MICA: SRC inhibitors as potential antipsychotics: human testing with psilocybin

The aim of this project is to test the efficacy of a novel compound AZD0530 (saracatinib) in attenuating the changes in brain function in healthy human volunteers after a single dose of psilocybin. Psilocybin is a naturally occurring compound that is found in some species of mushroom. It is structurally similar to the brain neurotransmitter serotonin - which is implicated in mood and schizophrenia. Psilocybin produces its effects by acting at a specific brain receptor site - the serotonin 2A (5-HT2A) receptor. Successfully blocking the effects of psilocybin may represent a new avenue for the treatment of schizophrenia, including treatment of symptoms which are not well treated at the moment. Schizophrenia is a devastating disorder comprising positive symptoms such as hallucinations and delusions, negative symptoms such as apathy and cognitive symptoms such as poor memory. It affects around 1% of people across the lifespan and current medicines, while successful, do not treat the full range of symptoms and also carry a risk of significant side effects.

This study is stimulated by the recent discovery that psilocybin and similar drugs produce their effects through a specific pathway in brain cells and that this pathway can be blocked by saracatinib. Current drugs that block 5-HT2A receptors are not specific for this pathway. This suggests that this saracatinib should be tested for its ability to block psilocybin effects in humans. Using brain imaging with MRI combined with intravenous psilocybin, we recently found brain changes that were related to the subjective effects. Here we propose to use brain imaging and subjective measures to test two doses of saracatinib for their ability to block or attenuate the effects of psilocybin. Twenty four volunteers who are healthy will be given placebo then psilocybin on one day, and saracatinib and then psilocybin on two other days. Neither the volunteers, nor the research staff will know which drugs are given. The brain changes and subjective ratings should show some reversal if saracatinib is successful in blocking the cell pathways mediating psilocybin effects. If successful this will potentially stimulate research into a whole new treatment approach for schizophrenia.

This double-blind, randomised, placebo-controlled, study will involve 24 healthy volunteers. The main objective is to test the ability of the Src-kinase second messenger inhibitor AZD0530 (saracatanib) to attenuate the neuroimaging and subjective markers responsive to psilocybin infusion. Psilocybin is found in some species of mushroom. It is structurally similar to the brain neurotransmitter serotonin - which is implicated in mood and schizophrenia. Volunteer screening will comprise medical history, physical examination, psychiatric interview, safety blood screening and urine dipstick tests for drugs of abuse, pregnancy test (females) and electrocardiogram. Volunteers will be excluded if they suffer from cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or psychiatric or neurological disorders capable of significantly affecting the safety or validity of the study. Failed drugs of abuse screening, weekly alcohol intake over recommended levels or caffeine intake equivalent of >6 cups of coffee per day or failure to pass the MRI screening will also constitute exclusion. Subjects will have had prior psilocybin experience.

The duration of the study participation will be approximately 4 weeks, with at least 1 week between study visits to allow adequate wash out of the oral drug. Each participant will receive: placebo + psilocybin infusion (2mg in 10mL saline) or 50mg saracatanib + psilocybin or 175mg saracatanib + psilocybin. Four hours after oral drug administration scanning will comprise: resting state fMRI, a visual coherence task, perfusion imaging (during which psilocybin will be infused) followed by a repeat of the resting state and visual coherence task. The primary outcome will be reduction in perfusion signal in the anterior cingulate cortex and the attenuation of this in a dose dependent manner by saracatanib.

The primary beneficiaries of this research will be patients, with the opening up of a new avenue for treatment development in psychoses. If successful this project will show in humans that Src-kinase inhibitors have a role in blocking a model of psychosis, potentially stimulating the development of a new class of compounds and trials of Src-kinase inhibitors in patients. By moving early into human models of selective dysfunction of specific pathways rapid translation and lateral advances (e.g. testing against other accepted models such as ketamine) are both viable research pathways. The collaboration with AstraZeneca will assist here because of the close partnership between academics and industrial researchers.
The unmet needs in psychoses are notable. For example, schizophrenia is typically a lifelong illness with a lifetime prevalence of almost 1% with treatments targeting only a subset of symptoms. In addition pharmacological treatment side effects and noncompliance are major problems. Thus, the burden on health services are great as emphasised in the Lancet summary of the UK strategic needs for mental health and wellbeing (Sahakian et al., 2010) and the development of large-scale initiatives to address assessment of unmet needs (Marder, 2006). The unfortunate reality is that even small improvements in the effect sizes of response or small reductions in non-compliance are likely to have a large impact due to the scale of the problem. The research team assembled to complete this project are passionate about the hypotheses, methods and potential of this project and committed to ensuring it is successfully conducted to completion.

Marder SR (2006) The NIMH-MATRICS project for developing cognition-enhancing agents for schizophrenia. Dialogues Clin Neurosci 8:109-113.
Sahakian BJ, Malloch G, Kennard C (2010) A UK strategy for mental health and wellbeing. Lancet 375:1854-1855.