The Corpus Callosum

Poor treatment response in patients with schizophrenia is an important clinical problem, and one possible strategy is concurrent treatment with more than one antipsychotic (polypharmacy). We analyzed the evidence base for this strategy using a translational research model focused on clozapine-antipsychotic polypharmacy (CAP). We considered 3 aspects of the existing knowledge base and translational research: the link between basic science and clinical studies of efficacy, the evidence for effectiveness in clinical research and the implications of research for the health care delivery system. Although a rationale for CAP can be developed from receptor pharmacology, there is little available preclinical research testing these concepts in animal models. Randomized clinical trials of CAP show minimal or no benefit for overall severity of symptoms. Most studies at the level of health services are limited to estimates of CAP prevalence and some suggestion of increased costs. Increasing use of antipsychotic polypharmacy in general may be a factor contributing to the under-utilization of clozapine and long delays in initiating clozapine monotherapy. Translational research models can be applied to clinical questions such as the value of CAP. Better linkage between the components of translational research may improve the appropriate use of medications such as clozapine in psychiatric practice.

The basic idea of translational research is this: you start with information derived from basic research.  That is nice, but if you are a doctor or a patient, it is not what you really want.  Fortunately, it can be used to get what you want.

What you want, is clinically-useful knowledge.  In order to turn basic research into clinically-useful knowledge, you have to go through a multi-step process.  These steps are the translations.  This process is illustrated in the figure (click to enlarge).

The first step is to take the basic knowledge, and use it do clinical trials.  This gives you knowledge of clinical efficacy.  That is, it tells you if the drug really works.  While that has clinical utility, it still is not what you really want.  So you take that information, and use it to do additional studies to find out who benefits from the treatment, and what problems may ensue.  That is pretty good, but it still is not what you really want.  Because you usually have more than one treatment option, you need to go to the next step.  The final step assesses the overall real-world costs, as well as the magnitude of improvement in the quality of life. 

It may seem crass to think of the cost, when it comes to treating a serious condition such as schizophrenia.  But let's put this is perspective.  The least-expensive generic clozapine costs about $2.40 for one 100mg tablet, in lots of 100.  Most people need to take at least 300mg per day.  Doses of 600mg (or more) per day are fairly common.  That comes to $14.40 per day, $52,560 (or more) per year.  Plus you need to get blood tests every week, and have a lot of clinic visits, etc.  Now, you want to do polypharmacy?  Try adding risperidone 1mg twice per day.  Find the cheapest generic, at about $1.53 per 1mg pill.  That's another $1,086 per year.  Say you start taking this at age 30, and continue until you die at age 65.  Total cost of the medication: roughly $2,000,000.  You get the picture. 

Part 2 to follow...
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William G. Honer, MD, Ric M. Procyshyn, PhD, Eric Y.H. Chen, MD, G. William MacEwan, MD, & Alasdair M. Barr, PhD (2009). A translational research approach to poor treatment response in patients with schizophrenia: clozapine-antipsychotic polypharmacy J Psychiatry Neurosci, 39 (6), 433-442