The promise and challenges of drug repurposing in psychiatry
Authors: Maurizio Fava
Journal: World Psychiatry (2018)

The term "repurposing" literally means to give a new purpose or use to a drug. Some researchers have sub-classified repurposing into "reformulation", which is the development of a different formulation for the same drug, and "repositioning", which is the process of identifying a new therapeutic use for an already known drug1. One may argue that only repositioning is closely aligned with the term repurposing. Therefore, the focus of this paper will be only on the repositioning form of repurposing. Drug repurposing is viewed as an approach to rediscovering value in "old molecules" and finding new therapeutic uses, particularly in areas with high risk of failure, such as psychiatry. It is considered a cost-effective and de-risked strategy2: having already established the safety and tolerability of a compound diminishes the risks of further development. The importance of repurposing was recently acknowledged by the European Commission, which formed the Commission Expert Group on Safe and Timely Access to Medicines for Patients (STAMP). STAMP aims to recognize the importance of comprehensive investigation of different opportunities that a molecule could bring to patients, with faster development times, and at reduced costs and risk for pharmaceutical companies3. The scope and extent of drug repurposing in the central nervous system (CNS) area has been recently reviewed4. The authors performed an extensive search of compounds, with the initial and target indication and the type of repurposing strategy (repositioning, reformulation or both). Their study identified 118 source products which were repurposed 203 times, with 80 products repurposed once, 16 products repurposed twice and 22 products repurposed three times or more4. Among products repurposed multiple times, over two thirds (68%) came from the CNS area, and half of the new indications (102 cases) were approved3. Most of the cases were repositioned (N=171), while only 16 were reformulated, and 16 were reformulated and repositioned at the same time4. Among new therapeutic indications, Alzheimer's disease was targeted most often (22 cases), followed by substance dependence (alcohol, opioids, tobacco), bipolar disorder, depression, neuropathy/neuralgia, multiple sclerosis and schizophrenia, with 10 or more cases each4. A prototypical example of a repurposed drug in psychiatry is valproic acid/valproate5. The anticonvulsant properties of N-dipropylacetic acid (valproic acid) were discovered in 1967 and the drug quickly became widely used in epilepsy, generally in the form of sodium valproate. Antimanic and prophylactic activity in bipolar disorder was only subsequently demonstrated for both valproic acid and sodium valproate, with divalproex (an equimolar combination of valproic acid and sodium valproate) being approved by the US Food and Drug Administration (FDA) in 1995 for this new indication5. Traditionally, there have been three major approaches to drug repurposing/repositioning. One approach is the discovery at the bedside, where a clinician observes/discovers the benefit in a given condition of a compound approved for a different condition. A classic example is bupropion for smoking cessation. Bupropion was first approved by the FDA for the treatment of depression in the 1980s. L. Ferry, at the time Chief of Preventive Medicine at the Loma Linda Veterans Hospital, and her colleagues tried the drug in the mid 1990s in a small group of smokers, with impressive results, as about half were able to quit smoking for at least a year. This led to a series of positive placebo-controlled trials and to the approval of bupropion for smoking cessation in 19976. Another approach involves leveraging the knowledge of the potential benefits of specific pharmacological actions in certain conditions, and identifying compounds initially developed for the treatment of other conditions and sharing similar pharmacological actions. A clear example of this is atomoxetine. This compound, a norepinephrine reuptake inhibitor, was originally developed for the treatment of depression and then abandoned despite good tolerability. T. Spencer, J. Biederman and colleagues, whose group at Massachusetts General Hospital had shown the efficacy in attention deficit disorder of desipramine7, a tricyclic antidepressant with norepinephrine reuptake inhibition properties, approached the maker of atomoxetine about testing it in this condition, and showed it to be effective8. Atomoxetine was subsequently approved by the FDA in December 2002 for the treatment of attention-deficit/hyperactivity disorder. The third approach to drug repurposing comes from the advances in the understanding of the neurobiology and genetics of psychiatric disorders. The identification of specific neural pathways associated with certain genetic polymorphisms can lead to the use of approved compounds which have shown to affect those molecular targets. Alternatively, the identification of subtypes associated with specific biomarkers may lead to the exploitation of compounds addressing the specific neurobiological target. An example of this approach is the development of anti-inflammatory compounds for the treatment of the subtype of major depressive disorder associated with chronic inflammation. A recent publication on the antidepressant properties of ixekizumab, approved by the FDA in 2016 for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy, exemplifies this9. One of the issues related to the repurposing of older molecules can be the relatively short patent protection, once the drug is approved for the new indication. Some drug companies have used the approach of adding deuteriums (instead of plain hydrogens) to drug structures. Deuterated forms of older compounds can have a more extended patent protection. The first example of this was the approval in August 2017 of deutetrabenazine tablets for the treatment of tardive dyskinesia in adults, nine years after the FDA approval of the older compound (tetrabenazine) to treat chorea associated with Huntington's disease. In light of the recent and continuous advances in the understanding of the neuroscience of psychiatric disorders, repurposing drugs is likely to yield even greater promise in the future. Having already established the safety and tolerability of a compound diminishes the risk of its further development and, therefore, would allow the use of more cost-effective study designs10, which require smaller sample sizes and would reduce the cost of the clinical development. Maurizio Fava Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA