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

February 21, 2022 / Depression, Mushrooms / Psilocybin, Papers, Psychotherapy / Leave a Comment / By / , , , , , , , , ,

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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Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission

February 6, 2022 / LSD, Neuroscience, Papers, Psychology, Psychopharmacology / Leave a Comment / By / , , , , , , , , , , , , , ,

Abstract

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptor f/f :Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptor f/f :Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

De Gregorio, D., Popic, J., Enns, J. P., Inserra, A., Skalecka, A., Markopoulos, A., Posa, L., Lopez-Canul, M., Qianzi, H., Lafferty, C. K., Britt, J. P., Comai, S., Aguilar-Valles, A., Sonenberg, N., & Gobbi, G. (2021). Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission. Proceedings of the National Academy of Sciences of the United States of America, 118(5), e2020705118. https://doi.org/10.1073/pnas.2020705118

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Increased sensitivity to strong perturbations in a whole-brain model of LSD

February 6, 2022 / LSD, Neuroscience, Papers / Leave a Comment / By / , , , , , , , ,

Abstract

Lysergic acid diethylamide (LSD) is a potent psychedelic drug, which has seen a revival in clinical and pharmacological research within recent years. Human neuroimaging studies have shown fundamental changes in brain-wide functional connectivity and an expansion of dynamical brain states, thus raising the question about a mechanistic explanation of the dynamics underlying these alterations. Here, we applied a novel perturbational approach based on a whole-brain computational model, which opens up the possibility to externally perturb different brain regions in silico and investigate differences in dynamical stability of different brain states, i.e. the dynamical response of a certain brain region to an external perturbation. After adjusting the whole-brain model parameters to reflect the dynamics of functional magnetic resonance imaging (fMRI) BOLD signals recorded under the influence of LSD or placebo, perturbations of different brain areas were simulated by either promoting or disrupting synchronization in the regarding brain region. After perturbation offset, we quantified the recovery characteristics of the brain area to its basal dynamical state with the Perturbational Integration Latency Index (PILI) and used this measure to distinguish between the two brain states. We found significant changes in dynamical complexity with consistently higher PILI values after LSD intake on a global level, which indicates a shift of the brain’s global working point further away from a stable equilibrium as compared to normal conditions. On a local level, we found that the largest differences were measured within the limbic network, the visual network and the default mode network. Additionally, we found a higher variability of PILI values across different brain regions after LSD intake, indicating higher response diversity under LSD after an external perturbation. Our results provide important new insights into the brain-wide dynamical changes underlying the psychedelic state – here provoked by LSD intake – and underline possible future clinical applications of psychedelic drugs in particular psychiatric disorders.

Jobst, B. M., Atasoy, S., Ponce-Alvarez, A., Sanjuán, A., Roseman, L., Kaelen, M., Carhart-Harris, R., Kringelbach, M. L., & Deco, G. (2021). Increased sensitivity to strong perturbations in a whole-brain model of LSD. NeuroImage, 230, 117809. https://doi.org/10.1016/j.neuroimage.2021.117809

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Psychedelics, placebo effects, and set and setting: Insights from common factors theory of psychotherapy

February 6, 2022 / Other substances, Papers, Psychotherapy / Leave a Comment / By / ,

Abstract

Psychedelic-assisted treatment is at first glance markedly different in structure and approach from mainstream forms of psychotherapy in the West. A major criticism of clinical psychedelic research rests on the difficulty of executing placebo-controlled studies and distinguishing drug effects from those of the psychotherapeutic container in which psychedelics are typically presented. Detractors also tend to find fault in spiritual or mystical themes that often arise in the context of psychedelic use. Common factors theory of psychotherapy is a useful and extensively studied framework that can help make sense of these issues, and has much to contribute to our understanding of contextual effects that are often discussed in psychedelic literature as “set and setting.” In this article, we examine four major contextual “common factors” shared by various healing traditions: 1) the therapeutic relationship; 2) the healing setting; 3) the rationale, conceptual scheme, or myth; and 4) the ritual. We explain how these factors show up in psychedelic-assisted treatment and how they may contribute to therapeutic effects. Lastly, we discuss the implications of these factors for the concept of placebo, and for future research.

Gukasyan, N., & Nayak, S. M. (2021). Psychedelics, placebo effects, and set and setting: Insights from common factors theory of psychotherapy. Transcultural psychiatry, 1363461520983684. Advance online publication. https://doi.org/10.1177/1363461520983684

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Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway

March 14, 2022 / Medicine, Other disciplines, Other subjects, Other substances, Papers / Leave a Comment / By / , , , , , , ,

Abstract

Aims: Glioblastoma is one of the most invasive tumors of the central nervous system, and has a high degree of malignancy and poor prognosis. Harmine, an active ingredient extracted from perennial herbs, has been reported to have obvious antitumor effects on various tumors. However, the effects of harmine on glioblastoma growth remain unknown. We here explored the effects of harmine on glioblastoma and its underlying molecular mechanisms related to tumorigenesis.

Materials and methods: CCK-8 and immunofluorescent assay were performed to measure anti-proliferative effect of harmine on U251-MG and U373-MG cells. Wound healing assay was performed to measure the effects of harmine on cell migration. qRT-PCR and western blot were performed to detect the protein/gene expression. BALB/c nude mice bearing U251-MG xenografts was used to measure the effects of harmine on the growth of glioblastoma in vivo.

Key findings: Harmine treatment significantly suppressed the proliferation of U251-MG and U373-MG cells in a dose and time-dependent way. Mechanistically, harmine reduced the basal and EGF-enhanced the phosphorylation level of FAK and AKT. Moreover, harmine inhibited the cell viability of U251-MG and U373-MG cells by downregulating the phosphorylation of the FAK/AKT pathway. Besides, harmine significantly suppressed the migration of U251-MG cells by suppressing the expression of MMP2, MMP9 and VEGF. Subsequently, orthotopic xenograft models revealed that harmine treatment dramatically inhibited the growth of glioblastoma in vivo.

Significance: In conclusion, these results suggest that harmine suppresses the proliferation and migration of U251-MG and U373-MG cells by inhibiting the FAK/AKT signaling pathway. Our findings elucidate harmine could be a promising drug for glioblastoma therapy.

Zhu, Y. G., Lv, Y. X., Guo, C. Y., Xiao, Z. M., Jiang, Q. G., Kuang, H., Zhang, W. H., & Hu, P. (2021). Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway. Life sciences, 270, 119112. https://doi.org/10.1016/j.lfs.2021.119112

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Within-treatment changes in a novel addiction treatment program using traditional Amazonian medicine

March 14, 2022 / Addiction, Ayahuasca, Papers, Psychology, Psychopharmacology, Psychotherapy / Leave a Comment / By / , , , ,

Abstract

Aims: The therapeutic use of psychedelics is regaining scientific momentum, but similarly psychoactive ethnobotanical substances have a long history of medical (and other) uses in indigenous contexts. Here we aimed to evaluate patient outcomes in a residential addiction treatment center that employs a novel combination of Western and traditional Amazonian methods.

Methods: The study was observational, with repeated measures applied throughout treatment. All tests were administered in the center, which is located in Tarapoto, Peru. Data were collected between 2014 and 2015, and the study sample consisted of 36 male inpatients who were motivated to seek treatment and who entered into treatment voluntarily. Around 58% of the sample was from South America, 28% from Europe, and the remaining 14% from North America. We primarily employed repeated measures on a psychological test battery administered throughout treatment, measuring perceived stress, craving frequency, mental illness symptoms, spiritual well-being, and physical and emotional health. Addiction severity was measured on intake, and neuropsychological performance was assessed in a subsample from intake to at least 2 months into treatment.

Results: Statistically significant and clinically positive changes were found across all repeated measures. These changes appeared early in the treatment and were maintained over time. Significant improvements were also found for neuropsychological functioning.

Conclusion: These results provide evidence for treatment safety in a highly novel addiction treatment setting, while also suggesting positive therapeutic effects.

O’Shaughnessy, D. M., Berlowitz, I., Rodd, R., Sarnyai, Z., & Quirk, F. (2021). Within-treatment changes in a novel addiction treatment program using traditional Amazonian medicine. Therapeutic advances in psychopharmacology, 11, 2045125320986634. https://doi.org/10.1177/2045125320986634

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

March 14, 2022 / Depression, Ketamine, Neuroscience, Papers / Leave a Comment / By / , , , , , , , , ,

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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Clinically meaningful changes on depressive symptom measures and patient-reported outcomes in patients with treatment-resistant depression

January 6, 2022 / Depression, Ketamine, Papers / Leave a Comment / By / , , , , , , , ,

Abstract

Objective: To use the Clinical Global Impression-Severity (CGI-S) scale to estimate clinically meaningful and clinically substantial changes as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), the Sheehan Disability Scale (SDS), and the Patient Health Questionnaire-9 (PHQ-9) in patients with treatment-resistant depression (TRD).

Methods: Pooled data were derived from two 4-week, randomized, active-controlled studies evaluating esketamine nasal spray (ESK) plus oral antidepressant (OAD) or OAD plus placebo nasal spray (PBO) in adults with TRD (N = 565). CGI-S, MADRS, SDS, and PHQ-9 scores were obtained at baseline and over 4 weeks of treatment. In this post hoc analysis, change scores on the MADRS, SDS, and PHQ-9 that corresponded to a clinically meaningful (1-point) or clinically substantial (2-point) change on the CGI-S scale were identified.

Results: Clinically meaningful changes in CGI-S scores after 28 days corresponded to 6-, 4-, and 3-point changes from baseline on the MADRS, SDS, and PHQ-9, respectively. Similarly, a 2-point CGI-S score change (clinically substantial change) corresponded to a 12-, 8-, and 6-point change on the MADRS, SDS, and PHQ-9, respectively. The proportion of patients showing substantial clinical improvement in the ESK plus OAD group versus the OAD plus PBO group after 28 days of treatment favored ESK plus OAD: 69.0% vs 55.3% (MADRS), 64.5% vs 48.9% (SDS), and 77.1% vs 64.7% (PHQ-9).

Conclusion: We provide a basis for identifying clinically meaningful and clinically substantial changes as assessed with commonly used outcome measures for depression to facilitate the translation of clinical trial results into clinical practice.

Turkoz, I., Alphs, L., Singh, J., Jamieson, C., Daly, E., Shawi, M., Sheehan, J. J., Trivedi, M. H., & Rush, A. J. (2021). Clinically meaningful changes on depressive symptom measures and patient-reported outcomes in patients with treatment-resistant depression. Acta psychiatrica Scandinavica, 143(3), 253–263. https://doi.org/10.1111/acps.13260

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Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants

January 7, 2022 / Depression, Ketamine, Neuroscience, Other substances, Papers, Psychiatry, Psychopharmacology, Psychotherapy / Leave a Comment / By / , , , , , ,

Abstract

Background: The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that “classic” serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period.

Methods: This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed.

Results: Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research.

Conclusions: Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.

Kadriu, B., Greenwald, M., Henter, I. D., Gilbert, J. R., Kraus, C., Park, L. T., & Zarate, C. A. (2021). Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants. The international journal of neuropsychopharmacology, 24(1), 8–21. https://doi.org/10.1093/ijnp/pyaa087

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Classical Psychedelics as Therapeutics in Psychiatry – Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders

February 6, 2022 / Addiction, Depression, Other substances, Papers, Psychiatry, Psychotherapy / Leave a Comment / By / ,

Abstract

Classical psychedelics, primarily psilocybin and lysergic acid diethylamide (LSD), have been used and extensively studied in Western medicine as part of substance-assisted psychotherapy in the 1950s and 1960s. Modern clinical research is currently gaining momentum and provides new evidence for the safety and efficacy of classical psychedelics (primarily psilocybin, but also LSD and ayahuasca) in the treatment of different psychiatric conditions, including substance use and mood disorders.In this review article, we outline common pathological mechanisms of substance use disorders (SUD) and unipolar depression. Next, the current literature on the effects of psychedelics is summarized in order to generate hypotheses regarding their potential therapeutic mechanisms of action in treating these psychiatric conditions. Finally, we review and discuss clinical trials published since 2011 investigating the effects of psychedelics in SUD and depression.While results from those modern clinical trials are promising, most of them do not meet the methodological requirements to allow firm conclusions on the clinical efficacy of psychedelics. Larger, blinded, randomized controlled trials (RCT) with clearly defined patient groups and well-defined primary endpoints are needed. Additionally, the therapeutic mechanisms of classical psychedelics are currently unknown. This review presents hypotheses derived from preclinical and human studies that need to be tested in future trials to better understand the clinical potential of psychedelic substances in modern psychiatry.

Mertens, L. J., & Preller, K. H. (2021). Classical Psychedelics as Therapeutics in Psychiatry – Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders. Pharmacopsychiatry, 54(4), 176–190. https://doi.org/10.1055/a-1341-1907

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14 May - Psychedelics & Psychosis with Phoebe Friesen and Dirk Corstens

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