A failed drug for stroke and hearing loss, ebselen, is being repurposed to curb the kind of impulsivity that drives addiction, pathological gambling, and suicide. Impulse control disorders affect millions, yet the only drug that reliably reduces impulsivity—lithium—causes severe side effects including kidney damage. Lithium’s mechanism is poorly understood, but it likely works by inhibiting the enzyme IMPase. Ebselen does the same thing, but has already been shown safe in humans without lithium’s renal toxicity. This project will test whether ebselen reduces impulsivity in animals and humans, and whether the effect is dose-dependent and sustained. If successful, ebselen could become the first well-tolerated drug for impulse control disorders. That would directly change the lives of people with bipolar disorder, addiction, or pathological gambling, who currently face a choice between lithium’s toxicity and no treatment at all. It could also reduce suicide rates and relapse in substance dependence—outcomes strongly linked to impulsivity. The research is translational, not fundamental: it takes a known safe compound and tests a specific clinical hypothesis, with a clear path to patient trials if the evidence holds.
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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.
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