Dr. Grossi's Blog
When drug therapy is involved in treatment, a frequent conversation revolves around the use of generic drugs in place of the brand-name drug. In the United States generics account for about 72% of the market and that is projected to rise to about 90% in the next six or seven years. For most patients, generic substitution is acceptable and cost effective. For particular circumstances switching to a generic or between generics may present problems of efficacy or tolerability.
In the United States the FDA reviews studies submitted by pharmaceutical companies and either authorizes of denies authorization to the company to market their drug for a particular purpose. In the case of generic authorization, the efficacy and safety of the molecule is a given and so the FDA only requires bioequivalence studies which must demonstrate that the generic product delivers 90% to 125% of the name brand drug. These studies typically have a small n and require a confidence interval of 90%. To say this another way, various pharmacokinetic parameters such as max concentration, time to max concentration, area under the curve, and absorption time fall within the 90% to 125% seen in the branded drug. The FDA does not compare one generic to another but only to the branded drug.
In my office I routinely advise patients to avoid generic substitutes for Tegretol, Effexor, Parnate, Ritalin, and Lamictal (for the first prescription). I also advise patients to examine the prescription label for the name of the generic manufacturer. It is common to discover that one generic product is less effective than another. In those instances, this should be discussed with the pharmacist.
The ultimate resource for generic drugs is the Orange Book which is maintained and updated daily by the FDA.
For my inaugural blog I have chosen an inherently risky topic which is the future of psychiatry. We call it the future because it is unknown. What follows is an educated guess based on current knowledge, advances in technologies, and extant trends.
The major psychiatric disorders of schizophrenia, bipolar disorder, autism, attention deficit hyperactivity disorder, obsessive-compulsive disorder are heterogeneous syndromes with extraordinarily varied phenotypic presentations. Indeed they are so varied that any psychiatrist making such a diagnosis should present it as a probability and not as a Boolean, true/false diagnosis, but as a probability judgment by the psychiatrist. The underlying genetics and cellular chemical cascades are largely unknown. In addition it is becoming clear that these disorders are polygenetic, produce disruptions in chemical pathways in different neural circuits which in turn result in shared clinical symptoms that lead to the same or different clinical diagnoses. If this weren't daunting enough, recent work with copy number variations (CNV) in these disorders (Cook and Scherer, Neuron, 2008) and the increasing realization of the importance of epigenetic factors point to a prolonged research effort. Gone are the days when the newly sequenced genome was thought by many to yield the answers to disease etiology within a decade. Mother Nature is quite an adversary.
A law of technology is that people invariably overestimate the short term impact (as above), but underestimate the long term impact. The research effort will proceed along two tracks: Genomics and Circuit Analysis. Over the last ten years, the speed of sequencing DNA has increased 100,000 fold and the cost has fallen from about ten million to about $10,000. This dramatic progress now allows researchers to sequence entire genomes for thousands of individuals and to use computational analysis to assess them. Gone are the days of hypothesis-driven GWAS. Many amplified or deleted segments of DNA are needed for nerve cell function and not other tissue types. In a recent discussion Tom Insel, Director NIMH, called attention to the fact that many of the mutations are seen only once and he referred to them as "private mutations."
Expert consensus now expects that many hundred mutations are involved in the disruption of neural circuits that produce psychiatric phenotypes. Identifying the distribution, structure, function, and dysfunction of these neural circuits will be crucial in unraveling the mystery of psychiatric etiology. Researchers Maybery, Shah, and Baxter have already added significantly in this area. Recent advances in diffusion tensor imaging (DTI) allow better tracing of neural circuits and connections. Other new strategies to study circuits include multiphoton imaging and calcium imaging. At the animal level, knockout and knockin mice will be used to study psychiatric phenotypes as more genes are identified in human DNA of individuals with these disorders.
Lest we forget, these psychiatric phenotypes typically strike people early in life, are life-long, are often disabling, adversely influence interpersonal relationships, and generate an enormous cost to the society as a whole to say nothing of the enormous anguish draped over the sufferer.
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.