Old drugs and new tricks: Repurposing drugs to treat psychiatric disorders
By: Nancy Butcher
There is no question that major advances have been made in treating psychiatric illnesses over the past six decades. The serendipitous discoveries in the 1950s of the antidepressant effects of the antituberculosis drug iproniazid and the antipsychotic effects of the anaesthetic chlorpromazine ushered in a golden age of psychopharmacology. Patients previously considered untreatable were discharged from psychiatric hospitals in record numbers. Some successfully reintegrated back into the community and resumed relatively normal lives. Although others responded minimally or not at all to these new treatments, it was hoped that improved drugs would be just around the corner. After decades of research and advances in the biology underlying mental illnesses, better drugs are still desperately needed for essentially all psychiatric disorders.(1)
The need for improved psychiatric treatments and better patient outcomes is substantial—one in five Canadians will experience a mental illness in their lifetime, and these illnesses come with high personal and socioeconomic costs.(2) Although some patients do respond very well to current medications, there is little evidence that our very best treatments have reduced the overall prevalence or disability associated with any major psychiatric disorder.3 Only recently have new therapeutic targets for major psychiatric disorders begun to emerge, following advances in molecular and bioinformatics research. But who is going to develop these new drugs? The major pharmaceutical companies are shutting down their neuroscience laboratories or redirecting their research programs. Research and development (R&D) dollars are being shifted away from mental illness and into more biologically tractable disorders like cancers.(1,3) The reason is simple: companies are not getting enough bang for their buck by pursuing new treatments for psychiatric illnesses. This issue is further compounded by the abundance of generic drugs now on the market, lack of novel validated targets and biomarkers, increased regulatory challenges, and the absence of valid animal models for mental illnesses.(3)
As industry retreats from psychiatric drug development, we must give current translational research practices in psychiatry a sober second thought. The pipeline of drugs is running dry and there is a crisis in drug development for mental illness. Repurposing old drugs is one of many suggested alternatives but it may provide the fastest and cheapest results.(1) The number of molecular pathways implicated in mental illnesses is exploding, and some may already be targeted by old medications. This could provide an unprecedented opportunity to rapidly identify, evaluate, and bring new psychiatric drugs to market and to the patients who need them.
A study published last month in Nature Communications on bipolar disorder exemplifies the promise that drug repurposing holds for rapidly advancing mental health discoveries and treatment.(4) Bipolar disorder is a serious mental illness that affects approximately 1 in 100 people. Individuals with bipolar disorder experience alternating periods of mania and depression, sometimes known as “highs and lows.” Lithium has remained the gold standard of treatment in bipolar disorder for the last 60 years, but it is toxic at only twice the therapeutic dosage. Lithium is also known for its many unpleasant or serious side effects including tremors, weight gain, and kidney damage. To find a safer but equally effective drug, the study authors combed through the U.S. National Institutes of Health Clinical Collection—a library of drugs known to be safe with no current clinical use—to find drugs that act in similar way as lithium. Ebselen, an out of patent antioxidant originally developed for stroke patients, was identified as a good candidate for a safer alternative to lithium. Testing mice showed that ebselen does indeed act in the brain by blocking the same key enzyme as lithium. Human testing of ebselen can now quickly follow.
In addition to drugs designed for another disease, medications already tested in psychiatric disorders may be worth a careful second look. In recent years, the primary targets of psychiatric medications and clinical endpoints have begun to dramatically shift. Medication targets are moving away from the traditional model of correcting chemical imbalances (e.g. blocking dopamine receptors to treat psychosis) to addressing dysfunctional brain circuitry.(1) Previous clinical trials may have missed important but subtle improvements in patients. New measures of success including improvements in symptoms that cut across different psychiatric diagnoses such as social and working memory deficits, may help identify new roles for old or discarded candidate psychiatric drugs.
For example, early trials of baclofen in the treatment of schizophrenia were not encouraging because the study endpoint was a reduction in psychotic symptoms. The effect of the drug on the highly disabling cognitive and negative symptoms of schizophrenia, including flattened affect and social withdrawal, were not investigated. Baclofen is currently approved for muscle relaxation and spasticity but it is regaining interest as a treatment for mental illness, and not just for schizophrenia. A recent study found that baclofen improved social deficits and spatial memory in mice with brain abnormalities common to a spectrum of psychiatric disorders, including schizophrenia, intellectual disability, and autism spectrum disorders.(5) Baclofen was well-tolerated by individuals with schizophrenia in the original exploratory trials, suggesting that it may be a viable new treatment for social and cognitive deficits if it proves similarly effective in new clinical studies.
Although the repurposing of drugs does show promise in short-term deliverables for new treatments of psychiatric disorders, it is not without its challenges. Repurposed drugs will need to be tested carefully against current gold-standard treatments as well as against each other. Safety issues in psychiatric populations may be a concern. Intellectual property and patent issues must be resolved. Similar to currently available psychiatric medications, it is likely that not all patients will respond to treatment or even respond to the same degree. But at this stage, should we even expect them to? Despite their distinct diagnostic classifications, there is increasing evidence that individual mental illnesses are actually a biologically heterogeneous collection of diseases. New personalized medicine approaches to treatment selection, informed by biomarkers and genetics, have the potential to dramatically increase treatment success rates. Measures of success also need to be refocused, with a new emphasis on treatment in the early stages of the disease when outcomes might be better, and a therapeutic goal of complete and not partial recovery.(6) Treating complex illnesses like psychiatric disorders is not easy, but it is possible. With the potential of drug repurposing in identifying novel treatments for serious mental illnesses emerging, hope is on the horizon.
1. Insel TR. Next-generation treatments for mental disorders. Sci Transl Med. 2012; 4:1-9.
2. Health Canada [homepage on the Internet]. A Report on Mental Illness in Canada; 2002 [updated 2012 Jan 5; cited 2013 Feb 8]. Available from http://www.phac-aspc.gc.ca/publicat/miic-mmac/chap_1-eng.php.
3. Brady LS, Insel TR. Translating discoveries into medicine: psychiatric drug development in 2011. Neuropsychopharmacol. 2012; 37:281-3.
4. Singh N, Halliday A, Thomas J et al. A safe lithium mimetic for bipolar disorder. Nat Commun. 2013; 4:1332.
5. Gandal MS, Sisti J, Klook K et al. GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction. Transl Psychiatry; 2:e142.
6. Insel TR, Sahakian BJ, Voon V, et al. Drug research: a plan for mental illness. Nature 2012;483:269.