Beyond dopamine receptors in Schizophrenia - evaluating the role of Phosphodiesterase 10A in disease and treatment using PET imaging.

What is the challenge we are addressing:
Schizophrenia is a serious and disabling mental illness. It strikes nearly 1 in 100 people, usually in their early adulthood, and is usually manifested with a range of symptoms - delusions, paranoia, hallucinations along with loss of interest and drive and difficulties with concentration and memory. Not surprisingly, less than 1 in 10 people with schizophrenia find work, and few marry or have families. The current treatment involves medications (called antipsychotics) and various forms of therapies. The current antipsychotics have their origins in discoveries nearly 50 years ago, and they all (nearly 20 such drugs are actively used now) block the dopamine system of the brain. While this works for about two-thirds of the patients - these approaches do not work for all patients. Even in the patients in whom they calm the delusions and hallucinations, the current drugs to not help with loss of drive or memory/concentration difficulties. Thus, one has to find an alternative to the dopamine-system treatments.

What is our approach:
Basic science research and research in animals suggests that another way to help patients with Schizophrenia would be to block another chemical PDE10A, as it works downstream from the dopamine system. This approach is being adopted by drug companies, nearly 20 of them have filed patents, and five of them have active programs. However, these programs are based on data in test-tubes and animal models and no one has looked at the PDE10A system in Schizophrenia. This has been difficult as there was no imaging method (brain scan) that could help measure the PDE10A signal. We have overcome this difficulty. Using a particular kind of brain scanning, called PET imaging, we have developed a method [using a chemical called IMA107] which can give us an accurate measure of PDE10A system in patients before and after treatment.

What would we like to do now:
We now have the first opportunity to measure the levels of PDE10A in patients. We have already shown that this method can be used in healthy volunteers, it is safe, and gives a good readout. We would now like to enroll 20 patients with schizophrenia and 20 healthy controls and see if the levels of PDE10A are changed in patients. Secondly, there are indications from animal studies that the drugs currently used to treat schizophrenia, may also secondarily have an effect on PDE10A. We will test for that too by examining patients before they have any treatment, and then again after they have been treated for a few weeks.

What are the benefits of this:
This research will be the first direct measurement of PDE10A in patients. This will have three potential implications. First, regardless of the outcome, the study will answer a fundamental question about the brain chemistry of schizophrenia. Second, if there is a change in PDE10A in schizophrenia, it will provide a clear rationale for the drugs that are in the early stages of development. Finally, the imaging method that we have developed can also be used to measure the effect of the new drugs on the brain - this may allow the scientists developing those drugs to choose the appropriate dose and frequency of administration for best effects.

In the 60 years since the first antipsychotic was discovered, the reduction of neurotransmission through the D2 receptor have been the only proven therapeutic mechanism for schizophrenia. However, this mechanism is successful in only 2/3 of all patients, and even in these it is limited by the lack of efficacy against negative and cognitive symptoms. Therefore, there is an urgent need to identify new molecular targets that can address the various symptom dimensions of schizophrenia. Altering neurotransmitter signaling by targeting intracellular mechanisms is a recent approach in the development of novel therapeutic agents. An attractive intracelular target is the phosphodiesterase 10A (PDE10A), a class of enzymes that co-segregates with dopamine D1 and D2 receptors and degrades the intracellular second messengers triggered by dopamine signalling. Interestingly, in preclinical studies PDE10A inhibitors shows a broad-based 'antipsychotic-like' effect, with efficacy against positive as well as cognitive and negative symptoms. These has encouraged several pharmaceutical companies pursuing PDE10A antipsychotic program. However, despite preclinical data and pharmaceutical interest, the status of PDE10A in patients with schizophrenia is unknown as until now there were no reliable methods to assess this in humans. We have recently developed a selective PET radiotracer - [11C]-IMA107 - and used it to image the PDE10A system in healthy controls, showing an effective binding potential and a good signal-to-noise. Our project will use this novel radiotracer to examine if there is an alteration in PDE10A expression in unmedicated schizophrenia patients when compared to healthy volunteers, and if treatment with antipsychotic medication lead to changes in PDE10A expression. This study will provide the first evidence of PDE10 involvement in Schizophrenia and will provide a rational platform and specific guidance for the ongoing pharmaceutical and therapeutic development.

Schizophrenia is a chronic psychiatric illness and despite extensive research a lot remains to be understood. Current antipsychotics exert their action through the blockade of the dopamine D2 receptors, but primarily address the positive symptoms of schizophrenia, having limited efficacy in the treatment of other domains such as cognitive deficits and negative symptoms. The cost of schizophrenia to the economy in England has been estimated at 6.7 billion pounds a year. A significant portion of this cost is related to lack of efficacy of current antipsychotic medication. Therefore, an important priority in the treatment of schizophrenia is to find drugs that improve positive symptoms via a non-D2 mechanism, and have effectiveness against cognitive and negative symptoms. PDE10A antagonists have shown to be a promising target, with preclinical studies showing that inhibiting PDE10A could have not only an antipsychotic, but also pro-cognitive and negative symptom efficacy.

Despite the development of PDE10A inhibitors drugs by at least five different pharmaceutical companies - most of this PDE10A drug development have been done without direct knowledge on the role of this enzyme in schizophrenia and its relation with current antipsychotic medication. Since PDE10A signalling is downstream from dopamine signalling - it has potential relevance to all neurological disorders involving dopaminergic neurotransmission abnormalities, such as Parkinson or Huntingtons Disease.

The most predictable impact of this project (regardless of the direction of results) will be an improved understanding of the neurobiology of schizophrenia.

If the results show significant differences between patients and controls, or a significant effect of current medications on PDE10A levels, it would provide a strong rationale and guidance for the drug development. Once the baseline levels of PDE10A in schizophrenia are known, the [11C]-IMA107 PET Imaging could also be used for making "occupancy" measurements to guide the dosing and frequency of the developing compounds.

Beyond this, any impacts are speculative. If indeed, new PDE10A drugs for schizophrenia became available - they will certainly provide new options for clinicians and patients, and likely better efficacy and outcomes from a socioeconomic perspective.