The goal in my office is to get well. For those who simply get better, I am often asked whether there any new drugs available or on the horizon. The last twenty-five years have witnessed the introduction of many new agents for the treatment of depression, anxiety, and mood stability. These were largely the outcome of serendipitous observations made when treating tuberculous patients in the 1950s and the further research that ultimately led to the introduction of the SSRIs, SNRIs, and the NDRIs. Lithium was first used in Australia in the 1950s and was approved for use in the United States in 1970. Depakote, which was originally synthesized as an organic solvent in the 1880s in Germany, was observed to have an effect on Bipolar patients in France in the 1960s and was studied in the United States starting about 1980.
Where are we now and why are we there? The current environment is one of stagnation with few new molecules available and even fewer on the horizon. The reasons are complex. First, big pharma is reducing its spending because it believes that the problems of depression, anxiety, schizophrenia, and bipolar disorders are ones where the likelihood of success is low and the expenditures are high. These were the exact reasons given when GlaxoSmithKline and AstraZeneca announced earlier this year that they were reducing their research budgets by over one-half a billion dollars. Second, there are few candidate targets because our fundamental understanding of these problems is very sketchy. Third, we have probably witnessed the peak in the small molecule pharmacology. The coming agents will likely be large molecules which will likely work on the folding of proteins or other mechanisms that are yet to be discovered.
Big pharma has reduced its R & D expenditures for a variety of reasons. Patents on many blockbuster drugs has expired recently or are about to expire, and there does not appear to be another product to replace their sales. (The whole model of a blockbuster drug or drugs providing the revenue to support other drugs and activities may be broken.) In 2009 and 2010, all the following have gone off patent: Topomax, Lamictal, Imitrex, Suboxone, Keppra, Aricept, and Effexor. In 2010 and 2012, Zyprexa, Seroquel, Lexapro, Geodon, and Provigil will go off patent. Where is the cash flow to support R & D going to come from? The other main reason is difficulty of getting psychiatric drugs approved. They are approved at about half the rate of other categories of drugs and the cost of developing them is higher because they tend to fail in late stage development when much of the costs have already been incurred. Also, psychiatric problems tend to be intermittent, their symptom presentation quite varied, and at lest currently, few if any objective measurements of symptom and response. So, while I am unhappy about pharma's decision to de-emphasize neuroscience, it does make sense in that they are likely to be more successful at a lower cost in other areas.