MICA: SRC inhibition as a potential target for Parkinson's disease psychosis

Parkinson's disease (PD) is a devastating neurological condition. It affects over 10million people worldwide and UK data shows that the number of people affected will increase by 28% by 2020. The most obvious symptoms are altered motor functioning, although many patients experience non-motor symptoms. Up to half experience psychosis during the course of the disease. Visual hallucinations (seeing things that are not there) and delusions can be extremely distressing resulting in poorer quality of life and increased caregiver burden. Existing treatments for Parkinson's disease replace lost dopamine (a brain chemical) in the brain, but do not help with psychosis symptoms. Existing treatments for psychosis (as would be given to patients with schizophrenia) are ineffective or come with troubling side effects (sedation, heart and liver function) and regular monitoring visits. Brain imaging studies have shown that another brain chemical, serotonin, is involved in psychosis symptoms. We have gathered evidence to indicate that serotonin signalling through a particlar pathway in brain cells called the src-kinase pathway may be responsible for PD psychosis symptoms. If we can reduce activity in this pathway patients may see improvements in their symptoms and quality of life. A drug from cancer called saracatinib has been made available that reduces activity in the src-kinase pathway of the brain. Studies so far have shown that it can affect brain function and is well-tolerated. We wish to test this drug in patients with PD psychosis to show that this drug can reduce or normalise brain function in the brain areas that are associated with visual hallucinations and other disturbances. We will test the effects of 10 days of saracatinib against a dummy drug (or placebo) in 20 patients with PD psychosis and compare the effects to those without PD psychosis to see if it normalises brain function. We will use two brain measurements that are safe and well-tolerated for this study and ask patients to perform visual recognition tests or just rest while we take these measurements. If successful, this study will provide the basis to test the drug in larger samples which is necessary to develop a new treatment.

Parkinson's disease (PD) psychosis can affect around half of the patient population. The visual hallucinations and other disturbances can be extremely distressing and debilitating resulting in poorer quality of life and increased caregiver burden. While dopaminergic treatments are central to treating psychoses unrelated to PD, the serotonin system is implicated in PD psychosis and pimavanserin, a 5-HT2A inverse agonist, has recently received approval for treatment of PD psychosis in the USA. The serotoninergic dysfunction underpinning PD psychosis is not understood although studies in animals and with psychedelics point to dimerisation of the 5-HT2A and mGlu2 receptors and overrecruitment of specific downstream signalling pathways. Src kinase inhibition is a potential mechanisms for blocking the 'hallucinogenic' effects of the 5-HT2A receptor agonism. We have already demonstrated that the src-kinase inhibitor saracatinib can reduce the intensity of psilocybin-induced psychedelic effect and attenuate social cognition changes and brain responses in healthy volunteers. We propose to test the effects of 10 days of saracatinib or placebo (2-way cross-over design) in 20 patients with PD psychosis as a proof of concept for the specific molecular pathway of this disease symptom cluster. Existing literature suggests PD psychosis can result from aberrent bottom-up and top-down processing so we will use functional imaging and EEG to test the effects of saracatinib on brain networks associated with visual processing and their higher level components of perception. Patients will be tested twice, after 10 days of placebo and after 10 days x 100 mg saracatinib, assessing effects on visual processing networks with fMRI and prediction error markers with mismatch negativity EEG. Subjective ratings will also be recorded.

The ultimate impact of this work is a new therapy for Parkinson's disease (PD) psychosis. The proposed study is a vital proof of mechanism trial in patients with PD psychosis for the novel treatment mechanism.

The need for a novel, targeted treatment is great for three main reasons. First, psychosis symptoms are identified as a priority by patients as part of the 'non-motor' symptoms of PD, which also includes sleep difficulties and cognitive impairment [1]. Second, PD psychosis can affect nearly half of all patients and neurodegenerative conditions, such as PD, are set to rise 28% by 2020 [1, 2]. Third, current antipsychotics include antagonist action at dopamine receptors (in opposition to the dopamine treatment for the movement symptoms), have problematic side effects and are incompletely effective [3]. In fact, current treatment options are limited and are poorly targeted to the associated pathology related to the psychosis. A number of candidate systems are implicated including noradrenergic and cholinergic. It is, however, the serotonergic system that has known differences in PD psychosis, evidenced from both molecular imaging and post-mortem studies. The recent registration of the 5-HT2a drug pimavanserin for PD psychosis in the USA provides a clear impetus for further examination of the 5-HT2a receptor pathway. The registration of this novel drug is clearly a major advance, but we must remain committed to providing even better options for patients. Indeed, the cardiovascular and hepatic side effects may restrict its use in some patients and there is a lack of evidence for reductions in troubling visual hallucinations, one of the most common symptoms of PD psychosis [3].

Pimavanserin is a 5-HT2a receptor inverse agonist/antagonist and this receptor is known to mediate its effects, intracellularly through multiple cascades. The ability to work in a completely novel way to modulate the 5-HT2a system, targeting the cascade behind psychedelic induced effects (which notably include visual hallucinations) is an opportunity afforded by the availability of a well-tolerated compound such as saracatinib. Nothing similar exists in our pharmacopeia.

If successful, the outcome of this research will be to provide evidence that inhibition of the src kinase protein using saracatinib can reduce the neural basis of PD psychosis. There are no treatments to date that have been validated mechanistically PD psychosis. Our findings would lend critical support to a larger phase 2 clinical trial and comparative neuroimaging trials against pimavanserin.

There will be broader impacts. First, the validation of the methods will provide a positive evaluation for imaging and EEG in the early validation of potential new treatments and serve as an exemplar for the approach. Thus, if successful this study can act as a stimulus for mechanistically-driven repositioning of existing compounds. In addition, it will provide justification for the application of the methods for the post-hoc understanding of the basis for existing treatments in modulation of brain systems (which is severely lacking). This can serve to underline what constitutes success in mechanistic studies (i.e. existing drugs as positive controls), and broaden understanding of limitations of treatment and may even help stratify patients by identifying those with and without significant brain changes. The presence of treatments for psychosis symptoms and evidence that they reduce brain differences can also help in programmes to reduce stigma.

1. Qamar MA, et al. Public and patient involvement (PPI) at King's: Community for Research Involvement and Support for people with Parkinson's (CRISP). ACNR. 2017;16:5-8.
2. Broadstock M, et al. Novel pharmaceuticals in the treatment of psychosis in Parkinson's disease. Expert Rev Clin Pharmacol. 2014;7(6):779-86.
3. ffytche DH, et al. The psychosis spectrum in Parkinson's disease. Nat Rev Neurol. 2017;(in press).