Drug therapy for obsessive-compulsive disorder targeting dopamine D1 signal of striatum corpus

Abstract

The invention provides a pharmaceutical composition for treating obsessive-compulsive disorder. More specifically, the present invention relates to: (1) a pharmaceutical composition containing a dopamine D1 receptor stimulating substance as an active ingredient for the treatment of obsessive-compulsive disorder; and / or (2) a pharmaceutical composition containing a dopamine D1 and D2 receptor stimulating substance, the dopamine D2 receptor inhibiting substance being administered in combination, for the purpose of stimulating a striatum dopamine D1 receptor; and / or (3) a pharmaceutical composition containing a dopamine D2 receptor inhibiting substance, the dopamine D1 and D2 receptor stimulating substance being administered in combination.

Description

Technical Field

[0001] This patent application claims priority and benefits under the Paris Convention based on Japanese Patent Application No. 2022-096675 (filed on June 15, 2022) and PCT / JP2022 / 048379 (filed on December 27, 2022), and all the contents described in the above applications are incorporated herein by reference.

[0002] The present invention relates to a drug therapy for treating obsessive-compulsive disorder. Specifically, the present invention belongs to the field of drug therapy for treating obsessive-compulsive disorder using a dopamine D1 receptor stimulating substance and / or a combination of a dopamine D1 and D2 receptor stimulating substance and a dopamine D2 receptor inhibiting substance for the purpose of selectively stimulating the dopamine D1 receptor of the striatum. Background Art

[0003] Obsessive-compulsive disorder (OCD) is a group of diseases that are described as "obsessive-compulsive and related disorders" (Obsessive Compulsive and Related Disorders) according to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) disease name / term translation guide, and is a core disease of the category of obsessive-compulsive-related disorders characterized by obsessive symptoms such as obsessions or compulsive behaviors. Obsessive symptoms include: repetitive / persistent thoughts, impulses, and obsessions bound by images; and compulsive behaviors such as repeated mental actions such as washing hands or checking, ritual behaviors, chanting mantras, and counting numbers. Although patients with obsessive-compulsive disorder try to control obsessions or compulsive behaviors, they are unable to control them due to anxiety and pain, which causes entanglement and stress (Non-patent Literature 1, 2).

[0004] The prevalence of obsessive-compulsive disorder is 1% to 2%, and the male-female ratio is roughly the same. The average age of onset is around 20 years old, and there is a tendency for males to develop earlier (Non-patent Documents 1, 2). The treatment of obsessive-compulsive disorder usually uses oral selective serotonin reuptake inhibitors (SSRIs), a type of antidepressant, and cognitive behavioral therapy (Non-patent Documents 2, 3). It is recommended that SSRIs be taken orally for 4 to 6 weeks at the maximum dose within 12 weeks from the start of administration (Non-patent Documents 2, 3, 4). In the past, SSRIs were the first choice for the treatment of obsessive-compulsive disorder, but they required long-term medication at a higher dose than depression. In long-term prognosis studies, only about half of the obsessive-compulsive disorder patients responded to SSRI treatment even after more than 10 years, and the maximum improvement rate was only 30% to 40%, and most of them would relapse even if they were temporarily relieved (Non-patent Document 2). In the clinic of obsessive-compulsive disorder, it is expected to develop a drug treatment with high therapeutic efficiency to replace SSRI.

[0005] Prior art literature

[0006] Non-patent literature

[0007] Non-patent literature 1: American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed.Text Revision.APA.WashingtonD.C.

[0008] Non-patent literature 2: Koran, LM Hanna, GL, Hollander.E., et al: Practice 0 guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry. 164 (supplement); 1-56, 2007

[0009] Non-patent document 3: March.J., Frances.A., Kahn.D., et al Expert consensus guidelines: Treatment of obsessive-compulsive disorder.J Clin Psychiatry, 58(suppl.4); 1-72, 1997

[0010] Non-patent literature 4: Denys, D.: Pharmacotherapy of obsessive-compulsivedisorder and obsessive-compulsive spectrum disorders. Psychiatr Clin NorthAm. 29; 553-584, 2006

[0011] Non-patent document 5: Goodman WK, Price LH, Rasmussen SA et al: The Yale-Brown obsessive compulsive scale II. Validity. Arch Gen Psychiatry 46: 1012-1016, 1989

[0012] Non-patent document 6: Steketee, G and Neziroglu, E: Assessment of obsessive-compulsive disorder and spectrum disorders. Bref Treat. Crisis Interv., 3: 169-185, 2003

[0013] Non-patent literature 7: Storch EA, De Nadai AS, Conceicao do Rosario M et alDefining severity in adults with obsessive compulsive disorder. ComprPsychiatry 63: 30-35, 2015 Summary of the invention

[0014] Problems to be solved by the invention

[0015] As described above, there is no medicine / method that can adequately treat obsessive-compulsive disorder, and an effective treatment method is sought.

[0016] Solutions for solving problems

[0017] Under such background, the present inventors found that, in the treatment of patients with involuntary movement disorder, a small amount of levodopa and a small amount of chlorpromazine or metoclopramide were occasionally administered, and the obsessive-compulsive disorder was improved within 4 weeks, and the present invention was completed. Specifically, it was found for the first time that a dual dopamine regulation therapy using L-3,4-dihydroxyphenylalanine (L-DOPA; levodopa) (dopamine D1 and D2 receptor stimulator) and chlorpromazine (CPZ) or metoclopramide (D2 receptor blocking substance) showed an effect on the treatment of obsessive-compulsive disorder in an amount less than the standard maintenance amount and in a period shorter than the usual treatment period.

[0018] Therefore, the present invention includes the following aspects.

[0019] <Pharmaceutical Composition>

[0020] [1] A pharmaceutical composition for treating obsessive-compulsive disorder, the pharmaceutical composition comprising a dopamine D1 receptor stimulating substance.

[0021] [2] The pharmaceutical composition according to [1], wherein the dopamine D1 receptor stimulating substance is selected from the group consisting of a dopamine D1 receptor agonist and a dopamine D1 receptor-positive allosteric modulator.

[0022] [3] The pharmaceutical composition according to [2], wherein the dopamine D1 receptor stimulating substance is a dopamine D1 receptor agonist.

[0023] [4] The pharmaceutical composition according to [3], wherein the dopamine D1 receptor agonist is selected from SKF81297, SKF38393, SKF83959, SKF82526 (fenoldopam), dihydrexidine hydrochloride, ABT-431, A-86929, A-77636, A-68930, PF-06649751 (tavapadon), and PF-06412.

[0024] [5] The pharmaceutical composition according to [2], wherein the dopamine D1 receptor stimulating substance is a dopamine D1 receptor-positive allosteric modulator.

[0025] [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)ethane-1-one), mevidalan, 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.

[0026] [7] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising dopamine D1 and D2 receptor agonists and a dopamine D2 receptor inhibitory substance administered in combination.

[0027] [8] The pharmaceutical composition according to [7], wherein the dopamine D2 receptor inhibitory substance is selected from the group consisting of a dopamine D2 receptor antagonist and a dopamine D2 receptor-negative allosteric modulator.

[0028] [9] The pharmaceutical composition according to [8], wherein the dopamine D2 receptor inhibitory substance is a dopamine D2 receptor antagonist.

[0029]

[10] The pharmaceutical composition according to [9], wherein the dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, methoxybutrazine, fluphenazine, perphenazine, prochlorperazine, cyanthiazide, haloperidol, amide peridone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiroperidone, nemopride, temiperone, and perospirone.

[0030]

[11] The pharmaceutical composition according to [8], wherein the dopamine D2 receptor inhibitory substance is a dopamine D2 receptor-negative allosteric modulator.

[0031]

[12] The pharmaceutical composition according to

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

[0032]

[13] The pharmaceutical composition according to [7], wherein the dopamine D1 and D2 receptor agonist is selected from levodopa, levodopa / carbidopa hydrate as a levodopa mixture, levodopa / carbidopa / entacapone combination preparation, levodopa / benserazide hydrochloride combination preparation, and pergolide and rotigotine as dopamine agonists.

[0033]

[14] The pharmaceutical composition according to

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

[0034]

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

[14] , characterized in that it is used for oral administration in an amount of levodopa that is no more than half of the standard maintenance dose for the treatment of Parkinson's disease.

[0035]

[16] The pharmaceutical composition according to

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

[0036]

[17] The pharmaceutical composition according to

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

[0037]

[18] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D2 receptor inhibitory substance and dopamine D1 and D2 receptor agonists administered in combination.

[0038]

[19] The pharmaceutical composition according to

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

[0039]

[20] The pharmaceutical composition according to

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

[0040]

[21] The pharmaceutical composition according to

[20] , wherein the dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, methoxybutrazine, fluphenazine, perphenazine, prochlorperazine, cyanthiazide, haloperidol, amide peridone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiroperidone, nemopride, temiperone, and perospirone.

[0041]

[22] The pharmaceutical composition according to

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

[0042]

[23] The pharmaceutical composition according to

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

[0043]

[24] The pharmaceutical composition according to

[19] , wherein the dopamine D1 and D2 receptor agonists are selected from levodopa, levodopa / carbidopa hydrate as a levodopa mixture, levodopa / carbidopa / entacapone combination preparations, levodopa / benserazide hydrochloride combination preparations, and pergolide and rotigotine as dopamine agonists.

[0044]

[25] The pharmaceutical composition according to

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

[0045]

[26] The pharmaceutical composition according to

[25] , characterized in that chlorpromazine is orally administered in an amount of less than half of the antipsychotic therapeutic dose of chlorpromazine hydrochloride.

[0046]

[27] The pharmaceutical composition according to

[26] , wherein the amount of chlorpromazine hydrochloride is less than half of the antipsychotic therapeutic dose, that is, 5 to 30 mg per day.

[0047]

[28] The pharmaceutical composition according to

[27] , wherein the amount of chlorpromazine hydrochloride is less than half of the antipsychotic therapeutic dose, that is, 5 mg per day.

[0048]

[29] A pharmaceutical composition for treating obsessive-compulsive disorder, wherein the pharmaceutical composition comprises a dopamine D1 receptor stimulating substance and a dopamine D2 receptor inhibitory substance administered in combination.

[0049]

[30] The pharmaceutical composition according to

[29] , wherein the dopamine D1 receptor stimulating substance is selected from dopamine D1 receptor agonists and dopamine D1 receptor-positive allosteric modulators, and the dopamine D2 receptor inhibitory substance is selected from dopamine D2 receptor antagonists and dopamine D2 receptor-negative allosteric modulators.

[0050] Effects of the Invention

[0051] The present invention can provide a pharmaceutical product that is extremely excellent in effectiveness and safety for obsessive-compulsive disorder. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 middle, Figure 1 (Left) is a graph showing the individual values ​​of five obsessive-compulsive disorder patients evaluated using the YBOCS (self-administered YALE-BROWN Obsessive-compulsive Scale). CPZ (Dongmianling Granules) and LDOPA (DOPACOL Tablets) were used as therapeutic drugs. Figure 1 (Right) is a graph showing the average values ​​of YBOCS of 5 patients with obsessive compulsive disorder before and after treatment. *, P<0.05 (t-test).

[0053] Figure 2 middle, Figure 2 (Left) is a graph showing individual markers of the measured values ​​of 20 patients with obsessive-compulsive disorder evaluated using the YBOCS (self-administered YALE-BROWN Obsessive-compulsive Behavior Scale). Figure 2 (Right) is a graph showing the average values ​​of YBOCS of 20 obsessive compulsive disorder patients before and after treatment. ****, P<0.001 (t-test). CPZ (Dongmianling fine granules) and LDOPA (DOPACOL compound tablets) were used as therapeutic drugs.

[0054] Figure 3 Yes means Figure 2 The graph shown is a graph of the relationship between the YBOCS (self-administered YALE-BROWN obsessive-compulsive idea / compulsive behavior rating scale) and the oral dosage of 20 patients with obsessive-compulsive disorder. The oral dosage of the therapeutic drugs CPZ (Dongmianling fine granules) and LDOPA (DOPACOL combined tablets) was increased step by step to evaluate the therapeutic effect.

[0055] Figure 4 middle, Figure 4 (Left) is a graph showing individual markers of the measured values ​​of 12 patients with obsessive-compulsive disorder evaluated using the YBOCS (self-administered YALE-BROWN Obsessive-compulsive Behavior Scale). Figure 4 (Right) is a graph showing the average values ​​of YBOCS of 12 obsessive-compulsive disorder patients before and after treatment. ****, P<0.001 (t-test). CPZ (Dongmanling granules) and Rotigotine (Rotigotine patch: Upro patch) were used as therapeutic drugs.

[0056] Figure 5 Yes means Figure 4 The graph shown is a graph of the relationship between the YBOCS (self-administered Yale-Brown Obsessive-Compulsive Scale) and the oral dosage / patch dosage of 12 patients with obsessive-compulsive disorder. The oral dosage and patch dosage of the therapeutic drug CPZ (Dongmenling Granules) and Rotigotine (Rotigotine patch: Upro Patch) were gradually increased to evaluate the therapeutic effect.

[0057] Figure 6 This is a graph showing the individual values ​​of two patients with obsessive-compulsive disorder evaluated using the YBOCS (self-administered YALE-BROWN Obsessive-compulsive Behavior Rating Scale). Figure 6For the two patients, dopamine D2 receptor blockers other than CPZ (Dongmenling fine granules) were used as treatment drugs. In series 1, sulpiride (Dogmatyl tablets) replaced CPZ and was used in combination with LDOPA (DOPACOL combination tablets), and in series 2, metoclopramide (Primperan tablets) replaced CPZ and was used in combination with LDOPA (DOPACOL combination tablets).

[0058] Figure 7 The results of measuring the severity of blepharospasm before and after the drug challenge test based on the visual analogue scale (VAS), blepharospasm disability index (BSDI), modified VAS (mVAS), and Jankovic Rating Scale (JRS). Before: before the drug challenge test, After: after the drug challenge test. The number of patients in the L-DOPA group (upper section), CPZ group (middle section), and L-DOPA+CPZ group (lower section) were all 7. The line graph (upper section) shows the values ​​for all cases, and the graph (lower section) shows the average values ​​for all cases. *, P < 0.05 (Wilcoxon signed-rank test). DETAILED DESCRIPTION

[0059] <Pharmaceutical Composition>

[0060] The present invention relates to a pharmaceutical composition for treating obsessive-compulsive disorder, which contains a dopamine D1 receptor stimulating substance, as one embodiment. As shown in the following paragraph of this specification, the present inventors have found that LDOPA+CPZ can treat dystonia, which is a past achievement. At this time, based on previous reports that dystonia often coexists with obsessive-compulsive disorder and depression, the present inventors inferred that LDOPA+CPZ has the same therapeutic effect on the latter disease, and actually proved for the first time that the drug can treat obsessive-compulsive disorder.

[0061] The following can be cited as conventional reports, but none of them leads to the present invention.

[0062] (1)Psychiatric disorders in adult-onset focal dystonia: a case-control study.

[0063] Fabbrini G, Berardelli I, Moretti G, Pasquini M, Bloise M, Colosimo C, Biondi M, Berardelli A. Mov Disord. 2010Mar 15;5(4):459-65.doi:10.1002 / mds.22983.

[0064] Here, it was shown that 51 (57.3%) of the 89 patients with idiopathic dystonia had some mental symptoms such as depression, anxiety disorder, and obsessive-compulsive disorder.

[0065] (2)Obsessive compulsive disorder among idiopathic focal dystoniapatients: an epidemiological and family study.Cavallaro R, Galardi G, CavalliniMC, Henin M, Amodio S, Bellodi L, Comi G.Biol Psychiatry.2002Aug 15;52(4):356-61.doi:10.1016 / s0006-3223(02)01332-x.

[0066] Here, it was reported that 19.7% of patients with focal dystonia also suffered from obsessive-compulsive disorder.

[0067] (3)Psychiatric symptoms associated with focal hand dystonia.Voon V, Butler TR, Ekanayake V, Gallea C, Ameli R, Murphy DL, Hallett M.Mov Disord.2010Oct15;25(13):2249-52.doi:10.1002 / mds.23250.

[0068] Here, it was reported that 12.82% of patients with focal dystonia of the hand also suffered from obsessive-compulsive disorder, and 17.95% also suffered from depressive symptoms.

[0069] According to such existing research, the mechanism of manifestation of stereotyped symptoms, which is a common element of dystonia and obsessive-compulsive disorder, is suspected to be the dysfunction of the striatal parenchyma. In other words, several hypothesis papers (Professor Ann Graybiel) have been published, suggesting that diseases accompanied by stereotypes such as dystonia and obsessive-compulsive disorder may be related to the dysfunction of the striatal parenchyma.

[0070] (4) Graybiel AM, Canales JJ, Capper-Loup C. Levodopa-induced dyskinesias and dopamine-dependent stereotypies: a new hypothesis. TrendsNeurosci. (2000) 23: S71-S77. doi: 10.1016 / s1471-1931(00)00027-6

[0071] This suggests that due to the decreased function of the striatal compartment, a dopamine excess state is induced in the matrix compartment, which may manifest dystonia and obsessive-compulsive disorder accompanied by stereotyped symptoms.

[0072] (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

[0073] Here, it is summarized that in many basal ganglia diseases such as Parkinson's disease, Huntington's disease, dystonia, and obsessive-compulsive disorder, there are functional abnormalities (imbalance) in the striatal corpuscle partitioning and matrix partitioning.

[0074] (6)Amemori KI, Gibb LG, Graybiel AM. Shifting responsibly: the importance of striatal modularity to reinforce learning in uncertain environments. Front Hum Neurosci. (2011) 5: 47. doi: 10.3389 / fnhum.2011.00047

[0075] Here, it is hypothesized that the striatum is responsible for modular reinforcement learning (RL) that is the basis of stereotypy. Through computer simulation, if the balance between the striatum partition and the matrix partition is unbalanced, it may cause dystonia, Huntington's disease, obsessive-compulsive disorder, depression, etc.

[0076] However, these documents do not go beyond the scope of hypothesis and do not contain any specific records related to the treatment of human diseases.

[0077] Furthermore, the discovery of the present inventors that the dysfunctionality of the striatum can be improved by stimulating substances of dopamine D1 receptors is not recorded in existing studies or in hypothesis papers suggesting its possibility. The current situation is that although "dysfunctionality of the striatum" is mentioned, whether it is a decrease in function or an increase in function in dystonia and obsessive-compulsive disorder varies among researchers.

[0078] (7) Japanese Patent Gazette No. 2015-52117

[0079] Here, it is described that the drug addiction and impulsivity can be reduced by combining a PDE7 inhibitor with a dopamine receptor agonist using a rodent model of drug dependence (cocaine dependence, nicotine dependence).

[0080] First, in the comparison between the rodent drug dependence model in this document and the obsessive compulsive disorder in humans in the present invention, it is important to note that the distribution pattern of D1 / D2 receptors in the striatum of rodents is very different from that in the striatum of humans from the perspective of comparative anatomy. In basal ganglia diseases involving dopamine receptors, the possibility that the therapeutic effects observed in rodent animal models can be reproduced in human diseases as they are is low.

[0081] The present inventors have published the following paper to elaborate on this point: Specificity of striataldopamine D1 system in humans: implications for clinical use of D1 receptor-agonists in Parkinson's disease. Goto S. Front Hum Neurosci. 2023Apr 26; 17: 1178616. doi: 10.3389 / fnhum.2023.1178616. eCollection 2023.

[0082] "Pharmacological therapy for obsessive-compulsive disorder targeting dopamine D1 signaling in the striatum" utilizes the human specificity of the dopamine D1 system to normalize the striatum D1 signaling, but the paper reports that in the human striatum, dopamine D1 receptors are selectively and predominantly present in the striatum partition, but in rodents, dopamine D1 receptors are also evenly distributed in the matrix partition, and no preference for the striatum partition is observed.

[0083] In addition, the intensity of "(drug) addiction / impulsivity" observed in the rodent drug dependence model cannot be directly regarded as similar to the "intensity of obsession (in normal daily life), obsessions or compulsions" in human obsessive-compulsive disorder. In the "DSM-5", which is the American Psychiatric Association's guide for the classification and diagnosis of mental illnesses, drug dependence is classified as "substance-related disorders and addictive disorders group", which is specified as a different title from "obsessive-compulsive disorder and related disorders group / obsessive-compulsive disorder and related disorders group". Therefore, it is impossible to directly predict the improvement of the severity score (YBOCS) of human obsessive-compulsive disorder based on the improvement of addiction to addictive substances in the rodent drug dependence model.

[0084] (8)CHEN, Fu-Feng et al., Brain Research, 2020, Vol.1749, #147136, and PONNUSAMY, Ravikumar et al., Learning&Memory, 2005, Vol.12, No.4, p.399-406

[0085] The former states that in a model using fear-conditioned rodents, administration of a D1 receptor stimulator (SKF83959) can induce long-term loss of fear memory. In addition, the latter states that in a similar model using fear-conditioned rodents, single injection of the D2 receptor antagonist sulpiride is effective in eliminating fear memory.

[0086] In the "DSM-4", which is the American Psychiatric Association's guide for the classification and diagnosis of mental illnesses, obsessive-compulsive disorder is classified as one of the "anxiety disorders", but according to the updated "DSM-5", obsessive-compulsive disorder has been removed from the category of "anxiety disorders" and classified into the category of "obsessive-compulsive disorder and related disorders group / obsessive-compulsive disorder and related disorders group". Therefore, "anxiety disorders" and "obsessive-compulsive disorder" are currently considered to be different disease groups. In other words, anxiety disorders and obsessive-compulsive disorders should not be considered the same. It should be noted that this means that the elimination of conditioned fear in animal models will not be used as an explicit model in "anxiety disorders such as obsessive-compulsive disorder". In other words, as in literature (7), it is difficult to use the rodent conditioned fear elimination model to directly predict the improvement of the severity score (YBOCS) of human obsessive-compulsive disorder.

[0087] (9)Elia Mota et al.Br J Pharmacol.2021Dec;178(24):4873-4890.doi:10.1111 / bph.15664.Epub 2021Oct 4

[0088] The results of research on the effect of PDE10a on dopamine D1 cells and D2 cells in the striatum are described, but there is no description on obsessive-compulsive disorder.

[0089] In the present invention, the dopamine D1 receptor stimulating substance is selected from the group consisting of a dopamine D1 receptor agonist and a dopamine D1 receptor-positive allosteric modulator.

[0090] In the present invention, "dopamine D1 receptor agonist" refers to a substance that stimulates the D1-like receptor family (D1 receptor and D5 receptor) that bears excitatory properties among the five 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, "dopamine D1 receptor agonist" does not refer to an agonist specific to dopamine D1 receptors, and does not exclude the stimulating effect of other receptors such as D5 receptor in the D1-like receptor family.

[0091] Specific examples of dopamine D1 receptor agonists include SKF81297, SKF38393, SKF83959, SKF82526 (fenoldopam), dihydrexidine hydrochloride, ABT-431, A-86929, A-77636, A-68930, PF-06649751 (Tavapadon), PF-06412 and the like (Jones-Tabah J, et al. The Signaling and Pharmacology of the Dopamine D1 Receptor. Front Cell Neurosci. 2022.). Currently, there are no drugs that have passed human clinical trials and have been approved as D1 receptor agonists.

[0092] In the present invention, "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 the same effect as the dopamine D1 receptor agonist can be expected. It is abbreviated as D1-PAM (D1-Positive Allosteric Modulator). In relation to allosteric modulators (Allosteric Modulator: allosteric modulator), in the case of receptors, a ligand that binds to an allosteric site that promotes the agonist activity of an endogenous agonist is called a positive allosteric modulator (Positive Allosteric Modulator, PAM), and conversely an allosteric ligand that inhibits the agonist activity is called a negative allosteric modulator (NAM).

[0093] As dopamine D1 receptor-positive allosteric modulator, specifically selected from:

[0094] (1) DETQ (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropane-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one) (Neuropharmacology 128(2018)351e365; Advances in Pharmacology Volume 86, 2019, Pages273-305; Psychopharmacology (2023)240:1033-1048);

[0095] (2) Mevidalen (LY3154207) (Cell 184, 943-956, February 18, 2021; Clinical Pharmacology in Drug Development 2022, 11 (3) 324-332);

[0096] (3) MLS1082 (Mol Pharmacol 94: 1197-1209, October 2018; Bioorg Med ChemLett. 2021January 01; 31);

[0097] (4) MLS6585 (Mol Pharmacol 94: 1197-1209, October 2018; Bioorg Med ChemLett. 2021January 01; 31);

[0098] (5) Pyrazolyl-dihydroisoquinoline (ACS Med. Chem. Lett. 2020, 11, 4-4);

[0099] (6) DPTQ (Psychopharmacology (2023) 240: 1033-1048);

[0100] (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);

[0101] (8) LY3154885 (J. Med. Chem. 2022, 65, 3786-3797); and

[0102] (9) ASP4345 (Neuropsychopharmacology (2021) 46: 1145-1151). Currently, there is no drug that has passed human clinical trials and has been approved as a D1 receptor-positive allosteric modulator.

[0103] The present invention, as one embodiment, 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 obtains the effect of a dopamine D1 receptor stimulating substance by combining a "dopamine D1 and D2 receptor agonist" usually administered for the treatment of Parkinson's disease and the like and a "dopamine D2 receptor inhibitor" usually administered for the treatment of mental illness.

[0104] The present invention, as one embodiment, relates to the following pharmaceutical composition for treating obsessive-compulsive disorder, which is (1) a pharmaceutical composition comprising a dopamine D1 receptor stimulating substance; and / or (2) a pharmaceutical composition comprising dopamine D1 and D2 receptor agonists, in which a dopamine D2 receptor inhibitory substance is administered in combination; and / or (3) a pharmaceutical composition comprising a dopamine D2 receptor inhibitory substance, in which a dopamine D1 and D2 receptor agonists are administered in combination.

[0105] In the present invention, "combined administration" refers to an administration method including administration of dopamine D1 and D2 receptor agonists or dopamine D2 receptor inhibitors, for example, simultaneously, with a time difference, or alternately. Therefore, when dopamine D1 and D2 receptor agonists or dopamine D2 receptor inhibitors are administered simultaneously, they can be administered as the same pharmaceutical composition, or they can also be administered simultaneously as separate pharmaceutical compositions. Dopamine D1 and D2 receptor agonists or dopamine D2 receptor inhibitors can be administered separately, for example, with a time difference of seconds, minutes, hours, days, or weeks. Moreover, dopamine D1 and D2 receptor agonists or dopamine D2 receptor inhibitors can be administered before other medicines, or they can be administered after other medicines.

[0106] In the present invention, dopamine D1 and D2 receptor agonists or dopamine D2 receptor inhibitors may be administered in the same manner or in different manners, for example, both may be administered as oral preparations, or one compound may be administered orally and the other may be administered topically.

[0107] In the present invention, the "dopamine D1 receptor stimulating substance" is selected from the group consisting of a dopamine D2 receptor antagonist and a dopamine D2 receptor-negative allosteric modulator.

[0108] In the present invention, "dopamine D2 receptor antagonist" refers to a substance that inhibits the inhibitory D2-like receptor family (D2 receptor, D3 receptor and D4 receptor) among the five dopamine receptors, namely D1, D2, D3, D4 and D5 receptors, and is also called a dopamine D2 receptor blocking drug or a dopamine D2 receptor inhibitory substance. Therefore, in the present invention, "dopamine D2 receptor antagonist" does not refer to an antagonist specific to dopamine D2 receptors, but only refers to a substance that inhibits or blocks dopamine D2 receptors, and does not exclude the inhibitory or blocking effects of other receptors of the D2-like receptor family, such as D3 receptors and D4 receptors.

[0109] Examples of dopamine D2 receptor antagonists include chlorpromazine, metoclopramide, domperidone, levomepromazine, fluphenazine, perphenazine, prochlorperazine, propericiazine, haloperidol, pipamperone, bromperidol, droperidol, quetiapine, and styraxone. etiapine), Asenapine, Sulpiride, Sultopride, Tiapride, Risperidone, Mosapramine, Zotepine, Paliperidone, Clocapramine, Spiperone, Nemonapride, Timiperone, Perospirone, etc.

[0110] In the present invention, "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 can be expected to have the same effect as the dopamine D2 receptor agonist. It is abbreviated as D2-NAM (D2-Negative Allosteric Modulator). As for dopamine D2 receptor-negative allosteric modulators, an overview is given in Molecules 2023, 28, 178. https: / / doi.org / 10.3390 / molecules28010178.

[0111] 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, there are no drugs that have passed human clinical trials and have been approved as D2 receptor-negative allosteric modulators.

[0112] Examples of dopamine D1 and D2 receptor agonists include levodopa, levodopa / carbidopa hydrate as a levodopa mixture, levodopa / carbidopa / entacapone combination preparations, levodopa / benserazide hydrochloride combination preparations, and pergolide and rotigotine as dopamine agonists.

[0113] Levodopa, also known as L-3,4-dihydroxyphenylalanine (L-DOPA or LDOPA), is a direct precursor of dopamine and a full agonist for D1 and D2 receptors (D1R and D2R).

[0114] When using levodopa as dopamine D1 and D2 receptor agonist, levodopa is decomposed by levodopa decarboxylase at the stage of the extremities (before transferring to the brain), and cannot be transferred to the brain, so carbidopa and benserazide that inhibit the metabolism of levodopa at the extremities are combined in the levodopa preparation. Its example is the combined preparation (main trade name: NEODOPASTON, MENESIT) of levodopa and carbidopa, and the combined preparation (main trade name: ECDoparl, NEODOPASOL, MADOPAR) of levodopa and benserazide. In the present invention, as dopamine D1 and D2 receptor agonist, any combined preparation can also be utilized, preferably DOPACOL combined tablets. In this specification, when administering DOPACOL combined tablets, its substantial drug effect is derived from levodopa, so the administration of DOPACOL combined tablets can be regarded as substantially the same as the administration of levodopa.

[0115] The present invention, as one embodiment, relates to a pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D1 receptor stimulating substance, in which a dopamine D2 receptor inhibitor is administered in combination. Compared with the use of a dopamine D1 receptor stimulating substance alone, a combination with a dopamine D2 receptor inhibitor is expected to have a higher effect for treating obsessive-compulsive disorder. The reason for this is that even if the D1 receptor is stimulated alone, the activity of the D2 receptor may be increased by a secondary effect. Here, the definitions of the dopamine D1 receptor stimulating substance and the dopamine D2 receptor inhibitor are as described above.

[0116] As used herein, "treatment" refers to a method or process that has the following objectives: (1) slowing or stopping the development, aggravation, or worsening of symptoms of a disease or condition (e.g., obsessive-compulsive disorder); (2) alleviating the symptoms of a disease or condition; or (3) curing the disease or condition.

[0117] The present invention, as one embodiment, relates to a pharmaceutical composition, characterized in that the pharmaceutical composition is a pharmaceutical composition containing levodopa for treating obsessive-compulsive disorder, and is used in an oral administration manner in which the amount of levodopa is less than half of the standard maintenance dose for treating Parkinson's disease, and the amount of chlorpromazine is less than half of the antipsychotic therapeutic dose in terms of chlorpromazine hydrochloride, and the amount of metoclopramide is half of the dose used as an antiemetic agent.

[0118] The standard maintenance dose for Parkinson's disease treatment in terms of levodopa is 200 to 250 mg per time, 3 times a day = 600 to 750 mg per day. The antipsychotic treatment dose in terms of chlorpromazine hydrochloride is 30 to 100 mg per day. In the present invention, a pharmaceutical composition containing a "dopamine D1 and D2 receptor agonist" which is less than half of the standard maintenance dose for Parkinson's disease treatment in terms of levodopa, 50 to 300 mg per day, preferably 150 to 300 mg per day, and a pharmaceutical composition containing a "dopamine D2 receptor inhibitor" which is less than half of the antipsychotic treatment dose in terms of chlorpromazine hydrochloride, 5 to 30 mg per day, preferably 5 to 30 mg per day. In the present invention, both the pharmaceutical composition containing 50 mg / day, which is less than half of the standard maintenance dose for Parkinson's disease treatment in terms of levodopa, and the pharmaceutical composition containing 5 mg / day, which is less than half of the antipsychotic treatment dose in terms of chlorpromazine hydrochloride, have been shown to have the effects of the present invention.

[0119] In the present invention, the "pharmaceutical composition" comprises an effective amount of "dopamine D1 and D2 receptor agonists" or "dopamine D2 receptor inhibitors" and at least one pharmaceutically acceptable carrier or excipient. The term "effective amount" used in this specification refers to any amount of a compound or composition that is sufficient to meet its intended purpose, such as a desired biological or pharmacological response of a cell, tissue, system, or subject. For example, in a specific embodiment of the present invention, the purpose is to slow down, alleviate or stop the development, aggravation or deterioration of obsessive-compulsive disorder; to relieve the symptoms of the disease; and / or to treat obsessive-compulsive disorder.

[0120] "Pharmaceutically acceptable carriers or excipients" can be formulated together with the active ingredient and administered to a subject in need of the drug in a desired dosage through any appropriate route. Various delivery systems are known, including, for example, tablets, capsules, sustained-release preparations, injections, encapsulation agents in liposomes, powders, patches, microcapsules, nanoparticle preparations, etc.

[0121] The treatment in the present invention may consist of a single dose or multiple doses. Thus, the administration of the "dopamine D1 receptor stimulator", "dopamine D1 and D2 receptor agonist", "dopamine D2 receptor inhibitor" or pharmaceutical compositions thereof of the present invention may be fixed or periodic over a specific period and at specific intervals, such as once a few hours, once a day, once a week, once a month (e.g., timed release).

[0122] The present invention, as another embodiment, relates to a method for treating obsessive-compulsive disorder, wherein the method comprises administering a dopamine D1 receptor stimulator to a subject in need of such treatment. Further, the present invention relates to a method for treating obsessive-compulsive disorder, wherein the method comprises administering a combination of a dopamine D1 and D2 receptor agonist and a dopamine D2 receptor inhibitor to a subject in need of such treatment; and the present invention relates to a method for treating obsessive-compulsive disorder, wherein the method comprises administering a combination of a dopamine D2 receptor inhibitor and a dopamine D1 and D2 receptor agonist to a subject in need of such treatment.

[0123] Furthermore, the present invention, as another embodiment, relates to a dopamine D1 receptor stimulating substance 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.

[0124] The present invention, as another embodiment, relates to the use of a dopamine D1 receptor stimulating substance for manufacturing a medicine 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 manufacturing a medicine for treating obsessive-compulsive disorder.

[0125] Hereinafter, the present invention will be described in detail with reference to reference examples and examples, but it should be noted that these do not limit the scope of the present invention but are merely examples.

[0126] Example

[0127] Example 1

[0128] Drug challenge test 1

[0129] The self-administered Yale-Brown Obsessive / Compulsive Scale (YBOCS) is a standard for evaluating the severity of obsessive-compulsive symptoms designed to determine the effectiveness of drug therapy for patients with obsessive-compulsive disorder (Non-Patent Document 5). We used this standard to evaluate symptoms.

[0130] It should be noted that the relationship between YBOCS and the severity of obsessive compulsive disorder (OCD) was 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).

[0131] Table 1 [Table 1]

[0132]

[0133] Subject

[0134] In this study, 5 patients with obsessive-compulsive disorder (1 male and 4 females) aged 33 to 74 were enrolled. Obsessive-compulsive disorder was diagnosed as 8 points or more in the YBOCS (Non-Patent Document 6).

[0135] The severity of obsessive-compulsive disorder is evaluated using YBOCS (Non-Patent Documents 6 and 7).

[0136] drug

[0137] DOPACOL Tablets L50 (registered trademark) (L-DOPA 50 mg + carbidopa 5 mg, Nichiyoko Co., Ltd., Toyama Prefecture, Japan) and Dongmianling Fine Granules (10%) (registered trademark) (chlorpromazine phenol peptide salt 180 mg per 1 g, Shionogi Pharmaceutical Co., Ltd., Osaka Prefecture, Japan) were used. Hereinafter, DOPACOL Tablets L50 may be referred to as "DOPACOL" and Dongmianling Fine Granules (10%) may be referred to as "CPZ".

[0138] Dosing schedule for CPZ administration

[0139] Regarding case numbers 1 to 4. The following dosing schedule was formulated: DOPACOL (1 tablet (50 mg) / day) + CPZ (5 mg) / day for the first 4 weeks, DOPACOL (1 tablet × 2 (100 mg) / day) + CPZ (5 mg) × 2 / day for the next 4 weeks, and DOPACOL (1 tablet × 3 (150 mg) / day) + CPZ (5 mg) × 3 / day for the final 4 weeks.

[0140] About Case No. 5. The case using metoclopramide tablets (metoclopramide hydrochloride 5 mg, Takeda Pharmaceutical Company Limited) is as follows.

[0141] A 66-year-old woman developed symptoms at the age of 55. She was diagnosed at multiple medical institutions and hospitalized due to concerns about the disease. Her score on the YBOCS was 22, and she was diagnosed with moderate obsessive-compulsive disorder. She took 50 mg of levodopa and 5 mg of metoclopramide orally, and her symptoms completely disappeared after 8 weeks (YBOCS: 0 points).

[0142] The obtained results are shown in Table 2 and Figure 1 The above treatment plan was formulated, and symptom improvement was confirmed in all 5 cases at the initial introduction dose.

[0143] [Table 2]

[0144] LDOPA+D2 receptor inhibitor

[0145] (Case 1-4*: CPZ, Case 5**: Metoclopramide)

[0146]

[0147] *: Oral medication: LDOPA 50mg CPZ 5mg once a day in the morning

[0148] **: Oral medication: LDOPA 50mg, metoclopramide 5mg once a day in the morning

[0149] Here, the administered drug is DOPACOL compound tablets, but its substantial drug effect is derived from levodopa, so it is expressed as the administration of levodopa LDOPA.

[0150] As shown in Table 2 and Figure 1 As shown, the symptoms of all cases were improved by taking a small amount of dopamine D1, D2 receptor agonist and dopamine D2 receptor antagonist for a short period of time (the average improvement rate of YBOCS was 65%, which was effective in all cases). It is highly likely that the symptoms will be improved by further high-dose and long-term administration.

[0151] On the other hand, if the YBOCS improvement rate of SSRI, which is currently the first choice for OCD treatment, is 35%, it is considered effective, but it is reported that 40% to 61% of patients do not respond to SSRI (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;

[0152] Pallanti S, Hollander E, Bienstock C, et al. Treatment non-response in OCD: methodological issues and operational definitions. IntJ Neuropsychopharmacol. 2002; 5(2): 181-191. doi: 10.1017 / S1461145702002900).

[0153] In addition, for such SSRI-resistant OCD patients, additional administration of antipsychotic drugs (D2 receptor antagonists) is effective, but even in this case, it is reported that only about one-third of the total number of patients is effective (Zhou DD, Zhou XX, Lv Z, et al. Comparative efficacy and tolerability of antipsychotics asaugmentations 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;

[0154] 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).

[0155] Example 2

[0156] Effects of CPZ+LDOPA on 20 patients with obsessive compulsive disorder (OCD)

[0157] Subject

[0158] Twenty patients with obsessive-compulsive disorder aged 18 to 82 (8 males and 12 females) were enrolled. Obsessive-compulsive disorder was diagnosed as having an obsessive-compulsive disorder if the score was 8 or higher in the YBOCS (Non-Patent Document 6).

[0159] The severity of obsessive-compulsive disorder is evaluated using the YBOCS (Non-Patent Documents 6, 7). Figure 3 As shown, the efficacy of the treatment was continued while gradually increasing the oral dosage. Note: The 20 subjects in Example 2 include the 4 subjects with case numbers 1 to 4 in Example 1. Specifically, case numbers 4, 1, 2, and 3 in Example 1 (Table 2) correspond to the subjects with case numbers 1, 2, 4, and 6 in Example 2 (Table 3), respectively.

[0160] drug

[0161] DOPACOL Tablets L50 (registered trademark) (L-DOPA 50 mg + carbidopa 5 mg, Nichiyoko Co., Ltd., Toyama Prefecture, Japan) and Dongmianling Fine Granules (10%) (registered trademark) (chlorpromazine phenol peptide salt 180 mg per 1 g, Shionogi Pharmaceutical Co., Ltd., Osaka Prefecture, Japan) were used. Hereinafter, DOPACOL Tablets L50 may be referred to as "DOPACOL" and Dongmianling Fine Granules (10%) may be referred to as "CPZ".

[0162] Dosing schedule

[0163] The dosing schedule is in accordance with Example 1, but the period until the dose is increased to the next dose (increment interval) is individually set within the range of every 2 weeks to every 12 weeks according to the subject's hospital visit status and medication compliance (Table 3). It should be noted that, as for the increment interval, for example, the subject who can go to the hospital for a visit every 2 weeks is fixed to every 2 weeks, and the subject who can go to the hospital for a visit every 3 months is fixed to every 3 months. That is, for the same patient, no matter how many times the increment is made, the increment interval is fixed. The initial dose is set to DOPACOL (1 tablet (50 mg) / day) + CPZ (5 mg) / day, and after a fixed interval of more than 2 weeks, the next dose is set to DOPACOL (1 tablet × 2 (100 mg) / day) + CPZ (5 mg) × 2 (10 mg) / day, and the next dose is set to DOPACOL (1 tablet × 3 (150 mg) / day) + CPZ (5 mg) × 3 (15 mg) / day. Furthermore, in order to verify the dose-dependent effect, for two subjects (Case Nos. 5 and 10), the maximum dosage in the third increase was set to DOPACOL (1 tablet × 4 (200 mg) / day) + CPZ (5 mg) × 4 (20 mg) / day [each drug: 2 tablets in the morning, 1 tablet at noon, and 1 tablet in the evening], and for one subject (Case No. 4), the maximum dosage in the fourth increase was set to DOPACOL (1 tablet × 5 (250 mg) / day) + CPZ (5 mg) × 5 (25 mg) / day [each drug: 2 tablets in the morning, 2 tablets at noon, and 1 tablet in the evening].

[0164] Table 3 [Table 3]

[0165]

[0166] Here, the administered drug is DOPACOL compound tablets, but its substantial drug effect is derived from levodopa, so it is expressed as the administration of levodopa LDOPA.

[0167] The results obtained are shown in Table 3 and Figure 2 Table 3 and Figure 2The therapeutic effect of CPZ+LDOPA on 20 patients with obsessive-compulsive disorder (OCD) was shown. Based on the above-mentioned dosing schedule, symptom improvement was confirmed in all 20 cases (average improvement rate of YBOCS 70%, effective in all cases). If a t-test was performed on the average value of YBOCS before and after treatment, P = 0.0000004 (****P < 0.001), and a highly statistically significant difference was detected.

[0168] also, Figure 3 The results show the dose-dependent improvement effect on 20 patients with obsessive-compulsive disorder (OCD) who were treated with CPZ+LDOPA orally. In all 20 cases, the OCD symptoms (YBOCS) were improved in a dose-dependent manner by gradually increasing the dosage. It was confirmed that the symptoms were improved in a dose-dependent manner up to the maximum CPZ = 25 mg / day and LDOPA = 250 mg / day. For the subject of case number 4, the symptoms completely disappeared in the evaluation 10 weeks after the start of the drug administration (YBOCS = 0).

[0169] Example 3

[0170] Effects of CPZ oral administration + rotigotine patch treatment on 12 patients with obsessive compulsive disorder (OCD)

[0171] Subject

[0172] Twelve patients with obsessive-compulsive disorder aged 24 to 82 (5 males and 7 females) were enrolled. Obsessive-compulsive disorder was diagnosed as having an obsessive-compulsive disorder if the score was 8 or higher in the YBOCS (Non-Patent Document 6).

[0173] The severity of obsessive-compulsive disorder is evaluated using YBOCS (Non-Patent Documents 6 and 7).

[0174] drug

[0175] Upro patch (registered trademark) (Upro patch 4.5 mg, 9 mg, 13.5 mg: 4.5 mg, 9 mg, 13.5 mg of rotigotine per tablet, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan), and chlorpromazine granules (10%) (registered trademark) (180 mg of chlorpromazine phenol peptide salt per 1 g, Shionogi Pharmaceutical Co., Ltd., Osaka, Japan) were used. Hereinafter, Upro patch may be referred to as "NP" and chlorpromazine granules (10%) may be referred to as "CPZ". Upro patch is a patch for rotigotine, which is a dopamine receptor agonist.

[0176] Dosing schedule

[0177] The dosing schedule is in accordance with Example 1, but the period until the dose is increased to the next dose (increment interval) is individually set within the range of every 2 weeks to every 6 weeks according to the subject's hospital visit status and medication compliance (Table 4). The Upro patch is attached to normal skin on any part of the shoulder, upper arm, abdomen, flank, buttocks, and thigh, and the patch is replaced every 24 hours. CPZ is taken orally in accordance with Example 1. The initial dose is set to 4.5 mg / day of Upro patch + CPZ (5 mg) / day, and after a fixed interval of more than 2 weeks, the next dose is set to 9 mg / day of Upro patch + CPZ (5 mg) × 2 (10 mg) / day, and the maximum dose is set to 13.5 mg / day of Upro patch + CPZ (5 mg) × 3 (15 mg) / day.

[0178] Table 4 [Table 4]

[0179]

[0180] The obtained results are shown in Table 4 and Figure 4 Table 4 and Figure 4 The therapeutic effect of 12 patients with obsessive-compulsive disorder (OCD) who were treated with CPZ oral administration + Rotigotine patch was shown. Based on the above treatment plan, symptom improvement was confirmed in all 12 cases (the average improvement rate of YBOCS was 69%, which was effective in all cases). If a t-test was performed on the average value of YBOCS before and after treatment, P = 0.0000006 (****P < 0.001), and a very high statistically significant difference was detected.

[0181] also, Figure 5 The results showed a dose-dependent improvement effect on 12 patients with obsessive-compulsive disorder (OCD) treated with oral CPZ + rotigotine patch. In all 12 cases, the OCD symptoms (YBOCS) were improved in a dose-dependent manner by gradually increasing the dosage. For two subjects (Case 23 and Case 26), the symptoms completely disappeared (YBOCS=0) in the evaluation after 10 weeks (CPZ=15, NP=13.5) and 8 weeks (CPZ=10, NP=9) from the start of administration, respectively.

[0182] Example 4

[0183] Effects on 2 patients with obsessive-compulsive disorder (OCD) treated with a D2 receptor antagonist other than CPZ + LDOPA oral administration

[0184] The therapeutic effects of metoclopramide and sulpiride as D2 receptor antagonists in addition to CPZ were investigated substantially as described in Example 1.

[0185] The case of using metoclopramide tablets (metoclopramide hydrochloride 5 mg, Takeda Pharmaceutical Company Limited) is as follows.

[0186] 66-year-old female (Case No. 5 in Example 1): Onset at age 55. Worried about the disease, she was diagnosed at multiple medical institutions and hospitalized. Her score on the YBOCS was 22, and she was diagnosed with moderate obsessive-compulsive disorder. She took 50 mg of levodopa and 5 mg of metoclopramide orally, and her symptoms completely disappeared after 8 weeks (YBOCS: 0 points). Figure 1 The results of case number 5, which received metoclopramide, were drawn from the CPZ-administered group and marked on Figure 6 It should be noted that the administered drug is DOPACOL compound tablets, but its substantial drug effect is derived from levodopa, so it is presented as the administration of levodopa LDOPA.

[0187] The case of using Dogmatyl tablets (Sulpiride 50 mg, Nichiyoko Co., Ltd., Toyama, Japan) is described as follows. 55-year-old male. Onset at the age of 37. Existing compulsive behaviors such as confirmation failure, rewriting, and rereading, and life is painful. YBOCS is 11 points, diagnosed as mild obsessive-compulsive disorder. Take LDOPA = 50 mg and Sulpiride = 50 mg orally once a day in the morning, and evaluate YBOCS after 4 weeks. It should be noted that the administered drug is DOPACOL compound tablets, but its actual efficacy comes from levodopa, so it appears as the administration of levodopa and LDOPA.

[0188] The obtained results are shown in Figure 6 . Figure 6 The improvement effect of OCD symptoms (YBOCS) in 2 patients with obsessive-compulsive disorder (OCD) who were treated with oral administration of a D2 receptor antagonist other than CPZ + LDOPA was shown. One example of using metoclopramide instead of CPZ and one example of using sulpiride instead of CPZ both confirmed significant symptom improvement at the evaluation after 4 weeks at low initial doses (sulpiride 50 mg + LDOPA 50 mg, metoclopramide 5 mg + LDOPA 50 mg). In series 2 using metoclopramide, the symptoms completely disappeared (YBOCS=0), and in series 1 using sulpiride, the symptoms also almost disappeared (YBOCS=1). This suggests that a sufficiently effective clinical effect can be obtained by using a D2 receptor antagonist other than CPZ in combination with LDOPA.

[0189] It should be noted that, based on the facts of the following reference examples, the present inventors have discovered, as one embodiment, a pharmaceutical composition characterized in that the pharmaceutical composition is a pharmaceutical composition for treating dystonia, containing levodopa, and is used in an orally administered manner in an amount of levodopa that is less than half of the standard maintenance dose for treating Parkinson's disease, and chlorpromazine is orally administered in an amount of chlorpromazine hydrochloride that is less than half of the antipsychotic therapeutic dose. This point will be described.

[0190] Reference Example 1

[0191] Purpose

[0192] It was first clarified that dual dopamine regulation therapy using L-3,4-dihydroxyphenylalanine (L-DOPA; levodopa) and chlorpromazine (CPZ) showed therapeutic effects on blepharospasm, a type of focal dystonia. L-DOPA is a direct precursor of dopamine and a full agonist for D1 and D2 receptors (D1R and D2R), while CPZ is an effective antagonist for D2R.

[0193] Subject

[0194] In this study, 21 patients with blepharospasm (6 males and 15 females) aged 51 to 79 years were enrolled (mean age 68.7±7.8 years). Blepharospasm was diagnosed according to Fahn's 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). p. 332-58.).

[0195] Brain magnetic resonance imaging (MRI) was performed in conjunction with clinical examinations and genetic tests to exclude hereditary and secondary dystonia. In the genetic tests, pathogenic variants of known dystonia genes were screened by whole exome sequencing (OMIM Phenotypic Series PS128100). All patients who were indicated to receive botulinum toxin type A (BTX-A) treatment had a 3-month washout period from the last BTX-A injection to the start of this clinical trial. Imaging analysis was performed before and after the drug challenge test. The severity of blepharospasm was evaluated using four indicators: the visual analog scale (VAS) [Reference 12], the blepharospasm disability index (BSDI)

[13] , the modified VAS

[14] , and the Jankovic rating criteria (JRS) [13, 15].

[0196] drug

[0197] DOPACOL Tablets L50 (registered trademark) (L-DOPA 50 mg + carbidopa 5 mg, Nichiyoko Co., Ltd., Toyama Prefecture, Japan) and Dongmianling Fine Granules (10%) (registered trademark) (chlorpromazine phenol peptide salt 180 mg per 1 g, Shionogi Pharmaceutical Co., Ltd., Osaka Prefecture, Japan) were used. Hereinafter, DOPACOL Tablets L50 may be referred to as "DOPACOL" and Dongmianling Fine Granules (10%) may be referred to as "CPZ".

[0198] Patient classification and drug administration

[0199] According to the order of admission, the patients were randomly divided into 3 groups (L-DOPA, CPZ, L-DOPA+CPZ). According to the double-blind experimental method, the participants and the evaluators were unaware of the differences between the groups.

[0200] L-DOPA group: This group included 7 patients with blepharospasm (3 males and 4 females), who took DOPACOL alone. The age range was 51 to 79 years old (average age 66.0±10.1 years), and the average duration of illness was 10.7±9.5 years. The following prescriptions were given: DOPACOL (1 tablet / day) for the first 2 weeks, DOPACOL (1 tablet × 2 / day) for the next 2 weeks, and DOPACOL (1 tablet × 3 / day) for the last 4 weeks.

[0201] CPZ group: This group included 7 patients with blepharospasm (1 male and 6 females) who took CPZ alone. The age range was 60 to 72 years (mean age 66.4±3.9 years), and the average duration of illness was 8.4±5.9 years. The following prescriptions were given: CPZ (5 mg / day) for the first 2 weeks, CPZ (5 mg×2 / day) for the next 2 weeks, and CPZ (5 mg×3 / day) for the last 4 weeks.

[0202] L-DOPA+CPZ group: This group included 7 patients with blepharospasm (2 males and 5 females), who took both DOPACOL and CPZ. The age group was 66 to 78 years old (average age 73.5±5.9 years), and the average duration of illness was 8.0±7.6 years. The following prescriptions were used: DOPACOL (1 tablet / day) and CPZ (5 mg / day) for the first 2 weeks, DOPACOL (1 tablet × 2 / day) and CPZ (5 mg × 2 / day) for the next 2 weeks, and DOPACOL (1 tablet × 3 / day) and CPZ (5 mg × 3 / day) for the last 4 weeks.

[0203] Statistical analysis

[0204] Statistical significance was evaluated using the Wilcoxon signed-rank test or one-way analysis of variance (ANOVA). Statistical significance was set at P < 0.05. Statistical analysis was performed using SPSS statistical software (version 11.0 for Windows) (IMB Corp., Armonk, New York, USA).

[0205] result:

[0206] The severity of blepharospasm was evaluated using VAS and BSDI as subjective symptoms and mVAS and JRS as objective symptoms ( Figure 7 ). First, when comparing the severity of symptoms before the drug challenge test in all the L-DOPA, CPZ, and L-DOPA+CPZ groups, no significant differences were found in all subjective and objective symptoms (P>0.05, one-way ANOVA). In other words, it was confirmed that there was no significant deviation between the three groups in terms of the severity of symptoms before the drug challenge test.

[0207] Next, the severity of each symptom was compared before and after the drug challenge test.

[0208] L-DOPA group ( Figure 7 ;superior):

[0209] The severity of symptoms was significantly aggravated in the modified VAS [before drug challenge test 141.3±8.4 (n=7), after drug challenge test 178.8±24.3 (n=7), "before" vs. "after"; P<0.05, Wilcoxon signed-rank test], but not in VAS, BSDI, and JRS.

[0210] CPZ group ( Figure 7 ;central):

[0211] In all the judgments based on VAS, BSDI, mVAS, and JRS, no significant changes in the severity of the disease were observed before and after the drug challenge test.

[0212] L-DOPA+CPZ group ( Figure 7 ;Down):

[0213] The severity of all subjective and objective symptoms of VAS, BSDI, mVAS and JRS after the drug challenge test was significantly reduced by the administration of L-DOPA+CPZ compared with that before the drug challenge test. VAS [before drug challenge test 67.1±14.6 (n=7), after drug challenge test 44.8±27.5 (n=7), "before" vs. "after"; P<0.05, Wilcoxon signed rank test]; BSDI [before drug challenge test 15.1±6.6 (n=7), after drug challenge test 10.6±6.7 (n=7), "before" vs. "after"; P<0.05, Wilcoxon signed rank test]; m VAS [before drug challenge test, 148.0±17.4 (n=7); after drug challenge test, 116.5±14.5 (n=7), “before” vs. “after”; P<0.05, Wilcoxon signed-rank test]; and JRS [before drug challenge test, 5.9±2.2 (n=7), after drug challenge test, 3.0±2.3 (n=7), “before” vs. “after”; P<0.05, Wilcoxon signed-rank test].

[0214] No significant neurological or psychoneurological changes were observed in the drug challenge test in all the L-DOPA, CPZ, and L-DOPA+CPZ groups. Therefore, it was confirmed that the therapeutic effect on blepharospasm can only be produced by the combined use of DOPACOL (1 tablet × 3 / day) and CPZ (5 mg × 3 / day), rather than the administration of DOPACOL or CPZ alone.

[0215] Dystonia refers to a condition in which prolonged muscle contractions lead to abnormal postures and movement disorders. In children, most cases are generalized dystonias associated with gene mutations, but in adults, most cases are focal dystonias. The frequency of focal dystonias is high, and there are blepharospasm, spasmodic torticollis, writer's cramp, etc. The present inventors found and published a paper in the conference schedule: World Congress of Neurology-Kyoto, 16-21 September 2017, that dystonia was accidentally alleviated after prescribing levodopa and sulpiride or metoclopramide (World Congress of Neurology-Kyoto, 16-21 September 2017 Abstract Collection: VOLUME 381, SUPPLEMENT, 580, OCTOBER 15, 2017 Three cases of dystonia with effective levodopaand D2blocker combination therapy S.Marsumoto, M.Takahashi, DOI: https: / / doi.org / 10.1016 / j.jns.2017.08.1635).

[0216] Possible inventions in this scheme:

[0217] <Pharmaceutical composition containing levodopa for treating dystonia>

[0218] [1] A pharmaceutical composition, characterized in that the pharmaceutical composition is a pharmaceutical composition for treating dystonia, comprising levodopa, which is administered orally in an amount of levodopa equal to or less than half of a standard maintenance dose for treating Parkinson's disease, and chlorpromazine is administered orally in an amount of chlorpromazine hydrochloride equal to or less than half of an antipsychotic therapeutic dose; specifically, a pharmaceutical composition comprising levodopa equal to or less than half of a standard maintenance dose for treating Parkinson's disease, i.e., 50 to 300 mg per day, preferably 50 to 200 mg per day, and more preferably 100 to 150 mg per day, and a pharmaceutical composition comprising levodopa equal to or less than half of an antipsychotic therapeutic dose, i.e., 10 to 15 mg per day; and

[0219] <Medical composition containing chlorpromazine for treating dystonia>

[0220] [2] A pharmaceutical composition, characterized in that the pharmaceutical composition is a pharmaceutical composition for treating dystonia, comprising chlorpromazine, wherein the chlorpromazine is orally administered in an amount less than half of the antipsychotic therapeutic dose calculated as chlorpromazine hydrochloride, and levodopa is orally administered in an amount less than half of the standard maintenance dose for treating Parkinson's disease calculated as levodopa; specifically, the pharmaceutical composition comprises 5 to 300 mg per day, preferably 5 to 200 mg per day, and more preferably 10 to 15 mg per day, of chlorpromazine hydrochloride, which is less than half of the antipsychotic therapeutic dose, and the pharmaceutical composition comprises 100 to 150 mg per day, of chlorpromazine, which is less than half of the standard maintenance dose for treating Parkinson's disease calculated as levodopa.

[0221] As described above, the present invention may include the following aspects as another aspect.

[0222] <Pharmaceutical Composition>

[0223]

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

[0224]

[102] The pharmaceutical composition according to

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

[0225]

[103] The pharmaceutical composition according to

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

[0226]

[104] The pharmaceutical composition according to

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

[0227]

[105] The pharmaceutical composition according to

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

[0228]

[106] The pharmaceutical composition according to

[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)ethane-1-one), mevidalan, 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.

[0229]

[107] A pharmaceutical composition for treating obsessive-compulsive disorder, comprising dopamine D1 and D2 receptor agonists and a dopamine D2 receptor inhibitory substance administered in combination.

[0230]

[108] The pharmaceutical composition according to

[107] , wherein the dopamine D2 receptor inhibitory substance is selected from a dopamine D2 receptor antagonist and a dopamine D2 receptor-negative allosteric modulator.

[0231]

[109] The pharmaceutical composition according to

[107] or

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

[0232]

[110] The pharmaceutical composition according to

[109] , wherein the dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, methoxybutrazine, fluphenazine, perphenazine, prochlorperazine, cyanthiazide, haloperidol, amide peridone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiroperidone, nemopride, temiperone and perospirone.

[0233]

[111] The pharmaceutical composition according to

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

[0234]

[112] The pharmaceutical composition according to

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

[0235]

[113] The pharmaceutical composition according to any one of

[107] to

[112] , wherein the dopamine D1 and D2 receptor agonists are selected from levodopa, levodopa / carbidopa hydrate as a levodopa mixture, levodopa / carbidopa / entacapone combination preparations, levodopa / benserazide hydrochloride combination preparations, and pergolide and rotigotine as dopamine agonists.

[0236]

[114] The pharmaceutical composition according to

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

[0237]

[115] The pharmaceutical composition according to any one of

[107] to

[114] , characterized in that it is used in an oral administration manner in an amount of levodopa that is less than half of the standard maintenance dose for the treatment of Parkinson's disease.

[0238]

[116] The pharmaceutical composition according to

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

[0239]

[117] The pharmaceutical composition according to

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

[0240]

[118] A pharmaceutical composition for treating obsessive-compulsive disorder, the pharmaceutical composition comprising a dopamine D2 receptor inhibitory substance and dopamine D1 and D2 receptor agonists administered in combination.

[0241]

[119] The pharmaceutical composition according to

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

[0242]

[120] The pharmaceutical composition according to

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

[0243]

[121] The pharmaceutical composition according to

[120] , wherein the dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, methoxybutrazine, fluphenazine, perphenazine, prochlorperazine, cyanthiazide, haloperidol, amide peridone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiroperidone, nemopride, temiperone and perospirone.

[0244]

[122] The pharmaceutical composition according to

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

[0245]

[123] The pharmaceutical composition according to

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

[0246]

[124] The pharmaceutical composition according to any one of

[119] to

[124] , wherein the dopamine D1 and D2 receptor agonists are selected from levodopa, levodopa / carbidopa hydrate as a levodopa mixture, levodopa / carbidopa / entacapone combination preparations, levodopa / benserazide hydrochloride combination preparations, and pergolide and rotigotine as dopamine agonists.

[0247]

[125] The pharmaceutical composition according to

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

[0248]

[126] The pharmaceutical composition according to

[125] , characterized in that chlorpromazine is orally administered in an amount less than half of the antipsychotic therapeutic dose of chlorpromazine hydrochloride.

[0249]

[127] The pharmaceutical composition according to

[126] , wherein the amount of chlorpromazine hydrochloride is less than half of the antipsychotic therapeutic dose, that is, 5 to 30 mg per day.

[0250]

[128] The pharmaceutical composition according to

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

[0251]

[129] A pharmaceutical composition for treating obsessive-compulsive disorder, wherein the pharmaceutical composition contains a dopamine D1 receptor stimulating substance and a dopamine D2 receptor inhibitory substance administered in combination.

[0252]

[130] The pharmaceutical composition according to

[129] , wherein the dopamine D1 receptor stimulating substance is selected from dopamine D1 receptor agonists and dopamine D1 receptor-positive allosteric modulators, and the dopamine D2 receptor inhibitory substance is selected from dopamine D2 receptor antagonists and dopamine D2 receptor-negative allosteric modulators.

Claims

1. A pharmaceutical composition for treating obsessive-compulsive disorder, the pharmaceutical composition comprising a dopamine D1 receptor stimulating substance.

2. The pharmaceutical composition according to claim 1, wherein The dopamine D1 receptor stimulating substance is selected from the group consisting of a dopamine D1 receptor agonist and a dopamine D1 receptor-positive allosteric modulator.

3. The pharmaceutical composition according to claim 2, wherein A substance that stimulates the dopamine D1 receptor is a dopamine D1 receptor agonist.

4. The pharmaceutical composition according to claim 3, wherein The dopamine D1 receptor agonist is selected from SKF81297, SKF38393, SKF83959, SKF82526, i.e. fenoldopam, dihydrochloride of the second receptor agonist, ABT-431, A-86929, A-77636, A-68930, PF-06649751, i.e. tavapadone, and PF-06412.

5. The pharmaceutical composition according to claim 2, wherein The stimulatory substance of dopamine D1 receptor is dopamine D1 receptor-positive allosteric modulator.

6. The pharmaceutical composition according to claim 5, wherein The dopamine D1 receptor-positive allosteric modulator is selected from DETQ, i.e. 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropane-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-one, mevidalan, MLS1082, MLS6585, pyrazolyl-dihydroisoquinoline, DPTQ, CID 2886111, i.e. N-(6-tert-butyl-3-carbamoyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pyridine-4-carboxamide, LY3154885, and ASP4345.

7. A pharmaceutical composition for treating obsessive-compulsive disorder, comprising dopamine D1 and D2 receptor agonists and a dopamine D2 receptor inhibitory substance administered in combination.

8. The pharmaceutical composition according to claim 7, wherein The dopamine D2 receptor inhibitory substance is selected from the group consisting of dopamine D2 receptor antagonists and dopamine D2 receptor-negative allosteric modulators.

9. The pharmaceutical composition according to claim 8, wherein Dopamine D2 receptor inhibitors are dopamine D2 receptor antagonists.

10. The pharmaceutical composition according to claim 9, wherein The dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, methoxybutrazine, fluphenazine, perphenazine, prochlorperazine, cyanthiazide, haloperidol, amide peridone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiroperidone, nemopride, temiperone, and perospirone.

11. The pharmaceutical composition according to claim 8, wherein Dopamine D2 receptor inhibitors are dopamine D2 receptor-negative allosteric modulators.

12. The pharmaceutical composition according to claim 11, wherein The dopamine D2 receptor-negative allosteric modulator is SB269652.

13. The pharmaceutical composition according to claim 7, wherein The dopamine D1 and D2 receptor agonists are selected from levodopa, levodopa / carbidopa hydrate as a levodopa mixture, levodopa / carbidopa / entacapone combination preparations, levodopa / benserazide hydrochloride combination preparations, and pergolide and rotigotine as dopamine agonists.

14. The pharmaceutical composition according to claim 13, wherein Levodopa and chlorpromazine were administered in combination.

15. The pharmaceutical composition according to any one of claims 7 to 14, characterized in that The drug is used in a manner of oral administration in an amount of levodopa that is less than half of the standard maintenance dose for Parkinson's disease treatment.

16. The pharmaceutical composition according to claim 15, wherein The amount of levodopa is less than half of the standard maintenance dose for Parkinson's disease treatment, which is 50 to 300 mg per day.

17. The pharmaceutical composition according to claim 16, wherein The amount of levodopa is less than half of the standard maintenance dose for Parkinson's disease treatment, which is 50 mg per day.

18. A pharmaceutical composition for treating obsessive-compulsive disorder, comprising a dopamine D2 receptor inhibitory substance, and dopamine D1 and D2 receptor agonists are administered in combination.

19. The pharmaceutical composition according to claim 18, wherein The dopamine D2 receptor inhibitory substance is selected from the group consisting of dopamine D2 receptor antagonists and dopamine D2 receptor-negative allosteric modulators.

20. The pharmaceutical composition according to claim 19, wherein Dopamine D2 receptor inhibitors are dopamine D2 receptor antagonists.

21. The pharmaceutical composition according to claim 20, wherein The dopamine D2 receptor antagonist is selected from chlorpromazine, metoclopramide, domperidone, methoxybutrazine, fluphenazine, perphenazine, prochlorperazine, cyanthiazide, haloperidol, amide peridone, bromperidol, droperidol, quetiapine, asenapine, sulpiride, sultopride, tiapride, risperidone, mosapramine, zotepine, paliperidone, clocapramine, spiroperidone, nemopride, temiperone, and perospirone.

22. The pharmaceutical composition according to claim 19, wherein Dopamine D2 receptor inhibitors are dopamine D2 receptor-negative allosteric modulators.

23. The pharmaceutical composition according to claim 22, wherein The dopamine D2 receptor-negative allosteric modulator is SB269652.

24. The pharmaceutical composition according to claim 19, wherein The dopamine D1 and D2 receptor agonists are selected from levodopa, levodopa / carbidopa hydrate as a levodopa mixture, levodopa / carbidopa / entacapone combination preparations, levodopa / benserazide hydrochloride combination preparations, and pergolide and rotigotine as dopamine agonists.

25. The pharmaceutical composition according to claim 24, wherein Chlorpromazine and levodopa were administered in combination.

26. The pharmaceutical composition according to claim 25, characterized in that Chlorpromazine is administered orally in an amount less than half the antipsychotic therapeutic dose of chlorpromazine hydrochloride.

27. The pharmaceutical composition according to claim 26, wherein The dosage of chlorpromazine hydrochloride is less than half of the antipsychotic therapeutic dose, which is 5 to 30 mg per day.

28. The pharmaceutical composition according to claim 27, wherein Less than half of the antipsychotic therapeutic dose of chlorpromazine hydrochloride is 5 mg per day.

29. A pharmaceutical composition for treating obsessive-compulsive disorder, the pharmaceutical composition comprising a dopamine D1 receptor stimulating substance and a dopamine D2 receptor inhibitory substance administered in combination.

30. The pharmaceutical composition according to claim 29, wherein The dopamine D1 receptor stimulating substance is selected from dopamine D1 receptor agonists and dopamine D1 receptor-positive allosteric modulators, and the dopamine D2 receptor inhibitory substance is selected from dopamine D2 receptor antagonists and dopamine D2 receptor-negative allosteric modulators.

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