New method

Abstract

The present disclosure provides a method for the treatment of mental disorders caused by viral, bacterial or autoimmune encephalitis, and for the treatment of the psychiatric symptoms of viral, bacterial and autoimmune encephalitis, and for the protection or enhancement of the blood-brain barrier, the method comprising administering to a patient in need of said treatment or said protection or enhancement a therapeutically effective amount of 5-HT 2A . The present disclosure provides a method comprising administering a therapeutically effective amount of 5-HT to a patient in need of said treatment or said protection or enhancement.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority and the benefit of U.S. Provisional Patent Application No. 63 / 343,192, filed on May 18, 2022, the content of which is hereby incorporated by reference in its entirety into this specification.

[0002] Technical Field The present disclosure relates to the use of free form, pharmaceutically acceptable salt form or prodrug form of 5 - HT 2A or 5 - HT 2A / D2 receptor ligands, such as the substituted heterocyclic - fused γ - carbolines described herein, for the treatment of mental disorders caused by viral, bacterial or autoimmune encephalitis, and for the treatment of mental symptoms of viral, bacterial and autoimmune encephalitis, and for the protection or enhancement of the blood - brain barrier.

Background Art

[0003] Background of the Invention Substituted heterocyclic - fused γ - carbolines, such as lumateperone, are known to be 5 - HT 2A or 5 - HT 2A / D2 receptor ligands. These compounds are serotonin - 2A (5 - HT 2A)Antagonize receptors and / or modulate dopamine receptor signaling at the level of major intracellular phosphoproteins. These compounds are known to be useful primarily for the treatment of the positive and negative symptoms of schizophrenia. At the dopamine D2 receptor, these compounds have a dual nature and act both as postsynaptic antagonists and presynaptic partial agonists. They also specifically stimulate the phosphorylation of the glutamatergic NMDA NR2B or GluN2B receptor in the mesolimbic system. This local selectivity in brain regions thought to mediate the efficacy of antipsychotics, together with serotonergic, glutamatergic, and dopaminergic interactions, is thought to result in antipsychotic efficacy against the positive, negative, affective, and cognitive symptoms associated with schizophrenia. The compounds also exhibit serotonin reuptake inhibition and provide antidepressant activity for the treatment of schizoaffective disorder and co-morbid depression and / or as a stand-alone treatment for major depressive disorder. The described 5-HT 2A or 5-HT 2A / D2 receptor ligands are also useful for the treatment of bipolar disorder and other mental and neurodegenerative disorders, particularly the behavioral disorders associated with dementia, autism, and other CNS diseases. These characteristics can improve the quality of life of patients with schizophrenia, enhance social functioning, and allow the patient to more fully integrate into the patient's family and workplace. These compounds exhibit differential dose-dependent effects, selectively targeting the 5-HT 2A receptor at low doses, while interacting gradually with the D2 receptor at high doses. As a result, they are effective at low doses for the treatment of sleep, aggression, and agitation. They can treat acute exacerbation and residual type schizophrenia, bipolar disorder, and mood disorders at high doses.

[0004] Formula:

Chemical formula

[0005] Lumateperone and related compounds are described in U.S. Patent Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; Reissue Patent Invention No. 39,680, and Reissue Patent Invention No. 39,679 for conditions related to anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual disorders, migraine, headache, and social phobia, etc., 5-HT 2AIt is disclosed as a novel compound useful for the treatment of disorders related to receptor regulation. International Publication No. WO 2000 / 077002 and US Patent No. 7,071,186 also disclose methods for producing substituted heterocyclic-fused γ-carbolines, and the use of these γ-carbolines as serotonin agonists and antagonists useful for the control and prevention of central nervous system disorders such as addictive behavior and sleep disorders. International Publication No. WO 2009 / 145900 and US Patent No. 8,598,119, and International Publication No. WO 2013 / 155504 and US Patent No. 11,053,245, and International Publication No. WO 2013 / 155506 and US Patent No. 11,124,514 (each incorporated herein by reference) disclose the use of certain substituted heterocyclic-fused γ-carbolines for the treatment of combinations of psychiatric and depressive disorders, and sleep disorders, depressive disorders and / or mood disorders in psychiatric patients or patients with Parkinson's disease, for the treatment of post-traumatic stress disorder, impulse control disorders and related disorders, and for the treatment or prevention of disorders related to dementia, particularly behavioral or mood disorders such as agitation, irritability, reckless / aggressive behavior, anger, physical or emotional outbursts, and psychiatric and sleep disorders related to dementia. International Publication No. WO 2009 / 114181 and US Patent No. 8,648,077 (each incorporated herein by reference) disclose a method for producing a toluenesulfonic acid addition salt crystal of a certain substituted heterocyclic-fused γ-carboline, such as the toluenesulfonic acid addition salt of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone.

[0006] International Publication No. 2011 / 133224 and U.S. Patent No. 8,993,572 (each incorporated herein by reference) disclose prodrugs / metabolites of substituted heterocyclic-fused γ-carbolines for improved formulations, e.g., for sustained-release / controlled-release formulations. This application discloses that a heterocyclic-fused γ-carboline N-substituted by a 4-fluorophenyl(4-hydroxy)butyl moiety has high selectivity for the serotonin transporter (SERT) compared to a heterocyclic-fused γ-carboline containing 4-fluorophenylbutanone.

[0007] International Publication No. 2009 / 145900 and U.S. Patent No. 8,598,119 also disclose that selected substituted heterocyclic-fused γ-carboline compounds have nanomolar affinity for the serotonin reuptake transporter (SERT) and are thus selective serotonin reuptake inhibitors.

[0008] As disclosed in International Publication No. 2015 / 154025, U.S. Patent Application Publication No. 2017 / 0183350, U.S. Patent No. 10,077,267, International Publication No. 2017 / 165843, U.S. Patent Application Publication No. 2019 / 0231780, U.S. Patent No. 10,688,097, International Publication No. 2019 / 183546, and U.S. Patent Application Publication No. 2021 / 0008065 (each incorporated herein by reference), deuterated forms of lumateperone and related compounds have been shown to have improved metabolic stability.

[0009] International Publication No. WO 2019 / 178484 and US Patent Application Publication No. US 2021 / 0060009 (the entire content of each is incorporated herein by reference) disclose the use of lumateperone and related analogs for the treatment of acute depression and acute anxiety. Unlike conventional antidepressants, including selective serotonin reuptake inhibitors (SSRI) such as sertraline (Zoloft, Lustral), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac), paroxetine (Seroxat), and citalopram (Celexa), which generally take weeks or months to achieve full effect (SSRI usually take effect 3 - 4 weeks after starting daily administration), lumateperone is thought to exert efficacy within a short period of one week and also achieve immediate onset of action (e.g., within hours to days after the first dose). In this regard, lumateperone and its analogs share the functional advantages of ketamine. Ketamine has recently been tested as a rapid - acting antidepressant for treatment - resistant depression in bipolar disorder and major depressive disorder, but has significant side effects and a high risk of overdose and is not orally active. Lumateperone, alone or in combination with other anxiolytics or antidepressants, is promising as an orally administrable and immediate - acting treatment for depression and anxiety disorders, such as the treatment of acute depression and acute anxiety, which has the immediate - onset property characteristic of ketamine but is not accompanied by the side effects or lack of oral activity of ketamine. These actions are thought to be mediated through the activation of the mTOR (e.g., mTORC1) signaling pathway and, in parallel with anti - inflammatory properties, through the indirect enhancement of dopamine D1 receptor - dependent NMDA and AMPA currents.

[0010] Furthermore, unlike benzodiazepine-class drugs, lumateperone and related compounds are thought to be non-toxic and are thus particularly suitable for the treatment of acute depressive episodes, including suicidal ideation, severe acute depression, and / or severe acute anxiety. Lumateperone has already been approved by the US FDA as a treatment for schizophrenia and bipolar disorder under the trade name Caplyta®, and is in clinical trials as a treatment for major depressive disorder and other disorders.

[0011] Immunological disorders have been reported in subsets of patients suffering from generalized anxiety disorder, major depressive disorder (MDD) and / or schizophrenia. See, for example, Mechawar & Savitz, “Neuropathology of mood disorders: do we see the stigmata of inflammation?” Translational Psychiatry 6:e946-e946 (2016); Zhang et al., “Brain-derived Neurotrophic Factor (BDNF)-TrkB Signaling in Inflammation-related Depression and Potential Therapeutic Targets,” Curr. Neuropharmacol. 14:721-731 (2016); Herman & Pasinetti, “Principles of inflammasome priming and inhibition: Implications for psychiatric disorders,” Brain Behav. Immun. 73:66-84 (2018); Beurel et al., “The Bidirectional Relationship of Depression and Inflammation: Double Trouble,” Neuron 107:234-256 (2020). Furthermore, exposure to infectious agents and subsequent enhanced immune activity can also lead to transient depressive symptoms (e.g., anhedonia, fatigue, hypersomnia and depressive mood). See, for example, Nazimek et al., “The role of macrophages in anti-inflammatory activity of antidepressant drugs,” Immunobiology 222:823-830 (2017); Beurel et al., (2020).This concept is supported by studies in which the direct administration of inflammatory agents induced stress-like and / or depressive-like effects in patients or animals (Mechawar & Savitz, 2016), and studies showing that adverse symptoms are reversed by the direct blockade of specific immune pathways such as interleukin (IL)-1β (Koo & Duman, “IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress,” Proc. Nat. Acad. Sci. USA 105:751-756 (2008); Koo & Duman, “Evidence for IL-1 receptor blockade as a therapeutic strategy for the treatment of depression,” Curr. Opin, Invest. Drugs 10:664-671 (2009)).

[0012] Viral infection and mental illness have long been suspected to be related. As early as the late 1800s, it was pointed out that influenza epidemics were temporally associated with an increase in mental illness. More recently, evidence has suggested that chronic inflammation of the central nervous system (CNS) is often associated with mental states. To date, there have been several studies suggesting a causal relationship between viral infections of the CNS, including herpes simplex 1 and 2 and measles, and mental symptoms, including depression and schizophrenia. Some mental illnesses that were not previously suspected of having an infectious component have even been suggested to be examples of very mild encephalitis.

[0013] One of the most common causes of viral encephalitis is the herpes simplex virus (HSV). Important research has been conducted to examine the psychological outcomes of HSV encephalitis, and as a result, a significant number of HSV patients have been shown to develop neuropsychological impairments such as attention, executive function, retrograde memory, working memory, and visual-spatial processing impairments, as well as mood disorders including depression and anxiety. Some of these effects are known to persist long after the acute phase of the infection. It has also been shown that some of these impairments correlate with brain damage visible on MRI, such as medial temporal lobe damage.

[0014] West Nile virus (WNV) infections can be associated with neuroinvasive disease, causing encephalitis or meningitis. In such patients, depression has been reported as a prominent outcome. A study following WNV survivors for eight years showed a higher-than-expected rate of mild to severe depression in patients with no prior history of depression.

[0015] In the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), a new category of "psychopathological conditions due to general medical conditions" was introduced, including delirium, dementia, amnesia, psychosis, mood disorders (e.g., depression), anxiety disorders, sexual dysfunction, and sleep disorders. These are associated with severe infectious diseases such as bacterial or viral encephalitis and meningitis.

[0016] Inflammatory cytokines such as TNFα and IL-6 are mainly secreted from peripheral monocytes and macrophages and are also thought to be secreted from CNS microglial cells. These cytokines activate other cellular components of the inflammatory response to infection. Furthermore, the anti-inflammatory cytokines IL-4 and IL-10 are also secreted from monocytes and macrophages and probably from microglial cells as well. C-reactive protein (CRP) is a general marker of ongoing inflammatory responses. Recent evidence has shown that major depressive disorder (MDD) is also associated with higher levels of TNFα, IL-6, IL-1β, IL-2 and interferon γ. Furthermore, interferon α has been shown to induce severe depressive symptoms including suicidality in about one-third of patients. However, it is not clear whether this inflammatory state is the cause or the effect of MDD.

[0017] During the past 20 years, it has been discovered that a major cause of encephalitis is an autoimmune reaction against nerve proteins, particularly against NMDA receptors and leucine-rich glioma 1 (LGL-1) receptor proteins. This autoimmune encephalitis (AIE) presents with various neurological and psychiatric symptoms including amnesia, confusion, epileptic seizures, agnosia and mood disorders. At least 10 synaptic anti-neuronal and anti-glial antibodies have been identified and there are likely to be many more. The mainstay of AIE treatment remains intravenous immunoglobulin therapy to remove autoimmune antibodies such as rituximab.

[0018] 5-HT 2A or 5-HT 2A / D2 receptor ligands are known to be useful for the treatment of schizophrenia, including the acute treatment of depression or anxiety, and mood disorders such as depression and anxiety, but the compounds have not heretofore been suggested or disclosed for the treatment of mental disorders caused by encephalitis or for the treatment of the emotional symptoms of encephalitis.

[0019] There is an urgent need for new and improved methods for the treatment of mental disorders caused by viral, bacterial or autoimmune encephalitis, as well as for the treatment of the psychiatric symptoms of viral, bacterial and autoimmune encephalitis. There is also an urgent need for new and improved methods for the protection and strengthening of the blood-brain barrier.

SUMMARY OF THE INVENTION

[0020] Brief Summary of the Invention We have surprisingly found that the substituted heterocyclic-fused γ-carbolines described herein, particularly lumateperone, are effective in reducing abnormally elevated levels of pro-inflammatory cytokines in both the brain and serum, altering key pathways involved in tissue integrity and maintenance of the blood-brain barrier (BBB), conferring anxiolytic and antianhedonic properties in rats, and enhancing BBB protection during inflammatory and stress challenges. This suggests that the compound is effective in the treatment of mental disorders caused by viral, bacterial or autoimmune encephalitis, as well as in the treatment of the psychiatric symptoms of viral, bacterial and autoimmune encephalitis.

[0021] Thus, the present disclosure provides a method for the treatment of mental disorders caused by viral, bacterial or autoimmune encephalitis, as well as for the treatment of the psychiatric symptoms of viral, bacterial and autoimmune encephalitis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a (i) 5-HT 2A or 5-HT 2A / D2 receptor ligand, such as a substituted heterocyclic-fused γ-carboline in free base form, pharmaceutically acceptable salt form or prodrug form, as described herein.

[0022] In another aspect, the present disclosure provides a method for the protection or strengthening of the blood-brain barrier, the method comprising administering to a patient in need thereof a (i) 5-HT 2A or 5-HT2A A method is provided that includes administering a therapeutically effective amount of a D2 receptor ligand, such as a substituted heterocyclic-fused γ-carboline in free base form, pharmaceutically acceptable salt form, or prodrug form as described herein.

[0023] In some embodiments, the present disclosure further provides the above method that includes concurrent administration of a PDE1 inhibitor, such as a compound represented by Formula II disclosed herein. The compound is disclosed, for example, in U.S. Patent No. 9,545,406 as being useful in the treatment of central nervous system diseases, disorders and injuries, and as a neuroprotective agent and / or a neuroregenerative agent (the description thereof is incorporated herein by reference in its entirety). The compound is further disclosed, for example, in International Publication No. WO 2018 / 049417 as being useful in the treatment of diseases and disorders characterized by neuroinflammation (the description thereof is incorporated herein by reference in its entirety). DETAILED DESCRIPTION

[0024] Detailed Description Lumateperone is a therapeutic agent that binds potently to the 5-HT 2A receptor (Ki = 0.5 nM) and moderately to the D1 and D2 receptors and the serotonin transporter (SERT). Functionally, receptor binding can generally result in either agonist activity, partial agonist activity, or antagonist activity. Lumateperone is a 5-HT 2AIt has been found to exhibit potent antagonist activity at receptors and SERT, and agonist / antagonist mixed activity at D1 and D2 receptors (depending on cell type). In particular, lumateperone has activity as a mesolimbic / mesocortical selective dopamine receptor protein phosphorylation modulator consistent with presynaptic D2 receptor partial agonism and postsynaptic D2 receptor antagonism (Ki = 32 nM) in vivo, high D1 receptor affinity (Ki = 52 nM), and inhibition of serotonin transporter (SERT) activity (Ki = 26 - 62 nM, using different assays for SERT activity). Lumateperone also indirectly enhances NMDA-mediated and AMPA-mediated neurotransmission (Titulaer et al., “Lumateperone increases glutamate release in the rat medial prefrontal cortex,” Eur. Neuropsychopharmacol. 53:S556 - S557 (2022)). Lumateperone is approved as a treatment for schizophrenia and bipolar depression in the United States and is being studied as a treatment for major depressive disorder, agitation in dementia including Alzheimer's disease, and other mental disorders.

[0025] Unexpectedly, it has been found that lumateperone has the potential to relieve pathological levels of inflammation in the brain, microglia, and serum, and to maintain the integrity of the BBB after immunological challenge and stress in rodents. Lumateperone reduces major pro-inflammatory markers that are elevated by inflammogens (e.g., lipopolysaccharide, LPS) or acute restraint stress when administered at various doses at various time points. Strikingly, the cytokines IL-1β, IL-6, and TNFα, which are normalized by lumateperone treatment, are known to be elevated in patients with mental disorders and in human postmortem tissues including the prefrontal cortex from suicide victims.

[0026] Lumateperone treatment reduces the expression of the Nlrp3 inflammasome, a large multi - protein complex that includes NLRP3, a cytoplasmic sensor involved in innate immunity. The inflammasome has no baseline activity, but when activated by stress, infection, or other stimuli, this complex is thought to generate the active forms of the inflammatory cytokines IL - 1β and IL - 18. In pre - clinical studies, Nlrp3 null mutant mice have been reported to be resilient to the effects of stress on depressive - like behavior, and increased expression of Nlrp3 has been observed in peripheral blood mononuclear cells (PBMCs) from untreated MDD patients.

[0027] This disclosure has shown that lumateperone treatment reduces Nlrp3 transcript levels under conditions that induce pathological inflammation, which may partly contribute to the antidepressant - like effects of lumateperone. Furthermore, lumateperone has been shown to have anxiolytic - like effects and reverse anhedonia in rats.

[0028] Stress and inflammation are thought to impair the integrity and functionality of the BBB in many pathological conditions. The BBB protects brain tissue from harmful substances while regulating ion and nutrient exchange between the brain and the blood. BBB dysfunction can lead to chemical exposure and infections, and there are reports suggesting that the BBB may be impaired in patients with mental disorders such as schizophrenia or depression, or neurodegenerative diseases such as Alzheimer's disease (there is sufficient evidence to demonstrate BBB disruption in these diseases).

[0029] The present disclosure provides evidence of an increase in the RNA copy number of hippocampal Cldn5 in naive mice administered lumateperone 2 hours prior to measurement, and confirms these results in the brains of acute stress mice or LPS-treated mice. Claudins such as Cldn5 are small proteins (20-27 kDa) expressed at tight junctions between brain endothelial cells and serve to maintain the integrity of the BBB. In mice, Cldn5 disruption enhances BBB permeability and allows the infiltration of large proteins (e.g., IL-6) up to about 69 kD into the brain parenchyma; this result is associated with depressive-like behaviors and behavioral impairments characteristic of schizophrenia and depression. Thus, lumateperone-mediated upregulation of Cldn5 gene expression is consistent with the enhanced protein expression observed in mice treated with other chronic antipsychotics or antidepressants. Chronic, but not acute, imipramine treatment rescued social avoidance and restored Cldn5 levels altered by social defeat stress, whereas acute lumateperone treatment was unexpectedly effective in improving a similar behavioral state.

[0030] This finding highlights another potential difference between classical antidepressant treatment and lumateperone treatment. Since a decrease in sodium fluorescein (NaFl) brain uptake and differences in anti-inflammatory cytokine expression between the central nervous system and periphery have been observed, it is theorized that Cldn5 changes early after lumateperone administration, resulting in maintenance of BBB integrity and limitation of the infiltration of large proteins (e.g., IL-6), infectious agents, and other potential inflammatory stimuli into the CNS. Furthermore, TNFα / NFκ-B signaling increases BBB permeability by decreasing the expression of the tight junction protein Cldn5.

[0031] Classical antidepressants have also been reported to modulate the levels of ICAM-1 involved in leukocyte brain infiltration and increased BBB permeability. The levels of ICAM-1, a cell adhesion molecule and a member of the immunoglobulin gene superfamily, have been shown to increase in the orbitofrontal cortex of depressed patients. The present disclosure shows that lumateperone acutely decreases Icam1 expression in preclinical models. These findings are also consistent with the literature showing that ICAM1 upregulation promotes leukocyte migration through the endothelium and vessel wall that regulate the BBB. Taken together, the results described herein suggest that lumateperone modulates a repertoire of signaling networks involved in various biological processes related to the maintenance of BBB integrity and controls detrimental inflammatory states.

[0032] Increased BBB integrity is known to activate microglia and result in changes in microglial phenotype. In the CNS, microglia are an important component of the local brain immune response. Here, it is disclosed that in an acute inflammatory condition, lumateperone significantly increases the expression of genes related to microglial physiological function and anti-inflammatory phenotype, and decreases the expression of microglial markers related to immune regulation. Unexpectedly, abundant hippocampal microglia were shown to recapitulate the anti-inflammatory response seen in whole brain homogenates. One of the genes overexpressed in the hippocampus from LPS-treated mice was Csf1. This gene encodes a ligand for the microglial receptor CSF1R, which is involved in maintaining microglial viability and immunological surveillance. The increase in Csf1 expression induced by LPS was found to be significantly decreased by co-administration of lumateperone. Furthermore, the results described herein show that lumateperone upregulates the anti-inflammatory cytokine IL-10, which may contribute to the repertoire of mechanisms of inflammation resolution after abnormal levels of stress and inflammation, perhaps by affecting microglial function. Overall, the data described herein indicate that the ability of lumateperone to alter microglial gene expression and decrease Csf1 gene expression after an inflammatory challenge can prevent the activation of microglial function after exposure to an inflammatory stimulus.

[0033] Stress and factors that induce neuroinflammation are strongly implicated in the etiology of a diverse range of brain diseases, including neurodegenerative disorders, psychiatric disorders (e.g., schizophrenia), and mood disorders (e.g., bipolar disorder, depression, and anxiety). Many infectious agents, including herpes simplex virus 1 and 2, Epstein–Barr virus, and cytomegalovirus (CMV), can be elevated in individuals with psychiatric conditions, including bipolar disorder and schizophrenia. Furthermore, viruses such as CMV can contribute to psychiatric pathology, in part, by directly elevating pro-inflammatory cytokines, including TNFα and IL-6. Coronaviruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19) infection, can induce a hyperimmune response (cytokine storm) that can trigger psychiatric episodes in infected patients, although the exact triggering event (e.g., stress or the virus itself) remains unclear. However, the ability of the SARS-CoV-2 virus to cross the BBB in mice and the human olfactory mucosa supports potential routes / mechanisms of viral entry into brain tissue and is worthy of note. Thus, without being bound by theory, therapeutic agents with anti-inflammatory effects, such as lumateperone and its analogs, may provide additional benefits in normalizing abnormal neuroinflammatory events and, particularly with respect to maintaining BBB integrity, in reducing the impact on brain dysfunction.

[0034] Unconstrained by theory, BBB perturbation is thought to underlie the development of various mental disorders, including schizophrenia, autism spectrum disorder (ASD), and mood disorders. Increased BBB permeability is a common factor in these disorders and is thought to increase the infiltration of peripheral substances into the brain, leading to neuroinflammation and oxidative stress. Loss of BBB integrity is a prominent early pathological feature of neuroinflammatory disorders. BBB permeability increases in response to many pro-inflammatory stimuli, such as lipopolysaccharide, tumor necrosis factor α (TNFα), IL-6, MCP-1, and IL-1β, and is accompanied by concomitant downregulation of tight junction proteins such as claudin 5 (Cldn5). In response to danger signals, brain endothelial cells become activated and are characterized by upregulation of the expression of cell adhesion molecules such as ICAM-1 and VCAM-1 and downregulation of claudin 5, promoting leukocyte invasion into the CNS and promoting the immune response. Thus, measurement of the presence, absence, or concentration of these various biomarker signals can indicate the presence of neuroinflammation and breakdown of BBB integrity.

[0035] In certain embodiments, the disclosure is a method for treating mental disorders caused by viral, bacterial, or autoimmune encephalitis, as well as for treating the psychiatric symptoms of viral, bacterial, and autoimmune encephalitis, the method comprising administering to a patient in need thereof a 5-HT 2A or 5-HT 2A / D2 receptor ligand, for example, in deuterated form, which may be in free base form, pharmaceutically acceptable salt form, or prodrug form, of formula I: [wherein, X is -N(H)-, -N(CH3)- or -O-; Y is -C(=O)-, -C(H)(OH)- or -C(H)(OR1)-; R1 is -C(O)-C alkyl (e.g., -C(O)-C 1-21 alkyl (e.g., -C(O)-C1-5 alkyl, -C(O)-C 6-15 alkyl or -C(O)-C 16-21 alkyl), preferably, the alkyl is linear, may be saturated or unsaturated, and may be substituted with one or more hydroxy or C 1-22 alkoxy (e.g., ethoxy) groups, for example, R1 is -C(O)-C6 alkyl, -C(O)-C7 alkyl, -C(O)-C9 alkyl, -C(O)-C 11 alkyl, -C(O)-C 13 alkyl or -C(O)-C 15 alkyl) administering a therapeutically effective amount of a compound represented by formula (wherein the compound hydrolyzes to form a residue of a natural or non-natural, saturated or unsaturated fatty acid, for example, the compound hydrolyzes to form a hydroxy compound on one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand), a method (Method 1). For example, Method 1 may be as follows:

[0036] 1.1. Method 1, wherein X in the compound represented by formula I is -N(H)-, -N(CH3)- or -O-;

[0037] 1.2. Method 1 or 1.1, wherein X in the compound represented by formula I is -N(H);

[0038] 1.3. Method 1 or 1.1, wherein X in the compound represented by formula I is -N(CH3)-;

[0039] 1.4. Method 1 or 1.1, wherein X in the compound represented by formula I is -O-;

[0040] 1.5. Method 1, or any one of formulas 1.1 to 1.4, wherein Y in the compound represented by formula I is -C(=O)-, -C(H)(OH)- or -C(H)(OR1)-;

[0041] 1.6. In the compound represented by formula I, Y is -C(=O)-, Method 1, or any of formulas 1.1 to 1.4;

[0042] 1.7. In the compound represented by formula I, Y is -C(H)(OH)-, Method 1, or any of formulas 1.1 to 1.4;

[0043] 1.8. In the compound represented by formula I, Y is -C(H)(OR1)-, Method 1, or any of formulas 1.1 to 1.4;

[0044] 1.9. In the compound represented by formula I, R1 is -C(O)-C 1-21 alkyl (for example, -C(O)-C 1-5 alkyl, -C(O)-C 6-15 alkyl or -C(O)-C 16-21 alkyl), preferably, the alkyl is linear, may be saturated or unsaturated, and may be substituted with one or more hydroxy or C 1-22 alkoxy (for example, ethoxy) groups. For example, R1 is -C(O)-C6 alkyl, -C(O)-C7 alkyl, -C(O)-C9 alkyl, -C(O)-C 11 alkyl, -C(O)-C 13 alkyl or -C(O)-C 15 alkyl, where the compound hydrolyzes to form residues of natural or non-natural, saturated or unsaturated fatty acids. For example, the compound hydrolyzes to form a hydroxy compound on one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand; for example, here, in the compound represented by formula I, R1 is -C(O)-C 6-15 alkyl, for example, -C(O)-C9 alkyl; or in the compound represented by formula I, R1 is -C(O)-C 1-5 alkyl, for example, -C(O)-C3 alkyl, Method 1, or any of 1.1 to 1.5 or 1.8;

[0045] 1.10. The compound represented by formula I is [Chemical] which is Method 1, or any one of 1.1 to 1.5 or 1.7;

[0046] 1.11. The compound represented by Formula I is [Chemical] which is Method 1, or any one of 1.1 to 1.5 or 1.7;

[0047] 1.12. The compound represented by Formula I is lumateperone: [Chemical] which is Method 1, or any one of 1.1, 1.3, 1.5 or 1.6;

[0048] 1.13. The compound represented by Formula I is in the form of a pharmaceutically acceptable salt, for example, in the form of tosylate, Method 1, or any one of 1.1 to 1.12, for example, Method 1.12;

[0049] 1.14. The compound represented by Formula I is in the form of a free base, Method 1 or any one of 1.1 to 1.12, for example, Method 1.12;

[0050] 1.15. The compound represented by Formula I is in a deuterated form, for example, the deuterium:protium ratio of specific carbon-bonded hydrogen atoms is significantly higher than the natural isotope ratio, for example, at least 2 times, for example, at least 10 times higher, Method 1, or any one of 1.1 to 1.14;

[0051] 1.16. The compound represented by Formula I is, for example, in the form of a free base or a pharmaceutically acceptable salt form, for example, tosylate form [Chemical] [wherein D represents a hydrogen position that substantially exceeds natural deuterium incorporation (i.e., substantially exceeds 0.0156%), for example, exceeds 60%, or exceeds 70%, or exceeds 80%, or exceeds 90%, or exceeds 95%, or exceeds 96%, or exceeds 97%, or exceeds 98%, or exceeds 99%] Method 1.15, which is a deuterated form of lumateperone selected from;

[0052] 1.17. 5-HT 2A or 5-HT 2A Any of the above methods, wherein the 5-HT / D2 receptor ligand is administered in an amount corresponding to a daily dose of 1 to 100 mg of the free base, for example, an amount corresponding to 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of the free base, in free base form or in a pharmaceutically acceptable salt form, such as tosylate form, of the compound of formula I;

[0053] Method 1.17, wherein the method comprises once-daily oral administration of a unit dosage form for oral administration, such as a tablet or capsule, comprising a compound of formula I in free base form or in a pharmaceutically acceptable salt form, such as tosylate form, in an amount corresponding to 1 to 100 mg of the free base, for example, an amount corresponding to 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg, or 1 to 5 mg, or 40 to 60 mg, or 20 to 40 mg, or 10 to 20 mg, or about 60 mg, or about 40 mg, or about 30 mg, or about 20 mg, or about 10 mg, or about 5 mg of the free base, and a pharmaceutically acceptable diluent or carrier;

[0054] 1.19. A method comprising once-daily administration of a unit dosage form for transmucosal administration, such as a sublingual or buccal orally disintegrating tablet, a wafer or a film, comprising a compound of formula I in free base form or in a pharmaceutically acceptable salt form, such as tosylate form, in an amount corresponding to 0.5 to 30 mg of the free base, for example 1 to 30 mg, or 1 to 20 mg, or 1 to 15 mg, or 1 to 10 mg, or 20 to 30 mg, or 10 to 20 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg of the free base, and a pharmaceutically acceptable diluent or carrier; Method 1.17;

[0055] 1.20. Any of the above methods, wherein the condition to be treated is alleviated within one week, for example within 3 days, for example within 1 day;

[0056] 1.21. Any of the above methods, wherein the method is a method for treating mental disorders caused by viral, bacterial or autoimmune encephalitis;

[0057] 1.22. Any of the above methods, wherein the method is a method for treating mental symptoms of viral, bacterial and autoimmune encephalitis;

[0058] 1.23. Method 1.21 or 1.22, wherein the encephalitis is viral encephalitis;

[0059] 1.24. Method 1.23, wherein the encephalitis is caused by or suspected of being caused by herpes simplex virus type 1, herpes simplex virus type 2, West Nile virus, Nipah virus, human immunodeficiency virus, rabies virus, Epstein-Barr virus, cytomegalovirus, coronavirus (e.g., MERS-CoV, SARS-Cov, SARS-Cov2), or influenza virus (e.g., influenza A virus, e.g., H1N1, H2N2, H3N2, H5N1, H7N7);

[0060] 1.25. Method 1.23 or 1.24, wherein the patient has acute viral encephalitis;

[0061] 1.26. The method of 1.21 or 1.22, wherein the encephalitis is bacterial encephalitis;

[0062] 1.27. The method of 1.26, wherein the encephalitis is caused by or is suspected of being caused by toxoplasmosis, rickettsia, mycoplasma, borrelia (e.g., Lyme disease), or malaria;

[0063] 1.28. The method of 1.21 or 1.22, wherein the encephalitis is autoimmune encephalitis;

[0064] 1.29. The method of 1.28, wherein the encephalitis is caused by or is suspected of being caused by autoantibodies against NMDA receptor, AMPA receptor, voltage-gated potassium channel (VGKC), LGL1 protein, GABA receptor, glycine receptor, glutamate receptor, or CASPR2 receptor;

[0065] 1.30. Any of the above methods, wherein the mental disorder and / or mental symptoms are depression (e.g., acute depression, depression in MDD, depression in bipolar disorder), anxiety (e.g., acute anxiety), psychosis (e.g., schizophrenia), post-traumatic stress disorder, anhedonia, memory loss, impairment of executive functioning, difficulty in concentration, seizure, sleep difficulty, hallucination, personality change, or a combination thereof;

[0066] 1.31. Any of the above methods, wherein the mental disorder and / or mental symptoms are depression (e.g., acute depression, depression in MDD, depression in bipolar disorder);

[0067] 1.32. Any of the above methods, wherein the mental disorder and / or mental symptoms are anxiety (e.g., acute anxiety);

[0068] 1.33. Any of the above methods, wherein the mental disorder and / or mental symptoms are anhedonia;

[0069] 1.34. Any of the above methods, wherein the patient has been diagnosed as having suicidal thoughts and / or suicidal tendencies;

[0070] 1.35. Any of the above methods, wherein the patient has no history of mental disorders or mental symptoms;

[0071] 1.36. 5-HT 2A or 5-HT 2A / D2 receptor ligand is administered in combination with a therapeutically effective amount of an anxiolytic or antidepressant (e.g., a fixed combination in unit dosage form, or a free combination administered sequentially or simultaneously or within 24 hours), any of the above methods;

[0072] 1.37. The anxiolytic or antidepressant is one or more compounds in free base form or pharmaceutically acceptable salt form selected from selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA) and atypical antipsychotics, e.g., (a) Selective serotonin reuptake inhibitors (SSRI), e.g., Citalopram (Celexa), Escitalopram (Lexapro, Cipralex), Paroxetine (Paxil, Seroxat), Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft, Lustral); (b) Serotonin–norepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella), tofenacin (Elamol, Tofacine), venlafaxine (Effexor); (c) Tricyclic antidepressants (TCAs), for example, Amitriptyline (Elavil, Endep), Amitriptyline Oxide (Amioxid, Ambivalon, Equilibrin), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Pipofezine (Azafen / Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil)); (d) Compounds selected from benzodiazepines, such as 2-keto compounds (e.g., chlorazepate, diazepam, flurazepam, halazepam, prazepam); 3-hydroxy compounds (lorazepam, lormetazepam, oxazepam, temazepam); 7-nitro compounds (e.g., clonazepam, flunitrazepam, nimetazepam, nitrazepam); triazolo compounds (e.g., adinazolam, alprazolam, estazolam, triazolam); and imidazo compounds (climazolam, loprazolam, midazolam). Method 1.36, selected from one or more compounds in free base form or pharmaceutically acceptable salt form selected from;

[0073] 1.38. 5-HT 2A or 5-HT 2A / D2 receptor ligand, for example, the compound represented by formula I is administered intranasally, subcutaneously, intramuscularly, intravenously, orally, sublingually, intraperitoneally, or buccally, for example, an orally disintegrating tablet, wafer, or film that dissolves in the mouth for transmucosal absorption, any of the above methods;

[0074] 1.39. The method further includes co-administration of an antidepressant (e.g., selected from selective serotonin reuptake inhibitors (SSRI), serotonin reuptake inhibitors (SRI), tricyclic antidepressants, monoamine oxidase inhibitors, norepinephrine reuptake inhibitors (NRI), dopamine reuptake inhibitors (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitors), serotonin receptor antagonists, or combinations thereof), administered, for example, simultaneously, separately, or sequentially, any of the above methods;

[0075] 1.40. Any of the above methods, wherein the method further comprises co - administration of an NMDA receptor antagonist selected from, for example, ketamine (e.g., S - ketamine and / or R - ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine, and agmatine, or combinations thereof, which are administered, for example, simultaneously, separately, or sequentially.

[0076] 1.41. Any of the above methods, wherein the method further comprises co - administration of an NMDA receptor allosteric modulator, for example, an NMDA receptor glycine site modulator such as lapastinel, nebostinel, apimostinel, D - cycloserine, or combinations thereof, which are administered, for example, simultaneously, separately, or sequentially.

[0077] 1.42. Any of the above methods, wherein the method provides a patient with an acute response to treatment with a therapeutic agent (e.g., 5 - HT 2A or 5 - HT 2A / D2 receptor ligand, a compound of formula I, or a combination of a compound of formula I and a compound of formula II, and / or a further antidepressant).

[0078] 1.43. Method 1.42, wherein the patient shows an acute response to treatment within less than 3 weeks, for example, within less than 2 weeks, or within less than 1 week, or within 1 - 7 days, or within 1 - 5 days, or within 1 - 3 days, or within 1 - 2 days, or within about 1 day, or within less than 2 days, or within less than 1 day (e.g., within 12 - 24 hours, within 6 - 12 hours, or within 3 - 6 hours).

[0079] 1.44. Any of the above methods, wherein the patient has not responded, or has not fully responded, or has suffered from undesirable side effects, to treatment with any one or more of another antidepressant, such as a selective serotonin reuptake inhibitor (SSRI), serotonin reuptake inhibitor (SRI), tricyclic antidepressant, monoamine oxidase inhibitor, norepinephrine reuptake inhibitor (NRI), dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor) or serotonin receptor antagonist;

[0080] 1.45. Any of the above methods, wherein the mental disorder or symptom is not associated with schizophrenia or dementia;

[0081] 1.46. Any of the above methods, wherein the patient does not have (or has never been diagnosed with) schizophrenia or dementia;

[0082] 1.47. Any of the above methods, wherein the method protects or enhances the blood-brain barrier;

[0083] 1.48. Any of the above methods, wherein the patient has an elevated level of pro-inflammatory cytokines such as TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18 in the CNS (e.g., in cerebrospinal fluid), or an elevated level of C-reactive protein (CRP) of Csf1, and / or a decreased level of anti-inflammatory cytokines such as TNFβ, IFN-α, IL-4 and IL-10 in the CNS (e.g., in cerebrospinal fluid);

[0084] 1.49. 5-HT 2A or 5-HT 2A / D2 receptor ligand has an IC 2A for activity (agonism and / or antagonism) at the 5-HT 50 receptor of less than 250 nM or an EC 50, for example, having an IC 50 or an EC 50 less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM for the activity (agonism or antagonism) at the receptor in any of the above methods;

[0085] 1.50.5 - HT 2A or 5 - HT 2A / D2 receptor ligand having an IC 50 or an EC 50 less than 250 nM for the activity (agonism and / or antagonism) at the D2 receptor, for example, having an IC 50 or an EC 50 less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM for the activity (agonism or antagonism) at the receptor in any of the above methods;

[0086] 1.51.5 - HT 2A or 5 - HT 2A / D2 receptor ligand having an IC 50 or an EC 50 less than 250 nM for the activity (agonism and / or antagonism) at the D1 receptor, for example, having an IC 50 or an EC 50 less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM for the activity (agonism or antagonism) at the receptor in any of the above methods;

[0087] 1.52.5 - HT 2A or 5 - HT 2AThe / D2 receptor ligand has an IC 50 or an EC 50 less than 250 nM for activity (agonism and / or antagonism) at the serotonin transporter (SERT), e.g., an IC 50 or an EC 50 less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM for activity (agonism or antagonism) at the transporter;

[0088] 1.53.5 - HT 2A or 5 - HT 2A The / D2 receptor ligand is lumateperone, which may be in deuterated form, either in free base form or in a pharmaceutically acceptable salt form;

[0089] 1.54.5 - HT 2A or 5 - HT 2A The / D2 receptor ligand is lumateperone, which may be in deuterated form in tosylate salt form (e.g., monotosylate), and may be in crystalline or amorphous tosylate salt form;

[0090] 1.55.5 - HT 2A or 5 - HT 2A The / D2 receptor ligand is lumateperone, which may be in deuterated form in free base form;

[0091] 1.56.5 - HT 2A or 5 - HT 2A The / D2 receptor ligand is administered in the form of a long - acting injectable (LAI) composition, e.g., for intramuscular or subcutaneous injection;

[0092] 1.57. The dose of the LAI composition is released over a period ranging from about 1 week to about 3 months, for example, from about 1 week to about 8 weeks, or from about 1 week to about 6 weeks, or from about 1 week to about 4 weeks, or from about 1 week to about 3 weeks, or from about 1 week to about 2 weeks, and is sufficient to provide an amount corresponding to a daily dose of 1 to 100 mg of the free base, for example, 1 to 75 mg of the free base, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of the free base; Method 1.56;

[0093] 1.58. The LAI composition contains a compound represented by Formula I dissolved, dispersed, suspended, or encapsulated in a polymer matrix; Method 1.56 or 1.57;

[0094] 1.59. The polymer matrix contains one or more biocompatible and biodegradable polymers as defined herein, for example, poly(hydroxycarboxylic acid), poly(amino acid), cellulose polymer, modified cellulose polymer, polyamide, and polyester; Method 1.58;

[0095] 1.60. The one or more polymers include polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-β-hydroxybutyric acid, poly(lactic acid - glycolic acid) copolymer, 2-hydroxybutyric acid - glycolic acid copolymer, polylactic acid - polyethylene glycol copolymer, polyglycolic acid - polyethylene glycol copolymer, PEG-PLGA copolymer or block copolymer, PEG-PLGA copolymer or block copolymer, poly(alkyl α-cyanoacrylate), for example, poly(butyl cyanoacrylate) or poly(2-octyl cyanoacrylate), poly(orthoester), polycarbonate, polyorthocarbonate, polyamino acid, (for example, polyγ-L-alanine, polyγ-benzyl-L-glutamic acid or poly-γ-methyl-L-glutamic acid), and / or hyaluronic acid ester; Method 1.59;

[0096] 1.61. The method 1.60, wherein the one or more polymers comprise a polyorthoester (POE), polylactic acid, polyglycolic acid, polycitric acid, polyapple acid, or a poly(lactic acid-glycolic acid) copolymer;

[0097] 1.62. The method 1.60, wherein the one or more polymers comprise a poly(lactic acid-glycolic acid) copolymer, such as poly-d,l-lactide-co-glycolide (PLGA), for example, having a molar ratio of lactide to glycolide of about 50:50 to 90:10, or 50:50 to 85:15, or 50:50 to 75:25, and / or a PLGA copolymer having a molecular weight of 5,000 to 500,000 daltons, or 5,000 to 150,000 daltons, or 20,000 to 200,000 daltons, or 24,000 to 38,000 daltons;

[0098] 1.63. 5-HT 2A or 5-HT 2A / D2 receptor ligand is administered as monotherapy and is not administered concurrently or in combination with, for example, an antidepressant, antipsychotic, or anxiolytic drug, in any of the above methods;

[0099] 1.64. 5-HT 2A or 5-HT 2A / D2 receptor ligand is administered without direct supervision by a medical professional (e.g., the compound is self-administered by the patient), in any of the above methods;

[0100] 1.65. The method does not include supervision or observation of the patient by a medical professional during or after administration of the dose of the 5-HT 2A or 5-HT 2A / D2 receptor ligand (e.g., within 2 hours after administration), in any of the above methods;

[0101] 1.66. The method does not expose the patient to a risk of sedation, dissociation, abuse, misuse, or suicidal ideation, in any of the above methods;

[0102] 1.67. The method is such that 5-HT2A or 5-HT 2A does not cause hypertension (e.g., systolic and / or diastolic hypertension) within 4 hours after administration of the dose of the 5-HT / D2 receptor ligand, e.g., does not cause an increase in systolic and / or diastolic blood pressure of more than 10 mmHg, or more than 20 mmHg, or more than 30 mmHg, or more than 40 mmHg within 30 minutes to 4 hours after such administration, any of the above methods;

[0103] 1.68. The method, any of the above methods, that does not cause cognitive decline;

[0104] 1.69. The method, any of the above methods, wherein the patient has (e.g., is diagnosed with) or is at risk of having an aneurysmal vascular disease (e.g., thoracic aortic aneurysm, abdominal aortic aneurysm, intracranial aneurysm, or peripheral aneurysm), arteriovenous malformation or intracerebral hemorrhage;

[0105] 1.70. The method, any of the above methods, wherein the patient is under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0106] 1.71. The method, any of the above methods, wherein the patient is not under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0107] 1.72. The method, any of the above methods, wherein the patient does not respond to ketamine (e.g., S-ketamine) or, e.g., is contraindicated for the patient and thus cannot be treated with ketamine (e.g., S-ketamine);

[0108] 1.73. 5-HT 2A or 5-HT 2A or the 5-HT / D2 receptor ligand is administered to the patient in free base form or in pharmaceutically acceptable salt form in parallel with (e.g., simultaneously, separately or sequentially) a PDE1 (cyclic nucleoside phosphodiesterase 1) inhibitor, any of the above methods;

[0109] 1.74. The PDE1 inhibitor is in free base form or a pharmaceutically acceptable salt form of Formula II:

Chemical formula

[0110] 1.75. In the compound represented by Formula II, wherein R6 is phenylamino or 4-fluorophenylamino, Method 1.74;

[0111] 1.76. In the compound represented by Formula II, wherein R 10 is 3-fluoropyrid-2-yl or methylcarbonyl, Method 1.74;

[0112] 1.77. In the compound represented by Formula II, wherein R6 is phenylamino or 4-fluorophenylamino and R 10 is 3-fluoropyrid-2-yl or methylcarbonyl, Method 1.74;

[0113] 1.78. The compound represented by formula II is in free base form or a pharmaceutically acceptable salt form, [Chemical formula] in any of methods 1.74 to 1.77;

[0114] 1.79. The compound represented by formula II is in the form of a monophosphate, method 1.77;

[0115] 1.80. The compound represented by formula I may be in deuterated form in free base form or a pharmaceutically acceptable salt form, such as tosylate form, [Chemical formula] wherein; the compound represented by formula II is in free base form or a pharmaceutically acceptable salt form, such as monophosphate form, [Chemical formula] in any of methods 1.74 to 1.79;

[0116] 1.81. Administration of a pharmaceutical composition comprising a therapeutically effective amount of both the compound represented by formula I and the compound represented by formula II, in any of methods 1.74 to 1.80;

[0117] 1.82. 5-HT 2A or 5-HT 2A / D2 receptor ligand is a compound represented by formula I which may be in deuterated form in free base form or a pharmaceutically acceptable salt form, and the compound is dissolved or dispersed in a polymer matrix containing a pharmaceutically acceptable carrier and a polymer selected from polyorthoester (POE), polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic acid-glycolic acid) copolymer, and is administered in the form of a long-acting injectable (LAI) composition containing the compound represented by formula I, in any of the above methods;

[0118] 1.83. The pharmaceutically acceptable carrier comprises water (e.g., aqueous buffer) and / or an organic solvent (e.g., water-miscible organic solvent), Method 1.82;

[0119] 1.84. The polymer comprises polylactic acid and / or polyglycolic acid polymer, Method 1.82 or 1.83;

[0120] 1.85. The polymer comprises a poly(lactic-co-glycolic acid) copolymer, e.g., poly-d,l-lactide-co-glycolide (PLGA), e.g., having a molar ratio of lactide to glycolide of about 50:50 to 90:10, or 50:50 to 85:15, or 50:50 to 75:25, and / or having a molecular weight of 5,000 to 500,000 daltons, or 5,000 to 150,000 daltons, or 20,000 to 200,000 daltons, or 24,000 to 38,000 daltons, PLGA copolymer, Method 1.82 or 1.83;

[0121] 1.86. The LAI composition is administered by intramuscular injection or subcutaneous injection, or is formulated for administration by intramuscular injection or subcutaneous injection, any of Methods 1.82 - 1.85;

[0122] 1.87. The patient has no history of depression, Method 1, or any of 1.1 - 1.86;

[0123] 1.88. The patient has evidence of brain injury or brain disease on magnetic resonance imaging (MRI) before administration of a 5-HT 2A or 5-HT 2A / D2 receptor ligand, Method 1, or any of 1.1 - 1.87;

[0124] 1.89. The patient has a 5-HT 2A or 5-HT 2ABefore administration of the D2 receptor ligand, for one or more of herpes simplex virus type 1, herpes simplex virus type 2, West Nile virus, Nipah virus, human immunodeficiency virus, rabies virus, Epstein - Barr virus, cytomegalovirus, coronavirus (e.g., MERS - CoV, SARS - Cov, SARS - Cov2), or influenza virus (e.g., influenza A, e.g., H1N1, H2N2, H3N2, H5N1, H7N7), the serum antibody or antigen test is positive, Method 1, or any of 1.1 to 1.88;

[0125] 1.90. The patient has a positive serum antibody test for autoantibodies against NMDA receptor, AMPA receptor, voltage - gated potassium channel (VGKC), LGL1 protein, GABA receptor, glycine receptor, glutamate receptor, or CASPR2 receptor, Method 1, or any of 1.1 to 1.89;

[0126] 1.91. The patient has an increase in the level of one or more biomarkers indicating CNS inflammation selected from, for example, TNFα, IFN - γ, IL - 1 (IL - 1α and / or IL - 1β), IL - 6, IL - 8, IL - 12, IL - 15, IL - 17, IL - 18, CRP, SAA, Csf1, ICAM - 1, VCAM - 1, YKL - 40, Nlrp3, and Flt - 1 in blood, plasma, serum, peripheral blood mononuclear cells (PBMC) (e.g., isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., isolated from CSF), any of the above methods;

[0127] 1.92. The patient has a change in the level of one or more biomarkers indicating CNS inflammation and / or loss of BBB integrity in serum or CSF, for example, an increase in the level of ICAM - 1, VCAM - 1, E - selectin, P - selectin, or their soluble isoforms (e.g., sICAM - 1, sVCAM1, sP - selectin, sE - selectin), or a decrease in the level of Cldn5, occludin, and ZO - 1, any of the above methods;

[0128] 1.93. Any of the above methods, wherein the patient has a decrease in the level of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction in blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., those isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., those isolated from CSF), such as TNFβ, IFN-α, IL-4, and IL-10;

[0129] 1.94. 5-HT 2A or 5-HT 2A Any of the above methods, wherein after treatment with a 5-HT / D2 receptor ligand (e.g., a compound represented by the formula, which may be in deuterated form), the patient has a decrease in the level of one or more biomarkers indicative of CNS inflammation in blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., those isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., those isolated from CSF), such as TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, ICAM-1, VCAM-1, YKL-40, Nlrp3, and Flt-1, for example, within 28 days from the start of treatment compared to the pre-treatment baseline;

[0130] 1.95. Method 1.94, wherein the patient has a decrease of at least 5%, 10%, 15%, 20%, or 25%, 30%, 35%, 40%, 45%, or 50% in the level of one or more biomarkers indicative of CNS inflammation, for example, within 28 days from the start of treatment;

[0131] 1.96. 5-HT 2A or 5-HT 2AAfter treatment with a D2 receptor ligand (e.g., a compound of the formula, which may be in deuterated form), the patient has, for example, within 28 days from the start of treatment, compared to the pre-treatment baseline, a favorable change in the level of one or more biomarkers indicating CNS inflammation and / or loss of BBB integrity in serum or CSF, e.g., a decrease in the level of ICAM-1, VCAM-1, E-selectin, P-selectin, or their soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), or an increase in the level of Cldn5, occludin, and ZO-1, any of the above methods;

[0132] 1.97. The patient has, for example, within 28 days from the start of treatment, at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% decrease or increase in the level of one or more biomarkers indicating CNS inflammation, method 1.96;

[0133] 1.98. 5-HT 2A or 5-HT 2A After treatment with a D2 receptor ligand (e.g., a compound of the formula, which may be in deuterated form), the patient has, for example, within 28 days from the start of treatment, compared to the pre-treatment baseline, an increase in the level of one or more anti-inflammatory biomarkers indicating CNS inflammatory dysfunction in blood, plasma, serum, peripheral blood mononuclear cells (PBMC) (e.g., those isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., those isolated from CSF), e.g., TNFβ, IFN-α, IL-4, and IL-10, any of the above methods;

[0134] 1.99. The patient has, for example, within 28 days from the start of treatment, at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase in the level of one or more anti-inflammatory biomarkers indicating CNS inflammatory dysfunction, method 1.98;

[0135] 1.100. The method further comprises 5-HT 2A or 5-HT2A Before the start of treatment with a D2 receptor ligand (e.g., a compound represented by the formula, which may be in a deuterated form), and / or after the start of the treatment, examining one or more body fluids or tissues from a patient for the presence and / or concentration of one or more biomarkers indicative of CNS inflammation or CNS inflammatory dysfunction or loss of BBB integrity, comparing the pre-treatment results with the one or more post-treatment results to quantify the effectiveness of the treatment in the patient, and adjusting the treatment regimen, which may be included in any of the above methods;

[0136] 1.101. The biomarker is selected from one or more of TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, YKL-40, Nlrp3, Flt-1, ICAM-1, VCAM-1, E-selectin, P-selectin, Cldn5, occludin, and ZO-1, its soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNFβ, IFN-α, IL-4, and IL-10, Method 1.100;

[0137] 1.102. The one or more body fluids or tissues are selected from blood, plasma, serum, peripheral blood mononuclear cells (PBMC) (e.g., those isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., those isolated from CSF), or brain biopsy tissue samples, Method 1.100 or 1.101;

[0138] 1.103. The method further comprises 5-HT 2A or 5-HT 2ABefore the initiation of treatment with a D2 receptor ligand (e.g., a compound represented by the formula, which may be in a deuterated form), and / or after the initiation of such treatment, non-invasively examining the central nervous system of a patient for the presence and / or concentration of one or more biomarkers indicative of CNS inflammation or CNS inflammatory dysfunction, comparing the pre-treatment results with one or more post-treatment results to quantify the effectiveness of the treatment in the patient, and adjusting the treatment regimen, which may be included in any of the above methods;

[0139] 1.104. The method according to 1.103, wherein the biomarker is selected from one or more of TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, YKL-40, Nlrp3, Flt-1, ICAM-1, VCAM-1, E-selectin, P-selectin, Cldn5, occludin, and ZO-1, their soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNFβ, IFN-α, IL-4, and IL-10;

[0140] 1.105. The method according to 1.103 or 1.104, wherein the step includes imaging methods such as magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI), etc. to evaluate the presence and / or concentration of the biomarker;

[0141] 1.106. The method according to any of 1.100 to 1.105, wherein the method includes initiating, changing, or terminating a treatment regimen (e.g., a selected 5-HT 2A or 5-HT 2A / D2 receptor ligand, its dosage, its route of administration, its frequency of administration, its dosage form, and / or a combination of a selected 5-HT 2A or 5-HT 2A / D2 receptor ligand and another therapeutic agent) based on the observed changes in one or more levels of the biomarker;

[0142] In another aspect, the present disclosure provides a 5-HT, for use in the treatment of mental disorders caused by viral, bacterial or autoimmune encephalitis, and for use in the treatment of mental symptoms of viral, bacterial and autoimmune encephalitis, for example, for use in any of Method 1 etc., 2A or a 5-HT 2A / D2 receptor ligand, for example, a compound represented by Formula I described above herein, for example, lumateperone which may be in deuterated form, in free base form or in salt form.

[0143] In another aspect, the present disclosure provides for the use of a 5-HT, for use in the manufacture of a medicament for the treatment of mental disorders caused by viral, bacterial or autoimmune encephalitis and for the treatment of mental symptoms of viral, bacterial and autoimmune encephalitis, for example, for use in any of Method 1 etc., 2A or a 5-HT 2A / D2 receptor ligand, for example, a compound represented by Formula I described above herein, for example, lumateperone which may be in deuterated form, in free base form or in salt form.

[0144] In certain embodiments, the present disclosure provides a method for protecting or enhancing the blood-brain barrier, the method comprising administering to a patient in need of such protection or enhancement a 5-HT 2A or a 5-HT 2A / D2 receptor ligand, for example, Formula I which may be in deuterated form, in free base form, pharmaceutically acceptable salt form or prodrug form: [Chemical formula] [wherein, X is -N(H)-, -N(CH3)- or -O-; Y is -C(=O)-, -C(H)(OH)- or -C(H)(OR1)-; R1 is -C(O)-C 1-21 alkyl (for example, -C(O)-C 1-5 alkyl, -C(O)-C 6-15 alkyl or -C(O)-C 16-21(alkyl), preferably the alkyl is linear, may be saturated or unsaturated, and may have one or more hydroxy or C 1-22 It may be substituted with an alkoxy (e.g., ethoxy) group. For example, R1 is -C(O)-C6 alkyl, -C(O)-C7 alkyl, -C(O)-C9 alkyl, -C(O)-C 11 alkyl, -C(O)-C 13 alkyl or -C(O)-C 15 alkyl) A method (Method 2) is provided that includes administering a therapeutically effective amount of a compound represented by (where the compound hydrolyzes to form a residue of a natural or non-natural, saturated or unsaturated fatty acid. For example, the compound hydrolyzes to form a hydroxy compound on the one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand). For example, Method 2 can be as follows:

[0145] 2.1. Method 2, wherein X in the compound represented by Formula I is -N(H)-, -N(CH3)- or -O-;

[0146] 2.2. Method 2 or 2.1, wherein X in the compound represented by Formula I is -N(H);

[0147] 2.3. Method 2 or 2.1, wherein X in the compound represented by Formula I is -N(CH3)-;

[0148] 2.4. Method 2 or 2.1, wherein X in the compound represented by Formula I is -O-;

[0149] 2.5. Method 2, or any of Formulas 2.1 - 2.4, wherein Y in the compound represented by Formula I is -C(=O)-, -C(H)(OH)- or -C(H)(OR1)-;

[0150] 2.6. Method 2, or any of Formulas 2.1 - 2.4, wherein Y in the compound represented by Formula I is -C(=O)-;

[0151] 2.7. Method 2, or any of Formulas 2.1 to 2.4, wherein Y in the compound represented by Formula I is -C(H)(OH)-;

[0152] 2.8. Method 2, or any of Formulas 2.1 to 2.4, wherein Y in the compound represented by Formula I is -C(H)(OR1)-;

[0153] 2.9. In the compound represented by Formula I, R1 is -C(O)-C 1-21 alkyl (e.g., -C(O)-C 1-5 alkyl, -C(O)-C 6-15 alkyl or -C(O)-C 16-21 alkyl), preferably, the alkyl is linear, may be saturated or unsaturated, and may be substituted with one or more hydroxy or C 1-22 alkoxy (e.g., ethoxy) groups. For example, R1 may be -C(O)-C6 alkyl, -C(O)-C7 alkyl, -C(O)-C9 alkyl, -C(O)-C 11 alkyl, -C(O)-C 13 alkyl or -C(O)-C 15 alkyl. Here, the compound hydrolyzes to form residues of natural or unnatural, saturated or unsaturated fatty acids. For example, the compound hydrolyzes to form a hydroxy compound on one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand. For example, here, in the compound represented by Formula I, R1 is -C(O)-C 6-15 alkyl, e.g., -C(O)-C9 alkyl; or R1 in the compound represented by Formula I is -C(O)-C 1-5 alkyl, e.g., -C(O)-C3 alkyl. Method 2, or any of 2.2 to 2.5 or 2.8;

[0154] 2.10. The compound represented by Formula I is

Chemical formula

[0155] 2.11. The compound represented by formula I is [Chemical formula] that of Method 2, or any one of 2.1 to 2.5 or 2.7;

[0156] 2.12. The compound represented by formula I is lumateperone: [Chemical formula] that of Method 2, or any one of 2.1, 2.3, 2.5 or 2.6;

[0157] 2.13. The compound represented by formula I is in the form of a pharmaceutically acceptable salt, for example, in the form of a tosylate, of Method 2, or any one of 2.1 to 2.12, for example, Method 2.12;

[0158] 2.14. The compound represented by formula I is in the form of a free base, of Method 2, or any one of 2.1 to 2.12, for example, Method 2.12;

[0159] 2.15. The compound represented by formula I is in a deuterated form, for example, the deuterium:protium ratio of specific carbon-bonded hydrogen atoms is significantly higher than the natural isotope ratio, for example, at least 2 times higher, for example, at least 10 times higher, of Method 2, or any one of 2.1 to 2.14;

[0160] 2.16. The compound represented by formula I is, for example, in the form of a free base or a pharmaceutically acceptable salt form, for example, a tosylate form [Chemical formula] [wherein, D represents a hydrogen position that substantially exceeds natural deuterium incorporation (i.e., exceeds 0.0156% substantially), for example, exceeds 60%, or exceeds 70%, or exceeds 80%, or exceeds 90%, or exceeds 95%, or exceeds 96%, or exceeds 97%, or exceeds 98%, or exceeds 99%] Method 2.15, which is a deuterated form of lumateperone selected from;

[0161] 2.17. 5-HT 2A or 5-HT 2A Any of the above methods, wherein the 5-HT / D2 receptor ligand is administered in an amount corresponding to a daily dose of 1 to 100 mg of the free base, for example, an amount corresponding to 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of the free base, in free base form or in a pharmaceutically acceptable salt form, such as tosylate form, of the compound of formula I;

[0162] Method 2.17, wherein the method comprises once-daily oral administration of a unit dosage form for oral administration, such as a tablet or capsule, containing a compound of formula I in free base form or in a pharmaceutically acceptable salt form, such as tosylate form, in an amount corresponding to 1 to 100 mg of the free base, for example, an amount corresponding to 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg, or 1 to 5 mg, or 40 to 60 mg, or 20 to 40 mg, or 10 to 20 mg, or about 60 mg, or about 40 mg, or about 30 mg, or about 20 mg, or about 10 mg, or about 5 mg of the free base, and a pharmaceutically acceptable diluent or carrier;

[0163] 2.19. A unit dosage form for transmucosal administration, such as a sublingual or buccal orally disintegrating tablet, a wafer, or a film, containing a compound of formula I in free base form or in a pharmaceutically acceptable salt form, such as tosylate form, in an amount corresponding to 0.5 to 30 mg of the free base, for example, 1 to 30 mg, or 1 to 20 mg, or 1 to 15 mg, or 1 to 10 mg, or 20 to 30 mg, or 10 to 20 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg of the free base, and a pharmaceutically acceptable diluent or carrier, including once-daily administration of the same; Method 2.17;

[0164] 2.20. Any of the above methods, wherein the patient has a viral, bacterial, or autoimmune encephalitis caused by or suspected of being caused by, for example, herpes simplex virus type 1, herpes simplex virus type 2, West Nile virus, Nipah virus, human immunodeficiency virus, rabies virus, Epstein - Barr virus, cytomegalovirus, coronavirus (e.g., MERS - CoV, SARS - Cov, SARS - Cov2), influenza virus (e.g., influenza A, e.g., H1N1, H2N2, H3N2, H5N1, H7N7), toxoplasmosis, rickettsia, mycoplasma, Borrelia (e.g., Lyme disease), malaria, or autoantibodies against NMDA receptor, AMPA receptor, voltage - gated potassium channel (VGKC), LGL1 protein, GABA receptor, glycine receptor, glutamate receptor, or CASPR2 receptor;

[0165] 2.21. Any of the above methods, wherein the patient is diagnosed as having suicidal ideation and / or suicidal tendency;

[0166] 2.22. Any of the above methods, wherein the patient is diagnosed with a mental disorder or mental symptoms, such as depression (e.g., acute depression, depression in MDD, depression in bipolar disorder), anxiety (e.g., acute anxiety), psychosis (e.g., schizophrenia), post-traumatic stress disorder, anhedonia, memory loss, impairment of executive functioning, difficulty concentrating, seizure, sleep difficulty, hallucination, personality change, or a combination thereof;

[0167] 2.23. Any of the above methods, wherein the patient shows acute signs of mental illness, even without a history of mental disorder or mental symptoms;

[0168] 2.24. Any of the above methods, wherein the patient is at risk of damage or compromise of the blood-brain barrier due to, for example, CNS inflammation, CNS infection (e.g., encephalitis), neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, or brain trauma (e.g., traumatic brain injury, such as concussion);

[0169] 2.25. Any of the above methods, wherein the patient has an increase in the levels of pro-inflammatory cytokines, such as TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, or an increase in the level of C-reactive protein (CRP) of Csf1, and / or a decrease in the levels of anti-inflammatory cytokines, such as TNFβ, IFN-α, IL-4, and IL-10, in the CNS (e.g., in cerebrospinal fluid);

[0170] 2.26. 5-HT 2A or 5-HT 2AThe / D2 receptor ligand is administered in combination with a therapeutically effective amount of an anxiolytic or antidepressant (e.g., a fixed combination in a unit dosage form, or a free combination administered sequentially or simultaneously or within 24 hours), any of the above methods;

[0171] 2.27. The anxiolytic or antidepressant is one or more compounds in free base form or pharmaceutically acceptable salt form selected from selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA) and atypical antipsychotics, for example, (a) selective serotonin reuptake inhibitors (SSRI), for example, citalopram (Celexa), escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), fluvoxamine (Luvox), sertraline (Zoloft, Lustral); (b) serotonin-norepinephrine reuptake inhibitors (SNRI), for example, desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella), tofenacin (Elamol, Tofacine), venlafaxine (Effexor); (c) Tricyclic antidepressants (TCA), for example, Amitriptyline (Elavil, Endep), Amitriptyline Oxide (Amioxid, Ambivalon, Equilibrin), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Pipofezine (Azafen / Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil); (d) Compounds selected from benzodiazepines, such as 2-keto compounds (e.g., chlorazepate, diazepam, flurazepam, halazepam, prazepam); 3-hydroxy compounds (lorazepam, lormetazepam, oxazepam, temazepam); 7-nitro compounds (e.g., clonazepam, flunitrazepam, nimetazepam, nitrazepam); triazolo compounds (e.g., adinazolam, alprazolam, estazolam, triazolam); and imidazo compounds (climazolam, loprazolam, midazolam). Method 2.26, selected from one or more compounds in free base form or pharmaceutically acceptable salt form selected from;

[0172] 2.28. 5-HT 2A or 5-HT 2A / D2 receptor ligand, for example, the compound represented by formula I is administered intranasally, subcutaneously, intramuscularly, intravenously, orally, sublingually, intraperitoneally, or buccally, for example, an orally disintegrating tablet, a wafer, or a film that dissolves in the mouth for transmucosal absorption, any of the above methods;

[0173] 2.29. The method further includes co-administration of an antidepressant (e.g., selected from selective serotonin reuptake inhibitors (SSRI), serotonin reuptake inhibitors (SRI), tricyclic antidepressants, monoamine oxidase inhibitors, norepinephrine reuptake inhibitors (NRI), dopamine reuptake inhibitors (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor), serotonin receptor antagonists, or combinations thereof), for example, administered simultaneously, separately, or sequentially, any of the above methods;

[0174] 2.30. Any of the above methods, wherein the method further comprises co - administration of an NMDA receptor antagonist selected from, for example, ketamine (e.g., S - ketamine and / or R - ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine, and agmatine, or combinations thereof, which are administered, for example, simultaneously, separately or sequentially;

[0175] 2.31. Any of the above methods, wherein the method further comprises co - administration of an NMDA receptor allosteric modulator, for example, an NMDA receptor glycine site modulator, such as lapastinel, nebostinel, apimostinel, D - cycloserine, or combinations thereof, which are administered, for example, simultaneously, separately or sequentially;

[0176] 2.32. Any of the above methods, wherein the method provides the patient with an acute response to treatment with a therapeutic agent (e.g., 5 - HT 2A or 5 - HT 2A / D2 receptor ligand, a compound of formula I, or a combination of a compound of formula I and a compound of formula II, and / or an additional antidepressant);

[0177] 2.33. Method 2.32, wherein the patient shows an acute response to treatment within less than 3 weeks, for example, within less than 2 weeks, or within less than 1 week, or within 1 - 7 days, or within 1 - 5 days, or within 1 - 3 days, or within 1 - 2 days, or within about 1 day, or within less than 2 days, or within less than 1 day (e.g., within 12 - 24 hours, within 6 - 12 hours, or within 3 - 6 hours);

[0178] 2.34. Any of the above methods, wherein the patient has not responded, has not sufficiently responded, or has suffered from undesirable side effects to treatment with any one or more of another antidepressant, such as a selective serotonin reuptake inhibitor (SSRI), serotonin reuptake inhibitor (SRI), tricyclic antidepressant, monoamine oxidase inhibitor, norepinephrine reuptake inhibitor (NRI), dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor) or serotonin receptor antagonist;

[0179] 2.35. Any of the above methods, wherein the patient does not have (or has never been diagnosed with) schizophrenia or dementia;

[0180] 2.36. 5-HT 2A or 5-HT 2A / D2 receptor ligand has an IC 2A or an EC 50 of less than 250 nM for activity (agonism and / or antagonism) at the 5-HT 50 receptor, e.g., an IC 50 or an EC 50 of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM for activity (agonism or antagonism) at said receptor;

[0181] 2.37. 5-HT 2A or 5-HT 2A / D2 receptor ligand has an IC 50 or an EC 50, for example, having an IC 50 or an EC 50 less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM for activity (agonism or antagonism) at the receptor;

[0182] 2.38. 5-HT 2A or 5-HT 2A / D2 receptor ligand having an IC 50 or an EC 50 less than 250 nM for activity (agonism and / or antagonism) at the D1 receptor, for example, having an IC 50 or an EC 50 less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM for activity (agonism or antagonism) at the receptor;

[0183] 2.39. 5-HT 2A or 5-HT 2A / D2 receptor ligand having an IC 50 or an EC 50 less than 250 nM for activity (agonism and / or antagonism) at the serotonin transporter (SERT), for example, having an IC 50 or an EC 50 less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM for activity (agonism or antagonism) at the transporter;

[0184] 2.40. 5-HT 2A or 5-HT 2AAny of the above methods, wherein the D2 receptor ligand is lumateperone, which may be in deuterated form, either in free base form or in pharmaceutically acceptable salt form;

[0185] 2.41.5-HT 2A or 5-HT 2A Any of the above methods, wherein the D2 receptor ligand is lumateperone, which may be in deuterated form in tosylate form (e.g., monotosylate), and may be in crystalline or amorphous tosylate form;

[0186] 2.42.5-HT 2A or 5-HT 2A Any of the above methods, wherein the D2 receptor ligand is lumateperone, which may be in deuterated form in free base form;

[0187] 2.43.5-HT 2A or 5-HT 2A Any of the above methods, wherein the D2 receptor ligand is administered in the form of a long-acting injectable (LAI) composition, e.g., for intramuscular or subcutaneous injection;

[0188] Method 2.43, wherein the dose of the LAI composition provides an amount corresponding to a daily dose of 1 to 100 mg of free base, e.g., 1 to 75 mg of free base, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of free base, and is released over a period ranging from about 1 week to about 3 months, e.g., from about 1 week to about 8 weeks, or from about 1 week to about 6 weeks, or from about 1 week to about 4 weeks, or from about 1 week to about 3 weeks, or from about 1 week to about 2 weeks;

[0189] Method 2.43 or 2.44, wherein the LAI composition comprises a compound of formula I dissolved, dispersed, suspended, or encapsulated in a polymer matrix;

[0190] 2.46. The polymer matrix comprises one or more biocompatible and biodegradable polymers as defined herein, such as poly(hydroxycarboxylic acid), poly(amino acid), cellulose polymer, modified cellulose polymer, polyamide, and polyester, Method 2.45;

[0191] 2.47. The one or more polymers include polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-β-hydroxybutyric acid, poly(lactic acid-glycolic acid) copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer, polyglycolic acid-polyethylene glycol copolymer, PEG-PLGA copolymer or block copolymer, poly(alkyl α-cyanoacrylate), such as poly(butyl cyanoacrylate) or poly(2-octyl cyanoacrylate), poly(orthoester), polycarbonate, polyorthocarbonate, polyamino acid, (e.g., poly-γ-L-alanine, poly-γ-benzyl-L-glutamic acid or poly-γ-methyl-L-glutamic acid), and / or hyaluronic acid ester, Method 2.46;

[0192] 2.48. The one or more polymers include poly(orthoester) (POE), polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic acid-glycolic acid) copolymer, Method 2.46;

[0193] 2.49. The one or more polymers include a poly(lactic acid-glycolic acid) copolymer, such as poly-d,l-lactide-co-glycolide (PLGA), for example, having a molar ratio of lactide to glycolide of about 50:50 to 90:10, or 50:50 to 85:15, or 50:50 to 75:25, and / or a PLGA copolymer having a molecular weight of 5,000 to 500,000 daltons, or 5,000 to 150,000 daltons, or 20,000 to 200,000 daltons, or 24,000 to 38,000 daltons, Method 2.46;

[0194] 2.50. 5-HT 2Aor 5-HT 2A Any of the above methods, wherein the 5-HT or 5-HT / D2 receptor ligand is administered as a monotherapy and not in parallel with or in combination with, for example, an antidepressant, antipsychotic, or anxiolytic drug;

[0195] 2.51.5-HT 2A or 5-HT 2A Any of the above methods, wherein the 5-HT or 5-HT / D2 receptor ligand is administered without the direct supervision of a medical professional (e.g., the compound is self-administered by the patient);

[0196] 2.52. The method, wherein the 5-HT 2A or 5-HT 2A Any of the above methods, which does not include the supervision or observation of the patient by a medical professional during or after the administration of a dose of the 5-HT or 5-HT / D2 receptor ligand (e.g., within 2 hours after administration);

[0197] 2.53. The method, wherein the method does not expose the patient to the risk of sedation, dissociation, abuse, misuse, or suicidal ideation;

[0198] 2.54. The method, wherein the 5-HT 2A or 5-HT 2A Any of the above methods, which does not result in hypertension (e.g., systolic and / or diastolic hypertension) within 4 hours after the administration of a dose of the 5-HT or 5-HT / D2 receptor ligand, for example, does not result in an increase in systolic and / or diastolic blood pressure of more than 10 mmHg, or more than 20 mmHg, or more than 30 mmHg, or more than 40 mmHg within 30 minutes to 4 hours after the administration;

[0199] 2.55. The method, wherein the method does not result in cognitive decline;

[0200] 2.56. The method, wherein the patient has (e.g., is diagnosed with) or is at risk of having an aneurysmal vascular disease (e.g., thoracic aortic aneurysm, abdominal aortic aneurysm, intracranial aneurysm, or peripheral aneurysm), arteriovenous malformation, or intracerebral hemorrhage;

[0201] 2.57. Any of the above methods, wherein the patient is under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0202] 2.58. Any of the above methods, wherein the patient is not under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0203] 2.59. Any of the above methods, wherein the patient does not respond to ketamine (e.g., S-ketamine) or cannot be treated with ketamine (e.g., S-ketamine), for example, because it is contraindicated for the patient;

[0204] 2.60. 5-HT 2A or 5-HT 2A / D2 receptor ligand is administered to the patient in free base form or pharmaceutically acceptable salt form in parallel with a PDE1 (cyclic nucleoside phosphodiesterase 1) inhibitor (e.g., simultaneously, separately, or sequentially);

[0205] 2.61. The PDE1 inhibitor is in free base form or pharmaceutically acceptable salt form of formula II:

Chemical formula

[0206] 2.62. In the compound represented by Formula II, R6 is phenylamino or 4-fluorophenylamino, Method 2.61;

[0207] 2.63. In the compound represented by Formula II, R 10 is 3-fluoropyrid-2-yl or methylcarbonyl, Method 2.61;

[0208] 2.64. In the compound represented by Formula II, R6 is phenylamino or 4-fluorophenylamino, and R 10 is 3-fluoropyrid-2-yl or methylcarbonyl, Method 2.61;

[0209] 2.65. The compound represented by Formula II is in free base form or a pharmaceutically acceptable salt form of

Chemical formula

[0210] 2.66. The compound represented by Formula II is in the form of a monophosphate, Method 2.65;

[0211] 2.67. The compound represented by Formula I may be in deuterated form in free base form or a pharmaceutically acceptable salt form, such as tosylate form,

Chemical formula

[0212] 2.68. Any one of Methods 2.61 to 2.67, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of both a compound represented by Formula I and a compound represented by Formula II;

[0213] 2.69. 5-HT 2A or 5-HT 2A / D2 receptor ligand is a compound represented by Formula I, which may be in deuterated form in free base form or pharmaceutically acceptable salt form, and the compound is dissolved or dispersed in a polymer matrix containing a pharmaceutically acceptable carrier and a polymer selected from polyorthoester (POE), polylactic acid, polyglycolic acid, polycitric acid, polyapple acid, or poly(lactic acid - glycolic acid) copolymer, and is administered in the form of a long-acting injectable (LAI) composition comprising the compound represented by Formula I; any of the above methods;

[0214] 2.70. The method 2.69, wherein the pharmaceutically acceptable carrier comprises water (e.g., aqueous buffer) and / or an organic solvent (e.g., water-miscible organic solvent);

[0215] 2.71. The method 2.69 or 2.70, wherein the polymer comprises polylactic acid and / or polyglycolic acid polymer;

[0216] 2.72. The method 2.69 or 2.70, wherein the polymer comprises a poly(lactic acid - glycolic acid) copolymer, e.g., poly-d,l-lactide-co-glycolide (PLGA), e.g., having a molar ratio of lactide to glycolide of about 50:50 to 90:10, or 50:50 to 85:15, or 50:50 to 75:25, and / or a PLGA copolymer having a molecular weight of 5,000 to 500,000 daltons, or 5,000 to 150,000 daltons, or 20,000 to 200,000 daltons, or 24,000 to 38,000 daltons;

[0217] 2.73. Any of methods 2.69 to 2.72, wherein the LAI composition is administered by intramuscular injection or subcutaneous injection, or is formulated for administration by intramuscular injection or subcutaneous injection;

[0218] 2.74. Method 2, or any of 2.1 to 2.74, wherein the patient has no history of depression;

[0219] 2.75. Method 2, or any of 2.1 to 2.75, wherein the patient has 2A or 2A evidence of brain injury or brain disease on magnetic resonance imaging (MRI) before administration of the 5-HT or 5-HT / D2 receptor ligand;

[0220] 2.76. Method 2, or any of 2.1 to 2.75, wherein the patient has 2A or 2A a positive serum antibody or antigen test for one or more of herpes simplex virus type 1, herpes simplex virus type 2, West Nile virus, Nipah virus, human immunodeficiency virus, rabies virus, Epstein-Barr virus, cytomegalovirus, coronavirus (e.g., MERS-CoV, SARS-Cov, SARS-Cov2), or influenza virus (e.g., influenza A, e.g., H1N1, H2N2, H3N2, H5N1, H7N7) before administration of the 5-HT or 5-HT / D2 receptor ligand;

[0221] 2.77. Method 2, or any of 2.1 to 2.76, wherein the patient has a positive serum antibody test for autoantibodies against NMDA receptor, AMPA receptor, voltage-gated potassium channel (VGKC), LGL1 protein, GABA receptor, glycine receptor, glutamate receptor, or CASPR2 receptor;

[0222] 2.78. Any of the above methods, wherein the patient has an elevated level of one or more biomarkers indicative of CNS inflammation selected from, for example, TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, ICAM-1, VCAM-1, YKL-40, Nlrp3, and Flt-1 in blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., those isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., those isolated from CSF);

[0223] 2.79. Any of the above methods, wherein the patient has a change in the level of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity in serum or CSF, for example, an elevated level of ICAM-1, VCAM-1, E-selectin, P-selectin, or their soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), or a decreased level of Cldn5, occludin, and ZO-1;

[0224] 2.80. Any of the above methods, wherein the patient has a decreased level of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, for example, TNFβ, IFN-α, IL-4, and IL-10 in blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., those isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., those isolated from CSF);

[0225] 2.81. 5-HT 2A or 5-HT 2AAfter treatment with a D2 receptor ligand (e.g., a compound of the formula, which may be in deuterated form), the patient has, within, for example, 28 days from the start of treatment, a decrease in the level of one or more biomarkers indicative of CNS inflammation, such as TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, ICAM-1, VCAM-1, YKL-40, Nlrp3, and Flt-1, in blood, plasma, serum, peripheral blood mononuclear cells (PBMC) (e.g., isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., isolated from CSF), compared to the pre-treatment baseline;

[0226] 2.82. The patient has a decrease of at least 5%, 10%, 15%, 20%, or 25%, 30%, 35%, 40%, 45%, or 50% in the level of one or more biomarkers indicative of CNS inflammation within, for example, 28 days from the start of treatment; Method 1.94;

[0227] 2.83. 5-HT 2A or 5-HT 2A After treatment with a D2 receptor ligand (e.g., a compound of the formula, which may be in deuterated form), the patient has, within, for example, 28 days from the start of treatment, a favorable change in the level of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity, such as an increase in the level of ICAM-1, VCAM-1, E-selectin, P-selectin, or their soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), or a decrease in the level of Cldn5, occludin, and ZO-1, in serum or CSF, compared to the pre-treatment baseline; any of the above methods;

[0228] 2.84. Method 2.83, wherein the patient has at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% decrease or increase in the level of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity, e.g., within 28 days of initiating treatment;

[0229] 2.85.5-HT 2A or 5-HT 2A any of the above methods, wherein after treatment with a D2 receptor ligand (e.g., a compound of the formula, which may be in a deuterated form), the patient has elevated levels of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, e.g., TNFβ, IFN-α, IL-4, and IL-10, in blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., isolated from CSF), compared to a pre-treatment baseline, e.g., within 28 days of initiating treatment;

[0230] 2.86. Method 2.85, wherein the patient has at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase in the level of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, e.g., within 28 days of initiating treatment;

[0231] 2.87. The method further comprises: 2A or 5-HT 2A / any of the above methods, optionally including testing one or more bodily fluids or tissues from the patient for the presence and / or concentration of one or more biomarkers indicative of CNS inflammation or CNS inflammatory dysfunction prior to and / or after initiation of treatment with a D2 receptor ligand (e.g., a compound of formula: which may be in a deuterated form), and comparing pre-treatment results with one or more post-treatment results to quantify the effectiveness of the treatment in the patient and adjust the treatment regimen;

[0232] 2.88. The method according to 2.87, wherein the biomarker is selected from one or more of TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, YKL-40, Nlrp3, Flt-1, ICAM-1, VCAM-1, E-selectin, P-selectin, Cldn5, occludin, and ZO-1, its soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNFβ, IFN-α, IL-4, and IL-10;

[0233] 2.89. The method according to 2.87 or 2.88, wherein the one or more body fluids or tissues are selected from blood, plasma, serum, peripheral blood mononuclear cells (PBMC) (e.g., isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., isolated from CSF), or a brain biopsy tissue sample;

[0234] 2.90. The method may further include non-invasively examining the central nervous system of a patient for the presence and / or concentration of one or more biomarkers indicative of CNS inflammation or CNS inflammatory dysfunction before and / or after initiation of treatment with 5-HT 2A or 5-HT 2A / D2 receptor ligand (e.g., a compound represented by a formula, which may be in a deuterated form), comparing the pre-treatment results with the one or more post-treatment results to quantify the effectiveness of the treatment in the patient, and adjusting the treatment regimen, according to any of the above methods;

[0235] 2.91. The method 2.90, wherein the biomarker is selected from one or more of TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, YKL-40, Nlrp3, Flt-1, ICAM-1, VCAM-1, E-selectin, P-selectin, Cldn5, occludin, and ZO-1, its soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNFβ, IFN-α, IL-4, and IL-10;

[0236] 2.92. The method 2.90 or 2.91, wherein the step includes imaging methods such as magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI), etc. for evaluating the presence and / or concentration of the biomarker;

[0237] 2.93. The method according to any one of 2.90 to 2.92, wherein the method includes a step of starting, changing, or ending a treatment regimen (e.g., a selected 5-HT 2A or 5-HT 2A / D2 receptor ligand, its dosage, its administration route, its administration frequency, its dosage form, and / or a combination of a selected 5-HT 2A or 5-HT 2A / D2 receptor ligand with other therapeutic agents) based on the observed change in one or more levels of the biomarker.

[0238] In another aspect, the present disclosure provides a 5-HT 2A or 5-HT 2A / D2 receptor ligand, for example, a compound represented by Formula I described above herein, for example, lumateperone, which may be in deuterated form, in free base form or salt form, for use in protecting or enhancing the blood-brain barrier, for example, for use in any of the methods such as method 2.

[0239] In another aspect, the present disclosure provides a 5-HT2A or 5-HT 2A / D2 receptor ligand, for example, the use of lumateperone, which may be in deuterated form, either in free base form or in salt form, such as the compounds represented by Formula I described above herein.

[0240] In certain embodiments, the present disclosure is a method for treating a mental disorder in a patient in need thereof, wherein the patient has an increase in the levels of pro-inflammatory cytokines such as TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, etc., or an increase in the levels of C-reactive protein (CRP) or Csf1, and / or a decrease in the levels of anti-inflammatory cytokines such as TNFβ, IFN-α, IL-4 and IL-10 in the CNS (e.g., in cerebrospinal fluid), and the method comprises administering to the patient 5-HT 2A or 5-HT 2A / D2 receptor ligand, for example, a compound represented by Formula I, which may be in deuterated form, in free base form, pharmaceutically acceptable salt form or prodrug form:

Chemical formula

[0241] 3.1. Method 3, wherein X in the compound represented by Formula I is -N(H)-, -N(CH3)-, or -O-;

[0242] 3.2. Method 3 or 3.1, wherein X in the compound represented by Formula I is -N(H);

[0243] 3.3. Method 3 or 3.1, wherein X in the compound represented by Formula I is -N(CH3)-;

[0244] 3.4. Method 3 or 3.1, wherein X in the compound represented by Formula I is -O-;

[0245] 3.5. Method 3, or any of Methods 3.1 to 3.4, wherein Y in the compound represented by Formula I is -C(=O)-, -C(H)(OH)-, or -C(H)(OR1)-;

[0246] 3.6. Method 3, or any of Methods 3.1 to 3.4, wherein Y in the compound represented by Formula I is -C(=O)-;

[0247] 3.7. Method 3, or any of Methods 3.1 to 3.4, wherein Y in the compound represented by Formula I is -C(H)(OH)-;

[0248] 3.8. Method 3, or any of Methods 3.1 to 3.4, wherein Y in the compound represented by Formula I is -C(H)(OR1)-;

[0249] 3.9. In the compound represented by formula I, R1 is -C(O)-C 1-21 alkyl (for example, -C(O)-C 1-5 alkyl, -C(O)-C 6-15 alkyl or -C(O)-C 16-21 alkyl), preferably, the alkyl is linear, may be saturated or unsaturated, and may be substituted with one or more hydroxy or C 1-22 alkoxy (for example, ethoxy) groups. For example, R1 may be -C(O)-C6 alkyl, -C(O)-C7 alkyl, -C(O)-C9 alkyl, -C(O)-C 11 alkyl, -C(O)-C 13 alkyl or -C(O)-C 15 alkyl. Here, the compound hydrolyzes to form residues of natural or non-natural, saturated or unsaturated fatty acids. For example, the compound hydrolyzes to form a hydroxy compound on one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand. For example, here, in the compound represented by formula I, R1 is -C(O)-C 6-15 alkyl, for example, -C(O)-C9 alkyl; or R1 in the compound represented by formula I is -C(O)-C 1-5 alkyl, for example, -C(O)-C3 alkyl, method 3, or any of 3.1 - 3.5 or 3.8;

[0250] 3.10. The compound represented by formula I is

Chemical formula

[0251] 3.11. The compound represented by formula I is

Chemical formula

[0252] 3.12. The compound represented by formula I is lumateperone: [Chemical formula] Method 3, or any of 3.1, 3.3, 3.5, or 3.6;

[0253] 3.13. The compound represented by formula I is in the form of a pharmaceutically acceptable salt, for example, tosylate, Method 3, or any of 3.1 - 1.12, for example, Method 1.12;

[0254] 3.14. The compound represented by formula I is in the form of a free base, Method 3, or any of 3.1 -, for example, Method 1.12;

[0255] 3.15. The compound represented by formula I is in a deuterated form, for example, the deuterium:protium ratio of certain carbon - bonded hydrogen atoms is significantly higher than the natural isotope ratio, for example, at least 2 times higher, for example, at least 10 times higher, Method 3, or any of 3.1 - 1.14;

[0256] 3.16. The compound represented by formula I is, for example, in the free base form or a pharmaceutically acceptable salt form, for example, tosylate form, [Chemical formula] [wherein D represents a hydrogen position that substantially exceeds natural deuterium incorporation (i.e., substantially exceeds 0.0156%), for example, exceeds 60%, or exceeds 70%, or exceeds 80%, or exceeds 90%, or exceeds 95%, or exceeds 96%, or exceeds 97%, or exceeds 98%, or exceeds 99%] and is a deuterated form of lumateperone selected from:

[0257] 3.17. 5 - HT 2A or 5 - HT 2AAny of the above methods, wherein the D2 receptor ligand is administered in an amount corresponding to a daily dose of 1 to 100 mg of the free base, for example, an amount corresponding to 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 20 mg, or 1 to 10 mg of the free base, in free base form or in a pharmaceutically acceptable salt form, such as tosylate form, of the compound of formula I;

[0258] 3.18. Method 3.17, wherein the method comprises once-daily administration of an oral dosage form, such as a tablet or capsule, comprising a compound of formula I in free base form or in a pharmaceutically acceptable salt form, such as tosylate form, in an amount corresponding to a daily dose of 1 to 100 mg of the free base, for example, an amount corresponding to 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg, or 1 to 5 mg, or 40 to 60 mg, or 20 to 40 mg, or 10 to 20 mg, or about 60 mg, or about 40 mg, or about 30 mg, or about 20 mg, or about 10 mg, or about 5 mg of the free base, and a pharmaceutically acceptable diluent or carrier;

[0259] 3.19. Method 3.17, wherein the method comprises once-daily administration of a transmucosal dosage form, such as a sublingual or buccal orally disintegrating tablet, a wafer or a film, comprising a compound of formula I in free base form or in a pharmaceutically acceptable salt form, such as tosylate form, in an amount corresponding to a daily dose of 0.5 to 30 mg of the free base, for example, an amount corresponding to 1 to 30 mg, or 1 to 20 mg, or 1 to 15 mg, or 1 to 10 mg, or 20 to 30 mg, or 10 to 20 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg of the free base, and a pharmaceutically acceptable diluent or carrier;

[0260] 3.20. Any of the above methods, wherein the condition to be treated is alleviated within 1 week, for example within 3 days, for example within 1 day;

[0261] 3.21. Any of the above methods, wherein the patient has or is diagnosed with viral, bacterial, or autoimmune encephalitis;

[0262] 3.22. Method 3.21, wherein the patient's mental disorder is caused by or suspected of being caused by viral, bacterial, or autoimmune encephalitis;

[0263] 3.23. Method 3.21 or 3.22, wherein the encephalitis is viral encephalitis;

[0264] 3.24. Method 3.23, wherein the viral encephalitis is caused by or suspected of being caused by herpes simplex virus type 1, herpes simplex virus type 2, West Nile virus, Nipah virus, human immunodeficiency virus, rabies virus, Epstein - Barr virus, cytomegalovirus, coronavirus (e.g., MERS - CoV, SARS - Cov, SARS - Cov2), or influenza virus (e.g., influenza A, e.g., H1N1, H2N2, H3N2, H5N1, H7N7);

[0265] 3.25. Method 3.21, 3.22 or 3.23, wherein the viral encephalitis is acute viral encephalitis;

[0266] 3.26. Method 3.21, wherein the encephalitis is bacterial encephalitis;

[0267] 3.27. Method 3.26, wherein the encephalitis is caused by or thought to be caused by toxoplasmosis, rickettsia, mycoplasma, Borrelia (e.g., Lyme disease), or malaria;

[0268] 3.28. Method 3.21, wherein the encephalitis is autoimmune encephalitis;

[0269] 3.29. The method 3.28, wherein encephalitis is caused by, or is suspected to be caused by, autoantibodies against NMDA receptor, AMPA receptor, voltage-gated potassium channel (VGKC), LGL1 protein, GABA receptor, glycine receptor, glutamate receptor, or CASPR2 receptor;

[0270] 3.30. Any of the methods 3.21 - 3.29, wherein the patient does not have a history of mental disorder or psychiatric symptoms prior to the diagnosis of encephalitis;

[0271] 3.31. Any of the methods 3.21 - 3.29, wherein the patient does not have a history of any one or more of depression, anxiety, psychosis, post-traumatic stress disorder, anhedonia, dementia, memory loss, impairment of executive function, difficulty in concentration, seizure, sleep difficulty, hallucination, or personality change prior to the diagnosis of encephalitis;

[0272] 3.32. Any of the above methods, wherein the mental disorder is depression (e.g., acute depression, depression in MDD, depression in bipolar disorder), anxiety (e.g., acute anxiety), psychosis (e.g., schizophrenia), post-traumatic stress disorder, anhedonia, memory loss, impairment of executive functioning, difficulty in concentration, seizure, sleep difficulty, hallucination, personality change, or a combination thereof;

[0273] 3.33. Any of the above methods, wherein the mental disorder is depression (e.g., acute depression, depression in MDD, depression in bipolar disorder);

[0274] 3.34. Any of the above methods, wherein the mental disorder is anxiety (e.g., acute anxiety);

[0275] 3.35. Any of the above methods, wherein the mental disorder is anhedonia;

[0276] 3.36. Any of the above methods, wherein the patient is diagnosed as having suicidal ideation and / or suicidal tendency;

[0277] 3.37. 5-HT 2A or 5-HT 2A The / D2 receptor ligand is administered in combination with a therapeutically effective amount of an anxiolytic or antidepressant (e.g., a fixed combination in unit dosage form, or a free combination administered sequentially or simultaneously or within 24 hours), any of the above methods;

[0278] 3.38. The anxiolytic or antidepressant is one or more compounds in free base form or pharmaceutically acceptable salt form selected from selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA) and atypical antipsychotics, for example, (a) Selective serotonin reuptake inhibitors (SSRI), such as citalopram (Celexa), escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), fluvoxamine (Luvox), sertraline (Zoloft, Lustral); (b) Serotonin-norepinephrine reuptake inhibitors (SNRI), such as desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella), tofenacin (Elamol, Tofacine), venlafaxine (Effexor); (c) Tricyclic antidepressants (TCAs), for example, amitriptyline (Elavil, Endep), amitriptyline oxide (Amioxid, Ambivalon, Equilibrin), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), dibenzepin (Noveril, Victoril), dimetacrine (Istonil), dosulepin (Prothiaden), doxepin (Adapin, Sinequan), imipramine (Tofranil), lofepramine (Lomont, Gamanil), melitracen (Dixeran, Melixeran, Trausabun), nitroxazepine (Sintamil), nortriptyline (Pamelor, Aventyl), noxiptiline (Agedal, Elronon, Nogedal), pipofezine (Azafen / Azaphen), protriptyline (Vivactil), trimipramine (Surmontil); (d) Compounds selected from benzodiazepines, such as 2-keto compounds (e.g., chlorazepate, diazepam, flurazepine, halazepam, prazepam); 3-hydroxy compounds (lorazepam, lormetazepam, oxazepam, temazepam); 7-nitro compounds (e.g., clonazepam, flunitrazepam, nimetazepam, nitrazepam); triazolo compounds (e.g., adinazolam, alprazolam, estazolam, triazolam); and imidazo compounds (climazolam, loprazolam, midazolam), Method 3.37 selected from one or more compounds in free base form or pharmaceutically acceptable salt form selected from;

[0279] 3.39. 5-HT 2A or 5-HT 2A / D2 receptor ligand, for example, the compound represented by formula I is administered intranasally, subcutaneously, intramuscularly, intravenously, orally, sublingually, intraperitoneally, or buccally, for example, an orally rapidly dissolving tablet, wafer or film agent that dissolves in the mouth for transmucosal absorption, any of the above methods;

[0280] 3.40. The method further includes co-administration of an antidepressant (e.g., selected from selective serotonin reuptake inhibitors (SSRI), serotonin reuptake inhibitors (SRI), tricyclic antidepressants, monoamine oxidase inhibitors, norepinephrine reuptake inhibitors (NRI), dopamine reuptake inhibitors (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor), serotonin receptor antagonists, or combinations thereof), which are administered, for example, simultaneously, separately or sequentially, any of the above methods;

[0281] 3.41. Any of the above methods, wherein the method further comprises co - administration of an NMDA receptor antagonist selected from, for example, ketamine (e.g., S - ketamine and / or R - ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine, and agmatine, or combinations thereof, which are administered, for example, simultaneously, separately or sequentially;

[0282] 3.42. Any of the above methods, wherein the method further comprises co - administration of an NMDA receptor allosteric modulator, for example, an NMDA receptor glycine site modulator such as rapastinel, nebostinel, apimostinel, D - cycloserine, or combinations thereof, which are administered, for example, simultaneously, separately or sequentially;

[0283] 3.43. Any of the above methods, wherein the method provides a patient with an acute response to treatment with a therapeutic agent (e.g., 5 - HT 2A or 5 - HT 2A / D2 receptor ligand, a compound of formula I, or a combination of a compound of formula I and a compound of formula II, and / or a further antidepressant);

[0284] 3.44. Method 3.43, wherein the patient shows an acute response to treatment within less than 3 weeks, for example, within less than 2 weeks, or within less than 1 week, or within 1 - 7 days, or within 1 - 5 days, or within 1 - 3 days, or within 1 - 2 days, or within about 1 day, or within less than 2 days, or within less than 1 day (e.g., within 12 - 24 hours, within 6 - 12 hours, or within 3 - 6 hours);

[0285] 3.45. Any of the above methods, wherein the patient has not responded, or has not sufficiently responded, or has suffered from undesirable side effects to treatment with any one or more of another antidepressant, for example, a selective serotonin reuptake inhibitor (SSRI), serotonin reuptake inhibitor (SRI), tricyclic antidepressant, monoamine oxidase inhibitor, norepinephrine reuptake inhibitor (NRI), dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor) or serotonin receptor antagonist;

[0286] 3.46. Any of the above methods, wherein the mental disorder is not associated with schizophrenia or dementia;

[0287] 3.47. Any of the above methods, wherein the patient does not have (or has never been diagnosed with) schizophrenia or dementia;

[0288] 3.48. Any of the above methods, wherein the method protects or enhances the blood-brain barrier;

[0289] 3.49. 5-HT 2A or 5-HT 2A / D2 receptor ligand has an IC 2A for activity (agonism and / or antagonism) at the 5-HT 50 receptor of less than 250 nM or an EC 50 of less than 250 nM, for example, an IC 50 or EC 50 for activity (agonism or antagonism) at the receptor of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM, and any of the above methods having the same;

[0290] 3.50. 5-HT 2A or 5-HT 2A / D2 receptor ligand has an IC for activity (agonism and / or antagonism) at the D2 receptor of less than 250 nM 50 or an EC of less than 250 nM 50 , for example, an IC for activity (agonism or antagonism) at the receptor of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM 50 or an EC 50 having any of the above methods;

[0291] 3.51.5 - HT 2A or 5 - HT 2A / D2 receptor ligand has an IC for activity (agonism and / or antagonism) at the D1 receptor of less than 250 nM 50 or an EC of less than 250 nM 50 , for example, an IC for activity (agonism or antagonism) at the receptor of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM 50 or an EC 50 having any of the above methods;

[0292] 3.52.5 - HT 2A or 5 - HT 2A / D2 receptor ligand has an IC for activity (agonism and / or antagonism) at the serotonin transporter (SERT) of less than 250 nM 50 or an EC of less than 250 nM 50 , for example, an IC for activity (agonism or antagonism) at the transporter of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM 50 or an EC 50 having any of the above methods;

[0293] 3.5 3.5 - HT 2A or 5 - HT 2A Any of the above methods, wherein the 5 - HT / D2 receptor ligand is lumateperone, which may be in deuterated form, either in free base form or in a pharmaceutically acceptable salt form;

[0294] 3.5 4.5 - HT 2A or 5 - HT 2A Any of the above methods, wherein the 5 - HT / D2 receptor ligand is lumateperone, which may be in deuterated form in tosylate form (e.g., monotosylate), and may be in crystalline or amorphous tosylate form;

[0295] 3.5 5.5 - HT 2A or 5 - HT 2A Any of the above methods, wherein the 5 - HT / D2 receptor ligand is lumateperone, which may be in deuterated form in free base form;

[0296] 3.5 6.5 - HT 2A or 5 - HT 2A Any of the above methods, wherein the 5 - HT / D2 receptor ligand is administered in the form of a long - acting injectable (LAI) composition, for example, for intramuscular or subcutaneous injection;

[0297] Method 3.56, wherein the dose of the LAI composition provides an amount corresponding to a daily dose of 1 - 100 mg of free base, for example, 1 - 75 mg of free base, or 1 - 60 mg, or 1 - 40 mg, or 1 - 20 mg, or 1 - 10 mg of free base, and is released over a period ranging from about 1 week to about 3 months, for example, from about 1 week to about 8 weeks, or from about 1 week to about 6 weeks, or from about 1 week to about 4 weeks, or from about 1 week to about 3 weeks, or from about 1 week to about 2 weeks;

[0298] Methods 3.56 or 3.57, wherein the LAI composition contains a compound of formula I dissolved, dispersed, suspended, or encapsulated in a polymer matrix;

[0299] 3.59. The polymer matrix comprises one or more biocompatible and biodegradable polymers as defined herein, such as poly(hydroxycarboxylic acid), poly(amino acid), cellulose polymer, modified cellulose polymer, polyamide, and polyester, Method 3.58;

[0300] 3.60. The one or more polymers include polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-β-hydroxybutyric acid, poly(lactic - glycolic acid) copolymer, 2-hydroxybutyric acid - glycolic acid copolymer, polylactic acid - polyethylene glycol copolymer, polyglycolic acid - polyethylene glycol copolymer, PEG - PLGA copolymer or block copolymer, poly(alkyl α-cyanoacrylate), such as poly(butyl cyanoacrylate) or poly(2-octyl cyanoacrylate), poly(orthoester), polycarbonate, polyorthocarbonate, polyamino acid, (e.g., polyγ-L-alanine, polyγ-benzyl-L-glutamic acid or poly-γ-methyl-L-glutamic acid), and / or hyaluronic acid ester, Method 3.59;

[0301] 3.61. The one or more polymers include poly(orthoester) (POE), polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic - glycolic acid) copolymer, Method 3.60;

[0302] 3.62. The one or more polymers include poly(lactic - glycolic acid) copolymer, such as poly-d,l-lactide-co-glycolide (PLGA), for example, having a molar ratio of lactide to glycolide of about 50:50 to 90:10, or 50:50 to 85:15, or 50:50 to 75:25, and / or a molecular weight of 5,000 to 500,000 daltons, or 5,000 to 150,000 daltons, or 20,000 to 200,000 daltons, or 24,000 to 38,000 daltons, Method 3.60;

[0303] 3.63. 5-HT 2Aor 5-HT 2A / D2 receptor ligand is administered as a monotherapy and is not administered in parallel with or in combination with, for example, an antidepressant, an antipsychotic, or an anxiolytic; any of the above methods

[0304] 3.64. 5-HT 2A or 5-HT 2A / D2 receptor ligand is administered without direct supervision by a medical professional (e.g., the compound is self-administered by the patient); any of the above methods

[0305] 3.65. The method is 5-HT 2A or 5-HT 2A / D2 receptor ligand does not include supervision or observation of the patient by a medical professional during or after administration of the dose (e.g., within 2 hours after administration); any of the above methods

[0306] 3.66. The method does not expose the patient to the risk of sedation, dissociation, abuse, misuse, or suicidal ideation; any of the above methods

[0307] 3.67. The method does not result in hypertension (e.g., systolic and / or diastolic hypertension) within 4 hours after administration of the dose of 5-HT 2A or 5-HT 2A / D2 receptor ligand, for example, does not result in an increase in systolic and / or diastolic blood pressure exceeding 10 mmHg, or 20 mmHg, or 30 mmHg, or 40 mmHg within 30 minutes to 4 hours after the administration; any of the above methods

[0308] 3.68. The method does not result in cognitive decline; any of the above methods

[0309] 3.69. The patient has or is at risk of having an aneurysmal vascular disease (e.g., thoracic aortic aneurysm, abdominal aortic aneurysm, intracranial aneurysm, or peripheral aneurysm), arteriovenous malformation, or intracerebral hemorrhage (e.g., so diagnosed); any of the above methods

[0310] 3.70. Any of the above methods, wherein the patient is under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0311] 3.71. Any of the above methods, wherein the patient is not under concurrent treatment with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0312] 3.72. Any of the above methods, wherein the patient does not respond to ketamine (e.g., S-ketamine) or cannot be treated with ketamine (e.g., S-ketamine), for example, because it is contraindicated for the patient;

[0313] 3.73. 5-HT 2A or 5-HT 2A / D2 receptor ligand is administered to the patient in free base form or pharmaceutically acceptable salt form in parallel with a PDE1 (cyclic nucleoside phosphodiesterase 1) inhibitor (e.g., administered simultaneously, separately, or sequentially), any of the above methods;

[0314] 3.74. The PDE1 inhibitor is in free base form or pharmaceutically acceptable salt form of formula II:

Chemical formula

[0315] 3.75. In the compound represented by formula II, R6 is phenylamino or 4-fluorophenylamino, Method 3.74;

[0316] 3.76. In the compound represented by formula II, R 10 is 3-fluoropyrid-2-yl or methylcarbonyl, Method 3.74;

[0317] 3.77. In the compound represented by formula II, R6 is phenylamino or 4-fluorophenylamino, and R 10 is 3-fluoropyrid-2-yl or methylcarbonyl, Method 3.74;

[0318] 3.78. The compound represented by formula II is in free base form or a pharmaceutically acceptable salt form of,

Chemical formula

[0319] 3.79. The compound represented by formula II is in the form of monophosphate, Method 3.77;

[0320] 3.80. The compound represented by formula I may be in deuterated form in free base form or a pharmaceutically acceptable salt form, such as tosylate form,

Chemical formula

[0321] 3.81. Any one of Methods 3.74 to 3.80, including administration of a pharmaceutical composition comprising a therapeutically effective amount of both a compound represented by Formula I and a compound represented by Formula II;

[0322] 3.82. The 5-HT 2A or 5-HT 2A / D2 receptor ligand is a compound represented by Formula I, which may be in deuterated form in free base form or pharmaceutically acceptable salt form, and the compound is dissolved or dispersed in a polymer matrix containing a pharmaceutically acceptable carrier and a polymer selected from polyorthoester (POE), polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic acid-glycolic acid) copolymer, and is administered in the form of a long-acting injectable (LAI) composition comprising the compound represented by Formula I; any of the above methods

[0323] 3.83. The method 3.82, wherein the pharmaceutically acceptable carrier comprises water (e.g., aqueous buffer) and / or an organic solvent (e.g., water-miscible organic solvent);

[0324] 3.84. The method 3.82 or 3.83, wherein the polymer comprises a polylactic acid and / or a polyglycolic acid polymer;

[0325] 3.85. The method 3.82 or 3.83, wherein the polymer comprises a poly(lactic acid-glycolic acid) copolymer, such as poly-d,l-lactide-co-glycolide (PLGA), for example, with a molar ratio of lactide to glycolide of about 50:50 to 90:10, or 50:50 to 85:15, or 50:50 to 75:25, and / or a PLGA copolymer having a molecular weight of 5,000 to 500,000 daltons, or 5,000 to 150,000 daltons, or 20,000 to 200,000 daltons, or 24,000 to 38,000 daltons;

[0326] 3.86. Any of methods 3.82 to 3.85, wherein the LAI composition is administered by intramuscular injection or subcutaneous injection, or is formulated for administration by intramuscular injection or subcutaneous injection;

[0327] 3.87. Method 3, or any of 3.1 to 3.86, wherein the patient does not have a history of depression;

[0328] 3.88. Method 3, or any of 3.1 to 3.87, wherein the patient shows evidence of brain injury or brain disease by magnetic resonance imaging (MRI) before administration of the 5-HT 2A or 5-HT 2A / D2 receptor ligand;

[0329] 3.89. Method 3, or any of 3.1 to 3.88, wherein the patient has a positive serum antibody or antigen test for one or more of herpes simplex virus type 1, herpes simplex virus type 2, West Nile virus, Nipah virus, human immunodeficiency virus, rabies virus, Epstein - Barr virus, cytomegalovirus, coronavirus (e.g., MERS-CoV, SARS-Cov, SARS-Cov2), or influenza virus (e.g., influenza A, e.g., H1N1, H2N2, H3N2, H5N1, H7N7) before administration of the 5-HT 2A or 5-HT 2A / D2 receptor ligand;

[0330] 3.90. Method 3, or any of 3.1 to 3.89, wherein the patient has a positive serum antibody test for autoantibodies against NMDA receptor, AMPA receptor, voltage - gated potassium channel (VGKC), LGL1 protein, GABA receptor, glycine receptor, glutamate receptor, or CASPR2 receptor;

[0331] 3.91. Any of the above methods, wherein the patient has an elevated level of one or more biomarkers indicative of CNS inflammation selected from, for example, TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, ICAM-1, VCAM-1, YKL-40, Nlrp3, and Flt-1 in blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., those isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., those isolated from CSF);

[0332] 3.92. Any of the above methods, wherein the patient has a change in the level of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity in serum or CSF, for example, an elevated level of ICAM-1, VCAM-1, E-selectin, P-selectin, or their soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), or a decreased level of Cldn5, occludin, and ZO-1;

[0333] 3.93. Any of the above methods, wherein the patient has a decreased level of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, for example, TNFβ, IFN-α, IL-4, and IL-10 in blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., those isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., those isolated from CSF);

[0334] 3.94. 5-HT 2A or 5-HT 2AAfter treatment with a D2 receptor ligand (e.g., a compound of the formula which may be in deuterated form), the patient has, within, for example, 28 days from the start of treatment, in blood, plasma, serum, peripheral blood mononuclear cells (PBMC) (e.g., isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., isolated from CSF), a decrease in the level of one or more biomarkers indicative of CNS inflammation, such as TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, ICAM-1, VCAM-1, YKL-40, Nlrp3, and Flt-1, compared to the pre-treatment baseline, any of the above methods;

[0335] 3.95. The patient has, within, for example, 28 days from the start of treatment, at least a 5%, 10%, 15%, 20%, or 25%, 30%, 35%, 40%, 45%, or 50% decrease in the level of one or more biomarkers indicative of CNS inflammation, method 3.94;

[0336] 3.96. 5-HT 2A or 5-HT 2A After treatment with a D2 receptor ligand (e.g., a compound of the formula which may be in deuterated form), the patient has, within, for example, 28 days from the start of treatment, a favorable change in the level of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity, such as an increase in the level of ICAM-1, VCAM-1, E-selectin, P-selectin, or their soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), or a decrease in the level of Cldn5, occludin, and ZO-1, in serum or CSF, compared to the pre-treatment baseline, any of the above methods;

[0337] 3.97. Method 3.96, wherein the patient has at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% decrease or increase in the level of one or more biomarkers indicative of CNS inflammation, e.g., within 28 days of starting treatment;

[0338] 3.98.5-HT 2A or 5-HT 2A any of the above methods, wherein after treatment with a D2 receptor ligand (e.g., a compound of the formula, which may be in a deuterated form), the patient has elevated levels of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, e.g., TNFβ, IFN-α, IL-4, and IL-10, in blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., isolated from CSF), compared to a pre-treatment baseline, e.g., within 28 days of initiating treatment;

[0339] 3.99. Method 3.98, wherein the patient has at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase in the level of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, e.g., within 28 days of initiating treatment;

[0340] 3.100. The method further comprises: 2A or 5-HT 2A / Any of the above methods, comprising testing one or more bodily fluids or tissues from the patient for the presence and / or concentration of one or more biomarkers indicative of CNS inflammation or CNS inflammatory dysfunction prior to and / or after initiation of treatment with a D2 receptor ligand (e.g., a compound of formula: which may be in a deuterated form), and optionally comparing pre-treatment results with one or more post-treatment results to quantify the effectiveness of the treatment in the patient and adjust the treatment regimen;

[0341] 3.101. The biomarker is selected from one or more of TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, YKL-40, Nlrp3, Flt-1, ICAM-1, VCAM-1, E-selectin, P-selectin, Cldn5, occludin, and ZO-1, its soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNFβ, IFN-α, IL-4, and IL-10, method 3.100;

[0342] 3.102. The one or more body fluids or tissues are selected from blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., isolated from blood), urine, CSF, and / or CNS microglial cells (e.g., isolated from CSF), or a brain biopsy tissue sample, method 3.100 or 3.101;

[0343] 3.103. The method further includes, before the start of treatment with 5-HT 2A or 5-HT 2A / D2 receptor ligand (e.g., a compound represented by a formula, which may be in a deuterated form), and / or after the start of the treatment, non-invasively examining the patient's central nervous system for the presence and / or concentration of one or more biomarkers indicating CNS inflammation or CNS inflammatory dysfunction, comparing the pre-treatment results with the one or more post-treatment results to quantify the effectiveness of the treatment in the patient, and adjusting the treatment regimen, any of the above methods;

[0344] 3.104. The method according to 3.103, wherein the biomarker is selected from one or more of TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, YKL-40, Nlrp3, Flt-1, ICAM-1, VCAM-1, E-selectin, P-selectin, Cldn5, occludin, and ZO-1, its soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNFβ, IFN-α, IL-4, and IL-10;

[0345] 3.105. The method according to 3.103 or 3.104, wherein the process comprises imaging methods such as magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI), etc. to evaluate the presence and / or concentration of the biomarker;

[0346] 3.106. The method according to any one of 3.100 to 3.105, wherein the method comprises starting, changing or ending a treatment regimen (e.g., a selected 5-HT 2A or 5-HT 2A / D2 receptor ligand, its dosage, its administration route, its administration frequency, its dosage form, and / or a combination of a selected 5-HT 2A or 5-HT 2A / D2 receptor ligand with other therapeutic agents) based on the observed changes in one or more levels of the biomarker.

[0347] In another aspect, the present disclosure provides a 5-HT for use in the treatment of a mental disorder in a patient in need thereof, for example, for use in any of the methods such as method 3, etc. 2A or 5-HT 2A / D2 receptor ligands, such as the compounds represented by Formula I described above herein, such as lumateperone, which may be in deuterated form, in free base form or salt form, where the patient has an increase in the levels of pro-inflammatory cytokines such as TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, etc. in the CNS (e.g., in cerebrospinal fluid), or an increase in the levels of C-reactive protein (CRP) or Csf1, and / or a decrease in the levels of anti-inflammatory cytokines such as TNFβ, IFN-α, IL-4, and IL-10 in the CNS (e.g., in cerebrospinal fluid).

[0348] In another aspect, the present disclosure relates to the manufacture of a medicament for the treatment of a mental disorder in a patient in need thereof, for any of, for example, Method 3, etc., 5-HT 2A or 5-HT 2A / D2 receptor ligands, such as the compounds represented by Formula I described above herein, such as lumateperone, which may be in deuterated form, in free base form or salt form, where the patient has an increase in the levels of pro-inflammatory cytokines such as TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, etc. in the CNS (e.g., in cerebrospinal fluid), or an increase in the levels of C-reactive protein (CRP) or Csf1, and / or a decrease in the levels of anti-inflammatory cytokines such as TNFβ, IFN-α, IL-4, and IL-10 in the CNS (e.g., in cerebrospinal fluid).

[0349] In some embodiments described herein, patients particularly suitable for the practice of the disclosed methods can be envisioned by measuring the levels of specific biomarkers in bodily fluids or tissues from the patient. These biomarkers can indicate the presence of CNS inflammation or the presence of CNS inflammatory dysfunction, due to infection, autoimmunity, or other causes. Thus, psychological symptoms in the patient can be particularly due to such inflammatory changes and can particularly benefit from the unique properties and activities of the compounds described herein. Biomarkers indicative of CNS inflammation include TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, CRP, SAA, Csf1, ICAM-1, VCAM-1, YKL-40, Nlrp3, and Flt-1, which can be identified or quantified in samples taken from blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., those isolated from blood), urine, cerebrospinal fluid (CSF), and / or microglial cells isolated from CSF. In particular, changes in specific biomarkers such as ICAM-1, VCAM-1, E-selectin, P-selectin, Cldn5, occludin, and ZO-1, or their soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin) indicate disruption of the blood-brain barrier integrity, which can be identified or quantified in serum or CSF. When the BBB is disrupted, cell damage and lysis can occur, and membrane-bound tight junction proteins are normally present in CSF and plasma. Alternatively, CNS inflammation induced by inflammatory cytokines can upregulate proteins that loosen the BBB or downregulate proteins that tighten the BBB to allow infiltration of immune cells into the CSF. Changes in the levels of any or all of these biomarkers can indicate inflammation of the CNS and / or BBB damage or loss of BBB integrity. Similarly, another class of biomarkers is related to anti-inflammatory properties such as anti-inflammatory cytokines.Such a decrease in biomarker levels may indicate CNS inflammatory dysfunction, i.e., dysfunction of the normal physical control against cellular inflammation. Examples of such biomarkers include NFβ, IFN-α, IL-4, and IL-10, which can similarly be identified or quantified in samples taken from blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., those isolated from blood), urine, cerebrospinal fluid (CSF), and / or microglial cells isolated from CSF. In addition to the detection of these biomarkers in body fluids and tissues, many studies have been done on non-invasive imaging techniques (e.g., MRI, PET) to obtain the same information, especially in difficult-to-access body compartments such as the CNS.Additional information regarding such methods of measuring biomarkers and the interpretation of changes in these biomarker values can be found in Zhu et al., “Circulating tight junction proteins mirror blood-brain barrier integrity in leukaemia central nervous system metastasis,” Hematol Oncol, 35(3):365-373 (2017); Abe, et al. “Soluble cell adhesion molecules in hypertriglyceridemia and potential significance on monocyte adhesion,”. Arterioscler. Thromb. Vasc. Biol., 18(5): 723-31 (1998); Janelidze et al., “CSF Biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease,” Neurology, 91(9):e867-e877 (2018); Beanio et al., “Towards PET imaging of the dynamic phenotypes of microglia.” Clinical and Experimental Immunology, 206(3): 282-300 (2021).

[0350] The term “5-HT 2A receptor ligand” refers to, at least, a compound that exhibits pharmacological activity at the serotonin 5-HT 2A receptor, e.g., an IC 50 for activity (agonism and / or antagonism) at the receptor of less than 250 nM or an EC 50refers to a compound having []. In some embodiments, this term refers to a compound having an IC for activity (agonism or antagonism) at the receptor of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM 50 or an EC 50 refers to a compound having [].

[0351] The term "5-HT 2A / D2 receptor ligand" refers to a compound that exhibits pharmacological activity at least at both the serotonin 5-HT 2A receptor and the D2 receptor, e.g., a compound having an IC for activity (agonism and / or antagonism) at the receptor of less than 250 nM 50 or an EC of less than 250 nM 50 refers to a compound having []. In some embodiments, this term refers to a compound having an IC for activity (agonism or antagonism) at one or both of these receptors of less than 200 nM, or less than 150 nM, or less than 100 nM, or less than 75 nM, or less than 60 nM, or less than 50 nM, or less than 40 nM, or less than 30 nM, or less than 20 nM 50または EC 50 refers to a compound having [].

[0352] The terms "treatment" and "treating" are to be understood as appropriately encompassing the prevention and treatment or alleviation of the symptoms of a disease and / or the treatment of the cause of the disease. In certain embodiments, the terms "treatment" and "treating" refer to the prevention or alleviation of the symptoms of a disease.

[0353] The term "patient" can include a human patient or a non-human patient.

[0354] Unless otherwise specified or apparent from the context, the following terms in this specification have the following meanings:

[0355] As used herein, "alkyl" is, for example, a saturated or unsaturated hydrocarbon moiety having a carbon atom length of 1 to 21, and unless otherwise specified, can be linear or branched (e.g., n-butyl or tert-butyl), preferably linear. For example, "C 1-21 alkyl" refers to an alkyl group having 1 to 21 carbon atoms. In one embodiment, the alkyl may be substituted with one or more hydroxy or C 1-22 alkoxy (e.g., ethoxy) groups. In a preferred embodiment, the alkyl contains 1 to 21 carbon atoms, is preferably linear, and may be saturated or unsaturated. For example, when R1 is cleaved from a compound represented by formula I, for example, it can be an alkyl chain containing 1 to 21 carbon atoms, preferably 6 to 15 carbon atoms, or 16 to 21 carbon atoms, which together with the attached -C(O)- forms a residue of a natural or non-natural saturated or unsaturated fatty acid.

[0356] 5-HT 2A or 5-HT 2A / D2 receptor ligands, such as the substituted heterocyclic fused γ-carbolines described herein, can be in free base form, pharmaceutically acceptable salt form or prodrug form. Pharmaceutically acceptable salts include, for example, tosylate salts in the case of compounds represented by formula I. When the dose or amount of the salt is given by weight, such as mg / day or mg / unit dose, the dose of the salt is given as the weight of the corresponding free base, unless otherwise specified.

[0357] In any or all of the embodiments described herein, 5-HT 2A or 5-HT 2A / D2 receptor ligands may also be SERT ligands, i.e., the compound may be a 5-HT 2A / SERT or 5-HT 2A / D2 / SERT receptor ligand.

[0358] In any or all of the embodiments described herein, 5-HT 2A or 5-HT2A The / D2 receptor ligand may or may not have opioid receptor activity, or may substantially not have it (for example, it may or may not have μ opioid receptor activity, or may substantially not have it, for example, the IC 50 is more than 50 nM, or more than 100 nM, or more than 150 nM).

[0359] 5-HT 2A or 5-HT 2A The / D2 receptor ligand may in some cases be present in prodrug form. A prodrug form is a compound that is converted into an active compound in the body. For example, a compound containing a hydroxy or carboxy substituent can form a physiologically hydrolysable and acceptable ester. As used herein, "physiologically hydrolysable and acceptable ester" means an ester that is hydrolysable under physiological conditions and that itself yields an acid (in the case of a compound having a hydroxy substituent) or an alcohol (in the case of a compound having a carboxy substituent) that is physiologically tolerable at the administered dose. For example, when Y of the compound represented by formula I is -C(H)(OR1) and R1 is -C(O)-C 1-21 alkyl, for example, -C(O)-C3 alkyl or -C(O)-C9 alkyl, these compounds are hydrolysed under physiological conditions to yield, on the one hand, a compound represented by formula I in which Y is -C(H)(OH) and, on the other hand, C 1-21 alkyl-C(O)OH, for example, C3 alkyl-C(O)OH or C9 alkyl-C(O)OH. As will be appreciated, this term thus encompasses conventional pharmaceutical prodrug forms. When using a prodrug (for example, a compound represented by formula (I) in which R1 is -C(O)-C 1-21 alkyl), the dose is calculated on the basis of the amount of the compound represented by formula (I) in free base form in which Y is -C(=O)- or -CH(OH)-.

[0360] When referring to therapeutic use, the term "concurrently" means the administration of two or more active agents to a patient as part of a regimen for the treatment of a disease or disorder, whether the two or more active agents are administered at the same time or at different times, or by the same route of administration or different routes of administration. Concurrent administration of two or more active ingredients can be at different times on the same day, or on different days, or at different frequencies.

[0361] When referring to therapeutic use, the term "simultaneously" means the simultaneous or almost simultaneous administration of two or more active ingredients by the same route of administration.

[0362] When referring to therapeutic use, the term "separately" means the simultaneous or almost simultaneous administration of two or more active ingredients by different routes of administration.

[0363] 5-HT 2A or 5-HT 2A Regarding the concurrent treatment using a 5-HT / D2 receptor ligand (e.g., a compound represented by Formula I) and an NMDA receptor antagonist (e.g., ketamine), without being bound by theory, the combination of these agents enables the use of lower doses of both agents for the treatment of depression or other neuropsychiatric disorders described herein, while minimizing the dissociative effects caused by the NMDA receptor antagonist and maximizing the synergistic antidepressant effects.

[0364] The doses used in the practice of the present disclosure will, of course, vary depending on, for example, the particular disease or condition being treated, the particular active compound being used, the mode of administration, and the desired therapy. Unless otherwise specified, the amount of the active compound for administration (whether administered as the free base or in salt form) refers to or is based on the amount of the compound in the free base form (i.e., the amount calculation does not take into account the weight of the counterion in the case of salts and is based on the amount of the active moiety in the free base form).

[0365] 5-HT 2Aor 5-HT 2A / D2 receptor ligands can be administered by a suitable route including oral, intramuscular, subcutaneous, parenteral, transmucosal, or transdermal, but are preferably administered orally or transmucosally. 5-HT 2A or 5-HT 2A / D2 receptor ligands can be administered, for example, in the form of tablets, capsules, wafers, injections (e.g., intravenous injection, intramuscular injection, subcutaneous injection), or orally disintegrating tablets, wafers, or films for sublingual or buccal administration.

[0366] To avoid misunderstanding, the disclosure of a numerical range, e.g., an amount "up to X", is intended to include the upper limit value X. Thus, the disclosure of "up to 60 mg" is intended to include 60 mg.

[0367] Pharmaceutical compositions containing the compounds of the present disclosure can be prepared using conventional diluents or excipients and techniques known in the art of galenics. Thus, oral dosage forms include tablets, capsules, solutions, suspensions, etc.

[0368] The compounds of the present disclosure can be included as a long-acting injectable formulation (i.e., a depot formulation) by, for example, dispersing, dissolving, suspending, or encapsulating the compounds of the present invention in a polymeric matrix as described herein, such that the compound is continuously released as the polymer degrades over time. The release of the compounds of the present invention from the polymeric matrix provides, for example, from a pharmaceutical depot composition, controlled release and / or delayed release and / or sustained release of the compound to a warm-blooded animal, such as a human, to which the pharmaceutical depot is administered. Thus, the pharmaceutical depot delivers the compounds of the present invention to the subject over a duration, for example, from 1 week to 3 months, at a concentration effective for the treatment of a particular disease or condition.

[0369] Examples of polymers useful for the polymer matrix in the composition of the present invention (e.g., the depot composition of the present invention) include polyesters of hydroxy fatty acids and their derivatives, or other agents such as polylactic acid, polyglycolic acid, polycitric acid, poly(lactic acid), poly-β-hydroxybutyric acid, ε-caprolactone ring-opening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, poly(lactic acid)-polyethylene glycol copolymer or polyglycolic acid-polyethylene glycol copolymer), PEG-PLGA copolymer or block copolymer, polymer of alkyl α-cyanoacrylate (e.g., poly(butyl 2-cyanoacrylate)), polyalkylene oxalate (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoester, polycarbonate (e.g., polyethylene carbonate or polyethylene propylene carbonate), polyorthocarbonate, polyamino acid (e.g., polyγ-L-alanine, polyγ-benzyl-L-glutamic acid or poly-γ-methyl-L-glutamic acid), hyaluronic acid ester, etc. One or more of these polymers can be used.

[0370] When the polymer is a copolymer, it may be any of a random copolymer, a block copolymer, and / or a graft copolymer. When the above α-hydroxycarboxylic acid, hydroxy dicarboxylic acid, and hydroxy tricarboxylic acid have optical activity in their molecules, any one of the D-isomer, L-isomer, and / or DL-isomer can be used. Among them, α-hydroxycarboxylic acid polymers (preferably, lactic acid-glycolic acid polymers), their esters, poly α-cyanoacrylate esters, etc. can be used, and lactic acid-glycolic acid copolymers (also called poly(lactide-α-glycolide) or poly(lactic acid-co-glycolic acid)), hereinafter also referred to as PLGA) are preferred. Therefore, in one aspect, the polymer useful for the polymer matrix is PLGA. As used in this specification, the term PLGA includes polymers of lactic acid (also referred to as polylactide, poly(lactic acid), or PLA). Most preferably, the polymer is a biodegradable poly(d,l-lactide-co-glycolide) polymer, for example, PLGA 50:50, PLGA 85:15, and PLGA 90:10.

[0371] In a preferred embodiment, the polymer matrix of the present invention is a biocompatible and biodegradable polymer material. The term "biocompatible" is defined as a polymer material that is non-toxic, non-carcinogenic, and does not significantly induce inflammation in body tissues. The matrix material should be biodegradable, where the polymer material should be easily disposable in the body into products that can be used in vivo by the body's processes and should not accumulate in the body. In that the polymer matrix is biocompatible with the body, the biodegradation products should also be biocompatible with the body. Particularly useful examples of polymer matrix materials include poly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid, the copolymers thereof, poly(aliphatic carboxylic acid), copolyoxalate, polycaprolactone, polydioxanone, poly(orthocarbonate), poly(acetal), poly(lactic acid-caprolactone), polyorthoester, poly(glycolic acid-caprolactone), polyanhydride, and natural polymers including albumin, casein, and waxes, such as glycerol mono- and distearates. Preferred polymers for use in the practice of this aspect of the present disclosure are polylactide, polyglycolide, and poly(d,l-lactide-co-glycolide). The molar ratio of lactide to glycolide in such copolymers is preferably in the range of about 75:25 to 50:50.

[0372] In the case of polyester polymers including polylactide, polyglycolide, and poly(d,l-lactide-co-glycolide), it is understood that the polymer can have either carboxylic acid end groups or carboxylic acid ester end groups. Particularly useful are poly(d,l-lactide-co-glycolide) copolymers (PLGA copolymers) in which the molar ratio of lactide to glycolide is about 50:50 to 90:10, or 50:50 to 85:15, or 50:50 to 75:25, and / or the molecular weight is 5,000 to 500,000 daltons, or 5,000 to 150,000 daltons, or 20,000 to 200,000 daltons, or 24,000 to 38,000 daltons.

[0373] Useful PLGA polymers can have a weight average molecular weight of about 5,000 to 500,000 Daltons, preferably about 150,000 Daltons. Depending on the degradation rate to be achieved, polymers of different molecular weights can be used. For the diffusion mechanism of drug release, the polymer should remain unchanged until all the drug is released from the polymer matrix and then degrade. The drug can also be released from the polymer matrix as the polymeric excipient bioerodes.

[0374] PLGA can be prepared by conventional methods or may be commercially available. For example, PLGA can be produced by ring-opening polymerization using a suitable catalyst from cyclic lactide, glycolide, etc. (see European Patent No. 0058481 B2; Influence of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

[0375] PLGA is considered to be biodegradable by the degradation of the entire solid polymer composition by hydrolysis and enzymatic cleavage of the ester bonds that are hydrolyzable and enzymatically cleavable under biological conditions (e.g., in the presence of water and biological enzymes found in the tissues of warm-blooded animals such as humans), forming lactic acid and glycolic acid. Both lactic acid and glycolic acid are water-soluble and non-toxic products of normal metabolism and may further biodegrade to form carbon dioxide and water. That is, PLGA is thought to degrade in the body of warm-blooded animals such as humans by hydrolysis of its ester groups in the presence of water, producing lactic acid and glycolic acid and forming an acidic microclimate. Lactic acid and glycolic acid are by-products of various metabolic pathways in the body of warm-blooded animals such as humans under normal physiological conditions and are therefore highly tolerated and produce minimal systemic toxicity.

[0376] In the case of long-acting injectable compositions, 5-HT 2A or 5-HT 2AThe 5-HT / D2 receptor ligand can be dissolved, dispersed, or suspended in a polymeric matrix and / or further admixed with a pharmaceutically acceptable diluent or carrier. Such carriers may be aqueous, such as water suitable for injection (e.g., aqueous buffer solutions), or non-aqueous, such as organic solvents or mixtures of water and organic solvents (e.g., water-miscible organic solvents). In some embodiments, the 5-HT 2A or 5-HT 2A / D2 receptor ligand is encapsulated in microspheres or microparticles suspended or dispersed in a pharmaceutically acceptable diluent or carrier as described in U.S. Patent Nos. 9,708,322 and 9,956,227, the entire disclosures of each of which are incorporated herein by reference. Further information regarding the preparation of microparticles can be found in U.S. Patent Application Publication No. 2008 / 0069885, the entire disclosure of which is incorporated herein by reference.

Example

[0377] Drugs and experimental design. Lumateperone, also known as ITI-007 or IC200056 tosylate, is a compound of formula I in the form of the tosylate, where X is N(CH3) and Y is C=O:

Chemical formula

[0378] All other reagents, unless otherwise specified, were obtained in the highest purity available from Sigma-Aldrich (St. Louis, MO). In most experiments, at least 8-week-old mice or rats were intraperitoneally (IP) injected with lumateperone (0.3, 1, 3, or 8 mg / kg) or its vehicle (v / v: 5% DMSO, 5% Tween20, 15% polyethylene glycol [PEG] 400, and 75% pure HPLC water). Some rodents were also subcutaneously (SC) injected with lipopolysaccharide (LPS, 500 μg / kg; Sigma-Aldrich, ref#0127: B8) diluted in 0.9% injectable saline, and control group animals were injected with all vehicles matching the experimental conditions. In experiments examining the delayed administration of lumateperone, mice (n = 4 - 9 per group) were first subcutaneously injected with LPS or saline, and then 30 minutes later were IP injected with lumateperone (3 mg / kg) or its vehicle. In experiments using restraint stress, mice assigned to the restraint stress group were singly injected with lumateperone (3 mg / kg) or its vehicle and immediately placed in a restraint bag for rodents. In behavioral experiments, rats were pretreated on day 1 with lumateperone (1 mg / kg) or its vehicle. On day 2, naive rats were either not injected or were injected with saline or LPS (1 mg / kg, SC). On day 3, rats were reinjected with either lumateperone or saline and examined the next day (day 4).

[0379] Animals. C57BL / 6 male adult mice weighing 28 - 30 g at the time of the experiment were housed in small cages in groups of 4 or 5. Sprague-Dawley male adult rats weighing 175 - 200 grams at arrival after shipment were housed in pairs. All animals were housed under standard laboratory breeding conditions with free access to food and water on a 12-hour light / dark cycle.

[0380] The organization takes. Mice are euthanized 2 hours after lumateperone injection (for co-treatment experiments with LPS) or application of restraint stress for sample collection. Rats are euthanized 18 hours after LPS injection for sample collection. The hippocampi from mice and rats are rapidly dissected under RNAse-free conditions and placed into 1.5 mL Eppendorf tubes. When appropriate, samples are snap-frozen in liquid nitrogen and stored at -80 °C until further analysis is performed. Trunk blood is collected from mice into serum collection tubes, allowed to clot at room temperature for 1 hour, and then centrifuged at 1,500 g for 10 minutes at 4 °C.

[0381] Multiplex assay. In mouse serum, the protein levels of IL-1β, IL-6, IL-10, and TNFα are measured using the V-Plex Meso Scale Discovery (MSD) Multiplex spot assay Mouse Neuroinflammation 1 panel (Meso Scale Diagnostics, Rockville, MD). All samples are run in duplicate or triplicate according to the manufacturer's instructions and analyzed using MSD Discovery Workbench software (Meso Scale Diagnostics).

[0382] Quantitative real-time PCR. Mouse hippocampal tissue is homogenized using glass beads in 1 mL of TRIzol reagent with a BeadBeater (Biospec Products, Bartlesville, OK). Heavy phase-lock gel tubes are used to allow phase separation after adding 400 μL of chloroform to the sample and centrifuging at 12,000 rpm for 10 minutes at room temperature. RNA is extracted using the Qiagen Rneasy kit (Qiagen, Hilden, Germany). 2 μg of total RNA is used for cDNA synthesis (SuperScript IV Reverse Transcriptase; ThermoFisher Scientific, Waltham, MA). The purity and concentration of RNA are measured with a Nanodrop spectrophotometer; the optical density (OD) 260 / 280 and OD 260 / 230 are within 1.8 - 2.3. In the hippocampus, four major markers of inflammatory and anti-inflammatory cytokines and chemokines (IL1b: ID Mm00434228_m1, Tnfa: ID Mm00443258_m1, IL6: ID Mm00446190_m1, and IL10: ID Mm01288386_m1; ThermoFisher Scientific) are initially selected for analysis (n = 5 - 12 / group). In subsequent experiments, transcripts of other inflammatory markers including Icam1 (ID Mm00516023_m1; a cell adhesion molecule involved in immune cell migration), Cldn5 (ID Mm00727012_s1; a tight junction protein), colony-stimulating factor 1 (Csf1: ID Mm00432686_m1; a factor regulating microglial function) and its receptor Csf1r (ID Mm01266652_m1), and the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome complex (Nlrp3: Mm00840904_m1) are selected for analysis. Gapdh (ID Mm99999915_g1) is selected as the housekeeping gene.QuantStudio 7 (ThermoFisher Scientific) is used for the analysis of plates (MicroAmp Optical 384-well plate; Applied Biosystems, Waltham, MA, and ThermoFisher Scientific) loaded with TaqMan Universal Master Mix II without uracil-DNA glycosylase at a reaction volume of 20 μl using 100 ng of cDNA per well. All mRNAs are measured by qRT-PCR on an ABI Prism 7900HT system using TaqMan Gene Expression Assays. The Ct value of the gene of interest is normalized to the Ct value of a reference gene (Gapdh).

[0383] NanoString. The mouse neuropathology panel contains 770 genes related to the themes of neurotransmission, neuron-glia interaction, neuroplasticity, cellular structural integrity, neuroinflammation, and metabolism. A total of 13 housekeeping genes are used for normalization of expression (Aars: NM_146217.4, Asb10: NM_080444.4, Ccdc127: NM_024201.3, Cnot10: NM_153585.5, Csnk2a2: NM_009974.3, Fam104a: NM_138598.5, Gusb: NM_010368.1, Lars: NM_134137.2, Mto1: NM_026658.2, Supt7l: NM_028150.1, Tada2b: NM_001170454.1:3224, Tbp: NM_013684.3:70, and Xpnpep1: NM_133216.3:1826, see Figure 1-1). Hippocampal RNA was extracted using the Qiagen microkit (Qiagen) and evaluated with an Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA) to assess RNA concentration, quality, and integrity. Sample preparation, hybridization, and detection (100 ng per sample, n = 5 - 6 / group) were performed according to the manufacturer's instructions (NanoString Technologies, Seattle, WA). The normalized data were converted to log2 scores to represent fold changes. NanoString results (raw counts and normalized counts) were derived from the RCC file using nSolver software (version 2.6; NanoString Technologies). The complementary gene software analysis tool ROSALIND® Advanced Analysis Software (NanoString Technologies) was also used, providing a comprehensive free cloud-based data analysis of nCounter data by directly analyzing the raw RCC file generated from NanoString.The data is imported into ROSALIND® Advanced Analysis Software, where normalization, calculation of fold change, P - values, identification of enriched pathways, and heat maps are performed.

[0384] Enrichment of microglia. In male adult rats (8 - 9 weeks old, n = 8 - 12 per group) pretreated 1 day prior (18 hours prior) with either LPS and lumateperone or vehicle, the hippocampus was dissected and placed in 1 mL of medium A solution containing 0.6% glucose and 15 mM HEPES. Subsequently, the brain tissue was processed with a Dounce homogenizer and passed through 16 - gauge and 20 - gauge needles. 1 mL of medium A was added to the washed cell suspension, passed through a 70 - mm cell strainer, and stored on ice. Next, 6 mL of 100% Percoll solution (9 parts Percoll [GE Healthcare, Chicago, IL] and 1 part HBSS) was added to obtain a 75% Percoll solution. Then, the 75% Percoll cell suspension was placed under the layer of 25% Percoll solution containing phenol red, with a layer of PBS on top. To isolate hippocampal microglia, a discontinuous Percoll density gradient was layered as follows: 75%, 25%, and 0% isotonic Percoll (PBS). The gradient solution was then centrifuged at 3,000 rpm for 25 minutes at 4°C in a swinging bucket with minimal acceleration and deceleration and no brake. After centrifugation, the upper layer (interface PBS / 25% Percoll) containing myelin and debris was removed, and the cell layer at the 25% / 75% interphase was recovered and washed. In pilot experiments, gene expression in different fractions was compared to verify the presence of microglia in the interphase layer. The final pellet was resuspended in 350 μL of Buffer RLT from the Qiagen microkit (Qiagen), and RNA extraction was performed according to the manufacturer's instructions.

[0385] Restraint stress protocol. Acute restraint stress is performed using a traditional triangular special rodent "decapicone" restraint bag (Braintree Scientific, Braintree, MA; ref# MDC-200). Mice (n = 11 - 13 per group) are placed in the restraint bag and left at room temperature in a safe location for 2 hours. At the end of the 2-hour stress session, the mice are euthanized and whole hippocampal samples are collected. Control non-stressed mice are kept in their home cages in the adjacent room and euthanized at the same time point as the stressed mice for sample collection.

[0386] BBB Permeability Assay. The fluorescein sodium (NaFl) permeability assay is performed as previously described with some modifications (Olsen et al., “Correlation between breakdown of the blood-brain barrier and disease outcome of viral encephalitis in mice,” Antiviral Res. 75:104-112 (2007)). Mice (n = 4-8 per group) are administered lumateperone and either LPS is administered or they are restrained as described above. Forty-five minutes prior to tissue collection, mice are administered 200 μl of 10% NaFl (Cat# F6377, MilliporeSigma) IP. The mice are then euthanized by overdose of isoflurane, blood is collected by cardiac stick and allowed to clot while protected from light. The mice are perfused with 15 ml of 1× PBS solution. The brains are removed and snap frozen while protected from light. Serum is collected from the blood samples by centrifugation at 1,500 g for 10 minutes at 4°C. The brains are homogenized in 1× PBS and centrifuged at 10,000 g for 10 minutes at 4°C, and the supernatant is recovered for protein concentration determination by Pierce BCA Protein Assay and further analysis. Proteins are extracted from both serum and tissue homogenates by trichloroacetic acid precipitation (Cat# T6399, MilliporeSigma) on ice and centrifuged at 10,000 g for 10 minutes at 4°C. Samples are measured in duplicate using a FITC Filter spectrophotometer (EnVision 2105; PerkinElmer, Waltham, MA; excitation: 485 nm, emission: 535 nm). The mean fluorescence of sham mice is subtracted from each value prior to calculation. The tissue homogenate fluorescence measurements are first normalized to the total protein concentration and the cerebral / serum ratio in arbitrary fluorescence units is calculated.

[0387] Behavioral Assessment. All behavioral tests are performed in the morning using male adult Sprague-Dawley rats (n = 9-11 per group in the LPS experiments and n = 13-14 per group in naive rats).

[0388] Novelty Suppressed Feeding Test (NSFT). This test measures the consumption of familiar food in a novel environment by taking advantage of the aversion of mice to feeding in a new environment after a fasting period (Ramaker and Dulawa, “Identifying fast-onset antidepressants using rodent models,” Mol. Psychiatry 22:656-665 (2017)). Rats are fasted overnight and placed in an open field (76.5×76.5×40 cm 3 ) with a small amount of food pellets (a total of 6 pellets). During the test, the rats are first exposed to the open field (novelty) and allowed to explore for up to 15 minutes under red light. The latency until the animal approaches the food pellet and takes the first bite is manually scored. Subsequently, a Home Cage Feeding Test (HCFT) is performed to confirm that the latency measured by NSFT is not due to differences in hunger levels. In the home cage feeding analysis, the amount of food (g) eaten in the 10 minutes after the end of all test sessions is evaluated.

[0389] Novelty Induced Hypophagia (NIH). This conflict-based behavioral task evaluates the impact of environmental stress factors on conditioned approach responses to a palatable food reward (Ramaker and Dulawa, 2017). Rats are habituated for 1 hour daily for 3 consecutive days in the home cage with diluted (milk / water = 1:3) sweetened condensed milk. First, the animals are tested in the home cage under normal lighting. In the post-drug treatment test, the rats are placed in a new, clean cage of the same dimensions, without bedding, with white paper placed under the cage to enhance aversion, and under dim lighting (approximately 50 lux), and then the drinking latency is recorded.

[0390] Open Field Test (OFT). Rats are placed in an open field box (76.5×76.5×40 cm 3 ) under dim illumination, and spontaneous locomotor activity is measured for 10 minutes using ANY-Maze Software (Stoelting Co., Wood Dale, IL).

[0391] Reward Sniffing Test (also known as female urine sniffing test (FUST)): In this anhedonia-based assay, rats are taken to a well-ventilated testing room under dim illumination. A sterile cotton swab is attached to one side of the wall inside the home cage for 1 hour to acclimatize the rats to this new object. For the two stages of the 5-minute test, the rats are first exposed to a new cotton swab soaked in sterile water as a control and removed after 5 minutes; 45 minutes later, another cotton swab pre-soaked in fresh rat urine collected from females of the same strain is attached to the cage wall. The behavior of the male rats is video-recorded, and the latency to first sniff the cotton swab and the total time spent sniffing the cotton swab are measured.

[0392] Statistical analysis. Data are presented as mean ± SEM. All statistical analyses were performed using GraphPad version 9 or earlier (GraphPad Software, San Diego, CA). Sample sizes for experiments were calculated using the effect size and variance expected based on past data. The Kolmogorov–Smirnov test was used for normality testing. Unpaired two-sided t-tests were used for comparisons between two groups. When a normal distribution was not confirmed, the Mann–Whitney U test was used to compare the mean ranks of the two groups. Multiple group comparisons were performed using one-way ANOVA followed by Bonferroni post hoc test or Tukey's multiple comparison test. NanoString nCounter analysis was based on multivariate linear regression with Benjamani–Yekutieli adjustment. p-values are indicated in each figure, and details of the specific tests used are described in the figure legends. Outliers were removed using the median absolute deviation (MAD) formula (median ± 2.5 times MAD for outlier detection).

[0393] Example 1: Lumateperone normalizes the pro-inflammatory state in a dose-dependent manner. In the serum or plasma of patients with MDD and other mental disorders, certain cytokines are elevated. Here, the gene and protein expression of a subset of pro-inflammatory and anti-inflammatory cytokines are measured in the brains of mice challenged with inflammation using a single administration of LPS (500 μg / kg) to induce acute encephalitis. Samples are taken 2 hours after co-injection of LPS and lumateperone or vehicle. mRNA is isolated and analyzed by qRT-PCR or the NanoString Neuropath panel. The ability of lumateperone to improve the LPS-induced changes in hippocampal mRNA levels of these cytokines is studied using three doses of lumateperone (0.3 mg / kg, 3 mg / kg, and 8 mg / kg, IP). These doses fall within the effective dose range of lumateperone for the modulation of antipsychotic-like and antidepressant-like activities in rodents (see Snyder et al., “Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission,” Psychopharmacology 232:605-621 (2015)). The results are shown in Table 1A as the relative changes in mRNA levels of each cytokine gene (IL1b, IL6, Tnfa, IL10) normalized to the control group using the Dct method (n = 5-12 per group):

[0394] [Table 1]

[0395] As expected and as determined by one-way ANOVA, LPS treatment significantly increased the gene expression of pro-inflammatory cytokines in the hippocampus but did not significantly change the expression of the anti-inflammatory cytokine IL10 compared to control mice (effect of LPS treatment on the level of IL1b: F (4,40) = 16.48, P <.01; Il6: F (4,43) = 11.57, P <.001; Tnfa: F (4,43) = 24.51, P <.001; Il10: F(4,41) = 13.15, P >.99).

[0396] The results showed that lumateperone dose-dependently decreased the LPS-induced increase in the hippocampal mRNA levels of the inflammatory genes IL1b, Tnfa, and IL6 when administered simultaneously with LPS (IL1b: doses 3 mg / kg and 8 mg / kg, P <.001; IL6: dose 3 mg / kg, P <.001, dose 8 mg / kg, P <.01; Tnfa: all doses, P <.001). Furthermore, lumateperone significantly increased the hippocampal mRNA levels of the anti-inflammatory cytokine IL10 at doses of 3 mg / kg and 8 mg / kg compared to the levels seen in animals administered LPS alone (post hoc comparison of means: P =.004 and P <.001 for lumateperone 3 mg / kg and 8 mg / kg, respectively, compared to LPS).

[0397] To investigate whether lumateperone also decreases the LPS-induced increase in the protein levels of inflammatory cytokines in peripheral blood, based on the data from the above dose-response study in hippocampal tissue, a dose of 3 mg / kg of lumateperone was selected for further analysis. As an additional control, an additional experimental group receiving an injection of lumateperone alone was also included. Protein concentrations were measured using the Multiplex MSD assay V-Plex technology. The results are expressed in pg / mL, except for IL-6 which is measured in ng / mL.

[0398]

Table 2

[0399] Examining the protein levels of inflammatory biomarkers in serum, a pattern of results similar to that seen for the changes in gene expression in hippocampal tissue was obtained. Two-way ANOVA revealed a significant effect of LPS, with an increase in the protein levels of all the biomarkers studied (Tukey multiple comparison vs control; IL-1b: F (1,17)=15.21, P <.0012; IL-6: F (1,19) =27.77, P <.0001; TNF-a: F (1,20) =69.12, P <.0001; IL-10: F (1,16) =38.24, P <.001).

[0400] It can be seen that lumateperone treatment reduces the circulating protein levels of the pro-inflammatory cytokines IL-1β, TNF-α, and IL-6 in the serum compared to mice treated with LPS alone (IL-1β: LPS vs LPS + lumateperone, P =.0081; IL-6: LPS vs LPS + lumateperone, P <.0001; TNF-α: LPS vs LPS + lumateperone, P <.0001). Previous studies have shown that LPS, a cell wall component of Gram-negative bacteria, binds to Toll-like receptor 4 (TLR4) and activates nuclear factor κB (NFκB) signaling (Hoshino et al., “Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product,” J. Immunol. 162:3749-3752 (1999)). Moreover, it is known that primary rodent microglia also upregulate IL-10 signaling molecules and thus have a mixed gene profile that is not strictly pro-inflammatory.

[0401] In contrast to brain tissue, it was found that LPS challenge increased the IL-10 protein levels in the serum. In two-way ANOVA, no drug effect was observed for the IL-10 protein levels in the serum (F (1,16)(F(1,38)=0.03489, P = 0.8542), lumateperone treatment alone without LPS induced a significant increase in IL-10 when compared to control only. These data indicate that lumateperone increases the protein level of the anti-inflammatory cytokine IL-10 while normalizing specific pro-inflammatory cytokines elevated by LPS in serum and brain compared to vehicle.

[0402] To better understand the transcriptional pathways and regulatory mechanisms altered by lumateperone in relation to heightened inflammation, NanoString nCounter-based analysis was performed after co-injection of LPS (500 μg / kg) and lumateperone (3 mg / kg), and samples were collected 2 hours after injection. The NanoString platform has been effectively used to quantitatively measure in vivo gene expression of target genes in several neuropathological mouse models. As shown in the table below, when co-injected with LPS, analysis with NanoString software confirmed that lumateperone significantly decreased the expression of genes involved in the inflammatory process:

[0403]

Table 3

[0404] Generally, the indicated global significance score measures how much a given gene is upregulated or downregulated with respect to a given covariate. This is calculated in the same way as the one-way global significance score, but taking into account the sign of the t-statistic. The score was calculated with nSolver software using the control group as a reference.

[0405] Therefore, here, the indicated global significance score measures how much a given gene set is upregulated or downregulated compared to the control group. The results show that the LPS + lumateperone treatment downregulates gene expression sets involved in cytokine signaling, inflammatory signaling, innate immune response, and the NF-kB pathway. Pathway analysis also shows that genes related to angiogenesis, epigenetic regulation, and the Notch and Wnt pathways are increased in the group injected with lumateperone.

[0406] Surprisingly, it is found that lumateperone alone changes the gene expression of some of these pathways to the same extent (i.e., with a similar score) as the LPS + lumateperone combination treatment.

[0407] The following table shows the top genes among those involved in microglial function, neuroprotection, and inflammation that showed changes in the LPS + lumateperone group compared to the LPS group.

[0408]

Table 4

[0409] As shown in the above table, analysis with NanoString software also shows that the combination of LPS + lumateperone increases the expression of neuroprotection markers such as Fos, Egr1, Cldn5, Vegfa, and Ngf, while significantly decreasing the expression of genes involved in inflammation such as Casp4, Ccr2, Socs3, Lrg1, Il1b, Osmr, Ly6a, Myd88, Il1r1, Nfkb2, Tnfrsf1, and Ikbkb compared to LPS alone.

[0410] Constitutive microglial markers, including Maff, Cx3cr1, Cd36, Trem100, Trem144, and P2ry12, were found to be upregulated by lumateperone, further supporting the potential protective properties of lumateperone in acute inflammatory conditions.

[0411] Next, using ROSALIND® Advanced Analysis Software, a heatmap of cytokine-specific gene expression comparing filters with P <.04999, LPS + lumateperone, and LPS alone was obtained. Data analysis using ROSALIND® confirmed that lumateperone significantly downregulates genes promoting inflammation (e.g., Osmr, Tnfrsf1a, Tnfrsf11b, Prl, and Il1r1). A Venn diagram based on this analysis reveals some overlap of significantly changed gene expression changes (p ≤.04999) when group comparisons are made. The results show that the receptor for advanced glycation end products (RAGE) pathway changes significantly when comparing LPS with the control; the brain-derived neurotrophic factor (BDNF) signaling pathway is one of the most significantly changed pathways in the LPS + lumateperone group compared to LPS; and the regulation of IL-6 is one of the most changed pathways when comparing lumateperone with LPS. In summary, lumateperone has been found to reverse acute inflammatory conditions by enhancing gene signatures indicative of tissue protection and repair while normalizing major pathways involved in inflammation.

[0412] Example 2: Lumateperone reduces pre-established LPS-induced inflammatory cytokine mRNA levels in the hippocampus. Based on these findings, it was desired to study whether the delayed administration of lumateperone could change an established pro-inflammatory state and thereby re-establish immune system homeostasis. Adult mice were first subcutaneously injected with an LPS injection (500 μg / kg) or vehicle (0.9% saline), and 30 minutes later, lumateperone (3 mg / kg) or vehicle (5% DMSO, 5% Tween-20, 15% PEG-400, 75% water) was injected IP. Samples were taken 1.5 hours later (i.e., 2 hours after LPS injection). The results are shown in Table 2A as the relative changes in the hippocampal mRNA levels of each cytokine gene (IL1b, IL6, Tnfa, IL10) normalized to the control group using the Dct method as in Example 1 (n = 4 - 9 per group):

[0413]

Table 5

[0414] It was found that LPS significantly increased the mRNA levels of IL1b, IL6 and Tnfa in the hippocampus (two-way ANOVA, LPS effect: IL1b: F (1,19) = 94.51, P <.0001; Il6: F (1,20) = 8.008, P =.0104; Tnfa: F (1,20) = 63.35, P <.0001), and it was found that the delayed injection of lumateperone decreased the mRNA levels (IL1b: LPS vs LPS + lumateperone, P =.0433; Il6: LPS vs LPS + lumateperone, P =.0078; Tnfa: LPS vs LPS + lumateperone, P <.0001). These results indicate that lumateperone shows a similar effect whether co-injected with LPS or administered 30 minutes after LPS injection. It also shows that the mRNA level of IL10 is increased by lumateperone whether in the presence or absence of LPS. The two-way ANOVA analysis of IL10 showed an effect of LPS (F (1,20) = 21.31, P =.0002) and an effect of lumateperone (F (1,20)= 69.02, P <.0001), confirming that lumateperone regulates the hippocampal mRNA levels of this anti-inflammatory cytokine.

[0415] Supplementary major markers revealed by NanoString analysis are also examined in the same procedure as above.

[0416]

Table 6

[0417] Significant interactions between Cldn5 and Icam1, and treatment effects (lumateperone) on the treatment (LPS) effect are found. Lumateperone decreases the Icam1 level (LPS vs LPS + lumateperone, P <.0001), and co-administration of LPS and lumateperone increases Cldn5 (LPS vs LPS + lumateperone, P <.0001). Analysis of the level of Csf1 mRNA shows an interaction between the drug and treatment and the drug effect, indicating that lumateperone decreases Csf1 compared to the LPS group (LPS vs LPS + lumateperone, P =.0009). Collectively, these results indicate that administration of lumateperone after LPS-induced inflammation initiates transcriptional regulation of genes related to inflammation and tissue repair.

[0418] Example 3: Lumateperone enhances the BBB integrity of the hippocampus. Systemic inflammation is associated with enhanced BBB permeability, which has been discussed as a potential factor underlying the pathophysiology of depression. In this experiment, lumateperone (3 mg / kg, IP) is injected into mice either simultaneously (co-injection) with LPS injection or 30 minutes later (delayed injection). 45 minutes before sample collection, mice are injected with NaFl (200 μl of 10% solution, IP) (Table 3).

[0419]

Table 7

[0420] In mice treated with LPS, the brain permeability of NaFl was significantly increased, which was significantly suppressed in both the lumateperone co-injection group and the lumateperone delayed injection group (normalized to control = 1, LPS = 1.406, control vs LPS: Tukey's multiple comparison test P <.05; LPS + lumateperone = 0.863, LPS vs LPS + lumateperone: P <.01; LPS + lumateperone (delayed) = 0.652, LPS vs LPS + lumateperone (delayed): P <.001 - all units are arbitrary units normalized to the control. F (3,21) = 11.49, P =.0001. (Table 1). These data indicate that the combined administration of lumateperone and LPS restored the integrity of the BBB.

[0421] Example 4: Lumateperone suppresses stress-induced inflammation and BBB permeability. To examine whether lumateperone can normalize the pathological inflammation of the brain induced by acute stress factors, restraint stress, a stress factor known to induce an increase in inflammation, is used. Immediately after a single injection of lumateperone (3 mg / kg, IP) or vehicle (5% DMSO, 5% Tween-20, 15% PEG-400, 75% water) into mice, they are placed in a restraint bag for rodents for 2 hours. Control mice receive vehicle treatment and are returned to their home cages before sample collection. Protein concentration is measured using the Multiplex MSD assay V-Plex technology and normalized to the control group. The results are expressed in pg / mL.

[0422]

Table 8

[0423] Acute restraint stress results in a significant increase in serum IL-1β, IL-6, and TNF-α levels, but in mice administered with lumateperone, each of these proteins is significantly decreased to control levels (IL-1β: stress vs. stress + lumateperone, Bonferroni's multiple comparison test P <.001; IL-6: stress vs. stress + lumateperone, P <.001; TNF-α: stress vs. stress + lumateperone, P =.007, compared with the control group). For hippocampal mRNA expression, corresponding data are collected according to the procedure of Example 1. The results are shown in Table 4B as the relative changes in mRNA levels of each cytokine gene (IL1β, IL6, Tnfa, IL10) normalized to the control group using the Dct method:

[0424]

Table 9

[0425] In the hippocampus of the same mice, acute restraint stress resulted in an increase in the mRNA level of IL1β (control = normalized to zero, P =.007), but no significant decrease was observed after administration of lumateperone. At this time point, the mRNA levels of Tnfa and IL6 were not changed by acute restraint stress. Interestingly, both the serum protein level and hippocampal mRNA level of IL-10 increase with lumateperone compared to the control (IL-10 protein level: control vs. stress + lumateperone, Bonferroni's multiple comparison test P =.001; IL10 mRNA level: control is normalized to zero, stress + lumateperone, P <.001).

[0426] Using the same procedure as above, serum corticosterone concentration and hippocampal Cldn5 mRNA expression are also measured (corticosterone is measured using a commercially available ELISA kit).

[0427]

Table 10

Table 11

[0428] This data shows that the corticosterone concentration in the serum of stressed mice increases, and the increased level is significantly suppressed by lumateperone (stress vs. stress + lumateperone: P <.001; F (2,27) = 124.2, P <.001). Also, it is confirmed that lumateperone significantly increases the transcriptional product of Cldn5 in stressed animals (stress vs. stress + lumateperone: P <.001; F (2,36) = 11.44, P <.001).

[0429] In another cohort, it is found that acute restraint stress does not significantly increase NaFl brain penetration (normalized to 1 for control, stress = 1.132). However, lumateperone alone significantly reduces the brain penetration of NaFl in the stress + lumateperone cohort compared to the stress cohort (stress + lumateperone = 0.7278; stress vs. stress + lumateperone: independent t-test P <.05; t (7) = 2.373; see Table 3 above).

[0430] Example 5: Lumateperone reduces anxiety and normalizes LPS-induced anhedonia. LPS is administered to rats to induce a transient state of anhedonia, and the behavior dependent on the reward system is measured by using female urine as a reward stimulus to examine whether lumateperone can rescue the transient LPS-induced disorder.

[0431] In a pilot study, the dose of LPS is varied to create a dose-response curve in order to select the optimal dose for inducing anhedonia response in rats. Based on these studies, an SC dose of 1 mg / kg of LPS is selected. Rats are first injected with lumateperone (1 mg / kg; IP) or vehicle as a pretreatment. Twenty-four hours later, LPS (1 mg / kg; SC) is injected. Then, 24 hours later, rats are injected with lumateperone (1 mg / kg; IP) or vehicle. Control rats are administered saline instead of LPS and vehicle instead of lumateperone. Anhedonia is evaluated using FUST (female urine olfactory test), and the latency to sniff the reward and the time spent sniffing the reward are measured together. The latency to sniff water is used as a control. The results of removing outliers using the MAD method are shown in the following table (time is in seconds):

[0432]

Table 12

[0433] The results show that when exposed to a reward cue (female urine), LPS-treated male rats administered lumateperone have a decreased latency to sniff the cotton swab soaked in urine compared to the LPS group. Overall, it can be seen that lumateperone-treated rats sniffed the reward cue for about the same amount of time as control rats during the 5-minute test period. Importantly, there was no significant difference in the time spent exploring the cotton swab soaked in water, which was conducted as a control test, among the rats. Spontaneous locomotion in an open field (track length is in meters) is also measured as a control. As shown in the following table, spontaneous locomotor activity is also affected regardless of the group:

[0434]

Table 13

[0435] The basal level of anxiety is also tested using the novelty-suppressed feeding test (NSFT) and the novelty-induced hypophagia (NIH), two commonly used tests in the absence of LPS. It is well known that rodents experience an increase in stress levels when placed in a new environment (Ramaker and Dulawa, 2017). These two tests utilize this characteristic by measuring the latency to feeding in food-deprived rats (NSFT) or the latency to receive a reward that they have been habituated to prior to the test (NIH).

[0436] As in previous studies, on days 1 and 3, rats are injected with lumateperone (1 mg / kg; IP). Lumateperone is found to shorten the feeding latency in the NSFT (Control: 657.8 seconds, Lumateperone: 507.9 seconds, Mann-Whitney U test P =.0009, Table 6).

[0437]

Table 14

[0438] In contrast, as shown by the HCFT (used as a control for the NSFT), it is found that there is no effect on feeding itself. Similarly, in the NIH test, which measures anxiety in a slightly different setting and does not require food deprivation, lumateperone is found to shorten the latency to drink a reward when rats are placed in a new empty bright cage that induces stress (i.e., diluted condensed milk; Control: 65.4 seconds, Lumateperone: 30.5 seconds, Mann-Whitney U test P =.0257, Table 2). Again, locomotor activity evaluated in the open field did not reveal a significant effect of lumateperone between treatment groups (Table 6).

[0439] In summary, these results confirm that lumateperone may reduce anhedonia and lower the basal level of anxiety in stressful situations.

[0440] Example 6: Lumateperone acts on microglia isolated from the hippocampus of rats after LPS-induced inflammation. Based on the associations revealed by the above gene ontology analysis, it was desirable to investigate the possibility that microglia are involved in the reduction of LPS-induced inflammation mediated by lumateperone administration. Microglia, the resident immune cells of the brain, have emerged as a powerful effector for initiating and resolving neuroinflammation in various states and disorders. Therefore, specifically monitor the effect of lumateperone on the in vivo inflammatory activity of hippocampal microglia while examining the time window in which inflammation would be detected in enriched preparations of rat brain microglia.

[0441] From exploratory experiments, it becomes clear that in the microglia-enriched fraction from the rat hippocampus, inflammation approaches background levels at +26 hours after LPS administration. Therefore, an early time point of +18 hours after LPS injection is selected to assess potential changes indicating inflammation. Rats are pretreated with the same dose of LPS (500 μg / kg diluted in 0.9% saline) as used in the biochemical and RNA-based experiments and receive lumateperone (3 mg / kg in vehicle) or vehicle injection (5% DMSO, 5% Tween-20, 15% PEG-400, 75% water) 16 hours later.

[0442] The hippocampi from both sides of the brain are collected 2 hours later (+18 hours after LPS injection), and microglia are rapidly isolated from the fraction concentrated by Percoll gradient solution. RNA is extracted from the resulting reconstituted cell pellet and RT-qPCR is performed. The results are shown in Table 7 as the relative changes in the mRNA levels of each cytokine gene (IL1b, IL6, Tnfa, Nlrp3, Csf1r) normalized to the control group using the Dct method (n = 8 - 12 per group):

[0443]

Table 15

[0444] The results show that LPS administration leads to a significant increase in the expression of the IL1b and IL6 genes in isolated hippocampal microglia; these increases are significantly suppressed by lumateperone administration (IL1b: one-way ANOVA F (2,17) = 15.05, P <.001; Il6: one-way ANOVA F (2,20) = 6.622, P =.006). For Nlrp3, lumateperone significantly reduces the gene expression level compared to LPS alone (one-way ANOVA, F (2,26) = 4.302, P =.02). However, at this point, the expression of the Tnfa gene was not different from the control, and it was most likely reflecting a different response time course in isolated microglia compared to what was observed in the whole tissue.

[0445] Nevertheless, it can be seen that lumateperone administration leads to a decrease in the Tnfa mRNA level when compared to microglia isolated from either control rats or LPS-treated rats (Tnfa: one-way ANOVA F (2,20) = 3.868, P =.04). LPS shows a tendency to increase the Csf1r mRNA level in microglia, while lumateperone has a tendency to reduce this response (one-way ANOVA F (2,29) = 0.9725, P =.39). This tendency is parallel to the effect of lumateperone treatment observed in the whole tissue. In summary, this data suggests that lumateperone suppresses LPS induction of a subset of inflammation-inducing genes expressed in hippocampal microglia.

[0446] Example 7: Post-hoc analysis of the phase 3 clinical trial of lumateperone in patients with schizophrenia. An unblinded, randomized, placebo-controlled, phase 3 clinical trial was conducted in 450 patients with schizophrenia aged 18 to 60 years who had experienced an acute exacerbation of psychosis. Patients were eligible if they had a total score of 15 or more out of 40 on the Brief Psychiatric Rating Scale, a score of 4 or more on two or more positive symptoms, and had experienced an acute exacerbation of psychosis defined as an acute episode onset within 4 weeks from screening. Patients were required to have a score of 4 or more on the Clinical Global Impression-Severity of Illness (CGI-S) at screening and baseline, indicating moderate to severe disease severity. The severity of illness was confirmed at baseline by a total score of 70 or more on the Positive and Negative Syndrome Scale (PANSS), indicating moderate to extreme symptoms of schizophrenia. A subgroup of these patients had comorbid depressive symptoms at baseline (defined as a Calgary Depression Scale for Schizophrenia (CDSS) score of more than 6 at baseline). Details of the clinical trial are reported in Correll et al., JAMA Psychiatry, 77(4): 349-358 (2020).

[0447] Patients were randomly assigned 1:1:1 (150 patients per group) to receive once-daily lumateperone tosylate 60 mg (free base 42 mg), lumateperone tosylate 40 mg (free base 28 mg), or placebo for 28 days.

[0448] The primary efficacy endpoint was the mean change from baseline in the total score on the Positive and Negative Syndrome Scale (PANSS) up to Day 28. The key secondary efficacy endpoint was the Clinical Global Impression-Severity of Illness (CGI-S) score. PANSS subscale scores, social function, safety, and tolerability were also evaluated. The primary and key secondary efficacy endpoints were evaluated weekly. Safety was evaluated by treatment-emergent adverse events (TEAEs), modified physical examinations, 12-lead electrocardiograms (ECGs), vital signs, and clinical laboratory tests (blood and urine samples for clinical laboratory analysis were collected from all subjects at screening and on Days 1, 8, 28, and 33 after an overnight fast).

[0449] The results of the trial showed that lumateperone was effective in improving the symptoms of schizophrenia and had a favorable safety profile.

[0450] Using the blood samples preserved from this trial, a post hoc analysis of inflammatory biomarkers in peripheral blood mononuclear cells (PBMCs) of patients with schizophrenia and co-existing depression will be conducted. Analyses will be performed on samples at Day 0 and Day 28 from patients treated with lumateperone 60 mg. Samples at Day 0 are available for 20 patients, while samples at Day 28 are available for only 18 patients. The baseline mean Calgary Depression Scale for Schizophrenia (CDSS) for the selected patients was 10.0, and the baseline mean PANSS total score was 88.7.

[0451] Samples were processed to isolate PBMCs according to standard procedures using the Ficoll-Paque method. Statistical analysis was performed using a paired two-sided t-test. Samples were assayed for C-reactive protein (CRP), serum amyloid A (SAA), soluble ICAM-1, soluble VCAM-1, IL-1β, TNFα, IL-6, IL-10, IL-2, IL-8, IL-13, and IFN-γ. ICAM-1 and VCAM-1 are expressed by vascular endothelium, macrophages, and lymphocytes. Upon cytokine stimulation, their concentrations increase significantly. ICAM-1 can be induced by IL-1β and TNF. ICAM and VCAM proteins may also be involved in the migration of pathogens to the CNS.

[0452] Results are shown in the table below (biomarker levels are shown in ng / mL; for samples where biomarker levels are below the minimum value for quantification, some N values are less than the total number of patients:

[0453]

Table 16

[0454] These data indicate that patients with schizophrenia and comorbid depression have high levels of inflammatory biomarkers in blood cells (PBMCs) at baseline, and these levels decrease significantly after 28 days of lumateperone treatment. These results also indicate that patients with schizophrenia with depressive symptoms can be pre-identified by measuring inflammatory biomarkers in the blood.

[0455] Interestingly, unlike the measurement of depressive symptoms (CDSS), the placebo group did not show a significant change in biomarker levels (data not shown).

Claims

1. A method for treating mental disorders caused by viral, bacterial or autoimmune encephalitis, and for treating the mental symptoms of viral, bacterial and autoimmune encephalitis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a 5-HT 2A or 5-HT 2A / D2 receptor ligand.

2. The ligand may be in deuterated form, in free base form, pharmaceutically acceptable salt form or prodrug form, of Formula I: 【Chemical 1】 [wherein, X is --N(H)--, --N(CH 3 )-- or --O--; Y is -C(=O)-, -C(H)(OH)- or -C(H)(OR 1 )-; R 1 is -C(O)-C 1-21 alkyl (e.g., -C(O)-C 1-5 alkyl, -C(O)-C 6-15 alkyl or -C(O)-C 16-21 alkyl), preferably the alkyl is straight-chain, may be saturated or unsaturated, and may be substituted with one or more hydroxy or C 1-22 alkoxy (e.g., ethoxy) groups, for example, R 1 is -C(O)-C 6 alkyl, -C(O)-C 7 alkyl, -C(O)-C 9 alkyl, -C(O)-C 11 alkyl, -C(O)-C 13 alkyl or -C(O)-C 15 alkyl] The compound represented by (wherein the compound hydrolyzes to form a residue of a natural or non-natural, saturated or unsaturated fatty acid, for example, the compound hydrolyzes to form a hydroxy compound on the one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand), the method according to claim 1.

3. The method according to claim 2, wherein X in the compound represented by formula I is -N(H)-, -N(CH 3 )- or -O-.

4. The method according to claim 3, wherein X in the compound represented by formula I is -N(CH 3 )-.

5. The method according to claim 3 or 4, wherein Y in the compound represented by Formula I is -C(=O)-.

6. The compound represented by Formula I is lumateperone: 【Chemical Formula 2】 The method according to claim 2.

7. The method according to claim 6, wherein the compound represented by Formula I is in free base or pharmaceutically acceptable salt form, for example, tosylate form.

8. The method comprises once-daily administration of an oral dosage form, such as a tablet or capsule, comprising a compound of Formula I in free base form or pharmaceutically acceptable salt form, such as tosylate form, in an amount corresponding to 1 to 100 mg of the free base, for example, 1 to 75 mg, or 1 to 60 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg, or 1 to 5 mg, or 40 to 60 mg, or 20 to 40 mg, or 10 to 20 mg, or about 60 mg, or about 40 mg, or about 30 mg, or about 20 mg, or about 10 mg, or about 5 mg of the free base, and a pharmaceutically acceptable diluent or carrier. The method according to any one of claims 2 to 7.

9. The method comprises once-daily administration of a transmucosal dosage form, such as a sublingual or buccal orally disintegrating tablet, an oblate (wafer) or a film, comprising a compound of Formula I in free base form or pharmaceutically acceptable salt form, such as tosylate form, in an amount corresponding to 0.5 to 30 mg of the free base, for example, 1 to 30 mg, or 1 to 20 mg, or 1 to 15 mg, or 1 to 10 mg, or 20 to 30 mg, or 10 to 20 mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg of the free base, and a pharmaceutically acceptable diluent or carrier. The method according to any one of claims 2 to 7.

10. 5-HT 2A or 5-HT 2A The method according to any one of claims 1 to 7, wherein the 5-HT / D2 receptor ligand is administered in the form of a long-acting injectable (LAI) composition, for example, for intramuscular or subcutaneous injection.

11. The method according to any one of claims 1 to 10, wherein the encephalitis is viral encephalitis.

12. The method according to claim 11, wherein the encephalitis is caused by or suspected of being caused by herpes simplex virus type 1, herpes simplex virus type 2, West Nile virus, Nipah virus, human immunodeficiency virus, rabies virus, Epstein-Barr virus, cytomegalovirus, coronavirus (e.g., MERS-CoV, SARS-CoV, SARS-CoV-2), or influenza virus (e.g., influenza A virus, e.g., H1N1, H2N2, H3N2, H5N1, H7N7).

13. The method according to any one of claims 1 to 10, wherein the encephalitis is bacterial encephalitis.

14. The method according to claim 13, wherein the encephalitis is caused by or considered to be caused by toxoplasmosis, rickettsia, mycoplasma, Borrelia (e.g., Lyme disease), or malaria.

15. The method according to any one of claims 1 to 10, wherein the encephalitis is autoimmune encephalitis.

16. The method according to claim 15, wherein the encephalitis is caused by or considered to be caused by autoantibodies against NMDA receptor, AMPA receptor, voltage-gated potassium channel (VGKC), LGI1 protein, GABA receptor, glycine receptor, glutamate receptor, or CASPR2 receptor.

17. The method according to any one of claims 1 to 16, wherein the mental disorder and / or mental symptoms are depression (e.g., acute depression, depression in MDD, depression in bipolar disorder), anxiety (e.g., acute anxiety), psychosis (e.g., schizophrenia), post-traumatic stress disorder, anhedonia, memory loss, impairment of executive functioning, difficulty concentrating, seizure, sleep difficulty, hallucination, personality change, or a combination thereof.

18. The method according to any one of claims 1 to 17, wherein the method protects or enhances the blood-brain barrier.

19. The method according to any one of claims 1 to 18, wherein the patient has an increase in the levels of pro-inflammatory cytokines such as TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, etc. in the CNS (e.g., in cerebrospinal fluid), or an increase in the level of C-reactive protein (CRP) of Csf1, and / or a decrease in the levels of anti-inflammatory cytokines such as TNFβ, IFN-α, IL-4 and IL-10 in the CNS (e.g., in cerebrospinal fluid).

20. 5-HT 2A or 5-HT 2A / D2 receptor ligand or a compound of formula I is administered intranasally, subcutaneously, intramuscularly, intravenously, orally, sublingually, intraperitoneally, or buccally and is dissolved in the mouth for transmucosal absorption, such as an orally disintegrating tablet, a wafer, or a film, according to any one of claims 1 to 19.

21. The method according to any one of claims 1 to 20, wherein the patient did not respond, or did not respond sufficiently, or suffered from undesirable side effects to treatment with any one or more of another antidepressant, such as a selective serotonin reuptake inhibitor (SSRI), serotonin reuptake inhibitor (SRI), tricyclic antidepressant, monoamine oxidase inhibitor, norepinephrine reuptake inhibitor (NRI), dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor) or serotonin receptor antagonist.

22. A method for protecting or enhancing the blood-brain barrier, the method comprising administering to a patient in need thereof a therapeutically effective amount of a 5-HT 2A or 5-HT 2A / D2 receptor ligand.

23. A method for treating a mental disorder in a patient in need thereof, wherein the patient has an increase in the levels of pro-inflammatory cytokines such as TNFα, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, etc. in the CNS (e.g., in cerebrospinal fluid), or an increase in the levels of C-reactive protein (CRP) or CSF1, and / or a decrease in the levels of anti-inflammatory cytokines such as TNFβ, IFN-α, IL-4 and IL-10 in the CNS (e.g., in cerebrospinal fluid), and the method comprises administering to the patient a therapeutically effective amount of a 5-HT 2A or 5-HT 2A / D2 receptor ligand.

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