COMPOSITIONS AND METHODS FOR TREATING MOOD DISORDERS AND CIRCADIAN RHYTHM SLEEP DISORDERS

Abstract

Compositions and methods for treating depression, anxiety and/or circadian rhythm sleep disorders using deuterium oxide and various compounds thereof.

Claims

1. A method for treating psychiatric disorders, the method comprising administering a therapeutically effective non-toxic dose of deuterium oxide to a patient suffering from a psychiatric disorder.

2. The method of claim 1, wherein the psychiatric disorders are selected from depression, anxiety and circadian rhythm sleep disorder.

3. The method of claim 1, wherein the concentration of deuterium oxide in water consumed by the patient is from about 0.05% to about 100%.

4. The method of claim 1, wherein the concentration of deuterium oxide in water consumed by the patient is from about 0.1 % to about 15%.

5. The method of claim 1, wherein the total dosage in grams of deuterium oxide provided to the patient is about 0.5% by weight of the patient’s total body water to about 10% of the patient’s total body water.

6. The method of claim 1, wherein the total dosage in grams of deuterium oxide provided to the patient is about 1% by weight of the patient’s total body water to about 5% of the patient’s total body water.

7. The method of claim 1, wherein the daily amount of deuterium oxide administered is from about 1 gram to about 1500 grams.

8. The method of claim 1, wherein the daily amount of deuterium oxide administered is from about 150 grams to about 500 grams.

9. The method of claim 1, further comprising administering the dose of deuterium oxide in a single dose and administering it with a dose of scopolamine.

10. A composition for treating psychiatric disorders comprising a therapeutically effective non-toxic dose of deuterium oxide.

11. The composition of claim 10, wherein the psychiatric disorders are selected from depression, anxiety and circadian rhythm sleep disorder.

12. The composition of claim 10, wherein the total dose of deuterium oxide is from about 1 gram to about 1500 grams.

13. The composition of claim 10, wherein the total dose of deuterium oxide is from about 150 grams to about 500 grams.

14. The composition of claim 10, further comprising scopolamine.

15. The composition of claim 10, wherein the dose of deuterium oxide is about 500 ml in solution with about 0.3 mg to about 0.6 mg of scopolamine.

16. A method of manufacturing a composition for the treatment of psychiatric disorders, the method comprising diluting a dose of deuterium oxide in water.

17. The method of claim 16, wherein the psychiatric disorders are selected from depression, anxiety and circadian rhythm sleep disorder.

18. The method of claim 16, wherein the dose of deuterium oxide is from about 1 gram to about 1500 grams.

19. The method of claim 16, wherein the dose of deuterium oxide is from about 150 grams to about 500 grams.

20. The method of claim 16, further comprising mixing scopolamine with the diluted deuterium oxide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0051] As discussed in the background of the present application, mood can be defined as a predisposition for a particular type of activity or inactivity. The first such internally controlled predispositions were circadian rhythms. The symptoms and longitudinal history of Major Depressive Disorder (“MDD”) are intertwined with numerous circadian and circa-annual rhythms. MDD is related to a disruption in the master circadian clock generation and synchronization of circadian rhythms. Currently, a few empirically-validated chronotherapies utilize a zeitgeber such as bright light or early-morning-awakening (and perhaps induction of a generalized seizure) that resets and resynchronizes circadian rhythms controlled by the suprachiasmatic nucleus (“SCN”). Deuterium oxide penetrates the SCN and slows the period of the circadian rhythms generated and synchronized by the SCN.

[0052] Embodiments of the present invention are directed to an acute 100-fold elevation of deuterium oxide concentration in the SCN to reset/resynch the disordered circadian rhythms underlying the pathophysiology of MDD. Given the response time for other efficacious chronobiological treatments, it is hypothesized that the antidepressant effect of the deuterium oxide treatment will be rapid--within a day or so of receiving the deuterium oxide.

[0053] The theory underlying an embodiment of the present invention is that circadian rhythm abnormalities are involved in the pathophysiology of mood disorder. More speculatively, if mood is viewed as a predisposition for certain types of action or inaction, the evolutionary roots of mood itself are based in the ability of subsystems within the organism to activate or depress readiness for certain types of activity or inactivity. Organisms early on developed subsystems—periodic clocks--to anticipate rhythmically changing conditions on the earth as it spun on its axis and rotated about the sun. Sleep/wake cycles, hormonal and neurotransmitter circadian cycles, hibernation, migration patterns, and seasonal estrous cycles are examples of timing systems which put the organism “in the mood for” the appropriate activity at the appropriate time. Theoretically, altering these timing subsystems will enable one to manipulate mood itself.

[0054] Chronobiological theory applied to psychiatric disorders is a major part of this theoretical basis for this invention. A classic book in the field summarizes the theory succinctly: “There are several reasons to consider the role of circadian rhythm disturbances in affective illness. Because of its inherent cyclicity, the illness itself is a kind of abnormal biological rhythm spanning weeks, months, or years. Circadian rhythms are implicated in some of the symptoms of depression, such as early awakening and diurnal variation in mood. The possible importance of the circadian system in its pathogenesis is suggested by the capacity of experimental alterations in the timing of sleep and wakefulness to alter clinical state.” (Circadian Rhythms in Psychiatry, T.A. Wehr and F.K. Goodwin, 1983, pg. 5). Similarly, the circadian rhythm sleep disorders are viewed from the perspective of chronobiological theory since, by definition, they are the subset of sleep disorders involving circadian rhythm disruption.

[0055] The next underpinning of this invention is from biological studies which demonstrate that deuterium oxide is able to alter the body’s master clock (located in the brain’s suprachiasmatic nucleus). In general, “the living clock is virtually intractable to exogenous chemical manipulation.” (The Chronomutagenic Effect of Deuterium Oxide on the Period and Entrainment of a Biological Rhythm, H.B. Dowse and J.D. Palmer, Biol. Bulletin 143:513, 1972). Deuterium oxide, however, alters the clock powerfully and reliably in all species studied since 1960.

[0056] Another theoretical underpinning of this invention is from chemical studies. The hydrogen isotope deuterium has the same single electron configuration as the protium isotope of hydrogen and therefore enters into essentially the same chemical reactions. With the added mass of an additional neutron, however, the reactions are generally slower (a “kinetic isotope effect”). While deuterium oxide permeates the entire body water, its slowing effect may be particularly significant in the living clock. Other mechanisms of action are possibly also involved in the demonstrated ability of deuterium oxide to alter circadian rhythms. The ability of embodiments of the present invention to treat depression, anxiety and circadian rhythm sleep disorders may also turn out to be due to as yet unknown theoretical factors.

[0057] Other scientific fields drawn upon to create this invention are infant nutrition and hydration, pediatrics, human cholesterol synthesis, radiology, and other scientific disciplines where human subjects have safely been given varying amounts of deuterium oxide over short-term and long-term studies since 1949. Research showing it could be given safely to mammals was conducted shortly after the isotope was discovered in 1932.

[0058] According to an embodiment of the present invention, a person suffering from the psychiatric disorders depression or anxiety or a circadian rhythm sleep disorder is preferably given a therapeutically effective, non-toxic dose of deuterium oxide. The biological grade deuterium oxide is preferably undiluted or in solution with water. The deuterium oxide is preferably drunk in a single dose to achieve therapeutic effect. It might also be consumed in divided doses, consumed over one or many days. Single doses of less than about 500 grains of deuterium oxide are preferably used. Prophylactic medication to eliminate or mitigate common unpleasant side effects may be administered before or in combination with the dose of deuterium oxide. Dilution of the deuterium oxide in water may be done to reduce the possibility of side effects. The total deuterium oxide amount given is kept below that which causes toxic effect; daily doses less than about 1000 grams, and replacement of less than about 5% of total body water with deuterium oxide would likely be upper safety limits for a short period of time (e.g. less than one week). Exact determination of the patient’s total body water (“Total Body Water” or “TBW”) can be calculated from the bodily fluid sample taken shortly after the first deuterium oxide dose by the general formula: (Dose D20 Concentration) x (Dose Volume) = (Sample D20 Concentration) x (Total Body Water Volume).

[0059] In general, the Total Body Water is approximately 65% of a human’s body weight. Since deuterium oxide freely and rapidly enters the total body water, non-invasive testing of urine or saliva can be used to measure for the presence of toxic or therapeutic levels in the blood. Currently available mass spectrometry, infrared spectrophotometry, or other methods can be used to determine the deuterium oxide concentration in the body fluid. The deuterium oxide is preferably given in a large enough dose and for long enough time to alleviate the depression.

[0060] Preferably, a total quantity of deuterium oxide equal to approximately 1 % of the patient’s Total Body Water (TBW) would be given. For example, a 70 kg patient with 45 L of TBWwould be given a total of 450 g of deuterium oxide to achieve a 1% concentration of deuterium oxide in the TBW (450 g deuterium oxide /45,000 g water). This deuterium oxide dosage would preferably be given without further dilution in water. The dosage would preferably be preceded by prophylactic use of appropriate medication to eliminate or mitigate unpleasant side effects often associated with ingestion of deuterium oxide. The deuterium oxide would preferably be given until the depression is alleviated, and could also be continued subsequently for a longer therapeutic period as well. The deuterium oxide could also be combined with other treatment modalities for depression, such as other antidepressant medications, sleep deprivation therapy, light therapy, or other psychiatric medications, or other treatments used for depression, to improve their response rate, reduce their time of onset of action, allow the use of lower dosages or duration of treatment, or improve their ability to treat depression in other ways.

[0061] As discussed above, the total dosage of deuterium oxide, solutions thereof, pharmaceutical compositions made therefrom and combination therapies that incorporate deuterium oxide and treatments using the same vary depending on the intended effect, characteristics of the patient (e.g., weight, age, sex), the severity of the patient’s condition and the sensitivity of the patient to any side effects of the deuterium oxide. Preferably, the total dosage of deuterium oxide over a given amount of time ranges from about 0.1% of total body water to about 15% of total body water, more preferably about 0.5% of total body water to about 10% of total body water, and most preferably about 1 % total body water to about 5% total body water.

[0062] In another embodiment of the present invention, the concentration of deuterium oxide in water consumed by the patient is from about 0.05% to about 100%. In another embodiment, the concentration of deuterium oxide in water consumed by the patient is from about 0.1% to about 15%.

[0063] In another embodiment of the present invention, daily amount of deuterium oxide administered is from about 1 gram to about 1500 grams. In another embodiment, the daily amount of deuterium oxide administered is from about 150 grams to about 500 grams.

[0064] A person suffering from a circadian rhythm sleep disorder, such as jet lag type or shift work type, would be given a therapeutically effective, non-toxic dose of deuterium oxide to treat this disorder.

[0065] Embodiments of the present invention comprise various mediums of delivering the deuterium oxide. Preferably, the deuterium oxide is delivered orally in liquid form. In some embodiments, the deuterium oxide is delivered in combination with other potable liquids in order to reduce side effects or to improve tolerability.

[0066] In summary, deuterium oxide, an established potent chronomutagenic agent, will be administered to provide a more effective treatment for depression, anxiety or circadian rhythm sleep disorders, yielding an effective, rapidly-acting, safe, non-addicting medication which can be precisely dosed and easily measured in the patient with non-invasive procedures.

Additional Examples of Compositions and Methods

[0067] Additional embodiments of the present invention are discussed below.

[0068] Beginning with concerns for safety, a deuterium oxide dosage sufficient to achieve a 1 % concentration of deuterium oxide in Total Body Water is given. In order to eliminate or mitigate a possible unpleasant side effect of dizziness, nausea, or vertigo, a prophylactic dose of scopolamine is combined into the administered therapeutic mixture. As noted above, the dose-limiting side effect for deuterium oxide would most likely be this unpleasant “motion sickness” side effect. As an example of dosage amounts, a 70 kg male with 65% total body water would have a Total Body Water estimate of 45 L, and would be given 450 g of 99+% biological grade deuterium oxide to drink. This dose would result in about a 1 % concentration of deuterium oxide in the patient’s total body water. This dose of about 0.5 L, about 2 cups, is preferably taken orally (by drinking) in one dose. If needed, the dose could be diluted and/or split into a three-times-a-day regimen for improved tolerability. The dosage of scopolamine in the 0.5 L therapeutic mixture is preferably about 0.3-0.6 mg. The usual half-life of scopolamine is 8 hours. It is anticipated that deuterating the scopolamine will likely prolong this half-life. Preferably, the scopolamine would be deuterated, or might occur naturally if the scopolamine remains in the deuterium oxide mixture at room temperature for a sufficient time.

[0069] The estimated Therapeutic Index (ratio of toxic dose to therapeutic dose) of this acute treatment is conservatively estimated at about 15. A deuterium oxide dose that replaces 15% or more of TBW with deuterium oxide over a long term is toxic; a dose achieving 1 % total body water concentration of deuterium oxide is deemed safe over the long-term. The proposed experiment would involve short term exposure to deuterium oxide. Deuterium oxide is excreted by the kidneys with an elimination half-life of up to 10 days. Any bodily fluid (saliva, urine, blood) can be sampled to track the deuterium oxide concentration at which therapeutic benefit and/or adverse events occur. Such ease of monitoring is not available for any other psychiatric medication. Since pure heavy water tastes slightly sweet, a small amount of sweetener is preferably added to the placebo natural water.

[0070] Preferably, the treatment would then follow the bedtime dose of the deuterium oxide/scopolamine solution with early (3:00am) awakening of the patient, to achieve a synergistic effect with the proven short-term antidepressant effect of Wake Therapy chronobiological treatment.

[0071] The subjects would be diagnosed with Major Depressive Disorder. No particular exclusions would be needed. Severity of depression would be measured by a standard instrument, such as Ham-D. Ideally the rating instrument would be sensitive to short-term, daily change. Depression status would be monitored each day for a few days after deuterium oxide treatment. If effective, the described treatment regimen is predicted to take effect by day 2.

[0072] Embodiments of the present invention can include every combination of features that are disclosed herein independently from each other. Although the invention has been described in detail with particular reference to the disclosed embodiments, other embodiments can achieve the same results. Variations and modifications of the present invention will be obvious to those skilled in the art and it is intended to cover all such modifications and equivalents. The entire disclosures of all references, applications, patents, and publications cited above and/or in the attachments, and of the corresponding application(s), are hereby incorporated by reference. Unless specifically stated as being “essential” above, none of the various components or the interrelationship thereof are essential to the operation of the invention. Rather, desirable results can be achieved by substituting various components and and/or reconfiguration of their relationships with one another. The various embodiments of the present invention described herein as methods should also be interpreted to describe compositions. For example, a method of administering deuterium oxide also inherently describes a composition comprising the particular dose of deuterium oxide described by the method.

[0073] Note that in the specification and claims, “about” or “approximately” means within twenty percent (20%) of the numerical amount cited. As used herein “a”, “the” and “an” means one or more unless the context clearly indicates otherwise.

[0074] A “patient” or “subject,” as used herein, is intended to include either a human or non-human animal, preferably a mammal, e.g., a monkey. Most preferably, the subject or patient is a human.