Clinical, Neurocognitive, and Emotional Effects of Psilocybin in Depressed Patients - Proof of Concept

• ClinicalTrials.gov Identifier: NCT03715127
• Recruitment Status: Completed
• First Posted: October 22, 2018
• Last Update Posted: April 29, 2022
• Sponsor: University of Zurich
• Collaborator: Schweizerischer Nationalfonds
• Information provided by (Responsible Party): University of Zurich

Tracking Information

• First Submitted Date: October 16, 2018
• First Posted Date: October 22, 2018
• Last Update Posted Date: April 29, 2022
• Actual Study Start Date: March 11, 2019
• Actual Primary Completion Date: October 12, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 19, 2018)

• Montgomery Asberg Depression Scale [ Time Frame: Day 32 ]
  observer-rated score for depression
• Beck Depression Inventory [ Time Frame: Day 32 ]
  self-rated score for depression

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 19, 2018)

• Changes in BOLD signal over time as measured by fMRI [ Time Frame: Day 17, 20, 32 ]
  3 times assessement of fMRI
• 5 Dimensions- Altered States of consciousness(5D-ASC) [ Time Frame: Day 18 ]
  Assessment of subjective alterations in state of conciousness

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Clinical, Neurocognitive, and Emotional Effects of Psilocybin in Depressed Patients - Proof of Concept
• Official Title: Phase II, Randomized, Double Blind, Placebo Controlled, Parallel Group, Single Center Study of Psilocybin Efficacy in Major Depression
• Brief Summary: 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

Detailed Description

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. Suicide is the second leading cause of death in individuals 15-24 years of age (Insel & Charney 2003).

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-dimethyltryptamine) 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 brain-derived neurotrophic factor (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 (0.215 mg/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, the investigators will analyze 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

placebo-controlled, quadruple-blind, randomized, mono-centric

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

quadruple-blind

Primary Purpose: Treatment

• Condition: Depressive Disorder, Major

Intervention

• Drug: Psilocybine oral capsule
  single dose of psilocybin (0.215mg / kg body weight)
• Drug: Placebo oral capsule
  single dose of placebo (100% mannitol)

Study Arms

• Placebo Comparator: Placebo
  one oral dose of 100% mannitol (placebo)
  Intervention: Drug: Placebo oral capsule
• Active Comparator: Psilocybin
  one oral dose of 0.215mg/kg psilocybin (verum)
  Intervention: Drug: Psilocybine oral capsule

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 21, 2022): 55
• Original Estimated Enrollment (submitted: October 19, 2018): 60
• Actual Study Completion Date: April 12, 2022
• Actual Primary Completion Date: October 12, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Capable of giving informed consent
• Informed consent as documented by signature
• Male and female in- and outpatients 18 years to 60 years of age
• Right-handedness
• DSM-IV-diagnosis of mild or moderate major depressive episode without psychotic features (based on clinical assessment and confirmed by the SCID Interview)
• Score of ≥ 10 and ≤40 on the Montgomery-Asberg Depression Rating Scale (MADRS) at both screening and baseline visits.
• Drug free from any psychotropic medication for at least two weeks (or five weeks for fluoxetine) before enrolling in the study
• Judged clinically not to be a serious suicide risk
• Good physical health with no unstable medical conditions, as determined by medical history, physical examination, routine blood labs, electrocardiogram, urineanalysis, and urine toxicology
• Normal level of language comprehension and German or Swiss-German as first language
• Willing to refrain from drinking alcohol the day before testing days, from drinking alcohol and caffeinated drinks during the testing days and from consuming psychoactive substances 2 weeks before enrolling in the study and for the remainder of the study
• Women of childbearing potential must be using an effective, established method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices. Note: female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential.
• Have a family member or friend who can pick them up and stay with them overnight after the psilocybin administration sessions (driving is forbidden at drug treatment days)

Exclusion Criteria:

• Lifetime history of bipolar disorder (I, II, not otherwise specified)
• Lifetime history of schizophrenia, schizoaffective disorder, or psychosis not otherwise specified
• History of DSM-IV drug or alcohol dependence or abuse (except for caffeine or nicotine) within three months prior to enrollment
• Comorbid Axis I anxiety disorder diagnoses will be permitted if they do not require current treatment
• Family history of schizophrenia or schizoaffective disorder, or bipolar disorder type 1 (first or second degree relatives)
• Lifetime history of hallucinogen use on more than 10 occasions
• Getting psychotherapeutic or psychological treatment from third parties during the study is forbidden
• Abnormal electrocardiogram
• Any unstable illness as determined by history or laboratory tests
• BMI <17 or >35
• Uncorrected hypo- or hyperthyroidism
• Women who are pregnant or breast feeding, or have the intention to become pregnant during the course of the study
• Contraindications to magnetic resonance imaging (MRI safety form)
• During the study, new use or dose changes of already existing concomitant medication without prior informing the investigators is forbidden
• Allergy, hypersensitivity, or other adverse reaction to previous use of psilocybin or other hallucinogens
• High risk of adverse emotional or behavioral reaction based on investigator's clinical evaluation (e.g., evidence of serious personality disorder, antisocial behavior, serious current stressors, lack of meaningful social support)
• Participation in another study with investigational drug within the 30 days preceding and during the present study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT03715127
• Other Study ID Numbers: PSIDEPR128
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: University of Zurich
• Original Responsible Party: Franz Xaver Vollenweider, University of Zurich, Prof. Dr. med.
• Current Study Sponsor: University of Zurich
• Original Study Sponsor: Franz Xaver Vollenweider
• Collaborators: Schweizerischer Nationalfonds
• Investigators: Not Provided
• PRS Account: University of Zurich
• Verification Date: April 2022