A novel lithium-mimetic drug for the management of impulse control disorder

A common account of impulsivity is 'actions that are poorly conceived, prematurely expressed, unduly risky, or inappropriate to the situation and that often result in undesirable outcomes'. A healthy level of impulsivity can be beneficial (eg. to seize opportunities and gain valuable new experiences) but high levels of impulsivity are often socially unacceptable and can be personally and financially costly. Moreover, deficits in impulse control are a prominent feature of diverse psychiatric illnesses including bipolar and related mood disorders, addictions and impulse conduct disorders. Impulsivity is also strongly associated with suicidality and relapse to drug-seeking behaviour, and is a significant predictor of relapse and worse clinical outcomes in alcohol and substance dependence, and pathological gambling. Drug therapies of impulsivity are few, and those available are poorly tolerated as exemplified by lithium. Lithium is the mainstay therapy for bipolar disorder, reduces risk of suicide, and is effective in clinical trials of ICDs such as pathological gambling. Despite its significant benefits lithium is poorly tolerated, and has severe side-effects including kidney damage. All this makes a compelling case to develop alternative drugs to control impulsivity. The solution may be a drug that has the unique therapeutic profile of lithium without its adverse effects. Lithium's mechanism is unclear but a leading idea is inhibition of the enzyme inositol monophosphatase (IMPase), causing reduced transmitter signalling via the phosphoinositide (PI) pathway. Recently, we "reprofiled" a library of drugs found safe but without efficacy in trials for other indications, and identified a potent IMPase inhibitor, ebselen. Ebselen is reported safe in humans, and without adverse renal effects. In animals ebselen inhibits IMPase at clinical doses, and has lithium-like effects in various neuropharmacological models that are linked to decreased impulsivity. This proposal will initiate a developmental pathway comprising an animal to human study of ebselen's potential for reducing impulsivity. The pathway will seek critical evidence that ebselen reduces impulsivity, and that this effect is dose-dependent and maintained. Efficacy in our models will fast-track ebselen to clinical trials in patient groups characterised by poor impulse control.

Deficits in impulse control are a prominent feature of diverse psychiatric illnesses including bipolar and related mood disorders, addictions and impulse conduct disorders. Impulsivity is also strongly associated with suicidality and relapse to drug-seeking behaviour, and is a significant predictor of relapse and worse clinical outcomes in alcohol and substance dependence, and pathological gambling. Drug therapies of impulsivity are few, and those available are poorly tolerated as exemplified by lithium. Lithium is the mainstay therapy for bipolar disorder, reduces risk of suicide, and is effective in clinical trials of pathological gambling. Despite its significant benefits lithium is poorly tolerated, and has severe side-effects including renal damage. All this makes a compelling case to develop alternative drugs to control impulsivity. The solution may be a drug that has the unique therapeutic profile of lithium without its adverse effects. Lithium's mechanism is unclear but a leading idea is inhibition of inositol monophosphatase (IMPase), causing reduced transmitter signalling via the phosphoinositide (PI) pathway. Recently, we "reprofiled" a library of drugs found safe but without efficacy in clinical trials for other indications, and identified a potent IMPase inhibitor, ebselen. Ebselen is reported safe in humans, and without signs of lithium's adverse effects. In animals ebselen inhibits IMPase at clinical doses, and has lithium-like effects including reduced 5-HT2 and dopamine receptor function. These effects are important as they can be linked to decreased impulsivity. This proposal will initiate a developmental pathway comprising an animal to human study of ebselen's potential for reducing impulsivity. The pathway will seek critical evidence that ebselen reduces impulsivity, and that this effect is dose-dependent and maintained. Efficacy in our models will fast-track ebselen to clinical trials in patient groups characterised by poor impulse control.

The aim of this proposal is to initiate a translational developmental pathway comprising a fundamental animal to human psychopharmacological investigation of the actions of the lithium-mimetic ebselen on impulsivity. This developmental pathway will identify proof that ebselen lowers impulsivity in humans, and establish the doses at which ebselen has this effect. This will provide the essential stepping point to take ebselen to clinical trials in patient groups characterised by poor impulse control.

We expect the activities linked to this research to impact on a large community of academic researchers across broad areas of fundamental and applied neuroscience (see Academic beneficiaries) but also non-academic beneficiaries in commercial, charity and education sectors as well as members of the public including patients with impulse control and related disorders and their carers.

If we can establish that ebselen has value to control impulsivity, then the longer term potential for impact at the socioeconomic level will increase dramatically. Thus, currently the incidence of psychiatric patients with impulse control disorder is high, and the symptoms are a major source of disability and poor quality of life, and a burden for patients, their carers and the teams of health professionals involved in their management. Moreover, available drug treatments of these symptoms like lithium suffer from serious safety problems and adverse effects or are ineffectual, and opportunities for the pharmaceutical industry currently lay unexplored and unrealised.

We envisage that specific non-academic beneficiaries would benefit from the proposed research and its related activities, in the following ways:

i) The benefits of communicating and engaging the general public with the proposed science are likely to be many, ranging from being is a source of both inspiration to aspiring young people and support and reassurance for patients, to helping confront the stigma often associated with disorders of the brain such psychiatric illness.

ii) Our proposed inter-disciplinary collaborations with groups in Oxford and Vancouver, will add much to the research capacity, and thus impact, of the proposed research by increasing the critical mass of researchers focused on our research questions. A highly valued capacity of our proposed research is the generation of young researchers with experience and skills in in vivo methods. The need for researchers with in vivo skills to take advantage of new developments in molecular and genetic science, has been stressed by UK scientific societies and the pharmaceutical industry, and major UK biomedical research funders including the research councils have strategic funding initiatives to generate extra capacity in this area.

iii) We expect that pharmaceutical companies will be interested in our research as it aims to identify sources of new therapeutic targets. Our planned interactions with the pharmaceutical industry will be of mutual benefit, for example through offering opportunities for exchange of knowledge, materials and personal, joint research grants and studentships, and attracting R&D investment. There may well be follow on opportunities arising from the current proposal, either through an Oxford-based organisation specialising in experimental medicine and facilitating academic-industrial collaborations, or via identification of a commercial partner using technology transfer expertise the Oxford University.

iv) All of the applicants currently influence scientific policy relating to neuropsychiatric research at local, national and international levels through membership of scientific advisory boards, scientific societies, scientific journal editorial boards and senior academic appointment panels. During the course of the project we expect to make particular contributions to University policy development for improved care and welfare of animals through the enhanced delivery of the 3R's.