Compositions and methods for treating anxiety-related conditions

Abstract

The present application relates to compositions and methods for treating anxiety-related conditions. The present invention provides methods, compositions, and kits for treating anxiety-related conditions, including OCD and SAD, in a subject in need thereof, and for reducing anxiety, conceptual compulsive behavior, or compulsive behavior in a subject in need thereof.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of January 31, 2020, application number "202080012194.0", and invention name "Compositions and methods for treating anxiety-related disorders". The original application is the Chinese national phase application of international application PCT / US2020 / 016086.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 800,016, filed on February 1, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0004] The present invention generally relates to compositions, kits and methods for treating anxiety-related disorders, including obsessive-compulsive disorder (OCD) and social anxiety disorder (SAD), in patients in need thereof, and for reducing anxiety, obsessions or compulsions in patients in need thereof. Background Art

[0005] Mental health disorders are usually diagnosed using the criteria shown in the American Psychiatric Association's Diagnostic and Statistical Manual (DSM). The fourth edition of the DSM (DSM-IV) classified OCD as an anxiety disorder along with Generalized Anxiety Disorder (GAD), panic disorder, Post-traumatic Stress Disorder (PTSD), and Social Anxiety Disorder (SAD). However, the fifth edition of the DSM (DSM-V) removed OCD from the list of anxiety disorders and placed it in its own chapter.

[0006] Autism spectrum disorder (“Autism Spectrum Disorder, ASD” or “autism”) is a developmental disorder characterized by difficulties with social interaction, communication, and behavior. Individuals with ASD also often experience anxiety and are frequently diagnosed with comorbid anxiety disorders. One study estimated that 40% of children with ASD also suffer from at least one DSM-IV anxiety disorder (specific phobia: 30%; obsessive-compulsive disorder: 17%; social anxiety disorder / agoraphobia: 17%; generalized anxiety disorder: 15%; separation anxiety disorder: 9%; panic disorder: 2%). See van Steensel et al., Anxiety Disorders in Children and Adolescents with Autistic Spectrum Disorders: A Meta-Analysis, Clin Child Fam Psychol Rev (2011) 14:302–317.

[0007] In addition, ASD is often comorbid with multiple genetic conditions. For example, ASD rates are elevated in individuals with epilepsy, schizophrenia, 22q deletion syndrome, Angelman syndrome, CHARGE syndrome, Cornelia deLange syndrome, Down syndrome, Duchenne Muscular Dystrophy, Prader-Willi syndrome, Smith-Lemli-Opitz syndrome, Retts syndrome, Fragile X syndrome, Smith Magenis syndrome, Sotos syndrome, and tuberous sclerosis. See https: / / www.carautismroadmap.org / asd-and-other-genetic-conditions / .

[0008] Obsessions and / or compulsions are cardinal symptoms of OCD and may also be symptoms of other neurological conditions, including autism spectrum disorder (ASD), depression, psychotic disorders, schizophrenia, and Sotos syndrome.

[0009] DSM-V defines obsessions as: (1) recurrent and persistent thoughts, impulses, or urges that are sometimes felt to be intrusive and unwanted during the disturbance and that cause significant anxiety or distress in most individuals; and (2) the individual attempts to ignore or suppress such thoughts, impulses, or images, or to neutralize them with other thoughts or actions (i.e., by performing compulsions). DSM-V defines compulsions as: (1) repetitive behaviors (e.g., washing hands, sorting, checking) or mental acts (e.g., praying, counting, repeating words silently) that the individual feels compelled to perform in response to obsessions or according to rules that must be strictly enforced; and (2) these behaviors or mental acts are intended to prevent or relieve anxiety or distress, or to prevent some feared event or situation; however, these behaviors or mental acts are not related in a realistic way to those they are intended to neutralize or prevent, or are clearly excessive. See DSM-V.

[0010] SAD is an anxiety disorder characterized by a fear or anxiety specific to social situations in which the person feels noticed, observed, or scrutinized, and in which social interactions persistently cause distress, and in which social interactions are either avoided or endured painfully and unwillingly. As used herein, SAD is diagnosed according to the criteria set forth in either DSM-IV or DSM-V.

[0011] Common treatments for anxiety-related disorders OCD and SAD include cognitive behavioral therapy and psychopharmacological medications. Medications used to treat anxiety-related disorders include serotonin reuptake inhibitors (e.g., Anafranil), selective serotonin reuptake inhibitors (SSRIs; e.g., Sertraline (brand name Zoloft), Fluoxetine (brand name Prozac), Fluvoxamine (brand name Luvox) and Paroxetine (brand name Paxil), Citalopram (brand name Celexa) and Escitalopram (brand name Lexapro), serotonin-norepinephrine reuptake inhibitors (SSRIs; e.g., Sertraline (brand name Zoloft), Fluoxetine (brand name Prozac), Fluvoxamine (brand name Luvox) and Paroxetine (brand name Paxil), Citalopram (brand name Celexa) and Escitalopram (brand name Lexapro), serotonin-norepinephrine reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SSRIs). inhibitor, SNRI; for example, Venlafaxine (trade name Effexor), Duloxetine (trade name Cymbalta).

[0012] ASD is currently treated mainly with behavioral therapies, such as social skills training, applied behavior analysis, physical therapy, and occupational therapy. Psychopharmacological drugs, including serotonin reuptake inhibitors (SSRIs), antianxiety drugs, and stimulants, have been used to treat a variety of symptoms of ASD. For example, risperidone and aripiprazole have been approved to treat irritability associated with autism. Some studies have also shown that risperidone, fluvoxamine, fluoxetine, and valproate help with repetitive behaviors in autism. E. Anagnostou, and E. Hollander, "4 drugs can improve autism's repetitive behaviors" Current Psychiatry. 2006 April; 5 (4): 55-64.

[0013] However, psychopharmacological drugs have serious adverse side effects, including inducing suicidal ideation. Thus, there is a need for additional drugs that reduce anxiety in patients suffering from anxiety-related disorders. Summary of the invention

[0014] The present invention provides methods of treating anxiety-related disorders by administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor. In some embodiments, the anxiety-related disorder is obsessive-compulsive disorder or social anxiety disorder.

[0015] The present invention also provides methods for reducing anxiety, obsessions or compulsions by administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor.

[0016] In some embodiments, the tyrosine hydroxylase inhibitor is α-methyl-DL-tyrosine.

[0017] In other embodiments, the present invention provides pharmaceutical compositions comprising a tyrosine hydroxylase inhibitor. Also provided are pharmaceutical kits comprising a tyrosine hydroxylase inhibitor and packaging therefor. DETAILED DESCRIPTION

[0018] The subject matter of the present invention may be more readily understood by reference to the following detailed description which forms a part of the present disclosure. It should be understood that the present invention is not limited to the specific products, methods, conditions or parameters described and / or illustrated herein, and that the terminology used herein is for the purpose of describing specific embodiments by way of example only and is not intended to limit the claimed invention.

[0019] Unless otherwise defined herein, scientific and technical terms used in conjunction with this application should have the meanings commonly understood by those of ordinary skill in the art. In addition, unless the context requires otherwise, nouns modified by quantifiers represent one / kind or more / kind.

[0020] As employed above and throughout this disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings.

[0021] Unless otherwise clearly indicated in the context, nouns modified by quantifiers in the present disclosure represent one / kind or more / kind, and reference to a specific numerical value includes at least the specific value. Therefore, for example, reference to "compound" is a reference to one or more such compounds and equivalents known to those skilled in the art, and so on. The term "multiple / kind" used herein means more than one / kind. When expressing the range of values, another embodiment includes from a specific value and / or to another specific value. Similarly, when a value is expressed as an approximate value by using the preceding "about", it should be understood that the specific value forms another embodiment. All ranges are inclusive and combinable.

[0022] As used herein, the terms "component", "composition", "composition of compounds", "compound", "drug", "pharmacologically active agent", "active agent", "therapeutic agent", "therapy", "treatment" or "agent" are used interchangeably herein and refer to one or more compounds or compositions of matter that induce a desired pharmacological and / or physiological effect through local and / or systemic action when administered to a subject (human or animal).

[0023] As used herein, the term "treat" or "therapy" (and its various forms) includes preventative (e.g., prophylactic), curative, or palliative treatment. As used herein, the term "treat" includes alleviating or alleviating at least one adverse or negative effect or symptom of a condition, disease, or disorder.

[0024] "Pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problematic complications and commensurate with a reasonable benefit / risk ratio.

[0025] In the present invention, the disclosed compounds can be prepared in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, wherein the parent compound is modified by preparing its acid salt or base salt. Some examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); alkali or organic salts of acidic residues (e.g., carboxylic acids); and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like. These physiologically acceptable salts are prepared by methods known in the art, for example, by dissolving the free amine base with an excess of acid in an aqueous alcohol solution, or by neutralizing the free carboxylic acid with an alkali metal base (e.g., hydroxide) or with an amine.

[0026] The compounds described herein can be prepared in alternative forms. For example, many amino-containing compounds can be used or prepared as acid addition salts. Typically, such salts improve the separation and handling characteristics of the compounds. For example, depending on the reagents, reaction conditions, etc., the compounds described herein can be used or prepared, for example, as their hydrochloride or tosylate salts. Isostructural crystalline forms, all chiral and racemic forms, N-oxides, hydrates, solvates, and acid salt hydrates are also contemplated within the scope of the present invention.

[0027] Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compound (including free acid, free base and zwitterion) are considered within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxyl groups usually exist in equilibrium with their zwitterionic forms. Therefore, any compound described herein containing, for example, both amino and carboxyl groups also includes reference to its corresponding zwitterion.

[0028] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. The term "enantiomers" refers to stereoisomers that are non-superimposable mirror images of each other.

[0029] The term "administering" refers to directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog that will form an equivalent active compound or substance in vivo.

[0030] The terms "subject," "individual," and "patient" are used interchangeably herein and refer to a human being provided treatment (including prophylactic treatment) with a pharmaceutical composition according to the present invention.

[0031] The term "inhibitor" as used herein includes compounds that inhibit the expression or activity of a protein, polypeptide or enzyme, and does not necessarily mean that the expression and / or activity is completely inhibited. Instead, inhibition includes inhibiting the expression and / or activity of a protein, polypeptide or enzyme to a degree and for a time sufficient to produce the desired effect.

[0032] The present invention provides methods for treating anxiety-related disorders by administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor.

[0033] As used herein, the term "anxiety-related disorders" refers to obsessive compulsive disorder (OCD), generalized anxiety disorder (GAD), panic disorder, post-traumatic stress disorder (PTSD), and social anxiety disorder (SAD).

[0034] In some embodiments, the anxiety-related disorder is OCD.OCD as used herein refers to a disorder diagnosed according to DSM-IV or DSM-V criteria.

[0035] In some embodiments, the anxiety-related disorder is SAD. As used herein, SAD refers to a disorder diagnosed according to DSM-IV or DSM-V criteria.

[0036] In some embodiments, the anxiety-related disorder is OCD or SAD.

[0037] In some embodiments, the anxiety-related disorder is GAD.GAD as used herein refers to a disorder diagnosed according to DSM-IV or DSM-V criteria.

[0038] In some embodiments, the anxiety-related disorder is panic disorder. As used herein, panic disorder refers to a disorder diagnosed according to DSM-IV or DSM-V criteria.

[0039] In some embodiments, the anxiety-related disorder is PTSD.PTSD as used herein refers to a disorder diagnosed according to DSM-IV or DSM-V criteria.

[0040] In some aspects, the invention relates to methods of reducing anxiety, obsessions, or compulsions by administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor.

[0041] In some embodiments, the methods of the invention relate to reducing anxiety. Anxiety as used herein may include fear associated with meeting and talking to people, avoidance of social situations that previously caused significant anxiety, anxiety in anticipation of social situations, or inability to initiate conversations with others.

[0042] In some such embodiments, the method is performed on an object experiencing anxiety. Anxiety is a symptom of a variety of conditions, including PTSD, ASD, OCD, GAD, and SAD. In some embodiments, the object experiencing anxiety has been diagnosed as suffering from ASD. ASD used herein includes ASD diagnosed according to the guidelines shown in DSM-V and as proposed in previous versions of DSM (i.e., DSM-IV) "autism", "pervasive developmental disorder", "Asperger's Disorder", "Rhett's Disorder" or "Childhood Disintegrative Disorder".

[0043] In other embodiments, the subject experiencing anxiety has been diagnosed with OCD. In some embodiments, the subject experiencing anxiety has been diagnosed with GAD. In some embodiments, the subject experiencing anxiety has been diagnosed with SAD. In some embodiments, the subject experiencing anxiety has been diagnosed with ASD.

[0044] In other embodiments, the invention relates to a method of reducing obsessive-compulsive behavior or compulsive behavior in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor.

[0045] In some embodiments, obsessions or compulsions include rituals and repetitive / restrictive behaviors, and obsessions make it difficult for the patient to complete tasks or concentrate on conversations.

[0046] In some such embodiments, the method is performed on an object experiencing obsessions or compulsions. Obsessions or compulsions are symptoms of a variety of conditions, including obsessive-compulsive disorder (OCD), autism spectrum disorder (ASD), depression, psychotic neurosis, schizophrenia, and Sotos syndrome. In some embodiments, the object experiencing obsessions or compulsions has been diagnosed as suffering from OCD. In other embodiments, the object experiencing obsessions or compulsions has been diagnosed as suffering from ASD. In some embodiments, the object experiencing obsessions or compulsions has been diagnosed as suffering from depression. In other embodiments, the object experiencing obsessions or compulsions has been diagnosed as suffering from psychotic neurosis. In some embodiments, the object experiencing obsessions or compulsions has been diagnosed as suffering from schizophrenia. In other embodiments, the object experiencing obsessions or compulsions has been diagnosed as suffering from recognized anxiety-related syndromes, such as Sotos syndrome. In some embodiments, the method of the present disclosure is performed on an object diagnosed as suffering from ASD and another form of anxiety (e.g., OCD) simultaneously.

[0047] The present invention is intended to alleviate obsessive-compulsive behaviors or compulsions. As used herein, obsessive-compulsive behaviors are behaviors that meet the definition of obsessions as shown in DSM-V. Obsessive-compulsive behaviors or compulsions as used herein are defined according to DSM-V by the following (1) and (2): (1) recurrent and persistent thoughts, impulses, or urges that are sometimes felt as intrusive and unwanted during the disturbance and that cause significant anxiety or distress in most individuals; and (2) the individual attempts to ignore or suppress such thoughts, impulses, or images, or to neutralize such thoughts, impulses, or images with other thoughts or actions (i.e., by engaging in compulsions).

[0048] Compulsive behavior used herein is the behavior that meets the definition of compulsive behavior described in DSM-V. Compulsive behavior used herein is defined by the following (1) and (2) according to DSM-V: (1) individuals feel forced to respond to obsessive ideas or repeated behaviors (e.g., washing hands, sorting, checking) or mental activities (e.g., praying, counting, repeating words silently) according to rules that must be strictly applied; and (2) these behaviors or mental activities are intended to prevent or reduce anxiety or pain, or prevent some feared events or situations; however, these behaviors or mental activities are not related to those they are intended to neutralize or prevent in a realistic manner, or are obviously excessive. See DSM-V.

[0049] In some embodiments, the methods of the present disclosure reduce obsessive-compulsive behaviors in patients in need thereof. In other embodiments, the methods of the present disclosure reduce compulsive behaviors in patients in need thereof. In some embodiments, the methods of the present disclosure reduce obsessive-compulsive behaviors and compulsive behaviors in patients in need thereof.

[0050] As used herein, the term "relief" as used when referring to anxiety, or obsessive-compulsive behavior or compulsive behavior refers to a reduction in the frequency or severity of the symptom in question. Relief can be detected by measuring at baseline (i.e., at the beginning of treatment) and measuring the frequency or severity of the symptom again after a period of treatment. In some embodiments, the treatment period is 4 weeks.

[0051] The frequency or severity of anxiety can be assessed using any clinically recognized assessment tool, such as the following: for example, the Generalized Anxiety Disorder 7-item (GAD-7) scale (Source: Spitzer RL, Kroenke K, Williams JBW, Lowe BA brief measure for assessing generalized anxiety disorder. Arch Intern Med. 2006; 166: 1092-1097), Hamilton Anxiety Rating Scale (HAM-A), Generalized Anxiety Disorder Severity Scale (GADSS), Beck Anxiety Inventory (BAI), Trait Anxiety subscale of the State-Trait Anxiety Inventory (STAI-T), and Penn State Worry Questionnaire (Penn State Worry Questionnaire). The questionnaire included the Social Phobia Inventory (PSWQ), the Liebowitz Social Anxiety Scale (PSWQ), the Social Phobia Inventory (Social Phobia Inventory), the Brief Social Phobia Scale (Brief Social Phobia Scale), the Disability Profile (Disability Profile), the Liebowitz Self-Rated Disability Scale (Liebowitz Self-Rated Disability Scale), the Social Phobia Safety Behaviors Scale (Social Phobia Safety Behaviors Scale), the Self-Statements During Public Speaking Scale (Self-Statements During Public Speaking Scale), the Aberrant Behavior Checklist-Community (Aberrant Behavior Checklist-Community), the Spence Children's Anxiety Scale (Spence Children's Anxiety Scale), the Social Responsiveness Scale (Social Responsiveness Scale), and the Clinical Global Impression Scale (Clinical Global Impression Scale).See World J Psychiatry. 2012 Oct 22; 2(5): 83–85. See also, Osório FL, Crippa JAS, Loureiro SR. Instruments for the Evaluation of Social Phobia. In: Axelby CP, ed. Social Phobia: Etiology, Diagnoses and Treatment. Hauppauge: Nova Science Publishers; 2009. pp. 1–66.

[0052] The frequency or severity of obsessive thoughts and compulsive behaviors can be assessed using any clinically recognized assessment tool, such as the Yale-Brown Obsessive-Compulsive Scale (YBOCS), the Children's Yale-Brown Obsessive-Compulsive Scale (CYBOCS), and / or self-report tools, such as the Obsessive-Compulsive Inventory (OCI; OCI-R), the Padua Inventory, the Repetitive Behavior Scale, the Spence Children's Anxiety Rating Scale, the Social Responsiveness Scale, and the Clinical Global Impression Scale.

[0053] The method of the present disclosure includes administering an effective amount of a tyrosine hydroxylase inhibitor or a pharmaceutically acceptable salt thereof to a subject in need thereof. The term "effective amount" as used above and throughout the disclosure refers to an amount that effectively achieves the desired result for the treatment of the associated disorder, condition or side effect within the dosage and necessary time period. It should be understood that the effective amount of the components of the present invention will vary from patient to patient and is not only related to the specific compound, component or composition selected, the concomitant drug, the route of administration, and the ability of the component to cause the desired result in the individual, but also to factors such as the following: the disease state or severity of the condition to be alleviated, the hormone level, age, sex, weight of the individual, the patient's state at the time and the severity of the pathological condition being treated, the special diet followed by the particular patient during the concurrent medication or then, and other factors that will be appreciated by those skilled in the art, and the appropriate dosage is determined by the attending physician. The dosage regimen can be adjusted to provide an improved therapeutic response. An effective amount is also an amount in which the beneficial effects of the component in treatment outweigh any toxic or deleterious effects.

[0054] Administration of the tyrosine hydroxylase inhibitor according to the methods of the present disclosure can be carried out by a variety of routes including oral, nasal, subcutaneous, intravenous, intramuscular, transdermal, vaginal, rectal, or any combination thereof.

[0055] In certain embodiments, the tyrosine hydroxylase inhibitor is a tyrosine derivative. The tyrosine derivative may be present in different isomeric forms (including stereoisomers and enantiomers). The tyrosine derivative may, for example, exist in both L-form or D-form. The tyrosine derivative may also, for example, exist in racemic form. Representative tyrosine derivatives include one or more of the following: (2R)-2-amino-3-(2-chloro-4-hydroxyphenyl)propionic acid methyl ester, D-tyrosine ethyl ester hydrochloride, (2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl)propionic acid methyl ester, HD-tyrosine (tBu)-allyl ester hydrochloride, (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl)propionic acid methyl ester] ) methoxy] phenyl) propionic acid methyl ester, (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propionic acid methyl ester, (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propionic acid methyl ester, 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy] benzylmalonate diethyl, (2R)-2-amino-3-(3-chloro-4-methoxyphenyl) propionic acid methyl ester, (2R)-2-amino-3-(3-chloro-4-methoxyphenyl) propionic acid methyl ester, (2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propionic acid methyl ester, (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxy phenyl)propionic acid methyl ester, (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propionic acid methyl ester, H-DL-tyrosine methyl ester hydrochloride, H-3,5-diiodo-tyrosine methyl ester hydrochloride, HD-3,5-diiodo-tyrosine methyl ester hydrochloride, HD-tyrosine methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, D-tyrosine-methyl ester hydrochloride, methyl D-tyrosine ester hydrochloride, HD-tyrosine methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, HD-tyrosine methyl ester hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl)propionic acid, (2R)-2-amino-3-(4-hydroxyphenyl)propionic acid, phenyl) methyl ester hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid methyl ester hydrochloride, (2R)-2-azanyl-3-(4-hydroxyphenyl) propionic acid methyl ester hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-tyrosine (3,5-I2)-OSu, Fmoc-tyrosine (3-NO2)-OH, α-methyl-L-tyrosine, α-methyl-D-tyrosine, α-methyl-DL-tyrosine, and C1-C2 of α-methyl-DL-tyrosine. 12 Alkyl ester salts, for example α-methyl-DL-tyrosine methyl ester hydrochloride.

[0056] In certain embodiments of the invention, the tyrosine derivative is α-methyl-L-tyrosine. In other embodiments, the tyrosine derivative is α-methyl-D-tyrosine. In other embodiments, the tyrosine derivative is a racemic form of α-methyl-DL-tyrosine.

[0057] In a suitable embodiment of the present invention, the tyrosine hydroxylase inhibitor is administered daily. In another suitable embodiment of the present invention, the tyrosine hydroxylase inhibitor is administered in divided doses. In some embodiments, the tyrosine hydroxylase inhibitor is administered three times a day. In some embodiments, the tyrosine hydroxylase inhibitor is required for a long time, while in other embodiments, it can be stopped after satisfactory results are obtained. In some embodiments, the plasma half-life (t 1 / 2 ) is 6 to 12 hours. In some such embodiments, the tyrosine hydroxylase inhibitor is preferably administered two to three times a day.

[0058] In some aspects, about 10 to 2000 mg of a tyrosine hydroxylase inhibitor (e.g., α-methyl-DL-tyrosine) is administered daily, preferably 100 to 1200 mg of a tyrosine hydroxylase inhibitor is administered daily, and most preferably 200 to 900 mg of a tyrosine hydroxylase inhibitor (e.g., α-methyl-DL-tyrosine) is administered daily. The tyrosine hydroxylase inhibitor (e.g., α-methyl-DL-tyrosine) is preferably administered orally. The daily dose may be administered as a single dose or as divided doses throughout the day. Separate administration is particularly preferred. The daily dose may be administered as divided, substantially equal doses.

[0059] Some preferred aspects of the present disclosure relate to a method for alleviating the obsessions or compulsions of a patient by administering an effective amount of α-methyl-DL-tyrosine to the patient. These methods result in at least one of the obsessions or compulsions of the patient as defined in DSM-5 being alleviated. In some embodiments, these methods also result in at least one dimension of the obsessions or compulsions assessed using the following being reduced: Abnormal Behavior Checklist-Community (ABC-C), Autism Diagnostic Observation Schedule (ADOS), Conners Parent Rating Scale (CPRS), Yale-Brown Obsession Scale (YBOCS), Children's Yale-Brown Obsession Scale (CYBOCS), Obsession Scale (OCI; OCI-R), Padua Scale, Repetitive Behavior Scale, Spence Children's Anxiety Scale, Social Reaction Scale or Clinical Global Impression Scale. According to these aspects, about 10 to 2000 mg of α-methyl-DL-tyrosine is administered daily, preferably 100 to 1200 mg of α-methyl-DL-tyrosine is administered daily, more preferably 200 to 900 mg of α-methyl-DL-tyrosine is administered daily. α-methyl-DL-tyrosine is preferably administered orally. The daily dose can be administered as a single dose or in divided doses over the course of a day. The daily dose can be administered as divided, substantially equal doses. Three, substantially equal daily doses of α-methyl-DL-tyrosine are particularly preferred.

[0060] In some embodiments of the invention, a method is provided that also includes assessing obsessive-compulsive behavior or compulsive behavior in a subject. The assessing step may be performed before the administering step or after the administering step. The assessing step may be performed using an assessment tool suitable for the target behavior and may include one or more standard assessment tools known in the art, including, for example, the Vineland Adaptive Behavior Scale 2nd Edition. ndedition, VABS II, VABS) questionnaire, Autism Diagnostic Observation Schedule (ADOS), Aberrant Behavior Checklist-Community (ABC-C), Spencer Anxiety Scale (SAS), Repetitive Behavior Score–Revised (RBS-R), Social Responsiveness Scale (SRS), Connors Parent Rating Scale, Yale-Brown Obsessive-Compulsive Scale (YBOCS), Yale-Brown Obsessive-Compulsive Scale for Children (CYBOCS), Obsessive-Compulsive Inventory (OCI; OCI-R), Padua Scale, Repetitive Behavior Scale, Spence Children's Anxiety Scale, Social Responsiveness Scale, or Clinical Global Impression Scale. This assessment step can also be performed by the treating physician through clinical observation.

[0061] Other preferred aspects of the present disclosure relate to methods for alleviating the anxiety of patients by administering an effective amount of α-methyl-DL-tyrosine to patients. These methods result in the reduction of the anxiety of patients. In some embodiments, these methods result in the reduction of at least one dimension of the anxiety assessed using one of the following: Hamilton Anxiety Rating Scale (HAM-A), Generalized Anxiety Severity Scale (GADSS), Beck Anxiety Inventory (BAI), State-Trait Anxiety Inventory's Trait Anxiety Subscale (STAI-T), and Pennsylvania State University Worry Questionnaire (PSWQ), Liebowitz Social Anxiety Scale, Social Phobia Scale, Brief Social Phobia Scale, Disability Profile, Liebowitz Self-Assessment Disability Scale, Social Phobia Safety Behavior Scale and Speech Self-Assessment Scale, Social Phobic Disorders Severity and Change Form (SPD-SC Table), Abnormal Behavior Checklist-Community, Spence Children's Anxiety Scale, Social Reaction Scale and Clinical Global Impression Scale. According to these aspects, about 10 to 2000 mg of α-methyl-DL-tyrosine is administered daily, preferably 100 to 1200 mg of α-methyl-DL-tyrosine is administered daily, more preferably 200 to 900 mg of α-methyl-DL-tyrosine is administered daily. α-methyl-DL-tyrosine is preferably administered orally. The daily dose can be administered as a single dose or in divided doses over the course of the day. The daily dose can be administered as divided, substantially equal doses. Three, substantially equal daily doses of α-methyl-DL-tyrosine are particularly preferred.

[0062] In some embodiments of the present invention, there is provided a method further comprising assessing anxiety in a subject. The assessment step may be performed before or after the application step. The assessment step may be performed using an assessment tool suitable for anxiety symptoms, and may include one or more standard assessment tools known in the art, including, for example, Vineland Adaptive Behavior Scale, 2nd Edition (VABS II, VABS) Questionnaire, Autism Diagnostic Observation Schedule (ADOS), Abnormal Behavior Checklist-Community (ABC-C), Spencer Anxiety Rating Scale (SAS), Repetitive Behavior Score-Revised (RBS-R), Social Responsiveness Scale (SRS), Connors Parent Rating Scale, Yale-Brown Obsessive-Compulsive Scale (YBOCS), Yale-Brown Obsessive-Compulsive Scale for Children (CYBOCS), Obsessive-Compulsive Scale (OCI; OCI-R), Padua Scale, Hamilton Anxiety Rating Scale (HAM-A), Liebowitz Social Anxiety Scale (LSA S), Social Phobia Severity and Change Schedule (SPD-SC), Generalized Anxiety Disorder Severity Scale (GADSS), Beck Anxiety Inventory (BAI), Trait Anxiety Subscale of State-Trait Anxiety Inventory (STAI-T), Pennsylvania State University Worry Questionnaire (PSWQ), Brief Social Phobia Scale, Disability Profile, Liebowitz Self-Rating Disability Scale, Social Phobia Safety Behavior Scale or Self-Rating Speech Scale, Aberrant Behavior Checklist-Community, Spence Children's Anxiety Scale, Social Responsiveness Scale, and / or Clinical Global Impression Scale. This assessment step can also be performed by the physician who is treating the patient through clinical observation.

[0063] In some embodiments of the methods of the present invention, a tyrosine hydroxylase inhibitor is administered to a patient in combination with other drugs. As used herein, the combined administration of a drug does not mean any specific dosing regimen, but rather means that the two drugs are present in or on the patient's body at the same time. Therefore, the drugs administered in combination may be administered simultaneously, or may be administered sequentially (e.g., at different times of the day).

[0064] In some embodiments, tyrosine hydroxylase inhibitors are administered in combination with gamma-aminobutyric acid (γ-aminobutyricacid, GABA). GABA can be administered simultaneously with tyrosine hydroxylase inhibitors. In other aspects, GABA can be administered separately from tyrosine hydroxylase inhibitors, i.e., administered at another time of the day. In some aspects, GABA is administered before bedtime. Typically, the dosage of GABA is from about 5 mg to about 30 mg, such as 5, 10, 15, 20, 25 or about 30 mg of GABA, and 15 mg of GABA is particularly preferred.

[0065] Thus, in some embodiments, the disclosure provides a method of treating an anxiety-related disorder in a subject in need thereof or a method of reducing anxiety, obsessive-compulsive behavior, or compulsive behavior in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor and GABA. In some embodiments, the disclosure provides a method of treating an anxiety-related disorder in a subject in need thereof or a method of reducing anxiety, obsessive-compulsive behavior, or compulsive behavior in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of α-methyl-DL-tyrosine and GABA.

[0066] In other embodiments, a tyrosine hydroxylase inhibitor is administered in combination with serotonin or melatonin, or a pharmaceutically acceptable salt thereof. Serotonin or melatonin may be administered simultaneously with a tyrosine hydroxylase inhibitor. In other aspects, serotonin or melatonin may be administered separately from a tyrosine hydroxylase inhibitor, i.e., at another time of the day. In some aspects, serotonin or melatonin is administered before bedtime. In some embodiments, the disclosure provides a method for treating anxiety-related disorders in a subject in need thereof or a method for alleviating anxiety, obsessive-compulsive behavior, or compulsive behavior in a subject in need thereof, comprising administering an effective amount of a tyrosine hydroxylase inhibitor and serotonin or melatonin to a subject in need thereof. In some embodiments, the disclosure provides a method for treating anxiety-related disorders in a subject in need thereof or a method for alleviating anxiety, obsessive-compulsive behavior, or compulsive behavior in a subject in need thereof, comprising administering an effective amount of α-methyl-DL-tyrosine and serotonin or melatonin, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0067] In other aspects, the tyrosine hydroxylase inhibitor is administered in combination with another drug commonly used to treat ASD, attention deficit hyperactivity disorder (ADHD), OCD, GAD or SAD. For example, the tyrosine hydroxylase inhibitor can be administered together with drugs that affect neurotransmission (e.g., amphetamine, methylphenidate, etc.), such as psychotropic drugs (e.g., risperidone), neurotransmitter reuptake inhibitors (e.g., fluoxetine), compounds that stimulate glutamine transmission (e.g., LY2140023) and / or compounds that affect cholinergic, serotonergic, vasopressin, oxytocin or glutamate-regulated neurotransmission (e.g., galantamine), or pharmaceutically acceptable salts thereof. Thus, the present disclosure also relates to methods wherein an effective amount of a tyrosine hydroxylase inhibitor (e.g., α-methyl-DL-tyrosine) is administered in combination with an effective amount of a compound that affects neurotransmission, such as a psychotropic agent, a neurotransmitter reuptake inhibitor, a compound that stimulates glutaminergic transmission, and / or a compound that affects cholinergic, serotonergic, vasopressin, oxytocin or glutamate-regulated neurotransmission, or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the tyrosine hydroxylase inhibitor is administered in combination with a beta-adrenergic agonist (also known as a beta receptor agonist), such as albuterol, levalbuterol, fenoterol, formoterol, isoproterenol, metaproterenol, salmeterol, terbutaline, clenbuterol, isoetarine, pirbuterol, procaterol, ritodrine, epinephrine, or a pharmaceutically acceptable salt thereof, and combinations thereof. Salbutamol is a particularly preferred beta-adrenergic agonist.

[0069] In other embodiments, the tyrosine hydroxylase inhibitor is administered in combination with a psychopharmacological agent such as aripiprazole, pimavanserin, olanzapine, asenapine, clozapine, quetiapine, risperidone, lurasidone, cariprazine, paliperidone, brexpiprazole, iloperidone, ziprasidone or balovaptan, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the tyrosine hydroxylase inhibitor is α-methyl-DL-tyrosine and the psychopharmacological agent is aripiprazole, risperidone or balovaptan.

[0070] In other embodiments, the tyrosine hydroxylase inhibitor is administered in combination with a vasopressin or vasopressin analog, such as, for example, desmopressin, felypressin, ornitropressin, selepressin, and terlipressin. In some embodiments, the tyrosine hydroxylase inhibitor is administered in combination with desmopressin.

[0071] In other embodiments, the tyrosine hydroxylase inhibitor is administered in combination with an antidepressant, such as, for example, a selective serotonin reuptake inhibitor (SSRI) (e.g., fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, and paroxetine, or a pharmaceutically acceptable salt thereof). In some preferred embodiments, the tyrosine hydroxylase inhibitor is α-methyl-DL-tyrosine, and the antidepressant is fluoxetine or sertraline.

[0072] In other embodiments, tyrosine hydroxylase inhibitors are administered in combination with other antianxiety agents, such as barbiturates, carbamates, antihistamines (e.g., hydroxyzine, chlorpheniramine, or diphenhydramine), opioids (e.g., hydrocodone, fentanyl, buprenorphine), benzodiazepines, benzodiazepines (e.g., alprazolam, clonazepam, diazepam, lorazepam, oxazepam, chlordiazepoxide), beta-blockers (e.g., propranolol, atenolol), tricyclic antidepressants (e.g., imipramine, desipramine, nortriptyline, amitriptyline, doxepin, clomipramine), tetracyclic antidepressants (e.g., mirtazapine), other antidepressants (e.g., trazodone), monoamine oxidase inhibitors (MAOIs), inhibitor, MAOI) (e.g., phenelzine, tranylcypromine, isocarboxazid, moclobemide), serotonin-norepinephrine reuptake inhibitor (SNRI) (e.g., venlafaxine, duloxetine), mild sedatives (e.g., buspirone), anticonvulsants (valproate, pregabalin, gabapentin), bupropion, alpha-receptor blockers (e.g., prazosin), or pharmaceutically acceptable salts thereof.

[0073] While not intending to be bound by any particular mechanism of operation, it is believed that the tyrosine hydroxylase inhibitors according to the present invention function by inhibiting the first and rate-limiting step in catecholamine synthesis, namely the conversion of tyrosine to dihydroxyphenylalanine (DOPA) and thereby reducing the synthesis and subsequent synaptic release of dopamine (DA), norepinephrine (NE) and epinephrine (E).

[0074] Also provided herein are kits containing tyrosine hydroxylase inhibitors and packaging therefor. In some embodiments, the kits further contain other drugs that can be used to treat OCD or SAD, including, for example, GABA, serotonin, melatonin, beta adrenergic agonists, anxiolytics, psychopharmacological drugs, antidepressants. In some embodiments, the kit comprises a tyrosine hydroxylase inhibitor and a drug selected from the group consisting of albuterol, alprazolam, amitriptyline, aripiprazole, asenapine, atenolol, balovaptan, epiprazole, buprenorphine, bupropion, buspirone, cariprazine, chlordiazepoxide, chlorpheniramine, citalopram, clenbuterol, clomipramine, clonazepam, clozapine, desipramine, diazepam, diphenhydramine, doxepin, duloxetine, epinephrine, escitalopram, fenoterol, fentanyl, fluoxetine, fluvoxamine, formoterol, gabapentin, hydrocodone, hydroxyzine, iloperidone , imipramine, isocarboxazid, isotharine, isoproterenol, levsalbutamol, lorazepam, lurasidone, metaproterenol, mirtazapine, moclobemide, nortriptyline, olanzapine, oxazepam, paliperidone, paroxetine, phenelzine, pimavanserin, pirbuterol, prazosin, pregabalin, procaterol, propranolol, quetiapine, risperidone, ritodrine, salmeterol, sertraline, terbutaline, tranylcypromine, trazodone, valproate / ester, venlafaxine, desmopressin, felypressin, ornitropressin, celippressin, terlipressin or ziprasidone, or its pharmaceutically acceptable salt. Such a medicine box can be used for implementing the method of the present disclosure. The tyrosine hydroxylase inhibitor can be a tyrosine derivative. The tyrosine derivative can include a tyrosine derivative that can exist in an isomeric form. The tyrosine derivative may include the tyrosine derivative in its L form or its D form. The tyrosine derivative may also exist, for example, in a racemic form.Representative tyrosine derivatives include one or more of the following: methyl (2R)-2-amino-3-(2-chloro-4-hydroxyphenyl)propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl)propanoate, HD-tyrosine (tBu)-allyl ester hydrochloride, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)propanoate, methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propanoate, methyl (2R)-2-amino-3-(4-[(2-chloro-6-fluorophenyl)methoxy]phenyl)propanoate, methyl (2R)-2-amino -3-(2-chloro-3,4-dimethoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl)propionic acid methyl ester, 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzylmalonic acid diethyl ester, (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propionic acid methyl ester, H-DL-tyrosine Acid-methyl ester hydrochloride, H-3,5-diiodo-tyrosine-methyl ester hydrochloride, HD-3,5-diiodo-tyrosine-methyl ester hydrochloride, HD-tyrosine-methyl ester hydrochloride, D-tyrosine-methyl ester hydrochloride, methyl D-tyrosine ester hydrochloride, HD-tyrosine-methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, HD-tyrosine-methyl ester hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl)propionic acid, (2R)-2-amino-3-(4-hydroxyphenyl)propionic acid methyl ester hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl)propionic acid methyl ester hydrochloride, (2R)-2-azanyl-3-(4-hydroxyphenyl)propionic acid In some embodiments of the present invention, the tyrosine derivative is α-methyl-L-tyrosine. In other specific embodiments of the present invention, the tyrosine derivative is α-methyl-D-tyrosine. In other embodiments, the tyrosine derivative is a racemic form of α-methyl-DL-tyrosine.

[0075] The following examples are provided to supplement the previous disclosure and provide a better understanding of the subject matter described herein. These examples should not be considered as limiting the subject matter described. It should be understood that the examples and embodiments described herein are only for illustrative purposes, and that various modifications or variations thereof will be apparent to those skilled in the art, and will be included in the true scope of the present invention and can be made without departing from the true scope of the present invention.

[0076] Example 1

[0077] During the course of the studies described below, patients with OCD or SAD were observed to have improved anxiety-related symptoms.

[0078] Study Name: A double-blind, randomized, placebo-controlled, dose-ranging study of L1-79 in the treatment of autism

[0079] Study design: Blind, randomized, 4-group, 4-week treatment period. Treatment groups consisted of 100 mg or 200 mg doses of α-methyl-DL-tyrosine (ie, L1-79) or placebo three times daily (tid).

[0080] Sample size: N = 30; randomized and divided into 4 groups with 10 open markers:

[0081] Group 1 (n=10) 100 mg L1-79 (1×100 mg capsule + 1 placebo) TID Group 2 (n=5) 100 mg L1-79 (1×100 mg capsule + 1 placebo) TID Group 3 (n=10) 200 mg L1-79 (2 x 100 mg capsules) TID

[0082] Group 4 (n-5) 200 mg L1-79 (2 x 100 mg capsules) TID

[0083] Group 5 (n=10) Placebo (3 placebos) TID

[0084] Study Population: Male subjects aged 13 to 21 years diagnosed with autism who met the inclusion criteria and were able to complete standardized measures allowing them to participate in this study.

[0085] Main inclusion criteria: males aged 13 to 21 years, signed informed consent, normal clinical laboratory values, DSM-5 compliant diagnosis of autism spectrum disorder confirmed by the Autism Diagnosis Interview Review (ADIR) and by Autism Diagnostic Observation Schedule (ADOS) scores consistent with autism diagnosis, no more than one concomitant medication, stable concomitant medication for at least 2 weeks prior to enrollment, and no planned changes during the trial under psychosocial intervention.

[0086] Major exclusion criteria: Any comorbidity, including fragile X syndrome, epilepsy, Rett syndrome, ADHD, or other diseases or syndromes requiring treatment in addition to autism. Any other psychiatric disorder, or laboratory values ​​out of range. DSM-5 diagnosis of schizophrenia, schizoaffective disorder, alcohol use disorder; Active medical problems: unstable epilepsy (>2 times in the past month), severe physical illness;

[0087] Experimental treatment: L1-79 was administered at a dose of 100 or 200 mg 3 times a day for 4 weeks.

[0088] Non-experimental treatment: Placebo.

[0089] Dosage and Administration: L1-79 or placebo was orally administered according to the above schedule as per randomization.

[0090] Assessment Schedule: Subjects will be assessed within one week prior to study entry, weekly throughout the dosing period, and again 4 weeks after cessation of treatment.

[0091] Safety Measures: Complete history and physical examinations at regularly scheduled times, including orthostatic blood pressure measurement, vital signs, CBC, differential, platelet count, urinalysis; serum enzymes, including total protein, albumin, glucose, BUN, creatinine, direct and total bilirubin, alkaline phosphatase, phosphorus, calcium, AST, ALT, sodium, potassium, chloride, bicarbonate, T4, TSH, and adverse event assessments. Electrocardiograms were obtained at the study screening visit and at the Week 4 treatment visit (end of dosing).

[0092] Study Endpoints: The primary endpoint was an assessment of the safety of L1-79 based on reported adverse events and changes from baseline in physical examination parameters including orthostatic blood pressure, clinical laboratory measurements, and ECG. Secondary endpoints included attending physician assessment, as quantified by the Clinical Global Impression Scale, based on changes from baseline in multiple psychological tests, including the Vineland Adaptive Behavior Scale, 2nd Edition (VABS II, VABS) questionnaire, Autism Diagnostic Observation Schedule (ADOS), Aberrant Behavior Checklist-Community (ABC-C), Spencer Anxiety Rating Scale (SAS), Repetitive Behavior Score-Revised (RBS-R), Social Responsiveness Scale (SRS), as well as their personal observations in the clinic, as well as video graphic information obtained during ADOS testing (according to the protocol) and anecdotes provided by caregivers during the study.

[0093] Improvement of obsessive compulsive symptoms

[0094] During the course of this study, patients diagnosed with ASD and one or more of OCD and attention-deficit / hyperactivity disorder experienced a reduction in obsessive compulsive symptoms, as demonstrated through the case studies below.

[0095] Obsessive-compulsive symptoms can include ritualistic and repetitive / restrictive behaviors, and obsessive thoughts that make it difficult for people to complete tasks or concentrate on conversations.

[0096] All patients received 100 to 200 mg of L1-79 three times daily. None of the patients in the OCD symptom improvement group received medication for OCD.

[0097] Obsessive-compulsive symptoms were recorded initially at baseline and at the end of active treatment using the Repetitive Behaviors Scale, Spence Children's Anxiety Scale, Social Responsiveness Scale, Clinical Global Impression Scale, and direct parent report.

[0098] Subject 02-002 showed a reduction in OCD symptoms as measured by a decrease from a severe score of 96 to a moderate score of 73 in Repetitive Behavior and Restrictive Interests according to the SRS / DSM-5.

[0099] Subject 02-003 showed improvement in OCD symptoms, from severe to moderate in repetitive behaviors and restricted interests according to SRS / DSM-5 at week 4.

[0100] Subject 02-004 was rated "Much Improved" on the Stereotypic and RestrictedInterests portion of the CGI-I.

[0101] Subject 02-007's OCD symptoms were reduced from moderate to within the normal range according to the SRS / DSM-5 Repetitive Behaviors and Restricted Interests subscale, and according to the Spence Children's Anxiety Rating Scale for OCD score (3.0 for children with anxiety disorders to 0 for normal / no OCD).

[0102] Subject 02-012 showed normalization of OCD symptoms from a score of 80 (severe) to a score of 46 (within normal range) on the SRS / DSM-5 Repetitive Behaviors and Restricted Interests and was rated "much improved" on the CGI-I. Parent commented, "He doesn't look the same as he does now."

[0103] Subject 02-16's SRS / DSM-5 repetitive behaviors and restricted interests ranged from 65 (mild) to 46 (within normal range). The CGI-Severity Scale ranged from mild III to normal for stereotyped behaviors and restricted interests.

[0104] Subject 02-020 showed improvement in OCD symptoms from a score of 85 (severe) to a score of 73 (moderate) on the SRS / DSM-5 scale for repetitive behaviors and restricted interests.

[0105] A patient who at baseline could not talk about anything other than his area of ​​obsessive interest was able to converse about other people's interests after 4 weeks of active medication because he was less focused on his own obsessions.

[0106] One patient who experienced self-injurious compulsive behaviors at baseline completely stopped self-injury after 3 weeks of active medication.

[0107] Improvement in social anxiety symptoms

[0108] During the course of this study, patients diagnosed with ASD and one or more of social anxiety disorder and generalized anxiety disorder experienced a reduction in social anxiety symptoms, as demonstrated through the case studies below.

[0109] Social anxiety symptoms included one or more of the following: fear related to meeting and talking with people, avoidance of social situations that previously caused significant anxiety, anxiety in anticipation of social situations, and inability to initiate conversations with others. The presence of social anxiety symptoms was recorded at baseline using the Aberrant Behavior Checklist-Community, the Spence Children's Anxiety Scale, the Social Responsiveness Scale, and / or the Clinical Global Impression Scale and direct parent report.

[0110] All patients received 100 to 200 mg of L1-79 three times daily. None of the patients in the social anxiety symptom improvement group were receiving medication for social anxiety disorder.

[0111] Subject 02-002 showed a significant improvement from 98% to 75% on the ABC-C Social Withdrawal. Based on the SRS / DSM-5 Social Communication scale, the subject went from being in the severe range to the moderate range after 4 weeks of using L1-79. Based on the CGI-I Social Interaction and Communication at week 4, the subject was rated as "very improved."

[0112] Subject 02-007 showed a significant improvement in the ABC-C social withdrawal from 75% to less than 40% by 4 weeks of treatment.

[0113] Subject 02-009 showed a significant improvement in ABC-C social withdrawal from 91% to 63% at week 4 of treatment with L1-79.

[0114] Subject 02-012 showed a significant improvement from 84% to less than 40% on the ABC-C social withdrawal. Based on the SRS / DSM-5 social communication scale, the subject went from being in the severe range to being in the normal range after 4 weeks of using L1-79. Based on the CGI-I social interaction and communication at week 4, the subject was rated as "very improved". The CGI severity scores ranged from moderate III to critical III.

[0115] Subject 02-014 showed improvement in social anxiety symptoms, based on a CGI-I score of "much improved" in terms of social interaction and communication. In terms of social interaction, the CGI severity score ranged from marked III to moderate III.

[0116] Subject 02-016 showed improvement in social anxiety according to the SRS / DSM-5 Social Communication Scale. The subject went from being in the mildly impaired range to being in the normal range after 4 weeks of using L1-79. Based on the CGI-I Social Interaction and Communication at Week 4, the subject was rated as "much improved". The CGI severity score ranged from Mild III to Normal in Social Interaction and Communication. At Week 4, Subject 02-016 stated "I find it easier to talk to others. I also notice that I have calmed down a lot."

[0117] Subject 02-022 showed improvement in social anxiety based on the CGI-I Social Interaction and Communication domain. This subject was rated as "much improved" at week 4 of treatment with L1-79.

[0118] Example 2 Case Study Demonstrating Reduction of Obsessive-compulsive Thoughts and Compulsive Behaviors

[0119] ASD patient (subject JW) had a history of obsessions and compulsions that negatively impacted his functioning. Due to the intensity of the obsessions, the obsessions made it difficult for JW to engage in meaningful conversations with others or understand what was around him. When taking L1-79 (100 to 200 mg, three times a day), the obsessions were significantly reduced to the point where JW was able to engage in meaningful conversations with others, understand concepts, and make observations that would not otherwise occur due to the intensity of the obsessions. Rigidity and stubborn thoughts were also reduced. Compulsions / routines could be delayed or skipped because there were other interesting things to do that replaced the need to engage in compulsions or hold on to obsessions.

[0120] This disclosure also relates to the following aspects:

[0121] Aspect 1. A method for treating an anxiety-related disorder, the method comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor.

[0122] Aspect 2. The method of aspect 1, wherein the anxiety-related disorder is obsessive-compulsive disorder or social anxiety disorder.

[0123] Aspect 3. The method of aspect 2, wherein the anxiety-related disorder is obsessive-compulsive disorder.

[0124] Aspect 4. The method of aspect 2, wherein the anxiety-related disorder is social anxiety disorder.

[0125] Aspect 5. A method for reducing anxiety, obsessive thoughts and behaviors, or compulsive behaviors, the method comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor.

[0126] Aspect 6. The method of aspect 5, wherein the method is used to reduce anxiety.

[0127] Aspect 7. The method of aspect 5, wherein the method is used to reduce obsessive thoughts or compulsive behaviors.

[0128] Aspect 8. The method of any one of Aspects 1 to 7, wherein the tyrosine hydroxylase inhibitor is (2R)-2-amino-3-(2-chloro-4-hydroxyphenyl)propionic acid methyl ester, D-tyrosine ethyl ester hydrochloride, (2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl)propionic acid methyl ester, HD-tyrosine (tBu)-allyl ester hydrochloride, (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(4 -[(2-chloro-6-fluorophenyl)methoxy]phenyl)propanoic acid methyl ester, (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl)propanoic acid methyl ester, (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl)propanoic acid methyl ester, 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzylmalonate, (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoic acid methyl ester, (2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl)propanoic acid methyl ester, (2R)-2-amino-3-(2,6 -dichloro-3-hydroxy-4-methoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propionic acid methyl ester, H-DL-tyrosine methyl ester hydrochloride, H-3,5-diiodo-tyrosine methyl ester hydrochloride, HD-3,5-diiodo-tyrosine methyl ester hydrochloride, HD-tyrosine methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, D-tyrosine-methyl ester hydrochloride, methyl D-tyrosine ester hydrochloride, HD-tyrosine methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, HD-tyrosine methyl ester hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl)propionic acid, ( 2R)-2-amino-3-(4-hydroxyphenyl)methyl ester hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl)propionic acid methyl ester hydrochloride, (2R)-2-azanyl-3-(4-hydroxyphenyl)propionic acid methyl ester hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL-meta-tyrosine, DL-o-tyrosine, Boc-tyrosine (3,5-I2)-OSu, Fmoc-tyrosine (3-NO2)-OH, α-methyl-L-tyrosine, α-methyl-D-tyrosine or α-methyl-DL-tyrosine.

[0129] Aspect 9. The method of aspect 8, wherein the tyrosine hydroxylase inhibitor is α-methyl-DL-tyrosine.

[0130] Aspect 10. The method of any one of aspects 1 to 9, wherein the tyrosine hydroxylase inhibitor is administered orally.

[0131] Aspect 11. The method of any of the preceding aspects, wherein 100 to 1200 mg of the tyrosine hydroxylase inhibitor is administered daily.

[0132] Aspect 12. The method of aspect 11, wherein 200 to 900 mg of the tyrosine hydroxylase inhibitor is administered daily.

[0133] Aspect 13. The method of any of the preceding aspects, wherein the tyrosine hydroxylase inhibitor is administered in divided, substantially equal doses.

[0134] Aspect 14. The method of any of the preceding aspects, further comprising administering an effective amount of GABA.

[0135] Aspect 15. The method of any of the preceding aspects, further comprising administering an effective amount of serotonin or melatonin, or a pharmaceutically acceptable salt thereof.

[0136] Aspect 16. The method of any of the preceding aspects, further comprising administering an effective amount of vasopressin or a vasopressin analog.

[0137] Aspect 17. The method of aspect 16, wherein the vasopressin analog is desmopressin, felypressin, ornitropressin, celecoxib or terlipressin.

[0138] Aspect 18. The method of any of the preceding aspects, further comprising administering an effective amount of a compound that affects neurotransmission.

[0139] Aspect 19. The method of aspect 18, wherein the compound affecting neurotransmission is a psychotropic drug, a neurotransmitter reuptake inhibitor, a compound that stimulates glutaminergic transmission, or a compound that affects cholinergic, serotonergic, vasopressin, oxytocin or glutamate-regulated neurotransmission.

[0140] Aspect 20. The method of any of the preceding aspects, further comprising administering an effective amount of a beta-adrenergic agonist, a psychopharmacological drug, an anxiolytic, or an antidepressant.

[0141] Aspect 21. The method of Aspect 20, wherein the beta-adrenergic agonist is albuterol, levalbuterol, fenoterol, formoterol, isoproterenol, metaproterenol, salmeterol, terbutaline, clenbuterol, isotretol, pirbuterol, procaterol, ritodrine or epinephrine, or a pharmaceutically acceptable salt thereof.

[0142] Aspect 22. The method of Aspect 20, wherein the psychopharmacological drug is aripiprazole, pimavanserin, olanzapine, asenapine, clozapine, quetiapine, risperidone, lurasidone, cariprazine, paliperidone, epiprazole, iloperidone, ziprasidone or balovaptan, or a pharmaceutically acceptable salt thereof.

[0143] Aspect 23. The method of aspect 20, wherein the anxiolytic is a barbiturate, a carbamate, an antihistamine, an opioid, a benzodiazepine beta-blockers, tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mild sedatives, anticonvulsants, bupropion, or alpha-blockers.

[0144] Aspect 24. The method of Aspect 23, wherein the anxiolytic is hydroxyzine, chlorpheniramine, diphenhydramine, hydrocodone, fentanyl, buprenorphine, alprazolam, clonazepam, diazepam, lorazepam, oxazepam, chlordiazepoxide, propranolol, atenolol, imipramine, desipramine, nortriptyline, amitriptyline, doxepin, clomipramine, mirtazapine, trazodone, phenelzine, tranylcypromine, isocarboxazid, moclobemide, escitalopram, citalopram, venlafaxine, duloxetine, buspirone, valproate / ester, pregabalin, gabapentin, bupropion, prazosin, or a pharmaceutically acceptable salt thereof.

[0145] Aspect 25. The method of aspect 20, wherein the antidepressant is fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine or paroxetine, or a pharmaceutically acceptable salt thereof.

[0146] Aspect 26. A method of treating an anxiety-related disorder, the method comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor.

[0147] Aspect 27. The method of aspect 26, wherein the anxiety-related disorder is obsessive-compulsive disorder or social anxiety disorder.

[0148] Aspect 28. The method of aspect 27, wherein the anxiety-related disorder is obsessive-compulsive disorder.

[0149] Aspect 29. The method of Aspect 27, wherein the anxiety-related disorder is social anxiety disorder.

[0150] Aspect 30. A method of reducing anxiety, obsessive thoughts and behaviors, or compulsive behaviors, the method comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor.

[0151] Aspect 31. The method of aspect 30, wherein the method is used to reduce anxiety.

[0152] Aspect 32. The method of aspect 30, wherein the method is used to reduce obsessive thoughts or compulsive behaviors.

[0153] Aspect 33. The method of any one of Aspects 26 to 32, wherein the tyrosine hydroxylase inhibitor is (2R)-2-amino-3-(2-chloro-4-hydroxyphenyl)propionic acid methyl ester, D-tyrosine ethyl ester hydrochloride, (2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl)propionic acid methyl ester, HD-tyrosine (tBu)-allyl ester hydrochloride, (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(4-[ Methyl (2-chloro-6-fluorophenyl)methoxy]phenyl)propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl)propanoate, methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl)propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzylmalonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl)propanoate, methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propionate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propionate, H-DL-tyrosine methyl ester hydrochloride, H-3,5-diiodo-tyrosine methyl ester hydrochloride, HD-3,5-diiodo-tyrosine methyl ester hydrochloride, HD-tyrosine methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, D-tyrosine-methyl ester hydrochloride, methyl D-tyrosine ester hydrochloride, HD-tyrosine methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, HD-tyrosine methyl ester hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl)propionic acid, (2R)-2-amino-3-( 4-hydroxyphenyl) methyl ester hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid methyl ester hydrochloride, (2R)-2-azanyl-3-(4-hydroxyphenyl) propionic acid methyl ester hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-tyrosine (3,5-I2)-OSu, Fmoc-tyrosine (3-NO2)-OH, α-methyl-L-tyrosine, α-methyl-D-tyrosine, α-methyl-DL-tyrosine, or a C1-C2 derivative of α-methyl-DL-tyrosine. 12 Alkyl ester salts, for example α-methyl-DL-tyrosine methyl ester hydrochloride.

[0154] Aspect 34. The method of aspect 33, wherein the tyrosine hydroxylase inhibitor is α-methyl-DL-tyrosine.

[0155] Aspect 35. The method of any one of Aspects 26 to 34, wherein the tyrosine hydroxylase inhibitor is administered orally.

[0156] Aspect 36. The method of any one of Aspects 26 to 35, wherein 100 to 1200 mg of the tyrosine hydroxylase inhibitor is administered daily.

[0157] Aspect 37. The method of aspect 36, wherein 200 to 900 mg of the tyrosine hydroxylase inhibitor is administered daily.

[0158] Aspect 38. The method of any one of Aspects 26 to 37, wherein the tyrosine hydroxylase inhibitor is administered in divided, substantially equal doses.

[0159] Aspect 39. The method of any one of Aspects 26 to 38, further comprising administering an effective amount of GABA.

[0160] Aspect 40. The method of any one of Aspects 26 to 39, further comprising administering an effective amount of serotonin or melatonin, or a pharmaceutically acceptable salt thereof.

[0161] Aspect 41. The method of any one of Aspects 26 to 40, further comprising administering an effective amount of vasopressin or a vasopressin analog.

[0162] Aspect 42. The method of aspect 41, wherein the vasopressin analog is desmopressin, felypressin, ornitropressin, cerepressin or terlipressin.

[0163] Aspect 43. The method of any one of Aspects 26 to 42, further comprising administering an effective amount of a compound that affects neurotransmission.

[0164] Aspect 44. The method of Aspect 43, wherein the compound affecting neurotransmission is a psychotropic drug, a neurotransmitter reuptake inhibitor, a compound that stimulates glutaminergic transmission, or a compound that affects cholinergic, serotonergic, vasopressin, oxytocin or glutamate-regulated neurotransmission.

[0165] Aspect 45. The method of any one of Aspects 26 to 44, further comprising administering an effective amount of a beta-adrenergic agonist, a psychopharmacological drug, an anxiolytic, or an antidepressant.

[0166] Aspect 46. The method of Aspect 45, wherein the beta-adrenergic agonist is albuterol, levalbuterol, fenoterol, formoterol, isoproterenol, metaproterenol, salmeterol, terbutaline, clenbuterol, isotretol, pirbuterol, procaterol, ritodrine or epinephrine, or a pharmaceutically acceptable salt thereof.

[0167] Aspect 47. The method of Aspect 45, wherein the psychopharmacological drug is aripiprazole, pimavanserin, olanzapine, asenapine, clozapine, quetiapine, risperidone, lurasidone, cariprazine, paliperidone, epiprazole, iloperidone, ziprasidone or balovaptan, or a pharmaceutically acceptable salt thereof.

[0168] Aspect 48. The method of aspect 45, wherein the antianxiety drug is a barbiturate, a carbamate, an antihistamine, an opioid, a benzodiazepine beta-blockers, tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mild sedatives, anticonvulsants, bupropion, or alpha-blockers.

[0169] Aspect 49. The method of Aspect 48, wherein the anxiolytic is hydroxyzine, chlorpheniramine, diphenhydramine, hydrocodone, fentanyl, buprenorphine, alprazolam, clonazepam, diazepam, lorazepam, oxazepam, chlordiazepoxide, propranolol, atenolol, imipramine, desipramine, nortriptyline, amitriptyline, doxepin, clomipramine, mirtazapine, trazodone, phenelzine, tranylcypromine, isocarboxazid, moclobemide, escitalopram, citalopram, venlafaxine, duloxetine, buspirone, valproate / ester, pregabalin, gabapentin, bupropion, prazosin, or a pharmaceutically acceptable salt thereof.

[0170] Aspect 50. The method of Aspect 45, wherein the antidepressant is fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine or paroxetine, or a pharmaceutically acceptable salt thereof.

[0171] This application also relates to the following implementation schemes:

[0172] 1. A method for treating an anxiety-related disorder, the method comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor.

[0173] 2. The method of embodiment 1, wherein the anxiety-related disorder is obsessive-compulsive disorder or social anxiety disorder.

[0174] 3. The method of embodiment 2, wherein the anxiety-related disorder is obsessive-compulsive disorder.

[0175] 4. The method of embodiment 2, wherein the anxiety-related disorder is social anxiety disorder.

[0176] 5. A method of reducing anxiety, obsessive thoughts and behaviors, or compulsive behaviors, the method comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor.

[0177] 6. The method of embodiment 5, wherein the method is used to reduce anxiety.

[0178] 7. The method of embodiment 5, wherein the method is used to reduce obsessive thoughts or compulsive behaviors.

[0179] 8. The method of any one of embodiments 1 to 7, wherein the tyrosine hydroxylase inhibitor is (2R)-2-amino-3-(2-chloro-4-hydroxyphenyl)propionic acid methyl ester, D-tyrosine ethyl ester hydrochloride, (2R)-2-amino-3-(2,6-dichloro-3,4-dimethoxyphenyl)propionic acid methyl ester, HD-tyrosine (tBu)-allyl ester hydrochloride, (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(4-[(2- 2-(Acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzylmalonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl)propionate, methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl)propionate, diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl)oxy]benzylmalonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl)propionate, methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy- 4-methoxyphenyl)propionic acid methyl ester, (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl)propionic acid methyl ester, H-DL-tyrosine methyl ester hydrochloride, H-3,5-diiodo-tyrosine methyl ester hydrochloride, HD-3,5-diiodo-tyrosine methyl ester hydrochloride, HD-tyrosine methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, methyl D-tyrosine ester hydrochloride, HD-tyrosine methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, HD-tyrosine methyl ester hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl)propionic acid, (2R)-2-amino-3-(4 -hydroxyphenyl) methyl ester hydrochloride, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid methyl ester hydrochloride, (2R)-2-azanyl-3-(4-hydroxyphenyl) propionic acid methyl ester hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc-tyrosine (3,5-I2)-OSu, Fmoc-tyrosine (3-NO2)-OH, α-methyl-L-tyrosine, α-methyl-D-tyrosine, α-methyl-DL-tyrosine, or C1-C2 of α-methyl-DL-tyrosine 12 Alkyl ester salts, for example α-methyl-DL-tyrosine methyl ester hydrochloride.

[0180] 9. The method of embodiment 8, wherein the tyrosine hydroxylase inhibitor is α-methyl-DL-tyrosine.

[0181] 10. The method of embodiment 8, wherein the tyrosine hydroxylase inhibitor is administered orally.

[0182] 11. The method of embodiment 8, wherein 100 to 1200 mg of the tyrosine hydroxylase inhibitor is administered daily.

[0183] 12. The method of embodiment 11, wherein 200 to 900 mg of the tyrosine hydroxylase inhibitor is administered daily.

[0184] 13. The method of embodiment 8, wherein the tyrosine hydroxylase inhibitor is administered in divided, substantially equal doses.

[0185] 14. The method of embodiment 8, further comprising administering an effective amount of GABA.

[0186] 15. The method of embodiment 8, further comprising administering an effective amount of serotonin or melatonin, or a pharmaceutically acceptable salt thereof.

[0187] 16. The method of embodiment 8, further comprising administering an effective amount of vasopressin or a vasopressin analog.

[0188] 17. The method of embodiment 16, wherein the vasopressin analog is desmopressin, felypressin, ornitropressin, cerepressin, or terlipressin.

[0189] 18. The method of embodiment 8, further comprising administering an effective amount of a compound that affects neurotransmission.

[0190] 19. The method of embodiment 18, wherein the compound affecting neurotransmission is a psychotropic drug, a neurotransmitter reuptake inhibitor, a compound that stimulates glutaminergic transmission, or a compound that affects cholinergic, serotonergic, vasopressin, oxytocin or glutamate-regulated neurotransmission.

[0191] 20. The method of embodiment 8, further comprising administering an effective amount of a beta-adrenergic agonist, a psychopharmacological drug, an anxiolytic, or an antidepressant.

[0192] 21. The method of embodiment 20, wherein the beta-adrenergic agonist is albuterol, levalbuterol, fenoterol, formoterol, isoproterenol, metaproterenol, salmeterol, terbutaline, clenbuterol, isotretol, pirbuterol, procaterol, ritodrine, or epinephrine, or a pharmaceutically acceptable salt thereof.

[0193] 22. The method of embodiment 20, wherein the psychopharmacological drug is aripiprazole, pimavanserin, olanzapine, asenapine, clozapine, quetiapine, risperidone, lurasidone, cariprazine, paliperidone, epiprazole, iloperidone, ziprasidone or balovaptan, or a pharmaceutically acceptable salt thereof.

[0194] 23. The method of embodiment 20, wherein the antianxiety drug is a barbiturate, a carbamate, an antihistamine, an opioid, a benzodiazepine beta-blockers, tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mild sedatives, anticonvulsants, bupropion, or alpha-blockers.

[0195] 24. The method of embodiment 23, wherein the antianxiety drug is hydroxyzine, chlorpheniramine, diphenhydramine, hydrocodone, fentanyl, buprenorphine, alprazolam, clonazepam, diazepam, lorazepam, oxazepam, chlordiazepoxide, propranolol, atenolol, imipramine, desipramine, nortriptyline, amitriptyline, doxepin, clomipramine, mirtazapine, trazodone, phenelzine, tranylcypromine, isocarboxazid, moclobemide, escitalopram, citalopram, venlafaxine, duloxetine, buspirone, valproate / ester, pregabalin, gabapentin, bupropion, prazosin, or a pharmaceutically acceptable salt thereof.

[0196] 25. The method of embodiment 20, wherein the antidepressant is fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, or paroxetine, or a pharmaceutically acceptable salt thereof.

Claims

1. Use of a tyrosine hydroxylase inhibitor for the preparation of a medicament for treating anxiety-related disorders, wherein the anxiety-related disorder is generalized anxiety disorder or panic disorder, and the tyrosine hydroxylase inhibitor is α-methyl-L-tyrosine, α-methyl-D-tyrosine or α-methyl-DL-tyrosine, wherein the medicament is formulated for administering an effective amount of the tyrosine hydroxylase inhibitor to a subject in need thereof.

2. The method of claim 1, wherein the anxiety-related disorder is generalized anxiety disorder.

3. The use of claim 1, wherein the anxiety-related disorder is panic disorder.

4. Use of a tyrosine hydroxylase inhibitor for the preparation of a medicament for alleviating anxiety, obsessive-compulsive behavior or compulsive behavior in a patient diagnosed with an autism spectrum disorder, wherein the tyrosine hydroxylase inhibitor is α-methyl-L-tyrosine, α-methyl-D-tyrosine or α-methyl-DL-tyrosine, wherein the medicament is formulated for administering an effective amount of the tyrosine hydroxylase inhibitor to a subject in need thereof.

5. The use according to any one of claims 1 to 4, wherein the tyrosine hydroxylase inhibitor is α-methyl-DL-tyrosine.

6. The use of any one of claims 1 to 4, wherein the tyrosine hydroxylase inhibitor is formulated for oral administration.

7. The use of any one of claims 1 to 4, wherein the medicament is formulated for daily administration of 100 to 1200 mg of the tyrosine hydroxylase inhibitor.

8. The use of claim 7, wherein the medicament is formulated for daily administration of 200 to 900 mg of the tyrosine hydroxylase inhibitor.

9. The use of any one of claims 1 to 4, wherein the tyrosine hydroxylase inhibitor is formulated for administration in divided, substantially equal doses.