Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-02-12
2002-06-04
Arthur, Lisa B. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007100, C435S091500
Reexamination Certificate
active
06399310
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for improving the therapeutic response of human patients with major depression, particularly those carrying the gene for apolipoprotein E4.
BACKGROUND OF THE INVENTION
Psychiatric diseases generally provide a unique set of complications for clinicians, patients, and care givers. Major depression, for instance, is a major health problem and poses a tremendous financial burden on society due to lost self-support of individuals suffering from depression. Such individuals are often simply unable to function in everyday life situations, in part because of feelings of extreme hopelessness and worthlessness. There is also a serious risk of suicide among such individuals. The various forms of depression are defined and are separately diagnosed according to criteria given in handbooks for psychiatry, for example in the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) published by the American Psychiatric Association, Washington, D.C. (1994). The diagnostic criteria for major depression are well known to those skilled in the art, and comprise the criteria set forth, for example, at DSM-IV 296.2 and 296.3. Major depression, defined in more detail below, is also known as major depressive disorder and is estimated to affect between 5 to 10% of the human population.
Although treatments for different types of depression do exist, there is a continuous search for new methods of treatment of depression because existing methods still have disadvantages, such as the side effects of drugs, the long duration of treatments, and, more importantly, the partial efficacy (or inefficacy) of treatments. For example, there is wide variation in the response of patients with major depression to antidepressant pharmacotherapy. Some of this variation may be due to genetic differences among patients. Regardless, the result is that about 30% of patients with major depression who are treated with existing antidepressant drugs do not improve.
Among the various drugs available for therapy of depression, there are groups of drugs with totally different mechanisms of action. Such mechanisms include, for example, the blockage of reuptake of serotonin; the blockage of reuptake of noradrenaline; or the blockage of presynaptic receptors on noradrenergic or serotonergic nerve terminals. Such different mechanisms of action make it possible to make conscious choices regarding treatments for depression based on different biochemical mechanisms. However, it has not been known which characteristics of a patient predict a better response to one particular kind of drug over another, so treatment choices have been complicated by the fact that it often takes a significant period of treatment to determine whether or not a drug is having a therapeutic effect or is merely slower in having its therapeutic effect.
Accordingly, treatment with the most effective drug(s) is often delayed while the disease continues to disrupt daily functioning of the patient. Even a patient who may ultimately improve after weeks or months of treatment with one drug may have improved much faster with another drug if only it had been tried sooner. Thus the failure to treat the disease in the most effective manner results in lessened quality of life for the patient not only in the immediate time frame but also in the foreseeable future.
Currently, the expanding field of pharmacogenetics would like to identify DNA markers for differential medication response, thereby using these markers to individualize patient treatment in order to maximize therapeutic response and minimize side effects. Thus, a method which would allow one to predict which patients will respond to specific therapeutics and dosages would provide physical and psychological benefits. Specifically, the efficacy of antidepressant treatment would be greatly improved if there were better methods available to identify the patients which would respond the fastest and with the best therapeutical benefit to a particular kind of treatment.
One characteristic that has been studied extensively with respect to Alzheimer's Disease (AD) and possible treatments thereof is the gene for apolipoprotein E (apoE). The apoE gene on chromosome 19 has three common alleles (&egr;2, &egr;3, and &egr;4), which encode three major apoE isoforms (E2, E3, and E4). The three alleles correspond to six genotypes, i.e., &egr;2/&egr;2, &egr;2/&egr;3, &egr;2/&egr;4, &egr;3/&egr;3, &egr;3/&egr;4, and &egr;4/&egr;4. In typical populations, for example, &egr;3 is the most common allele, occurring on more than 75% of chromosomes. The average frequency of &egr;2 is 8% and the average frequency of &egr;4 is 15%. See, e.g., Farrer, L. A. et al., JAMA 278:1349-1356, 1997.
ApoE functions as a ligand in the process of receptor mediated internalization of lipid-rich lipoproteins, and it is probably also involved in reverse lipid transport. See, e.g., Mahley, R. W. et al., Biochem: Biophys. Acta. 737:197-222 (1983). In the central nervous system, apoE plays a central role in the mobilization and redistribution of cholesterol and phospholipid during membrane remodeling associated with synaptic plasticity. See, e.g., Poirier, J. et al., Mol. Brain. Res., 9:191-195 (1991); Poirier, J. et al., Mol. Brain. Res., 11:97-106 (1991); Poirier, J. et al., Neuroscience, 55:81-90(1993).
In view of the studies with Alzheimer's disease, the apoE &egr;4 allele has been found to be an established genetic risk factor for Alzheimer's disease. See, e.g., Hirono, N. et al., J. Neuropsych. Clin. Neurosci. 11:66-70 (1999). In contrast, the art provides no evidence that the apoE &egr;4 allele is a risk factor for major depression. See e.g., Mauricio, M. et al., Am. J. Geriatr. Psychiatr. 8:196-200 (2000); Forsell, Y. et al., Biol. Psychiatry 42: 898-903 (1997); Heidrich, A. et al., Biol. Psychiatry 41:912-914 (1997); Papassotiropoulos, A. et al., Dement. Geriatr. Cogn. Disord. 10:258-261 (1999); and Schmand, B. et al., Soc. Psychiatry Psychiatr. Epidemiol. 33: 21-26 (1998).
With respect to Alzheimer's, although it is not determinative of the disease, it has been found that human patients carrying at least one apoE &egr;4 allele have a much greater chance of developing the disease. See, e.g., Levy, M. et al., Biol. Psychiatry 45:422-425 (1999). In addition, the apoE &egr;4 allele has been associated with cognitive deficits in nondemented elderly in a number of studies. See, e.g., O'Hara, R. et al., J. Am. Geriatr. Soc. 46:1493-1498, (1998). There are several reasons why nondemented elderly patients who suffer from mild cognitive impairment associated with carrying the apoE &egr;4 allele may have been poorly responsive to certain antidepressant medication treatments. First, nondemented depressed subjects carrying the apoE &egr;4 allele may have mild brain dysfunction rendering them unresponsive to the therapeutic neurochemical changes induced by antidepressant agents. Second, recovery from depression is currently thought to depend in part on a restructuring of cognition and behavior that maintains the depressed mood. Mild cognitive impairment in apoE &egr;4 allele carriers may have made it difficult for these individuals to effect the cognitive changes necessary for recovery from depression. Finally, certain types of anti-depressant drugs, e.g., paroxetine, may negatively affect cognition, and subjects with the apoE &egr;4 allele may be more vulnerable to such effects than subjects without the allele.
Thus, one would have expected carriers of the apoE &egr;4 allele to be poor candidates for treatment of major depression.
SUMMARY OF THE INVENTION
Surprisingly, however, the inventors have found, as a result of clinical trials described herein, that for at least one antidepressant drug, mirtazapine, there are clear improvements in therapeutic response among patients with at least one apoE &egr;4 allele as opposed to those without an apoE &egr;4 allele. Specifically, mirtazapine has been found to be particularly effective as an antidepressant for apoE &eg
Murphy, Jr. Greer M.
Schatzberg Alan F.
Akzo Nobel N.V.
Arthur Lisa B.
Finnegan Henderson Farabow Garrett & Dunner LLP
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