WO2001034172A2

WO2001034172A2 - Methods and compositions for treating reward deficiency syndrome

Info

Publication number: WO2001034172A2
Application number: PCT/US2000/030312
Authority: WO
Inventors: Gregory M. Sullivan
Original assignee: Vela Pharmaceuticals Inc.
Priority date: 1999-11-05
Filing date: 2000-11-03
Publication date: 2001-05-17
Also published as: AU1359801A; WO2001034172A3

Abstract

The present invention relates to methods and compositions for treating Reward Deficiency Syndrome (RDS) using a therapeutically effective amount of a monoamine oxidase B inhibitor. The present invention also relates to compositions for treating RDS comprising selegiline in very low dose.

Description

METHODS AND COMPOSITIONS FOR TREATING REWARD DEFICIENCY SYNDROME

TECHNICAL FIELD OF THE INVENTION The present invention relates to methods for treating Reward Deficiency Syndrome by using a therapeutically effective amount of a monoamine oxidase B inhibitor. The present invention also relates to compositions for treating Reward Deficiency Syndrome comprising selegilme in very low dose.

BACKGROUND OF THE INVENTION

1.1 Monoamine Oxidase B Inhibitors Monoamine oxidases (MAO) are iron containing enzymes that exist as two isozymes A (MAOA) and B (MAOB) . Monoamine oxidases generate hydroxy radicals which may be involved in neurodegenerative disorders such as Parkinson's Disease. MAOA is thought to be primarily involved m the deammation of serotonin, epinephnne, norepinephnne and tyramme. MAOB is thought to be primarily involved m the deammation of dopamme and β-phenylethylamme . Some MAOB inhibitors known m the art are selegilme (Jumex©, Jumexal® Carbex®, Eldepryl®, Movergan®; Aptapryl®, Anipryl®; Eldeprme®; Plurimen®) , desmethylselegil e, paragylme (Eudatm®, Supirdyl®, Eutonyl®) [U.S. patent

3,155,584], rasagilme [R (+ ) N-propargyl-lammomdan] , 3-N-phenylacetylammo-2 , 5-pιperιdmedιone and caroxyazone .

Selegilme, also known as 1-deprenyl, is generally regarded as a selective MAO-B inhibitor at low doses (lOmgs/day or less m humans) or a non- selective MAO-A and MAO-B inhibitor at higher doses (e.g., Schaller, J.L. et al., J. Neuropsychiatry 9:302- 301 (1997); Reiderer, P., et al., J. Neural Transmission 43:217-226 (1978); Sunderland, T., Psvchophar acol. 86:432-437 (1985)). The smallest dosage forms of selegilme on the market is believed to be 5mg tablets or capsules, which are not scored (i.e., Carbex®) . The pharmacokmetics and pharmacodynamics of selegilme have been reported (e.g., Mahmood I, Clinical Pharmacokmet . 33:91-102 (1997)). Methods for preparing selegilme are known the art (e.g., J.S. Fowler, J. Orσ. Chem. 42:2637 (1977); U.S. patent 4,564,706) .

Clinical studies involving the administration of selegilme to humans and/or animals suffering from clinical depression, atypical depression, Parkinson' s disease, Attention-Deflcit/Hyperactivity Disorder, Tourette's Syndrome, Alzheimers' disease, and immune system dysfunctions have been reported. [Feigin, A., et al., Neurology 46:965-968 (1996); Quitkin, F.M., et al., Arch. Gen. Psychiatry 41:777-81 (1984); Wood, D.R., et al., Psvchopharmacol. Bull. 19:627-629 (1983); Taπot, P.N. et al . , Arch. Gen. Psychiatry 44:427-33 (1987); United States patent 5,387,615] For example, United States patent 4,868,218 proposes the transdermal administration of selegilme in an amount of 5mgs to 50mgs per day for the treatment of depression. However, no clinical data is provided. Subsequent clinical studies have shown that oral administration of less than lOmgs/day is not effective at treating depression whereas administration of greater than lOmgs/day of selegilme is effective for treating depression (e.g., Kuhn, W., et al . , J. Neural. Transm. Suppl ■ 48:85-93 (1996)). 1.2 Reward Deficiency Syndrome Reward Deficiency Syndrome (RDS) is a disorder first described by Blum and co-workers as a form of sensory deprivation of the brain' s pleasure mechanisms. [Blum, K., et al . , "Reward Deficiency Syndrome, " American Scientist, (March-April 1996) ] Subsequent studies have proposed that RDS has a biochemical basis that manifests as an inability to derive reward from ordinary, everyday activities. Id. Patients suffering from RDS may also suffer from impulsive, compulsive or addictive disorders such as severe alcoholism, Tourette' s Syndrome and Attention- Deficit Disorder. However, not all patients suffering from these impulsive, compulsive or addictive disorders also suffer from RDS.

Most, if not all, studies relating to impulsive, compulsive or addictive disorders have not investigated RDS. For example, in one study, a percentage of Attention Deficit Hyperactivity Disorder (ADHD) patients treated with a low dose of pargylme or selegilme reported improvement (Wender, P.H., J. Clin Psychiatry 59(suppl 7):76-79 (1998)). There was no indication whether any of the patients suffered from RDS. Similarly, in another study, a high percentage of children suffering from Tourette' s syndrome-ADHD treated with 5 to 15 mg/day of selegilme reported improvement (Jankovic, J., Arch. Neurol. 50:386-388 (1993) ) . Again, there was no indication that the children suffered from RDS. Currently, there is little or no clinical data describing a treatment for RDS patients .

Researchers have suggested that the dopamine system plays a role m the processing of reward information (Schultz, W., J. Neurophvsiol . 80:1-27 (1998)) . For example, some studies have suggested that the Al allele of the dopamine D2 receptor (DRD₂) may be important for the development of disorders such as alcoholism, obesity, attention deficit disorder and RDS (e.g., Blum, K., et al . , Pharmaco enetics 5:121-141 (1995)). Conversely, other studies have excluded linkage of the DRD gene with alcoholism (e.g., Gorman, D., et al., Alcohol 16:47-52 (1998); Suarez, B.K., et al., Geno ics 19:12-20 (1994)). Still others have suggested a correlation between the dopamine D4 receptor and alcoholism and nicotine dependence (Blum, K., et al . , American Scientist (March-April 1996)). Consequently, a direct link between reward processing m general and the dopamine metabolic pathway and/or RDS has yet to be established.

SUMMARY OF THE INVENTION The present invention relates to methods and compositions for treating a patient suffering from Reward Deficiency Syndrome using a therapeutically effective amount of a monoamine oxidase B inhibitor (MAOB-I) . Thus, an object of this invention is to provide a method for treating RDS by administering an amount of MAOB-I necessary to inhibit MAOB but cause little or reduced inhibition of MAOA activity. In one embodiment, the MAOB-I is selegilme administered in an amount of lOmgs/day or less per day. In a preferred embodiment, selegilme is administered in an amount of less than lOmgs/day. Another object of this invention is to provide a composition comprising selegilme for treating RDS, which is better suited for treating RDS than the currently available dosage forms. Thus, a selegilme composition of this invention would be prepared as a single unit comprising less than 2.5 mg of selegilme or as a unit that is pre-prepared into separable portions, each portion of which comprises less than 2.5 mg of selegilme, such that selegilme may be administered accurately and quantitatively to patients in the low dosages necessary to treat RDS. An advantage of this composition is that a practitioner may be better able to determine the appropriate dosage regimen for a patient.

DETAILED DESCRIPTION

A MAOB inhibitor according to this invention is a compound that inhibits MAOB but causes much less or no inhibition of MAOA activity or a compound that selectively inhibits MAOB (e.g., within a particular dosage range) . Hereinafter, the activity of a MAOB inhibitor as used according to this invention will be referred to as "selective MAOB-I activity." In one embodiment, the MAOB inhibitor is selected from the group consisting of selegilme, desmethylselegilme, paragylme, rasagilme [R (+ ) N-propargyl-lammomdan] , 3-N-phenylacetylammo-2, 5-pιpeπdmedιone and caroxyazone. In another embodiment, the MAOB inhibitor is a derivative or metabolite of selegilme, desmethylselegilme, paragylme, rasagilme [R(+)N- propargyl-la momdan] , 3-N-phenylacetylammo-2, 5- pipeπdmedione and caroxyazone. Said derivative or metabolite should have substantially the same or better selective MAOB-I activity as its undeπvatized or unmetabolized form. A MAOB inhibitor of this invention, including selegilme, pargylme, or a derivative or metabolite thereof, as used herein may be administered m the form of a prodrug, i.e., drugs that are metabolized m vivo into the active agent. Prodrugs useful according to this invention have substantially the same selective MAOB-I activity or better than the non-prodrug form. Methods for making prodrugs are readily known m the art (e.g., Balant, L.P., "Prodrugs for the Improvement of Drug Absorption Via Different Routes of Administration, " Eur . J. Drug Metab. Pharmacokmet . 15:143-153 (1990); and Bundgaard, H., "Novel Chemical Approaches m Prodrug Design, " Drugs of the Future 16:443-458 (1991); incorporated by reference herein). The term MAOB inhibitor according to this invention, including selegilme, pargylme, or a derivative or metabolite thereof, as used herein includes pharmaceutically acceptable salts of those compounds and their prodrugs. Pharmaceutically acceptable salts of MAOB-I, selegilme or pargylme useful according to the methods of this invention are salts prepared from pharmaceutically acceptable reagents known m the art. In one preferred embodiment, said pharmaceutically acceptable salt is the hydrochloride salt of selegilme or pargylme.

Methods for evaluating the activity of monoamine oxidase B and monoamine oxidase A known in the art can be used for selecting MAOB inhibitors according to this invention. For example, blood samples may be drawn to determine platelet MAO activity using radiolabelled benzylamme or phenylethylamme . (i.e., evaluating MAOB inhibitory activity). [Murphy, D.L., et a., Psvchopharm. 62:129-132 (1979); Murphy, D.L., et al., Biochem. Med. 16:254-265 (1976); all incorporated by reference herein] In one embodiment, MAOB activity should be decreased greater than 80% compared to MAOB enzyme activity before treatment. In a preferred embodiment, MAOB activity is decreased greater than 90% or 95% compared to MAOB activity before treatment.

For example, MAOA inhibitory activity may be evaluated by measuring levels of 3-methoxy-4- hydroxyphenylglycol (MHPG) or 5-hydroxymdoleacetιc acid (5-HIAA) m the plasma of blood or m cerebral spinal fluid (CSF) by using gas chromatography-mass spectroscopy (gc-ms) . [Murphy, D.L., et al., "Selective Amme Oxidase Inhibitors: Basic to Clinical Studies and Back, " Clinical Pharmacology Psychiatry, 3rd

Series., Eds. Dahl, Gram, Paul, and Potter, Sprmger- Verlag: 1987; Major, L.F., et al., J. Neurochem. 39:229-231 (1979); Jimerson, D.C., et al . , Biomed. Mass. Spectrom. 8:256-259 (1981); all incorporated by reference herein] In one embodiment, after administration of the MAOB-I, plasma MHPG levels should not be reduced lower than 45% of pretreatment levels of plasma MHPG. In a preferred embodiment, after administration of the MAOB-I, plasma MHPG or CSF 5-HIAA levels should not be reduced more than 80% of pretreatment levels of MHPG or 5-HIAA levels, respectively.

MAOB inhibitors for use in this invention may be prepared as a composition comprising a therapeutically effective amount of MAOB inhibitor and a pharmaceutically acceptable carrier.

A preferred composition according the present invention comprises a pharmaceutically acceptable carrier together with less than 2.5 mg of selegilme or a prodrug thereof, formulated into a single unit, or a unit that is pre-prepared into separable portions (hereinafter, "separable composition"), each portion of which comprises less than 2.5 gs of seleglme or a prodrug thereof. In one embodiment, the composition or each portion of the separable composition comprises less than 2.5 mgs of seleglme or a prodrug thereof. In another embodiment, the composition or each portion of the separable composition comprises less than or equal to 2 mg or 1 mg of seleglme or a prodrug thereof. For example, a separable composition is a scored tablet.

A composition according the present invention may further comprise another therapeutic agent. In one embodiment of this invention, the therapeutic agent is a benzodiazepme . Benzodiazepmes useful according to this invention include chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, alprazolam, clonazepam, flunitrazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, and triazolam.

Said therapeutic agents may be administered according to methods of this invention before, during or after the administration of the MAOB inhibitor.

"Reward Deficiency Syndrome" or RDS according to this invention is a chronic and pervasive inability or deficient ability to experience pleasure and/or comfort from ordinary daily activities that are generally emotionally-rewarding m nature. For example, patients suffering from RDS typically complain of two or more, if not all of the following: lack of satisfaction or enjoyment from work, lack of satisfaction or enjoyment from social interaction with friends or family, and lack of satisfaction or enjoyment from hobbies and interests. Individuals suffering soley from an inability to work or socialize, often associated with depression, should not be confused with RDS patients who are unable to obtain or have a reduced capacity to obtain pleasure from activities. An RDS patient will have experienced RDS throughout his/her life, but usually acknowledges the severity of some of the symptoms of RDS as early as puberty. One hallmark of an RDS patient is the inability to complete projects or hobbies. As a result of this inability or deficient ability, the patient may feel uncomfortable, anxious, angry, depressed and/or crave the ability to experience reward and pleasure. However, a patient suffering from any one of those emotions may not necessarily suffer from RDS. Behavior symptoms that an RDS patient may experience include:

1) a depressed mood and/or anhedonia;

2) social anxiety;

3) frequent agitation, aggressiveness and/or explosive temper;

4) easy irritability;

5) low frustration tolerance;

6) Attention Deflcit/Hyperactivity Disorder

(ADHD) or subsyndromal ADHD that includes inattentive and/or impulsive symptom criteria; and

7) Tourette' s syndrome.

The reward-deprived emotional state may result frequent attempts to experience pleasure, comfort, or relief m ways that may be self-damagmg such as danger/thrill-seekmg behavior involving life threatening activities, damaging activities or illegal activities; compulsive gambling; binge eatmg/overeatmg; addictive behavior (e.g., alcohol, substance use, tobacco use, sexually compulsive behavior); and suicidal ideation and/or attempts. All RDS patients have clinically significant distress or impairment m social, occupational, or other important areas of functioning. However, an individual suffering from any one of those behavioral symptoms or self- damagmg proclivities may not necessarily suffer from RDS.

According to this invention, the methods and compositions provided herein are useful for treating RDS or one or more of the symptoms of RDS m a patient suffering from RDS. Accordingly, the methods of this invention are useful for RDS patients who do not also suffer from any one of the following symptoms selected from the group consisting of: depressed mood and/or anheαonia, social anxiety, frequent agitation, aggressiveness and/or explosive temper, easy irritability, low frustration tolerance, Attention Deflcit/Hyperactivity Disorder (ADHD) , and subsyndromal ADHD that includes inattentive and/or impulsive symptom criteria, Tourette' s syndrome, compulsive or addictive behavior such as substance abuse or sexually compulsive behavior, self-damagmg behavior and suicidal ideation. A patient according to this invention is a human, including children and adults, suffering from RDS.

Any suitable route of administration may be employed for providing the patient with an effective dosage of an MAOB-I of this invention. For example, oral, rectal, parenteral, transdermal, subcutaneous, sublmgual, mtranasal, intramuscular, mtrathecal and the like may be employed as appropriate. The term parenteral as used herein includes subcutaneous, mtracutaneous, intravenous, intramuscular, mtra- articular, mtrasynovial, mtrasternal, mtrathecal, tralesional and mtracranial injection or infusion techniques .

Dosage forms include tablets, scored tablets, coated tablets, caplets, capsules (e.g., hard gelatin capsules) , troches, dragees, dispersions, suspensions, solutions, transdermal patches and the like, including sustained release formulations well known in the art. In one preferred embodiment, the dosage form is a scored tablet or a transdermal patch.

The compositions and separable compositions useful according to this invention include those suitable for oral, rectal, transdermal, sublmgual, and parenteral administration (including subcutaneous, intramuscular, mtrathecal and intravenous), and transdermal, although the most suitable route m any given case may depend on the patient and the nature and/or severity of the condition being treated. A preferred route of administration according to the methods of the present invention is the oral route or the transdermal route. The composition may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. The compositions or separable compositions of this invention may be orally administered m any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration m a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. The compositions according to this invention may be m the form of a sterile mjectable preparation, for example, as a sterile mjectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known m the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile mjectable preparation may also be a sterile mjectable solution or suspension m a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution m 1 , 3-butanedιol . Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and lsotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides . Fatty acids, such as oleic acid and its glyceride derivatives are useful m the preparation of mjectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially m their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.

Methods for making transdermal patches including selegilme transdermal patches have been described m the art. [U.S. patent 4,868,218, incorporated by reference herein] Compositions or separable compositions of this invention may also be administered m the form of suppositories for rectal administration. These compositions or separable compositions can be prepared by mixing a compound of this invention w th a suitable non-imtatmg excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt m the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols .

The compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known m the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizmg or dispersing agents known m the art.

The magnitude of a prophylactic or therapeutic dose of the active ingredient (i.e., MAOB inhibitor) m the prevention or treatment of a human will vary with the symptoms being exhibited, the severity of the patient's affliction and the route of administration. The dose and dose frequency will also vary according to the age, weight and response of the individual patient. Generally, however, treatment for RDS will be ongoing although the intensity of treatment may vary depending on the patient' s condition and exposure to biochemical and environmental stimuli that may warrant a variation on the treatment. In a preferred embodiment, selegilme is given twice a day (bid) , m the morning and late afternoon. The treating physician will know how to increase, decrease or interrupt treatment based upon the patient's response. For example, qualitative determinations of improvement may be assessed by the patient's reports of improved enjoyment or satisfaction of several ordinary activities such as work, social interaction with friends or family, hobbies and interests .

The various terms described above such as "therapeutically effective amount, " are encompassed by the above-described dosage amounts and dose frequency schedule. Generally, a therapeutically effective amount is that amount at which monoamine oxidase B is inhibited but monoamine oxidase A exhibits slight or no reduction m activity m the patient. In one embodiment, the dosage of selegilme is an amount equal to or less than lOmgs per day. In a preferred embodiment, selegilme is administered m an amount less than lOmgs/day. In another embodiment, the dosage of pargylme is less than 30 mgs/day.

Throughout this specification and claims, the word "comprise, " or variations such as "comprises" or "comprising, " will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention m any way.

EXAMPLE Patient X is a man m his late 40' s who works as a professional. He was m the midst of a divorce from his first and only marriage at the time of his initial visit. He has three children. He presented with depressed mood and suicidal ideation. He described a daily mood pattern of severe depression upon awakening that was severe for about three hours and became less in the late morning. He would often go to his job about an hour late because of this mood. The rest of the day, his mood was improved but was in the depressive range. The patient's suicidal ideation was relatively constant and severe, often including plans that were easy to accomplish. He experienced prominent, generalized anxiety. His sleep was not significantly disturbed, though he had much difficulty getting out of bed in the morning because of his low mood and energy.

The patient felt that there was a paucity of pleasure or enjoyment in any aspect of his life. He pursued no interests and was totally preoccupied with his psychiatric syndrome. He carried out his role as father without deriving any pleasure from his interactions with his children.

He alternated between being hostile and aggressive and having feelings of hopelessness and believing that there was no cure or relief from his constant suffering.

His family history included a grandmother who had been hospitalized with depression and a son with panic attacks, agoraphobia and frequent agitated, hostile behavior.

The patient had no history of alcohol or substance abuse. His treatment history over the past 30 years by various physicians includes a wide list of drug treatments. The patient's previous drug treatments are indicated in Table I below.

TABLE I. Prior Treatment History

Subsequently, patient X came to the applicant for treatment. He was initially treated with lithium up to 900mgs/day together with gabapentin up to 32000mg/day and light therapy. The timing of his worst period of depression was moved back by 30 minutes, but the severity of his depression did not decrease. Melatonin was added to his treatment, but it had no effect. The melatonin treatment was discontinued. Applicant next administered bupropion at 37.5 mg bid. However, the patient became agitated, extremely irritable, and had excessive suicidal ideation. The bupropion treatment was rapidly discontinued. Applicant noted the patients' frequent, chronic complaints about the inability to reach destinations without distraction. The patient was then given 60- 80mg/day of methylphenidate (i.e., Ritalin®). The patient experienced improved morning mood (from a depressed to a euthymic state) and experienced new desires. However, during the course of the day, he also experienced rapid and abrupt deteriorations in mood. Further, the positive effects of methylphenidate treatment decreased after the initial weeks of treatment. Applicant decreased the patient's doses of lithium and gabapentin and then discontinued them. Applicant added clonazepam to the treatment. However, the patient experienced no clinical change. Applicant discontinued administering Ritalin®.

Next, the patient was prescribed selegiline at 2.5mg/day up to two times/day. At 2.5mg/day of selegline, The patient felt a rapid and remarkable response. He described new episodes of enjoying time with his family. He experienced feelings of pride when partaking in a religious holiday with his parents. His chronic suicidal ideation completely stopped. The patient stated that he was experiencing reward in everyday activities and interactions.

When his dosage regimen was increased to 7.5mgs/day dose, the patient experienced increased irritability and a return of previously familiar distressing symptoms. Applicant instructed the patient to return to the 2.5 mgs bid treatment schedule. His current regimen of medications is selegiline at 2.5mgs bid, clonazepam at 0.25 mg bid to tid and melatonin at 12 mgs at bedtime. The clonazepam appears to calm his anxious, "wired" feeling that may either be a side effect of taking selegiline or of an untreated component of his syndrome.

Patient X has begun to develop a new life. He has a new interest in pursuing love relationships, and he pursues many hobbies and activities that he never considered possible in the past. He has begun an exercise regimen and changed his diet to one that is more nutritious and less caloric thereby allowing him to lose weight. He has not experienced any manic, hypomanic, or agitated behavior during his treatment with selegiline.

At one point, patient X ran out of selegline and went a few days without it. Within a day or so, he experienced a dramatic return of suicidal ideation and previous mood and anxiety symptoms as well as a loss of the pleasure he had been feeling.

The embodiments of the present invention described above are intended to be merely exemplary and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. All such equivalents are considered to be within the scope of the present invention and are covered by the following claims.

Claims

1. A method for treating reward deficiency syndrome (RDS) in a mammal in need of treatment for RDS comprising the step of administering a therapeutically acceptable amount of a monoamine oxidase B inhibitor (MAOB-I) .

2. The method according to claim 1, wherein the mammal is a human.

3. The method according to claim 1, wherein the MAOB-I is selected from the group consisting of selegiline, pargyline, des ethylselegiline, rasagiline, 3-N-phenylacetylamino-2, 5-piperidinedione and caroxyazone .

4. The method according to claim 3, wherein selegiline is administered in an amount of 10 mgs or less per day.

5. The method according to claim 3, wherein selegiline is administered in an amount of 5 mgs or less per day.

6. The method according claim 5, wherein selegiline is administered in an amount of 2.5 mgs or less per day.

7. The method according to claim 5, wherein selegiline is administered in an amount of 1 mg or less per day.

8. The method according to any one of claims 1-7, wherein the MAOB-I is administered orally, parentally or transdermally.

9. The method according to any one of claims 1-7, wherein the MAOB-I is administered as a tablet, a capsule or a transdermal patch.

10. A composition comprising less than 2.5 mg of selegiline or a derivative thereof as a single unit or as a unit that is pre-prepared into separable portions, each portion of which comprises less than 2.5 mgs of selegiline.

11. The composition according to claim 10, wherein the single unit or each separable portion comprises less than or equal to 2.0 mgs of selegiline thereof.

12. The composition according to claim 10, wherein the single unit or each separable portion comprises less than or equal to 1.0 mg of selegiline thereof.

13. The composition according to claim 10, further comprising a therapeutic agent.

14. The composition according to claim 13, wherein the therapeutic agent is a benzodiazepine.

15. The composition according to claim 14, wherein the benzodiazepine is selected from the group consisting of chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, alprazolam, clonazepam, flunitrazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, and triazolam.