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Effects of serotonin 2A/1A receptor stimulation by psilocybin on mood and emotion processing in major depressive disorder: a randomized double-blind placebo-controlled study

English title Effects of serotonin 2A/1A receptor stimulation by psilocybin on mood and emotion processing in major depressive disorder: a randomized double-blind placebo-controlled study
Applicant Vollenweider Franz Xaver
Number 169260
Funding scheme Project funding (Div. I-III)
Research institution Psychiatrische Universitätsklinik Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurology, Psychiatry
Start/End 01.01.2018 - 31.05.2022
Approved amount 356'788.00
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Keywords (8)

Psilocybin; serotonin 5-HT2A receptor; glutamate; Major depression; Emotion Processing; Neuroplasticity; Psychotherapy; Randomized double-blind placebo-controlled (RCT)

Lay Summary (German)

Lead
Diese klinische Studie untersucht die antidepressive Wirksamkeit und die zugrundeliegenden neurobiologischen Wirkmechanismen von Psilocybin in Kombination mit Psychotherapie als neuartigen therapeutischen Ansatz in der Depressionsbehandlung.
Lay summary

Depressionen sind sehr häufige und überwiegend wiederkehrende und chronische Erkrankungen, die für den Betroffenen und seine Umgebung zu einer erheblichen Behinderung in Alltag, Beziehungen und Beruf führen. Die zur Behandlung von Depressionen erhältlichen Medikamente müssen über Wochen oder Monate verabreicht werden, um eine Symptom-Verbesserung zu erreichen, und trotz ausreichend langer Behandlungsdauer sprechen nur etwa 50% der Patienten auf die Behandlung an. Die Entwicklung neuer Medikamente mit alternativen Wirkmechanismen ist daher dringend notwendig.

In der aktuellen klinischen Studie wollen wir einen neuen Wirkmechanismus zur Behandlung von Depressionen untersuchen. Typische Symptome der Depression sind nebst einem anhaltenden Stimmungstief vor allem auch eine erhöhte Aufmerksamkeit auf negative Umweltreize und Ausrichtung auf negative Gedanken. In vorgängigen Studien haben wir gezeigt, dass der Wirkstoff Psilocybin bei Gesunden die Grundstimmung anhebt und die Verarbeitung negativer Umweltreize abschwächt. Zudem verdichten sich Hinweise, dass Psilocybin nicht nur eine vorübergehende Stimmungsanhebung bewirkt, sonder über den Botenstoff Glutamat die Neuroplastizität des Gehirns anregt, was somit in Kombination mit Psychotherapie eine anhaltende Verhaltensveränderung begünstigen dürfte. Deshalb wollen wir in dieser Studie erstens untersuchen, ob eine einmalige moderate Dosis von Psilocybin zu einer raschen und anhaltenden Symptom-Verbesserung bei depressiven Patienten führt. Zweitens, wollen wir die neurobiologischen Wirkmechanismen von Psilocybin mittels funktioneller Bildgebung (Magnetresonanztomographie) weiter aufklären, um diesen neuartigen therapeutischen Ansatz weiter zu optimieren.

Die aus der Studie gewonnenen Erkenntnisse können zu einem innovativen Behandlungsansatz der Depression führen und damit einen wichtigen Beitrag zur Milderung der individuellen, gesellschaftlichen und ökonomischen Last depressiver Erkrankungen leisten.

Direct link to Lay Summary Last update: 10.11.2016

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Abstract

Major depressive disorder (MDD) is one of the world’s greatest contributor to the global burden of disease and MDD affects around 17% of the Swiss population (Tomonaga et al. 2013). It is a chronic condition and can cause the affected person to suffer greatly and function poorly at work, at school and in the family. More than 1’000 suicides were recorded in Switzerland in 2014, about 90% of these fatalities were related to depression or other psychiatric problems. Current pharmacotherapies, including monoaminergic-acting antidepressants, require prolonged administration (weeks if not months) for clinical improvement. This lag time, as well as a high non-response rate, emphasizes the need for better and faster-acting antidepressant medications. However, psychopharmacological research has largely failed to produce novel and more efficacious treatment options for MDD since decades. Advanced pharmaceutical antidepressants should ideally facilitate the psychotherapeutic process for patients, reduce the time onset of antidepressant efficacy, and prime neuroplastic adaptations relevant to symptom improvement. Such novel therapeutics are much needed and would address this detrimental public health problem, particularly in treatment-resistant patients. Early clinical studies using the psychotropic compound psilocybin (4-phosphoryloxy-N,N-dimethyl- tryptamine) as an adjunct in psychotherapy reported a significant improvement of clinical symptoms in depression and anxiety disorder (Leuner 1961, 1981). Psilocybin is the main psychoactive principle of the group of hallucinogenic fungi (Hofmann 1968), commonly known as magic mushrooms, and acts as partial agonist at cortical and sub-cortical serotonin 5-HT2A and 5-HT1A receptors. At moderate doses, psilocybin produces a dream-like state of consciousness (Kraehenmann et al. 2016) characterized by perceptual alterations, enhanced mood, facilitated autobiographic memory recollection, and a change of perspective on the self (Leuner 1981; Studerus et al. 2011). Recent clinical studies applying placebo-controlled designs support and extend these early findings by showing that a single dose of psilocybin leads to a fast and sustained reduction in anxiety and depression as well as an improvement of quality of life in advanced cancer patients (Griffiths 2015, Grob et al. 2011). Furthermore, a recent open-label feasibility study showed rapid-onset, sustained symptom improvements over 3 weeks in a small sample of treatment-resistant depressed patients following two psilocybin treatment sessions (Carhart-Harris et al. 2016). Accumulating evidence from pharmacological and neuroimaging studies suggests that psilocybin may produce its antidepressant effects via activation of 5-HT2A receptors located in prefrontal-limbic structures that are also implicated in the pathophysiology of depression (Kraehenmann & Vollenweider et al. 2015; Vollenweider und Kometer 2010; Disner et al. 2011). In addition, molecular studies suggest that the enduring symptom improvement after a single dose of psilocybin may be mediated through downstream effects on the glutamate system and a subsequent activation of neuroplastic factors such as BDNF (Catlow et al. 2013, Barre et al. 2016).The present clinical trial aims at investigating the putative antidepressant effects of a single moderate dose of psilocybin (0.2mg/kg) in patients suffering from MDD by applying a randomized, double-blind, placebo-controlled design. The specific aims of this project are: 1. To investigate whether psilocybin in combination with short-term focused psychotherapy will reduce core symptoms in patients with MDD. 2. Using functional magnetic resonance imaging (fMRI) to longitudinally assess whether a single dose of psilocybin will post-acutely change the negative emotion processing bias in patients with MDD and whether the change in emotion processing bias will predict subsequent symptom improvement. In addition, we will investigate whether psilocybin will lead to sustained changes in functional neuronal network connectivity (FC), e.g. in amygdala-prefrontal FC. 3. To investigate whether psilocybin will increase BDNF plasma concentration and whether the change in BDNF is related to changes in fMRI markers and the subsequent mood improvement.Recent reviews indicate that impaired neuroplasticity is at the core of the pathophysiology moods and stress-related disorders. Current available antidepressants have been developed with the aim of providing symptom relief rather than targeting neuroplastic impairments. In contrast to this, the present proposal builds on promising new findings that single dose of psilocybin, presumably via a 5-HT2A receptor driven glutamatergic mechanism, leads to a rapid enhancement in neuronal resilience and a to a change in the function of neuronal networks underlying depressive symptoms and behavior. Targeting neuroplasticity with such novel approaches appears to be important for reversing cognitive schemata and emotion processing biases, fostering enduring improvements in mood and cognitive flexibility (Krystal et al. 2009). Expected value: this is the first randomized, double-blind, placebo-controlled clinical trial (RCT) of psilocybin treatment in MDD. Using state-of-the art behavioral, neuroimaging, and neuroplasticity methodology, the results of this study will help elucidate urgently needed new treatment mechanisms in MDD. Should it turn out that a single moderate dose of psilocybin vs. placebo in conjunction with psychotherapy may rapidly and sustainedly reduce depressive symptoms, this will be a major breakthrough in finding a novel and fast acting treatment strategy in depressed patients. Therefore, the results of this study will have high impact on the field of pharmacological research into novel antidepressant medication.
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