment-resistant depression

Aim: Approximately one-third of patients with major depressive disorder develop treatment-resistant depression. One-third of patients with treatment-resistant depression demonstrate resistance to ketamine, which is a novel antidepressant effective for this disorder. The objective of this study was to examine the utility of resting-state functional magnetic resonance imaging for the prediction of treatment response to ketamine in treatment-resistant depression.

Methods: An exploratory seed-based resting-state functional magnetic resonance imaging analysis was performed to examine baseline resting-state functional connectivity differences between ketamine responders and nonresponders before treatment with multiple intravenous ketamine infusions.

Results: Fifteen patients with treatment-resistant depression received multiple intravenous subanesthetic (0.5 mg/kg/40 minutes) ketamine infusions, and nine were identified as responders. The exploratory resting-state functional magnetic resonance imaging analysis identified a cluster of significant baseline resting-state functional connectivity differences associating ketamine response between the amygdala and subgenual anterior cingulate gyrus in the right hemisphere. Using anatomical region of interest analysis of the resting-state functional connectivity, ketamine response was predicted with 88.9% sensitivity and 100% specificity. The resting-state functional connectivity of significant group differences between responders and nonresponders retained throughout the treatment were considered a trait-like feature of heterogeneity in treatment-resistant depression.

Conclusion: This study suggests the possible clinical utility of resting-state functional magnetic resonance imaging for predicting the antidepressant effects of ketamine in treatment-resistant depression patients and implicated resting-state functional connectivity alterations to determine the trait-like pathophysiology underlying treatment response heterogeneity in treatment-resistant depression.

Nakamura, T., Tomita, M., Horikawa, N., Ishibashi, M., Uematsu, K., Hiraki, T., Abe, T., & Uchimura, N. (2021). Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment-resistant depression. Neuropsychopharmacology reports, 41(2), 168–178. https://doi.org/10.1002/npr2.12165

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Single, Fixed-Dose Intranasal Ketamine for Alleviation of Acute Suicidal Ideation. An Emergency Department, Trans-Diagnostic Approach: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial

Abstract

Background: Suicidal patients often present to the emergency department, where specific anti-suicidal treatment is lacking. Ketamine, a Glutamate modulator and a rapidly acting antidepressant with anti-suicidal properties, might offer relief.

Aims: Evaluation of single, fixed-dosed intranasal ketamine for acute suicidal ideation in the emergency department.

Methods: Between August 2016 and April 2018, 30 eligible suicidal subjects, scheduled for psychiatric hospitalization, independently of their psychiatric diagnosis, were randomized to intranasal ketamine 40 mg or saline placebo. Safety and efficacy evaluations were scheduled for 30, 60, 120 and 240 min post administration and on days 1, 2, 3, 4, 5, 7, 21 and 28. Primary outcome was suicidal ideation.

Results: Fifteen subjects were randomized for each study group. All were analyzed for primary and secondary outcomes. Four hours post administration, the mean difference in suicidal symptoms between the groups, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) item of suicidal thoughts (MADRS-SI), was 1.267 (95% confident interval 0.1-2.43, p < 0.05) favoring treatment. Remission from suicidal ideation was evident in 80% for the ketamine group compared with 33% for the controls (p < 0.05). The mean difference in depressive symptoms, measured by MADRS, at the same time was 9.75 (95% confident interval 0.72-18.79, p < 0.05) favoring ketamine. Treatment was safe and well-tolerated. Conclusions: Single, fixed-dose, intranasal ketamine alleviated suicidal ideation and improved depressive symptoms four hours post administration. We present here an innovative paradigm for emergency department management of suicidal individuals. Future larger-scale studies are warranted. ClinicalTrials.gov Identifier: NCT02183272.

Domany, Y., & McCullumsmith, C. B. (2021). Single, Fixed-Dose Intranasal Ketamine for Alleviation of Acute Suicidal Ideation. An Emergency Department, Trans-Diagnostic Approach: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial. Archives of suicide research : official journal of the International Academy for Suicide Research, 1–16. Advance online publication. https://doi.org/10.1080/13811118.2021.1878078

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What is the clinical evidence on psilocybin for the treatment of psychiatric disorders? A systematic review

Abstract

Background: Psilocybin is a predominant agonist of 5HT1A and 5HT2A/C receptors and was first isolated in 1958, shortly before it became a controlled substance. Research on the potential therapeutic effects of this compound has recently re-emerged alongside what is being addressed as a psychedelic renaissance.

Methods: In this paper we performed a systematic review of the clinical trials conducted so far regarding the therapeutic effects of psilocybin on psychiatric disorders. The eligibility criteria included clinical trials that assessed psilocybin’s potential therapeutic effects on patients with psychiatric disorders. Nine hundred seven articles were found and screened in regard to the title, from which 94 were screened through abstract and 9 met the eligibility criteria and were included.

Results: The papers published focused on 3 disorders: depression, obsessive-compulsive disorder (OCD) and substance use disorder (namely tobacco and alcohol). Psilocybin has shown a relatively safe profile and very promising results, with reductions found on most of the psychiatric rating scales’ scores. Research on depression showed the most solid evidence, supported by 3 randomized controlled trials. Studies on OCD and substance use disorder showed more limitations due to their open-label design.

Conclusions: Altogether, the results from the studies reviewed in this paper suggest a substantial therapeutic potential. This calls for further research to confirm the results observed so far and further explain the underlying mechanisms.

Castro Santos, H., & Gama Marques, J. (2021). What is the clinical evidence on psilocybin for the treatment of psychiatric disorders? A systematic review. Porto biomedical journal, 6(1), e128. https://doi.org/10.1097/j.pbj.0000000000000128

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Development and Evaluation of a Therapist Training Program for Psilocybin Therapy for Treatment-Resistant Depression in Clinical Research

Abstract

Introduction: Psychological support throughout psilocybin therapy is mandated by regulators as an essential part of ensuring participants’ physical and psychological safety. There is an increased need for specially trained therapists who can provide high-quality care to participants in clinical studies. This paper describes the development and practical implementation of a therapist training program of psychological support within a current phase IIb international, multicenter, randomized controlled study of psilocybin therapy for people experiencing treatment-resistant depression. Description of Training Program: This new and manualized approach, based on current evidence-based psychotherapeutic approaches, was developed in partnership with different mental health researchers, practitioners, and experts; and has been approved by the FDA. Training consists of four components: an online learning platform; in-person training; applied clinical training; and ongoing individual mentoring and participation in webinars.This paper provides a brief overview of the method of support, the rationale and methodology of the training program, and describes each stage of training. The design and implementation of fidelity procedures are also outlined. Lessons Learned: As part of the phase IIb study of psilocybin therapy for treatment-resistant depression, 65 health care professionals have been fully trained as therapists and assisting therapists, across the US, Canada and Europe. Therapists provided informal feedback on the training program. Feedback indicates that the didactic and experiential interactive learning, delivered through a combination of online and in-person teaching, helped therapists build conceptual understanding and skill development in the therapeutic approach. Clinical training and engagement in participant care, under the guidance of experienced therapists, were considered the most beneficial and challenging aspects of the training. Conclusions: Clinical training for therapists is essential for ensuring consistently high-quality psilocybin therapy. Development of a rigorous, effective and scalable training methodology has been possible through a process of early, active and ongoing collaborations between mental health experts. To maximize impact and meet phase III and post-approval need, enhanced online learning and establishing pathways for clinical training are identified as critical points for quality assurance. This will require close public, academic and industry collaboration.

Tai, S. J., Nielson, E. M., Lennard-Jones, M., Johanna Ajantaival, R. L., Winzer, R., Richards, W. A., Reinholdt, F., Richards, B. D., Gasser, P., & Malievskaia, E. (2021). Development and Evaluation of a Therapist Training Program for Psilocybin Therapy for Treatment-Resistant Depression in Clinical Research. Frontiers in psychiatry, 12, 586682. https://doi.org/10.3389/fpsyt.2021.586682

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Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression

Abstract

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.

Siegel, J. S., Palanca, B., Ances, B. M., Kharasch, E. D., Schweiger, J. A., Yingling, M. D., Snyder, A. Z., Nicol, G. E., Lenze, E. J., & Farber, N. B. (2021). Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression. Psychopharmacology, 238(4), 1157–1169. https://doi.org/10.1007/s00213-021-05762-6

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21 March - Ketamine Discussion with Celia Morgan, Filip Tylš & Will Barone

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