WO2008106659A2

WO2008106659A2 - Methods of treating bipolar disorder and memory and/or cognitive impairment associated therewith

Info

Publication number: WO2008106659A2
Application number: PCT/US2008/055562
Authority: WO
Inventors: David Lowe; Christopher J. Leonard; Michael De Vivo; Geoffrey Tombaugh
Original assignee: Memory Pharmaceuticals Corporation
Priority date: 2007-03-01
Filing date: 2008-02-29
Publication date: 2008-09-04
Also published as: WO2008106659A3

Abstract

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 an effective amount of at least one calcium channel modulator selected from (1 ) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of a 1,4-dihydropyridine compound, other than (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)- l,4- dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate.

Description

METHODS OF TREATING BIPOLAR DISORDER AND MEMORY AND/OR COGNITIVE IMPAIRMENT ASSOCIATED THEREWITH

CROSS REFERENCE TO RELATED APPLICATION

[01 ] This application claims priority of US Provisional Patent Application No. 60/892,455 filed on March 1, 2007, the benefit of which is hereby claimed under 35 U. S. C. § 1 19 and the disclosure of which is herein incorporated by reference in its 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 an effective amount of at least one calcium channel modulator selected from (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of certain 1 ,4- dihydropyridine compounds.

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] 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

[06] 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 by administering a therapeutically effective amount of at least one calcium channel modulator ("CCM") selected from (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of a 1 ,4-dihydropyridine compound, other than (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l ,4- dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate. According to a preferred embodiment, the chemical structure of the R-enantiomer of the 1,4-dihydropyridine is:

or a pharmaceutically acceptable salt thereof, where

R¹ is methyl or -CN;

R² is Ci-C₄ alkyl optionally substituted with Ci-C₄ alkoxy, NR⁵R⁶, or -OC(O)- (Ci-C₄ alky 1)

R³ is Ci-C₄ alkyl;

R⁴ is (i) phenyl substituted with one or more substituents selected from halogen and NO₂ or (ii) benzofused heterocyclic group; and

R⁵ and R⁶ are independently Ci-C₄ alkyl, aryl, or aryl(C]-C₄ alkyl), or R⁵ and R⁶ together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted by one or two CpC₄ alkyl or aryl groups.

According to one embodiment, the CCM is the R-enantiomer of amlodipine, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, nimodipine, nifedipine, nicardipine or nitrendipine.

[07] Patients administered the R-enantiomer of one of the aforementioned dihydropyridines can be treated for the disorders without inducing cardiovascular effects commonly associated with racemic 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.

[08] The invention also relates to a method of prophylactically treating the recurrence of mixed or manic episodes associated with bipolar I disorder or memory and/or cognitive impairment associated therewith in a patient by administration of an effective amount of at least one CCM. The patient may be in remission and not currently experiencing symptoms associated with bipolar I disorder.

[09] The invention further relates to a method of treating depressive episodes associated with bipolar I disorder in a patient by administration of an effective amount of at least one CCM.

[10] The invention further relates to a method of maintenance treatment of bipolar I disorder in a patient by administration of an effective amount of at least one CCM. In one embodiment, the treatment delays the time to occurrence of mood episodes (such as depression, mania, hypomania, and mixed episodes).

[1 1 ] The invention further relates to a method of relapse prevention in patients with bipolar I disorder by administration of an effective amount of at least one CCM.

[12] The patient may be of any age, such as a child, an adolescent, or an adult, or may be elderly. Furthermore, the CCM is effective in treatment-refractory patients.

[13] The duration of the treatment is preferably at least 3 weeks. According to one embodiment, patients treated with a therapeutically effective amount of at least one CCM have at least a 30% reduction in the Young Mania Rating Scale after about 3 weeks of treatment.

[14] The CCM may be administered as the sole active ingredient, 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 (Lamictal^®), 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 (Seroquel^®), risperidone (Risperdal^®), thioridazine (Mellaril^®), haloperidol (Haldol^®) and ziprasidone (Geodon^®)); benzodiazepines (e.g., clonazepam (Klonopin^®), diazepam (Valium^®), and lorazepam); and L-type calcium channel blockers (other than CCM) (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, antipsychotics, and other psychotropic drugs can be administered with the CCM in the treatment methods of the present invention.

[15] The CCM can be administered by any route of administration known in the art. Oral administration is preferred. DETAILED DESCRIPTION OF THE INVENTION

Definitions

[16] Preferably, the R-enantiomers of the dihydropyridines described herein have 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 R-enantiomer of the dihydropyridine based on the total weight of R and S enantiomers of the dihydropyridine). The dihydropyridines and their optically pure enantiomers may be prepared by methods known in the art. The dihydropyridines described herein may be administered in their free base form or, when appropriate, as pharmaceutically acceptable salts (e.g., acid addition salts such as hydrochloride salts, besylate salts, and maleate salts) of the dihydropyridine.

[17] The term "halogen" as used herein refers to F, Cl, Br, and I. Preferred halogens are F and Cl. More preferred is Cl.

[18] The term "alkyl" as used herein refers to a straight-chain or branched- chain aliphatic hydrocarbon radical. Suitable alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

[19] The term "alkoxy" as used herein refers an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are - OCH₃ and -OC₂H₅.

[20] The term "aryl" as used herein refer to an aromatic carbocyclic radical containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl.

[21] In the "aryl(C_rC₄ alkyl)" groups, "alkyl" refers to a divalent alkylene group having 1 to 4 carbon atoms. A preferred aryKCpCj alkyl) group is benzyl. [22] The term "hetereocyclic ring" refers to a 5- or 6- membered non-aromatic, saturated or partially unsaturated, cyclic group containing at least one hetero-ring atom, preferably nitrogen. A preferred heterocyclic ring is piperidinyl.

[23] The term "benzofused heterocyclic group" refers to a phenyl group fused to a heterocyclic ring, such as a benzo[c][l,2,5]oxadiazole.

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

[25] 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.

[26] As used herein, the terms "bipolar [ disorder," "manic episode." ''mixed episode," and "major depressive disorder," and other clinical terms have the definitions provided for them in DSM-IV-TR (4^th Fd.. 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.

[27] 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.

[28] 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.

[29] 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).

[30] The term "Young Mania Rating Scale" (YMRS) refers to an 1 1 -item instrument used to assess the severity of mania in patients, and is administered b\ a trained clinician who assigns a severity rating for each item based on a personal interview . The 1 1 items are elevated mood, increased motor activity energ> . 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)).

[31] The term ''memory and/or cognitive impairment," as used herein, refers to difficulty w ith, 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.

[32] The term "treatment refractory" as used herein refers to patients who have failed at least one treatment other than a CCM of the present invention 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). [33] All weight amounts of CCM described herein are provided based upon a molar equivalent of the free base unless otherwise indicated.

Methods of Treatment

[34] In the methods described herein, the CCM is typically administered in an amount sufficient for the desired effect. The amount can be determined by methods known in the art. Preferably, the amount of the CCM is less than that which causes a significant hypotensive effect.

[35] The CCM may be administered by any route. For example, the CCM may be administered parenterally, such as by one or multiple injection. Preferably, the CCM 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 CCM.

[36] According to one embodiment,

(1) from about to 0.5 about 20 mg of R-amolidipine (or a pharmaceutically acceptable salt thereof),

(2) from about 0.5 to about 20 mg of R-felodipine (or a pharmaceutically acceptable salt thereof),

(3) from about 0.5 to about 20 mg of R-isradipine (or a pharmaceutically acceptable salt thereof),

(4) from about 0.5 to about 10 mg of R-lacidipine (or a pharmaceutically acceptable salt thereof),

(5) from about 0.5 to about 20 mg of R-lercanidipine (or a pharmaceutically acceptable salt thereof),

(6) from about 0.5 to about 40 mg of R-manidipine (or a pharmaceutically acceptable salt thereof), (7) from about 0.5 to about 40 mg of R-nisoldipine (or a pharmaceutically acceptable salt thereof),

(8) from about 5 to about 90 mg of R-nifedipine (or a pharmaceutically acceptable salt thereof),

(9) from about 2 to about 60 mg of R-nicardipine (or a pharmaceutically acceptable salt thereof), or

(10) from about to about mg of R-nitrendipine (or a pharmaceutically acceptable salt thereof) is orally administered daily.

[37] The CCM may be administered as the sole active ingredient, 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 (Lamictal^®), 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 (Seroquel^®), risperidone (Risperdal^®), thioridazine (Mellaril^®), haloperidol (Haldol^®) and ziprasidone (Geodon^®)); benzodiazepines (e.g., clonazepam (Klonopin^®), diazepam (Valium^®), and lorazepam); and L-type calcium channel blockers (other than CCM) (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, antipsychotics, and other psychotropic drugs can be administered with the CCM in the treatment methods of the present invention. The second agent may be administered with the CCM in a unitary dosage form (i.e., a dosage form containing both the CCM and the second agent), or concurrently in separate dosage forms, which may be administered by the same or different routes of administration.

Formulations

[38] The CCM 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. The CCM 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.

[39] Suitable solid oral dosage forms include, but are not limited to, tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The CCM 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 the CCM and optionally the second agent. For example, the dosage form can be a time release capsule, tablet or gel.

[40] 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 CCM and/or the second agent. The dosage form can be injected, for example, intravenously, in the form of an isotonic sterile solution.

[41] Suppositories for rectal administration of the CCM and optionally the second agent can be prepared by mixing the CCM 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.

[42] 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.

[43] The CCM 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 CCM 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 CCM is provided in the equivalent weight of the free base.

[44] 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.

[45] 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.

Claims

We claim:

1. A method of treating mixed or manic episodes associated with bipolar I disorder in a patient comprising administering an effective amount of at least one calcium channel modulator selected from (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of a 1,4-dihydropyridine compound, other than (+)- isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl- pyridine-3,5-dicarboxylate.

2. The method of claim 1, wherein the calcium channel modulator has the formula:

or a pharmaceutically acceptable salt thereof, where

R¹ is methyl or -CN;

R² is Ci-C₄ alkyl optionally substituted with C]-C₄ alkoxy, NR⁵R⁶, or -OC(O)- (C₁-C₄ alkyl)

R³ is C-C₄ alkyl;

R⁵ and R⁶ are independently C-C₄ alkyl, aryl, or aryl(d-C₄ alkyl), or R⁵ and R⁶ together with the nitrogen atom to which they are attached may form a heterocyclic ring optionally substituted by one or two Ci -C₄ alkyl or aryl groups.

3. The method of claim 1 , wherein the calcium channel modulator is the R- enantiomer of a dihydropyridine selected from amlodipine, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, nimodipine, nifedipine, nicardipine and nitrendipine.

4. The method of any of claims 1-3, wherein the calcium channel modulator is administered at least once daily for at least 3 weeks.

5. The method of claim 4, wherein the patient has at least a 30% reduction in the Young Mania Rating Scale after about 3 weeks of treatment.

6. The method of any of claims 1-5, wherein the calcium channel modulator is administered as the sole active ingredient.

7. The method of any of claims 1-5, wherein the calcium channel modulator is administered in combination with a second agent for treating bipolar I disorder.

8. The method of claim 7, wherein the second agent is selected from anticonvulsants, mood stabilizers, antidepressants, antipsychotics, and calcium channel blockers.

9. The method of claim 7, 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, aripiprazoie, 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.

10. A method of treating manic and mixed episodes associated with bipolar I disorder in a patient in need thereof comprising administering an effective amount of at least one calcium channel modulator selected from (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of a 1,4-dihydropyridine compound, other than (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate.

1 1. A method of treating depressive episodes associated with bipolar 1 disorder in a patient in need thereof comprising administering an effective amount of at least one calcium channel modulator selected from (1 ) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of a 1,4-dihydropyridine compound, other than (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6- dimethyl-pyridine-3,5-dicarboxylate.

12. A method for maintenance treatment of bipolar I disorder in a patient in need thereof comprising administering an effective amount of at least one calcium channel modulator selected from (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of a 1 ,4-dihydropyridine compound, other than (+)- isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l ,4-dihydro-2,6-dimethyl- pyridine-3,5-dicarboxylate.

13. The method of claim 12, wherein the treatment delays the time to occurrence of mood episodes.

14. The method of claim 13, wherein the mood episodes are selected from depression, mania, hypomania, and mixed episodes.

15. A method of treating or preventing memory and/or cognitive impairment in a patient suffering from bipolar I disorder comprising administering an effective amount of at least one calcium channel modulator selected from (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of a 1 ,4- dihydropyridine compound, other than (+)-isopropyI 2-methoxyethyl 4-(2-chloro-3- cyano-phenyl)-l ,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate.

16. The method of claim 15, further comprising administering a second therapeutic agent for treating memory and/or cognitive impairment.

17. A method of relapse prevention in patients with bipolar I disorder comprising administering an effective amount of at least one calcium channel modulator selected from (1) amlodipine, bepridil, clevidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, niguldipine, nilvadipine, nisoldipine, or nitrendipine, or (2) the R-enantiomer of a 1,4-dihydropyridine compound, other than (+)-isopropyl 2- methoxyethyl 4-(2-chloro-3-cyano-phenyl)-l,4-dihydro-2,6-dimethyl-pyridine-3,5- dicarboxylate.