Methods for preventing antipsychotic-induced weight gain

Details Methods for preventing antipsychotic-induced weight gain Methods for preventing antipsychotic-induced weight gain

2002-07-22

2004-01-20

Criares, Theodore J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S172000, C514S180000

Reexamination Certificate

active

06680310

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the discovery that agents capable of inhibiting the biological action of the glucocorticoid receptor can be used in the methods for preventing weight gain induced by antipsychotic medications.
BACKGROUND OF THE INVENTION
Antipsychotic (AP) medications are among the most important therapeutic tools for treating various psychotic disorders. For these medications to be maximally beneficial, their adverse side effects, especially those associated with long-term administration, must be minimized. Numerous reports based on extensive clinical studies have, however, indicated that 40-80% of patients who are under chronic AP administration experience substantial weight gain, ultimately exceeding their ideal body weight by 20% or more (see, e.g., Umbricht et al.,
J Clin. Psychiatry
55 (Suppl. B):157-160, 1994; Baptista,
Acta Psychiatr. Scand.
100:3-16, 1999). Such undesirable weight gain can significantly compromise the effectiveness of treatment for psychotic disorders. First of all, a person whose body weight significantly exceeds the healthful range is exposed to a dramatically increased risk in many serious health problems associated with obesity, such as cardiovascular disease, stroke, hypertension, type II diabetes, and certain types of cancer. Secondly, unwanted weight gain is one of the most common reasons for a patient's non-compliance of AP administration schedule, which necessarily leads to the failure of the treatment for the psychotic disorder.
The degree of weight gain induced by different AP medications varies. The newer, or atypical, AP drugs, such as clozapine and olanzapine, have shown greater ability to induce weight gain (Allison et al.,
Am. J Psychiatry
156:1686-1696, 1999). Although studies have suggested that insulin, leptin, and certain reproductive hormones play important roles in the process, the precise mechanism of AP-induced weight gain remains to be fully understood as it is believed to involve multiple factors and intricate interactions amongst them.
Insulin is synthesized and secreted by the pancreatic &bgr;-cells in response to, among other things, elevated blood glucose concentration. Acting through cell surface receptors, insulin stimulates cellular glucose uptake and may cause body weight fluctuation though a direct effect on adipose tissue and through affecting appetite via hypoglycemia (Melkersson & Hulting,
Psychopharmacology
154:205-212, 2001). Leptin is another important hormone in body weight regulation. Encoded by the ob gene, leptin is primarily produced by adipose tissue, its circulating level positively correlating with body fat percentage and basal level of insulin. Together, leptin and insulin integrate the long-term homeostasis of body fat storage with lipid and carbohydrate metabolism (Baptista et al.,
Pharmacopsychiatry
33:81-88, 2000).
Glucocorticoid hormones are synthesized in the adrenal cortex under the control of the hypothalamic-pituitary-adrenal axis. An important element in responsiveness to many physical and psychological stresses, they are pivotal in regulating salt and water metabolism, blood pressure, immune functions, and metabolism. Cortisol is the main glucocorticoid hormone in humans. Its deficiency (Addison's disease or hypopituitarism) has been linked to postural hypotension, weight loss, and hypoglycemia, while its excess (Cushing's syndrome) has been linked to hypertension, obesity, and glucose intolerance. Cortisol's effects are, at least in part, dependent upon its antagonism of the actions of insulin, i.e., by inducing a state of insulin resistance (Andrews & Walker,
Clin. Sci.
96:513-523, 1999).
Researchers have reported in patients under long term AP administration hormonal abnormalities, which include elevated levels of insulin and leptin, as well as altered levels of reproductive hormones in both genders (see, e.g., Baptista et al.,
Pharmacopsychiatry
33:81-88, 2000; Melkersson & Hulting,
Psychopharmacology
154:205-212, 2001). These studies, however, have yet to establish any clear and consistent correlation between AP-induced weight gain and levels of particular hormones, such as insulin and cortisol. Hence, there has been no evidence prior to this invention that a glucocorticoid receptor antagonist can be an effective agent to prevent or reverse weight gain induced by AP medications, especially in patients having cortisol levels that fall within a normal range. Many of the actions of cortisol are mediated by binding to the type I (mineralocorticoid) receptor, which is preferentially occupied, relative to the type II (glucocorticoid) receptor, at physiological cortisol levels. As cortisol levels increase, more glucocorticoid receptors are occupied and activated. Because cortisol plays an essential role in metabolism, inhibition of all cortisol-mediated activities, however, would be fatal. Therefore, antagonists that specifically prevent type II glucocorticoid receptor functions, but do not antagonize type I mineralocorticoid receptor functions are of particular use in this invention. RU486 and similar antagonists are examples of this category of receptor antagonists.
The present inventors have determined that glucocorticoid receptor antagonists such as RU486 are effective agents for preventing or reversing AP-induced weight gain in patients with normal, increased, or decreased cortisol levels. The present invention therefore fulfills the need for an effective preventive measure for the undesirable weight gain caused by AP medications by providing methods of administering glucocorticoid receptor antagonists to patients under a long-term AP regimen.
SUMMARY OF THE INVENTION
The invention provides a method of inhibiting or reversing weight gain induced by AP medications in a patient. The method comprises administration of a therapeutically effective amount of a glucocorticoid receptor antagonist to the patient, with the proviso that the patient be not otherwise in need of treatment of with a glucocorticoid receptor antagonist and that the patient be not suffering from psychotic major depression.
In one embodiment of the invention, the methods of inhibiting or reversing AP-induced weight gain are practiced on a patient being treated with an atypical antipsychotic medication.
In another embodiment of the invention, the methods of inhibiting or reversing AP-induced weight gain are practiced on a patient being treated with an antipsychotic medication selected from the group consisting of clozapine, olanzapine, risperidone, quetiapine, and sertindole.
In another embodiment of the invention, a glucocorticoid receptor antagonist is administered to a patient who has gained at least 2 kg of weight over a ten-week period of treatment with the antipsychotic medication.
In another embodiment of the invention, a glucocorticoid receptor antagonist is administered to a patient who is at least 20% above the healthful weight range.
In another embodiment of the invention, the glucocorticoid receptor antagonist comprises a steroidal skeleton with at least one phenyl-containing moiety in the 11-beta position of the steroidal skeleton. The phenyl-containing moiety in the 11-beta position of the steroidal skeleton can be a dimethylaminophenyl moiety. In alternative embodiments, the glucocorticoid receptor antagonist comprises mifepristone, or, the glucocorticoid receptor antagonist is selected from the group consisting of RU009 and RU044.
In other embodiments, the glucocorticoid receptor antagonist is administered in a daily amount of between about 0.5 to about 20 mg per kilogram of body weight per day; between about 1 to about 10 mg per kilogram of body weight per day; or between about 1 to about 4 mg per kilogram of body weight per day. The administration can be once per day. In alternative embodiments, the mode of glucocorticoid receptor antagonist administration is oral, or by a transdermal application, by a nebulized suspension, or by an aerosol spray.
The invention also provides a kit for inhibiting or reversing AP-induced weight gain in a hum

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