DISCUSSION

Given the need for better treatments for schizophrenia and bipolar disorder, it is important to explore all available resources. The repurposing of drugs being used to treat other diseases, over-the-counter drugs, and neutraceuticals represent a neglected resource. NIMH’s recent publication From Discovery to Cure also noted that “repurposing medications used for other indications remains a very real opportunity.”92 Repurposing trials are especially timely, since major pharmaceutical companies are currently reducing efforts to find novel treatment for these diseases.

One major problem with repurposed drug trials is making the information available to clinicians. Since there is little or no financial incentive for pharmaceutical companies to promote repurposed drugs, there are no three-page, glossy ads or drug representatives to purchase pizza for the clinician’s office staff. In the U.S., pharmaceutical companies employ 90,000 drug representatives, one for every 4.7 office-based clinicians, and support more than 60% of the cost of continuing medical education.93-95 Drugs for schizophrenia and bipolar disorder are major sources of revenue for pharmaceutical companies, and it is unrealistic to expect the companies to promote less expensive alternatives. One can argue that the results of repurposed drug trials are available in psychiatric journals, but studies of physicians have shown that such articles, by themselves, play a very small role in clinician decisions to try new drugs.96

“NIMH’s recent publication From Discovery to Cure also noted that ‘repurposingmedications used for other indicationsremains a very real opportunity.'”

Another consideration in doing studies of repurposed drugs is cost. Many of these drugs are very inexpensive compared to drugs still under patent. If some of these prove useful, they could help reduce the costs of psychiatric care, both in the U.S. and especially in less developed countries, where medication costs are critical.

For many of these drugs, there are suggestions that some patients respond and others do not. One of the major challenges is to identify biomarkers that will allow us to predict who will respond. For example, do markers of inflammation predict responders to aspirin or celecoxib, or do serum folate levels predict response to folate? Given the heterogeneity of both schizophrenia and bipolar disorder, we should not expect everyone to respond. Also missing, to date, are head-to-head trials of repurposed drugs against each other and against traditional treatments.

Another problem with evaluating the results of repurposed drug trials is that some studies are initiated by enthusiasts who zealously seek confirmatory data and positive results. It is, thus, important to verify the findings from one or more initial positive studies by doing larger, confirmatory studies using different investigators. In many cases, the confirmatory study will be negative, as has been the case with some of our own studies.

It is premature to outline an algorithm for the use of these repurposed drugs since sufficient data are not yet available regarding their effectiveness and target population. Among them, omega-3 fatty acids with EPA have promise for unipolar and some bipolar patients, and other benefits of taking omega-3 are well established. Folate may also have other benefits. Mirtazapine and estrogen also have shown promise in schizophrenia, but the definitive trials are not yet complete.

As with all treatment decisions, repurposed drugs should not be utilized without a careful assessment of possible risks and benefits. Even drugs such as aspirin, folic acid, and omega-3 fish oil can have side effects in some individuals, and drugs like celecoxib and estrogen should be used very cautiously. The risks of aspirin, celecoxib, estrogen and raloxifene, folate, minocycline, mirtazapine, and the omega-3 fatty acids are well known, since they have been well studied for many indications in general medicine. There is an unknown risk of pramipexole in patients with schizophrenia and bipolar disorder because of the possibility that it could exacerbate these disorders, a risk that may not occur in patients with Parkinson’s disease or restless legs syndrome. Pregnenolone, although used for many years and sold in health food stores, has not been well studied in contemporary studies.

“As with all treatment decisions,repurposed drugs should not be utilized without a careful assessment of possible risks and benefits.”

In summary, a number of repurposed drugs are available as adjunct treatment of treatment-resistant patients with schizophrenia and bipolar disorder. If used with attention to their possible side effects, they may be reasonable therapeutic alternatives when you are out of ideas.

ACKNOWLEDGMENTS

This work was supported by the Stanley Medical Research Institute. Ms. Judy Miller provided administrative support.