A method for diagnosing and treating a subject having a single nucleotide polymorphism at chromosome 2, locus 2:107,510,000-107,540,000.

Abstract

Methods and products for identifying individuals who are likely to have a positive (beneficial) or negative (adverse) response to pharmacological drug treatments intended to treat or prevent neuropsychiatric disorders, including but not limited to Alzheimer's disease, schizophrenia, autism and attention disorders, neurodegeneration, sleep-wake cycles, based on single nucleotide polymorphisms (SNPs) at chromosome 2, 2:107,510,000-107,540,000 locus (disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37)).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 187,078, filed May 11, 2021, which is hereby incorporated by reference in its entirety as part of this specification.

[0002] Sequence Listing Reference This application contains a sequence listing that has been submitted in electronic form. The "Sequence Listing" submitted electronically with this application in computer readable form (CRF) is entitled "2007-145_ST25.txt", was created on April 10, 2022, and is 4,096 bytes in size. The information in the Sequence Listing in electronic form is part of this application and is hereby incorporated by reference in its entirety as part of this specification.

[0003] Field of the Disclosure The present disclosure relates to methods for treating a subject, including improving mental and intellectual abilities in patients with a psychiatric disorder, based on a single nucleotide polymorphism at chromosome 2, locus 2:107,510,000-107,540,000, referred to as the 2:107,510,000-107,540,000 locus (as disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37)), and a predicted benefit or harm from administering a given pharmaceutical agent to the subject. [Background technology]

[0004] background The decline in memory, mental abilities, and intellectual abilities in patients with neurological and neurodegenerative diseases is notoriously difficult to understand and treat. Patients respond differently to treatment for mysterious and unknown reasons. Therefore, the symptoms and signs of patients suffering from such diseases remain inadequately addressed by medicine.

[0005] Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia in the elderly population. In people with advanced AD, distressing changes in memory, thinking, function, and behavior occur that worsen over time. These changes increasingly affect patients' daily lives, reducing their independence, and eventually these patients become completely dependent on others (Querfurth and LaFerla, 2010). Globally, it is estimated that approximately 50 million people suffer from dementia, with 10 million new cases occurring each year. Alzheimer's disease accounts for 60%-70% of these patients (who.int / news-room / fact-sheets / detail / dementia-dated September 21, 2020). Episodic memory is the most prominent impairment in early AD (Gold and Budson, 2008). With the growing elderly population, the number of early AD patients who progress to dementia is expected to nearly double every 20 years, affecting 115 million people by 2050 (Duthey, 2013). As the world's population continues to age, there is an urgent need for effective treatments for this devastating disease.

[0006] In the early, mild stages, AD symptoms include impairment of delayed recall, memory loss, and problems with concentration. In the intermediate, longest, moderate stage, symptoms include difficulty remembering events, difficulty organizing thoughts and actions to solve problems, impulsive behavior, shortened attention span, language problems, and possibly restlessness and / or agitation. In the later, severe stages, patients are unable to communicate and become completely dependent on others for care. AD progression is inevitable and leads to death within 5 to 10 years.

[0007] Among the various theories proposed to explain the pathophysiology of AD, oxidative stress induced by the deposition of amyloid beta protein (Aβ) has attracted much attention. Other theories include tau, apolipoprotein E (apoE) / lipid / lipoprotein receptors, neurotransmitter receptors, neurogenesis, inflammation, oxidative stress, cell death, protein homeostasis / proteinopathy, metabolism / bioenergetics, vasculature, growth factors, hormones, synaptic plasticity / neuroprotection, and epigenetics. Studies using postmortem brain samples from AD patients have consistently shown excessive lipid, protein and DNA oxidation. The presence of abnormal tau protein, mitochondrial dysfunction and protein hyperphosphorylation have all been demonstrated in neural tissues from AD patients. In addition, AD patients exhibit severe sleep / wake disorders and insomnia, which are associated with rapid cognitive decline and memory impairment. The cost of AD is increasing at an accelerating rate and is projected to reach $1 trillion worldwide in 2018 and $2 trillion in 2030. There is an urgent need for means to prevent, delay the onset, slow the progression, and ameliorate the symptoms of AD. Although there are medications available to attempt to alleviate the symptoms of Alzheimer's disease, such as decline in memory and attention, no drugs have been approved to alter the course of the disease.

[0008] Schizophrenia is a chronic mental illness that impairs multiple cognitive functions, including memory, thinking, perception, and will. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdrawal, reduced emotional expression, and apathy. Approximately 0.5% to 1% of the world's population is affected. There were an estimated 1.1 million new cases in 2017, with a total of 20 million cases worldwide in 2019. Patients aged 55 years or older will soon account for more than 25% of the total number of schizophrenia patients worldwide. In the United States, the prevalence of schizophrenia in older adults is expected to double by 2025, reaching 1.1 million. Older adults with schizophrenia include those with early onset and persisting into later life, and those with late onset symptoms. Elderly people with schizophrenia have significant cognitive impairments in executive function, processing speed, attention / vigilance, working memory, verbal learning, visual learning, reasoning, and problem solving. (Daban C,et al.J Psychiatr Res.2005;39:391-8,Schappi L,et al..Front Psychiatry.2018;9:129). It is difficult to distinguish schizophrenia from Alzheimer's disease with psychosis in elderly people (Radhakrishnan et al Advances in psychiatric treatment 2012,vol.18,144-153). It is intriguing that elderly people with schizophrenia and high anticholinergic drug burden show a cognitive impairment profile consistent with that observed in Alzheimer's dementia.

[0009] The causes of schizophrenia include genetic and environmental factors. Genetic factors include a variety of common and rare gene variants. Serotonin (5-HT) receptors have been suggested to play an important role in psychosis, cognitive function and mood through their effects on neurotransmitters, synaptic integrity and neuroplasticity. Specifically, genetic evidence suggests that single nucleotide polymorphisms (SNPs) in the 5-HT1A, 5-HT2A and 5-HT2C receptors are associated with psychotic symptoms, cognitive impairment and treatment response in schizophrenia (Sumiyoshi et al Adv Ther.2008;25(10):1037-1056.).

[0010] A rare copy number variation (deletion or duplication; CNV) in chromosome 2, region 2q12.2 (2:106992995-108507424 in GRCh37) (near or including locus 2:107,510,000-107,540,000) has been reported in 3 of 1656 (0.18%) patients with schizophrenia and 1 of 4036 (0.2%) healthy individuals (Magri et al PLos ONE 2010;5(Issue 10)e134222010, Kirov et al. Hum Mol Genet 2009;18:1497-1503., Need et al. PLoS Genet 2009;5:e1000373, Grozeva et al Arch Gen Psychiatry. 2010;67(4):318-327), has been suggested as a risk factor for susceptibility to schizophrenia, but has not been formally associated with schizophrenia or symptomatic Alzheimer's disease. None of the genes in the deleted segment have been implicated in schizophrenia. None of these publications disclose the highly proximal SNPs of the present invention and their high frequency (approximately 25%) in patients with early symptomatic Alzheimer's disease.

[0011] Autism or autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by persistent difficulties in social interaction and communication, as well as restricted interests and repetitive behaviors. ASD is typically diagnosed during the first 3 years of life and is manifested in characteristic symptoms and behavioral traits (core symptoms). The diagnosis of ASD now includes several conditions that were previously diagnosed separately: autistic disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome. All of these conditions are encompassed by the diagnostic criteria for autism spectrum disorder as outlined in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). In addition to the spectrum of symptoms seen with these major diagnostic criteria, individuals with autism may also experience co-occurring conditions such as depression, anxiety disorders, insomnia, behavioral disorders (e.g., irritability, hyperactivity, aggression), intellectual disability, epilepsy, and non-neurological comorbidities such as serum serotoninemia, immune dysregulation, and gastrointestinal (GI) dysfunction (e.g., chronic constipation, diarrhea, abdominal pain, gastroesophageal reflux disease).

[0012] Melatonin receptor agonists (e.g., melatonin, ramelteon, agomelatine, piromelatine) have been investigated for the treatment and prevention of neurodegenerative disorders including Alzheimer's disease, ischemic stroke, depression, schizophrenia, and autism spectrum disorder (ASD) (Srinivasan et al Int J Alzheimer's Dis 2010Dec 8;2011:741974, Wade et al Clin Interv Aging.2014Jun 18;9:947-61, Altinyazar and Kiylioglu Ther Adv Psychopharmacol.2016;6(4):263-268, US Patents No US8242163B2, Cho et al., Brain Research 755:335-338,1997; Reiter et al al., Exp. Biol. Med. 230:104-17, 2005, Norman and Olver Expert Opinion on Pharmacotherapy 2019,20:647-656, Morera-Fumero and Abreu-Gonzalez Int. J. Mol. Sci. 2013,14,9037-9050, Gagnon and Godbout Current Developmental Disorders Reports 2018;5:197-206). However, none of these have been shown to be clearly effective in such studies.

[0013] 5-HT1 receptor agonists have been investigated for enhancing cognitive function in schizophrenia (Sumiyoshi et al Adv Ther. 2008;25(10):1037-1056.), Alzheimer's disease (Verdurand and Zimmer, Neuropharmacology 2017;123:446-454), depression, anxiety and psychotic disorders (Celada et al CNS Drugs (2013;27:703-716)). However, the pharmaceutical industry has repeatedly failed to develop effective treatments for Alzheimer's disease and schizophrenia, with a series of recent failed products including pimavanserin, bitopertin, luvadaxistat, crenezumab, troriluzole, solanezumab, gantenerumab, semagacestat, avagacestat, verubecestat, atabecestat, and lanabecestat.

[0014] Thus, there exists a long-felt and compelling unmet need to provide products for treating memory, mental status and intellectual ability in subjects suffering from neurological and neurodegenerative diseases, including Alzheimer's disease, schizophrenia, attention disorders, ASD and related conditions. Summary of the Invention [Means for solving the problem]

[0015] SUMMARY OF THE PRESENT APPLICATION The present invention relates to a method for identifying a distinct subgroup of symptomatic Alzheimer's disease patients having a polymorphism at chromosome 2, 2:107,510,000-107,540,000 locus (disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37)), hereinafter referred to as the 2:107,510,000-107,540,000 locus, and for identifying predictors of response to treatment of a psychiatric disorder, particularly treatment aimed at improving intellectual ability in patients suffering from a psychiatric disorder, specifically predicting whether such patients will be harmed or benefited from administration of a particular pharmaceutical agent. The method also includes treating the patient according to the disclosed method based on the patient's identified genotype.

[0016] The present disclosure includes a method of identifying the genotype of a human subject suffering from a neurological disorder or disease, and then treating the human subject with an appropriate treatment.The present disclosure includes determining whether the human subject has a single nucleotide polymorphism (SNP) at chromosome 2:107,510,000-107,540,000 locus, and administering a melatonin / 5-HT1A receptor agonist to the human subject if a) the human subject is diagnosed with schizophrenia or autism spectrum disorder and has the SNP at chromosome 2:107,510,000-107,540,000 locus, or b) the human subject is diagnosed with symptomatic Alzheimer's disease and does not have the SNP at chromosome 2:107,510,000-107,540,000 locus.

[0017] The present disclosure includes a method of treating a patient diagnosed with symptomatic Alzheimer's disease and having a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, comprising administering to the patient an Alzheimer's disease therapeutic that is not a melatonin / 5-HT1A receptor agonist.

[0018] The present disclosure includes a method of treating a patient diagnosed with schizophrenia and having a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, comprising administering piromelatine to the patient.

[0019] The present disclosure provides a method for predicting a subject's response to a treatment comprising a melatonin / 5-HT1A receptor agonist by determining whether the subject has a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618. (i) predicting that if the subject has been diagnosed with symptomatic Alzheimer's disease and has a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, the subject will have a negative response to treatment comprising a melatonin / 5-HT1A receptor agonist. and (ii) predicting that the subject will show a positive response to treatment comprising a melatonin / 5-HT1A receptor agonist if the subject has been diagnosed with schizophrenia or an autism spectrum disorder and has a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618.

[0020] The present disclosure includes a method of assessing the risk of cognitive deterioration in a symptomatic Alzheimer's disease patient treated with melatonin / 5-HT1A receptor agonist therapy, comprising determining whether the patient has a SNP in at least one of rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, and determining that the subject is at risk of cognitive deterioration from administration of melatonin / 5-HT1A receptor agonist therapy if the patient has the SNP.

[0021] The present disclosure includes a method of improving attention and concentration in a subject with attention disorders associated with schizophrenia, attention deficit disorder, or autism spectrum disorder, comprising determining whether the subject has a SNP in at least one of rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, and administering a melatonin / 5-HT1A receptor agonist therapy to the subject if the patient has the SNP.

[0022] The present disclosure relates to a method of identifying a genotype that is prognostic of a subject's response to an agent for treating a psychiatric disorder and / or intellectual performance in a human subject, the method comprising determining the subject's genotype at at least one position of a single nucleotide polymorphism (SNP) selected from 2:107516926, and / or 2:107521253, and / or 2:107522069, and / or 2:107523546, and / or 2:107525598, and / or 2:107535946, and / or a single nucleotide polymorphism in linkage disequilibrium with any one of the foregoing SNPs, wherein said SNPs are disclosed in GRCh37, and the following: At least one C allele (T>C) at rs12328439; and / or At least one A allele (T>A) at rs62155556; and / or At least one T allele (G>T) at rs62155557; and / or At least one A allele (G>A) at rs62155558; and / or At least one G allele (A>G) at rs17033479; and / or The presence of at least one A allele (T>A) at rs9789618 is associated with The methods include those indicating that the subject will respond positively to a melatonin / 5-HT1A receptor agonist if the subject has been diagnosed with schizophrenia, attention disorder, or autism spectrum disorder, or indicating that the subject will respond negatively to a melatonin / 5-HT1A receptor agonist if the subject has been diagnosed with symptomatic Alzheimer's disease.

[0023] The present disclosure includes methods of administering a melatonin / 5-HT1A receptor agonist to a subject diagnosed with schizophrenia, attention disorder, or autism spectrum disorder.

[0024] The present disclosure includes a method of treating a patient suffering from schizophrenia, attention disorder, or autism spectrum disorder, comprising determining that the patient has a SNP in at least one of rs12328439, rs62155556, rs62155557, rs62155558, rs17033479, and rs9789618, and administering a melatonin / 5-HT1A receptor agonist to the subject.

[0025] In one embodiment, the subject is diagnosed with an autism spectrum disorder, Alzheimer's disease, schizophrenia, attention deficit disorder, or attention deficit and / or hyperactivity disorder.

[0026] In one embodiment, the subject has intellectual disability, epilepsy, anxiety disorder, mood disorder, impaired social interaction, irritability, aggression, self-injury, hyperactivity and / or inattention. In one embodiment, the subject has fragile X syndrome.

[0027] Other features and characteristics of the subject matter of the present disclosure, as well as its method of operation, function of related elements of structure and combination of parts, and economies of manufacture, will become more apparent from a consideration of the following description and appended claims, all of which are incorporated herein by reference. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 shows a flow chart of the method of the present disclosure.

[0029] [Figure 2-1] FIG. 2 shows chromosome 2, 2:107,510,000-107,540,000 locus (disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37)) (ncbi.nlm.nih.gov / genome / gdv / browser / genome / ?id=GCF_000001405.25). [Figure 2-2] Same as above.

[0030] [Diagram 3] FIG. 3 shows the wild-type DNA sequence and each of the SNPs rs12328439, rs62155556, rs62155557, rs62155558, rs17033479, and rs9789618 (as disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Detailed Description of the Invention Although aspects of the subject matter of the present disclosure may be embodied in a variety of forms, the following description is intended to disclose some of these forms merely as specific examples of the subject matter encompassed by the present disclosure, and therefore, the subject matter of the present disclosure is not intended to be limited to the described forms or embodiments.

[0032] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0033] As used herein and as is well understood in the art, the term "treat" or "treatment" refers to an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, reduction in the extent of disease, stable disease (i.e., not worsening), slowing or retarding disease progression, amelioration or palliation of disease, reduction in recurrence of disease, and remission (whether partial or complete). "Treat" or "treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. In addition to being useful as a treatment method, the methods described herein can be useful for prevention or prophylaxis of disease.

[0034] Concentrations, amounts and other numerical data may be expressed or presented in a range format herein. It should be understood that such range formats are used merely for convenience and brevity, and thus should be interpreted flexibly to include not only the numerical values ​​explicitly recited as the upper and lower limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were explicitly recited. For example, a numerical range of "about 0.01 to 2.0" should be interpreted to include not only the explicitly recited numerical value of about 0.01 to 2.0, but also the individual numerical values ​​and subranges within the indicated range. Thus, this numerical range includes individual numerical values ​​such as 0.5, 0.7 and 1.5, as well as subranges such as 0.5 to 1.7, 0.7 to 1.5, and 1.0 to 1.5. Moreover, such interpretation should be applied regardless of the breadth of the range or the properties being described. Furthermore, it should be noted that all percentages are by weight unless otherwise noted.

[0035] In understanding the scope of the present disclosure, as used herein, the terms "including" or "comprising" and their derivatives are intended to be open-ended terms specifying the presence of stated features, elements, components, groups, integers and / or steps, but not excluding the presence of other unstated features, elements, components, groups, integers and / or steps. The above also applies to terms having a similar meaning, such as the terms "including" and "having" and their derivatives. As used herein, the term "consisting" and its derivatives are intended to be closed terms specifying the presence of stated features, elements, components, groups, integers and / or steps, but excluding the presence of other unstated features, elements, components, groups, integers and / or steps. As used herein, the term "consisting essentially of" is intended to specify the presence of the recited features, elements, components, groups, integers, and / or steps, as well as the presence of those that do not materially affect the basic and novel characteristics of the features, elements, components, groups, integers, and / or steps. Reference to any one of these transitional phrases (i.e., "comprising," "consisting," or "consisting essentially of") is understood to directly support the substitution of the other transitional phrase not specifically used. For example, the modification of the term "comprising" to "consisting essentially of" can find direct support in this definition.

[0036] As used herein, the term "about" is used to provide flexibility to the endpoints of a numerical range by providing that a given value may be "a little above" or "a little below" the endpoint. The degree of flexibility of this term can be determined by the particular variable and will be within the ability of a person skilled in the art to determine based on experience and the relevant descriptions herein. For example, in one embodiment, the degree of flexibility may be within about ±10% of the numerical value. In another embodiment, the degree of flexibility may be within about ±5% of the numerical value. In further embodiments, the degree of flexibility may be within ±2%, ±1%, or ±0.05% of the numerical value.

[0037] Generally, in this specification the term "or" includes "and / or".

[0038] As used herein, a plurality of compounds, elements or steps may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, the individual members of such lists should not be construed as de facto equivalents of other members of the same list solely based on presentation in a common group, unless otherwise indicated.

[0039] Furthermore, certain compositions, elements, excipients, ingredients, disorders, conditions, properties, steps, etc. may be discussed in the context of one particular embodiment or aspect in separate paragraphs or sections of this disclosure. This is merely for convenience and brevity, and it is intended that such disclosures apply equally to and be combined with any other embodiment or aspect found in any of the present disclosure and claims, all of which form the present application and the claimed invention as filed. For example, a method step, active agent, kit or composition described with respect to a therapeutic agent or a method of treating a particular subject is intended to, and finds direct support for, embodiments relating to compositions, formulations, therapeutic active agents, and methods described in other parts of this disclosure, even if those method steps, active agents, kits, or compositions are not listed again in the context or section of that embodiment or aspect.

[0040] In a first aspect, the method of the present disclosure is based on the surprising paradoxical response of a subject to a methionine / 5-HT1A agonist agent based on the state of the disease / disorder diagnosed in the subject in combination with the subject's genotype.The inventors have identified six single nucleotide polymorphisms at the 2:107,510,000-107,530,000 locus that are independent predictors of the paradoxical (favorable or unfavorable) response of a subject to a methionine / 5-HT1A agonist agent treatment, where the favorable (i.e., beneficial) or unfavorable (i.e., harmful) treatment depends on the subject's diagnosed disease / disorder.In particular, the presence of one or more of these SNPs predicts favorable response to treatment in intellectual ability and neuropsychiatric measures, such as may be useful in schizophrenia, attention disorder and ASD patients, but at the same time, the presence of one or more of these SNPs is associated with unfavorable (harmful) response in neurodegeneration related to symptomatic Alzheimer's disease patients. Thus, the present disclosure provides novel and unexpected methods of using endophenotypic variations at the 2:107,510,000-107,530,000 locus and novel cognitive enhancing drugs.

[0041] The phrase "symptomatic Alzheimer's disease" refers to clinical manifestations of Alzheimer's disease symptoms in a subject.

[0042] Suitable melatonin and / or 5-HT1a receptor agonists for use in the present invention include, but are not limited to, compounds such as those described in U.S. Pat. Nos. 7,635,710, 8,569,355, 5,151,446; 5,318,994; 5,385,944; 5,403,851; and International Publication Nos. WO2007 / 093880A2 and WO2007 / 093880A3, which are hereby incorporated by reference in their entireties.

[0043] In one non-limiting exemplary embodiment, the present invention provides a compound having the following chemical formula (I): Ar-B-Ar'(I) [In the formula, B represents -XYZ-, X represents -(CH2)n- (wherein n is 0-6), where the alkyl moiety is linear or branched; Y represents oxygen, sulfur, >NH or is absent; Z represents >C=O, >O, >COO or is absent; where at least one of X, Y and Z must be present; Ar is the indole core ring system: [ka] Represents; Ar' is an alpha-, beta- or gamma-pyrone core ring system: [ka] Represents; Here, R 1-4 each of which substitutes the ring Ar at any available position (including the N-position); 1’-2’ each of which substitutes the ring Ar′ at any available position, where R 1-4 and R 1’-2’ each of which is independently hydrogen, oxygen, halo, halo-C 1-5 independently selected from alkyl, aryl, acyl; nitrogen, oxygen, or sulfur; 1-3 C containing heteroatoms 5-7 Heterocyclic groups; C containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur 6-8 Heteroaryl group; C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, Aryl-C 1-5 Alkyl, Aryl-C 2-5 Alkenyl, Aryl-C 2-5 Alkynyl, Hydroxy-C 1-5 Alkyl, nitro, amino, cyano, cyanamide, guanidino, amidino, acylamide, C 1-5 Alkylamines, C 1-5 Alkylamide, hydroxy, thiol, acyloxy, azide, C1-5 alkoxy, carboxy, carbonylamido, or styryl; wherein the arylalkyl, arylalkenyl, arylalkynyl, or styryl group is optionally selected from hydrogen, halo, halo-C 1-5 alkyl, aryl; C containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur 5-7 Heterocyclic groups; heteroaryl groups containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; C 1-5 Alkyl, C 2-5 Alkenyl, C 2-5 Alkynyl, Aryl-C 1-5 Alkyl, Aryl-C 1-5 Alkenyl, Aryl-C 2-5 Alkynyl, Hydroxy-C 1-5 may be ring substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, nitro, amino, cyano, cyanamido, guanidino, amidino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, S-alkyl, or alkylthiol; and either R3 or R4 may further comprise or represent a bond to B; wherein Ar can be bonded to B at any position on the Ar ring that is not substituted with R1 or R2, including the N-position, and Ar' can be bonded to B at any carbon on the Ar' ring that is not substituted with R1' or R2'. or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0044] As used herein, "aryl" refers to phenyl or naphthyl.

[0045] Without prejudice to the generality of the compounds of the invention, a subgroup of presently preferred compounds are those compounds of formula (I) in which X is -(CH)-, Y is >NH or >O, Z is >C=O, Ar is an indole containing a bond from R to X at the 3-position of the indole ring, R is a methoxy at the 5-position of the indole ring, each of R and R is hydrogen, and (a) Ar' is a gamma pyrone attached to Z at the 2-position of the pyrone ring, R 1’ is a hydrogen or hydroxyl group at the 5-position of the pyrone ring, and R 2’ is a hydrogen or carboxy group at the 6-position of the gamma pyrone ring, or (b) Ar' is an α-pyrone ring bonded to Z at the 5-position of the pyrone ring, and R 1’ and R 2’ are hydrogens at the 3-, 4-, or 6-positions of the pyrone ring, respectively, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0046] Also, as used herein, reference to "a" compound, salt, stereoisomer, or racemic mixture of formula (I) is intended to encompass "one or more" such compounds, salts, or stereoisomers. Further, reference to a "compound" of formula (I) is also intended to include a salt, stereoisomer, or racemic mixture of the compound, such as in the discussion of pharmaceutical formulations below.

[0047] In a preferred embodiment, X is -(CH2)n-, where n is any of 0-6, preferably any of 1-6, Y is >NH or >O, and Z is >CO.

[0048] Without prejudice to the generality of the compounds of the present invention, in a preferred embodiment of the compounds defined by formula (I) or a pharma- ceutically acceptable salt, stereoisomer, or racemic mixture thereof, X is -(CH2)2-, Y is >NH or >O, Z is >C=O, Ar is an indole containing a bond from R3 to X at the 3-position of the indole ring, R1 is a methoxy at the 5-position of the indole ring, each of R2 and R4 is hydrogen, Ar' is a gamma pyrone attached to Z at the 2-position of the pyrone ring, and R 1’ is a hydrogen or hydroxyl group at the 5-position of the pyrone ring, and R 2’ is a hydrogen or a carboxy group at the 6-position of the gamma pyrone ring. In a second preferred embodiment, Ar is as defined above, Ar' is an α-pyrone ring bonded to Z at the 5-position of the α-pyrone ring, and R 1’ and R 2’ is hydrogen; or a pharma- ceutically acceptable salt, stereoisomer, or racemic mixture thereof. Some exemplary compounds include, for example, N-[2-(1H-indol-3-yl)-ethyl]-coumanylamide, N-[2-(5-methoxy-indol-3-yl)-ethyl]-coumanylamide, and 2-methyl-4-oxo-4H-pyran-3-yl[2-(5-methoxy-1H-indol-3-yl)ethyl]carbamate.

[0049] Suitable pharmaceutically acceptable salts of the compound of formula (I) include, for example, the salts that can be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid.Pharmaceutically acceptable acids include, but are not limited to, hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, benzoic acid, tartaric acid, carbonic acid, phosphoric acid or sulfuric acid.Salts of amine groups can also include quaternary ammonium salts in which the amino nitrogen atom has an alkyl, alkenyl, alkynyl or aralkyl group.When a compound has an acidic group, for example, a carboxylic acid group, the present invention also contemplates its salts, preferably its non-toxic pharmaceutically acceptable salts, such as its sodium, potassium and calcium salts. Representative pharma- ceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiocyanate, thiocarbam ... Examples of suitable salts include, but are not limited to, phosphate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucoate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate.

[0050] In some embodiments, the functional groups of the compounds of formula (I) useful in the present invention may be modified to enhance the pharmacological availability of the compounds. Such modifications are well within the knowledge of one of ordinary skill in the art and include, but are not limited to, esters, amides, ethers, N-oxides, and prodrugs of the compounds of formula (I). Examples of modifications that can enhance the activity of the compounds of formula (I) include esterification, such as, for example, the formation of C1-C6 alkyl esters, preferably C1-C4 alkyl esters, where the alkyl group is linear or branched. Other acceptable esters include, for example, C1-C7 cycloalkyl esters and aryl alkyl esters, such as benzyl esters. Such esters can be prepared from the compounds described herein using conventional methods well known in the art of organic chemistry.

[0051] In embodiments where the compound of formula (I) useful in the present invention has at least one chiral center, it is understood that the compound can exist as chemically distinct enantiomers. Furthermore, when the compound has two or more chiral centers, the compound can exist as diastereomers. All such isomers and their mixtures are included within the scope of the indicated compound of formula (I). Similarly, when the compound has a structural arrangement that allows the structure to exist as a tautomer, such tautomers are included within the scope of the indicated compound. Furthermore, in crystalline form, the compound can exist as polymorphs; in the presence of a solvent, the compound can form solvates, for example, with water or common organic solvents. Such polymorphs, hydrates and other solvates are also included within the scope of the present invention as defined herein.

[0052] The present invention also includes within its scope pharmaceutical compositions comprising as active substance a therapeutically effective amount of a compound of formula (I) or a therapeutically effective amount of a salt thereof and any stereoisomer encompassed by formula (I), in association with one or more pharma- ceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients or carriers conventionally used in pharmaceutical and veterinary formulations. The pharmaceutical formulations of the invention may be adapted for administration to humans and / or animals.

[0053] The dosage of the active agent in the composition of the present disclosure may vary, provided that a therapeutic amount is administered. Such a therapeutic amount is generally the minimum dosage required to achieve the desired therapeutic effect, which may be, for example, the amount approximately required to alleviate symptoms of dementia, for example, to enhance episodic memory. Desirably, the active agent is administered at a dosage that provides optimal pharmaceutical efficacy to the patient (human or animal) in need of such treatment. The dosage selected depends on the nature and severity of the disease or disorder to be treated, the desired therapeutic effect, the route of administration, and the duration of treatment. The dosage will vary from patient to patient, depending on the nature and severity of the disease, the patient's body weight, the special diet that the patient will then follow, concomitant medications, the bioavailability of the compound when administered, and other factors that those skilled in the art will recognize. The therapeutic dose generally ranges from 0.1 to 1000 mg / day, for example, 0.1 to 500 mg / day, 0.5 to 500 mg / day, 0.5 to 100 mg / day, 0.5 to 50 mg / day, 0.5 to 20 mg / day, 0.5 to 10 mg / day, or 0.5 to 5 mg / day, and the actual dose is determined by a physician taking into account relevant circumstances such as the severity of dementia, the age and weight of the patient, the general condition of the patient, the cause of dementia, the route of administration, etc. In some embodiments, the therapeutically effective amount includes one or more doses per day that are 0.10 mg, 0.15 mg, 0.20 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, or 50 mg. As a non-limiting example, the compounds of the invention can be administered by repeated or continuous administration for at least 3 days, or for example, 3, 4, 5, 6, 7, 8, 9, or 10 days, or chronically. As a further example, the compounds can be administered multiple times per day, such as twice per day, three times per day, four times per day, or more.

[0054] The pharmaceutical compositions useful in the present invention include an active compound (i.e., a compound of formula (I)) and, if desired, can further include an excipient such as a pharma- ceutically acceptable carrier or diluent, which is any carrier or diluent that has no substantial long-term or permanent adverse effects when administered to a subject. Such excipients are generally mixed with the active compound or are allowed to dilute or encapsulate the active compound. The carrier can be a solid, semi-solid, or liquid agent that acts as an excipient or vehicle for the active compound. Examples of pharma-ceutically acceptable carriers and diluents include, but are not limited to, water, such as distilled water or deionized water; saline; and other aqueous media. It is understood that the active ingredient can be soluble or can be delivered as a suspension in the desired carrier or diluent.

[0055] The term "SNP" or "single nucleotide polymorphism" has its general meaning in the art and refers to a single nucleotide variation in a gene sequence that occurs with assessable frequency in a population. A single nucleotide variation can be a substitution, or an addition or deletion. There are millions of SNPs in the human genome. Most commonly, these variations are found in DNA segments between genes.

[0056] In accordance with the present invention, the term "genotype" refers to the 5' to 3' nucleotide sequence found at a set of one or more polymorphic sites at a locus on a single chromosome or on both chromosomes from a single individual.

[0057] According to the present invention, the term "biological sample" refers to any sample isolated from a patient from which DNA can be extracted. By way of example and not limitation, this may include body fluids and / or tissue extracts, such as homogenates or solubilized tissues obtained from a patient. Tissue extracts are routinely obtained from tissue biopsies and autopsies or oral / nasal mucus. Body fluids useful in the present invention include blood, urine, saliva, other body secretions or derivatives thereof.

[0058] As used herein, "blood" includes whole blood, isolated mononuclear cells / lymphocytes (nucleated T cells, B cells, natural killer cells and monocytes, respectively), plasma, serum, circulating epithelial cells, blood components, or any derivative of blood. In a preferred embodiment of the present invention, the sample to be tested is blood.

[0059] The term "patient responsiveness", "responder patient" or "responsive patient" refers to a patient who shows the desired response in disease (e.g., alleviation or slowing of progression of Alzheimer's disease or symptoms, or improvement of intellectual ability in schizophrenia) upon treatment. The severity of the disease can be measured according to the criteria of the general knowledge in the art (CGK).

[0060] Single nucleotide polymorphisms in chromosome 2, 2:107,510,000-107,540,000 locus (as disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37)) according to the present invention refer to one to six single nucleotide polymorphisms in chromosome 2; rs12328439 (2:107516926) and / or rs62155556 (2:107521253) and / or rs62155557 (2:107522069) and / or rs62155558 (2:107523546) and / or rs17033479 (2:107525598) and / or rs9789618 (2:107535946).

[0061] One embodiment of the present disclosure relates to an in vitro method for the identification of genomic loci predictive of responsiveness to pharmaceutical treatment in a patient suffering from a psychiatric disorder (e.g., Alzheimer's disease, ASD, schizophrenia, or attention disorder), comprising genotyping a single nucleotide polymorphism (SNP) at the chromosome 2, 2:107,510,000-107,540,000 locus in a biological sample obtained from the patient.

[0062] In some embodiments, the genotype of a patient is determined in a nucleic acid sample obtained from a biological sample from said patient. The nucleic acid sample can be obtained from any cell source or tissue biopsy. Non-limiting examples of available cell sources include, but are not limited to, blood cells, buccal cells, epithelial cells or fibroblasts. Cells can also be obtained from body fluids such as blood or lymph. DNA can be extracted using any method known in the art, for example as described in Dilhari et al., AMB Express volume 7,179,(2017).

[0063] SNPs can be detected in nucleic acid samples, preferably after amplification.For example, isolated DNA can be subjected to amplification by polymerase chain reaction (PCR) using oligonucleotide primers that are specific for one defined genotype or allow the amplification of the region containing the polymorphism of interest.In the first option, the conditions for primer annealing can be selected to ensure specific reverse transcription (if appropriate) and amplification; the appearance of the amplification product thereby diagnoses the presence of a specific genotype.In one embodiment, DNA can be amplified, and then genotypes can be determined in the amplified sequence by hybridization with a suitable probe or direct sequencing, or any other suitable method known in the art.

[0064] In some embodiments, the detecting step is carried out using allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, sequencing, 5' nuclease digestion, molecular beacon assay, oligonucleotide ligation assay (OLA), size analysis, single-stranded conformation polymorphism analysis (SSCP), or denaturing gradient gel electrophoresis (DGGE).

[0065] In some embodiments, the disclosure includes the use of an amplified polynucleotide that includes a SNP at a position defined herein, wherein the amplified polynucleotide is between about 16-1,000 nucleotides in length, e.g., 20-100 nucleotides in length.

[0066] In some aspects, the disclosure includes the use of isolated polynucleotides, or their complementary sequences, that specifically hybridize to nucleic acid molecules that contain a single SNP at a position defined herein.

[0067] In some embodiments, the isolated polynucleotide is an allele-specific probe, an allele-specific primer.

[0068] In some embodiments, the disclosure includes kits comprising a polynucleotide as defined herein, a buffer, and an enzyme, such as a DNA polymerase.

[0069] In some embodiments, the disclosure includes an allele-specific probe, and the enzyme is a ligase, and the 3' end of the allele-specific probe aligns with the SNP, and the kit further includes a second probe, which hybridizes to a segment of the nucleic acid molecule immediately adjacent 3' to the allele-specific probe.

[0070] In some embodiments, SNPs can be identified by using suitable DNA chip technology. Non-limiting examples include those described in EP1065280A2 and WO2002101094A1, which are hereby incorporated by reference in their entirety as part of this specification.

[0071] In one aspect, the disclosure includes a method in which administration of melatonin and or a 5-HT1A receptor agonist is contraindicated in patients suffering from symptomatic Alzheimer's disease, e.g., having a SNP at chromosome 2, 2:107,510,000-107,540,000 locus, e.g., 1-6.

[0072] In one embodiment, the disclosure includes a method of identifying the genotype of a human subject suffering from a neurological disorder or disease by determining whether the human subject has a single nucleotide polymorphism (SNP) at the 2:107,510,000-107,540,000 locus, and administering a melatonin / 5-HT1A receptor agonist to the human subject if: a) the human subject is diagnosed with schizophrenia or autism spectrum disorder and has the SNP at the 2:107,510,000-107,540,000 locus, or b) the human subject is diagnosed with symptomatic Alzheimer's disease and does not have the SNP at the 2:107,510,000-107,540,000 locus, and then treating the human subject with an appropriate treatment.

[0073] In one embodiment, if the human subject is diagnosed with symptomatic Alzheimer's disease and has a SNP at the 2:107,510,000-107,540,000 locus, the method further comprises administering to the subject a pharmaceutical agent for treating symptomatic Alzheimer's disease that is not a melatonin / 5-HT1A receptor agonist.

[0074] In one embodiment, if the human subject is diagnosed with schizophrenia or an autism spectrum disorder and does not have a SNP at the 2:107,510,000-107,540,000 locus, the method further comprises administering to the subject a pharmaceutical agent for treating schizophrenia or an autism spectrum disorder that is not a melatonin / 5-HT1A receptor agonist.

[0075] The determining step is carried out in vitro using a nucleic acid-containing sample obtained from the subject.

[0076] In one embodiment, the SNP is selected from 2:107516926 and / or 2:107521253 and / or 2:107522069 and / or 2:107523546 and / or 2:107525598 and / or 2:107535946, and / or a SNP in linkage disequilibrium with any one of the foregoing SNPs disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37), and a human subject having the SNP is At least one C allele (T>C) at rs12328439; and / or At least one A allele (T>A) at rs62155556; and / or At least one T allele (G>T) at rs62155557; and / or At least one A allele (G>A) at rs62155558; and / or At least one G allele (A>G) at rs17033479; and / or Having at least one A allele (T>A) at rs9789618.

[0077] In one embodiment, the subject's genotype at said SNP position is determined indirectly by determining the subject's genotype at a SNP position that is in linkage disequilibrium with said SNP position.

[0078] In one embodiment, the determining step comprises extracting and / or amplifying DNA from a sample obtained from the subject; and contacting the DNA with an array comprising a plurality of probes for determining the identity of at least one allele at a defined SNP position.

[0079] In one embodiment, the array is a DNA array, a DNA microarray or a bead array.

[0080] In one embodiment, the administering step comprises administering a pharmaceutical composition comprising N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide (piromelatine) and a pharma- ceutically acceptable carrier. [ka]

[0081] In one embodiment, the pharmaceutical composition contains 1-100 mg of piromelatine. In one embodiment, 5-100 mg, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of piromelatine is administered to the subject per day. In one embodiment, 20, 50, or 100 mg of piromelatine is administered.

[0082] In one embodiment, the method further comprises administering the pharmaceutical composition in combination therapy with an additional Alzheimer's disease therapeutic if the human subject is diagnosed with symptomatic Alzheimer's disease, or administering the pharmaceutical composition in combination therapy with an additional schizophrenia therapeutic if the human subject is diagnosed with schizophrenia, or administering the pharmaceutical composition in combination therapy with an additional autism spectrum disorder therapeutic if the human subject is diagnosed with autism spectrum disorder.

[0083] In one aspect, the disclosure includes treating a patient diagnosed with symptomatic Alzheimer's disease and having a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, comprising administering to the patient a therapeutic agent for symptomatic Alzheimer's disease that is not a melatonin / 5-HT1A receptor agonist.

[0084] In one embodiment, the disclosure includes treating a patient diagnosed with schizophrenia and having a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, comprising administering piromelatine to the patient.

[0085] In one embodiment, the disclosure includes predicting a subject's response to a treatment comprising a melatonin / 5-HT1A receptor agonist by determining whether the subject has a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, wherein the subject has been diagnosed with symptomatic Alzheimer's disease and has a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618. 3479 and / or rs9789618, the subject is predicted to have a negative response to treatment comprising a melatonin / 5-HT1A receptor agonist, and if the subject has been diagnosed with schizophrenia or autism spectrum disorder and has a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, the subject is predicted to have a positive response to treatment comprising a melatonin / 5-HT1A receptor agonist.

[0086] In one embodiment, the method includes obtaining a nucleic acid-containing sample from a subject and contacting the nucleic acid with an array comprising a plurality of probes suitable for determining the identity of at least one allele at a SNP position.

[0087] In one embodiment, the disclosure includes assessing the risk of cognitive deterioration in a symptomatic Alzheimer's disease patient treated with melatonin / 5-HT1A receptor agonist therapy, comprising determining whether the patient has a SNP in at least one of rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, and determining that if the patient has the SNP, the subject is at risk of cognitive deterioration from administration of melatonin / 5-HT1A receptor agonist therapy.

[0088] In one aspect, the disclosure includes improving attention and concentration in a subject with attention disorders associated with schizophrenia, attention deficit disorder, or autism spectrum disorder, comprising determining whether the subject has a SNP in at least one of rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, and administering a melatonin / 5-HT1A receptor agonist therapy to the subject if the patient has the SNP.

[0089] In one embodiment, the disclosure includes identifying a genotype that is prognostic of a subject's response to an agent for treating a psychiatric disorder and / or intellectual performance in a human subject, the method comprising determining the subject's genotype at at least one position of a single nucleotide polymorphism (SNP) selected from 2:107516926 and / or 2:107521253 and / or 2:107522069 and / or 2:107523546 and / or 2:107525598 and / or 2:107535946, and / or a SNP in linkage disequilibrium with any one of said SNPs, wherein said SNPs are disclosed in GRCh37; and at least one C allele (T>C) at rs12328439; and / or At least one A allele (T>A) at rs62155556; and / or At least one T allele (G>T) at rs62155557; and / or At least one A allele (G>A) at rs62155558; and / or At least one G allele (A>G) at rs17033479; and / or The presence of at least one A allele (T>A) at rs9789618 is associated with This includes identifying, if the subject has been diagnosed with schizophrenia, attention disorder, or autism spectrum disorder, which indicates that the subject will respond positively to a melatonin / 5-HT1A receptor agonist, or, if the subject has been diagnosed with symptomatic Alzheimer's disease, which indicates that the subject will respond negatively to a melatonin / 5-HT1A receptor agonist.

[0090] In one embodiment, the determining step is performed in vitro using a nucleic acid-containing sample obtained from the subject.

[0091] In one embodiment, the genotype of a subject at a SNP position is determined indirectly by determining the genotype of a subject at a SNP position that is in linkage disequilibrium with the SNP position.

[0092] In one embodiment, determining the subject's genotype at the SNP positions comprises: (i) extracting and / or amplifying DNA from a sample obtained from a subject; (ii) contacting the DNA with an array comprising a plurality of probes suitable for determining the identity of at least one allele at the position of the SNP.

[0093] All publications and patent documents cited in this specification are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any acknowledgement as to their contents or date. Although the invention has been described above in the detailed description of the invention, those skilled in the art will appreciate that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are intended to be illustrative, and not limiting, of the scope of the appended claims. EXAMPLES

[0094] Example 1 - Preparation of pyromelatine tablets (10,000 tablets per batch):

[0095] All ingredients were first sieved through a 30 mesh screen. Starch 1500 (binder and disintegrant, 375 grams) and pyromelatin (200 grams) were mixed in a V-blender for 5 minutes. Microcrystalline cellulose (filler / compression aid, 1550 grams) was added to the previously combined mixture and mixed in a V-blender for an additional 5 minutes to complete the internal phase. Microcrystalline cellulose (300 grams), colloidal silicon dioxide (flow agent, 37.5 grams) and magnesium stearate (lubricant, 37.5 grams) were separately combined in a V-blender as the external phase and mixed for 2 minutes. The two mixtures were then combined and mixed in a blender for 1 minute. The blend was compressed using a 6-station rotary tablet press equipped with an 8.0X16.0mm (2.0mm deep) oval concave die and punches.

[0096] Example 2

[0097] In a randomized, placebo-controlled trial of piromelatine (5, 20 and 50 mg per day for 6 months) in patients with early symptomatic Alzheimer's disease (n=352, age 60-85 years), no statistically significant differences were observed between drug and placebo treatments in intellectual performance as measured by the global composite score of the computerized Neuropsychological Test Battery (cNTB) and the Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog14, considered the gold standard for evaluating the efficacy of anti-dementia treatments). Surprisingly, however, it was found that patients showed a paradoxical response to the drug, with cNTB improving significantly whereas ADAS-Cog14 worsened.

[0098] DNA extraction and SNP genotyping were performed as follows: For 107 patients, whole blood was collected at enrollment and genomic DNA was extracted from peripheral lymphocytes using a commercial kit. Variant genotyping was performed by combining whole genome and whole exome sequencing. Detection of variants associated with response to treatment was performed by genome-wide association study (GWAS) analysis, which is a known case-control paradigm. This setting involves patients who responded to treatment as cases and patients who did not respond to treatment as controls. Common case-control allele testing was performed by Cochran-Armitage trend test. These results were cross-checked with potential confounding variables as stratification tests. Stratification was evaluated by complete-linkage hierarchical clustering with pairwise population matching as a constraint. SNP calling was performed on aligned BAM files using DRAGEN: support.illumina.com / help / DRAGEN_Germline_OLH_1000000083701 / Content / Source / Informatics / Apps / DRAGENGermlineSmallVarCaller_appDRAG.htm and VQSR: gatk.broadinstitute.org / hc / en-us / articles / 360035531612-Variant-Quality-Score-Recalibration-VQSR, to filter SNPs. The SNP caller program takes mapped and aligned DNA reads as input and calls SNPs and indels using a combination of column-wise detection and local de novo assembly of haplotypes. Callable reference regions are first identified with sufficient alignment coverage.Within these reference regions, a rapid scan of the sorted reads identifies active regions centered around pileup columns with variant evidence. Active regions are padded with sufficient context to cover significant nearby non-reference content, and further padded if there is evidence of indels.

[0099] result

[0100] In the GWAS of a representative sample of the study cohort, a specific subpopulation (27% of the sample) with 1-6 single nucleotide polymorphisms at chromosome 2, 2:107,510,000-107,540,000 locus, was identified in which piromelatine treatment resulted in a significant enhancement compared to baseline and a significant enhancement compared to placebo in the change from baseline in cNTB. However, in contrast to the cNTB results, we surprisingly found that piromelatine actually resulted in a worsening of ADAS-cog14 scores, suggesting worsening dementia in these patients (Table 1). In patients (73% of the sample) who were non-carriers of the 2:107,510,000-107,540,000 locus polymorphism, cNTB performance was on average poorer, but piromelatine treatment resulted in a significant improvement compared to placebo in ADAS-Cog14 (Table 1).

[0101] In a separate analysis, detection of six single nucleotide polymorphisms on chromosome 2; rs12328439 (T>C), rs6215556 (T>A), rs6215557 (G>T), rs6215558 (G>A), rs17033479 (A>G) and rs9789618 (T>A) was performed by a separate bioanalytical laboratory using bidirectional Sanger sequencing in a blinded evaluation of 11 extracted genomic DNA samples. The 11 samples were five carriers of the six SNPs, five non-carriers and one carrier of only the five SNPs (lacking the rs6215558 (G>A) SNP), representing the entire group of 107 samples analyzed in the GWAS approach. The retest results fully confirmed the presence or absence of the six SNPs determined by the GWAS approach. [Table 1]

[0102] In this study, to further explore the relationship between these paradoxical responses and other variables, the relationship between the change in ADAS-cog14 and other variables for the intermediate dose (20 mg) of piromelatine was analyzed (Table 2). In particular, it was found that the change from baseline in ADAS-cog14 for patients treated with 20 mg of piromelatine was contrasted between patients with and without the polymorphism (Table 2). Furthermore, in this study, 39% of patients who were non-carriers of the 2:107,510,000-107,540,000 locus polymorphism and received 20 mg of piromelatine showed an improvement (decrease) of 4 or more points on the ADAS-Cog14 and were considered "responders (beneficial response)," whereas only 8% of patients who were carriers of the 2:107,510,000-107,540,000 locus polymorphism and received 20 mg of piromelatine were responders (Table 2).

[0103] The main performance domains in the computerized neuropsychological test battery (cNTB) that improved when carriers of the 2:107,510,000-107,540,000 locus polymorphism were treated with a dose of 20 mg pyromelatine were the episodic memory domain composite score and the attention domain composite score. The main domain that worsened in the ADAS-cog14 test was difficulty in coordinating problem-solving thoughts and actions, a known difficulty in schizophrenia (Morris et al Schizophrenia Research 1995;14(Issue 3):235-246). In addition, the mean sleep quality index (PSQI) did not improve in carriers of the 2:107,510,000-107,540,000 locus polymorphism but improved in non-carriers, while the neuropsychiatric symptom assessment (neuropsychiatric inventory (NPI)) improved in carriers of the 2:107,510,000-107,540,000 locus polymorphism but not significantly in non-carriers. The improvement in the NPI in carriers of the 2:107,510,000-107,540,000 locus polymorphism was mainly due to improvement in abnormal movements, which are also commonly seen in schizophrenia (Schappi et al. Distinct Associations of Motor Domains in Relatives of Schizophrenia Patients-Different Pathways to Motor Abnormalities in Schizophrenia?. Front Psychiatry. 2018; 9: 129).

[0104] Surprisingly, the worsening of ADAS-cog14 in carriers of the 2:107,510,000-107,540,000 locus polymorphism was negatively correlated with the improvement of NPI (Table 2). On the other hand, the change in ADAS-cog14 in carriers of the 2:107,510,000-107,540,000 locus polymorphism was significantly correlated with the change in PSQI (both worsening), and the worsening of ADAS-Cog14 was associated with a paradoxical response in which the sleep-promoting effect of piromelatine led to sleep deprivation (Table 2). This association was not present in non-carriers. These findings suggest that the benefits of pyromelatine in carriers of the 2:107,510,000-107,540,000 locus polymorphism are more pronounced in the domains of intellectual ability, especially attention, and abnormal motor activity, and we assume that these patients' paradoxical response to the effects of melatonin / 5HT1 agonists will benefit patients with schizophrenia, ASD, and attention disorders in all of these areas. At the same time, we assume that if subjects with such SNP carriers suffer from Alzheimer's disease, such treatment will have a negative effect of reducing sleep quality, which will result in difficulties in successfully engaging in problem-solving thinking and behavior, which is also associated with schizophrenia. [Table 2]

[0105] Paradoxically, worsening ADAS-cog14 correlated significantly with improvement in NPI (Neuropsychiatric Symptom Index) and worse sleep quality.

[0106] The cognitive function improving effect of 20mg of pyromelatine in patients who are non-carriers of the 2:107,510,000-107,540,000 locus polymorphism using classical assessment tools such as the ADAS-cog14 scale was accompanied by an improvement in sleep quality. It is assumed that other melatonin / 5-HT1A agonists that activate the same receptors will cause similar responses. The binding data in Example 4 show that pyromelatine is an agonist of both receptors.

[0107] Example 3-2: Low-dose treatment of symptomatic AD patients who are carriers of the 107,510,000-107,540,000 locus polymorphism

[0108] In this study, to further explore the relationship between these paradoxical responses and other variables, we analyzed the changes in cNTB, ADAS-cog14 and PSQI for a low dose (5 mg) of pyromelatine (Table 3). Notably, patients with the polymorphism treated with 5 mg of pyromelatine showed no worsening or a tendency to improvement (Cohen's d>0.2) in ADAS-cog14 or PSQI (Table 3). However, only carriers of the 2:107,510,000-107,540,000 locus polymorphism showed improvement in the computerized neuropsychological test battery (cNTB) with treatment with a 5 mg dose of pyromelatine, with the main performance domains being the episodic memory domain composite score and the attention domain composite score. This finding suggests that patients with symptomatic Alzheimer's disease who are carriers of the 2:107,510,000-107,540,000 locus polymorphism may improve with low doses of piromelatine.

[0109] [Table 3]

[0110] Based on these results, the inventors assume that in this patient population of carriers of the 2:107,510,000-107,540,000 locus polymorphism and symptomatic AD patients, administration of pyromelatine and other melatonin / 5-HT1A agonists at doses up to half the clinically effective dose in non-carriers of the 2:107,510,000-107,540,000 locus polymorphism and symptomatic AD patients ("low dose" compositions), for example up to 10 mg, up to 8 mg, around 5 mg, will be effective. Other melatonin / 5-HT1A agonists that activate the same receptor are assumed to induce similar responses. The binding data in Example 4 show that pyromelatine is an agonist of both receptors.

[0111] Example 4 - Pyromelatin Binding Assay

[0112] For receptor binding assays, cells stably expressing 5-HT1a, 1b, 1d and 2c receptors (HEK-293, rat cerebral cortex, CHO and HEK-293, respectively) were incubated with 0.3 or 1 nM of each radioligand ( 3 H-OH-DPAT, 125 ICYP, 3 H serotonin and 3 H-mesullergine) alone or in the presence of 1 nM to 10 μM pyromelatine. Bound radioligand was measured. Nonspecific binding was assessed in reactions containing 8-OH-PTA, serotonin, and RS-10221 (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride).

[0113] For functional assays, Homogeneous Time Resolved Fluorescence (HTRF) was used to measure cAMP or IP1 as the product of functional agonist or antagonist binding of 5-HT1a, 2a, 2b, 2c, 4e, 6, and 7 with their respective ligands (8-OG-DPAT or serotonin). Cellular dielectric spectroscopy was used to measure impedance as the product of functional agonist or antagonist binding of 5HT1b with their respective ligands (serotonin).

[0114] In addition, a complete profile of binding parameters for 60 different ion channels and receptors for different neurotransmitters and hormones was performed (none of the 60 receptor assays yielded significant (>50%) inhibition by 10 μM pyromelatine, so data not shown).

[0115] result:

[0116] The results shown in Table 4 indicate that 5-HT is activated on specific 5-HT receptors. 1A , 5-HT 1B , 5-HT 2A , 5-HT 2C and 5-HT 2B 4 shows competition for piromelatine, which binds with low affinity to the receptor. [Table 4]

[0117] In functional assays, moderate agonist activity of piromelatine was detected for 5HT1a and 5-HT1d, and low agonist activity for 5-HT1b.

[0118] The results show that these melatonin / 5-HT1A,1D agonists induce responses similar to those of melatonin and serotonin in vitro. In addition, because these assays show less serotonergic activity at lower dose levels, we envision that the ratio between melatoninergic and serotonergic activity can be adjusted to obtain a desired treatment response.

[0119] Any of the above protocols or similar variations thereof may be described in various documents related to the pharmaceutical product. These documents may include, but are not limited to, protocols, statistical analysis plans, investigator brochures, clinical guidelines, medication guides, risk assessment and mediation programs, prescribing information, and other documents that may be related to the pharmaceutical product. It is specifically contemplated that such documents may be physically packaged with the pharmaceutical product according to the present disclosure as a kit, as may be beneficial or as required by regulatory authorities.

[0120] Although the subject matter of the present disclosure has been described and illustrated in some detail with reference to certain exemplary embodiments including various combinations and subcombinations of features, those skilled in the art will readily appreciate other embodiments and variations and modifications thereof as encompassed within the scope of the present disclosure. Moreover, the description of such embodiments, combinations and subcombinations is not intended to convey that the claimed subject matter requires features or combinations of features other than those expressly recited in the claims. Accordingly, the scope of the present disclosure is intended to include all modifications and variations encompassed within the spirit and scope of the following appended claims.

Claims

1. A method for identifying the genotype of a human subject suffering from a neurological disorder or disease and selecting an appropriate treatment. (i) determining whether a human subject has a single nucleotide polymorphism (SNP) at the 2:107,510,000-107,540,000 locus; and (ii) a) the human subject has been diagnosed with schizophrenia or an autism spectrum disorder and has a SNP at the 2:107,510,000-107,540,000 locus; or b) if the human subject has been diagnosed with symptomatic Alzheimer's disease and does not have a SNP at the 2:107,510,000-107,540,000 locus, determining to administer a melatonin / 5-HT1A receptor agonist to said human subject.

2. 2. The method of claim 1, further comprising the step of determining to administer to the subject a medication for treating Alzheimer's disease that is not a melatonin / 5-HT1A receptor agonist if the human subject has been diagnosed with symptomatic Alzheimer's disease and has a SNP at the 2:107,510,000-107,540,000 locus.

3. 2. The method of claim 1, further comprising determining to administer a melatonin / 5-HT1A receptor agonist to the subject if the human subject has been diagnosed with schizophrenia or an autism spectrum disorder and has a SNP at the 2:107,510,000-107,540,000 locus.

4. 2. The method of claim 1, further comprising the step of determining to administer to the subject a pharmaceutical agent for treating schizophrenia or an autism spectrum disorder that is not a melatonin / 5-HT1A receptor agonist if the human subject has been diagnosed with schizophrenia or an autism spectrum disorder and does not have a SNP at the 2:107,510,000-107,540,000 locus.

5. The method of claim 1, wherein step (i) is performed in vitro using a nucleic acid-containing sample obtained from a subject.

6. the SNP is selected from 2:107516926 and / or 2:107521253 and / or 2:107522069 and / or 2:107523546 and / or 2:107525598 and / or 2:107535946, and / or a SNP in linkage disequilibrium with any one of the foregoing SNPs disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37), and wherein 2. A human subject having a SNP: At least one C allele (T>C) in rs12328439; and / or At least one A allele (T>A) at rs62155556; and / or At least one T allele (G>T) at rs62155557; and / or At least one A allele (G>A) at rs62155558; and / or At least one G allele (A>G) in rs17033479; and / or The method of any one of claims 1 to 5, having at least one A allele (T>A) in rs9789618.

7. 7. The method of claim 6, wherein the genotype of the subject at the SNP position is determined indirectly by determining the genotype of the subject at a SNP position that is in linkage disequilibrium with the SNP position.

8. Step (i) comprises extracting and / or amplifying DNA from a sample obtained from a subject; and The following SNP positions: At least one C allele (T>C) in rs12328439; and / or At least one A allele (T>A) at rs62155556; and / or At least one T allele (G>T) at rs62155557; and / or At least one A allele (G>A) at rs62155558; and / or At least one G allele (A>G) in rs17033479; and / or 8. The method of claim 7, comprising contacting the DNA with an array comprising a plurality of probes for determining the identity of at least one allele in at least one A allele (T>A) in rs9789618.

9. The method of claim 8, wherein the array is a DNA array, a DNA microarray or a bead array.

10. A method according to any one of claims 1 to 5, wherein the step of deciding to administer a melatonin / 5-HT1A receptor agonist comprises a step of deciding to administer a pharmaceutical composition comprising pyromelatine and a pharma- ceutically acceptable carrier.

11. The method of claim 10, wherein the pharmaceutical composition comprises 1 to 100 mg of piromelatine.

12. The method of claim 11, wherein the pharmaceutical composition is for administration to a subject at a dose of 1 to 100 mg of piromelatine per day.

13. The method of claim 12, wherein the pharmaceutical composition is for administration to a subject at a dose of 5, 20 or 50 mg of piromelatine per day.

14. The method of claim 11, further comprising the step of determining to administer the pharmaceutical composition in combination therapy with an additional Alzheimer's disease therapeutic if the human subject is diagnosed with symptomatic Alzheimer's disease, or determining to administer the pharmaceutical composition in combination therapy with an additional schizophrenia therapeutic if the human subject is diagnosed with schizophrenia, or determining to administer the pharmaceutical composition in combination therapy with an additional autism spectrum disorder therapeutic if the human subject is diagnosed with autism spectrum disorder.

15. 1. A pharmaceutical composition comprising an Alzheimer's disease therapeutic agent that is not a melatonin / 5-HT1A receptor agonist for use in a method of treating a subject diagnosed with symptomatic Alzheimer's disease and having a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618.

16. A pharmaceutical composition comprising piromelatine for use in a method of treating a subject diagnosed with schizophrenia and having a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618.

17. 1. A method of predicting a subject's response to a treatment comprising a melatonin / 5-HT1A receptor agonist, comprising determining whether the subject has a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618; and (i) predicting that the subject will have a negative response to treatment comprising a melatonin / 5-HT1A receptor agonist if the subject has been diagnosed with symptomatic Alzheimer's disease and has a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618; and (ii) predicting that the subject will respond positively to treatment comprising a melatonin / 5-HT1A receptor agonist if the subject has been diagnosed with schizophrenia or an autism spectrum disorder and has a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618.

18. 18. The method of claim 17, comprising obtaining a nucleic acid-containing sample from a subject and contacting the nucleic acid with an array comprising a plurality of probes suitable for determining the identity of at least one allele at a SNP position described in claim 17.

19. 1. A method of assessing risk of cognitive deterioration in a symptomatic Alzheimer's disease subject being treated with melatonin / 5-HT1A receptor agonist therapy, comprising determining whether the subject has a SNP in at least one of rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, and determining that the subject is at risk of cognitive deterioration from administration of melatonin / 5-HT1A receptor agonist therapy if the subject has the SNP.

20. 1. A pharmaceutical composition comprising a melatonin / 5-HT1A receptor agonist for use in a method of improving attention and concentration in a subject with attention disorders associated with schizophrenia, attention deficit disorder, or autism spectrum disorder, said method comprising determining whether the subject has a SNP in at least one of rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, and administering to the subject the pharmaceutical composition if the subject has the SNP.

21. 1. A method of identifying a genotype for prognosis of a subject's response to an agent for treating a psychiatric disorder and / or intellectual performance in a human subject, the method comprising determining the subject's genotype at at least one position of a single nucleotide polymorphism (SNP) selected from 2:107516926 and / or 2:107521253 and / or 2:107522069 and / or 2:107523546 and / or 2:107525598 and / or 2:107535946, and / or a single nucleotide polymorphism in linkage disequilibrium with any one of the foregoing SNPs, wherein said SNPs are disclosed in GRCh37, and the following: At least one C allele (T>C) in rs12328439; and / or At least one A allele (T>A) at rs62155556; and / or At least one T allele (G>T) at rs62155557; and / or At least one A allele (G>A) at rs62155558; and / or At least one G allele (A>G) in rs17033479; and / or The presence of at least one A allele (T>A) in rs9789618 is A method indicating that the subject will respond positively to a melatonin / 5-HT1A receptor agonist if the subject has been diagnosed with schizophrenia, attention disorder, or autism spectrum disorder, or indicating that the subject will respond negatively to a melatonin / 5-HT1A receptor agonist if the subject has been diagnosed with symptomatic Alzheimer's disease.

22. 22. The method of claim 21, wherein the determining step is performed in vitro using a nucleic acid-containing sample obtained from the subject.

23. 22. The method of claim 21, wherein the genotype of the subject at the SNP position is determined indirectly by determining the genotype of the subject at a SNP position that is in linkage disequilibrium with the SNP position.

24. Determining the subject's genotype at the SNP positions, (i) extracting and / or amplifying DNA from a sample obtained from a subject; (ii) contacting the DNA with an array comprising a plurality of probes suitable for determining the identity of at least one allele at said SNP position; 22. The method of claim 21 , comprising:

25. 25. The method of claim 18 or 24, wherein the array is a DNA array, a DNA microarray or a bead array.

26. 22. The method of claim 21, further comprising the step of determining to administer a melatonin / 5-HT1A receptor agonist to a subject diagnosed with schizophrenia, attention disorder, or autism spectrum disorder.

27. 1. A pharmaceutical composition comprising a melatonin / 5-HT1A receptor agonist for use in a method of treating a subject suffering from symptomatic Alzheimer's disease, wherein the subject does not have any of the SNPs at rs12328439, rs62155556, rs62155557, rs62155558, rs17033479, and rs9789618.

28. 28. The pharmaceutical composition of claim 27, further comprising at least one additional Alzheimer's agent that is not a melatonin / 5-HT1A receptor agonist.

29. 1. A pharmaceutical composition comprising a melatonin / 5-HT1A receptor agonist for use in a method of treating a subject suffering from schizophrenia, attention disorder, or autism spectrum disorder, wherein the subject has a SNP at at least one of rs12328439, rs62155556, rs62155557, rs62155558, rs17033479, and rs9789618.

30. 30. The pharmaceutical composition of claim 29, further comprising at least one additional schizophrenia, attention disorder, or autism spectrum disorder therapeutic agent that is not a melatonin / 5-HT1A receptor agonist.

31. 2:107,510,000-107,540,000 locus, comprising the steps of genotyping a human subject for a SNP at the 2:107,510,000-107,540,000 locus, determining to exclude a human subject having at least one SNP at the 2:107,510,000-107,540,000 locus from administration of a medicament for treating dementia that is a melatonin / 5-HT1A receptor agonist if the human subject has been diagnosed with symptomatic Alzheimer's disease, and determining to treat the human subject with a medicament for treating dementia that is a melatonin / 5-HT1A receptor agonist if the human subject has been diagnosed with symptomatic Alzheimer's disease and does not have a SNP at the 2:107,510,000-107,540,000 locus.

32. 2:107,510,000-107,540,000 locus, wherein if the human subject has a SNP at the 2:107,510,000-107,540,000 locus and has been diagnosed with schizophrenia, autism spectrum disorder, or attention disorder, then treating the human subject with a melatonin / 5-HT1A receptor agonist medication for treating schizophrenia, autism spectrum disorder, or attention disorder. determining, if the human subject has been diagnosed with schizophrenia, autism spectrum disorder, or attention disorder and does not have the SNP at the 2:107,510,000-107,540,000 locus, to exclude the human subject who does not have the SNP at the 2:107,510,000-107,540,000 locus from administration of a medicament for treating schizophrenia, autism spectrum disorder, or attention disorder that is a melatonin / 5-HT1A receptor agonist.

33. 1. A method for genotyping and selecting an appropriate treatment for a population of human subjects diagnosed with symptomatic Alzheimer's disease, comprising: The method comprises: (i) identifying human subjects in the population having at least one single nucleotide polymorphism (SNP) at 2:107,510,000-107,540,000 and determining to exclude those human subjects from treatment with a melatonin / 5-HT1A receptor agonist; and (ii) identifying human subjects in the population that do not have at least one SNP in the 2:107,510,000-107,540,000 locus; A method comprising:

34. 34. The method of claim 33, further comprising determining to administer a melatonin / 5-HT1A receptor agonist to human subjects in the population that do not have at least one SNP in the 2:107,510,000-107,540,000 locus.

35. The human subject in (i) is At least one C allele (T>C) in rs12328439; and / or At least one A allele (T>A) at rs62155556; and / or At least one T allele (G>T) at rs62155557; and / or At least one A allele (G>A) at rs62155558; and / or At least one G allele (A>G) in rs17033479; and / or 34. The method of claim 33, having at least one A allele (T>A) in rs9789618.

36. 35. The method of claim 33 or 34, wherein the human subject in (ii) lacks the SNPs at 2:107516926, 2:107521253, 2:107522069, 2:107523546, 2:107525598, 2:107535946, and a SNP that is in linkage disequilibrium with any one of the preceding SNPs disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37).

37. 1. A method for genotyping and selecting an appropriate treatment for a population of human subjects diagnosed with schizophrenia, autism spectrum disorder, or attention disorder, the method comprising: (i) identifying human subjects in the population having at least one single nucleotide polymorphism (SNP) at 2:107,510,000-107,540,000; and (ii) identifying human subjects in the population that do not have at least one SNP in the 2:107,510,000-107,540,000 locus and determining to exclude those human subjects from treatment with a melatonin / 5-HT1A receptor agonist; A method comprising:

38. 38. The method of claim 37, further comprising determining to administer a melatonin / 5-HT1A receptor agonist to human subjects in said population having at least one SNP at the 2:107,510,000-107,540,000 locus.

39. The human subject in (i) is At least one C allele (T>C) in rs12328439; and / or At least one A allele (T>A) at rs62155556; and / or At least one T allele (G>T) at rs62155557; and / or At least one A allele (G>A) at rs62155558; and / or At least one G allele (A>G) in rs17033479; and / or 39. The method of claim 37 or 38, having at least one A allele (T>A) in rs9789618.

40. 38. The method of claim 37, wherein the human subject in (ii) lacks the SNPs at 2:107516926, 2:107521253, 2:107522069, 2:107523546, 2:107525598, 2:107535946, and a SNP that is in linkage disequilibrium with any one of the preceding SNPs disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37).

41. 1. A pharmaceutical composition comprising a melatonin / 5-HT1A receptor agonist for use in a method of treating a human subject suffering from a neurological disorder or disease, the method comprising: (i) identifying a human subject having a single nucleotide polymorphism (SNP) at the 2:107,510,000-107,540,000 locus; and (ii) administering to the human subject between 3 mg and 10 mg of a melatonin / 5-HT1A receptor agonist.

42. the SNP is selected from 2:107516926, and / or 2:107521253, and / or 2:107522069, and / or 2:107523546, and / or 2:107525598, and / or f2:107535946, and / or a SNP that is in linkage disequilibrium with any one of the foregoing SNPs disclosed in the Genome Reference Consortium, Human Genome Build 37 (GRCh37); wherein a human subject has a SNP: At least one C allele (T>C) in rs12328439; and / or At least one A allele (T>A) at rs62155556; and / or At least one T allele (G>T) at rs62155557; and / or At least one A allele (G>A) at rs62155558; and / or At least one G allele (A>G) in rs17033479; and / or 42. The pharmaceutical composition of claim 41, having at least one A allele (T>A) in rs9789618.

43. The pharmaceutical composition of claim 42, wherein the genotype of the subject at the SNP position is determined indirectly by determining the genotype of the subject at a SNP position that is in linkage disequilibrium with the SNP position.

44. The pharmaceutical composition of any one of claims 41 to 43, wherein the method comprises administering to a human subject 3 mg to 8 mg, 4 mg to 7 mg, 5 mg to 6 mg, or 5 mg of a melatonin / 5-HT1A receptor agonist.

45. The pharmaceutical composition according to any one of claims 20, 27, 29 and 41 to 43, wherein the melatonin / 5-HT1A receptor agonist is piromelatine.

46. The method described in claim 19 or 21, wherein the melatonin / 5-HT1A receptor agonist is pyromelatine.

47. 44. The pharmaceutical composition of any one of claims 41 to 43, wherein the melatonin / 5-HT1A receptor agonist is administered once daily.

48. The identifying step comprises extracting and / or amplifying DNA from a sample obtained from the subject; and At least one C allele (T>C) in rs12328439; and / or At least one A allele (T>A) at rs62155556; and / or At least one T allele (G>T) at rs62155557; and / or At least one A allele (G>A) at rs62155558; and / or At least one G allele (A>G) in rs17033479; and / or 44. The pharmaceutical composition of any one of claims 41 to 43, comprising a step of contacting the DNA with an array comprising a plurality of probes for determining the identity of at least one allele in at least one A allele (T>A) in rs9789618.

49. 49. The pharmaceutical composition of claim 48, wherein the array is a DNA array, a DNA microarray or a bead array.

50. The pharmaceutical composition of any one of claims 41 to 43, wherein the administering step comprises administering a pharmaceutical composition comprising piromelatine and a pharma- ceutically acceptable carrier.

51. 1. A pharmaceutical composition comprising a melatonin / 5-HT1A receptor agonist for use in a method of treating a subject diagnosed with symptomatic Alzheimer's disease and having a SNP selected from rs12328439 and / or rs62155556 and / or rs62155557 and / or rs62155558 and / or rs17033479 and / or rs9789618, the method comprising administering to the subject the melatonin / 5-HT1A receptor agonist at a dose of between 3 mg and 10 mg per day.

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