WO 2008/109343 Al

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization International Bureau

(43) International Publication Date (10) International Publication Number 12 September 2008 (12.09.2008) PCT WO 2008/109343 Al

(51) International Patent Classification: 10023 (US). LEONARD, Christopher, J. [US/US]; 764 AOlN 43/40 (2006.01) A61K 31/44 (2006.01) Goffle Road, Hawthorne, NJ 07506 (US).

(21) International Application Number: (74) Agent: FUJIKAWA, Shelly, M.; Darby & Darby RC, PCT/US2008/055297 P.O.Box 770, Church Street Station, New York, NY 10008- 0770 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 28 February 2008 (28.02.2008) kind of national protection available): AE, AG, AL, AM, AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, (25) Filing Language: English CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, (26) Publication Language: English EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KR KR, KZ, LA, LC, (30) Priority Data: LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, 60/892,424 1 March 2007 (0 1.03.2007) US MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, 60/893,1 13 5 March 2007 (05.03.2007) US PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (71) Applicant (for all designated States except US): MEM¬ ZA, ZM, ZW ORY PHARMACEUTICALS CORPORATION [US/US]; 100 Philips Parkway, Montvale, NJ 07645 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors; and GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (75) Inventors/Applicants (for US only): MURRAY, Stephen, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), R. [US/US]; 36 W. 69th Street, Apt. IB, New York, NY European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, [Continued on next page]

(54) Title: METHODS OF TREATING BIPOLAR DISORDER AND MEMORY AND/OR COGNITIVE IMPAIRMENT AS- SOCIATEDTHEREWITH WITH (+)-ISOPROPYL 2-METHOXYETHYL 4-(2-CHLORO-3 -CYANO-PHENYL)-1,4-DIHYDRO- 2,6-DIMETHYL-PYRIDINE-S S-DICARBOXYLATE

(57) Abstract: The present invention is Change In YMRS Total - mlTT Population a method of treating or preventing mixed and/or manic episodes associated with bipolar I disorder or memory and/or cognitive impairment associated therewith in a patient in need thereof by administering a therapeutically effective amount of (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3 ,5-dicarboxylate (referred to as "MEM- 1003" hereafter). FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, Published: NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, — with international search report CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). METHODS OF TREATING BIPOLAR DISORDER AND MEMORY AND/OR

COGNITIVE IMPAIRMENT ASSOCIATED THEREWITH WITH (-H)-ISOPROPYL

2-METHOXYETHYL 4-(2-CHLORO-3-CYANO-PHENYL)-l,4-DIHYDRO-2,6-

DIMETHYL-PYRIDINE-3,5-DICARBOXYLATE

CROSS REFERENCE TO RELATED APPLICATION

[01] This application claims priority of US Provisional Patent Application No.

60/892,424 filed on March 1, 2007, and US Provisional Patent Application No. 60/893,113 filed on March 5, 2007, the benefit of both of which are hereby claimed under 35 U.S.C. §

119 and the disclosure of which are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

[02] The present invention relates to methods of treating bipolar I disorder and memory and/or cognitive impairment associated therewith by administering (+)-isopropyl

2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5- dicarboxylate.

BACKGROUND OF THE INVENTION

[03] Bipolar I disorder is one of the most common, severe, and persistent mental illnesses. It is characterized by periods of deep, prolonged, and profound depressions that alternate with periods of excessively elevated and/or irritable mood (mania).

[04] Known treatments of bipolar I disorder, such as lithium, have a number of drawbacks. Lithium is often prescribed to control mania or prevent the recurrence of both manic and depressive episodes. However, many patients with mania do not react well to treatment with lithium (e.g., rapid cyclers). Furthermore lithium is not suitable for pregnant women as it has been associated with an increased incidence of Ebstein's anomaly, a heart malformation in newborns. Some patients cannot tolerate the side effects of lithium which can include, for example, nausea, stomach cramps, diarrhea, muscle weakness, and feelings of being somewhat tired, dazed, or sleepy. Mild hand tremors may also emerge as lithium dose is increased. Many patients treated with lithium drink more fluids than usual (polydipsia) without necessarily being aware of it, and consequently urinate more frequently (polyuria). Some patients experience weight gain as they drink greater quantities of high-calorie beverages. In patients who have low amounts of thyroid hormone, enlargement of the thyroid gland may develop. Long-term lithium therapy can also worsen certain skin conditions, especially acne and psoriasis, and may produce edema, or swelling. These effects can adversely affect a patient's appearance and sense of self esteem. The relatively narrow therapeutic range associated with lithium administration, and problems with compliance due to the above-mentioned side effects, further complicate long- term treatment with lithium (Singh, et al., Psychiatr. Clin. N. Am. , 28:301-323 (2005)).

[05] U.S. Patent No. 5,665,740 discloses racemic and optically pure isomers of isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-

3,5-dicarboxylate (shown below) and their use for the treatment of cerebral and neuronal disorders. [06] International Publication No. WO 05/051389 ("WO '389") discloses, inter alia, a method of treating mild memory and/or cognitive impairment with isopropyl 2- methoxyethyl 4-(2-chloro-3-cyano-phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5- dicarboxylate (including optically pure isomers and racemic and non-racemic mixtures of the compound) alone or in combination with certain other pharmaceutical agents. WO '389 also discloses a method of treating memory and/or cognitive impairment associated with bipolar disorder in a patient by administering simultaneously or sequentially isopropyl 2- methoxyethyl 4-(2-chloro-3-cyano-phenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5- dicarboxylate and another agent used in the treatment of bipolar disorder such as lithium,

Zyprexa®(olanzapine), and Depakote (valproic acid). WO '389 also discloses a method of treating memory and/or cognitive impairment associated with depression by administering to a patient simultaneously or sequentially isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano- phenyl)-l,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate and another agent used in the treatment of depression, such as Prozac (fluoxetine), Zoloft (sertraline), Paxil® and

Seroxat (paroxetine), Reboxetine®, Wellbutrin® (bupropion), Zyprexa® (olanzapine), Elavil and Tryptanol (amitriptyline), Tofranil® (imipramine), Pamelor® and Nortrilen

(nortriptyline), Nardil® (phenelzine), Parnate® (tranylcypromine), Desyrel (trazodone),

Effexor® (venlafaxine), Vivactil® (protriptyline), Sinequan® (doxepin), Serzone (nefazodone), Risperdal ® (risperidone), Haldol® (haloperidol), Faverin (fluvoxamine), or

Remeron ® (mirtazapine).

[07] U.S. Patent Publication No. 2005/0153953 discloses compositions for treating memory and/or cognitive impairment comprising a L-type calcium channel blocker, such as (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethylpyridine-3,5-dicarboxylate, and a cholinesterase inhibitor.

[08] There is a continuing need for new treatments for bipolar I disorder and memory and cognitive impairment associated therewith, which have improved efficacy and fewer side effects.

SUMMARY OF THE INVENTION

[09] The present invention is a method of treating or preventing mixed and/or manic episodes associated with bipolar I disorder or memory and/or cognitive impairment associated therewith in a patient in need thereof by administering a therapeutically effective amount of (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate (referred to as "MEM- 1003" hereafter). The method of the present invention is particularly effective in patients with a Young Mania Rating

Scale (YMRS) score of at least 28. The inventors have discovered that MEM- 1003 is surprisingly effective in the treatment of bipolar I disorder (including mixed and/or manic episodes associated with bipolar I disorder) and memory and/or cognitive impairment associated therewith at low doses (e.g., at most 300 mg of MEM- 1003 per day) without the significant cardiovascular side effects which are commonly associated with other dihydropyridine calcium channel blockers. Furthermore, the inventors have discovered that at higher daily doses (for example, at 360 mg of MEM- 1003 per day), the efficacy of MEM- 1003 in the treatment of mixed and/or manic episodes associated with bipolar I disorder diminishes.

[10] The invention also relates to a method of prophylactically treating the recurrence of mixed and/or manic episodes associated with bipolar I disorder or memory and/or cognitive impairment associated therewith in a patient in need thereof by administration of an effective amount of MEM- 1003. The patient may be in remission and not currently experiencing symptoms associated with any of the disorders.

[11] The invention further relates to a method of treating depressive episodes associated with bipolar I disorder in a patient in need thereof by administration of an effective amount of MEM- 1003.

[12] The invention further relates to a method of maintenance treatment of bipolar

I disorder in a patient in need thereof by administration of an effective amount of MEM-

1003. In one embodiment, the treatment delays the time to occurrence of mood episodes

(such as depression, mania, hypomania, and mixed episodes).

[13] The invention further relates to a method of relapse prevention in patients with bipolar I disorder by administration of an effective amount of MEM- 1003.

[14] Patients administered MEM- 1003 can be treated for the disorders without inducing cardiovascular effects commonly associated with calcium channel blockers, such as for example, hypotension or myocardial infarction. Patients who do not have hypertension or other cardiovascular symptoms may therefore be treated without adverse side effects.

[15] The patient may be of any age, such as a child, an adolescent, an adult, or may be elderly. Furthermore, MEM- 1003 may be administered to treatment refractory patients. [16] In the treatment methods of the present invention, MEM- 1003 is preferably administered at least twice daily. In one preferred embodiment, about 15 to about 150 mg of MEM- 1003 is administered twice daily to the patient. In another embodiment, about 60 to about 120 mg of MEM- 1003 is administered twice daily to the patient. In yet another embodiment, about 30 to about 90 mg of MEM-1003 (e.g., about 30 to about 60 mg) is administered twice daily to a patient in need of treatment. According to one embodiment, about 15 mg of MEM-1003 is administered at least twice daily to the patient (and preferably twice daily). According to another embodiment, about 30 mg of MEM-1003 is administered at least twice daily to the patient (and preferably twice daily). According to yet another embodiment, about 60 mg of MEM-1003 is administered at least twice daily to the patient (and preferably twice daily). According to yet another embodiment, about 90 mg of MEM-1003 is administered at least twice daily to the patient (and preferably twice daily). According to yet another embodiment, about 120 mg of MEM-1003 is administered at least twice daily to the patient (and preferably twice daily). The duration of the treatment is preferably at least 3 weeks. In all of these embodiments, the total amount of

MEM-1003 administered is not greater than 300 mg per day

[17] According to one embodiment, about 15 mg MEM-1003 is administered in the form of one or more pharmaceutical compositions (e.g., oral dosage forms such as tablets or capsules) which provide an in vivo plasma profile in humans (not previously treated with MEM-1003) having at least one of:

a mean Cmax of more than about 8 ng/niL,

a mean AUCo-t of less than about 20 ng h/ml (wherein t is the last time point with measurable concentrations),

a mean Tmax of more than about 0.7 hours, and a mean ϊ m of more than 3.5 hours.

According to a preferred embodiment, the pharmaceutical compositions provide an in vivo plasma profile in humans (not previously treated with MEM- 1003) having at least one of:

a mean Cmax ranging from about 10 to about 18 ng/niL,

a mean AUCo-t ranging from about 10 to about 20 ng h/ml (wherein t is the last time point with measurable concentrations),

a mean Tmax ranging from about 0.75 to about 0.9 hours, and

a mean ϊ m of ranging from about 4 to about 6 hours.

[18] According to another embodiment, about 30 mg MEM- 1003 is administered in the form of one or more pharmaceutical compositions which provide an in vivo plasma profile in humans (not previously treated with MEM- 1003) having at least one of:

a mean Cmax of more than about 8 ng/niL,

a mean AUCo-t of less than about 30 ng h/ml (wherein t is the last time point with measurable concentrations),

a mean Tmax of more than about 0.7 hour, and

a mean ϊ m of more than 6 hours.

According to a preferred embodiment, the pharmaceutical compositions provide an in vivo plasma profile in humans (not previously treated with MEM- 1003) having at least one of:

a mean Cmax ranging from about 10 to about 18 ng/niL,

a mean AUCo-t ranging from about 20 to about 30 ng h/ml (wherein t is the last time point with measurable concentrations),

a mean Tmax ranging from about 0.75 to about 1.25 hours, and

a mean ϊ m of ranging from about 7 to about 9 hours. [19] According to one embodiment, about 60 mg MEM-1003 is administered in the form of one or more pharmaceutical compositions (e.g., oral dosage forms such as tablets or capsules) which provide an in vivo plasma profile in humans, after 7 days of twice daily dosing, having at least one of:

a mean Cmax of more than about 30 ng/niL,

a mean AUCo- i2h of less than about 90 ng h/ml,

a mean Tmax of more than about 0.8 hours, and

a mean ti/2 of more than 6 hours.

According to a preferred embodiment, the pharmaceutical compositions provide an in vivo plasma profile in humans, after 7 days of twice daily dosing, having at least one of:

a mean Cmax ranging from about 30 to about 45 ng/niL,

a mean AUCo- i2h ranging from about 55 to about 80 ng h/ml,

a mean Tmax ranging from about 0.8 to about 1.2 hours, and

a mean ti/2 of ranging from about 7 to about 9.5 hours.

[20] According to another embodiment, about 120 mg MEM-1003 is administered in the form of one or more pharmaceutical compositions which provide an in vivo plasma profile in humans, after 7 days of twice daily dosing, having at least one of:

a mean Cmax of more than about 55 ng/niL,

a mean AUCo- i2h of less than about 160 ng h/ml,

a mean Tmax of more than about 0.8 hour, and

a mean ti/2 of more than 5 hours.

According to a preferred embodiment, the pharmaceutical compositions provide an in vivo plasma profile in humans, after 7 days of twice daily dosing, having at least one of:

a mean Cmax ranging from about 60 to about 75 ng/niL, a mean AUCo-i2h ranging from about 130 to about 155 ng h/ml,

a mean Tmax ranging from about 1 to about 1.5 hours, and

a mean ti/2 of ranging from about 6 to about 8 hours.

[21] According to one embodiment, patients treated with a therapeutically effective amount of MEM- 1003 have at least a 5 or 10 point and preferably a 15 point reduction in the Young Mania Rating Scale (YMRS) after about 3 weeks of treatment. In another embodiment, patients treated with a therapeutically effective amount of MEM- 1003 have a response rate of about 50 to about 60% (for example, compared to 25-30% placebo), in which a subject is a responder when the subject has at least a 50% improvement from baseline in the YMRS rating scale after about 3 weeks of treatment.

[22] MEM- 1003 may be administered as the sole active ingredient, typically in combination with psychotherapy, or in combination with one or more second therapeutic agents. A preferred second therapeutic agent is another bipolar I disorder-treating agent, such as lithium, a manic episode-treating agent, or a mixed episode treating agent.

Illustrative examples of such therapeutic agents include, but are not limited to: anticonvulsants (e.g., carbamazepine (Tegretol ®) , oxcarbazepine (Trileptal ®), ethosuximide

(Zarontin ) , felbamate (Felbatol ) , gabapentin (Neurontin ) , lamotrigine (LamictaO, phenobarbital (Luminal ) , phenytoin (Dilantin ) , topiramate (Topamax ®) , valproate, valproic acid, and divalproex sodium (Depakote ®)); mood stabilizers (e.g., lithium

(Lithobid and Eskalith )); antidepressants, such as bupropion (Wellbutrin ®), trazodone

(Dresyrel ®), serotonin-norepinephrine reuptake inhibitors (e.g., mirtazapine (Remeron ) , milnacipran, duloxetine, desipramine, nefazodone (Serzone ) , and venlafaxine (Effexor ®)) and selective serotonin reuptake inhibitors (e.g., sertraline (Zoloft ®) , fluoxetine (Prozac ®) , citalopram (Celexa ®), escitalopram (Lexapro ®), and paroxetine (Paxil ®)); antipsychotics (e.g., aripiprazole (Abilify®), chlorpromazine (Thorazine®), clozapine (Clozaril®), fluphenazine (Prolixin ) , olanzapine (Zyprexa®), quetiapine (Seroquef), risperidone

(Risperdal ) , thioridazine (Mellaril®), haloperidol (Haldol®) and ziprasidone (Geodon®)); benzodiazepines (e.g., clonazepam (Klonopin ) , diazepam (Valium ) , and lorazepam); and

[23] The MEM-1003 can be administered by any route of administration known in the medical art. Oral administration is preferred.

BRIEF DESCRIPTION OF THE DRAWINGS

[24] Figures 1-3 show the change in YMRS, MADRS, and CGI-BP scores in placebo and MEM-1003 patients in the modified intent-to-treat (mITT) population, which were treated according to the procedure described in Example 1 over 3 weeks.

[25] Figure 4 shows the change in YMRS scores in placebo and MEM-1003 patients in the intent-to-treat (ITT) population, which were treated according to the procedure described in Example 1 over 3 weeks.

[26] Figure 5 shows the change in YMRS scores for those patients in the intent- to-treat (ITT) population in the study described in Example 1 which had a YMRS score before treatment of at least 28. DETAILED DESCRIPTION OF THE INVENTION

Definitions

[27] MEM-1003 as used herein refers to (+)-isopropyl 2-methoxyethyl 4-(2- chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate. The MEM-

1003 is preferably administered in the form of the free base. Preferably, the (+)-isopropyl

2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5- dicarboxylate has an optical purity of at least 98, 98.5, 99, 99. 1, 99.2, 99.3, 99.4, 99.5,

99.6, 99.7, 99.8, or 99.9% (by weight) (i.e., the weight percentage of (+)-isopropyl 2- methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5- dicarboxylate based on the total weight of (+) and (-) isopropyl 2-methoxyethyl 4-(2- chloro-3-cyano-phenyl)- 1,4-dihydro-2 ,6-dimethyl-pyridine-3 ,5-dicarboxylate) . MEM- 1003 may be prepared by any method known in the art, such as that disclosed in U.S. Patent No.

5,665,740.

[28] As used herein, the term "patient" refers to a human, such as a man, woman, child, adolescent, adult, or elderly person.

[29] As used herein, the term "treating" refers to (1) preventing or delaying the appearance of clinical symptoms of a disease or condition in a patient that may be afflicted with or predisposed to the disease or condition, but does not yet experience or display clinical or subclinical symptoms of the disease or condition; (2) relieving the disease or condition, i.e., causing regression of the disease or condition or at least one of its clinical or sub-clinical symptoms; and (3) inhibiting the progression of the disease or condition, i.e., arresting or reducing its development or at least one clinical or sub-clinical symptom thereof. The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient and/or the physician. [30] As used herein, the terms "bipolar I disorder." "manic episode," "mixed episode," and major depressive disorder," and other clinical terms have the definitions provided for them in DSM-IV-TR (4lh Ed , 2000). According to the DSM-IV-TR, the essential feature of bipolar I disorder is a clinical course that is characterized by the occurrence of one or more manic episodes or mixed episodes. Often individuals have also had one or more major depressive episodes.

[31] A manic episode is defined by a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week

(or less if hospitalization is required). The criteria for a manic episode are:

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary).

B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:

(1) inflated self-esteem or grandiosity

(2) decreased need for sleep (e.g., feels rested after only 3 hours of sleep)

(3) more talkative than usual or pressure to keep talking

(4) flight of ideas or subjective experience that thoughts are racing

(5) distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)

(6) increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (7) excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

C. The symptoms do not meet criteria for a mixed episode.

D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.

E. The symptoms are not due to the direct physiological effects of a substance

(e.g., a drug of abuse, a medication, or other treatments) or a general medical condition (e.g., hyperthyroidism) .

Manic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of bipolar I disorder.

[32] A Mixed Episode is characterized by a period of time (lasting at least 1 week) in which the criteria are met both for a manic episode and for a major depressive episode nearly every day. The criteria for a mixed episode are:

A. The criteria are met both for a manic episode and for a major depressive episode (except for duration) nearly every day during at least a 1-week period.

B. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.

C. The symptoms are not due to the direct physiological effects of a substance

(e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism) . Mixed-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of bipolar I disorder.

[33] Signs and symptoms of depression (or a depressive episode) include, but are not limited to: lasting sad, anxious, or empty mood; feelings of hopelessness or pessimism; feelings of guilt, worthlessness, or helplessness; loss of interest or pleasure in activities once enjoyed, including sex; decreased energy, a feeling of fatigue or of being slowed down; difficulty concentrating, remembering, making decisions; restlessness or irritability; hypersomnolence, or insomnia; changes in appetite and/or unintended weight loss or gain; chronic pain or other persistent bodily symptoms that are not caused by physical illness or injury; thoughts of death or suicide, or suicide attempts agitation (DSM-IV-TR, 349-351).

[34] The term "Young Mania Rating Scale" (YMRS) refers to an 11-item instrument used to assess the severity of mania in patients, and is administered by a trained clinician who assigns a severity rating for each item based on a personal interview. The 11 items are elevated mood, increased motor activity energy, sexual interest sleep, irritability, speech (rate and amount), language-thought disorder, content disruptive-aggressive behavior, appearance, and insight. YMRS features operationally-defined anchor points and the normal expected score is greater than or equal to 20 (Young, et al., Br. J Psychiatry,

133:429-435 (1978)).

[35] The term "CGI modified for bipolar I disorder" (CGI-BP) is an adaptation of the original clinical global impression (CGI) scale assessment and allows for separate assessments of mania, depression, and overall bipolar disorder. The CGI-BP scale evaluates the severity of the subject's mental illness based on the clinicians' total experience with this patient population. Assessments for mania, depression, and overall bipolar I disorder are based on the previous week's experience. Rates for evaluated endpoints change relative to symptoms targeted and overall improvement (Spearing, et al., Psychiatry Research,

73: 159-171 (1973)).

[36] As used herein the Montgomery-Asberg Depression Rating Scale (MADRS) refers to a subscale of the Comprehensive Psychopathological Rating Scale, developed by

Montgomery and Asberg in 1979. This scale measures the effect of treatment on depression severity, as such, requires a baseline assessment (before treatment) with subsequent assessments during the course of treatment. The MADRS measures the severity of a number of symptoms on a scale of 0 to 6, including mood and sadness, tension, sleep, appetite, energy, concentration, suicidal ideation, and restlessness.

[37] The term "memory and/or cognitive impairment," as used herein, refers to difficulty with, or abnormality or loss (partial or complete) of: memory, perception, problem- solving abilities, conceptualization, spatial or temporal orientation, and/or problems with attention deficit. Memory and/or cognitive impairment can be present before, during, or after episodes associated with bipolar I disorder, and may be present before, during, or after any treatment for bipolar I disorder. Memory and/or cognitive impairment can manifest as confusion, inappropriate behavior, irritability, aggression, or other behaviors indicative of improper thought process. Finally, signs or symptoms of memory and/or cognitive impairment can be chronic, acute, continuous, non-continuous

(i.e., sporactic or intermittant), mild, or severe.

[38] The term "treatment refractory" as used herein refers to patients who have failed at least one treatment other than MEM- 1003 for their disorder. See, for example,

Vo, D., and Dunner, D .L., Treatment resistant bipolar disorder: a comparison of rapid cyclers and non-rapid cyclers, CNS Spectrums, 8:948-952 (2003). [39] The pharmacokinetic parameters described herein include area under the plasma concentration-time curve (AUCo -O, maximum plasma concentration (Cmax), time of

maximum plasma concentration (Tmax), and terminal elimination half-life (T 1 ). The time of maximum concentration, TmaX is determined as the time corresponding to Cmax. Area under the plasma concentration-time curve up to the time corresponding to the last measurable concentration (AUCo -O is calculated by numerical integration using the linear trapezoidal rule as follows:

AUC 0_t = 0.5 (C +C1 1 ) (f, - Eq. 1 ι=2 where C is the plasma concentrations at the corresponding sampling time point t and n is the number of time points up to and including the last quantifiable concentration. The terminal half-life (T1/2) is calculated using the following equation:

0.693 _ Tm = Eq. 2 λ z where Dz is the terminal elimination rate constant.

Methods of Treatment

[40] In the methods described herein, MEM- 1003 is typically administered in an amount sufficient for the desired effect.

[41] MEM- 1003 may be administered by any route. For example, MEM- 1003 may be administered parenterally, such as by one or multiple injection. Preferably, MEM-

1003 is administered orally, such as in the form of a tablet or capsule. The oral dosage form can be formulated for immediate release or controlled release of the MEM- 1003. [42] MEM- 1003 may be administered as the sole active ingredient, typically in combination with psychotherapy, or in combination with one or more second therapeutic agents. A preferred second therapeutic agent is another bipolar I disorder-treating agent, such as lithium, a manic episode-treating agent, or a mixed episode treating agent.

Illustrative examples of such therapeutic agents include, but are not limited to: anticonvulsants (e.g., carbamazepine (Tegretol ®), oxcarbazepine (Trileptal ®), ethosuximide

(Zarontin 4) , felbamate (Felbatol 4) , gabapentin (Neurontin 4) , lamotrigine (LamictaO, phenobarbital (Luminal ) , phenytoin (Dilantin ) , topiramate (Topamax ®), valproate, valproic acid, and divalproex sodium (Depakote®)); mood stabilizers (e.g., lithium

(Lithobid 4 and Eskalith )); antidepressants, such as bupropion (Wellbutrin ®), trazodone

(Dresyrel ®), serotonin-norepinephrine reuptake inhibitors (e.g., mirtazapine (Remeron 4) , milnacipran, duloxetine, desipramine, nefazodone (Serzone4) , and venlafaxine (Effexor ®)) and selective serotonin reuptake inhibitors (e.g., sertraline (Zoloft ®), fluoxetine (Prozac®), citalopram (Celexa®), escitalopram (Lexapro ®), and paroxetine (Paxil®)); antipsychotics

(e.g., aripiprazole (Abilify®), chlorpromazine (Thorazine ®), clozapine (Clozaril ®), fluphenazine (Prolixin ) , olanzapine (Zyprexa ®), quetiapine (Seroquef), risperidone

(Risperdal ) , thioridazine (Mellaril ®), haloperidol (Haldol®) and ziprasidone (Geodon®)); benzodiazepines (e.g., clonazepam (Klonopin4) , diazepam (Valium ) , and lorazepam); and

L-type calcium channel blockers (other than MEM-1003) (e.g., amlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, nitrendipine, niguldipine, clevidipine, nilvadipine, manidipine, and nisoldipine). This list of secondary agents is not limiting; it is contemplated that other mood stabilizers, antidepressants, anticonvulsants, calcium channel blockers, anti-psychotics, and other psychotropic drugs can be administered with MEM-1003 in the treatment methods of the present invention. The second agent may be administered with the MEM-1003 in a unitary dosage form (i.e., a dosage form containing both the MEM-1003 and the second agent), or concurrently in separate dosage forms, which may be administered by the same or different routes of administration.

Formulations

[43] MEM-1003 and optionally the second agent can be administered by any route including, but not limited to, orally, nasally, parenterally (subcutaneously, intraveneously, intramuscularly, intrasternally and by infusion), rectally, vaginally, topically and by ocular administration. MEM-1003 and optionally the second agent can be incorporated into a dosage form, such as a solid or liquid oral dosage form, suppository, vaginal dosage form, and topical dosage form. Such dosage forms typically contain one or more pharmaceutically acceptable carriers, diluents, and/or excipients.

[44] Suitable solid oral dosage forms include, but are not limited to, tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. MEM-1003 can be incorporated into the dosage form alone or in combination with one or more pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, and starches) and excipients, including but not limited to, suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, and lubricants.

The dosage form can provide controlled release of MEM-1003 and optionally the second agent. For example, the dosage form can be a time release capsule, tablet or gel.

[45] Suitable liquid oral dosage forms include, but are not limited to, aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain one or more suitable inert diluents, such as water, and excipients, such as preservatives, wetting agents, sweeteners, flavorants, and agents for emulsifying and/or suspending the MEM- 1003 and/or the second agent. The dosage form can be injected, for example, intravenously, in the form of an isotonic sterile solution.

[46] Suppositories for rectal administration of the MEM- 1003 and optionally the second agent can be prepared by mixing the MEM- 1003 and/or second agent with a suitable excipient, such as cocoa butter, salicylates or a polyethylene glycol. Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing the active ingredient(s) and one or more carriers.

[47] For topical administration the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. The topical formulation may be in the form of a transdermal patch.

[48] The MEM- 1003 and/or optional second agent can be present in these preparations in a concentration of 0.1 to 99.5% by weight and preferably at 0.5 to 95% by weight of the total formulation. In general, it has proven advantageous to administer

MEM- 1003 in total amounts of about 0.01 to about 50 mg/kg, preferably in total amounts of about 0. 1 mg/kg to 10 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired result. The amount of MEM- 1003 is provided in the equivalent weight of the free base.

[49] The following example illustrates the invention without limitation. All percentages are by weight unless otherwise indicated. Example 1

[50] A 2 1 day multi-center, double blind, placebo-controlled study was conducted to evaluate the efficacy and safety of (-l-)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano- phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate for the treatment of patients with bipolar I disorder suffering acute manic or mixed episodes. The response rate

(percentage of responders) was determined. Responders were defined as those subjects in the intent-to-treat population with at least a 50% reduction from day 0 to endpoint (day 21) in the Young Mania Rating Scale (YMRS). Changes in the subjects were also measured from day 1 to day 2 1 using the following parameters: YMRS; Modified Clinical Global

Impression-Bipolar Scale (CGI-BP) (improvement); and Montgomery-Asberg Depression

Rating Scale (MADRS). The safety profile of (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3- cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate was evaluated by monitoring adverse events (AEs), conducting various laboratory evaluations, measuring vital signs, performing electrocardiograms (ECGs), and giving physical examinations to study subjects. Finally, the pharmacokinetic profile (PK) of (+)-isopropyl 2-methoxyethyl

4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate administration was evaluated. Samples for population PK studies were obtained, and maximum plasma concentration (Cmax), area under the plasma concentration-time curve

(AUCO-24), and time of maximum plasma concentration (Tmax) were established.

Methods

[51] The study was a randomized, double-blind, multi-center study evaluating subjects with manic or mixed episodes of bipolar I disorder. Approximately 80 subjects participated in the study. The study consisted of a screening/washout phase, lasting from one to five days, with a single-blind placebo lead-in, a 2 1-day double-blind treatment phase, and an optional open-label treatment phase of up to 4 weeks.

[52] The 2 1-day treatment phase was subdivided into two periods: a mandatory inpatient hospitalization period from day one to day seven following randomization, and a subsequent outpatient treatment period which allowed the subjects to be discharged on or after day eight of randomization if the following two conditions were met: 1) the CGI-BP

Scale Severity-of-Illness (mania) score was < 3; and 2) the investigator judges decided that discharge to outpatient status would be in the best interests of the subject and study integrity. An overview of the study design is shown below:

Screening and Double-blind Treatment Optional Open-label Washout Phase Phase Period and Single-blind Run In

[53] During the outpatient treatment period, subjects who were discharged from the hospital were scheduled for weekly clinic visits (days 14 and 21) and two telephone visits (on or around days 10 and 17) for the remainder of the double-blind treatment phase.

At each weekly outpatient clinic visit, subjects underwent study assessments including, efficacy evaluations, AE assessment, compliance assessment, vital signs, ECG (day 2 1 only), review of concomitant medications, and clinical laboratory evaluations (day 2 1 only).

In addition to the above, subjects who remained hospitalized underwent AE assessment and vital sign measurement daily. Efficacy measures were obtained on days one and seven, and weekly thereafter. If, during outpatient status in the 21-day treatment phase, symptoms of bipolar I disorder re-emerged (e.g., mania or significant depression), the subject was discontinued from the study and were provided appropriate treatment as determined by the principal investigator.

[54] For subjects who successfully completed the study, an open-label, variable- duration, phase was available to facilitate a smooth transition back to the subjects routine maintenance care. During this period, subjects were transitioned to their standard therapy and monitored for safety and tolerability, including laboratory evaluation and efficacy assessments at termination.

[55] Subjects eligible for enrollment in the study were males and females aged

18-65 (inclusive) who (i) met the criteria for bipolar I disorder, acute manic or mixed episode, with or without psychotic features as established by the Mini International

Diagnostic Interview, Bipolar (MINI BP) (as determined by the DSM-IV-TR), (ii) had a

YMRS score of at least 20 at screening and baseline, with no more than 20% improvement between screening and baseline scores, and (iii) had a history of at least one previous manic or mixed episode requiring treatment in the last 10 years, with appropriate exclusions.

[56] (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate for oral administration was supplied as a hard white double-size 30 mg capsule. The dosage was started at 60 mg (two 30 mg capsules) twice per day (BID). There were two possible steps of dosage escalation: 1) from 60 mg BID

(two capsules) to 120 mg (four capsules) BID, starting on day 2 after randomization; and 2) from 120 mg (four capsules) BID to 180 mg (6 capsules) BID, starting after day 3 of randomization. These dose increases were based upon the investigator's overall judgment of the subject's response. Placebo for oral administration was also supplied in an identical form to the experimental drug.

[57] During the study, efforts were made to ensure that the same rater assessed each subject for each efficacy measurement throughout the entire study. Also, efficacy assessments were not completed within 8 hours after a subject received any rescue medication. Raters were certified by the study sponsor or its representative.

[58] A subject was deemed a responder if the subject had at least 50% improvement from the baseline on the YMRS at Day 21.

[59] Efficacy analyses were also conducted on the intent-to-treat (ITT) population, which was defined as all subjects who took at least one dose of study medication and were provided at least one post-baseline efficacy measurement. Safety analyses were performed on the safety population, which was defined as all subjects who took at least one dose of study medication and were provided at least one post-baseline efficacy measurement.

[60] 84 subjects met the inclusion/exclusion criteria and were randomized to one of the two treatment groups (42 subjects were randomized to each of the two treatment groups). All randomized subjects took study medication and were included in the safety and intent-to-treat efficacy analyses.

[61] For analysis purposes, the following populations were defined:

(a) Intent-to-Treat (ITT): All randomized patients who met study entry criteria, received at least one dose of study medication, had a valid baseline (Day 0) YMRS rating score, and had at least one non-missing post-baseline YMRS rating score. (b) Modified Intent-to-Treat (mITT): All randomized patients who met study entry criteria, received at least one dose of study medication, and had completed at least the

Day 7 assessments with no major protocol violations.

[62] Unless otherwise stated, all analyses were performed according to the

Statistical Analysis Plan (SAP), which was approved before the database was locked and treatment codes were unblinded. The primary efficacy variable, percent responders (i.e., subjects with at least 50% improvement from baseline in YMRS at day 21), was analyzed for the modified intent-to-treat population. Analysis results revealed no statistically significant treatment differences between the two treatment groups. The response rate was

38% for placebo and 26% for the MEM-1003 group (p=0.299).

[63] The change in YMRS, MADRS, and CGI-BP scores in placebo and MEM-

1003 patients in the modified intent-to-treat (mITT) population over the 3 week treatment time are shown in Figures 1-3, respectively. MEM-1003, however, was not statistically significantly different than placebo in the treatment of mania after 3 weeks of treatment.

[64] The change in YMRS score from baseline in the intent-to-treat population is shown in Table 1 below for all patients.

Table 1 Change from Baseline in YMRS Intent-to-Treat Population

Day Placebo (N=41) MEM 1003(N=42) Baseline N 4 1 42 Mean 28.9 27.8 SD 6.06 5.40 Median 29.0 27.0 Min, Max 20, 45 19, 42 The Values Below Are The Change from Baseline [65] Figure 4 shows the change in YMRS scores in placebo and MEM- 1003 patients in the intent-to-treat (ITT) population.

[66] The change in YMRS score from baseline is shown in Table 2 for those patients with an initial YMRS score of at least 28.

Table 2 Analysis results for change from baseline in YMRS (intent-to-treat population) (Baseline severity at least 28) [67] As shown by Figure 4, at day 3 the patients treated with MEM- 1003 which had an initial YMRS score of at least 28 exhibited a statistically significant reduction in

YMRS score compared to the placebo group (p < 0.05). At day 3, the daily dose of

MEM- 1003 was still increasing for most patients until it reached 180 mg bid daily; thus, suggesting that MEM- 1003 is effective at doses less than 180 mg bid daily (for example, at a dose of 120 mg bid).

[68] Although the invention herein has been described with reference to particular embodiments, these embodiments are merely illustrative of the principles and applications of the present invention. Therefore, numerous modifications may be made to the illustrative embodiments and other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

[69] All publications, patents, and published patent applications cited herein are incorporated by reference to the same extent as if each individual publication, patent, or published patent application was specifically and individually indicated to be incorporated herein by reference. We claim:

1. A method of treating mixed or manic episodes associated with bipolar I disorder in a patient comprising administering from about 15 to about 150 mg of (+)-isopropyl 2- methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5- dicarboxylate twice daily.

2. The method of claim 1, wherein from about 30 to about 90 mg of (+)-isopropyl 2- methoxyethyl-4-(2-chloro-3-cyano-phenyl)- 1,4-dihydro-2 ,6-dimethyl-pyridine-3 ,5- dicarboxylate is administered twice daily.

3. The method of claim 1, wherein from about 60 to about 120 mg of (+)-isopropyl

2-methoxyethyl-4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5- dicarboxylate is administered twice daily.

4. The method of claim 1, wherein about 15 mg of (+)-isopropyl 2-methoxyethyl-4-

(2-chloro-3-cyano-phenyl)- 1,4-dihydro-2 ,6-dimethyl-pyridine-3 ,5-dicarboxylate is administered twice daily.

5. The method of claim 4, wherein the about 15 mg (+)-isopropyl 2-methoxyethyl-4-

(2-chloro-3-cyano-phenyl)- 1,4-dihydro-2 ,6-dimethyl-pyridine-3 ,5-dicarboxylate is administered in the form of one or more pharmaceutical compositions which provide an in vivo plasma profile in humans (not previously treated with MEM- 1003) having at least one of: a mean Cmax of more than about 8 ng/mL,

a mean AUCo-t of less than about 20 ng h/ml (wherein t is the last time point with measurable concentrations),

a mean Tmax of more than about 0.7 hours, and

a mean ti/2 of more than 3.5 hours.

6 . The method of claim 1, wherein about 30 mg of (+)-isopropyl 2-methoxyethyl-4-

(2-chloro-3-cyano-phenyl)- 1,4-dihydro-2 ,6-dimethyl-pyridine-3 ,5-dicarboxylate is administered twice daily.

7 . The method of claim 6 , wherein the about 30 mg (+)-isopropyl 2-methoxyethyl-4-

a mean Cmax of more than about 8 ng/mL,

a mean AUCo-i2h of less than about 30 ng h/ml (wherein t is the last time point with measurable concentrations),

a mean Tmax of more than about 0.7 hour, and

a mean ti/2 of more than 6 hours.

8. The method of claim 1, wherein about 60 mg of (+)-isopropyl 2-methoxyethyl-4-

(2-chloro-3-cyano-phenyl)- 1,4-dihydro-2 ,6-dimethyl-pyridine-3 ,5-dicarboxylate is administered twice daily. 9 . The method of claim 8, wherein the about 60 mg (+)-isopropyl 2-methoxyethyl-4-

(2-chloro-3-cyano-phenyl)- 1,4-dihydro-2 ,6-dimethyl-pyridine-3 ,5-dicarboxylate is administered in the form of one or more pharmaceutical compositions which provide an in vivo plasma profile in humans, after 7 days of twice daily dosing, having at least one of:

a mean Cmax of more than about 30 ng/niL,

a mean AUCo- i2h of less than about 90 ng h/ml,

a mean Tmax of more than about 0.8 hours, and

a mean ti/2 of more than 6 hours.

10. The method of claim 1, wherein about 90 mg of (+)-isopropyl 2-methoxyethyl-4-

(2-chloro-3-cyano-phenyl)- 1,4-dihydro-2 ,6-dimethyl-pyridine-3 ,5-dicarboxylate is administered twice daily.

11. The method of claim 1, wherein about 120 mg of (+)-isopropyl 2-methoxyethyl-4-

(2-chloro-3-cyano-phenyl)- 1,4-dihydro-2 ,6-dimethyl-pyridine-3 ,5-dicarboxylate is administered twice daily.

12. The method of claim 11, wherein the about 120 mg (-l-)-isopropyl 2-methoxyethyl-

4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3, 5-dicarboxylate is administered in the form of one or more pharmaceutical compositions which provide an in vivo plasma profile in humans, after 7 days of twice daily dosing, having at least one of:

a mean Cmax of more than about 55 ng/niL,

a mean AUCo- i2h of less than about 160 ng h/ml, a mean Tmax of more than about 0.8 hour, and

a mean ti/2 of more than 5 hours.

13. The method of any of claims 1-12, wherein (+)-isopropyl 2-methoxyethyl 4-(2- chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate is administered at least twice daily for at least 3 weeks.

14. The method of claim 13, wherein the patient has at least a 5 point reduction in the

Young Mania Rating Scale after about 3 weeks of treatment.

15. The method of any of the preceding claims, wherein the patient has a Young Mania

Rating Scale score of at least 28 before treatment.

16. The method of any of claims 1-15, wherein (-l-)-isopropyl 2-methoxyethyl 4-(2- chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate is administered as the sole active ingredient.

17. The method of any of claims 1-15, wherein (-l-)-isopropyl 2-methoxyethyl 4-(2- chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate is administered in combination with a second agent for treating bipolar I disorder.

18. The method of claim 17, wherein the second agent is selected from anticonvulsants, mood stabilizers, antidepressants, antipsychotics, and calcium channel blockers. 19. The method of claim 17, wherein the second agent is selected from carbamazepine, oxcarbazepine, ethosuximide, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, valproic acid, divalproex sodium, lithium, bupropion, trazodone, mirtazapine, milnacipran, duloxetine, desipramine, nefazodone, venlafaxine, sertraline, fluoxetine, citalopram, escitalopram, paroxetine, aripiprazole, chlorpromazine, clozapine, fluphenazine, olanzapine, quetiapine, risperidone, thioridazine, haloperidol, ziprasidone, clonazepam, diazepam, lorazepam, donepezil, rivastigimine, galantamine, icopezil, pyridostigmine, edrophonium, neostigmine, physostigmine, Huperzine A, phenserine, and tacrine, amlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, nitrendipine, niguldipine, clevidipine, nilvadipine, manidipine, and nisoldipine.

20. A method of treating manic and mixed episodes associated with bipolar I disorder in a patient in need thereof comprising administering from about 15 to about 150 mg of

(+ )-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)- 1,4-dihydro-2 ,6-dimethyl- pyridine-3,5-dicarboxylate twice daily.

21. A method of treating depressive episodes associated with bipolar I disorder in a patient in need thereof comprising administering from about 15 to about 150 mg of (+)- isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-

3,5-dicarboxylate twice daily.

22. A method for maintenance treatment of bipolar I disorder in a patient in need thereof comprising administering from about 15 to about 150 mg of (+)-isopropyl 2- methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5- dicarboxylate twice daily.

23. The method of claim 22, wherein the treatment delays the time to occurrence of mood episodes.

24. The method of claim 23, wherein the mood episodes are selected from depression, mania, hypomania, and mixed episodes.

25. A method of treating or preventing memory and/or cognitive impairment in a patient suffering from bipolar I disorder comprising administering from about 15 to about

150 mg of (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate twice daily.

26. The method of claim 25, further comprising administering a second therapeutic agent for treating memory and/or cognitive impairment.

27. A method of relapse prevention in patients with bipolar I disorder comprising administering from about 15 to about 150 mg of (+)-isopropyl 2-methoxyethyl 4-(2- chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate twice daily.

INTERNATIONAL SEARCH REPORT International application No PCTVUS 08/55297

A CLASSIFICATION O F SUBJECT MATTER IPC(8) - A01 N 43/40, A61 K 31/44 (2008.04) USPC - 514/356 According to International Patent Classification (IPC) or to both national classification and IPC FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols) USPC - 514/356

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched USPC - 424/464, 546/321 (see search terms below)

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) WEST - PGPB,USPT,USOC,EPAB,JPAB; Dialog Classic Files 654, 652, 351, 349. 315, 6 , 155, 35, 65, USPTO Web Page, Google Scholar, Serach terms - manic episode, bipolar, depression. MEM-1003, cognitive, memory, dosage, Cmax, Tmax, Mama Rating Scale, relapse, combination agent

C DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where approp πate, of the relevant passages Relevant to claim No

US 2006/0094709 A 1 (KALALI et al ) 04 May 2006 (04 05 2006) para [0002], [0016], [0020]- 1-14, 20-27 [0021], [0025]-[0026] [0030], [00038], Fig 2

US 2005/0153953 A 1 (TRIPPODI-MURPHY θt al ) 14 July 2005 (14 07 2005) para [0002]- 1-14, 20-27 [0003], [0005]-[0006] [0008], [0015], [0034], [0045]

US 2005/0032799 A 1 (BUXTON et a l ) 10 February 2005 (10 02 2005) para [0002], [0019], 5, 7, 9, 12 [0055]

US 2006/0286167 A 1 (STAUNTON et al.) 2 1 December 2006 (21 12 2006) para [0003], [0041], 13-14, 22-24 [0045]

US 2006/0084692 A 1 (ERIK WONG et al ) 20 Apnl 2006 (20 04 2006) para [0004]-[0005] 27

Further documents are listed in the continuation of Box C

* Special categories of cited documents "T" later document published after the international filing date orpπoπty 'A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention 'E' earlier application or patent but published on orafter the international "X" document of particular relevance, the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive 'L" document which may throw doubts on priority claιm(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance, the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document published pnor to the international filing date but later than "&" document member of the same patent family the priority date claimed Date of the actual completion of the international search Date of mailing of the international search report

27 May 2008 (27 05 2008) 2 7 JUN 2008 Name and mailing address of the ISAAIS Authorized officer Mail Stop PCT, Attn ISA/US. Commissioner for Patents Lee W Young O Box 1450, Alexandria, Virginia 22313-1450 Facsimile No 571-273-3201 Form PCT/ISA/2 10 (second sheet) (April 2007) INTERNATIONAL SEARCH REPORT International application No PCT/US 08/55297

Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)

This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons

1 L J Claims Nos because they relate to subject matter not required to be searched by this Authority, namely

Claims Nos because they relate to parts of the international application that do not comply with the prescπbed requirements to such an extent that no meaningful international search can be carried out, specifically

Claims Nos 15-19 because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6 4(a)

Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet)

This International Searching Authority found multiple inventions in this international application, as follows

1 I I As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims

2 I I As all searchable claims could be searched without effort j ustifying additional fees, this Authority did not invite payment of additional fees

3 I I As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos

I No required additional search fees were timely paid by the -pplicant Consequently, this international search report is restricted to the invention first mentioned in the claims, it is covered by claims Nos

Remark on Protest I I The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee I I The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation I I No protest accompanied the payment of additional search fees Form PCT/ISA/2 10 (continuation of first sheet (2)) (April 2007)