# US 2019/0302102 A1 · Combination therapies for treating bipolar disorder, and methods for using the same > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2019/0302102 A1 - Document ID: US20190302102A1 - Status: Published application - Kind: A1 - Application number: 16/346,212 - Filed: 2017-10-26 - Published: 2019-10-03 - Earliest claimed: 2016-11-11 - Assignees: PsychNostics, LLC - Applicants: PsychNostics, LLC - Inventors: Alagu P. THIRUVENGADAM - Web page: https://patentgrep.com/patent/US20190302102A1 ## CPC - G01N 33/5044: {involving specific cell types} - A61K 33/00: Medicinal preparations containing inorganic active ingredients - A61K 33/06: Aluminium, calcium or magnesium; Compounds thereof {, e.g. clay} - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - G16H 20/10: relating to drugs or medications, e.g. for ensuring correct administration to patients - G01N 2800/304: Mood disorders, e.g. bipolar, depression - G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - G16H: HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA ## Abstract The present invention relates to pharmaceutical combinations and compositions, and methods of using the same for treatment of Bipolar Disorder (BD). More specifically, the invention relates to combination therapies for the treatment of BD, and methods for treating BD using such therapies. The present invention also relates to methods of determining an optimal combination drug treatment therapy for BD, methods of optimizing a combination drug treatment therapy for BD, methods of optimizing dosage of a drug in a combination drug treatment therapy for BD, as well as methods for monitoring the efficacy of a combination therapy for the treatment of BD. The present invention involves analyzing the membrane potential of cells isolated from a BD patient treated with the combination therapy, and calculating a membrane potential ratio therefrom. ## Claims ### Claim 1 A method of determining an optimal combination drug treatment therapy for a patient with bipolar disorder (BD), comprising: obtaining a ratio of a mean membrane potential that is a mean membrane potential of a first population of cells from the BD patient incubated in vitro in the presence of an agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of cells from the BD patient incubated in vitro in the absence of the test agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+; comparing the ratio of the mean membrane potential to (a) and/or (b): (a) a control ratio of a mean membrane potential of first population of control human cells known to not have BD incubated in vitro in the presence of the agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of the control human cells incubated in vitro in the absence of the agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+, (b) a bipolar control ratio of a mean membrane potential of first population of bipolar control human cells known to have BD incubated in vitro in the presence of the agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of the bipolar control human cells incubated in vitro in the absence of the agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+: identifying the optimal combination drug treatment therapy when the ratio of the mean membrane potential obtained is not significantly different from the control ratio in (a), is increased towards the control ratio in comparison to the bipolar control ratio of (b), and/or is significantly higher than the BD control ratio in (b). ### Claim 2 A method of optimizing a combination drug treatment therapy for a patient with bipolar disorder (BD), comprising the steps of: obtaining at least one sample from a BD patient in a drug therapy treatment for BD; performing on each sample, a mean membrane potential test comprising: obtaining a ratio of a mean membrane potential that is a mean membrane potential of a first population of cells from the sample incubated in vitro in the presence of an agent that alters diacylglycerol signaling and in the absence of K+ to a mean membrane potential of a second population of the sample incubated in vitro in the absence of the test agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+; comparing the ratio of the mean membrane potential to (a) and/or (b): (a) a control ratio of a mean membrane potential of a first population of control human cells known to not have BD incubated in vitro in the presence of the agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of the control human cells incubated in vitro in the absence of the agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+, (b) a bipolar control ratio of a mean membrane potential of a first population of bipolar control human cells known to have BD incubated in vitro in the presence of the agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of the bipolar control human cells incubated in vitro in the absence of the agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+: determining an optimal drug therapy treatment for the BD patient based on the mean membrane potential test when the ratio of the mean membrane potential obtained is not significantly different from the control ratio of (a), is increased towards the control ratio in comparison to the bipolar control ratio of (b), and/or is significantly higher than the BD control ratio of (b); and optionally, modifying at least one drug in the drug therapy treatment for BD when the least one drug treatment therapy for BD is determined to not be the optimal drug therapy treatment based on the mean membrane potential test. ### Claim 3 A method for determining an optimum dosage of a drug in a combination drug treatment therapy for the treatment of bipolar disorder (BD), said method comprising: obtaining at least one sample from a BD patient treated with a dosage of a drug in a combination therapy; performing on each sample, a mean membrane potential test comprising: obtaining a ratio of a mean membrane potential that is a mean membrane potential of a first population of cells from the BD patient incubated in vitro in the presence of an agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of cells from the BD patient incubated in vitro in the absence of the test agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+; comparing the ratio of the mean membrane potential to (a) and/or (b): (a) a control ratio of a mean membrane potential of a first population of cells from a control human known to not have said BD incubated in vitro in the presence of the agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of cells from the control human incubated in vitro in the absence of the agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+, (b) a bipolar control ratio of a mean membrane potential of a first population of cells from a bipolar control human known to have said BD incubated in vitro in the presence of the agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of cells from the bipolar control human incubated in vitro in the absence of the agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+; determining the dosage of the drug in the combination drug treatment therapy is an optimal dosage for treating BD in the combination therapy based on the mean membrane potential test when the ratio of the mean membrane potential obtained is not significantly different from the control ratio of (a), is increased towards the control ratio in comparison to the bipolar control ratio of (b), and/or is significantly higher than the BD control ratio of (b); and optionally, modifying the dosage of the drug in the combination drug treatment therapy when the dosage of the drug in the combination therapy is determined to be not the optimal dosage for treating BD based on the mean membrane potential test. ### Claim 4 A method for monitoring the efficacy of a combination drug treatment therapy for the treatment of bipolar disorder (BD), said method comprising: obtaining at least one sample from a BD patient treated with a combination drug treatment therapy for treating BD; performing on each sample, a mean membrane potential test comprising: obtaining a ratio of a mean membrane potential that is a mean membrane potential of a first population of cells from the BD patient incubated in vitro in the presence of an agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of cells from the BD patient incubated in vitro in the absence of the test agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+; comparing the ratio of the mean membrane potential to (a) and/or (b): (a) a control ratio of a mean membrane potential of a first population of cells from a control human known to not have said BD incubated in vitro in the presence of the agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of cells from the control human incubated in vitro in the absence of the agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+, (b) a bipolar control ratio of a mean membrane potential of a first population of cells from a bipolar control human known to have said BD incubated in vitro in the presence of the agent that alters diacylglycerol signaling and in the absence of K+, to a mean membrane potential of a second population of cells from the bipolar control human incubated in vitro in the absence of the agent that alters diacylglycerol signaling and in the presence of K+ or absence of K+; determining the combination drug treatment therapy is efficacious based on the mean membrane potential test when the ratio of the mean membrane potential obtained is not significantly different from the control ratio in (a), is increased towards the control ratio in comparison to the bipolar control ratio of (b), and/or is significantly higher than the BD control ratio in (b); and optionally, adjusting a dosage of one or more agents in the combination drug treatment therapy when the combination therapy is determined to be not efficacious based on the mean membrane potential test. ### Claim 5 (depends on 1, 2, 3) The method according to claim 1, 2, 3, or 4, further comprising obtaining an initial ratio of a mean membrane potential from an initial population of cells from the human patient before the obtaining step. ### Claim 6 (depends on 1, 2, 3) The method of claim 1, 2, 3, or 4, wherein the human cells is selected from the group consisting of red blood cells, lymphoblasts, erythocytes, platelets, leukocytes, macrophages, monocytes, dendritic cells, fibroblasts, epidermal cells, mucosal tissue cells, cells of cerebrospinal fluid, hair cells, and whole blood cells. ### Claim 7 (depends on 6) The method of claim 6, wherein the human cells is selected from the group consisting of red blood cells and lymphoblasts. ### Claim 8 (depends on 1, 2, 3) The method of claim 1, 2, 3, or 4, wherein the combination drug treatment therapy is synergistic combination. ### Claim 9 (depends on 8) The method of claim 8, wherein the combination drug treatment therapy comprises a lithium compound and at least one adjunctive agent. ### Claim 10 (depends on 9) The method of claim 9, wherein the lithium compound is present in an effective amount sufficient to provide a plasma lithium level of 1 mM or less. ### Claim 11 (depends on 10) The method of claim 10, wherein the plasma lithium level is 0.5 mM or less. ### Claim 12 (depends on 9) The method of claim 9, wherein the at least one adjunctive agent is selected from the group consisting of a mood stabilizer, an anticonvulsant, an antipsychotic, an anxiolytic, and a cholinergic agonist. ### Claim 13 (depends on 12) The method of claim 12, wherein the cholinergic agonist is selected from the group consisting of donepezil, galantamine, rivastigmine, tacrine, donepezil/memantine, methoctramine, AF-DX384, acetylcholine, methacholine, arecoline, bethanechol, carbachol, pilocarpine, muscarine, cevimeline, nicotine, and pharmaceutically acceptable salts thereof. ### Claim 14 (depends on 12) The method of claim 12, wherein the mood stabilizer is selected from the group consisting of valproate, divalproex, carbamazepine, lamotrigine, oxcarbazepine, and pharmaceutically acceptable salts thereof. ### Claim 15 (depends on 12) The method of claim 12, wherein the anticonvulsant is selected from the group consisting of lamotrigine, perampanel, mephobarbital, primidone, phenobarbital, diazepam, clonazepam, lorazepam, clobazam, felbamate, topiramate, acetazolamide, zonisamide, rufinamide, oxcarbazepine, carbamazepine, eslicarbazepine, valproic acid, divalproex sodium, gabapentin, gabapentin enacarbil, tiagabine, phenytoin, fosphenytoin, mephenytoin, ethotoin, magnesium sulfate, lacosamide, ezogabine, trimethadione, levetiracetam, ethosuximide, methsuximide, and pharmaceutically acceptable salts thereof. ### Claim 16 (depends on 12) The method of claim 12, wherein the antipsychotic is selected from the group consisting of haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, perphenazine, chlorpromazine, aripiprazole, clozapine, ziprasidone, risperidone, asenapine, cariprazine, olanzapine, quetiapine, lurasidone, olanzapine, loxapine, and pharmaceutically acceptable salts thereof. ### Claim 17 (depends on 12) The method of claim 12, wherein the antidepressant is selected from the group consisting of fluoxetine, ariprazole, doxepin, clomipramine, bupropion, amoxapine, nortriptyline, vortioxetine, citalopram, duloxetine, trazodone, venlafaxine, selegiline, perphenazine, amitriptyline, levomilnacipram, desvenlafaxine, lurasidone, lamotrigine, escitalopram, chlordiazepoxide, isocarboxazid, phenelzine, desipramine, trazodone, tranylcypromine, paroxetine, mirtazapine, quetiapine, nefazodone, doxepin, trimipramine, imipramine, vilazodone, protriptyline, sertraline, olanzapine, and pharmaceutically acceptable salts thereof. ### Claim 18 (depends on 12) The method of claim 12, wherein the anxiolytic is selected from the group consisting of secobarbital, mephobarbital, pentobarbital, phenobarbital, amobarbital, butabarbital, estazolam, alprazolam, flurazepam, diazepam, chlordiazepoxide, clorazepate, clonazepam, oxazepam, diazepam, triazolam, lorazepam, temazepam, midazolam, clobazam, diphenhydramine, zolpidem, chloral hydrate, doxepin, sodium oxybate, doxylamine, doxepin, hydroxyzine, meprobamate, ethchlorvynol, eszopiclone, buspirone, zalephon, ramelteon, suvorexant, tryptophan, tasimelteon, dexmedetomidine, and pharmaceutically acceptable salts thereof. ### Claim 19 (depends on 1, 2, 3) The method of claim 1, 2, 3, or 4, wherein the agent that alters diacylglycerol signaling is selected from the group consisting of a calcium-calmodulin (Ca2+/CaM) kinase inhibitor, a diacylglycerol kinase inhibitor, a protein kinase C inhibitor, and an agent that affects calcium-activated potassium (CaK) channels. ### Claim 20 (depends on 19) The method of claim 19, wherein the agent is a calcium-calmodulin (Ca2+/CaM) kinase inhibitor. ### Claim 21 (depends on 20) The method of claim 20, wherein the calcium-calmodulin (Ca2+/CaM) kinase inhibitor is autocamtide-2-related inhibitory peptide (AIP). ### Claim 22 (depends on 19) The method of claim 19, wherein the agent is a diacylglycerol kinase inhibitor. ### Claim 23 (depends on 22) The method of claim 22, wherein the diacylglycerol kinase inhibitor is 6-[2-[4-[(4-fluorophenyl)phenylmethylene]-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-alpyrimidin-5-one (ALX). ### Claim 24 (depends on 1, 2, 3) The method of claim 1, 2, 3, or 4, wherein the mean membrane potential test further comprises incubating the cells in vitro in buffer comprising a potential-sensitive dye, resuspending the cells in potential-sensitive dye free-buffer, and measuring the cell fluorescence. ### Claim 25 (depends on 1, 2, 3) The method of claim 1, 2, 3, or 4, wherein the agent that alters K+ channel activity is ethanol, amphetamine, ephedrine, cocaine, caffeine, nicotine, methylphenidate, lithium, δ-9-tetrahydrocannibinol, phencyclidine, lysergic acid diethylamide (LSD), mescaline, or combinations thereof. ### Claim 26 (depends on 25) The method of claim 25, wherein the agent that alters K+ channel activity is ethanol. ### Claim 27 A method of treating bipolar disorder (BD), comprising administering an effective amount of a lithium compound and at least one adjunctive agent to a human patient with BD. ### Claim 28 A method of increasing the therapeutic efficacy of a lithium compound for the treatment of bipolar disorder (BD), comprising administering an effective amount of a lithium compound with at least one adjunctive agent, to a human patient with BD. ### Claim 29 (depends on 27, 28) The method of claim 27 or 28, wherein the at least one adjunctive agent and the lithium compound form a synergistic combination or composition to treat said BD. ### Claim 30 (depends on 27, 28) The method of claim 27 or 28, wherein the effective amount of lithium compound is a dose amount that is less than a dosage of lithium required to provide a therapeutically efficacious plasma lithium level for BD therapy when used alone. ### Claim 31 (depends on 30) The method of claim 30, wherein the dose provides a plasma lithium level of 1 mM or less. ### Claim 32 (depends on 31) The method of claim 31, wherein the dose provides a plasma lithium level of 0.5 mM or less. ### Claim 33 (depends on 27, 28) The method of claim 27 or 28, wherein the at least one adjunctive agent is administered at a dose that is less than a dosage of the at least one adjunctive agent required to provide a therapeutically efficacious plasma level of the at least one adjunctive agent when administered alone. ### Claim 34 (depends on 27, 28) The method of claim 27 or 28, wherein the at least one adjunctive agent is selected from the group consisting of a mood stabilizer, an anticonvulsant, an antipsychotic, an anxiolytic, and a cholinergic agonist. ### Claim 35 (depends on 34) The method of claim 34, wherein the cholinergic agonist is selected from the group consisting of donepezil, galantamine, rivastigmine, tacrine, donepezil/memantine, methoctramine, AF-DX384, acetylcholine, methacholine, arecoline, bethanechol, carbachol, pilocarpine, muscarine, cevimeline, nicotine, and pharmaceutically acceptable salts thereof. ### Claim 36 (depends on 35) The method of claim 35, wherein the cholinergic agonist is carbachol and pharmaceutically acceptable salts thereof. ### Claim 37 (depends on 35) The method of claim 35, wherein the cholinergic agonist is donepezil and pharmaceutically acceptable salts thereof. ### Claim 38 (depends on 34) The method of claim 34, wherein the antipsychotic is selected from the group consisting of haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, perphenazine, chlorpromazine, aripiprazole, clozapine, ziprasidone, risperidone, asenapine, cariprazine, olanzapine, quetiapine, lurasidone, olanzapine, loxapine, and pharmaceutically acceptable salts thereof. ### Claim 39 (depends on 38) The method of claim 38, wherein said antipsychotic is clozapine and pharmaceutically acceptable salts thereof. ### Claim 40 (depends on 36) The method of claim 36, wherein the carbachol is administered to said patient to provide a plasma concentration of 10 μM or less. ### Claim 41 (depends on 37) The method of claim 37, wherein the donepezil is administered to said patient to provide a plasma concentration of 10 ng/ml or less. ### Claim 42 (depends on 39) The method of claim 39, wherein the clozapine is administered to said patient to provide a plasma concentration of 100 ng/ml or less. ### Claim 43 A pharmaceutical combination comprising a lithium compound and at least one adjunctive agent. ### Claim 44 A pharmaceutical composition comprising a lithium compound and at least one adjunctive agent; and a pharmaceutically acceptable carrier. ### Claim 45 (depends on 43, 44) The pharmaceutical combination or composition of claim 43 or 44, wherein the effective amount of lithium compound is a dose amount that is less than a dosage of lithium required to provide a therapeutically efficacious plasma lithium level for BD therapy when used alone. ### Claim 46 (depends on 45) The pharmaceutical combination or composition of claim 45, wherein the dose provides a plasma lithium level of 1 mM or less. ### Claim 47 (depends on 46) The pharmaceutical combination or composition of claim 46, wherein the dose provides a plasma lithium level of 0.5 mM or less. ### Claim 48 (depends on 43, 44) The pharmaceutical combination or composition of claim 43 or 44, wherein the at least one adjunctive agent is administered at a dose that is less than a dosage of the at least one adjunctive agent required to provide a therapeutically efficacious plasma level of the at least one adjunctive agent when administered alone. ### Claim 49 (depends on 43, 44) The pharmaceutical combination or composition of claim 43 or 44, wherein the at least one adjunctive agent is selected from the group consisting of a mood stabilizer, an anticonvulsant, an antipsychotic, an anxiolytic, and a cholinergic agonist. ### Claim 50 (depends on 49) The pharmaceutical combination or composition of claim 49, wherein the cholinergic agonist is selected from the group consisting of donepezil, galantamine, rivastigmine, tacrine, donepezil/memantine, methoctramine, AF-DX384, acetylcholine, methacholine, arecoline, bethanechol, carbachol, pilocarpine, muscarine, cevimeline, nicotine, and pharmaceutically acceptable salts thereof. ### Claim 51 (depends on 50) The pharmaceutical combination or composition of claim 50, wherein the cholinergic agonist is carbachol and pharmaceutically acceptable salts thereof. ### Claim 52 (depends on 50) The pharmaceutical combination or composition of claim 50, wherein the cholinergic agonist is donepezil and pharmaceutically acceptable salts thereof. ### Claim 53 (depends on 49) The pharmaceutical combination or composition of claim 49, wherein the antipsychotic is selected from the group consisting of haloperidol, loxapine, thioridazine, molindone, thiothixene, fluphenazine, mesoridazine, trifluoperazine, perphenazine, chlorpromazine, aripiprazole, clozapine, ziprasidone, risperidone, asenapine, cariprazine, olanzapine, quetiapine, lurasidone, olanzapine, loxapine, and pharmaceutically acceptable salts thereof. ### Claim 54 (depends on 53) The pharmaceutical combination or composition of claim 53, wherein said antipsychotic is clozapine and pharmaceutically acceptable salts thereof. ### Claim 55 (depends on 51) The pharmaceutical combination or composition of claim 51, wherein the carbachol is administered to said patient to provide a plasma concentration of 10 μM or less. ### Claim 56 (depends on 52) The pharmaceutical combination or composition of claim 52, wherein the donepezil is administered to said patient to provide a plasma concentration of 10 ng/ml or less. ### Claim 57 (depends on 54) The pharmaceutical combination or composition of claim 54, wherein the clozapine is administered to said patient to provide a plasma concentration of 100 ng/ml or less. ### Claim 58 A kit comprising: (a) a reference buffer; (b) a test buffer; (c) a potential-sensitive dye; and (d) instructions for performing an assay to determine an optimal combination drug treatment therapy for bipolar disorder. ### Claim 59 A kit comprising: (a) a reference buffer; (b) a test buffer; (c) a potential-sensitive dye; and (d) instructions for performing an assay to optimize a combination drug treatment therapy for bipolar disorder. ### Claim 60 A kit comprising: (a) a reference buffer; (b) a test buffer; (c) a potential-sensitive dye; and (d) instructions for performing an assay to determine an optimum dosage of a drug in combination drug treatment therapy for bipolar disorder. ### Claim 61 A kit comprising: (a) a reference buffer; (b) a test buffer, (c) a potential-sensitive dye; and (d) instructions for performing an assay to monitor the efficacy of a combination drug treatment therapy for bipolar disorder. ### Claim 62 (depends on 58, 59, 60) The kit of claim 58, 59, 60, or 61, wherein the reference buffer contains NaCl, Cacl2, glucose and hepes. ### Claim 63 (depends on 58, 59, 60) The kit of claim 58, 59, 60, or 61, wherein the test buffer contains ethyl alcohol, NaCl, Cacl2, glucose and hepes.