# US 2014/0194479 A1 · Compositions and methods for treating mood disorders

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- Number: US 2014/0194479 A1
- Document ID: US20140194479A1
- Status: Published application
- Kind: A1
- Application number: 14/207,791
- Filed: 2014-03-13
- Published: 2014-07-10
- Earliest claimed: 2011-09-14
- Inventors: Claudia SCHMAUSS; Amir LEVINE
- Web page: https://patentgrep.com/patent/US20140194479A1

## CPC

- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/138: Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377)
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/20: having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 25/00: Drugs for disorders of the nervous system
- C12Q 1/34: involving hydrolase
- 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
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- 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)

## Abstract

The present invention provides, inter alia, methods for enhancing the anti-depressant efficacy of a selective serotonin re-uptake inhibitor (SSRI) in a patient being treated for a mood disorder. These methods include administering to a patient in need thereof a therapeutically effective amount of an SSRI and a therapeutically effective amount of a modulator of histone expression. Also provided are methods for identifying a patient population that suffers from a mood disorder that is more likely to respond to SSRI treatment. Further provided are compositions for treating or ameliorating the effects of a mood disorder.

## Claims

### Claim 1

A method for enhancing the anti-depressant efficacy of a selective serotonin re-uptake inhibitor (SSRI) in a patient being treated for a mood disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of an SSRI and a therapeutically effective amount of a modulator of histone expression.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the modulator of histone expression is a class I histone deacetylase inhibitor (HDACi).

### Claim 3 (depends on 2)

The method according to claim 2, wherein the SSRI and HDACi are co-administered.

### Claim 4 (depends on 2)

The method according to claim 2, wherein the SSRI and HDACi are administered serially over time.

### Claim 5 (depends on 2)

The method according to claim 2, wherein the HDACi is selected from the group consisting of trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), MS-275, pyroxamide, azelaic-1-hydroxamate-9-anilide (AAHA), CRA-024781 (Pharmacyclics, Sunnyvale, Calif.), bombesin-2 (BB2) receptor antagonist, JNJ-16241199 (Johnson & Johnson, Langhorne, Pa.), Oxamflatin, CG-1521 (Errant Gene Therapeutics, LLC, Chicago, Ill.), CG-1255 (Errant Gene Therapeutics, LLC, Chicago, Ill.), SK-7068 (In2Gen/SK Chemical Co., Suweon, Korea), SK-7041 (In2Gen/SK Chemical Co., Suweon, Korea), m-carboxycinnamic acid bis-hydroxamide (CBHA), Scriptaid (N-Hydroxy-1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-hexan amide), SB-623 (Merrion Research I Limited, National Digital Park, Ireland), SB-639 (Merrion Research I Limited, National Digital Park, Ireland), SB-624 (Merrion Research I Limited, National Digital Park, Ireland), Panobinostat (LBH-589) (Novartis, Basel, Switzerland), NVP-LAQ824 (Novartis, Basel, Switzerland), butyrate, phenylbutyrate, valporic acid (VPA), Pivanex™ (Titan Pharmaceuticals, Inc.), AN-1 (Titan Pharmaceuticals, Inc.), tributyrin, compound G1, pivaloyloxymethyl butyrate, hyaluronic acid butyric acid ester (HA-But), Apicidine, Trapoxin-A, Trapoxin-B, cyclic hydroxamic acid-containing peptide 1 (CHAP-1), CHAP-31, CHAP-15, chlamidocin, HC-Toxin, WF-27082B (Fujisawa Pharmaceutical Company, Ltd., Osaka, Japan), Romidepsin (Gloucester Pharmaceuticals, Cambridge, Mass.), Spiruchostatin A, Depudesin, compound D1, Triacetylshikimic acid, Cyclostellettamine FFF1, Cyclostellettamine FFF2, Cyclostellettamine FFF3, Cyclostellettamine FFF4, MS-27-275 (Schering AG, Germany), Tacedinaline (N-acetyldinaline), ITF-2357 (Italfarmaco, Cinisello Balsamo, Italy), N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)benzamide (HDAC-42), MGCD-0103 (MethylGene Inc., Montreal, Quebec, Canada), PX-117794 (TopoTarget AS, København, Denmark), Belinostat (TopoTarget AS, Kobenhavn, Denmark), sulfonamide hydroxamic acid, mocetinostat (MethylGene), Entinostat (MS-275, Bayer AG), MG-2856 (MethylGene), MG-4230 (MethylGene), MG-4915 (MethylGene), MG-5026 (MethylGene), belinostat (TopoTarget AS), abexinostat (Celera), panobinostat (Novartis), CG-200745 (CrystalGenomi), SB-939 (S*BIO), chidamide (HUYA Bioscience), CHR-3996 (Chroma Therapeutics), AR-42 (Arno Therapeutics), RG-2833 (RepliGen), OCID-4681-S-01, (Orchid Pharmaceuticals), PCI-34051 (Pharmalcyclics), DAC-60 (Genextra), KAR-2581 (Karus Therapeutics), resminostat (Nycomed Pharma), 4SC-202 (Nycomed Pharma), YM-753 (Astellas), ACY-1216 (Acetylon), KAR-3000 (Karus Therapeutics), CU-906 (Curis), IKH-02 (IkerChem), ACY-257 (Acetylon), HDAC3 inhibitors (RepliGen), KAR-3166 (Karus Therapeutics), ONCO-101 (Oncoholdings), GSK424887 (GlaxoSmithKline), AGO178 (Novartis), TC5214 (AstraZeneca), pharmaceutically acceptable salts thereof, and combinations thereof.

### Claim 6 (depends on 5)

The method according to claim 5, wherein the HDACi is SAHA, VPA, pharmaceutically acceptable salts thereof, or combinations thereof.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the SSRI is selected from the group consisting of fluvoxamine, trazodone, indeloxazine, viloxazine, dapoxetine, duloxetin, fluoxetine, olanzapine, tramadol, tramadol, paroxetine mesylate, venlafaxine, citalopram, escitalopram, demexiptiline, vilazodone, nitroxazepine, paroxetine, desvenlafaxine, sertraline, venlafaxine, milnacipran, minaprine, quinupramine, amine transporter inhibitor (AMRI), venlafaxine (Auspex), DSP-1053 (Dainippon Sumitomo Pharma), SEP-228432 (Dainippon Sumitomo Pharma), DA-8031 (DA-8031), escitalopram (Lundbeck), NSD-788 (Neurosearch), SKL-10406 (SK Holdings), BMS-820836 (AMRI), pipamperone, doxepin (Winston Pharmaceuticals), levomilnacipran, clonazepam (Zydus) pharmaceutically acceptable salts thereof, and combinations thereof.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the SSRI is fluoxetine, pharmaceutically acceptable salts thereof, or combinations thereof.

### Claim 9 (depends on 1)

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

### Claim 10

A method for identifying a patient population that suffers from a mood disorder that is more likely to respond to SSRI treatment comprising:
(a) obtaining a biological sample from the patient;
(b) testing the biological sample to determine whether it has a reduced HDAC activity compared to a control population; and
(c) administering an effective amount of an SSRI to the patient, optionally together with an effective amount HDACi if the biological sample of the patient population has a reduced HDAC activity compared to the control population.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the biological sample is selected from the group consisting of body fluid, body tissue, and a portion thereof.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the biological sample is peripheral blood lymphocytes.

### Claim 13 (depends on 10)

The method according to claim 10, wherein the HDACi is selected from the group consisting of trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), MS-275, pyroxamide, azelaic-1-hydroxamate-9-anilide (AAHA), CRA-024781 (Pharmacyclics, Sunnyvale, Calif.), bombesin-2 (BB2) receptor antagonist, JNJ-16241199 (Johnson & Johnson, Langhorne, Pa.), Oxamflatin, CG-1521 (Errant Gene Therapeutics, LLC, Chicago, Ill.), CG-1255 (Errant Gene Therapeutics, LLC, Chicago, Ill.), SK-7068 (In2Gen/SK Chemical Co., Suweon, Korea), SK-7041 (In2Gen/SK Chemical Co., Suweon, Korea), m-carboxycinnamic acid bis-hydroxamide (CBHA), Scriptaid (N-Hydroxy-1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-hexan amide), SB-623 (Merrion Research I Limited, National Digital Park, Ireland), SB-639 (Merrion Research I Limited, National Digital Park, Ireland), SB-624 (Merrion Research I Limited, National Digital Park, Ireland), Panobinostat (LBH-589) (Novartis, Basel, Switzerland), NVP-LAQ824 (Novartis, Basel, Switzerland), butyrate, phenylbutyrate, valporic acid (VPA), Pivanex™ (Titan Pharmaceuticals, Inc.), AN-1 (Titan Pharmaceuticals, Inc.), tributyrin, compound G1, pivaloyloxymethyl butyrate, hyaluronic acid butyric acid ester (HA-But), Apicidine, Trapoxin-A, Trapoxin-B, cyclic hydroxamic acid-containing peptide 1 (CHAP-1), CHAP-31, CHAP-15, chlamidocin, HC-Toxin, WF-27082B (Fujisawa Pharmaceutical Company, Ltd., Osaka, Japan), Romidepsin (Gloucester Pharmaceuticals, Cambridge, Mass.), Spiruchostatin A, Depudesin, compound D1, Triacetylshikimic acid, Cyclostellettamine FFF1, Cyclostellettamine FFF2, Cyclostellettamine FFF3, Cyclostellettamine FFF4, MS-27-275 (Schering AG, Germany), Tacedinaline (N-acetyldinaline), ITF-2357 (Italfarmaco, Cinisello Balsamo, Italy), N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)benzamide (HDAC-42), MGCD-0103 (MethylGene Inc., Montreal, Quebec, Canada), PX-117794 (TopoTarget AS, Kobenhavn, Denmark), Belinostat (TopoTarget AS, Kobenhavn, Denmark), sulfonamide hydroxamic acid, mocetinostat (MethylGene), Entinostat (MS-275, Bayer AG), MG-2856 (MethylGene), MG-4230 (MethylGene), MG-4915 (MethylGene), MG-5026 (MethylGene), belinostat (TopoTarget AS), abexinostat (Celera), panobinostat (Novartis), CG-200745 (CrystalGenomi), SB-939 (S*BIO), chidamide (HUYA Bioscience), CHR-3996 (Chroma Therapeutics), AR-42 (Arno Therapeutics), RG-2833 (RepliGen), OCID-4681-S-01, (Orchid Pharmaceuticals), PCI-34051 (Pharmalcyclics), DAC-60 (Genextra), KAR-2581 (Karus Therapeutics), resminostat (Nycomed Pharma), 45C-202 (Nycomed Pharma), YM-753 (Astellas), ACY-1216 (Acetylon), KAR-3000 (Karus Therapeutics), CU-906 (Curis), IKH-02 (IkerChem), ACY-257 (Acetylon), HDAC3 inhibitors (RepliGen), KAR-3166 (Karus Therapeutics), ONCO-101 (Oncoholdings), GSK424887 (GlaxoSmithKline), AGO178 (Novartis), TC5214 (AstraZeneca), pharmaceutically acceptable salts thereof, and combinations thereof.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the HDACi is SAHA, VPA, pharmaceutically acceptable salts thereof, or combinations thereof.

### Claim 15 (depends on 10)

The method according to claim 10, wherein the SSRI is selected from the group consisting of fluvoxamine, trazodone, indeloxazine, viloxazine, dapoxetine, duloxetin, fluoxetine, olanzapine, tramadol, paroxetine, tramadol, paroxetine mesylate, venlafaxine, citalopram, escitalopram, demexiptiline, vilazodone, nitroxazepine, desvenlafaxine, sertraline, venlafaxine, milnacipran, minaprine, quinupramine, amine transporter inhibitor (AMRI), venlafaxine (Auspex), DSP-1053 (Dainippon Sumitomo Pharma), SEP-228432 (Dainippon Sumitomo Pharma), DA-8031 (DA-8031), escitalopram (Lundbeck), NSD-788 (Neurosearch), SKL-10406 (SK Holdings), BMS-820836 (AMRI), pipamperone, doxepin (Winston Pharmaceuticals), levomilnacipran, clonazepam (Zydus) pharmaceutically acceptable salts thereof, and combinations thereof.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the SSRI is fluoxetine, pharmaceutically acceptable salts thereof, or combinations thereof.

### Claim 17

A composition for treating or ameliorating the effects of a mood disorder comprising an effective amount of an SSRI, an HDACi, and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 1)

The method according to claim 1, wherein the patient has been chronically stressed.

### Claim 19 (depends on 1)

The method according to claim 1, wherein the patient has a history of early life stress.

### Claim 20 (depends on 1)

The method according to claim 1, wherein the HDACi selectively inhibits HDAC 1, 3, 8, and combinations thereof.

### Claim 21

A method for preventing, treating or ameliorating the effects of age-related cognitive deficits in a patient with a history of early life stress comprising administering to the patient in need thereof an effective amount of an HDACi.

### Claim 22

A composition for preventing, treating or ameliorating the effects of age-related cognitive deficits in a patient with a history of early life stress comprising an effective amount of an HDACi and a pharmaceutically acceptable carrier.

### Claim 23

A method for identifying and treating a patient population that suffers from a mood disorder that is more likely to respond to a combination SSRI/HDACi treatment comprising:
(a) treating a patient population with an SSRI;
(b) determining which patients in the patient population are not responding to or who have low responsiveness to the SSRI treatment in step (a); and
(c) to those patients determined to be not responding to or to have low responsiveness to the SSRI treatment, administering the SSRI and an HDACi in an amount effective to treat the mood disorder.

### Claim 24 (depends on 2)

The method according to claim 2, wherein the HDACi is Entinostat (MS-275, Bayer AG) or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 10)

The method according to claim 10, wherein the HDACi is Entinostat (MS-275, Bayer AG) or a pharmaceutically acceptable salt thereof.