Clinical, Neurocognitive, and Emotional Effects of Psilocybin in Depressed Patients - Proof of Concept
Condition: Depressive Disorder, Major
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Psilocybine oral capsule; Placebo oral capsule
Intervention type(s): Drug; Drug
Intervention description(s): single dose of psilocybin (0.215mg / kg body weight); single dose of placebo (100% mannitol)
Intervention MeSH terms: Psilocybin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: placebo-controlled, quadruple-blind, randomized, mono-centric
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Depression; 5HT-2A; Psilocybin; clinical efficacy; self; emotion regulation; placebo-controlled; proof-of-concept