The article I am discussing in
this post is the 2008 Heinz Lehmann Award paper, published in the
open-access Canadian journal, Journal of Psychiatry &
Neuroscience. It really covers two topics: translational
research, and antipsychotic polypharmacy in which one of the
antipsychotic medications is clozapine.
research is research that is intended to advance the process of
translating basic science into clinically useful knowledge. Clozapine
is the most effective antipsychotic drug we have. It typically is
used for persons with schizophrenia, who do not respond to other
medications. Polypharmacy is the practice of combining two or
more medications in the same person, at the same time.
The authors describe the process of translational research, and
illustrate the application of the process to a particularly vexing
problem in psychiatry. Even though clozapine is the most
effective drug, many patients who do not have a satisfactory
response. Clozapine carries more risk, compared to other
antipsychotics, of serious adverse effects. Polypharmacy
increases the risk.
When a person is not having a satisfactory response to clozapine, the
doctor and patient may be tempted to add another medication in an
effort to improve the response. But it would not make sense to do
that, unless the potential benefits outweigh the potential risk.
At present, little is known about either the potential benefits, or the
magnitude of the potential risk.
If the condition being treated were not serious, it would not make
sense to multiply the risk. However, schizophrenia can be
terribly debilitating, and can cause considerable distress. So we
really want to be able to solve this problem, but we want to solve it
with a reasonable risk-benefit balance.
William G. Honer, MD; Ric M. Procyshyn, PhD; Eric Y.H. Chen, MD; G.
William MacEwan, MD; Alasdair M. Barr, PhD
J Psychiatry Neurosci 2009;34(6):433-42.
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
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…
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),