CN114746097A

CN114746097A - Use of reboxetine for the treatment of neurological disorders

Info

Publication number: CN114746097A
Application number: CN202080083484.4A
Authority: CN
Inventors: 赫里奥特·塔布提奥
Original assignee: Antecip Bioventures II LLC
Current assignee: Antecip Bioventures II LLC
Priority date: 2019-12-03
Filing date: 2020-11-30
Publication date: 2022-07-12
Also published as: PE20230181A1; EP4069244A1; AU2020395082A1; CR20220247A; EP4069244A4; KR20220108122A; IL293536A; JP2023504685A; BR112022010677A2; CO2022007507A2; MX2022006630A; CA3163505A1

Abstract

Described herein are methods of treating cataplexy narcolepsy comprising administering reboxetine (including oxapredosine) to a human in need thereof. Reboxetine (including oxapredtin) can also be used in the manufacture of a medicament for the treatment of cataplexy narcolepsy. Also disclosed herein are kits comprising a pharmaceutical composition comprising reboxetine, including oxazetin, and instructions for using the pharmaceutical composition to treat cataplexy narcolepsy in a human.

Description

Use of reboxetine for the treatment of neurological disorders

The inventor: herriott Tabuyoto

Cross Reference to Related Applications

This application claims U.S. patent application serial No. 16/740,329 filed on 10.1/2020; U.S. patent application serial No. 16/740,409 filed on 11/1/2020; U.S. patent application serial No. 16/740,410 filed on 11/1/2020; U.S. patent application serial No. 16/740,411 filed on 11/1/2020; U.S. patent application serial No. 62/943,077 filed on 3/12/2019; and U.S. patent application serial No. 62/946,295 filed on 12/10/2019; all of these documents are incorporated herein by reference in their entirety.

Background

Narcolepsy is a severe and debilitating neurological condition that can lead to disturbances in the sleep-wake cycle and is clinically characterized by Excessive Daytime Sleepiness (EDS), cataplexy, pre-sleep hallucinations, sleep paralysis, and nocturnal sleep disturbances. Narcolepsy is estimated to afflict 185,000 individuals in the U.S. prediction. Cataplexy is observed in 70% of narcolepsy patients and is a sudden reduction or loss of muscle tone while the patient is awake, usually triggered by a strong emotion (e.g. laughing, fear, anger, tension or excitement). Narcolepsy type 1 includes cataplexy, whereas narcolepsy type 2 does not. Narcolepsy interferes with cognitive, psychological and social functions, increases the risk of work and driving related accidents, and is associated with a 1.5 times higher mortality rate. It has been reported that up to 57% of patients suffer from depression. Unfortunately, currently approved therapies are rarely used for this poorly diagnosed orphan condition (orphan Condition) and are limited by differences in efficacy between patients, tolerability issues, and the need for U.S. drug administration (DEA) scheduling.

Disclosure of Invention

Described herein are methods of treating neurological disorders comprising administering to a human in need thereof an antidepressant, e.g., a selective norepinephrine inhibitor, e.g., atomoxetine (atomoxetine), edioxetine (edivoxeine), reboxetine (reboxetine), or S, S-reboxetine.

Described herein are methods of treating cataplexy narcolepsy comprising administering to a human in need thereof an antidepressant, such as a selective norepinephrine inhibitor, e.g., atomoxetine, edixetine, or reboxetine (including S, S-reboxetine).

Some embodiments include the use of an antidepressant (e.g., a selective norepinephrine inhibitor, such as atomoxetine, edixetine, or reboxetine (including S, S-reboxetine)) in the manufacture of a medicament for the treatment of cataplexy narcolepsy.

Some embodiments include a kit comprising a pharmaceutical composition comprising an antidepressant, e.g., a selective norepinephrine inhibitor, e.g., atomoxetine, edixetine, or reboxetine (including S, S-reboxetine), and instructions for use of the pharmaceutical composition to treat cataplexy narcolepsy in a human.

In some embodiments, an antidepressant (e.g., a selective norepinephrine inhibitor, such as atomoxetine, edixetine, or reboxetine (including S, S-reboxetine)) is administered at least once daily for more than two weeks. In some embodiments, as a result of the treatment, the human experiences a reduction in the number of cataplexy episodes within a week, a reduction in the Epworth somnolence scale score (ESS), a reduction in the stay awake test (MWT) score, a reduction in the narcolepsy symptom rating score (NSAQ), a reduction in the patient 'S overall severity impression (PGI-S) score, a patient' S overall change impression (PGI-C) score of less than 4 points, or a reduction in the hamilton depression rating scale (HAM-D), or an improvement in attention focusing capacity (e.g., on NSAQ).

Some embodiments include a method of rapidly reducing the number of cataplexy episodes in a person with cataplexy narcolepsy, comprising administering to a person in need thereof about 8mg to about 10mg reboxetine daily for at least two weeks, wherein the person has at least 30% fewer cataplexy episodes than baseline one week after treatment initiation and the reduction in the number of cataplexy episodes is statistically significant compared to administration of placebo, wherein p < 0.01. In some embodiments, the reduction in the number of cataplexy episodes compared to administration of placebo is statistically significant, wherein p < 0.001.

Some embodiments include a method of improving attention-focus capacity comprising administering to a mammal or human in need thereof an antidepressant, such as a selective norepinephrine inhibitor, e.g., atomoxetine, edixetine, or reboxetine (including S, S-reboxetine).

Some embodiments include a method of improving attention-focusing ability in a person with cataplexy narcolepsy, comprising administering to a person in need thereof about 8mg to about 10mg reboxetine daily for at least two weeks, wherein the person has "average", "poor" or "very poor" attention-focusing ability before treatment initiation and the person has "good" or "very good" attention-focusing ability two weeks after the treatment initiation, as determined by the attention-focusing ability item of the narcolepsy symptom assessment questionnaire. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxazetin (esreboxetine).

Some embodiments include a method of reducing the number of unexpected naps in a person with cataplexy narcolepsy, the method comprising administering to a person in need thereof about 8mg to about 10mg of reboxetine daily for at least two weeks, wherein the person has at least 20% less unexpected naps per week two weeks after the start of treatment compared to the week before the patient first received reboxetine. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxapredosine.

Some embodiments include a method of improving sleep quality in a person having cataplexy narcolepsy, the method comprising administering to the person in need thereof about 8mg to about 10mg reboxetine daily for at least two weeks, wherein two weeks after the start of the treatment the person reports having improved sleep quality compared to the week before the patient first received reboxetine. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxapredosine.

Some embodiments include a method of reducing nocturnal arousals in a person having cataplexy narcolepsy, the method comprising administering to the person in need thereof about 8mg to about 10mg reboxetine daily for at least two weeks, wherein two weeks after the start of the treatment the person reports less nocturnal arousals than the week before the patient first received reboxetine. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxapredosine.

Some embodiments include a method of reducing sleep paralysis in a human suffering from cataplexy narcolepsy, the method comprising administering to a human in need thereof about 8mg to about 10mg of reboxetine daily for at least two weeks, wherein two weeks after the start of the treatment the human reports having fewer sleep paralysis episodes than the week before the patient first received reboxetine. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxazetin.

Some embodiments include a method of reducing pre-sleep hallucinations in a person with cataplexy narcolepsy, the method comprising administering to a person in need thereof about 8mg to about 10mg of reboxetine daily for at least two weeks, wherein two weeks after the start of the treatment the person reports less pre-sleep hallucinations than the week before the patient first received reboxetine. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxapredosine.

Some embodiments include a method of improving attention-focusing capacity in a person with narcolepsy comprising administering reboxetine to a person in need thereof. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxapredosine.

Some embodiments include a method of treating cataplexy narcolepsy, the method comprising administering reboxetine to a human in need thereof, wherein reboxetine is administered at least once daily for more than two weeks, wherein as a result of treatment, the human experiences a decrease in the number of cataplexy episodes within one week, a decrease in the Epworth somnolence scale score, a decrease in the cataplexy score of the ullinnina narcolepsy scale (NUS), or a decrease in the stay awake test score two weeks after initiation of treatment.

Some embodiments include the use of reboxetine in the manufacture of a medicament for the treatment of cataplexy narcolepsy, wherein reboxetine is administered at least once daily for at least three weeks. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxapredosine.

Some embodiments include a kit comprising a pharmaceutical composition comprising reboxetine and instructions for use of the pharmaceutical composition to treat cataplexy narcolepsy in a human, wherein reboxetine is administered at least once daily for at least three weeks. In some embodiments, the reboxetine is racemic reboxetine. In some embodiments, reboxetine is oxapredosine.

Some embodiments include a method of treating fibromyalgia comprising administering oxapredosine to a human in need thereof, wherein the daily dose of oxapredosine is from about 1mg to about 2mg for at least six weeks, wherein during the course of treatment, the human experiences greater reduction in fibromyalgia pain than the human experiences with administration of a placebo, as measured by a Visual Analog Scale (VAS) score.

Some embodiments include a method of treating fibromyalgia comprising administering oxapredosine to a human in need thereof, wherein a daily dose of about 2mg to about 4mg of oxapredosine is administered for at least six weeks, wherein the human experiences greater pain reduction during the course of treatment than the human experiences by administering a placebo, as measured by a Visual Analog Scale (VAS) score.

Some embodiments include a method of treating fibromyalgia comprising administering oxapredosine to a human in need thereof, wherein a daily dose of about 0.5mg to about 1mg of oxapredosine is administered for at least six weeks, wherein the human experiences greater pain reduction during the course of treatment than the human experiences by administering a placebo, as measured by a Visual Analog Scale (VAS) score.

Drawings

Figure 1 depicts the change in weekly cataplexy episodes for human patients receiving reboxetine and placebo as described in example 22.

Figure 2 depicts the number of human patients who received reboxetine or placebo as described in example 22 who had a 50% or more reduction in cataplexy episodes per week.

Figure 3 depicts the number of human patients with 75% or more reduction in cataplexy episodes per week who received reboxetine or placebo as described in example 22.

Figure 4 depicts the change in Epworth somnolence scale score for human patients receiving reboxetine and placebo as described in example 22.

Fig. 5 depicts the reduction in frequency of unexpected weekly dozes in human patients receiving reboxetine and placebo as described in example 22.

Fig. 6 depicts the number of human patients with a reduction in unexpected dozing of 50% or greater who received reboxetine or a placebo as described in example 22.

Figure 7 depicts the improvement in attention-focusing scores of human patients receiving reboxetine and placebo as described in example 22.

Figure 8 depicts the number of human patients with "very good" or "good" attention-focusing ability who received reboxetine or placebo as described in example 22.

Figure 9 depicts the proportion of human patients showing improvements in sleep quality, night wakefulness, sleep paralysis onset and pre-sleep hallucinations.

Detailed Description

Antidepressants, such as reboxetine or S, S-reboxetine, can be used to treat conditions such as nervous system disorders, including addictive disorders (including those caused by alcohol, nicotine, and other psychoactive substances), withdrawal syndromes, adjustment disorders (including depressed mood, anxiety, mixed anxiety and depressed mood, conduct disorders, and mixed mood and conduct disorders), depression (including major depression alone or in combination with other antidepressants), age-related learning or mental disorders (including alzheimer' S disease), anorexia nervosa, apathy, attention deficit (or another cognitive) disorder due to general medical conditions, Attention Deficit Hyperactivity Disorder (ADHD), bipolar disorders, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, chronic pain, anxiety, depression, anxiety, mixed anxiety and depressed mood disorders, and mixed mood disorders, anorexia nervosa, and bulimia nervosa, Conduct disorder, mood disorder, depression (including juvenile depression and mild depression), mood disorder, fibromyalgia and other somatoform disorders (including somatization disorder, transformation disorder, pain disorder, hypothalamic affective disorder, somatoform disorder, undifferentiated somatization disorder, and somatization NOS), Generalized Anxiety Disorder (GAD), urinary incontinence (i.e., stress incontinence, true stress urinary incontinence, and mixed urinary incontinence), stress urinary incontinence (stress incontinence), inhalation disorder, poisoning disorder (alcohol addiction), mania, migraine, obesity (e.g., reducing body weight in obese or overweight patients), obsessive compulsive disorder or related spectrum disorders, oppositional defiant disorder, panic disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder (i.e., premenstrual syndrome and luteal phase anxiety disorder), anxiety disorder, and mood disorder, Psychotic disorders (including schizophrenia, negative symptoms of schizophrenia, schizoaffective or schizophreniform disorders, alone or as adjunctive therapy), seasonal affective disorders, sleep disorders (such as narcolepsy or enuresis), social phobia (including social anxiety disorder), specific developmental disorders, selective 5-hydroxytryptamine reuptake inhibition (SSRI) "burn out" syndrome (i.e., wherein a patient fails to maintain a satisfactory response to SSRI therapy for an initial period of time), TIC disorders (e.g., tourette's disease), post-herpetic pain, painful diabetic peripheral neuropathy, post-herpetic neuralgia, syncope, and/or vasovagal syncope, and the like. In some embodiments, S-reboxetine is used to treat fibromyalgia. In some embodiments, reboxetine is used to treat fibromyalgia.

Treatment with reboxetine (including S, S-reboxetine) can result in an improvement in disease symptoms. For example, for pain conditions such as fibromyalgia, the patient may experience a pain reduction measured on a Visual Analog Scale (VAS), e.g., 0-100mm, which is greater than the pain reduction that would be experienced by administration of a placebo. In some embodiments, the VAS score improvement is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 70%, at least about 80%, at least about 90%, about 1-5%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g., at least about 50mm, at least about 40mm, at least about 30mm, at least about 20mm, at least about 10mm, about 0-10mm, about 10-20mm, about 20-30mm, or about 75-100%, greater than the VAS score improvement that would be experienced by administration of a placebo, About 30-40mm, about 40-50mm, about 0-25mm, or about 25-50 mm. In some embodiments, the VAS score improvement is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 1-5%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100% greater than baseline (e.g., just prior to initiation of treatment), e.g., at least about 50mm, at least about 40mm, at least about 30mm, at least about 20mm, at least about 10mm, about 0-10mm, about 10-20mm, about 10-5 mm, about 1-10%, about 10-20mm, or about 10-20mm greater, About 20-30mm, about 30-40mm, about 40-50mm, about 0-25mm, or about 25-50 mm.

Antidepressants, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chlorimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarbazide, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindane, benazelate, escitalopram, fluvoxamine, venlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensin, busofuran, moclobemine, sarageenan, nilaparine, niazidine, isonine, iproclozide, metolaclozide, iloperidone, ibolone, suloctreone, sulpirfenine, benzphedrine, indole, benzphetamine, indole, sulpirimipramine, nifedipine, indomethamine, clofibrate, clomipramine, and benzpyroline, Lofepramine, opipramol, norfluoxetine, dapoxetine, ketamine, and the like, including norepinephrine reuptake inhibitors (e.g., atomoxetine, edixetine, or reboxetine (including S, S-reboxetine)), have the potential to treat narcolepsy symptoms.

Many antidepressants, such as norepinephrine reuptake inhibitors (e.g., atomoxetine, edixetine, or reboxetine (including S, S-reboxetine)), lack DEA scheduling, which would represent a significant benefit to patients suffering from this condition.

If criteria A and B are met, a person may have narcolepsy type 1:

A. the patient has a daily non-suppressible sleep need or a daytime sleepy period occurring for at least 3 months

B. One or both of the following are present:

1. cataplexy (as defined under the baseline characteristics) on the Mean Sleep Latency Test (MSLT) performed according to standard techniques, <8 minutes mean sleep latency, and ≧ 2 sleep onset REM periods (SOREMP). SOREMP on previous laboratory-based Polysomnography (PSG) (within 15 minutes of sleep onset) may replace one of the SOREMP on MSLT

2. CSF hypothalamic secretin-1 concentration measured by immunoreactivity <110pg/mL or < 1/3 of the mean value obtained in normal subjects using the same assay

In young children, narcolepsy sometimes manifests as excessive nighttime sleep or resumption of a previously interrupted daytime nap. If narcolepsy type 1 is clinically strongly suspected but does not meet the B2 criteria, a possible strategy is repeat MSLT.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may have and/or may be selected to have a daily non-suppressible sleep need or a period of time during which daytime sleepiness is depressed occurs for at least about 3 months, at least 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 40 years, At least about 50 years, at least about 60 years, about 3-9 months, about 9-18 months, about 18 months to about 2 years, about 2-5 years, about 5-10 years, about 10-15 years, about 15-20 years, about 20-25 years, about 25-30 years, about 30-35 years, about 35-40 years, about 40-50 years, about 50-60 years, or longer.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may have and/or may be selected to have an average sleep latency of less than about 1 minute, less than about 2 minutes, less than about 3 minutes, less than about 4 minutes, less than about 5 minutes, less than about 6 minutes, less than about 7 minutes, less than about 8 minutes, about 0.1-1 minute, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, or about 8 minutes.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may have and/or may be selected to have at least 2, at least 3, or at least 4 soramp on MSLT (mean sleep latency test) performed according to standard techniques. SOREMP within 15 minutes of the onset of sleep on the PSG occurring during the previous night may replace one of the SOREMP on MSLT.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may have and/or may be selected to have a hypothalamic secretin-1 concentration of less than about 40pg/mL, less than about 50pg/mL, less than about 60pg/mL, less than about 70pg/mL, less than about 80pg/mL, less than about 90pg/mL, less than about 100pg/mL, less than about 110pg/mL, as measured by immunoreactivity.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may have and/or may be selected to have a CSF hypothalamic secretin-1 concentration, as measured by immunoreactivity, of less than about 1/10, less than about 1/9, less than about 1/8, less than about 1/7, less than about 1/6, less than about 1/5, less than about 1/4, or less than about 1/3 of the mean values obtained in normal subjects using the same assay.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may be and/or may be selected for young children who exhibit prolonged nocturnal sleep.

Some patients treated with antidepressants, including noradrenaline inhibitors such as reboxetine (including S, S-reboxetine), may be and/or may be selected for infants who exhibit recovery from a previously discontinued daytime doze.

Some patients treated with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may have and/or may be selected to have a diagnosis of cataplexy narcolepsy that meets the international sleep disorder classification, third edition (ICSD-3) criteria.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may have and/or may be selected to have a cataplexy score on the Unlinlina Narcolepsy Score (UNS) of at least 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, about 11, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11, about 2-4, about 4-6, about 6-8, about 8-10, about 2-6, or about 6-10, or any number between 1 and 11.

Some patients treated with antidepressants, including noradrenaline inhibitors such as reboxetine, including S, S-reboxetine, may have and/or may be selected to have a score on the Epworth Somnolence Scale (ESS) of at least about 10, greater than about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, about 10-11, about 11-12, about 12-13, about 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20, about 20-21, about 21-22, about 22-23, about 23-24, about 10-13, about 16-17, about 17-18, about 19, about 20-20, about 21-22, about 22-23, about 23-24, about 10-13, about, About 13-16, about 16-19, about 19-22, or about 22-24.

Some patients treated with antidepressants, including noradrenaline inhibitors such as reboxetine (including S, S-reboxetine), may have and/or may be selected to have at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 28, at least about 35, about 7-14, about 14-21, about 21-28, about 28-35, about 35-49, or about 49-70 cataplexy attacks per week.

Some patients treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may have and/or may be selected to have less than about 1 minute, less than about 2 minutes, less than about 3 minutes, less than about 4 minutes, less than about 5 minutes, less than about 6 minutes, less than about 7 minutes, less than about 8 minutes, less than about 9 minutes, less than about 10 minutes, less than about 11 minutes, less than about 12 minutes, less than about 13 minutes, less than about 14 minutes, less than about 15 minutes, less than about 16 minutes, less than about 17 minutes, less than about 18 minutes, less than about 19 minutes, less than about 20 minutes, about 0-1 minute, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, A stay awake test (MWT) score of about 7-8 minutes, about 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about 0-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16 minutes, about 16-20 minutes, or about 0-19 minutes.

In some embodiments, the patient has had and/or can be selected to have symptoms of narcolepsy for about 1-5 years, about 5-10 years, about 10-15 years, about 15-20 years, about 20-25 years, about 25-30 years, about 30-35 years, about 35-40 years, about 40-45 years, about 45-50 years, about 50-55 years, about 55-60 years, about 60-65 years, about 65-70 years, about 70-75 years, or longer than 75 years prior to receiving treatment with an antidepressant (including a noradrenaline inhibitor, such as reboxetine (including S, S-reboxetine)).

In some embodiments, prior to receiving treatment with an antidepressant drug (including a noradrenergic inhibitor, such as reboxetine (including S, S-reboxetine)), the patient has and/or can be selected to have an age of about 0-18 years, about 18-100 years, about 0-5 years, about 5-10 years, about 10-15 years, about 15-18 years, about 18-20 years, about 15-20 years, about 18-25 years, about 20-25 years, about 25-30 years, about 30-35 years, about 35-40 years, about 40-45 years, about 45-50 years, about 50-55 years, about 55-60 years, about 60-65 years, about 65-70 years, about 70-75 years, or greater than 75 years.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may be and/or may be selected for females. In some embodiments, the patient may be selected as non-nursing and non-pregnant women.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may be and/or may be selected for males.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have any accompanying sleep disorders. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have any concomitant sleep disorder other than mild sleep apnea (<15 events/hour) or mild to moderate sleep apnea (<30 events/hour) when using stable therapy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have any clinically significant condition that may cause EDS. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have any clinically significant psychiatric disorder. Some patients treated for narcolepsy (e.g., sudden-fall and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have any type of depression that is not caused by narcolepsy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have any lethargy caused by depression not due to narcolepsy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no affective disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have a psychiatric disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no brain dysfunction. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no dyskinesia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have dementia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no motor neuron disease.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not be concurrently taking sodium oxybate. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not be taking stimulants at the same time. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not be taking anticonvulsants concurrently. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not be taking clonidine (clonidine) at the same time. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not be concurrently taking a selective 5-hydroxytryptamine reuptake inhibitor (SSRI). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including noradrenaline inhibitors such as reboxetine (including S, S-reboxetine), may not be taking 5-hydroxytryptamine and a noradrenaline reuptake inhibitor (SNRI) simultaneously. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not be taking a monoamine oxidase inhibitor (MAOI) at the same time. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not be taking a tricyclic antidepressant (TCA) at the same time. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not be taking hypnotics at the same time. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not be taking anxiolytics at the same time. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not be taking sedating antihistamines concurrently. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not be taking antipsychotics at the same time. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not be taking any other medication for treating narcolepsy or cataplexy at the same time.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have a neurodegenerative disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no epileptic disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have convulsive disorders. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having a diagnosis of cancer (except for possible basal cell carcinoma) within the last 5 years.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have a bilirubin level greater than 2 times the upper normal limit. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have alanine transaminase levels greater than 2-fold the upper normal limit. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have a level of aspartate transaminase that is greater than 2-fold the upper normal limit. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have a 2-fold greater level of alkaline phosphatase than the upper normal limit.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no clinically significant hypertension. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have uncontrolled hypertension. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for having no history of cardiovascular disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no myocardial infarction. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have angina. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no dysrhythmia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have heart failure.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for having no history of narrow angle glaucoma. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have a gastric bypass. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have any condition that would be expected to affect drug absorption.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no headache. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have depression. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have major depression. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have treatment-resistant depression.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have treatment-resistant bipolar depression. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have bipolar disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no circulatory affective disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have seasonal affective disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no mood disorders. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have chronic depression (e.g., dysthymia). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have psychotic depression. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no history of psychiatric episodes. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no significant risk of self-injury, suicide, or attack on others.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have postpartum depression. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no premenstrual dysphoric disorder (PMDD). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have contextual depression. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have atypical depression. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no mania. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no anxiety disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no Attention Deficit Disorder (ADD).

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have attention deficit disorder with hyperactivity disorder (ADDH). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no attention deficit/hyperactivity disorder (AD/HD). Some patients treated for narcolepsy (e.g., sudden-fall and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having manic conditions. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have obsessive-compulsive disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no binge eating disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no obesity or weight gain. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have chronic fatigue syndrome.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have premenstrual syndrome. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no substance addiction or abuse. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have nicotine addiction. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having psycho-sexual dysfunction. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no pseudobulbar mood (pseudobulbar afffect). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no mood swings.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no anxiety disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no phobias. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have generalized anxiety disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no social anxiety disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have panic disorder. Some patients treated for narcolepsy (e.g., sudden-fall and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have agoraphobia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have obsessive-compulsive disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have post-traumatic stress disorder (PTSD). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no mania.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have manic-depressive symptoms. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have hypomania. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have unipolar depression. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no stress disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no somatoform disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no personality disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have a psychiatric disorder.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have schizophrenia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no delusional disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have schizoaffective disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having the schizophrenic disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having aggressive behavior. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have aggressive behavior in alzheimer' S disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no agonism. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no agonism in alzheimer' S disease.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to be drug independent. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have cocaine addiction. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having a psychostimulant addiction or dependency on a psychostimulant. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having a quickset addiction or dependence on quickset. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having cocaine addiction or dependence on cocaine. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having a rapid pill addiction or dependence on rapid pills. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having methamphetamine addiction or dependence on methamphetamine. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having nicotine addiction or dependence on nicotine.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having alcohol addiction or dependence on alcohol. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having opioid addiction or opioid dependence. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having an anxiolytic and/or hypnotic addiction or dependence on anxiolytic and/or hypnotic drugs. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having cannabis (canabis/marijuana) addiction or dependence on cannabis. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for having no addiction to or dependence on amphetamines. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no addiction to or dependence on a hallucinogen. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having phencyclidine addiction or dependency on phencyclidine.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no volatile solvent addiction or dependence on volatile solvents. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for having no volatile nitrite addiction or dependence on volatile nitrite. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have senile dementia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have dementia of the alzheimer type. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no memory loss. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have amnesia/amnesia syndrome. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no epilepsy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have a disturbance of consciousness.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no coma. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having a decrease in attention. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no speech impairment. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no sound cramping. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have parkinson' S disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have Lennox-Gastaut syndrome.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no autism. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no restless syndrome. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have schizophrenia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no stroke. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no cerebral infarction. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no cerebral hemorrhage. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have cerebral arteriosclerosis. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no cerebral venous thrombosis. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no craniocerebral injury.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no akinesia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having athetosis. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no ataxia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no toseism (ballismus). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have hemitosia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no bradykinesia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have cerebral palsy.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no chorea. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have huntington' S disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have rheumatic chorea. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have cedam chorea. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no dyskinesia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have tardive dyskinesia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have dystonia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no blepharospasm.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have spasmodic torticollis. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have dopamine-responsive dystonia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no Restless Leg Syndrome (RLS). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no tremor. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have primary tremor. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no Tourette' S syndrome. Some patients treated for narcolepsy (e.g., sudden-fall and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have wilson' S disease.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have vascular dementia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having dementia with lewy bodies. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have mixed dementia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have frontotemporal dementia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have Creutzfeldt-Jakob disease (Creutzfeldt-Jakob disease). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no normotensive hydrocephalus. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no weiick-kolsakov syndrome.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have pick' S disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have progressive bulbar palsy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having Primary Lateral Sclerosis (PLS). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have progressive muscular dystrophy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have Post Polio Syndrome (PPS). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have Spinal Muscular Atrophy (SMA).

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have spinal motor atrophy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no pizza-Sach' S disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have sandhoff. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have hereditary spastic paraplegia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have alzheimer' S disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no prion-related disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have cerebellar ataxia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no spinocerebellar ataxia (SCA).

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have Spinal Muscular Atrophy (SMA). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no bulbar muscular atrophy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have friedrich' S ataxia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no lewy body disease. Some patients treated for narcolepsy (e.g., sudden-collapse and/or EDS-type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have amyotrophic lateral sclerosis (ALS or Lou Gehrig' S disease). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have Multiple Sclerosis (MS). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have multiple system atrophy.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no summer-dreder syndrome (she-Drager syndrome). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no corticobasal degeneration. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have progressive supranuclear palsy.

Some patients treated for narcolepsy (e.g., sudden-fall and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have wilson' S disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no menkes disease. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no adrenoleukodystrophy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS-type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having autosomal dominant hereditary cerebral artery disease (cadail) with subcortical infarction and leukoencephalopathy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have muscle wasting disorders.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have chak-mali-dus disease (CMT). Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have familial spastic paraplegia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no neurofibromatosis. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have pons cerebellar atrophy or degeneration. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having striatal substantia nigra degeneration. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have guillain-barre syndrome. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have spastic paraplegia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no seizures. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no non-epileptic seizures. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no epilepsy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have febrile convulsions. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have partial seizures. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no simple partial seizures. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have jackson seizures. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for having no complex partial seizures. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having partial status epilepticus. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having generalized seizures. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no generalized tonic clonic episodes. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no absence seizures.

Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no dystonic seizures. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no myoclonic seizures. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have juvenile myoclonic seizures. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no infant spasticity. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having status epilepticus. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have rit' S syndrome. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no tinnitus. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have disturbance of consciousness. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no sexual dysfunction. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have sound disorders due to uncontrolled laryngeal muscle spasm. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no abductive spastic dysphonation. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no adductive spasmodic dysphoric disorder. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no dystonia. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no sound tremor. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no diabetic neuropathy. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no chemotherapy-induced neurotoxicity. Some patients treated for narcolepsy (e.g., sudden-fall and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to not have methotrexate neurotoxicity. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no stress urinary incontinence. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected not to have urge incontinence. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected for not having fecal incontinence. Some patients treated for narcolepsy (e.g., cataplexy and/or EDS type narcolepsy) with antidepressants, including norepinephrine inhibitors such as reboxetine (including S, S-reboxetine), may not have and/or may be selected to have no erectile dysfunction.

Cataplexy includes a sudden reduction or loss of muscle tone while the patient is awake, which may affect specific parts of the body or the entire body, such as eyelids, drooping, facial ptosis and/or twitching, slurred speech, jaw weakness, arm, shoulder or hand weakness, and/or knee flexion. Cataplexy may be symptomatic for narcolepsy. Cataplexy may be triggered by a strong emotion (e.g. laughing, happy, surprised or angry). Cataplexy can be partial or local (about 75% in a case) and is usually of short duration. The frequency of the cataplexy can vary widely. Cataplexy narcolepsy can be socially disabling and socially isolated.

Some patients being treated with antidepressants, including noradrenaline inhibitors, such as reboxetine (including S, S-reboxetine), may have and/or may be selected to have cataplexy type narcolepsy (type 1), an autoimmune disorder that results in the loss of neurons that produce hypothalamic secretin (orexin) in the CNS. Hypothalamic secretin (orexin) is a hypothalamic specific peptide having a neuroexcitatory activity. Patients who are being treated for cataplexy narcolepsy with antidepressants, including noradrenaline inhibitors, such as reboxetine (including S, S-reboxetine), are, and can be selected as, susceptible individuals with specific genetic markers, including human leukocyte antigens (HLA DQB1-06:02) and/or T cell receptor alpha variants. Some patients being treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may not have, and may be selected to not have, narcolepsy associated with hypothalamic secretin neuron loss. Some patients being treated with antidepressants, including norepinephrine inhibitors, such as reboxetine (including S, S-reboxetine), may have, or may be selected to have, narcolepsy caused by seasonal streptococcal infection, H1N1 influenza and/or H1N1 vaccination in genetically susceptible individuals.

Existing narcolepsy treatments address only some of the symptoms of narcolepsy, provide variable efficacy, and have significant side effects. In addition, all existing therapeutics are controlled substances.

According to the FDA, "thermal is a continuous, used for additional functional and/or therapeutic options for patients to improve the daily function of patients (there is still a need to provide additional effective and tolerable treatment options for patients to improve their daily function). "(The Voice of The property, A series of ports from The U.S. food and Drug Administration's (FDA's) property-Focused Drug Development Initiative, Narcollensy, 6 months 2014, page 25)

In some embodiments, administration of an antidepressant, including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine), can reduce daytime sleepiness by at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 1-5%, about 5-10%, about 10-20%, or (SNRI), e.g., as compared to baseline, placebo, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, selective 5-hydroxytryptamine reuptake inhibitor (SSRI), or Selective Noradrenaline Reuptake Inhibitor (SNRI), About 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) may reduce cataplexy by at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 1-5%, about 5-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI), e.g., as compared to baseline, placebo, or some other suitable control, including an active control, e.g., a stimulant (e.g., a methylphenidate.g., methylphenidate., amphetamine, SSRI, or SNRI) About 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant, including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine), can reduce the number of partial cataplexy episodes by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, about 50-60%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI), for example, as compared to baseline, placebo, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, or SSRI, or SNRI, About 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1/week, at least about 2/week, at least about 3/week, at least about 4/week, at least about 5/week, at least about 6/week, at least about 7/week, at least about 8/week, at least about 9/week, at least about 10/week, at least about 12/week, at least about 13/week, at least about 14/week, at least about 15/week, at least about 16/week, at least about 18/week, at least about 20/week, at least about 22/week, at least about 24/week, at least about 26/week, At least about 28 times/week, at least about 30 times/week, at least about 40 times/week, at least about 50 times/week, about 1-2 times/week, about 2-3 times/week, about 3-4 times/week, about 4-5 times/week, about 5-6 times/week, about 6-7 times/week, about 7-8 times/week, about 8-9 times/week, about 9-10 times/week, about 10-11 times/week, about 11-12 times/week, about 12-13 times/week, about 13-14 times/week, about 14-15 times/week, about 15-16 times/week, about 16-17 times/week, about 17-18 times/week, about 18-19 times/week, about 19-20 times/week, about, About 1-10 times per week, about 10-20 times per week, about 20-30 times per week, about 30-40 times per week, about 40-50 times per week, about 50-60 times per week or more. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant (p ≦ 0.05) compared to administration of placebo. This improvement may be rapid. For example, the average reduction in cataplexy episodes at the time of treatment of a human with reboxetine, or over a week of treatment, can be at least about 10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, or about 50-60%.

In some embodiments, administration of an antidepressant, including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine), can reduce the number of complete cataplexy attacks by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, about 50-60%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI), for example, as compared to baseline, placebo, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, or SSRI, or SNRI, About 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1/week, at least about 2/week, at least about 3/week, at least about 4/week, at least about 5/week, at least about 6/week, at least about 7/week, at least about 8/week, at least about 9/week, at least about 10/week, at least about 12/week, at least about 13/week, at least about 14/week, at least about 15/week, at least about 16/week, at least about 18/week, at least about 20/week, at least about 22/week, at least about 24/week, at least about 26/week, At least about 28 times/week, at least about 30 times/week, at least about 40 times/week, at least about 50 times/week, about 1-2 times/week, about 2-3 times/week, about 3-4 times/week, about 4-5 times/week, about 5-6 times/week, about 6-7 times/week, about 7-8 times/week, about 8-9 times/week, about 9-10 times/week, about 10-11 times/week, about 11-12 times/week, about 12-13 times/week, about 13-14 times/week, about 14-15 times/week, about 15-16 times/week, about 16-17 times/week, about 17-18 times/week, about 18-19 times/week, about 19-20 times/week, about, About 1-10 times/week, about 10-20 times/week, about 20-30 times/week, about 30-40 times/week, about 40-50 times/week, about 50-60 times/week or more. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant (p ≦ 0.05) compared to administration of placebo. This improvement may be rapid. For example, the mean reduction in the onset of cataplexy may be at least about 10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, or about 50-60% at the time of treatment of a human with reboxetine or over one week of treatment.

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) can reduce the total number of cataplexy episodes (partially + completely) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, or some other suitable control (including active controls, e.g., stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI, or SNRI), e.g., by at least about 10%, at least about 20%, at least about 30-40%, at least about 40-50%, at least about 1-10%, about 10-20%, about 30-30%, about 40-50%, or about 45-50%, e.g., as compared to baseline, placebo, or some other suitable control About 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, about 75-100%, about 40-60%, at least about 1/week, at least about 2/week, at least about 3/week, at least about 4/week, at least about 5/week, at least about 6/week, at least about 7/week, at least about 8/week, at least about 9/week, at least about 10/week, at least about 12/week, at least about 13/week, at least about 14/week, at least about 15/week, at least about 16/week, at least about 18/week, at least about 20/week, at least about 22/week, At least about 24 times/week, at least about 26 times/week, at least about 28 times/week, at least about 30 times/week, at least about 40 times/week, at least about 50 times/week, at least about 60 times/week, at least about 70 times/week, at least about 80 times/week, at least about 90 times/week, at least about 100 times/week, at least about 110 times/week, at least about 120 times/week, at least about 130 times/week, at least about 140 times/week, about 10-20 times/week, about 12-18 times/week, about 14-16 times/week, about 1-2 times/week, about 2-3 times/week, about 3-4 times/week, about 4-5 times/week, about 5-6 times/week, about 6-7 times/week, about, About 7-8 times/week, about 8-9 times/week, about 9-10 times/week, about 10-11 times/week, about 11-12 times/week, about 12-13 times/week, about 13-14 times/week, about 14-15 times/week, about 15-16 times/week, about 16-17 times/week, about 17-18 times/week, about 18-19 times/week, about 19-20 times/week, about 1-10 times/week, about 10-20 times/week, about 20-30 times/week, about 30-40 times/week, about 40-50 times/week, about 50-60 times/week, about 60-70 times/week, about 70-80 times/week, about 80-90 times/week, about, About 90-100 times/week, about 100-120 times/week, about 120-140 times/week, or more. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant (p ≦ 0.05) compared to administration of placebo. This improvement may be rapid. For example, the mean reduction in the onset of cataplexy may be at least about 10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, or about 50-60% at the time of treatment of a human with reboxetine or over one week of treatment.

In some embodiments, administration of an antidepressant drug (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) can result in a proportion of patients achieving a 50% or greater reduction in the number of cataplexy episodes per week, e.g., as compared to baseline, placebo, or some other suitable control (including active controls, e.g., stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI or SNRI), of about 40-50%, about 50-60%, 55-60%, about 60-70%, about 60-95%, about 70-80%, about 70-75%, about 75-80%, or about 74-78%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant (p ≦ 0.05) compared to administration of placebo.

In some embodiments, administration of an antidepressant drug (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) can result in a proportion of patients who achieve a 75% or greater reduction in the number of cataplexy episodes per week, e.g., as compared to baseline, placebo, or some other suitable control (including active controls, e.g., stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI or SNRI), of about 15-20%, about 20-30%, about 20-25%, about 25-30%, about 30-40%, about 40-50%, about 40-45%, about 45-50%, about 50-60%, about 60-70%, about 60-95%, or about 70-80%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant (p ≦ 0.05) compared to administration of placebo.

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) may result in a decrease in Epworth Somnolence Scale (ESS) score of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI), e.g., as compared to baseline, placebo, or some other suitable control, including an active control, e.g., sodium oxybate, a tricyclic antidepressant, or SSRI, About 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, about 24, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11, about 11-12, about 12-13, about 9-5, about 6-7, about 8-9, about 10-11, about 11-12, about 1-13, About 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20, about 20-21, about 21-22, about 22-23, about 23-24, about 1-4, about 4-8, about 8-12, about 12-16, about 16-20, about 20-24, about 1-12, or about 12-24. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment compared to administration of placebo can be statistically significant, where the p-value is ≦ 0.05, 0.01-0.05, <0.01, 0.005-0.01, 0.001-0.005, or about 0.003.

In some embodiments, administration of an antidepressant, including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine), can reduce the number of accidental dozes per week by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI, for example, as compared to baseline, placebo, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate.g., methylphenidate, amphetamine, SSRI, or SNRI) About 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, about 75-100%, about 20-40%, about 30-35%, or about 30-33%, at least about 1 doze/week, at least about 2 dozes/week, at least about 3 dozes/week, at least about 4 dozes/week, at least about 5 dozes/week, about 1-3 dozes/week, about 2-4 dozes/week, about 3-5 dozes/week, about 4-6 dozes/week, about 5-6 dozes/week. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment compared to administration of placebo can be statistically significant, where the p-value is ≦ 0.05, 0.03-0.05, 0.01-0.05, <0.01, 0.005-0.01, 0.001-0.005, about 0.003, or < 0.001. The patient may be selected for treatment based on a problem with unexpected dozing, such as that associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant drug (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) can result in a proportion of patients who achieve a 50% or greater reduction in the number of unexpected naps per week, e.g., as compared to baseline, placebo, or some other suitable control (including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI, or SNRI), of about 15-20%, about 20-30%, about 30-40%, about 30-35%, about 35-40%, about 40-50%, about 50-60%, about 60-70%, or about 70-80%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment can be statistically significant (p ≦ 0.05) compared to administration of placebo.

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) may result in a decrease in the wakefulness test (MWT) score of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI), e.g., as compared to baseline, placebo, or some other suitable control About 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about, About 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about 20-21 minutes, about 21-22 minutes, about 22-23 minutes, about 23-24 minutes, about 24-26 minutes, about 1-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16 minutes, about 16-20 minutes, about 1-10 minutes, or about 10-20 minutes. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant drug comprising a norepinephrine inhibitor, e.g., reboxetine (including S, S-reboxetine), may improve cognitive function, e.g., over a 1-week period or a 2-week period, as measured by the attention focusing capacity program of NSAQ. For example, an improvement in the attention-focusing score for a 5-point system (1-very good, 2-good, 3-mean, 4-poor, and 5-very poor) may be at least about-0.1, at least about-0.2, at least about-0.3, about-0.05 to about-0.5, about-0.05 to about-0.2, as compared to baseline, placebo, or some other suitable control, including an active control, such as a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI, about-0.2 to about-0.3, about 0.3 to about-0.4, about-0.4 to about-0.5, about-0.5 to-0.6, about-0.6 to about-0.7, or about-0.7 to about-0.8, wherein "-" indicates a decrease in the attention-focusing ability score. In some embodiments, the number of patients with "very good" or "good" attention-focusing abilities may be, for example, at least about 20%, at least 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 20-30%, about 30-40%, about 30-35%, about 35-40%, about 40-50%, about 40-45%, about 45-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, or some other suitable control (including active controls such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI, or SNRI) as compared to baseline, placebo, or some other suitable control (including active controls), such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI, or SNRI) About 90-100%, about 1-25%, about 15-25%, about 25-50%, about 50-75%, or about 75-100%, about 40-60%, about 35-40%, or about 40-45%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Such improvement in reboxetine treatment may be statistically significant (p ≦ 0.05) compared to administration of placebo, for example p ≦ 0.01-0.05, <0.01, 0.001-0.005, 0.005-0.01, 0.002, or 0.007. Patients may be selected for treatment based on having reduced cognitive function, such as that associated with narcolepsy (with or without cataplexy).

In some embodiments, the human has "average", "poor", or "very poor" attention-focusing capacity before treatment begins, and the human has "good" or "very good" attention-focusing capacity one week after treatment begins.

In some embodiments, the human has "average" attention focusing abilities before treatment begins, and the human has "good" attention focusing abilities one week after treatment begins.

In some embodiments, the human has "average" attention-focusing ability before treatment begins, and the human has "very good" attention-focusing ability one week after treatment begins.

In some embodiments, the human has "poor" attention focusing ability prior to initiation of treatment and the human has "good" attention focusing ability one week after initiation of treatment.

In some embodiments, the human has "poor" attention-focusing ability before treatment begins, and the human has "very good" attention-focusing ability one week after treatment begins.

In some embodiments, the person has "very poor" attention-focusing ability before treatment begins, and the person has "good" attention-focusing ability one week after treatment begins.

In some embodiments, the human has "very poor" attention-focusing ability before treatment begins, and the human has "very good" attention-focusing ability one week after treatment begins.

In some embodiments, the human has "average", "poor", or "very poor" attention-focusing abilities before treatment initiation, and the human has "good" or "very good" attention-focusing abilities two weeks after treatment initiation.

In some embodiments, the human has "average" attention-focusing abilities before treatment begins, and the human has "good" attention-focusing abilities two weeks after treatment begins.

In some embodiments, the human has "average" attention-focusing ability before treatment begins, and the human has "very good" attention-focusing ability two weeks after treatment begins.

In some embodiments, the human has "poor" attention focusing ability before treatment begins and the human has "good" attention focusing ability two weeks after treatment begins.

In some embodiments, the human has "poor" attention-focusing ability before treatment begins, and the human has "very good" attention-focusing ability two weeks after treatment begins.

In some embodiments, the human has "very poor" attention-focusing ability before treatment begins, and the human has "good" attention-focusing ability two weeks after treatment begins.

In some embodiments, the human has "very poor" attention-focusing ability before treatment begins, and the human has "very good" attention-focusing ability two weeks after treatment begins.

In some embodiments, administration of an antidepressant (including a norepinephrine inhibitor, such as reboxetine (including S, S-reboxetine)) may improve sleep quality. For example, the patient may report improved sleep quality. In some embodiments, the number of patients reporting improved quality of sleep can be, e.g., at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 40-60%, as compared to baseline, placebo, or some other suitable control, including active controls, e.g., stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI, or SNRI, About 42-47%. In some embodiments, a patient may have an improvement in sleep quality of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 40-45%, about 45-40%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, or some other suitable control (including active controls such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI, or SNRI), for example, as compared to baseline, placebo, or some other suitable control (including active controls) About 50-75%, or about 75-100%, about 40-60%, about 42-47%, or about 45%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Such improvement in reboxetine treatment can be statistically significant (p ≦ 0.05) compared to administration of a placebo, e.g., p ≦ 0.01-0.05, <0.01, 0.001-0.005, 0.005-0.01, or 0.007. Patients may be selected for treatment based on having sleep quality issues, such as sleep quality issues associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant, including a norepinephrine inhibitor, e.g., reboxetine (including S, S-reboxetine), can reduce the number of nighttime awakenings, e.g., as reported by the patient. For example, the number of patients reporting a reduction in the number of nighttime awakenings can be at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 40-60%, or some other suitable control (including active controls such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI or SNRI), for example, as compared to baseline, placebo, or some other suitable control (including active controls), such as stimulants (e.g., methylphenidate.g., amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI, or SNRI) About 42-47%. In some embodiments, the reduction in the number of nocturnal awakenings that the subject has can be, for example, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, as compared to baseline, placebo, or some other suitable control (including active controls, such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI, or SNRI), About 40-60%, about 42-47%, or about 30%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). This improvement in reboxetine treatment may be statistically significant (p ≦ 0.05) compared to administration of placebo, e.g., p ≦ 0.01-0.05, 0.04-0.05, or 0.044. The patient may be selected for treatment based on having a problem with nocturnal arousals, such as that associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant (including a norepinephrine inhibitor, such as reboxetine (including S, S-reboxetine)) may reduce the number of sleep paralysis episodes, e.g., as reported by the patient. For example, the number of patients with a reduction in the number of sleep paralysis episodes may be at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 50-70%, as compared to, for example, baseline, placebo, or some other suitable control (including active controls, such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI, or SNRI) About 52-57%. In some embodiments, the patient has a reduction in the number of sleep paralysis episodes that can be at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, as compared to, for example, baseline, placebo, or some other suitable control (including active controls, such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI, or SNRI) About 50-70%, about 52-57%, or about 55%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on having sleep paralysis problems, such as those associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant (including a norepinephrine inhibitor, e.g., reboxetine (including S, S-reboxetine)) may reduce the number of pre-sleep hallucinations, e.g., as reported by the patient. For example, the number of patients with a reduction in the number of pre-drowning hallucinations can be at least about 10%, at least about 20%, at least about 30%, at least about 40%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 30-50%, about 35-45%, for example, as compared to baseline, placebo, or some other suitable control, including active controls, such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, SSRI, or SNRI. In some embodiments, the patient has a reduction in the number of pre-drowsiness hallucinations that can be, for example, at least about 10%, at least about 20%, at least about 30%, at least about 40%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 30-50%, about 35-45%, or about 40% compared to baseline, placebo, or some other suitable control (including active controls, such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, about 50-60%, about 60-70%, about 70-80%, about 80-90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, about 30-50%, about 35-45%, or about 40%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on problems with pre-sleep hallucinations, such as those associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant drug (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) may result in a reduction in cataplexy score on the UNS of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 45-50%, about 50-60%, or some other suitable control (including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressant, SSRI, or SNRI), for example, as compared to baseline, placebo, or some other suitable control (including an active control), e.g., a stimulant (e.g., methylphenidate, amphetamine, modafinil, or SSRI) About 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, about 11, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 2-4, about 4-6, about 6-8, about 8-10, about 10-11, about 2-6, or about 6-10, about 5-11. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant drug (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) may result in an increase in sleep latency on MSLT of at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 50-60%, greater than 55%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 50-75%, or about 75-100%, at least about 1 minute, at least about 2 minutes, at least about 50-60%, or some other suitable control (including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI), for example, as compared to baseline, placebo, or some other suitable control At least about 3 minutes, greater than 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes, about, About 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about 1-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16 minutes, about 16-20 minutes, about 1-10 minutes, or about 10-20 minutes. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) can reduce the patient' S overall severity impression (PGI-S) score by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, e, e.g., reboxetine (including S), a placebo, or some other suitable control About 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, about 75-100%, at least about 0.1, at least about 0.5, at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, at least about 3.5, about 0.1-0.5, about 0.5-1, about 1-1.5, about 1.5-2, about 2-2.5, about 2.5-3, about 3-3.5, or about 3.5-4. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) can result in a patient having a global altered impression (PGI-C) score of about 1-2, about 2-3, or about 3-4, or reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, or an SSRI, e.g., as compared to baseline, placebo, or some other suitable control (including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI) About 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, about 75-100%, at least about 0.5, at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, about 0.5-1, about 1-2, about 2-3, about 3-4, about 4-5, or about 5-6. Such improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) may result in a reduction in the hamilton depression rating scale (HAM-D) score of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, or some other suitable control (including active controls, e.g., stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI, or SNRI), e.g., as compared to baseline, placebo, or some other suitable control (including an active control), e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressants, SSRI, or SNRI) About 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 30, at least about 40, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11, about 3-3, about 3-4, about 4-5-6, about 6-7, about 7-8, about 8-9-10, about 9-10, About 11-12, about 12-13, about 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20, about 20-21, about 21-22, about 22-23, about 23-27, about 27-30, about 30-35, about 35-40, about 40-45, about 45-50, about 1-4, about 4-8, about 8-12, about 12-16, about 16-20, about 20-24, about 24-30, about 30-40, about 40-50, about 1-12, about 12-24, about 24-36, or about 36-50. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) can reduce nightmare or unpleasant dreams (e.g., frequent nightmares or frequent unpleasant dreams) by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, or some other suitable control (including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI), for example, as compared to baseline, placebo, or some other suitable control About 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on problems with nightmares or unpleasant dreams (e.g., frequent nightmares or frequent unpleasant dreams), including nightmares or unpleasant dreams associated with narcolepsy (with or without cataplexy), such as frequent nightmares or frequent unpleasant dreams.

In some embodiments, administration of an antidepressant, including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine), can reduce hallucinations by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI), e.g., as compared to baseline, placebo, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, e.g., methylphenidate., amphetamine), SSRI, or SNRI) About 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). The patient may be selected for treatment based on having hallucinations, such as those associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) can reduce sleep paralysis, e.g., by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, or some other suitable control (including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI), as compared to baseline, placebo, or some other suitable control (including an active control), e.g., a stimulant (e.g., methylphenidate.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI) About 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on having a problem with sleep paralysis, such as sleep paralysis associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant, including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine), can reduce nocturnal sleep disorder by, e.g., at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI), as compared to baseline, placebo, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, or SSRI, or SNRI, About 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on having a problem with nocturnal sleep disorders, such as nocturnal sleep disorders associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) may reduce narcolepsy-related accidents by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI, e.g., as compared to baseline, placebo, or some other suitable control About 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on the problem with an accident associated with narcolepsy (with or without cataplexy).

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) can reduce narcolepsy-related damage by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, or some other suitable control, including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI, for example, as compared to baseline, placebo, or some other suitable control About 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.).

In some embodiments, administration of an antidepressant (including a noradrenaline inhibitor, e.g., reboxetine (including S, S-reboxetine)) can reduce, e.g., by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, or some other suitable control (including an active control, e.g., a stimulant (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium hydroxybutyrate, tricyclic antidepressant, SSRI, or SNRI) as compared to baseline, placebo, or some other suitable control, About 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%. Such an improvement in reboxetine treatment can be observed, for example, at 1 week, 2 weeks, whole body, or any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.). Patients may be selected for treatment based on being at risk of narcolepsy-related death events (for narcolepsy patients with or without cataplexy).

Reboxetine (having the structure shown below), including S, S-reboxetine, e.g., having the structure shown below, is a highly selective and potent norepinephrine reuptake inhibitor with the potential to address key symptoms of narcolepsy, such as cataplexy or EDS. Unlike existing narcolepsy treatments, reboxetine is not the controlled substance. Thus, treatment with reboxetine will be unregulated (scheduled).

(reboxetine)

(S, S-reboxetine)

Any reference to a compound herein (e.g. reboxetine) by structure, name, or any other means, unless otherwise specified, includes pharmaceutically acceptable salts; a free acid or base; alternate solid forms, such as polymorphs, solvates, hydrates, and the like; a tautomer; an enantiomer; deuterium modified compounds, such as deuterium modified reboxetine; or any chemical species that can be rapidly converted to a compound described herein under the conditions in which the compound is used as described herein.

In some embodiments, reboxetine is in the salt form, free base form, or can contain an excess (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) of (+) -reboxetine (also known as S, S-reboxetine or oxaprozin); or an excess (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) of (-) -reboxetine.

For treatment of narcolepsy, reboxetine (including S, S-reboxetine) can be administered in a manner that results in 1) a first local maximum in plasma concentration of reboxetine (including S, S-reboxetine) and 2) a second local maximum in plasma concentration of reboxetine (including S, S-reboxetine).

There are many potential routes for administering reboxetine (including S, S-reboxetine) in a manner that results in a first local maximum in reboxetine (including S, S-reboxetine) plasma concentration and a second local maximum in reboxetine (including S, S-reboxetine) plasma concentration. The local maximum described herein is the maximum in plasma concentration in an individual patient over a time period of interest, which is not necessarily C_{Maximum of}. The local maximum may be lower than or equal to C_{Maximum of}. A potential route for administering reboxetine (including S, S-reboxetine) in a manner that results in a first local maximum in plasma concentration of reboxetine (including S, S-reboxetine) and a second local maximum in plasma concentration of reboxetine (including S, S-reboxetine) is to administer a first dosage form containing reboxetine (including reboxetine) and to administer a second dosage form containing reboxetine (including S, S-reboxetine) at a later time. The dose is administered at a time that results in a first local maximum in a reboxetine (including S, S-reboxetine) plasma concentration and a second local maximum in a reboxetine (including S, S-reboxetine) plasma concentration. For example, it may be less than half a day after the first dosage form, e.g., about 1-8 hours, about 8-12 hours, about 2-6 hours, about 1-2 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours after the first dosage form, orThe second dosage form is administered at any time period within the range defined by any of these values.

Another method involves administering a single dosage form comprising a first release component and a second release component. Both the first release component and the second release component comprise reboxetine (including S, S-reboxetine).

In some embodiments, the first dosage form administered during a day (either the only dosage form administered during that day, or the first of two or more dosage forms administered during that day) is administered shortly after waking, e.g., within about 3 hours, within about 2 hours, within about 1.5 hours, within about 1 hour, within about 30 minutes, or within about 15 minutes of waking from overnight sleep.

For a single dosage form comprising a first release component and a second release component administered during a day, the first release component can release reboxetine (including S, S-reboxetine), can begin releasing reboxetine (including S, S-reboxetine), or can result in a first local maximum in reboxetine (including S, S-reboxetine) plasma concentration from about 0-30 minutes, from about 30-60 minutes, from about 60-90 minutes, or from about 90-120 minutes, or any time period within a range bounded by any of these values, after oral administration of the dosage form. The second release component can release reboxetine (including S, S-reboxetine) after the first release component releases reboxetine (including S, S-reboxetine); or may result in an increase in the plasma concentration of reboxetine (including S, S-reboxetine) or an increase in the plasma concentration of reboxetine (including S, S-reboxetine) at about 1-10 hours, about 2-6 hours, about 1-2 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours after the first release of reboxetine (including S, S-reboxetine) from the first release component, or at any time within the limits of any of these values, s-reboxetine) plasma concentration.

The first release component and the second release component may be incorporated into a single dosage form (e.g., a pill, tablet, capsule, caplet, or chewing gum). In one embodiment, the first release component will be located in one of the outer layers of the dosage form and the second release component will be located in one of the inner layers of the same dosage form.

In another embodiment, the first release component is located in a first layer of the dosage form and the second release component is located in a second layer of the same dosage form. The two layers are different and may or may not be in contact with each other. In some embodiments, the two layers are stacked on top of each other and physically bonded in a bilayer structure (e.g., the largest surfaces of the two layers are in contact with each other, or the layers are thinner than the other dimensions of the layers). In some embodiments, the two layers are placed adjacent to each other and physically bonded in a bilayer structure (e.g., where the layers are thicker than the other dimensions of the layers).

In another embodiment, the first release component and the second release component may be separately constructed in the form of their own specific particles, etc., wherein the first release component particles are formulated to release reboxetine (including S, S-reboxetine) before the second release component particles release reboxetine (including S, S-reboxetine), and wherein both the first release component particles and the second release component particles are combined together into a single dosage form, e.g., a capsule, pill, tablet, caplet, chewing gum, etc., and the two release components may or may not be physically bound to each other.

In some embodiments, the first local maximum plasma concentration of reboxetine (including S, S-reboxetine) occurs about 1-30 minutes, about 30-60 minutes, about 1-2 hours, about 2-3 hours, or about 3-4 hours after administration of a single dosage form or first dosage form, or any time within a range defined by any of these values. Typically, the second local maximum plasma concentration of reboxetine (including S, S-reboxetine) occurs less than half a day after the first local maximum plasma concentration of reboxetine (including S, S-reboxetine), e.g., about 1-10 hours, about 1-2 hours, about 2-6 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours, or any period of time within a range defined by any of these values.

For a dosage form comprising a first release component and a second release component, the first release component is associated with a first local maximum in plasma concentration of reboxetine (including S, S-reboxetine) because the reboxetine (including S, S-reboxetine) released by the first release component contributes to the first local maximum in plasma concentration of reboxetine (including S, S-reboxetine). For example, the first release component can release reboxetine (including S, S-reboxetine) faster or more rapidly than the second release component such that a majority of the reboxetine (including S, S-reboxetine) that contributed to the first local maximum plasma concentration of reboxetine (including S, S-reboxetine) is released from the first release component.

For a dosage form having a first release component and a second release component, the second release component is associated with a second local maximum in plasma concentration of reboxetine (including S, S-reboxetine) because the reboxetine (including S, S-reboxetine) released by the second release component contributes to the second local maximum in plasma concentration of reboxetine (including S, S-reboxetine). For example, the second release component can delay the release of its reboxetine (including S, S-reboxetine) such that when the reboxetine (including S, S-reboxetine) plasma concentration is decreasing after the first local maximum, the second release component releases a sufficient amount of reboxetine (including S, S-reboxetine) to again increase the reboxetine (including S, S-reboxetine) plasma concentration in order to reach the second local maximum of reboxetine (including S, S-reboxetine) plasma concentration.

For dosage forms containing a first delivery component and a second delivery component, reboxetine (including S, S-reboxetine) can be present in the first delivery component in any suitable amount, for example, about 1-10mg, about 0.1-2mg, about 0.5-1.5mg, about 1-2mg, about 1.5-2.5mg, about 2-3mg, about 2.5-3.5mg, about 3-4mg, about 3.5-4.5mg, about 4-5mg, about 4.5-5.5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 1-3mg, about 2-4mg, about 3-5mg, about 4-6mg, about 5-7mg, about 7-10mg, about 4mg, about 5mg, about 0.0003-0.006mmol, about 0.009mmol, About 0.009-0.012mmol, about 0.012-0.015mmol, about 0.015-0.018mmol, about 0.018-0.021mmol, about 0.021-0.024mmol, about 0.024-0.027mmol, about 0.027-0.03mmol, about 0.03-0.033mmol, or any amount within a range bounded by any of these values.

For dosage forms containing a first delivery component and a second delivery component, reboxetine (including S, S-reboxetine) can be present in the second delivery component in any suitable amount, for example, about 0.1-2mg, about 0.5-1.5mg, about 1-3mg, about 1-2mg, about 1.5-2.5mg, about 2-3mg, about 2.5-3.5mg, about 3-4mg, about 2-4mg, about 3-5mg, about 3.5-4.5mg, about 4-5mg, about 4.5-5.5mg, about 5-6mg, about 4-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 5-7mg, about 7-10mg, about 4mg, about 5mg, about 0.0003-0.006mmol, about 0.009mmol, about 0.012-0.012 mmol, About 0.012-0.015mmol, about 0.015-0.018mmol, about 0.018-0.021mmol, about 0.021-0.024mmol, about 0.024-0.027mmol, about 0.027-0.03mmol, about 0.03-0.033mmol, or any amount within a range defined by any of these values.

In some embodiments, the first release component can contain more reboxetine (including S, S-reboxetine) than the second release component, for example about 10-20% more, about 20-30% more, or about 30-40% more reboxetine (including S, S-reboxetine) than the second release component.

While the dosing regimen given above may be useful in many situations, the daily dosing regimen may be different from the dosing regimen described above. For example, a once daily dose may be administered. The twice daily dose may be administered by any suitable route, for example in the morning and evening, in the manner described above, or by some other route.

In some embodiments, the daily dose of reboxetine (including S, S-reboxetine) can be about 0.5-1mg, about 1-1.5mg, about 1.5-2mg, about 1-2mg, about 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 10-11mg, about 11-12mg, about 12-13mg, about 13-14mg, about 14-15mg, about 15-16mg, about 16-17mg, about 2-5mg, about 5-8mg, about 8-11mg, about 11-14mg, about 14-17mg, about 17-20mg, about 8-10mg, about 8-12mg, about 0.0015-0.003mmol, About 0.003-0.0045mmol, about 0.0045-0.006mmol, about 0.003-0.006mmol, about 0.006-0.009mmol, about 0.009-0.012mmol, about 0.012-0.015mmol, about 0.015-0.018mmol, about 0.018-0.021mmol, about 0.021-0.024mmol, about 0.024-0.027mmol, about 0.027-0.03mmol, about 0.03-0.033mmol, about 0.033-0.036mmol, about 0.036-0.039mmol, about 0.039-0.042mmol, about 0.042-0.045mmol, about 0.045-0.048mmol, about 0.048-0.051mmol, about 0.051-0.054mmol, about 0.054-0.057mmol, about 0.057-0.06mmol, about 0.06-0.063mmol, about 0.063-0.066mmol, about 0.066-0.069mmol, about 0.006-0.01mmol, about 0.01-0.02mmol, about 0.02-0.03mmol, about 0.03-0.04mmol, about 0.04-0.05mmol, about 0.05-0.06mmol, about 0.06-0.07mmol, or about 0.07-0.08 mmol. The daily dose refers to the total amount of reboxetine administered in a single day. The daily dose can be administered for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least 4 months, at least 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least 1.5 years, at least 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 20 years, or more. In some embodiments, the daily dose is administered for up to about 6 months, up to about 1 year, up to about 2 years, up to about 5 years, up to about 10 years, up to about 20 years, up to about 40 years, up to about 60 years, or up to about 90 years.

The dose of reboxetine (including S, S-reboxetine) can be gradually increased over time (e.g., for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days) to a maintenance dose that is a total dose administered daily (e.g., a 10mg maintenance dose can be a 10mg dose administered once a day, a 6mg dose in the morning and a 4mg dose in the afternoon, or a 5mg dose administered twice a day to achieve a total of 10mg per day). In some embodiments, the maintenance dose may be 2-3mg, about 3-4mg, about 4-5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 10-11mg, about 11-12mg, about 12-13mg, about 13-14mg, about 14-15mg, about 15-16mg, about 16-17mg, about 2-5mg, about 5-8mg, about 8-11mg, about 11-14mg, about 14-17mg, about 17-20mg, about 8-10mg, about 8-12mg, about 0.006-0.009mmol, about 0.009-0.012mmol, about 0.012-0.015mmol, about 0.015-0.018mmol, about 0.018-0.021mmol, about 0.021-0.024mmol, about 0.024-0.027-0.03 mmol, about 0.027-0.03-0.027 mmol, About 0.03-0.033mmol, about 0.033-0.036mmol, about 0.036-0.039mmol, about 0.039-0.042mmol, about 0.042-0.045mmol, about 0.045-0.048mmol, about 0.048-0.051mmol, about 0.051-0.054mmol, about 0.054-0.057mmol, about 0.057-0.06mmol, about 0.06-0.063mmol, about 0.063-0.066mmol, about 0.066-0.069mmol, about 0.006-0.01mmol, about 0.01-0.02mmol, about 0.02-0.03mmol, about 0.03-0.04mmol, about 0.04-0.05mmol, about 0.05-0.06mmol, about 0.06-0.08 mmol, or about 0.07 mmol. In some embodiments, the first dose (e.g., the first dose administered in the morning) may contain more reboxetine (including S, S-reboxetine) than the second dose administered in the day (e.g., the second dose administered in the afternoon). For example, a first dose of the day (e.g., a first dose administered in the morning) may have about 10-20% more, about 20-30% more, or about 30-40% more reboxetine (including S, S-reboxetine) than a second dose of the day (e.g., a second dose administered in the afternoon). The maintenance dose can be administered for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least 4 months, at least 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least 1.5 years, at least 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 20 years, or more. In some embodiments, the maintenance dose is administered for up to about 6 months, up to about 1 year, up to about 2 years, up to about 5 years, up to about 10 years, up to about 20 years, up to about 40 years, up to about 60 years, or up to about 90 years.

In some embodiments, the patient receives about 110-130mg reboxetine (including S, S-reboxetine) over a two week period.

In some embodiments, the first release component provides for immediate release of reboxetine (including S, S-reboxetine). In some embodiments, the first release component provides a delayed release of reboxetine (including S, S-reboxetine). In some embodiments, the first release component provides sustained release of reboxetine (including S, S-reboxetine).

In some embodiments, the second release component provides for immediate release of reboxetine (including S, S-reboxetine). In some embodiments, the second release component provides a delayed release of reboxetine (including S, S-reboxetine). In some embodiments, the second release component provides sustained release of reboxetine (including S, S-reboxetine).

In some embodiments, the first release component provides an immediate release of reboxetine (including S, S-reboxetine) and the second release component provides a delayed release of reboxetine (including S, S-reboxetine). In some embodiments, the first release component provides an immediate release of reboxetine (including S, S-reboxetine) and the second release component provides a sustained release of reboxetine (including S, S-reboxetine).

With respect to the method wherein reboxetine (including S, S-reboxetine) is administered in a first dosage form comprising reboxetine (including S, S-reboxetine) and a second dosage form comprising reboxetine (including S, S-reboxetine), any suitable amount of reboxetine (including S, S-reboxetine) can be present in the first dosage form, for example, about 1-10mg, about 0.1-1mg, about 0.1-2mg, about 0.5-1.5mg, about 1-3mg, about 1-2mg, about 1.5-2.5mg, about 2-3mg, about 2.5-3.5mg, about 3-4mg, about 3.5-4.5mg, about 4-5mg, about 4.5-5.5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, About 2-4mg, about 3-5mg, about 4-6mg, about 5-7mg, about 7-10mg, about 4mg, about 5mg, about 0.0003-0.006mmol, about 0.006-0.009mmol, about 0.009-0.012mmol, about 0.012-0.015mmol, about 0.015-0.018mmol, about 0.018-0.021mmol, about 0.021-0.024mmol, about 0.024-0.027mmol, about 0.027-0.03mmol, about 0.03-0.033mmol, or any amount within a range defined by any of these values.

With respect to the method in which reboxetine (including S, S-reboxetine) is administered in a first dosage form comprising reboxetine (including S, S-reboxetine) and a second dosage form comprising reboxetine (including S, S-reboxetine), any suitable amount of reboxetine (including S, S-reboxetine) may be present in the second dosage form, for example, about 0.1-1mg, about 0.1-2mg, about 0.5-1.5mg, about 1-3mg, about 1-2mg, about 1.5-2.5mg, about 2-3mg, about 2.5-3.5mg, about 3-4mg, about 3.5-4.5mg, about 4-5mg, about 4.5-5.5mg, about 5-6mg, about 6-7mg, about 7-8mg, about 8-9mg, about 9-10mg, about 2-4mg, about 4.5-5 mg, about 1.5-2.5mg, about 1-2.5 mg, about 2-2.5 mg, about 2-3mg, about 3.5mg, about 3-4mg, about, About 3-5mg, about 4-6mg, about 5-7mg, about 7-10mg, about 4mg, about 5mg, about 0.0003-0.006mmol, about 0.006-0.009mmol, about 0.009-0.012mmol, about 0.012-0.015mmol, about 0.015-0.018mmol, about 0.018-0.021mmol, about 0.021-0.024mmol, about 0.024-0.027mmol, about 0.027-0.03mmol, about 0.03-0.033mmol, or any amount within a range defined by any of these values.

In some embodiments, the first dosage form can contain more reboxetine (including S, S-reboxetine) than the second dosage form, e.g., about 10-20% more, about 20-30% more, or about 30-40% more reboxetine (including S, S-reboxetine) than the second dosage form.

In some embodiments, the first dosage form provides immediate release of reboxetine (including S, S-reboxetine). In some embodiments, the first dosage form provides a delayed release of reboxetine (including S, S-reboxetine). In some embodiments, the first dosage form provides sustained release of reboxetine (including S, S-reboxetine).

In some embodiments, the second dosage form provides immediate release of reboxetine (including S, S-reboxetine). In some embodiments, the second dosage form provides delayed release of reboxetine (including S, S-reboxetine). In some embodiments, the second dosage form provides sustained release of reboxetine (including S, S-reboxetine).

For a single dosage form containing both the first release component and the second release component, in some embodiments, a single dose is administered within two hours of waking from overnight sleep.

For some embodiments in which more than one dosage form is administered, the first dosage form may be administered within two hours of waking from overnight sleep.

There are many factors that can affect the total time required for a drug, such as reboxetine (including S, S-reboxetine), to be completely absorbed in a human and/or reach a maximum plasma concentration. Some of these factors include the age, weight, sex, stress level, gastric contents, gastric pH level, and the presence of other drugs in the human patient. The time required to reach the maximum plasma concentration of a drug, such as reboxetine (including S, S-reboxetine), may also be affected by the time of day that the drug, such as reboxetine (including S, S-reboxetine), is taken and the level of physical activity of the human patient. Another factor that can affect the time required to reach the maximum plasma concentration of a drug, such as reboxetine (including S, S-reboxetine), is the presence or absence of a controlled release coating on the drug, such as reboxetine (including S, S-reboxetine).

The controlled release includes: immediate release (immediatate release) of a drug, such as reboxetine (including S, S-reboxetine), at a certain time or at a certain region of the body; delayed release of drug (delayed release); sustained release of drug at a certain time or at a certain location in the body (refractory release); or delayed release of a drug, such as reboxetine (including S, S-reboxetine).

Reboxetine (including S, S-reboxetine) is typically rapidly absorbed in human patients, reaching maximum plasma concentrations in about 2-4 hours. To achieve a delay in the time required to reach maximum plasma concentration, a controlled release coating or mixture may be employed.

Delayed release is a general term for drug delivery, which describes an oral pharmaceutical form that does not immediately release its active pharmaceutical ingredient in the mouth or stomach of a patient. Although there are many ways in which delayed release can be achieved, delayed release of reboxetine (including S, S-reboxetine) can be achieved by surrounding reboxetine (including S, S-reboxetine), e.g., in the second release component, completely or partially with a coating or layer (e.g., an internal controlled release coating) that does not dissolve immediately upon swallowing. For example, the material of the coating or layer may slowly dissolve in the stomach, and/or slowly disintegrate in the stomach by a chemical reaction (e.g. by hydrolysis) until the layer can no longer prevent contact of reboxetine (including S, S-reboxetine) with gastric fluid.

In some embodiments, the delayed release coating ensures delivery through the stomach and into the intestine. Once in the duodenum, the coating can begin to break down and begin to release reboxetine (including S, S-reboxetine). In some cases, reboxetine (including S, S-reboxetine) can be completely released in the duodenum. In some embodiments, reboxetine (including S, S-reboxetine) can be released partially in the duodenum and partially in the jejunum. In some cases, reboxetine (including S, S-reboxetine) can be completely released in the jejunum. In some cases, reboxetine (including S, S-reboxetine) can be released partially in the jejunum and partially in the ilium. In some cases, reboxetine (including S, S-reboxetine) can be completely released in the ilium. In some cases, reboxetine (including S, S-reboxetine) can be partially released in the duodenum, jejunum, and ilium. In some embodiments, reboxetine (including S, S-reboxetine) can be partially released in the ilium and partially released in the colon. In some cases, reboxetine (including S, S-reboxetine) can be completely released in the colon.

The time of delayed release, e.g. the time between release of the first reboxetine (including S, S-reboxetine) component and the second reboxetine (including S, S-reboxetine) component, can be adjusted by using materials that dissolve or disintegrate more or less slowly in the digestive system, adjusting the thickness of the coating layer or coating material (e.g. thicker layers will provide a longer time) and/or by using materials whose properties are pH sensitive. For example, materials that are less stable to acidic pH or more soluble at acidic pH may dissolve or disintegrate more quickly in the stomach because the stomach pH is lower than the pH in the intestine. Conversely, materials that are stable at low pH, but less stable at higher pH, may later dissolve or disintegrate due to the time it takes for the dosage form to travel through the gastrointestinal tract.

Controlled release formulations containing reboxetine, including S, S-reboxetine, can be coated with one or more functional or nonfunctional coatings. Examples of functional coatings include controlled release polymer coatings (i.e., controlled release coatings), moisture barrier coatings, enteric polymer coatings, and the like.

Depending on the structure of the dosage form, the controlled release polymer may be used for sustained or delayed release. For example, dispersing reboxetine (including S, S-reboxetine) throughout a controlled release polymer can provide a sustained release since the drug is released as long as the polymer is present in the gastrointestinal tract. Delayed release may be achieved by creating a barrier (e.g., a coating) that is intended to last for a short period of time (e.g., less than 12 hours, less than 10 hours, less than 6 hours, less than 3 hours, etc.) such that reboxetine (including S, S-reboxetine) is released freely when the barrier is penetrated. The thickness of the barrier may be used to control the delay time.

Any suitable controlled release polymer may be used, for example, acrylic and methacrylic acid copolymers and their various esters, such as methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), alkylamine methacrylate copolymers, poly (methyl methacrylate), poly (methacrylic acid) (anhydride), polyacrylamide, poly (methacrylic anhydride), and glycidyl methacrylate copolymers.

Other suitable controlled release polymers include polymerizable quaternary ammonium compounds such as quaternized aminoalkyl esters and aminoalkyl amides of acrylic and methacrylic acids, such as β -methacryloyloxyethyltrimethylammonium methyl sulfate, β -acryloyloxypropyltrimethylammonium chloride, and trimethylaminomethanamide methyl sulfate. The quaternary ammonium atom may also be part of a heterocyclic ring, as in methacryloyloxyethyl methyl morpholine chloride or the corresponding piperidinium salt, or it may be attached to an acrylic group or methacrylic group via a heteroatom containing group, such as a polyglycol ether group. Other suitable polymerizable quaternary ammonium compounds include quaternized vinyl-substituted nitrogen heterocycles, such as methyl-vinylpyridine salts, vinyl esters of quaternized aminocarboxylic acids, styryl trialkylammonium salts, and the like. Other polymerizable quaternary ammonium compounds include benzyldimethylammonium ethyl-methacrylate chloride, diethylmethylammonium ethyl-acrylate and-methacrylate methyl sulfate, N-trimethylammonium propyl methacrylamide chloride, and N-trimethylammonium-2, 2-dimethylpropyl-1-methacrylate chloride.

Delayed release may also be achieved by using a controlled release polymer for a specific pH, wherein it is understood that by appropriate fasting or feeding, the specific pH may correspond to a specific time after administration.

For some controlled release polymers, the acrylic or methacrylic polymer includes one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers (such as those sold under the trade mark by Evonik)

Those sold by RS and RL) are fully polymerized copolymers of acrylic and methacrylic esters having a low content of quaternary ammonium groups. The ammonium group is attached to the ester portion of the methacrylate (as 2-trimethylammonium-ethyl ester). The charged ammonium groups in these polymers render them insoluble and highly permeable, and have pH-independent swelling. These properties make these polymers useful for tailored, time-controlled release of coated drugs. In order to obtain the desired dissolution profile for a given therapeutically active agent, such as reboxetine (including S, S-reboxetine), two or more ammonio methacrylate copolymers having different physical properties can be incorporated. For example, it is known that the permeability of the resulting coating can be modified by varying the molar ratio of pre-polymerized material containing quaternary ammonium groups to pre-polymerized material containing uncharged neutral methacrylic or acrylic esters.

In other embodiments, the controlled release coating further comprises a polymer whose permeability is pH dependent, such as an anionic polymer synthesized from methacrylic acid and methyl methacrylate. Such polymers are commercially available, for example under the trade name

L and

s was obtained from Evonik. The ratio of free carboxyl groups to esters is known to be

In L is 1:1, and in

The ratio of S in the product is 1: 2.

L is insoluble in acid and pure water but becomes increasingly permeable above pH 5.0. This results in

L is suitable for targeted release of coated drugs, such as coated reboxetine (including S, S-reboxetine), in the duodenum and jejunum of the small intestine. Thus, relative to uncoated or immediate release drugs, such as reboxetine (including S, S-reboxetine) in the first release component,

l coated drug may achieve a maximum plasma concentration delay of about 30 minutes to about 1 hour, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5 hours, about 2.5-3 hours, or about 3.5-4 hours.

S and

l is similar except that it becomes increasingly permeable above pH 7. This results in

S is suitable for targeted release of coated drugs, such as coated reboxetine (including S, S-reboxetine), in the ileum of the small intestine as well as in the colon. Due to the fact thatThis is in contrast to uncoated or immediate release drugs, such as reboxetine (including S, S-reboxetine) in the first release component,

the S-coated drug may achieve a maximum plasma concentration delay of about 1-2 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 8-9 hours, or about 9-10 hours.

The hydrophobic acrylic polymer coating may also include polymers based on dimethylaminoethyl methacrylate and neutral methacrylates (e.g.

E, commercially available from Evonik).

E is insoluble in saliva (making it useful for taste and odor masking) but soluble in gastric juice at pH 5 or lower, which provides for immediate release of the drug in the stomach. About 0-30 minutes, 30-60 minutes, 60-90 minutes, or 90-120 minutes after oral administration of the dosage form, or any time period within a range bounded by any of these values

The reboxetine (including S, S-reboxetine) surrounded by the E-coating can release the reboxetine (including S, S-reboxetine), can begin to release the reboxetine (including S, S-reboxetine), or can result in a first local maximum in plasma concentration of the reboxetine (including S, S-reboxetine).

The hydrophobic acrylic polymer coating may comprise a polymethacrylate-based neutral copolymer, such as commercially available from Evonik

NE (NE ═ neutral ester).

NE 30DThe paint film is insoluble in water and digestive juices, but is permeable and swellable, providing another option for controlled release over time.

NE has a pH independent sustained release effect that can release a drug such as reboxetine (including S, S-reboxetine) over a period of time or can delay release for a period of time, wherein the period of release or delay is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.

In some embodiments, the controlled release coating comprises a polymer comprising ethyl acrylate and methyl methacrylate in a 2:1 ratio: (a) ((ii))

EMM 30D，BASF)。

EMM 30D has a pH independent sustained release effect that can release a drug such as reboxetine (including S, S-reboxetine) over a period of time or can delay release for a period of time, where the period of release or delay is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.

In some embodiments, the controlled release coating comprises polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfate, e.g., sodium lauryl sulfate

SR30D (BASF). The dissolution characteristics can be varied by varying the relative amounts of different acrylic lacquer included in the coating. In addition, by varying the molar ratio of polymerizable penetration enhancer (e.g., quaternary ammonium compound) to neutral methacrylate, the penetration characteristics of the resulting coating (which affects dissolution characteristics) can be varied.

SR30D is another coating with a pH independent sustained release effect, which may be at one stageThe drug is released over time, such as reboxetine (including S, S-reboxetine), or the release can be delayed for a period of time, where the time of release or delay is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about 1-2 hours.

In some embodiments, the controlled release coating comprises ethylcellulose, which can be used as a dry polymer (e.g., ETHOCEL, Dow Chemical Company) that is solubilized in an organic solvent prior to use, or as an aqueous dispersion. One suitable commercially available aqueous dispersion of ethylcellulose is

(Danisco)。

ECD (aqueous ethylcellulose dispersion),

ARC (alcohol resistant ethyl cellulose aqueous dispersion) and

CPD (aqueous dispersion of cellulose acetate phthalate) is a commercially available controlled release coating. Another suitable aqueous dispersion of ethylcellulose is

(Colorcon, Inc.) is commercially available. The product can be prepared by incorporating a plasticizer into the dispersion during the manufacturing process. Hot melts of a polymer, a plasticizer (e.g., dibutyl sebacate), and a stabilizer (e.g., oleic acid) can be mixed and prepared as a homogeneous mixture, which is then diluted with a basic solution to obtain an aqueous dispersion that can be applied directly to a substrate. These coatings have a pH independent sustained release effect which releases the drug, such as reboxetine (including S, S-reboxetine), over a period of time or can delay the release for a period of time, wherein the release or delay is from about 1 to 24 hours, from about 1 to 18 hours, or,About 1-12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about 1-2 hours.

Other examples of polymers that may be used in the controlled release coating include cellulose acetate phthalate, cellulose acetate trimaleate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl alcohol phthalate, shellac, hydrogels and gel-forming materials such as carboxyvinyl polymers, sodium alginate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose-based cross-linked polymers (where the degree of cross-linking is low to facilitate the adsorption of water and the swelling of the polymer matrix), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, pullulan, collagen, casein, agar, cellulose acetate succinate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose, hydroxypropyl cellulose calcium, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose-based cross-linked polymers (where the degree of cross-linking is low to facilitate the adsorption of water and the swelling of the polymer matrix), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, pullulan, collagen, casein, agar, and gelatin, Gum arabic, sodium carboxymethylcellulose, (swellable hydrophilic polymers) poly (hydroxyalkyl methacrylates) (molecular weight 5k to 5000k), polyvinylpyrrolidone (molecular weight 10k to 360k), anionic and cationic hydrogels, zein, polyamides, polyvinyl alcohols with low acetate residues, swellable mixtures of agar and carboxymethylcellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectins (molecular weight 30k to 300k), polysaccharides such as agar, acacia, karaya, tragacanth, algin and guar, polyacrylamides, guar, and guar gums, and mixtures thereof,

Polyoxyethylene (molecular weight 100k to 5000k, Dow), AQUA

Acrylate polymers (consisting essentially of acrylic acid polymers, sodium salts), diesters of polydextrose, cross-linked polyvinyl alcohol and poly-N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methylcellulose, sodium or calcium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, nitrocellulose, and mixtures thereof,Carboxymethylcellulose, cellulose ethers, methylethylcellulose, ethylhydroxyethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamides, polyacrylic acid, natural gums, lecithin, pectin, alginates, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, agar and gums such as acacia, karaya, locust bean, tragacanth, carrageenan, guar gum, xanthan gum, scleroglucan, and mixtures and blends thereof.

In some embodiments, a dosage form of reboxetine (including S, S-reboxetine) is coated with a polymer to promote mucoadhesion in the gastrointestinal tract. Non-limiting examples of polymers that can be used for mucoadhesion include carboxymethylcellulose, polyacrylic acid, Carbopol^TM(Lubrizol), polycarbophil, gelatin, and other natural or synthetic polymers.

The polymeric coating of the present disclosure can be any of the coatings or can be a combination of two or more of the coatings to achieve a desired release profile for reboxetine (including S, S-reboxetine) release.

In addition to the modified-release dosage forms described herein, other modified-release techniques known to those skilled in the art can be used to achieve the modified-release formulations of the present disclosure, i.e., to provide the mean T of the drug described herein when administered (e.g., orally or by other modes of administration) to a human patient_{Maximum of}And/or other pharmacokinetic parameters. Such formulations may be formulated into modified release oral formulations in the form of suitable tablets or multiparticulate formulations known to those skilled in the art. In either case, the modified release dosage form may optionally comprise a controlled release carrier, either incorporated with the drug in a matrix or applied as a controlled release coating.

Any dosage form comprising an effective amount of reboxetine, including S, S-reboxetine, can further comprise binders, lubricants, and other conventional inert excipients.

Binders (sometimes also referred to as adhesives) may be added to the drug-filler mixture to increase the mechanical strength of the granules and tablets during formation. The binder may be added to the formulation in different ways: (1) as a dry powder, which is mixed with the other ingredients prior to wet agglomeration, (2) as a solution, which acts as an agglomeration liquid during wet agglomeration and is referred to as a solution binder, and (3) as a dry powder, which is mixed with the other ingredients prior to compaction. In this form, the adhesive is referred to as a dry adhesive. Solution binders are a common way to incorporate binders into granules. In certain embodiments, the binder used in the tablet is in the form of a solution binder. Non-limiting examples of useful binders include hydrogenated vegetable oils, castor oil, paraffin waxes, higher fatty alcohols, higher fatty acids, long chain fatty acids, fatty acid esters, waxy substances such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers having a hydrocarbon backbone, and mixtures thereof. Specific examples of the water-soluble polymer binder include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives such as Hydroxypropylmethylcellulose (HPMC) and Hydroxypropylcellulose (HPC), polyvinyl alcohol, and a mixture thereof. Any suitable amount of binder may be present, for example, about 0.5-5 wt.%, about 5-10 wt.%, about 10-15 wt.%, about 15-20 wt.%, about 20-25 wt.%, about 0.5-15 wt.%, about 1-6 wt.%, or about 3 wt.% based on the dry weight of the tablet. In some embodiments, the binder is polyvinyl alcohol.

A lubricant may be added to the pharmaceutical formulation to reduce any friction that occurs between the solid and the mold walls during tablet manufacture. High friction during tabletting can lead to a series of problems, including inadequate tablet quality (tablet is capped or even broken during ejection, and vertical scratches on the tablet edge) and possibly even production stops. Thus, lubricants may be added to the tablet formulation. Non-limiting examples of useful lubricants include glyceryl behenate, stearic acid,Hydrogenated vegetable oil (e.g. hydrogenated cottonseed oil)

Hydrogenated soybean oil (

HM) and hydrogenated Soybean oil and Castor wax ((II)

K) Stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000 and higher), magnesium stearate, glyceryl monostearate, stearic acid, polyethylene glycol, ethylene oxide polymers (for example, those which may be registered trade marks)

Available from Union Carbide, inc., Danbury, conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, mixtures thereof, and others known in the art. In some embodiments, the lubricant is glyceryl behenate (e.g.,

888). Any suitable amount of binder may be present, for example, about 0.5-5 wt.%, about 5-10 wt.%, about 10-15 wt.%, about 15-20 wt.%, about 20-25 wt.%, about 0.5-15 wt.%, about 1-6 wt.%, or about 3 wt.% based on the dry weight of the tablet.

In some embodiments, reboxetine (including S, S-reboxetine) is administered once daily or twice daily for at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least 1.5 years, at least 2 years, at least about 3 years, at least about 4 years, at least about 5 years, about 0.1-5 years, about 5-10 years, at least about 10 years, about 10-15 years, at least about 15-20 years, at least about 20 years, or more. In some embodiments, reboxetine (including S, S-reboxetine) is administered for up to about 6 months, up to about 1 year, up to about 2 years, up to about 5 years, up to about 10 years, up to about 20 years, up to about 40 years, up to about 60 years, or up to about 90 years.

Examples (without intending to limit the scope of the disclosure) of useful compositions for dosage forms containing about 5-10mg reboxetine (including S, S-reboxetine) are shown in table 1 below:

TABLE 1 examples of reboxetine dosage forms

Components	Amount (weight/weight)
		Reboxetine or S, S-reboxetine	30-70％
Lubricant agent	1-10％
		Diluent	20-70％
Disintegrating agent	1-10％

Treatment of cataplexy narcolepsy with reboxetine (including S, S-reboxetine) in the dosage forms described herein may not have as significant side effects as current treatment options. Treatment of cataplexy narcolepsy with reboxetine (including S, S-reboxetine) in the dosage forms described herein is well tolerated in mammals such as humans.

Some embodiments include a kit comprising a pharmaceutical composition comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 unit dosage forms), wherein one unit dosage form comprises about 0.1-5mg of reboxetine (including S, S-reboxetine); and instructions for using the pharmaceutical composition to treat narcolepsy.

Some embodiments include a kit comprising a pharmaceutical composition comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 unit dosage forms), wherein one unit of dosage form comprises about 5-10mg of reboxetine (including S, S-reboxetine); and instructions for using the pharmaceutical composition to treat narcolepsy.

Some embodiments include a kit comprising a pharmaceutical composition comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 unit dosage forms), wherein one unit dosage form comprises about 10-15mg of reboxetine (including S, S-reboxetine); and instructions for using the pharmaceutical composition to treat narcolepsy.

Some embodiments include a kit comprising a pharmaceutical composition comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 unit dosage forms), wherein one unit dosage form comprises about 15-20mg of reboxetine (including S, S-reboxetine); and instructions for using the pharmaceutical composition to treat narcolepsy.

Some embodiments include a kit comprising a pharmaceutical composition comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 unit dosage forms), wherein one unit dosage form comprises about 5-20mg reboxetine (including S, S-reboxetine); and instructions for using the pharmaceutical composition to treat narcolepsy.

The following embodiments are specifically contemplated.

Embodiment 1. a method of treating cataplexy narcolepsy, comprising administering reboxetine to a human in need thereof, wherein reboxetine is administered at least once daily for more than two weeks, wherein said human experiences a decrease in the number of cataplexy episodes within one week, a decrease in Epworth somnolen scale score, a decrease in the cataplexy score of ullina narcolepsy scale (NUS), or a decrease in the stay awake test score two weeks from the start of treatment as a result of treatment.

Embodiment 2 use of reboxetine in the manufacture of a medicament for the treatment of cataplexy narcolepsy, wherein reboxetine is administered at least once daily for at least three weeks.

Embodiment 3. a kit comprising a pharmaceutical composition comprising reboxetine and instructions for its use to treat cataplexy narcolepsy in a human, wherein reboxetine is administered at least once daily for at least three weeks.

Embodiment 4 the method, use or kit of embodiment 1, 2 or 3 wherein reboxetine is administered twice daily, wherein the first dosage form is administered in the morning and the second dosage form is administered about 2 hours to about 6 hours later.

Embodiment 5. the method, use or kit of embodiment 4, wherein the second dosage form is administered about 2 hours to about 3 hours after the first dosage form.

Embodiment 6 the method, use or kit of embodiment 4, wherein the second dosage form is administered about 3 hours to about 4 hours after the first dosage form.

Embodiment 7. the method, use or kit of embodiment 4, wherein the second dosage form is administered about 4 hours to about 5 hours after the first dosage form.

Embodiment 8 the method, use or kit of embodiment 4, wherein the second dosage form is administered about 5 hours to about 6 hours after the first dosage form.

Embodiment 9 the method, use or kit according to embodiment 1, wherein a single dosage form is administered daily, wherein the single dosage form contains a first release component comprising reboxetine and a second release component comprising reboxetine, wherein the first release component provides a first local maximum in reboxetine plasma concentration and the second release component provides a second local maximum in reboxetine plasma concentration, wherein the first local maximum in reboxetine plasma concentration occurs about 2 to about 6 hours before the second local maximum in reboxetine plasma concentration.

Embodiment 10 the method, use or kit according to embodiment 9, wherein the second local maximum in reboxetine plasma concentration occurs about 2 to about 3 hours after the first local maximum in reboxetine plasma concentration.

Embodiment 11 the method, use or kit according to embodiment 9, wherein the second local maximum in reboxetine plasma concentration occurs about 3 to about 4 hours after the first local maximum in reboxetine plasma concentration.

Embodiment 12 the method, use or kit according to embodiment 9, wherein the second local maximum in reboxetine plasma concentration occurs about 4 to about 5 hours after the first local maximum in reboxetine plasma concentration.

Embodiment 13 the method, use or kit according to embodiment 9, wherein the second local maximum in reboxetine plasma concentration occurs about 5 to about 6 hours after the first local maximum in reboxetine plasma concentration.

Embodiment 14 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, 12 or 13, wherein the human is selected not to suffer from depression.

Embodiment 15 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 wherein the dosage amount of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.006mmol to about 0.01 mmol.

Embodiment 16 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the dosage amount of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.01 to about 0.02 mmol.

Embodiment 17. the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.02 to about 0.03 mmol.

Embodiment 18 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.03 to about 0.04 mmol.

Embodiment 19. the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.04 to about 0.05 mmol.

Embodiment 20 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.05 to about 0.06 mmol.

Embodiment 21 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.06 to about 0.07 mmol.

Embodiment 22 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.07 to about 0.08 mmol.

Embodiment 23 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 wherein reboxetine is a dosage form and said dosage form contains about 5mg of reboxetine.

Embodiment 24 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 wherein reboxetine is a dosage form and said dosage form contains about 10mg of reboxetine.

Embodiment 25 the method, use or kit of embodiment 23, wherein the dosage form is administered once daily or twice daily for at least three weeks.

Embodiment 26 the method, use or kit of embodiment 24, wherein the dosage form is administered once daily or twice daily for at least three weeks.

Embodiment 27 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, wherein the human experiences an increase in sleep latency on Multiple Sleep Latency Test (MSLT).

Embodiment 28 the method, use or kit of embodiment 27, wherein the human experiences an increase in sleep latency of at least 10% on MSLT.

Embodiment 29 the method, use or kit of embodiment 27, wherein the human experiences an increase in sleep latency of at least 20% on MSLT.

Embodiment 30 the method, use or kit of embodiment 27, wherein the human experiences an increase in sleep latency of at least 30% on MSLT.

Embodiment 31 the method, use or kit of embodiment 27, wherein the human experiences an increase in sleep latency of at least 40% on MSLT.

Embodiment 32 the method, use or kit of embodiment 27, wherein the human experiences an increase in sleep latency of at least 50% on MSLT.

Embodiment 33 the method, use or kit of embodiment 27, wherein the human experiences an increase in sleep latency of at least 60% on MSLT.

Embodiment 34 the method, use or kit of

embodiments

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or 33, wherein the human experiences at least a 15% reduction in cataplexy score on UNS.

Embodiment 35 the method, use or kit of embodiment 34, wherein the human experiences at least a 20% reduction in cataplexy score on UNS.

Embodiment 36 the method, use or kit of embodiment 34, wherein the human experiences at least a 30% reduction in cataplexy score on UNS.

Embodiment 37. the method, use or kit of embodiment 34, wherein the human experiences at least a 40% reduction in cataplexy score on UNS.

Embodiment 38 the method, use or kit of embodiment 34, wherein the human experiences at least a 50% reduction in cataplexy score on UNS.

Embodiment 39 the method, use or kit of embodiment 34, wherein the human experiences at least a 60% reduction in cataplexy score on UNS.

Embodiment 40 the method, use or kit of embodiment 34, wherein the human experiences at least a 70% reduction in cataplexy score on UNS.

Embodiment 41 the method, use or kit of embodiment 34, wherein the human has a cataplexy score of about 0.

Embodiment 42. a method of improving attention-focusing ability of a person with narcolepsy, comprising administering reboxetine to a person in need thereof.

Embodiment 43 the method of embodiment 42, wherein the person is selected as needing improved ability to concentrate or having difficulty concentrating.

Embodiment 44 the method of embodiment 42 or 43, wherein the improvement in the attention focusing capacity program on NSAQ in the human is at least about-0.1 as compared to prior to administration of any reboxetine.

Embodiment 45 a method of treating fibromyalgia comprising administering oxathimidine to a human in need thereof at a daily dose of about 1mg to about 2mg for at least six weeks, wherein the human experiences greater reduction in fibromyalgia pain during the course of treatment than the human experiences by administration of a placebo as measured by a Visual Analog Scale (VAS) score.

Embodiment 46. the method of embodiment 45, wherein about 1 to about 2mg of oxapredosine is administered once daily.

Embodiment 47 the method of embodiment 45, wherein about 0.5mg to about 1mg of oxaprednate is administered twice daily.

Embodiment 48 the method of embodiments 45, 46 or 47, wherein the person is selected to have a global fatigue index score of at least about 8.

Embodiment 49 the method of embodiment 45, 46, 47 or 48, wherein after administration of oxapredosine daily for six weeks, the person's VAS score for fibromyalgia pain is reduced by at least 20% compared to the VAS score for fibromyalgia pain in the person immediately prior to administration of the first dose of oxapredosine.

Embodiment 50 the method of embodiment 45, 46, 47, 48 or 49, wherein after administration of dexipiptin daily for six weeks, the person's VAS score for fibromyalgia pain is reduced by at least 50% compared to the person's VAS score for fibromyalgia pain immediately prior to administration of the first dose of dexipiptin.

Embodiment 51. a method of treating fibromyalgia comprising administering oxathixene to a human in need thereof in a daily dose of about 2mg to about 4mg for at least six weeks, wherein the human experiences greater pain reduction during the course of treatment than does the human by administration of a placebo as measured by a Visual Analog Scale (VAS) score.

Embodiment 52. the method of embodiment 51, wherein about 1mg to about 2mg of oxaprednate is administered once daily.

Embodiment 53 the method of embodiment 51, wherein about 0.5mg to about 1mg of oxaprednate is administered twice daily.

Embodiment 54. the method of embodiment 51, 52 or 53, wherein the person is selected to have a global fatigue index score of at least about 8.

Embodiment 55 the method of embodiment 51, 52, 53 or 54, wherein after administration of oxapredosine daily for six weeks, the person's VAS score for fibromyalgia pain is reduced by at least 20% compared to the VAS score for fibromyalgia pain in the person immediately prior to administration of the first dose of oxapredosine.

Embodiment 56 the method of embodiment 51, 52, 53, 54 or 55, wherein after administration of dexrazoxane on a daily basis for six weeks, the human has at least a 50% reduction in the VAS score for fibromyalgia pain as compared to the VAS score for fibromyalgia pain in the human immediately prior to administration of the first dose of dexrazoxane.

Embodiment 57 a method of treating fibromyalgia comprising administering oxathixene to a human in need thereof in a daily dose of about 0.5mg to about 1mg for at least six weeks, wherein the human experiences greater pain reduction during the course of treatment than does the human by administration of a placebo as measured by a Visual Analog Scale (VAS) score.

Embodiment 58. the method of embodiment 57, wherein about 1mg to about 2mg of oxaprednate is administered once daily.

Embodiment 59 the method of embodiment 57, wherein about 0.5mg to about 1mg of oxaprednate is administered twice daily.

Embodiment 60 the method of embodiment 57, 58 or 59, wherein the person is selected to have a global fatigue index score of at least about 8.

Embodiment 61 the method of embodiments 57, 58, 59, or 60, wherein after administration of dexrazoxane on a daily basis for six weeks, the human has at least a 20% reduction in the VAS score for fibromyalgia pain as compared to the VAS score for fibromyalgia pain in the human immediately prior to administration of the first dose of dexrazoxane.

Embodiment 62. the method of embodiment 61, wherein after administering dexipiptin daily for six weeks, the human's VAS score for fibromyalgia pain is reduced by at least 50% compared to the human's VAS score for fibromyalgia pain immediately prior to administration of the first dose of dexipiptin.

Examples

Example 1

A 40 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After one week of treatment, the number of cataplexy attacks was reduced by 10-30%.

Example 2

A 20 year old female was diagnosed with cataplexy narcolepsy. She was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After one week of treatment, the number of cataplexy attacks was reduced by 30-60%.

Example 3

A 60 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After one week of treatment, the number of cataplexy episodes decreased by 60-100%.

Example 4

A 50 year old female was diagnosed with cataplexy narcolepsy. She was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. ESS scores dropped 10-30% after one week of treatment.

Example 5

A 25 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. ESS scores had dropped by 30-60% after one week of treatment.

Example 6

A 47 year old female was diagnosed with cataplexy narcolepsy. She was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. ESS scores dropped 60-100% after one week of treatment.

Example 7

A 19 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After one week of treatment, the MWT score decreased by 10-30%.

Example 8

A 42 year old female was diagnosed with cataplexy narcolepsy. She was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After one week of treatment, the MWT score decreased by 30-60%.

Example 9

A 33 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After one week of treatment, the MWT score decreased by 60-100%.

Example 10

A 54 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After three weeks of treatment, the number of cataplexy episodes decreased by 10-30%.

Example 11

A 27 year old female was diagnosed with cataplexy narcolepsy. She was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After three weeks of treatment, the number of cataplexy episodes decreased by 30-60%.

Example 12

A 52 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After three weeks of treatment, the number of cataplexy episodes decreased by 60-100%.

Example 13

A 66 year old female was diagnosed with cataplexy narcolepsy. She was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. ESS scores dropped 10-30% after three weeks of treatment.

Example 14

A 34 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the attention-focusing capacity on MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and NSAQ. ESS scores dropped 30-60% after three weeks of treatment.

Example 15

A 35 year old female was diagnosed with cataplexy narcolepsy. She was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the attention-focusing capacity on MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and NSAQ. ESS scores dropped 60-100% after three weeks of treatment.

Example 16

A 19 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After three weeks of treatment, the MWT score decreased by 10-30%.

Example 17

A 70 year old female was diagnosed with cataplexy narcolepsy. She was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After three weeks of treatment, the MWT score decreased by 30-60%.

Example 18

A 57 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. After three weeks of treatment, the MWT score decreased by 60-100%.

Example 19

A 20 year old female was diagnosed with cataplexy narcolepsy. She was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. HAM-D score decreased by 10-30% after three weeks of treatment.

Example 20

A 69 year old male was diagnosed with cataplexy narcolepsy. He was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. HAM-D score decreased by 30-60% after three weeks of treatment.

Example 21

A 56 year old female was diagnosed with cataplexy narcolepsy. She was given reboxetine and instructed to take 5mg of reboxetine at 8 am and 5mg of reboxetine at 1 pm for three weeks. Patients were evaluated prior to treatment and weekly to determine the MWT score, number of cataplexy episodes, PGI-C score, HAM-D score, ESS score, NSAQ score, and attention focusing capacity on NSAQ. HAM-D score decreased by 60-100% after three weeks of treatment.

Example 22

A phase 2, double blind, randomized, placebo controlled, crossover, multicenter trial of reboxetine was performed in narcolepsy patients. A total of 21 patients diagnosed with cataplexy narcolepsy were treated with reboxetine or with placebo for 2 weeks, followed by a 1-week washout and washout period followed by another treatment. Reboxetine was administered orally twice daily, with a total daily dose of 8mg at week 1, increasing to 10mg at week 2. Patients were randomized in the 1:1 ratio to treatment with reboxetine followed by placebo (sequence 1) or placebo followed by reboxetine (sequence 2). The average number of cataplexy attacks at baseline was 30. Key assessments were performed daily using an electronic diary. The pre-specified primary endpoint was the variation in the number of averaged cataplexy episodes per week over the 2-week treatment period (overall therapeutic effect). Secondary endpoints included changes in number of unplanned naps, cognition, and Epworth somnolence scale. Cognition was assessed using the attention-focusing ability item in the narcolepsy symptom assessment questionnaire, the patient reported outcome measure. The item was rated on a 5 point scale (1-very good to 5-very poor). All analyses were performed on an intentional therapeutic basis.

As shown in figure 1, reboxetine met the pre-specified primary endpoint by exhibiting a highly statistically significant reduction (overall therapeutic effect) of the averaged mean number of cataplexy episodes per week over the 2-week treatment period compared to placebo from baseline (p < 0.001). At week 2, reboxetine showed an average reduction of 14.6 cataplexy episodes per week compared to 2.6 cataplexy episodes for placebo (p ═ 0.002), representing an average reduction of 48.7% and 8.7% relative to baseline, respectively (figure 1). In addition, reboxetine treatment resulted in a rapid reduction in cataplexy episodes. Reboxetine showed an average reduction of 13.0 cataplexy episodes after 1 week of treatment compared to 0.3 episode reduction for placebo (p <0.001), representing an average reduction of 43.3% and 1.0% relative to baseline, respectively (figure 1). At week 2, the proportion of patients achieving a 50% or greater reduction in number of cataplexy episodes per week was 76.2% for reboxetine compared to 30.0% for placebo (p ═ 0.003) (fig. 2). At week 2, the proportion of patients achieving a 75% or greater reduction in the number of cataplexy episodes per week was 42.9% for reboxetine compared to 10.0% for placebo (p 0.018) (fig. 3). As early as week 1, the improvement of cataplexy by reboxetine was rapid, showing a significant benefit relative to placebo (p < 0.001).

Reboxetine significantly improved EDS (excessive daytime sleepiness) symptoms compared to placebo as measured by the Epworth Sleepiness Scale (ESS) and by the frequency of unexpected naps. As shown in fig. 4, the improvement in ESS with reboxetine treatment was two-fold that observed with placebo, where the reductions in ESS score relative to baseline for reboxetine and placebo were 6.0 and 3.1, respectively (p ═ 0.003). At week 2, reboxetine treatment resulted in an average reduction of 31.8% in the average number of accidental dozes per week relative to baseline, while the placebo had an average reduction of 5.3% (p <0.001) (fig. 5). As shown in fig. 6, reboxetine treatment resulted in a 50% or greater reduction in unexpected dozing (38.1%) in a greater number of patients compared to placebo (10.0%) (p ═ 0.036). As early as week 1, the improvement in frequency of unexpected dozing by reboxetine was rapid, showing a significant benefit relative to placebo.

Reboxetine significantly improved cognitive function compared to placebo over a 2 week treatment period as measured by the attention focusing ability item of the Narcolepsy Symptom Assessment Questionnaire (NSAQ), which was assessed daily (p <0.01) (fig. 7-8). For this assessment, patients rated their attention-focusing ability on a 5-point scale (1-very good, 2-good, 3-average, 4-poor, and 5-very poor). At the end of the 2-week treatment period, 42.9% of patients had "good" to "very good" attention-focusing capacity when treated with reboxetine, compared to 25.0% of patients had "good" to "very good" attention-focusing capacity when treated with placebo, and 0% of patients had "good" to "very good" attention-focusing capacity at baseline. As early as week 1, reboxetine improved attention-focusing rapidly, showing a significant improvement over placebo (38.1% versus 15.0%) (p ═ 0.007).

Reboxetine significantly improved the quality of sleep as measured by overall improvement and number of nighttime awakenings, and reduced sleep-related symptoms compared to placebo. As shown in figure 9, reboxetine treatment resulted in 45.0% of patients reporting improved sleep quality compared to placebo which resulted in 5.3% of patients reporting improved sleep quality (p 0.007). Reboxetine treatment resulted in a reduction in the number of nighttime awakenings reported in 30.0% of patients compared to a reduction in the number of nighttime awakenings reported in 5.3% of patients when placebo was used (p ═ 0.044). Reboxetine treatment also resulted in a greater proportion of patients with reduced episodes of sleep paralysis and reduced hallucinations prior to falling asleep compared to placebo.

Reboxetine is safe and well tolerated. No serious adverse events were reported in the trial, nor were there any discontinuations due to adverse events. The total percentage of patients experiencing adverse events with reboxetine was 42.9% and the total percentage of patients experiencing adverse events with placebo was 40.0%, with the adverse events most commonly reported with reboxetine treatment being anxiety, constipation, and insomnia. The completion rate for patients randomized to treatment sequence 1 (reboxetine followed by placebo) was 91% and for patients randomized to treatment sequence 2 (reboxetine followed by placebo) was 100%.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (e.g., amounts, percentages), and so forth, used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing embodiments (especially in the context of the following claims) and the absence of a numerical modifier is to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate embodiments and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is envisioned that one or more members of a group may be included in or deleted from the group for convenience and/or patentability. When any such inclusion or deletion occurs, the specification is to be considered as including the modified group, thus completing the written description of all markush groups used in the appended claims.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations of those described embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

Finally, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, and not limitation, alternative embodiments may be utilized in accordance with the teachings herein. Thus, the claims are not limited to the embodiments precisely as shown and described.

Claims

1. A method of rapidly reducing the number of cataplexy episodes in a person with cataplexy narcolepsy, comprising administering to a person in need thereof about 8mg to about 10mg reboxetine daily for at least two weeks, wherein the person has at least 30% fewer cataplexy episodes than baseline one week after initiation of treatment.

2. The method of claim 1, wherein the reduction in the number of cataplexy episodes compared to administration of placebo is statistically significant, wherein p < 0.01.

3. A method of improving attention focusing capacity in a person suffering from cataplexy narcolepsy, said method comprising administering to a person in need thereof about 8mg to about 10mg reboxetine per day for at least two weeks, wherein said person has "average", "poor" or "very poor" attention focusing capacity prior to the start of treatment and said person has "good" or "very good" attention focusing capacity two weeks after the start of said treatment, as determined by the attention focusing capacity items of the narcolepsy symptom assessment questionnaire.

4. A method of reducing the number of unexpected naps in a person with cataplexy narcolepsy, comprising administering to a person in need thereof about 8mg to about 10mg of reboxetine daily for at least two weeks, wherein the person has at least 20% less unexpected naps per week two weeks after the start of treatment compared to the week before the patient first received reboxetine.

5. A method of improving sleep quality in a person with cataplexy narcolepsy, comprising administering to a person in need thereof about 8mg to about 10mg reboxetine daily for at least two weeks, wherein two weeks after treatment initiation, said person reports having improved sleep quality compared to the week before the patient first received reboxetine.

6. A method of reducing nocturnal arousal in a person having cataplexy narcolepsy, the method comprising administering to the person in need thereof about 8mg to about 10mg reboxetine daily for at least two weeks, wherein two weeks after initiation of treatment the person reports having less nocturnal arousal than the week before the patient first received reboxetine.

7. A method of reducing sleep paralysis in a person suffering from cataplexy narcolepsy, said method comprising administering to a person in need thereof about 8mg to about 10mg reboxetine daily for at least two weeks, wherein two weeks after treatment initiation said person reports having fewer sleep paralysis episodes than the week before said patient first received reboxetine.

8. A method of reducing pre-sleep hallucinations in a person with cataplexy narcolepsy, the method comprising administering to a person in need thereof about 8mg to about 10mg of reboxetine daily for at least two weeks, wherein two weeks after initiation of treatment the person reports having less pre-sleep hallucinations than the week before the patient first received reboxetine.

9. A method of improving attention-focusing ability in a person suffering from narcolepsy, said method comprising administering reboxetine to a person in need thereof.

10. The method of claim 1, 2, 3, 4, 5, 6, 7, 8 or 9 wherein about 4mg reboxetine is administered to the human twice daily for at least a first week.

11. The method of claim 10, wherein about 4mg of reboxetine is administered to the human in the morning and about 4mg of reboxetine is administered to the human in the afternoon daily for at least a second week.

12. The method of claim 10, wherein about 6mg of reboxetine is administered to the human in the morning and about 4mg of reboxetine is administered to the human in the afternoon daily for at least a second week.

13. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the human is diagnosed with cataplexy narcolepsy in compliance with the international sleep disorder classification, third edition of criteria.

14. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the human has a minimum of 7 cataplexy episodes per week prior to receiving reboxetine.

15. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 wherein the human has an Epworth somnolence scale score of greater than 10 prior to receiving reboxetine.

16. The method of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the person is selected as in need of improved attention-focusing ability or difficulty of attention-focusing.

17. The method according to claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 wherein the human has a reduction in the attention focusing capacity program of NSAQ of at least about 0.1 as compared to prior to administration of any reboxetine.