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

January 6, 2022 / Depressive Disorders, 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 / Depressive Disorders, Ketamine, Neuroscience, Papers / 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 / Depressive Disorders, Papers, Substance Use Disorder / 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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A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT 2A Receptor Density in the Pig Brain

February 6, 2022 / Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers / Leave a Comment / By / , , , , , ,

Abstract

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (-15.21% to -50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in the hippocampus (+9.24%) and the PFC (+6.10%), whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT2AR density, which may play a role in psilocybin’s antidepressive effects.

Raval, N. R., Johansen, A., Donovan, L. L., Ros, N. F., Ozenne, B., Hansen, H. D., & Knudsen, G. M. (2021). A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain. International journal of molecular sciences, 22(2), 835. https://doi.org/10.3390/ijms22020835

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Pharmacological-assisted Psychotherapy for Post-Traumatic Stress Disorder: a systematic review and meta-analysis

February 21, 2022 / Anxiety Disorders / PTSD, MDMA, Papers / Leave a Comment / By / , , , , , , , , ,

Abstract

Background: Pharmacological-assisted psychotherapies, using conventional and novel drug agents, are increasingly being used both in clinical and experimental research settings, respectively. Objective: To determine the efficacy of conventional and novel pharmacological-assisted psychotherapies in reducing PTSD symptom severity. Method: A systematic review and meta-analysis of randomised-controlled trials were undertaken; 21 studies were included. Results: MDMA-assisted therapy was found to statistically superior to active and inactive placebo-assisted therapy in reduction of PTSD symptoms (standardised mean difference -1.09, 95% CI -1.60 to -0.58). There was no evidence of superiority over placebo for any other intervention. Conclusions: MDMA-assisted therapy demonstrated an impressive effect size; however, it is difficult to have confidence at this stage in this intervention due to the small numbers of participants included, and more research in this area is needed. There was no evidence to support the efficacy of any other drug-assisted interventions.

Hoskins, M. D., Sinnerton, R., Nakamura, A., Underwood, J., Slater, A., Lewis, C., Roberts, N. P., Bisson, J. I., Lee, M., & Clarke, L. (2021). Pharmacological-assisted Psychotherapy for Post-Traumatic Stress Disorder: a systematic review and meta-analysis. European journal of psychotraumatology, 12(1), 1853379. https://doi.org/10.1080/20008198.2020.1853379

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Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants

February 6, 2022 / Depressive Disorders, Papers / Leave a Comment / By / , , , , , ,

Abstract

Rationale: Major depressive disorder is one of the leading global causes of disability, for which the classic serotonergic psychedelics have recently reemerged as a potential therapeutic treatment option.

Objective: We present the first meta-analytic review evaluating the clinical effects of classic serotonergic psychedelics vs placebo for mood state and symptoms of depression in both healthy and clinical populations (separately).

Results: Our search revealed 12 eligible studies (n = 257; 124 healthy participants, and 133 patients with mood disorders), with data from randomized controlled trials involving psilocybin (n = 8), lysergic acid diethylamide ([LSD]; n = 3), and ayahuasca (n = 1). The meta-analyses of acute mood outcomes (3 h to 1 day after treatment) for healthy volunteers and patients revealed improvements with moderate significant effect sizes in favor of psychedelics, as well as for the longer-term (16 to 60 days after treatments) mood state of patients. For patients with mood disorder, significant effect sizes were detected on the acute, medium (2-7 days after treatment), and longer-term outcomes favoring psychedelics on the reduction of depressive symptoms.

Conclusion: Despite the concerns over unblinding and expectancy, the strength of the effect sizes, fast onset, and enduring therapeutic effects of these psychotherapeutic agents encourage further double-blind, placebo-controlled clinical trials assessing them for management of negative mood and depressive symptoms.

Galvão-Coelho, N. L., Marx, W., Gonzalez, M., Sinclair, J., de Manincor, M., Perkins, D., & Sarris, J. (2021). Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants. Psychopharmacology, 238(2), 341–354. https://doi.org/10.1007/s00213-020-05719-1

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Ketamine treatment for depression: qualitative study exploring patient views

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

Abstract

Background: Ketamine is a new and promising treatment for depression but comes with challenges to implement because of its potential for abuse.

Aims: We sought the views of patients to inform policy and practical decisions about the clinical use of ketamine before large-scale roll-out is considered.

Method: This qualitative study used three focus groups and three validation sessions from 14 patients with prior diagnoses of depression but no experience of ketamine treatment. Focus groups explored their views about clinical use of ketamine and the best way for ketamine to be administered and monitored. The qualitative data were analysed by three service-user researchers using thematic analysis.

Results: Five themes were generated: changing public perceptions, risks, monitoring, privacy and data protection, and practical aspects. Participants were conscious of the stigma attached to ketamine as a street drug and wanted better public education, and evidence on the safety of ketamine after long-term use. They felt that monitoring was required to provide evidence for ketamine’s safe use and administration, but there were concerns about the misuse of this information. Practical aspects included discussions about treatment duration, administration and accessibility (for example who would receive it, under what criteria and how).

Conclusions: Patients are enthusiastic about ketamine treatment but need more information before national roll-out. The wider societal impact of ketamine treatment also needs to be considered and patients need to be part of any future roll-out to ensure its success.

Jilka, S., Odoi, C. M., Wilson, E., Meran, S., Simblett, S., & Wykes, T. (2021). Ketamine treatment for depression: qualitative study exploring patient views. BJPsych open, 7(1), e32. https://doi.org/10.1192/bjo.2020.165

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Development of the Psychological Insight Questionnaire among a sample of people who have consumed psilocybin or LSD

February 6, 2022 / LSD, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By / , , , , ,

Abstract

Background: Several measures have been developed to examine acute psychedelic effects (e.g. mystical-type and challenging experiences), but no measure assesses acute psychologically insightful experiences that may occur during psychedelic experiences.

Aim: The purpose of this study was to develop and examine the psychometric properties of the Psychological Insight Questionnaire.

Method: A cross-sectional survey study among psilocybin and LSD users. Respondents (n=1661; Mage=22.9, standard deviation=8.5; Caucasian/White=83%; non-Hispanic=91%; men=72%; United States resident=66%) completed an Internet-based survey.

Results: The Psychological Insight Questionnaire consists of 23 items with two subscales: (a) Avoidance and Maladaptive Patterns Insights and (b) Goals and Adaptive Patterns Insights. Construct validity of the Psychological Insight Questionnaire was supported by strong correlations of the Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights and Goals and Adaptive Patterns Insights subscales) scores with the insight subscale of the Session Impacts Scale, and weak-to-moderate correlations with the Mystical Experiences and Challenging Experiences Questionnaires. Furthermore, Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights and Goals and Adaptive Patterns Insights subscales) scores were moderately-to-strongly correlated with retrospectively reported increases in psychological flexibility, and well-being/life satisfaction that were attributed to a memorable psychedelic experience. Lastly, incremental validity was established showing that the Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights subscale) scores predict unique variance in changes in psychological flexibility, and Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights and Goals and Adaptive Patterns Insights subscales) scores predict changes in well-being and life satisfaction, beyond measures of acute mystical-type and challenging effects.

Conclusions: The Psychological Insight Questionnaire has the potential to extend the understanding of the acute and enduring effects of psychedelics. Further longitudinal research is necessary to determine the long-term predictive validity of the Psychological Insight Questionnaire and to examine the role of psychological insight in predicting therapeutic outcomes.

Davis, A. K., Barrett, F. S., So, S., Gukasyan, N., Swift, T. C., & Griffiths, R. R. (2021). Development of the Psychological Insight Questionnaire among a sample of people who have consumed psilocybin or LSD. Journal of psychopharmacology (Oxford, England), 35(4), 437–446. https://doi.org/10.1177/0269881120967878

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The acute effects of classic psychedelics on memory in humans

February 6, 2022 / Papers, Psychology / Leave a Comment / By /

Abstract

Rationale: Memory plays a central role in the psychedelic experience. The spontaneous recall and immersive reliving of autobiographical memories has frequently been noted by researchers and clinicians as a salient phenomenon in the profile of subjective effects of classic psychedelic drugs such as psilocybin, LSD, and ayahuasca. The ability for psychedelics to provoke vivid memories has been considered important to their clinical efficacy.

Objective: This review aims to examine and aggregate the findings from experimental, observational, and qualitative studies on the acute modulation of memory by classic psychedelics in humans.

Method: A literature search was conducted using PubMed and PsycInfo as well as manual review of references from eligible studies. Publications reporting quantitative and/or qualitative findings were included; animal studies and case reports were excluded.

Results: Classic psychedelics produce dose-dependently increasing impairments in memory task performance, such that low doses produce no impairment and higher doses produce increasing levels of impairment. This pattern has been observed in tasks assessing spatial and verbal working memory, semantic memory, and non-autobiographical episodic memory. Such impairments may be less pronounced among experienced psychedelic users. Classic psychedelics also increase the vividness of autobiographical memories and frequently stimulate the recall and/or re-experiencing of autobiographical memories, often memories that are affectively intense (positively or negatively valenced) and that had been avoided and/or forgotten prior to the experience.

Conclusions: Classic psychedelics dose-dependently impair memory task performance but may enhance autobiographical memory. These findings are relevant to the understanding of psychological mechanisms of action of psychedelic-assisted psychotherapy.

Healy C. J. (2021). The acute effects of classic psychedelics on memory in humans. Psychopharmacology, 238(3), 639–653. https://doi.org/10.1007/s00213-020-05756-w

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The acute effects of classic psychedelics on memory in humans

February 21, 2022 / Ayahuasca, LSD, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By /

Abstract

Rationale: Memory plays a central role in the psychedelic experience. The spontaneous recall and immersive reliving of autobiographical memories has frequently been noted by researchers and clinicians as a salient phenomenon in the profile of subjective effects of classic psychedelic drugs such as psilocybin, LSD, and ayahuasca. The ability for psychedelics to provoke vivid memories has been considered important to their clinical efficacy.

Objective: This review aims to examine and aggregate the findings from experimental, observational, and qualitative studies on the acute modulation of memory by classic psychedelics in humans.

Method: A literature search was conducted using PubMed and PsycInfo as well as manual review of references from eligible studies. Publications reporting quantitative and/or qualitative findings were included; animal studies and case reports were excluded.

Results: Classic psychedelics produce dose-dependently increasing impairments in memory task performance, such that low doses produce no impairment and higher doses produce increasing levels of impairment. This pattern has been observed in tasks assessing spatial and verbal working memory, semantic memory, and non-autobiographical episodic memory. Such impairments may be less pronounced among experienced psychedelic users. Classic psychedelics also increase the vividness of autobiographical memories and frequently stimulate the recall and/or re-experiencing of autobiographical memories, often memories that are affectively intense (positively or negatively valenced) and that had been avoided and/or forgotten prior to the experience.

Conclusions: Classic psychedelics dose-dependently impair memory task performance but may enhance autobiographical memory. These findings are relevant to the understanding of psychological mechanisms of action of psychedelic-assisted psychotherapy.

Healy C. J. (2021). The acute effects of classic psychedelics on memory in humans. Psychopharmacology, 238(3), 639–653. https://doi.org/10.1007/s00213-020-05756-w

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