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Potential involvement of serotonergic signaling in ketamine's antidepressant actions: A critical review

/ Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / / , , , , ,

Abstract

A single i.v. infusion of ketamine, classified as an N-methyl-d-aspartate (NMDA) receptor antagonist, may alleviate depressive symptoms within hours of administration in treatment resistant depressed patients, and the antidepressant effect may last for several weeks. These unique therapeutic properties have prompted researchers to explore the mechanisms mediating the antidepressant effects of ketamine, but despite many efforts, no consensus on its antidepressant mechanism of action has been reached. Recent preclinical reports have associated the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) with the antidepressant-like action of ketamine. Here, we review the current evidence for a serotonergic role in ketamine’s antidepressant effects.

The pharmacological profile of ketamine may include equipotent activity on several non-NMDA targets, and the current hypotheses for the mechanisms responsible for ketamine’s antidepressant activity do not appear to preclude the possibility that non-glutamate neurotransmitters are involved in the antidepressant effects. At multiple levels, the serotonergic and glutamatergic systems interact, and such crosstalk could support the notion that changes in serotonergic neurotransmission may impact ketamine’s antidepressant potential. In line with these prospects, ketamine may increase 5-HT levels in the prefrontal cortex of rats, plausibly via hippocampal NMDA receptor inhibition and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In addition, a number of preclinical studies suggest that the antidepressant-like effects of ketamine may depend on endogenous activation of 5-HT receptors. Recent imaging and behavioral data predominantly support a role for 5-HT1A or 5-HT1B receptors, but the full range of 5-HT receptors has currently not been systematically investigated in this context. Furthermore, the nature of any 5-HT dependent mechanism in ketamine’s antidepressant effect is currently not understood, and therefore, more studies are warranted to confirm this hypothesis and explore the specific pathways that might implicate 5-HT.

du Jardin, K. G., Müller, H. K., Elfving, B., Dale, E., Wegener, G., & Sanchez, C. (2016). Potential involvement of serotonergic signaling in ketamine’s antidepressant actions: A critical review. Progress in Neuro-Psychopharmacology and Biological Psychiatry. http://dx.doi.org/10.1016/j.pnpbp.2016.05.007
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The potential use of ayahuasca in psychiatry

/ Ayahuasca, Papers, Psychology, Publications / / , , ,

Abstract

Ayahuasca is a decoctum made of admixture plants containing dimethyltryptamine and harmine. For millennia it has been used as a central element of spiritual, religious, initiation, and other – foremost healing – rituals, originally by the indigenous groups of the Amazon basin and later by the mestizo populations of the region. During the last two decades the brew has raised increased scientific and lay interest about its healing potentials within the framework of Western therapeutic settings. The typical ayahuasca effects consist of strong somatic reactions, vivid visions, relived personal memories, cathartic emotions, and insightful, introspective experiences when the emerging mental contents take different context and get deeper perspectives. The ayahuasca-experience can be exhausting necessitating the presence of an experienced leader for helping participants to pass difficult phases and for maximizing therapeutic benefits. No health damaging adverse effect has been confirmed thus far as result of its well-structured, institutionalized use. The scientific investigation of ayahuasca is hindered by legal issues, methodical problems, and sociocultural preconceptions. The present review outlines the therapeutic potentials of ayahuasca use in psychiatry with its psychobiological and spiritual background.

Frecska, E., Bokor, P., Andrassy, G., & Kovacs, A. (2016). The potential use of ayahuasca in psychiatry. Neuropsychopharmacologia Hungarica: a Magyar Pszichofarmakologiai Egyesulet lapja= official journal of the Hungarian Association of Psychopharmacology, 18(2), 79.
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Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: A double-blind, randomized, controlled trial

/ Depressive Disorders, Ketamine, Papers, Psychology, Publications / / , , , , , ,

Abstract

Background: Ketamine is a glutamate N-methyl-d-aspartate receptor antagonist capable of exerting antidepressive effects in single or repeated intravenous infusions. The objective of this study was to investigate the safety and the efficacy of oral ketamine vs. diclofenac monotherapy in reducing symptoms of mild to moderate depression among patients with chronic pain.

Methods: This study is a 6-week, randomized, double-blind, controlled, parallel-group trial with two intervention arms (ketamine, fixed daily dosage of 150 mg vs. diclofenac, fixed daily dosage of 150 mg). Twenty participants in each arm completed the trial program all of whom had two post-baseline measurements at week 3 and week 6. Reduction in depression symptoms was assessed using the Hamilton Depression Rating Scale (HDRS) and the hospital anxiety and depression subscale for depression (HADSDepression) scores at baseline and week 3 and week 6 post-intervention.

Results: Significantly lower HDRS scores were observed in the ketamine treatment group as early as 6 weeks post-intervention (P=0.008). By comparison, mean (±standard deviation) HADS depression subscale scores were significantly lower for individuals receiving ketamine compared to diclofenac for both post-baseline measures at week 3 (6.95±1.47 vs. 8.40±1.6, P=0.005) and week 6 (6.20±1.15 vs. 7.35±1.18, p=0.003).

Limitations: The limitations of the present study were its small sample size and the short-term follow-up period.

Conclusions: Oral ketamine appears to be a safe and effective option in improving depressive symptoms of patients with chronic pain with mild-to-moderate depression.

Jafarinia, M., Afarideh, M., Tafakhori, A., Arbabi, M., Ghajar, A., Noorbala, A. A., … & Akhondzadeh, S. (2016). Efficacy and Safety of Oral Ketamine versus Diclofenac to Alleviate Mild to Moderate Depression in Chronic Pain Patients: A Double-Blind, Randomized, Controlled Trial. Journal of Affective Disorders. http://dx.doi.org/10.1016/j.jad.2016.05.076

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Using the Theory of Planned Behavior to predict implementation of harm reduction strategies among MDMA/ecstasy users

/ MDMA, Papers, Psychology, Publications, Substance Use Disorder / / ,

Abstract

This prospective study was designed to test whether the variables proposed by the Theory of Planned Behavior (TPB) were associated with baseline intention to implement and subsequent use of 2 MDMA/ecstasy-specific harm reduction interventions: preloading/postloading and pill testing/pill checking. Using targeted Facebook advertisements, an international sample of 391 recreational ecstasy users were recruited to complete questionnaires assessing their ecstasy consumption history, and their attitudes, subjective norms, perceived behavioral control, habit strength (past strategy use), and intention to use these two strategies. Attitudes, subjective norms, and perceived behavioral control were significantly associated with baseline intention to preload/postload and pill test/pill check. Out of the 391 baseline participants, 100 completed the two-month follow-up assessment. Baseline habit strength and frequency of ecstasy consumption during the three months prior to baseline were the only significant predictors of how often participants used the preloading/postloading strategy during the follow-up. Baseline intention to pill test/pill check was the only significant predictor of how often participants used this strategy during the follow-up. These findings provide partial support for TPB variables as both correlates of baseline intention to implement and predictors of subsequent use of these two strategies. Future investigations could assess whether factors related to ecstasy consumption (e.g., subjective level of intoxication, craving, negative consequences following consumption), and environmental factors (e.g., accessibility and availability of harm reduction resources) improve the prediction of how often ecstasy users employ these and other harm reduction strategies.

Davis, A. K., & Rosenberg, H. (2016). Using the Theory of Planned Behavior to predict implementation of harm reduction strategies among MDMA/ecstasy users. Psychology of Addictive Behaviors, 30(4), 500.  http://dx.doi.org/10.1037/adb0000167
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LSD Acutely Impairs Fear Recognition and Enhances Emotional Empathy and Sociality

/ LSD, Papers, Psychology, Publications / / , , , ,

Abstract

Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, cross-over studies were conducted using 100 μg LSD in 24 subjects and 200 μg LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers (20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants’ desire to be with other people and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for LSD-assisted psychotherapy.

Dolder, P. C., Schmid, Y., Müller, F., Borgwardt, S., & Liechti, M. E. (2016). Lsd acutely impairs fear recognition and enhances emotional empathy and sociality. Neuropsychopharmacology. http://dx.doi.org/10.1038/npp.2016.82
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Ibogaine and addiction in the animal model, a systematic review and meta-analysis

/ Iboga / Ibogaine, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / / , , , , ,

Abstract

Ibogaine is a naturally occurring substance which has been increasingly used in the lay-scene to reduce craving and relapse in patients with substance use disorders (SUDs). Although human clinical trials on the safety and efficacy of ibogaine are lacking, animal studies do support the efficacy of ibogaine. In this systematic review and meta-analysis (MA), we summarise these animal findings, addressing three questions: (1) does ibogaine reduce addictive behaviour in animal models of SUDs?; (2) what are the toxic effects of ibogaine on motor functioning, cerebellum and heart rhythm?; (3) what are neuropharmacological working mechanisms of ibogaine treatment in animal models of SUDs? MA of 27 studies showed that ibogaine reduced drug self-administration, particularly during the first 24 h after administration. Ibogaine had no effect on drug-induced conditioned place preference. Ibogaine administration resulted in motor impairment in the first 24 h after supplementation, and cerebral cell loss even weeks after administration. Data on ibogaines effect on cardiac rhythm, as well as on its neuropharmacological working mechanisms are limited. Our results warrant further studies into the clinical efficacy of ibogaine in SUD patients in reducing craving and substance use, but close monitoring of the patients is recommended because of the possible toxic effects. In addition, more work is needed to unravel the neuropharmacological working mechanisms of ibogaine and to investigate its effects on heart rhythm.

Belgers, M., Leenaars, M., Homberg, J. R., Ritskes-Hoitinga, M., Schellekens, A. F. A., & Hooijmans, C. R. (2016). Ibogaine and addiction in the animal model, a systematic review and meta-analysis. Translational psychiatry, 6(5), e826. http://dx.doi.org/10.1038/tp.2016.71
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Psilocybine-ondersteunde therapie toont veelbelovende resultaten voor behandelingsresistente depressie

/ Mushrooms / Psilocybin /

psilocybin depression 2Het onderzoeksteam van het Imperial College in London heeft het potentieel van psilocybine-ondersteunde therapie om behandelingsresistente depressie te verlichten in een nieuw onderzoek getest. Uit statistieken blijkt dat 20% van mensen met zware depressieklachten niet reageren op conventionele behandelwijzen zoals SSRI-medicatie of cognitieve gedragstherapie (Carhart-Harris et al., 2016).

Twaalf deelnemers (zes mannen en zes vrouwen), allen gediagnosticeerd met zware depressie, deden mee aan de studie. Ze kregen twee orale doses psilocybine – 10 mg en 25 mg – waarbij de eerste de veiligheidsdosis was en de tweede, die zeven dagen later werd toegediend, de behandeldosis. De deelnemers werden geselecteerd uit 70 kandidaten; een van de belangrijkste selectiecriteria was de afwezigheid van psychotische voorvallen bij de kandidaten zelf, en bij hun naaste familieleden.

Alle participanten, in de leeftijd 30 tot 60, hadden een lange geschiedenis van depressie, en behandelpogingen hadden steeds slechts minimale effecten. Sommigen van hen leden al ongeveer 30 jaar aan middelzware tot zware depressie. Voorgaande behandelpogingen bestonden zowel uit chemische als psychologische middelen: medicatie zoals serotonine of dopamine heropname-inhibitoren (SSRI, NDRI, SNRI, etc.) en therapieën als cognitieve gedrags-, groeps-, en gesprekstherapie.

De farmacologie van psilocybine verschilt van die van selectieve serotonine heropname-inhibitoren (SSRI’s), de meest gebruikte medicatie voor dit type depressie. SSRI’s voorkomen dat de reeds afgegeven serotonine – een van de neurotransmitters die betrokken zijn in emotieregulatie – weer wordt opgenomen door dezelfde neuronen die het produceerden, zodat het kan worden opgenomen door serotoninereceptoren. Anders dan SSRI’s lijkt psilocybine structureel gezien op serotonine, waardoor het hetzelfde effect heeft als een algehele stijging van het serotonineniveau.

Gedurende het onderzoek werd psychologische steun gegeven voor, tijdens en na de psilocybinesessies. Tijdens de sessies was er minimale bemoeienis met de ervaringen van de patiënten. Hen werden enkel vragen gesteld die noodzakelijk waren om de effecten van de psilocybine op hun fysieke en mentale welzijn te kunnen evalueren. De meest voorkomende bijwerkingen waren misselijkheid, hoofdpijn, angst en verwarring, en deze waren alle van voorbijgaande aard. Slechts één patiënt had last van tijdelijke paranoia, die na een uur wegtrok.

Het onderzoek liet zien dat de depressiesymptomen bij alle 12 de deelnemers enigszins waren afgenomen. De scores op het Quick Inventory of Depressive Symptoms (QIDS) gaven aan dat het depressieniveau was gedaald van 16-20 (zware depressie) naar 6-10 (milde depressie). Vijf vervolgbeoordelingen vonden plaats tussen een week en drie maanden na de behandeling. De maximale positieve resultaten werden twee weken na de behandeling gehaald. Acht deelnemers ervoeren een week na de behandeling een complete remissie van hun depressie en bij zeven van hen bleef een significante afname van depressie na drie maanden aanhouden. Één patiënt beleefde een toename in depressieve klachten gedurende de drie maanden na de behandeling.

Dit onderzoek was het eerste dat de werkzaamheid van psilocybine bij de behandeling van zware depressie verkende, en toonde het potentieel van psilocybine aan voor het doen afnemen van zware, behandelingsresistente depressie en de veiligheid van de stof bij toediening onder de juiste omstandigheden. Voorgaand onderzoek met psilocybine-ondersteunde therapie had reeds aangetoond dat het angst bij terminale kanker kan verlichten (Grob C.S. et al., 2011).

Nader onderzoek onder striktere condities (placebo-gecontroleerd en op grotere schaal) is nodig om het potentieel van psilocybine voor de behandeling van zware depressie te bevestigen. Als deze belofte kan worden waargemaakt, dan zou dat voor miljoenen mensen die worstelen met zware depressie een nieuwe kans kunnen betekenen.

Verwijzingen:

Carhart-Harris R.L., Bolstridge M., Rucker J., Day C.M.J., Erritzoe D., Kaelen M., Bloomfield M., Rickard J.A., Forbes B., Fielding A., Taylor D., Pilling S., Curran V.H., Nutt D.J. (2016) Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. http://dx.doi.org/10.1016/S2215-0366(16)30065-7

Grob C.S., Danforth A.L., Chopra G.S., Hagerty M., McKay C.R., Halberstadt A.L. and Greer G.R. (2011) Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry, 68, pp. 71–78 http://dx.doi.org/10.1001/archgenpsychiatry.2010.116

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