Drug therapy for obsessive-compulsive disorder targeting dopamine d1 signal in striatal striosomes

Abstract

Provided is a pharmaceutical composition for treating obsessive-compulsive disorder.　The present invention pertains to: (1) a pharmaceutical composition containing a dopamine D1 receptor stimulant as an active ingredient for treating obsessive-compulsive disorder; and / or (2) a pharmaceutical composition containing a dopamine D1 and D2 receptor stimulant in order to stimulate the dopamine D1 receptors in the striatum, said pharmaceutical composition being administered after being combined with a dopamine D2 receptor inhibitor; and / or (3) a pharmaceutical composition containing a dopamine D2 receptor inhibitor, said pharmaceutical composition being administered after being combined with a dopamine D1 and D2 receptor stimulant.

Description

Pharmacotherapy for obsessive-compulsive disorder targeting dopamine D1 signaling in striatal striosomes

[0001] This patent application claims priority and the benefit of Japanese Patent Application No. 2022-096675 (filed June 15, 2022) and PCT / JP2022 / 048379 (filed December 27, 2022) under the Paris Convention, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a pharmacotherapy for treating obsessive-compulsive disorder. In particular, the present invention is in the field of pharmacotherapy for treating obsessive-compulsive disorder using a dopamine D1 receptor stimulant and / or a combination of a dopamine D1 and D2 receptor stimulant and a dopamine D2 receptor inhibitor to selectively stimulate the striatal dopamine D1 receptor.

[0003] Obsessive-compulsive disorder (OCD) is a core disorder in the category of obsessive-compulsive disorders, which includes a group of disorders referred to as "Obsessive Compulsive and Related Disorders" according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) guidelines for translation of names and terms. OCD is characterized by obsessive symptoms, such as obsessions or compulsions. Obsessive-compulsive symptoms include repetitive and persistent thoughts, impulses, and images, as well as compulsions, including repetitive mental behaviors such as hand washing, checking, ritualistic acts, chanting, and counting. Patients with OCD attempt to control their obsessions or compulsions, but are unable to do so due to anxiety and distress, resulting in conflict and stress (Non-Patent Documents 1, 2).

[0004] The prevalence of obsessive-compulsive disorder is 1-2%, with an almost equal gender ratio and an average age of onset around 20 years, with men tending to develop symptoms earlier (Non-Patent Documents 1, 2). Treatment of obsessive-compulsive disorder typically involves oral selective serotonin reuptake inhibitors (SSRIs), a type of antidepressant, combined with cognitive behavioral therapy (CBT) (Non-Patent Documents 2, 3). It is recommended that SSRIs be administered for 12 weeks from the start of treatment, with a maximum dose continued for 4-6 weeks (Non-Patent Documents 2, 3, 4). While SSRIs are currently the first-line treatment for obsessive-compulsive disorder, they require higher doses and longer durations than those for depression. Long-term prognosis studies have shown that only about half of obsessive-compulsive disorder patients respond to SSRI treatment over 10 years, with improvement rates of only 30-40% at best, and relapse is common even after initial improvement (Non-Patent Document 2). Clinical treatment for obsessive-compulsive disorder is eagerly awaited, with the development of more effective drug treatments to replace SSRIs.

[0005] American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Text Revision. APA. Washington D.C.Koran, L. M. Hanna, G.L., Hollander. E., et al: Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry. 164(supple); 1-56, 2007March. J., Frances. A., Kahn.D., et al Expert consensus guidelines: Treatment of obsessive-compulsive disorder. J Clin Psychiatry, 58(suppl.4); 1-72, 1997Denys, D.: Pharmacotherapy of obsessive-compulsive disorder and obsessive-compulsive spectrum disorders. Psychiatr Clin North Am.29; 553-584, 2006Goodman WK, Price LH, Rasmussen SA et al: The Yale-Brown obsessive compulsive scale II. Validity. Arch Gen Psychiatry 46: 1012-1016, 1989Steketee, G and Neziroglu, E:Assessment of obsessive-compulsive disorder and spectrum disorders. Bref Treat. Crisis Interv., 3: 169-185, 2003Storch EA, De Nadai AS, Conceicao do Rosario M et al Defining severity in adults with obsessive compulsive disorder.Compr Psychiatry 63: 30-35, 2015.

[0006] As mentioned above, there are no medicines or means that can adequately treat obsessive-compulsive disorder, and there is a strong demand for effective treatment methods.

[0007] Under these circumstances, the present inventors discovered by chance that prescribing a small dose of levodopa in addition to a small dose of chlorpromazine or metoclopramide during the treatment of a patient with involuntary movement disorder improved obsessive-compulsive disorder within four weeks, leading to the completion of the present invention. Specifically, they discovered for the first time that dual dopamine modulation therapy using L-3,4-dihydroxyphenylalanine (L-DOPA; levodopa) (a dopamine D1 and D2 receptor stimulator) and chlorpromazine (CPZ) or metoclopramide (a D2 receptor blocker) is effective in treating obsessive-compulsive disorder at a lower dose than the standard maintenance dose and within a shorter treatment period than usual.

[0008] Therefore, the present invention includes the following aspects. <Pharmaceutical Composition> [1] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D1 receptor stimulant. [2] The pharmaceutical composition of [1], wherein the dopamine D1 receptor stimulant is selected from a dopamine D1 receptor agonist and a dopamine D1 receptor-positive allosteric modulator. [3] The pharmaceutical composition of [2], wherein the dopamine D1 receptor stimulant is a dopamine D1 receptor agonist. [4] The pharmaceutical composition according to [3], wherein the dopamine D1 receptor agonist is selected from SKF81297, SKF38393, SKF83959, SKF82526 (Fenoldpam), dihydrexidine, ABT-431, A-86929, A-77636, A-68930, PF-06649751 (Tavapandon), and PF-06412. [5] The pharmaceutical composition according to [2], wherein the dopamine D1 receptor stimulant is a dopamine D1 receptor-positive allosteric modulator. [6] The pharmaceutical composition according to [5], wherein the dopamine D1 receptor-positive allosteric modulator is selected from DETQ (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one), mevidalene, MLS1082, MLS6585, pyrazolyl-dihydroisoquinoline, DPTQ, CID 2886111 ([N-(6-tert-butyl-3-carbamoyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pyridine-4-carboxamide]), LY3154885, and ASP4345.

[0009] [7] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D1 and D2 receptor agonist, wherein the pharmaceutical composition is administered in combination with a dopamine D2 receptor inhibitor. [8] The pharmaceutical composition of [7], wherein the dopamine D2 receptor inhibitor is selected from the group consisting of a dopamine D2 receptor antagonist and a dopamine D2 receptor-negative allosteric modulator. [9] The pharmaceutical composition of [8], wherein the dopamine D2 receptor inhibitor is a dopamine D2 receptor antagonist.

[10] The pharmaceutical composition of [9], wherein the dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, levomepromazine, fluphenazine, perphenazine, prochlorperazine, propericiazine, haloperidol, pipamperone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiperone, nemonapride, timiperone, and perospirone.

[11] The pharmaceutical composition of [8], wherein the dopamine D2 receptor inhibitor is a dopamine D2 receptor-negative allosteric modulator.

[12] The pharmaceutical composition of

[11] , wherein the dopamine D2 receptor-negative allosteric modulator is SB269652.

[13] The pharmaceutical composition of [7], wherein the dopamine D1 and D2 receptor agonist is selected from levodopa, levodopa-carbidopa hydrate (a levodopa combination drug), levodopa-carbidopa-entacapone combination drug, levodopa-benserazide hydrochloride combination drug, and the dopamine agonist pergolide or rotigotine.

[14] The pharmaceutical composition of

[13] , wherein levodopa and chlorpromazine are administered in combination.

[15] The pharmaceutical composition of any one of [7] to

[14] , wherein the amount of levodopa is orally administered at half or less of the standard maintenance dose for Parkinson's disease treatment.

[16] The pharmaceutical composition of

[15] , wherein the amount of levodopa is 50 to 300 mg per day (half or less of the standard maintenance dose for Parkinson's disease treatment).

[17] The pharmaceutical composition according to

[16] , wherein the amount of levodopa is 50 mg per day, which is half or less of the standard maintenance dose for treating Parkinson's disease.

[0010]

[18] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D2 receptor inhibitor, wherein a dopamine D1 and D2 receptor agonist are administered in combination.

[19] The pharmaceutical composition of

[18] , wherein the dopamine D2 receptor inhibitor is selected from the group consisting of a dopamine D2 receptor antagonist and a dopamine D2 receptor-negative allosteric modulator.

[20] The pharmaceutical composition of

[19] , wherein the dopamine D2 receptor inhibitor is a dopamine D2 receptor antagonist.

[21] The pharmaceutical composition of

[20] , wherein the dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, levomepromazine, fluphenazine, perphenazine, prochlorperazine, propericiazine, haloperidol, pipamperone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiperone, nemonapride, timiperone, and perospirone.

[22] The pharmaceutical composition of

[19] , wherein the dopamine D2 receptor inhibitor is a dopamine D2 receptor-negative allosteric modulator.

[23] The pharmaceutical composition of

[22] , wherein the dopamine D2 receptor-negative allosteric modulator is SB269652.

[24] The pharmaceutical composition of

[19] , wherein the dopamine D1 and D2 receptor agonist is selected from levodopa, levodopa-carbidopa hydrate (a levodopa combination drug), levodopa-carbidopa-entacapone combination drug, levodopa-benserazide hydrochloride combination drug, and the dopamine agonists pergolide and rotigotine.

[25] The pharmaceutical composition of

[24] , wherein chlorpromazine and levodopa are administered in combination.

[26] The pharmaceutical composition of

[25] , wherein chlorpromazine is orally administered at a dose equal to or less than half the antipsychotic therapeutic dose as chlorpromazine hydrochloride.

[27] The pharmaceutical composition of

[26] , wherein the dose equal to or less than half the antipsychotic therapeutic dose as chlorpromazine hydrochloride is 5 to 30 mg per day.

[28] The pharmaceutical composition according to

[27] , wherein the antipsychotic therapeutic dose of chlorpromazine hydrochloride is 5 mg per day.

[0011]

[29] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D1 receptor stimulant, wherein the pharmaceutical composition is administered in combination with a dopamine D2 receptor inhibitor.

[30] The pharmaceutical composition according to

[29] , wherein the dopamine D1 receptor stimulant is selected from the group consisting of a dopamine D1 receptor agonist and a dopamine D1 receptor-positive allosteric modulator, and the dopamine D2 receptor inhibitor is selected from the group consisting of a dopamine D2 receptor antagonist and a dopamine D2 receptor-negative allosteric modulator.

[0012] The present invention can provide a pharmaceutical agent that is extremely effective and safe for treating obsessive-compulsive disorder.

[0013] Figure 1 (left) is a graph showing individual plots of the measured values ​​in five patients with obsessive-compulsive disorder evaluated using the YBOCS (Yale-Brown Self-Report Obsessions and Compulsions Scale). CPZ (Wintermin Granules) and LDOPA (Dopacol Combination Tablets) were used as treatments. Figure 1 (right) is a graph showing the mean YBOCS scores in five patients with obsessive-compulsive disorder before and after treatment. *, P < 0.05 (t-test). Figure 2 (left) is a graph showing individual plots of the measured values ​​in 20 patients with obsessive-compulsive disorder evaluated using the YBOCS (Yale-Brown Self-Report Obsessions and Compulsions Scale). Figure 2 (right) is a graph showing the mean YBOCS scores in 20 patients with obsessive-compulsive disorder before and after treatment. ****, P < 0.001 (t-test). CPZ (Wintermin Granules) and LDOPA (Dopacol Combination Tablets) were used as treatments. Figure 3 shows the relationship between YBOCS (Yale-Brown Obsessions and Compulsions Scale) and oral dose in 20 patients with obsessive-compulsive disorder (OCD) shown in Figure 2. The therapeutic effects of the oral doses of CPZ (Wintermin Granules) and LDOPA (Dopacol Combination Tablets) were evaluated by gradually increasing the dose. Figure 4 (left) shows individual plots of the YBOCS (Yale-Brown Obsessions and Compulsions Scale) measured in 12 patients with OCD. Figure 4 (right) shows the mean YBOCS scores for 12 patients with OCD before and after treatment. ****, P < 0.001 (t-test). CPZ (Wintermin Granules) and rotigotine (rotigotine patch: Neupro Patch) were used as treatments. Figure 5 is a plot showing the relationship between YBOCS (Yale-Brown Self-Administered Obsessions and Compulsions Scale) and oral and topical doses in the 12 patients with obsessive-compulsive disorder shown in Figure 4. The oral and topical doses of the therapeutic drugs CPZ (Wintermin Granules) and rotigotine (rotigotine patch: Neupro Patch) were gradually increased, and the therapeutic effects were evaluated. Figure 6 is a graph showing individual plots of the measured values ​​in two patients with obsessive-compulsive disorder evaluated using the YBOCS (Yale-Brown Self-Administered Obsessions and Compulsions Scale).The two patients in Figure 6 were given a dopamine D2 receptor blocker other than CPZ (Wintermin Granules) as a treatment. In Series 1, sulpiride (Dogmatil Tablets) was used instead of CPZ, and in Series 2, metoclopramide (Primperan Tablets) was used in combination with LDOPA (Dopacol Combination Tablets).

[0014] Figure 7 shows the results of measuring the severity of blepharospasm before and after the drug challenge test using the visual analog scale (VAS), Blepharospasm Disability Index (BSDI), modified VAS (mVAS), and Jancovic Rating Scale (JRS). Before: Before the drug challenge test; after: After the drug challenge test. There were seven patients in each of the L-DOPA group (top), CPZ group (middle), and L-DOPA + CPZ group (bottom). The values ​​for all patients are plotted as a line graph (top), and the mean values ​​for all patients are plotted as a graph (bottom). *, P < 0.05 (Wilcoxon signed-rank test).

[0015] <Pharmaceutical Composition> In one aspect, the present invention relates to a pharmaceutical composition for treating obsessive-compulsive disorder, which contains a dopamine D1 receptor stimulant. As shown in the lower part of this specification, the present inventors have previously discovered the use of LDOPA+CPZ to treat dystonia. Based on previous reports that dystonia is often associated with obsessive-compulsive disorder and depression, the present inventors inferred that LDOPA+CPZ would have a similar therapeutic effect on the latter disorders, and were the first to actually demonstrate that this pharmaceutical can treat obsessive-compulsive disorder.

[0016] Previous reports include the following, but none of them call to mind the present invention: (1) Psychiatric disorders in adult-onset focal dystonia: a case-control study. Fabbrini G, Berardelli I, Moretti G, Pasquini M, Bloise M, Colosimo C, Biondi M, Berardelli A. Mov Disord. 2010 Mar 15; 5 (4):459-65. doi: 10.1002 / mds.22983. This study showed that 51 of 89 idiopathic dystonia patients (57.3%) had some kind of psychiatric symptom, such as depression, anxiety disorder, or obsessive-compulsive disorder. (2) Obsessive compulsive disorder among idiopathic focal dystonia patients: an epidemiological and family study. Cavallaro R, Galardi G, Cavallini MC, Henin M, Amodio S, Bellodi L, Comi G. Biol Psychiatry. 2002 Aug 15; 52 (4):356-61. doi: 10.1016 / s0006-3223(02)01332-x. This study reports that 19.7% of patients with focal dystonia also have obsessive-compulsive disorder. (3) Psychiatric symptoms associated with focal hand dystonia. Voon V, Butler TR, Ekanayake V, Gallea C, Ameli R, Murphy DL, Hallett M. Mov Disord. 2010 Oct 15; 25 (13):2249-52. doi: 10.1002 / mds.23250. This study reported that 12.82% of patients with focal hand dystonia also had obsessive-compulsive disorder, and 17.95% had depressive symptoms.

[0017] Based on these previous studies, dysfunction of the striosomal compartment in the striatum is suspected as a mechanism for the manifestation of stereotyped symptoms, a common element in dystonia and obsessive-compulsive disorder. In other words, several hypothesis papers have been published suggesting that disorders accompanied by stereotypy, such as dystonia and obsessive-compulsive disorder, may be related to dysfunction of the striosomal compartment (Professor Ann Graybiel). (4) Graybiel AM, Canales JJ, Capper-Loup C. Levodopa-induced dyskinesias and dopamine-dependent stereotypies: a new hypothesis. Trends Neurosci. (2000) 23: S71-S77. doi: 10.1016 / s1471-1931(00)00027-6. This suggests that a decrease in the function of the striosome fraction induces a state of dopamine excess in the matrix fraction, which can lead to dystonia and obsessive-compulsive disorder accompanied by stereotyped symptoms. (5) Crittenden JR, Graybiel AM. Basal ganglia disorders associated with imbalances in the striosome and matrix compartments. Front Neuroanat. (2011) 5; 59. doi: 10.3389 / fnana.2011.00059 This paper summarizes the existence of functional abnormalities (imbalances) in the striosome and matrix compartments in several basal ganglia diseases, including Parkinson's disease, Huntington's disease, dystonia, and obsessive-compulsive disorder.(6) Amemori KI, Gibb LG, Graybiel AM. Shifting responsibly: the importance of striatal modularity to reinforcement learning in uncertain environments. Front Hum Neurosci. (2011) 5:47. doi: 10.3389 / fnhum.2011.00047. This paper hypothesizes that the striatum is responsible for modular reinforcement learning (RL), which is the basis of stereotypy, and that computer simulations suggest that an imbalance between the striosome fraction and the matrix fraction may lead to dystonia, chorea, obsessive-compulsive disorder, depression, and other conditions.

[0018] However, none of these publications go beyond the realm of hypothesis, and no specific description of the treatment of human diseases is available. Furthermore, the present inventors' discovery that striosome dysfunction can be improved by stimulating the dopamine D1 receptor has not been described in previous research, nor in any hypothesis papers suggesting this possibility. Researchers are divided on whether "striosome dysfunction" in dystonia and obsessive-compulsive disorder is a hypofunction or hyperfunction.

[0019] (7) JP 2015-52117 A describes that, using a rodent model of drug addiction (cocaine addiction or nicotine addiction), the combination of a PDE7 inhibitor and a dopamine receptor agonist reduces drug preference and impulsivity. First, in comparing the rodent drug addiction model in this document with the human obsessive-compulsive disorder of the present invention, it is important to note that, from a comparative anatomical perspective, the distribution pattern of D1 / D2 receptors in the striatum of rodents is significantly different from that in humans. In basal ganglia diseases involving dopamine receptors, the therapeutic effects observed in rodent animal models are unlikely to be directly reproduced in human diseases. The inventors have published the following paper, which details this issue: Specificity of the striatal dopamine D1 system in humans: implications for clinical use of D1 receptor-agonists in Parkinson's disease. Goto S. Front Hum Neurosci. 2023 Apr 26;17:1178616. doi: 10.3389 / fnhum.2023.1178616. eCollection 2023. "Pharmacotherapy for obsessive-compulsive disorder targeting dopamine D1 signaling in striatal striosomes" utilizes the human specificity of the dopamine D1 system to normalize striosomal D1 signaling. This paper reports that in the human striatum, dopamine D1 receptors are selectively and predominantly present in the striosome fraction, whereas in rodents, dopamine D1 receptors are uniformly distributed in the matrix fraction as well, with no uneven distribution in the striosome fraction.

[0020] Furthermore, the strength of "drug addiction and impulsivity" seen in rodent drug addiction models cannot be directly considered similar to the "strong obsessions, obsessions, or compulsions in everyday life" seen in human obsessive-compulsive disorder. In the DSM-5, the American Psychiatric Association's classification and diagnostic guide for mental disorders, drug addiction is classified as "Substance-related and Addictive Disorders," and is defined as a separate category from "Obsessive-Compulsive Disorder and Related Disorders." Therefore, improvement in addiction to a substance in rodent drug addiction models does not immediately predict improvement in the severity score (YBOCS) of obsessive-compulsive disorder in humans.

[0021] (8) CHEN, Fu-Feng et al., Brain Research, 2020, Vol. 1749, #147136, and PONNUSAMY, Ravikumar et al., Learning & Memory, 2005, Vol. 12, No. 4, pp. 399-406. The former describes that administration of a D1 receptor agonist (SKF83959) can induce long-term loss of fear memory in a rodent model using fear conditioning. The latter also describes that a single injection of the D2 receptor antagonist sulpiride was effective in erasing fear memory in a rodent model using fear conditioning. In the American Psychiatric Association's classification and diagnostic manual, DSM-4, OCD was classified as an "anxiety disorder." However, in the more recent DSM-5, OCD was removed from the "anxiety disorder" category and placed in the "Obsessive-Compulsive and Related Disorders / Obsessive-Compulsive and Related Disorders" category. Therefore, "anxiety disorders" and "obsessive-compulsive disorder" are now considered separate disease groups. In other words, anxiety disorders and obsessive-compulsive disorder should not be equated. This also means that conditioned fear extinction in animal models is no longer used as an explicit model for "anxiety disorders, including obsessive-compulsive disorder." Therefore, as in Ref. (7), it is difficult to immediately predict improvement in the OCD severity score (YBOCS) in humans using the rodent conditioned fear extinction model.

[0022] (9) Elia Mota et al. Br J Pharmacol. 2021 Dec;178(24):4873-4890. doi: 10.1111 / bph.15664. Epub 2021 Oct 4. This study describes the effects of PDE10α on dopamine D1 and D2 cells in the striatum. However, there is no mention of obsessive-compulsive disorder.

[0023] In the present invention, the dopamine D1 receptor stimulator is selected from among a dopamine D1 receptor agonist and a dopamine D1 receptor-positive allosteric modulator.

[0024] In the present invention, a "dopamine D1 receptor agonist" refers to a substance that stimulates the D1-like receptor family (D1 receptor and D5 receptor), which are responsible for excitatory properties, among the five types of dopamine receptors, namely, D1, D2, D3, D4, and D5 receptors, and is also referred to as a D1 receptor stimulating substance. Therefore, in the present invention, the term "dopamine D1 receptor agonist" does not mean an agonist specific to the dopamine D1 receptor, and does not exclude the stimulatory effect of other receptors in the D1-like receptor family, such as the D5 receptor.

[0025] Specific examples of dopamine D1 receptor agonists include SKF81297, SKF38393, SKF83959, SKF82526 (Fenoldpam), dihydrexidine, ABT-431, A-86929, A-77636, A-68930, PF-06649751 (Tavapandon), and PF-06412 (Jones-Tabah J, et al. The Signaling and Pharmacology of the Dopamine D1 Receptor. Front Cell Neurosci. 2022.), but currently, no drugs have passed human clinical trials and been approved as D1 receptor agonists.

[0026] In the present invention, the term "dopamine D1 receptor-positive allosteric modulator" refers to a substance that binds to the allosteric site of the dopamine D1 receptor and promotes the agonist activity of the D1 receptor, and is expected to have effects equivalent to those of a dopamine D1 receptor agonist. This substance is abbreviated as D1-PAM (D1-Positive Allosteric Modulator). In relation to allosteric modulators (allosteric modulators), in the case of receptors, ligands that bind to the allosteric site to promote the agonist activity of endogenous agonists are called positive allosteric modulators (PAMs), while allosteric ligands that suppress agonist activity are called negative allosteric modulators (NAMs).

[0027] Specific examples of dopamine D1 receptor-positive allosteric modulators include: (1) DETQ (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one) (Neuropharmacology 128 (2018) 351e365; Advances in Pharmacology Volume 86, 2019, Pages 273-305; Psychopharmacology (2023) 240:1033-1048), and (2) Mevidalen (LY3154207) (Cell 184, 943-956, February 18, 2021; Clinical Pharmacology in Drug Development). 2022, 11(3) 324-332) (3) MLS1082 (Mol Pharmacol 94:1197-1209, October 2018; Bioorg Med Chem Lett. 2021 January 01; 31) (4) MLS6585 (Mol Pharmacol 94:1197-1209, October 2018; Bioorg Med Chem Lett. 2021 January 01; 31) (5) Pyrazolyl-dihydroisoquinoline (ACS Med. Chem. Lett. 2020, 11, 4-4) (6) DPTQ (Psychopharmacology (2023) 240:1033-1048) (7) CID 2886111 ([N-(6-tert-butyl-3-carbamoyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pyridine-4-carboxamide) (Mol Pharmacol 94:1232-1245, October 2018) (8) LY3154885 (J. Med. Chem. 2022, 65, 3786-3797) (9) ASP4345 (Neuropsychopharmacology (2021) 46:1145-1151).To date, no drugs have passed human clinical trials and been approved as D1 receptor-positive allosteric modulators.

[0028] In one embodiment, the present invention relates to a pharmaceutical composition for treating obsessive-compulsive disorder, which contains a "dopamine D1 and D2 receptor agonist" or a "dopamine D2 receptor inhibitor," and which achieves the effect of stimulating the dopamine D1 receptor by administering in combination a "dopamine D1 and D2 receptor agonist," which is typically administered to treat Parkinson's disease and the like, and a "dopamine D2 receptor inhibitor," which is typically administered to treat psychiatric disorders.

[0029] In one embodiment, the present invention relates to a pharmaceutical composition for treating obsessive-compulsive disorder, the pharmaceutical composition comprising: (1) a dopamine D1 receptor stimulant; and / or (2) a dopamine D1 and D2 receptor agonist, which is administered in combination with a dopamine D2 receptor inhibitor; and / or (3) a dopamine D2 receptor inhibitor, which is administered in combination with a dopamine D1 and D2 receptor agonist.

[0030] In the present invention, "administered in combination" refers to a dosage form that includes, for example, simultaneous, staggered, or alternating administration of dopamine D1 and D2 receptor agonists or dopamine D2 receptor inhibitors. Thus, when administered simultaneously, dopamine D1 and D2 receptor agonists or dopamine D2 receptor inhibitors may be administered in the same pharmaceutical composition, or simultaneously in separate pharmaceutical compositions. Dopamine D1 and D2 receptor agonists or dopamine D2 receptor inhibitors may be administered separately, for example, with a time difference of seconds, minutes, hours, days, or weeks. Furthermore, dopamine D1 and D2 receptor agonists or dopamine D2 receptor inhibitors may be administered before or after other drugs.

[0031] In the present invention, the dopamine D1 and D2 receptor agonists or dopamine D2 receptor inhibitors may be administered in the same dosage form or in different dosage forms, for example, both may be administered as oral formulations, or one compound may be administered orally and the other topically.

[0032] In the present invention, the "dopamine D1 receptor stimulator" is selected from among a dopamine D2 receptor antagonist and a dopamine D2 receptor-negative allosteric modulator.

[0033] In the present invention, a "dopamine D2 receptor antagonist" refers to a substance that inhibits the inhibitory D2-like receptor family (D2 receptor, D3 receptor, and D4 receptor) of the five dopamine receptors, namely, D1, D2, D3, D4, and D5 receptors, and is also referred to as a dopamine D2 receptor blocker or dopamine D2 receptor inhibitor. Therefore, in the present invention, a "dopamine D2 receptor antagonist" does not mean an antagonist specific to the dopamine D2 receptor, but is sufficient as long as it inhibits or blocks the dopamine D2 receptor, and does not exclude the inhibitory or blocking action of other receptors in the D2-like receptor family, such as the D3 receptor and the D4 receptor.

[0034] Examples of dopamine D2 receptor antagonists include chlorpromazine, metoclopramide, domperidone, levomepromazine, fluphenazine, perphenazine, prochlorperazine, propericiazine, haloperidol, pipamperone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiperone, nemonapride, timiperone, and perospirone.

[0035] In the present invention, a "dopamine D2 receptor-negative allosteric modulator" refers to a substance that binds to the allosteric site of the dopamine D2 receptor and inhibits the agonist activity of the D2 receptor, and is expected to have effects equivalent to those of a dopamine D2 receptor agonist. This is abbreviated as D2-NAM (D2-Negative Allosteric Modulator). Dopamine D2 receptor-negative allosteric modulators are outlined in Molecules 2023, 28, 178. https: / / doi.org / 10.3390 / molecules28010178.

[0036] Specific examples of dopamine D2 receptor-negative allosteric modulators include SB269652 (Mol Pharmacol 91:586-594, June 2017; J. Med. Chem. 2015, 58, 6819-6843; Biomedicines 2022, 10, 22. https: / / doi.org / 10.3390 / biomedicines10010022; J. Med. Chem. 2019, 62, 174-206). Currently, no drugs that are D2 receptor-negative allosteric modulators have passed human clinical trials and been approved.

[0037] Examples of dopamine D1 and D2 receptor agonists include levodopa, levodopa-carbidopa hydrate (a levodopa combination), levodopa-carbidopa-entacapone (levodopa-carbidopa-entacapone combination), levodopa-benserazide hydrochloride (levodopa-benserazide hydrochloride), and dopamine agonists such as pergolide and rotigotine. Levodopa, also known as L-3,4-dihydroxyphenylalanine (L-DOPA or LDOPA), is the direct precursor of dopamine and a full agonist at D1 and D2 receptors (D1R and D2R). When used as a dopamine D1 and D2 receptor agonist, levodopa is broken down by levodopa decarboxylase in the periphery (before it reaches the brain), preventing its entry into the brain. Therefore, levodopa formulations are often combined with carbidopa or benserazide to inhibit levodopa metabolism in the periphery. Examples include a combination preparation of levodopa and carbidopa (major trade names: Neodopaston, Menesit) and a combination preparation of levodopa and benserazide (major trade names: EC Dopar, Neodopasol, Madopar). In the present invention, any combination preparation can be used as the dopamine D1 and D2 receptor agonist, but dopacol combination tablets are preferably used. In this specification, when dopacol combination tablets are administered, the substantial medicinal effect comes from levodopa, and therefore administration of dopacol combination tablets can be considered substantially equivalent to administration of levodopa.

[0038] In one embodiment, the present invention relates to a pharmaceutical composition for treating obsessive-compulsive disorder, which contains a dopamine D1 receptor stimulant and is administered in combination with a dopamine D2 receptor inhibitor. It is expected that a combination of a dopamine D1 receptor stimulant and a dopamine D2 receptor inhibitor will be more effective in treating obsessive-compulsive disorder than a single dopamine D1 receptor stimulant. This is because stimulating the D1 receptor alone may result in a secondary effect of increased D2 receptor activity. The definitions of dopamine D1 receptor stimulant and dopamine D2 receptor inhibitor are as described above.

[0039] "Treatment," as used herein, means a method or process intended to (1) slow or stop the progression, worsening, or aggravation of the symptoms of a disease or condition (e.g., obsessive-compulsive disorder); (2) bring about amelioration of the symptoms of a disease or condition; or (3) cure a disease or condition.

[0040] In one embodiment, the present invention relates to a pharmaceutical composition containing levodopa for treating obsessive-compulsive disorder, characterized in that levodopa is orally administered at an amount equal to or less than half the standard maintenance dose for treating Parkinson's disease, and chlorpromazine is orally administered at an amount equal to or less than half the antipsychotic therapeutic dose as chlorpromazine hydrochloride, and metoclopramide is orally administered at half the dose as an antiemetic.

[0041] The standard maintenance dose of levodopa for treating Parkinson's disease is 200-250 mg per dose, three times a day, for a total of 600-750 mg per day. The antipsychotic therapeutic dose of chlorpromazine hydrochloride is 30-100 mg per day. In the present invention, pharmaceutical compositions containing a "dopamine D1 and D2 receptor agonist" in which the amount of levodopa is 50-300 mg per day, preferably 150-300 mg per day, or less than half the standard maintenance dose for treating Parkinson's disease, and pharmaceutical compositions containing a "dopamine D2 receptor inhibitor" in which the amount of chlorpromazine hydrochloride is 5-30 mg per day, preferably 5-30 mg per day, or less than half the antipsychotic therapeutic dose, are preferred. In the present invention, it has been demonstrated that the effects of the present invention are also achieved with a pharmaceutical composition containing a "dopamine D1 and D2 receptor agonist" in which the amount of levodopa is 50 mg per day, which is less than half the standard maintenance amount for treating Parkinson's disease, and a pharmaceutical composition containing a "dopamine D2 receptor inhibitor" in which the amount of chlorpromazine hydrochloride is 5 mg per day, which is less than half the antipsychotic therapeutic amount.

[0042] In the present invention, a "pharmaceutical composition" comprises an effective amount of a "dopamine D1 and D2 receptor agonist" or a "dopamine D2 receptor inhibitor" and at least one pharmaceutically acceptable carrier or excipient. As used herein, the term "effective amount" refers to any amount of a compound or composition that is sufficient to achieve its intended purpose, e.g., a desired biological or pharmacological response in a cell, tissue, system, or subject. For example, in certain embodiments of the present invention, the purpose is to slow, alleviate, or stop the progression, exacerbation, or worsening of obsessive-compulsive disorder, to bring about amelioration of symptoms of the disease, and / or to treat obsessive-compulsive disorder.

[0043] The "pharmaceutically acceptable carrier or excipient" can be formulated with the active ingredient and administered by any suitable route to a subject in need thereof at a desired dosage. Various delivery systems are known, including, for example, tablets, capsules, sustained-release formulations, injections, encapsulations in liposomes, powders, patches, microcapsules, nanoparticle formulations, and the like.

[0044] Treatment in the present invention may consist of a single dose or multiple doses. Thus, administration of the "dopamine D1 receptor stimulator," "dopamine D1 and D2 receptor agonist," "dopamine D2 receptor inhibitor," or pharmaceutical composition thereof of the present invention may be constant or regular over a specific period of time, and at specific intervals, such as once every few hours, once a day, once a week, or once a month (e.g., in a time-release form).

[0045] In another aspect, the present invention relates to a method for treating obsessive-compulsive disorder, comprising administering a dopamine D1 receptor stimulant to a subject in need of such treatment. Further, the present invention relates to a method for treating obsessive-compulsive disorder, comprising administering a dopamine D1 and D2 receptor agonist in combination with a dopamine D2 receptor inhibitor to a subject in need of such treatment, and a method for treating obsessive-compulsive disorder, comprising administering a dopamine D2 receptor inhibitor in combination with a dopamine D1 and D2 receptor agonist to a subject in need of such treatment.

[0046] In another aspect, the present invention relates to a dopamine D1 receptor stimulator for treating obsessive-compulsive disorder. Furthermore, the present invention relates to a combination of a dopamine D1 and D2 receptor agonist and a dopamine D2 receptor inhibitor for treating obsessive-compulsive disorder.

[0047] In yet another aspect, the present invention relates to the use of a dopamine D1 receptor stimulator for the manufacture of a medicament for treating obsessive-compulsive disorder.The present invention relates to the use of a combination of a dopamine D1 and D2 receptor agonist and a dopamine D2 receptor inhibitor for the manufacture of a medicament for treating obsessive-compulsive disorder.

[0048] The present invention will be described in detail below with reference to reference examples and examples, but it should be noted that these do not limit the scope of the present invention and are merely illustrative.

[0049] Example 1 Drug Challenge Test 1 The self-administered Yale-Brown Obsessive-Compulsive Scale (YBOCS) is a scale for assessing the severity of obsessive-compulsive symptoms, which was developed to assess the effectiveness of drug therapy for patients with obsessive-compulsive disorder (Non-Patent Document 5). We used this scale to evaluate symptoms.

[0050] The relationship between YBOCS and the severity of obsessive-compulsive disorder (OCD) has been evaluated as follows (Storch EA, De Nadai AS, Conceicao do Rosario M et al. Defining severity in adults with obsessive compulsive disorder. Compr Psychiatry 63:30-35, 2015). Table 1

[0051] Subjects: This study enrolled five patients with obsessive-compulsive disorder (OCD) aged 33 to 74 years (one male and four females). OCD was diagnosed as a score of 8 or higher on the YBOCS (Non-Patent Document 6). The severity of OCD was assessed using the YBOCS (Non-Patent Documents 6, 7).

[0052] Medications: Dopacol Tablets L50 (registered trademark) (L-DOPA 50 mg + carbidopa 5 mg, Nichi-Iko Pharmaceutical Co., Ltd., Toyama Prefecture, Japan) and Wintermin Granules (10%) (registered trademark) (chlorpromazine phenolphthalate 180 mg per 1 g, Shionogi & Co., Ltd., Osaka Prefecture, Japan) were used. Hereinafter, Dopacol Tablets L50 will be referred to as "DOPACOL" and Wintermin Granules (10%) will be referred to as "CPZ." CPZ Administration Regimen: For Cases 1-4, the administration regimen was as follows: DOPACOL (1 tablet (50 mg) / day) + CPZ (5 mg) / day for the first 4 weeks, DOPACOL (2 tablets (100 mg) / day) + CPZ (5 mg) x 2 / day for the next 4 weeks, and DOPACOL (3 tablets (150 mg) / day) + CPZ (5 mg) x 3 / day for the final 4 weeks.

[0053] Regarding Case No. 5, the following case involved the use of metoclopramide tablets (metoclopramide hydrochloride 5 mg, Takeda Pharmaceutical Co., Ltd.). A 66-year-old woman developed the condition at age 55. Concerns about her illness led to her visiting multiple medical institutions and even being hospitalized. She scored 22 on the YBOCS, and was diagnosed with moderate obsessive-compulsive disorder. She took levodopa 50 mg and metoclopramide 5 mg orally, and her symptoms completely disappeared after 8 weeks (YBOCS: 0 points).

[0054] The results are shown in Table 2 and Figure 1. The treatment plan was as described above, and all five cases showed improvement in symptoms with the initial dose.

[0055] Here, the administered drug is a dopacol combination tablet, but since the actual medicinal effect comes from levodopa, it is expressed as administration of levodopa LDOPA.

[0056] As shown in Table 2 and Figure 1, symptoms improved in all cases with short-term oral administration of small doses of dopamine D1 and D2 receptor agonists and dopamine D2 receptor antagonists (average YBOCS improvement rate 65%, effective in all cases). Higher doses and longer-term administration are likely to improve symptoms. Meanwhile, SSRIs, currently considered the first-line treatment for OCD, are considered effective if they achieve a 35% improvement rate on the YBOCS, but it has been reported that 40-61% of patients do not respond to SSRIs (Pallanti S, Grassi G, Cantisani A. Emerging drugs to treat obsessive-compulsive disorder. Expert Opin Emerg Drugs. 2014;19(1):67-77. doi:10.1517 / 14728214.2014.875157; Pallanti S, Hollander E, Bienstock C, et al. Treatment non-response in OCD: methodological issues and operational definitions. Int J Neuropsychopharmacol. 2002;5(2):181-191. doi:10.1017 / S1461145702002900).

[0057] Additionally, while the additional administration of antipsychotics (D2 receptor antagonists) has been shown to be effective for SSRI-resistant OCD patients, it has been reported that even in this case, the treatment is only effective in about one-third of patients (Zhou DD, Zhou XX, Lv Z, et al. Comparative efficacy and tolerability of antipsychotics as augmentations in adults with treatment-resistant obsessive-compulsive disorder: a network meta-analysis. J Psychiatr Res. 2019;111:51-58. doi:10.1016 / j.jpsychires.2019.01.014; Grassi G, Pallanti S. Current and up-and-coming pharmacotherapy for obsessive-compulsive disorder in adults. Expert Opin Pharmacother. 2018;19(14):1541-1550. doi:10.1080 / 14656566). 2018.1528230).

[0058] Example 2: Effect of Oral CPZ + LDOPA Treatment on 20 Patients with Obsessive-Compulsive Disorder (OCD) Subjects: Twenty patients with OCD (8 men, 12 women) aged 18 to 82 years were enrolled. OCD was diagnosed as a score of 8 or higher on the YBOCS (Non-Patent Document 6). The severity of OCD was assessed using the YBOCS (Non-Patent Documents 6, 7). As shown in Table 3 and Figure 3, the oral dosage was gradually increased during the trial. Note: The four subjects identified as Case Nos. 1 to 4 in Example 1 are included among the 20 subjects in Example 2. Specifically, Case Nos. 4, 1, 2, and 3 in Example 1 (Table 2) correspond to Case Nos. 1, 2, 4, and 6 in Example 2 (Table 3), respectively.

[0059] Drugs: Dopacol Tablets L50 (registered trademark) (L-DOPA 50 mg + carbidopa 5 mg, Nichi-Iko Pharmaceutical Co., Ltd., Toyama Prefecture, Japan) and Wintermin Granules (10%) (registered trademark) (chlorpromazine phenolphthalate 180 mg per 1 g, Shionogi & Co., Ltd., Osaka Prefecture, Japan) were used. Hereinafter, Dopacol Tablets L50 will be referred to as "DOPACOL" and Wintermin Granules (10%) will be referred to as "CPZ."

[0060] Dosage regimen: The dosing regimen was similar to that of Example 1, except that the interval between dose increases (dose increment interval) was individually set between every 2 weeks and every 12 weeks depending on the subject's attendance status and compliance (Table 3). For example, the dose increment interval was fixed at every 2 weeks for subjects who could attend the clinic every 2 weeks, and every 3 months for subjects who could attend the clinic every 3 months. In other words, the dose increment interval remained constant for the same patient, regardless of how many dose increments were administered. The initial dose was DOPACOL (1 tablet (50 mg) / day) + CPZ (5 mg) / day. After a fixed interval of at least 2 weeks, the next dose was DOPACOL (1 tablet x 2 (100 mg) / day) + CPZ (5 mg) x 2 (10 mg) / day, and the dose after that was DOPACOL (1 tablet x 3 (150 mg) / day) + CPZ (5 mg) x 3 (15 mg) / day. To further verify the dose-dependent effect, for two subjects (case numbers 5 and 10), the maximum dose was increased three times to DOPACOL (1 tablet x 4 (200 mg) / day) + CPZ (5 mg) x 4 (20 mg) / day [each tablet: 2 tablets in the morning, 1 tablet at noon, and 1 tablet in the evening], and for one subject (case number 4), the maximum dose was increased four times to DOPACOL (1 tablet x 5 (250 mg) / day) + CPZ (5 mg) x 5 (25 mg) / day [each tablet: 2 tablets in the morning, 2 tablets at noon, and 1 tablet in the evening]. Table 3

[0061] Here, the administered drug is a dopacol combination tablet, but since the actual medicinal effect comes from levodopa, it is expressed as administration of levodopa LDOPA.

[0062] The results are shown in Table 3 and Figure 2. Table 3 and Figure 2 show the therapeutic effects of oral CPZ + LDOPA treatment on 20 patients with obsessive-compulsive disorder (OCD). Based on the above-mentioned administration plan, symptoms improved in all 20 patients (average YBOCS improvement rate of 70%, effective in all patients). A t-test was performed on the mean YBOCS values ​​before and after treatment, revealing a highly statistically significant difference of P=0.0000004 (****P<0.001).

[0063] Figure 3 shows the dose-dependent improvement effect in 20 patients with obsessive-compulsive disorder (OCD) who received oral CPZ + LDOPA treatment. In all 20 patients, OCD symptoms (YBOCS) improved in a dose-dependent manner as the dosage gradually increased. Dose-dependent symptom improvement was observed up to a maximum of CPZ = 25 mg / day and LDOPA = 250 mg / day, and in subject No. 4, symptoms completely disappeared (YBOCS = 0) at the evaluation 10 weeks after the start of treatment.

[0064] Example 3: Effect of oral CPZ and rotigotine patch treatment on 12 patients with obsessive-compulsive disorder (OCD) Twelve patients with obsessive-compulsive disorder (OCD) aged 24 to 82 years (5 men, 7 women) were enrolled. Obsessive-compulsive disorder was diagnosed as a score of 8 or higher on the YBOCS (Non-Patent Document 6). The severity of obsessive-compulsive disorder was assessed using the YBOCS (Non-Patent Documents 6 and 7).

[0065] The medications used were Neupro Patch (registered trademark) (Neupro Patch 4.5 mg, 9 mg, 13.5 mg: rotigotine 4.5 mg, 9 mg, 13.5 mg per patch, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) and Wintermin Granules (10%) (registered trademark) (chlorpromazine phenolphthalate 180 mg per gram, Shionogi & Co., Ltd., Osaka, Japan). Hereinafter, Neupro Patch will be referred to as "NP" and Wintermin Granules (10%) as "CPZ." Neupro Patch is a patch containing rotigotine, a dopamine receptor agonist.

[0066] Dosage regimen: The dosing regimen was the same as in Example 1, but the interval between dose increases (dose increases) was individually set between every two weeks and every six weeks depending on the subject's attendance and compliance (Table 4). Neupro Patch was applied to intact skin on the shoulder, upper arm, abdomen, flank, buttocks, or thigh, and replaced every 24 hours. CPZ was administered orally as in Example 1. The initial dose was Neupro Patch 4.5 mg / day + CPZ (5 mg) / day, and the next dose, after a fixed interval of at least two weeks, was Neupro Patch 9 mg / day + CPZ (5 mg) x 2 (10 mg) / day, with the maximum dose being Neupro Patch 13.5 mg / day + CPZ (5 mg) x 3 (15 mg) / day. Table 4

[0067] The results are shown in Table 4 and Figure 4. Table 4 and Figure 4 show the therapeutic effects of oral CPZ + rotigotine patch treatment on 12 patients with obsessive-compulsive disorder (OCD). Based on the above treatment plan, symptoms improved in all 12 patients (average YBOCS improvement rate 69%, effective in all patients). A t-test of the mean YBOCS scores before and after treatment detected a highly statistically significant difference of P=0.0000006 (****P<0.001).

[0068] Figure 5 also shows the dose-dependent improvement in 12 patients with obsessive-compulsive disorder (OCD) who received oral CPZ and rotigotine patch treatment. In all 12 patients, OCD symptoms (YBOCS) improved dose-dependently with increasing dose. In two subjects (Case 23 and Case 26), symptoms completely disappeared (YBOCS=0) at 10 weeks (CPZ=15, NP=13.5) and 8 weeks (CPZ=10, NP=9) after the start of treatment.

[0069] Example 4: Effects on Two Patients with Obsessive-Compulsive Disorder (OCD) Treated with Oral LDOPA and Other D2 Receptor Antagonists (Excluding CPZ) The therapeutic effects of metoclopramide and sulpiride, other D2 receptor antagonists excluding CPZ, were investigated following essentially the procedures described in Example 1. The following case involved the use of metoclopramide tablets (metoclopramide hydrochloride 5 mg, Takeda Pharmaceutical Co., Ltd.). A 66-year-old woman (Case No. 5 in Example 1): Onset at age 55. Concerns about her illness led to multiple medical visits and even hospitalization. Her YBOCS score was 22, and she was diagnosed with moderate obsessive-compulsive disorder. After 8 weeks of oral administration of levodopa 50 mg and metoclopramide 5 mg, her symptoms completely resolved (YBOCS score: 0). The results for Case No. 5, who received metoclopramide, are plotted in Figure 6, extracted from the CPZ-treated group in Figure 1. Although the administered medication is a dopacol combination tablet, its actual efficacy comes from levodopa, so it is expressed as administration of levodopa LDOPA.

[0070] The following case involved the use of Dogmatil tablets (sulpiride 50 mg, Nichi-Iko Pharmaceutical Co., Ltd., Toyama, Japan). The patient was a 55-year-old man with onset of symptoms at age 37. He had compulsive behaviors, such as checking for mistakes, rewriting, and rereading, which caused him to suffer in life. His YBOCS score was 11, and he was diagnosed with mild obsessive-compulsive disorder. LDOPA 50 mg and sulpiride 50 mg were administered orally once daily in the morning, and the YBOCS was evaluated four weeks later. Note that although the administered medication was a dopacol combination tablet, its actual efficacy comes from levodopa, so this is referred to as administration of levodopa-LDOPA.

[0071] The results are shown in Figure 6. Figure 6 shows the improvement in OCD symptoms (YBOCS) in two patients with obsessive-compulsive disorder (OCD) treated with oral LDOPA plus a D2 receptor antagonist other than CPZ. In both patients, one treated with metoclopramide instead of CPZ and the other with sulpiride, significant symptom improvement was observed at the 4-week evaluation with low initial doses (sulpiride 50 mg + LDOPA 50 mg, metoclopramide 5 mg + LDOPA 50 mg). In series 2 with metoclopramide, symptoms completely disappeared (YBOCS = 0), and in series 1 with sulpiride, symptoms almost disappeared (YBOCS = 1). This suggests that the combination of a D2 receptor antagonist other than CPZ with LDOPA can also produce sufficiently effective clinical effects.

[0072] Based on the facts of the following Reference Examples, the present inventors have also discovered, as one embodiment, a pharmaceutical composition containing levodopa for treating dystonia, characterized in that levodopa is orally administered in an amount not more than half the standard maintenance amount for treating Parkinson's disease, and chlorpromazine is orally administered in an amount not more than half the antipsychotic therapeutic amount as chlorpromazine hydrochloride.

[0073] Reference Example 1 Abstract This study demonstrated for the first time that dual dopamine modulation therapy using L-3,4-dihydroxyphenylalanine (L-DOPA; levodopa) and chlorpromazine (CPZ) is effective in treating blepharospasm, a type of focal dystonia. L-DOPA is the direct precursor of dopamine and is a full agonist at the D1 and D2 receptors (D1R and D2R), while CPZ is an effective antagonist at the D2R.

[0074] Subjects: This study enrolled 21 patients with blepharospasm (6 men and 15 women) aged 51 to 79 years (mean age 68.7 ± 7.8 years). The diagnosis of blepharospasm was made according to the Fahn definition (1. Fahn S., Marsden CD. and Calne DB. "Classification and Investigation of Dystonia". In: Marsden CD and Fahn S, editors., Movement Disorders, Butterworths, London, (1987). pp. 332-58.). Clinical and genetic testing, along with brain magnetic resonance imaging (MRI), were performed to exclude hereditary and secondary dystonias. Genetic testing included whole-exome sequencing (OMIM Phenotypic Series PS128100) to screen for pathogenic variants in known dystonia genes. All patients treated with botulinum toxin type A (BTX-A) were instructed to follow a 3-month washout period between their last BTX-A injection and the start of the study. Video analysis was performed before and after the drug challenge test. The severity of blepharospasm was assessed using four indices: the visual analog scale (VAS)

[12] , the Blepharospasm Disability Index (BSDI)

[13] , the modified VAS

[14] , and the Jankovic Rating Scale (JRS) [13, 15].

[0075] Drugs: Dopacol Tablets L50 (registered trademark) (L-DOPA 50 mg + carbidopa 5 mg, Nichi-Iko Pharmaceutical Co., Ltd., Toyama Prefecture, Japan) and Wintermin Granules (10%) (registered trademark) (chlorpromazine phenolphthalate 180 mg per 1 g, Shionogi & Co., Ltd., Osaka Prefecture, Japan) were used. Hereinafter, Dopacol Tablets L50 will be referred to as "DOPACOL" and Wintermin Granules (10%) will be referred to as "CPZ."

[0076] Patient Sorting and Medication Administration: Patients were randomly assigned to one of three groups (L-DOPA, CPZ, or L-DOPA + CPZ) based on the order of their visit. A double-blind study was conducted, with participants and assessors blinded to the identity of each group. L-DOPA group: This group included seven patients with blepharospasm (three men and four women) who received dopacol alone. The age range was 51-79 years (mean age 66.0 ± 10.1 years), with a mean disease duration of 10.7 ± 9.5 years. Patients were prescribed dopacol (1 tablet daily) for the first two weeks, dopacol (1 tablet twice daily) for the next two weeks, and dopacol (1 tablet three times daily) for the final four weeks.

[0077] CPZ group: This group included seven patients with blepharospasm (one male and six females) who received CPZ alone. The age range was 60-72 years (mean age 66.4±3.9 years), and the mean disease duration was 8.4±5.9 years. CPZ (5 mg / day) was prescribed for the first two weeks, CPZ (5 mg x 2 / day) for the next two weeks, and CPZ (5 mg x 3 / day) for the final four weeks.

[0078] L-DOPA + CPZ group: This group included seven patients with blepharospasm (two men and five women) who received both DOPACOL and CPZ. The age range was 66-78 years (mean age 73.5 ± 5.9 years), and the mean disease duration was 8.0 ± 7.6 years. For the first two weeks, patients received DOPACOL (1 tablet / day) and CPZ (5 mg / day), for the next two weeks, DOPACOL (1 tablet x 2 / day) and CPZ (5 mg x 2 / day), and for the final four weeks, DOPACOL (1 tablet x 3 / day) and CPZ (5 mg x 3 / day).

[0079] Statistical analysis: Statistical significance was assessed using the Wilcoxon signed-rank test or one-way analysis of variance (ANOVA). Statistical significance was defined as P < 0.05. Statistical analyses were performed using SPSS statistical software (version 11.0 for Windows) (IMB Corp., Armonk, New York, USA).

[0080] Results: The severity of blepharospasm was assessed using the VAS and BSDI for subjective symptoms and the mVAS and JRS for objective symptoms (Figure 7). First, when comparing the severity of blepharospasm before the drug challenge test among the L-DOPA, CPZ, and L-DOPA+CPZ groups, no significant differences were found in any of the subjective or objective symptoms (P > 0.05, one-way ANOVA). In other words, it was confirmed that there was no clear bias in the severity of blepharospasm among the three groups before the drug challenge test.

[0081] Next, we compared the severity of each symptom before and after the drug challenge test. The L-DOPA group (Fig. 7, top): The modified VAS [before the drug challenge test: 141.3 ± 8.4 (n = 7), after the drug challenge test: 178.8 ± 24.3 (n = 7), "before" vs "after"; P < 0.05, Wilcoxon signed-rank test] showed a significant progression in symptom severity, but the VAS, BSDI, and JRS did not.

[0082] CPZ group (FIG. 7; center): No significant changes in severity were observed before and after the drug challenge test in all of the assessments using VAS, BSDI, mVAS, and JRS.

[0083] L-DOPA + CPZ group (Figure 7; bottom): Administration of L-DOPA + CPZ significantly reduced the severity of all subjective and objective symptoms of VAS, BSDI, mVAS, and JRS after the drug challenge test compared to before. VAS [67.1 ± 14.6 (n=7) before the drug challenge test, 44.8 ± 27.5 (n=7) after the drug challenge test, "before" vs "after"; P < 0.05, Wilcoxon signed-rank test], BSDI [15.1 ± 6.6 (n=7) before the drug challenge test, 10.6 ± 6.7 (n=7) after the drug challenge test, "before" vs "after"; P < 0.05, Wilcoxon signed-rank test], mVAS [148.0 ± 17.4 (n=7) before the drug challenge test, 116.5 ± 14.5 (n=7) after the drug challenge test, "before" vs "after"; P < 0.05, Wilcoxon signed-rank test], and JRS [5.9 ± 2.2 (n=7) before the drug challenge test, 10.6 ± 6.7 (n=7) after the drug challenge test, "before" vs "after"; P < 0.05, Wilcoxon signed-rank test]. 3.0±2.3 (n=7), "pre" vs "post"; P < 0.05, Wilcoxon signed-rank test].

[0084] No obvious neurological or neuropsychiatric changes were observed during the drug challenge test in any of the L-DOPA, CPZ, or L-DOPA+CPZ groups. Therefore, it was confirmed that the therapeutic effect for blepharospasm could only be achieved by the combination of DOPACOL (1 tablet x 3 / day) and CPZ (5 mg x 3 / day), rather than by the administration of DOPACOL or CPZ alone.

[0085] Dystonia is a condition in which sustained muscle contractions cause abnormal posture and movement disorders. While generalized dystonia associated with genetic mutations is common in children, focal dystonia is more common in adults. Focal dystonia is common and includes conditions such as blepharospasm, spasmodic torticollis, and writer's cramp. At the World Congress of Neurology, Kyoto, September 16-21, 2017, the inventors discovered that prescribing sulpiride or metoclopramide in addition to levodopa coincidentally alleviated dystonia, and presented their findings (World Congress of Neurology, Kyoto, September 16-21, 2017, Abstracts: VOLUME 381, SUPPLEMENT, 580, OCTOBER 15, 2017, Three cases of dystonia with effective levodopa and D2 blocker combination therapy, S. Marsumoto, M. Takahashi, DOI: https: / / doi.org / 10.1016 / j.jns.2017.08.1635).

[0086] Possible inventions in such embodiments: <Pharmaceutical composition containing levodopa for treating dystonia> [1] A pharmaceutical composition containing levodopa for treating dystonia, characterized in that the amount of levodopa is orally administered at half or less of the standard maintenance amount for treating Parkinson's disease, and chlorpromazine is simultaneously orally administered at half or less of the antipsychotic therapeutic amount as chlorpromazine hydrochloride; specifically, a pharmaceutical composition in which the amount of levodopa that is half or less of the standard maintenance amount for treating Parkinson's disease is 50 to 300 mg per day, preferably 50 to 200 mg per day, more preferably 100 to 150 mg per day, and a pharmaceutical composition in which the amount of chlorpromazine hydrochloride that is half or less of the antipsychotic therapeutic amount is 10 to 15 mg per day; and <Pharmaceutical composition containing chlorpromazine for treating dystonia> [2] A pharmaceutical composition containing chlorpromazine for treating dystonia, wherein chlorpromazine is orally administered in an amount equal to or less than half the antipsychotic therapeutic dose as chlorpromazine hydrochloride, and simultaneously levodopa is orally administered in an amount equal to or less than half the standard maintenance dose for treating Parkinson's disease; specifically, a pharmaceutical composition in which the amount equal to or less than half the antipsychotic therapeutic dose as chlorpromazine hydrochloride is 5 to 300 mg per day, preferably 5 to 200 mg per day, more preferably 10 to 15 mg per day, and a pharmaceutical composition for treating dystonia in which the amount equal to or less than half the standard maintenance dose for treating Parkinson's disease as levodopa is 100 to 150 mg per day.

[0087] As described above, the present invention can include the following embodiments as other aspects. <Pharmaceutical Composition>

[101] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D1 receptor stimulant.

[102] The pharmaceutical composition of

[101] , wherein the dopamine D1 receptor stimulant is selected from a dopamine D1 receptor agonist and a dopamine D1 receptor-positive allosteric modulator.

[103] The pharmaceutical composition of

[102] , wherein the dopamine D1 receptor stimulant is a dopamine D1 receptor agonist.

[104] The pharmaceutical composition of

[103] , wherein the dopamine D1 receptor agonist is selected from SKF81297, SKF38393, SKF83959, SKF82526 (Fenoldpam), dihydrexidine, ABT-431, A-86929, A-77636, A-68930, PF-06649751 (Tavapandon), and PF-06412.

[105] The pharmaceutical composition of

[102] , wherein the dopamine D1 receptor stimulant is a dopamine D1 receptor-positive allosteric modulator.

[106] The pharmaceutical composition of

[105] , wherein the dopamine D1 receptor-positive allosteric modulator is selected from DETQ (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one), mevidalene, MLS1082, MLS6585, pyrazolyl-dihydroisoquinoline, DPTQ, CID 2886111 ([N-(6-tert-butyl-3-carbamoyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pyridine-4-carboxamide]), LY3154885, and ASP4345.

[0088]

[107] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D1 and D2 receptor agonist, wherein the pharmaceutical composition is administered in combination with a dopamine D2 receptor inhibitor.

[108] The pharmaceutical composition of

[107] , wherein the dopamine D2 receptor inhibitor is selected from the group consisting of a dopamine D2 receptor antagonist and a dopamine D2 receptor-negative allosteric modulator.

[109] The pharmaceutical composition of

[107] or

[108] , wherein the dopamine D2 receptor inhibitor is a dopamine D2 receptor antagonist.

[110] The pharmaceutical composition of

[109] , wherein the dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, levomepromazine, fluphenazine, perphenazine, prochlorperazine, propericiazine, haloperidol, pipamperone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiperone, nemonapride, timiperone, and perospirone.

[111] The pharmaceutical composition of

[108] , wherein the dopamine D2 receptor inhibitor is a dopamine D2 receptor-negative allosteric modulator.

[112] The pharmaceutical composition of

[111] , wherein the dopamine D2 receptor-negative allosteric modulator is SB269652.

[113] The pharmaceutical composition of any one of

[107] to

[112] , wherein the dopamine D1 and D2 receptor agonist is selected from levodopa, levodopa-carbidopa hydrate (a levodopa combination drug), levodopa-carbidopa-entacapone combination drug, levodopa-benserazide hydrochloride combination drug, and the dopamine agonist pergolide or rotigotine.

[114] The pharmaceutical composition of

[113] , wherein levodopa and chlorpromazine are administered in combination.

[115] The pharmaceutical composition of any one of

[107] to

[114] , wherein the amount of levodopa is orally administered at half or less of the standard maintenance dose for Parkinson's disease treatment.

[116] The pharmaceutical composition of

[115] , wherein the amount of levodopa is 50 to 300 mg per day (half or less of the standard maintenance dose for Parkinson's disease treatment).

[117] The pharmaceutical composition according to

[116] , wherein the amount of levodopa is 50 mg per day, which is half or less of the standard maintenance dose for treating Parkinson's disease.

[0089]

[118] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D2 receptor inhibitor, wherein a dopamine D1 and D2 receptor agonist are administered in combination.

[119] The pharmaceutical composition of

[118] , wherein the dopamine D2 receptor inhibitor is selected from the group consisting of a dopamine D2 receptor antagonist and a dopamine D2 receptor-negative allosteric modulator.

[120] The pharmaceutical composition of

[119] , wherein the dopamine D2 receptor inhibitor is a dopamine D2 receptor antagonist.

[121] The pharmaceutical composition of

[120] , wherein the dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, levomepromazine, fluphenazine, perphenazine, prochlorperazine, propericiazine, haloperidol, pipamperone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiperone, nemonapride, timiperone, and perospirone.

[122] The pharmaceutical composition of

[119] , wherein the dopamine D2 receptor inhibitor is a dopamine D2 receptor-negative allosteric modulator.

[123] The pharmaceutical composition of

[122] , wherein the dopamine D2 receptor-negative allosteric modulator is SB269652.

[124] The pharmaceutical composition according to any one of

[119] to

[124] , wherein the dopamine D1 and D2 receptor agonist is selected from levodopa, levodopa-carbidopa hydrate (a levodopa combination drug), levodopa-carbidopa-entacapone combination drug, levodopa-benserazide hydrochloride combination drug, and the dopamine agonist pergolide or rotigotine.

[125] The pharmaceutical composition according to

[124] , wherein chlorpromazine and levodopa are administered in combination.

[126] The pharmaceutical composition according to

[125] , wherein chlorpromazine is orally administered at a dose equal to or less than half the antipsychotic therapeutic dose as chlorpromazine hydrochloride.

[127] The pharmaceutical composition according to

[126] , wherein the dose equal to or less than half the antipsychotic therapeutic dose as chlorpromazine hydrochloride is 5 to 30 mg per day.

[128] The pharmaceutical composition of

[127] , wherein half or less of the antipsychotic therapeutic dose of chlorpromazine hydrochloride is 5 mg per day.

[0090]

[129] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D1 receptor stimulant, wherein the pharmaceutical composition is administered in combination with a dopamine D2 receptor inhibitor.

[130] The pharmaceutical composition according to

[129] , wherein the dopamine D1 receptor stimulant is selected from the group consisting of a dopamine D1 receptor agonist and a dopamine D1 receptor-positive allosteric modulator, and the dopamine D2 receptor inhibitor is selected from the group consisting of a dopamine D2 receptor antagonist and a dopamine D2 receptor-negative allosteric modulator.

Claims

1. A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a combination of dopamine D1 and D2 receptor agonists and a dopamine D2 receptor antagonist.

2. The pharmaceutical composition according to claim 1, wherein the dopamine D1 and D2 receptor agonist is selected from levodopa, levodopa / carbidopa hydrate (a levodopa combination), levodopa / carbidopa / entacapone combination preparation, levodopa / benserazide hydrochloride combination preparation, pergolide (a dopamine agonist), and rotigotine.

3. The pharmaceutical composition according to claim 1, wherein the dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, levomepromazine, fluphenazine, perphenazine, prochlorperazine, propericiazine, haloperidol, pipemperone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiperone, nemonapride, thimiperone, and perospirone.

4. The pharmaceutical composition according to claim 1, wherein levodopa and chlorpromazine are administered in combination.

5. The pharmaceutical composition according to claim 4, characterized in that it is used to be administered orally in an amount of levodopa that is half or less of the standard maintenance dose for the treatment of Parkinson's disease.

6. The pharmaceutical composition according to claim 5, wherein the amount of levodopa is 50 to 300 mg per day, which is less than half of the standard maintenance dose for the treatment of Parkinson's disease.

7. The pharmaceutical composition according to claim 6, wherein the amount of levodopa is 50 mg per day, which is less than half of the standard maintenance dose for the treatment of Parkinson's disease.

8. The pharmaceutical composition according to claim 4, characterized in that chlorpromazine is administered orally as chlorpromazine hydrochloride in an amount less than half the antipsychotic therapeutic dose.

9. The pharmaceutical composition according to claim 8, wherein the amount of chlorpromazine hydrochloride is 5 to 30 mg per day, which is less than half the antipsychotic therapeutic dose.

10. The pharmaceutical composition according to claim 9, wherein the amount of chlorpromazine hydrochloride is 5 mg per day, which is less than half the antipsychotic therapeutic dose.

Images