Novel method

Abstract

The present disclosure provides methods for treating psychosis due to viral, bacterial, or autoimmune encephalitis, for treating psychiatric symptoms of viral, bacterial, or autoimmune encephalitis, and for protecting or enhancing the blood brain barrier, comprising administering to a patient in need thereof a therapeutically effective amount of 5-HT2A.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Application Serial No. 63 / 343,192, filed on May 18, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to 5-HT 2A 5-HT 2A Use of D2 receptor ligands, such as substituted heterocyclic fused γ-carbolines as described herein in free, pharmaceutically acceptable salt or prodrug form, in the treatment of psychiatric disorders caused by viral, bacterial or autoimmune encephalitis and in the treatment of psychiatric symptoms of viral, bacterial and autoimmune encephalitis and in protecting or strengthening the blood-brain barrier. Background of the Invention

[0005] Substituted heterocyclic fused γ-carbolines such as lumateperone are known to be 5-HT 2A 5-HT 2A / D2 receptor ligands, which can be used to treat central nervous system diseases. These compounds antagonize serotonin-2A (5-HT 2A ) receptors, and / or modulate dopamine receptor signaling at the level of key intracellular phosphoproteins. This class of compounds is known to be primarily useful for the treatment of positive and negative symptoms of schizophrenia. At dopamine D2 receptors, these compounds have dual properties and can act both as postsynaptic antagonists and as presynaptic partial agonists. They also stimulate phosphorylation of glutamatergic NMDA NR2B or GluN2B receptors in a medolimbic-specific manner. It is believed that this regional selectivity in brain regions thought to mediate the efficacy of antipsychotic drugs, as well as serotonergic, glutamatergic and dopaminergic interactions, can lead to the efficacy of antipsychotic drugs on positive, negative, affective and cognitive symptoms associated with schizophrenia. These compounds also exhibit serotonin reuptake inhibition, providing antidepressant activity for the treatment of schizoaffective disorder, comorbid depression and / or as an independent treatment for major depressive disorder. As described 5-HT 2A 5-HT 2A / D2 receptor ligands can also be used to treat bipolar disorder and other psychiatric and neurodegenerative diseases, especially behavioral disorders associated with dementia, autism and other CNS diseases. These features may be able to improve the quality of life of patients with schizophrenia and enhance social function so that they can more fully integrate into their families and workplaces. These compounds show different dose-dependent effects and selectively target 5-HT at low doses.2A At higher doses, they interact with D2 receptors, while at lower doses they gradually interact with D2 receptors. Therefore, at lower doses, they can be used to treat sleep, aggression, and restlessness. At higher doses, they can treat acute exacerbations and residual schizophrenia, bipolar disorder, and mood disorders.

[0006] Lumaperone has the formula:

[0007]

[0008] It is a new therapeutic agent with a potent (Ki = 0.5 nM) 5-HT 2A Receptor antagonism, activity as a mesolimbic / mesocortical selective modulator of dopamine receptor protein phosphorylation, consistent with partial agonism of presynaptic D2 receptors and postsynaptic D2 receptor antagonism in vivo (Ki=32nM), high D1 receptor affinity (Ki=52nM) and serotonin transporter (SERT) inhibition (Ki=26-62nM, using different SERT activity assays). Lumiperone has been approved in the United States for the treatment of schizophrenia and bipolar depression in adults, and is being clinically developed for the treatment of other neuropsychiatric disorders, such as major depressive disorder (MDD), agitation in dementia, including Alzheimer's disease.

[0009] Lumiperone and related compounds have been disclosed as useful in the treatment of 5-HT in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; USRE 39,680 and USRE 39,679. 2ANovel compounds for treating diseases related to receptor modulation, such as anxiety, depression, psychosis, schizophrenia, sleep disorders, sexual dysfunction, migraine, headache-related diseases and social phobia. WO 2000 / 077002 and U.S. Pat. No. 7,071,186 also disclose methods for preparing substituted heterocyclic fused γ-carbolines and the use of these γ-carbolines as serotonin agonists and antagonists for controlling and preventing central nervous system diseases, such as addictive behaviors and sleep disorders. WO 2009 / 145900 and US 8,598,119 and WO 2013 / 155504 and US 11,053,245 and WO 2013 / 155506 and US 11,124,514, each of which is incorporated herein by reference, disclose the use of certain substituted heterocyclic-fused gamma-carbolines for treating psychosis and depression and a combination of sleep, depression and / or mood disorders in patients suffering from psychosis or Parkinson's disease, for treating post-traumatic stress disorder, impulse control disorders and related disorders, and for treating or preventing disorders associated with dementia, in particular behavioral or mood disorders, such as agitation, irritation, aggressive / assaultive behavior, anger, physical or emotional outbursts, and psychosis and sleep disorders associated with dementia. WO 2009 / 114181 and US Pat. No. 8,648,077 (each incorporated herein by reference) disclose methods for preparing crystalline toluenesulfonic acid addition salts of specific substituted heterocyclic fused γ-carbolines, 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.

[0010] WO 2011 / 133224 and US Pat. No. 8,993,572 (each incorporated herein by reference) disclose prodrugs / metabolites of substituted heterocyclic fused γ-carbolines for improved formulations, such as extended release / controlled release formulations. The application discloses heterocyclic fused γ-carbolines N-substituted with 4-fluorophenyl(4-hydroxy)butyl moieties, which have been shown to be highly selective for the serotonin transporter (SERT) relative to heterocyclic fused γ-carbolines containing 4-fluorophenylbutanone.

[0011] WO 2009 / 145900 and US Pat. No. 8,598,119 also disclose that selected substituted heterocyclic fused gamma-carboline compounds have nanomolar affinity for the serotonin reuptake transporter (SERT) and are thus selective serotonin reuptake inhibitors.

[0012] As disclosed in WO2015 / 154025, US2017 / 0183350, US10,077,267, WO 2017 / 165843, US2019 / 0231780, US10,688,097, WO 2019 / 183546, and US2021 / 0008065 (each of which is incorporated herein by reference), deuterated forms of lumepirone and related compounds have been demonstrated to have improved metabolic stability.

[0013] WO2019 / 178484 and US2021 / 0060009 (their respective contents are incorporated by reference as a whole) disclose the use of lumepirone and related analogs in the treatment of acute depression and acute anxiety. Different from traditional antidepressants, including selective serotonin reuptake inhibitors (SSRI), such as sertraline (Zoloft, Lustral), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac), paroxetine (Seroxat) and citalopram (Celexa), they usually take weeks or months to reach their full effect (SSRI typically takes effect 3-4 weeks after daily administration), it is believed that lumepirone can be as short as 1 week or shorter. Rapid effect, and even immediate effect (such as a few hours to a few days after the first administration). In this regard, lumepirone and its analogs share functional benefits with ketamine. Ketamine has recently been tested as a rapid-acting antidepressant for the treatment of refractory depression, bipolar disorder, and major depressive disorder, but it has significant side effects and overdose risks and is not orally active. Lumiperone has been demonstrated to be an orally available, rapidly acting treatment for depression and anxiety that can be used alone or in combination with other anxiolytic or antidepressant drugs, for example, in the treatment of acute depression and acute anxiety with the rapid onset of action of ketamine but without ketamine's side effects or lack of oral activity. These effects are believed to be mediated through indirect dopamine D1 receptor-dependent enhancement of NMDA and AMPA currents, combined with activation of the mTOR (e.g., mTORC1) signaling pathway, and in parallel with anti-inflammatory properties.

[0014] In addition, benzodiazepines Unlike other drugs of this class, lumepirone and related compounds have been shown to be non-addictive and are therefore particularly suitable for the treatment of acute depressive episodes, including suicidal ideation and severe acute depression and / or severe acute anxiety. Lumiperone has been approved by the USFDA for the treatment of schizophrenia and bipolar disorder under the brand name Clinical studies are ongoing for the treatment of major depressive disorder and other disorders.

[0015] Immune disturbances have been reported in subsets of patients with generalized anxiety disorder, major depressive disorder (MDD), and / or schizophrenia. See, e.g., 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). In addition, exposure to infectious agents and subsequent enhanced immune activity can also lead to transient depressive symptoms (e.g., anhedonia, fatigue, lethargy, and low mood). See, e.g., 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 direct administration of proinflammatory factors induces stress-like and / or depression-like effects in patients or animals (Mechawar & Savitz, 2016), and studies have shown that directly blocking certain immune pathways such as interleukin (1L)-1b can reverse adverse symptoms (Koo & Duman, "IL-1betais 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 atherapeutic strategy for the treatment of depression," Curr. Opin, Invest. Drugs 10:664-671 (2009)).

[0016] The link between viral infections and mental illness has long been suspected. As early as the late 19th century, influenza epidemics were noted to be temporally associated with increases in mental illness. More recently, evidence has suggested that chronic inflammation of the central nervous system (CNS) is often reported to be associated with mental states. To date, several studies have suggested a causal relationship between viral infections of the CNS (including herpes simplex type 1 and 2 and measles) and psychiatric symptoms (including depression and schizophrenia). It has even been suggested that some mental illnesses that were never previously suspected of having an infectious element may actually be instances of extremely mild encephalitis.

[0017] One of the most common causes of viral encephalitis is herpes simplex virus (HSV). A lot of work has been done to examine the psychological consequences of HSV encephalitis, and the results show that a large number of HSV patients develop neuropsychological deficits, such as impaired attention, executive function, retrograde memory, working memory, and visual spatial processing, as well as mood disorders, including depression and anxiety. Some of these effects have been found to last for a long time and beyond the acute phase of infection. It has also been shown that some of these deficits are associated with brain damage visible by MRI (magnetic resonance imaging), such as damage to the medial temporal lobe.

[0018] West Nile virus (WNV) infection may also be associated with neuroinvasive disease, resulting in encephalitis or meningitis. Depression has been reported as a major outcome in such patients. An 8-year study of WNV survivors showed a higher-than-expected incidence of mild to severe depression in patients without a history of depression.

[0019] The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) introduced a new category, “psychopathological states due to a general medical condition,” which includes delirium, dementia, amnesia, psychosis, mood disorders (e.g., depression), anxiety, sexual dysfunction, and sleep disorders. These are associated with serious infections, such as bacterial or viral encephalitis and meningitis.

[0020] Proinflammatory cytokines, such as TNF-α and IL-6, are mainly secreted by peripheral monocytes and macrophages, and are also thought to be secreted by CNS microglia. These cytokines activate other cellular components of the inflammatory response to infection. In addition, the anti-inflammatory cytokines IL-4 and IL-10 are also secreted by monocytes and macrophages, and may also be secreted by microglia. C-reactive protein (CRP) is a common marker for persistent inflammatory responses. Recent evidence has shown that major depressive disorder (MDD) is also associated with higher levels of TNF-α, IL-6, IL-1β, IL-2, and interferon γ. In addition, interferon-α has been shown to cause severe depressive symptoms, including suicidal tendencies, in about one-third of patients. However, it is not clear whether this inflammatory state is the cause or effect of MDD.

[0021] In the past two decades, it has been found that an important cause of encephalitis is an autoimmune response to neuronal proteins, particularly NMDA receptors and leucine-rich glioma 1 (LGL-1) receptor proteins. This autoimmune encephalitis (AIE) exhibits a variety of neurological and psychiatric symptoms, including amnesia, confusion, seizures, cognitive deficits, and mood disorders. At least ten different synaptic anti-neuronal and anti-glial antibodies have been identified, and more are suspected. The mainstay of AIE treatment remains intravenous immunoglobulin therapy to clear autoimmune antibodies, such as rituximab.

[0022] Although it is known that 5-HT 2A 5-HT 2A D2 receptor ligands are used to treat schizophrenia and mood disorders, such as depression and anxiety, often including acute treatment of depression or anxiety, but compounds of this class have never before been suggested or disclosed for use in treating encephalitis-induced psychiatric disorders or for treating the affective symptoms of encephalitis.

[0023] There is an urgent need for new and improved methods to treat psychiatric disorders caused by viral, bacterial or autoimmune encephalitis, and to treat the psychiatric symptoms of viral, bacterial and autoimmune meningitis. There is also an urgent need for new and improved methods to protect and strengthen the blood-brain barrier. SUMMARY OF THE INVENTION

[0025] We have surprisingly found that the substituted heterocyclic fused γ-carbolines described herein, particularly lumepirone, effectively reduce abnormally elevated proinflammatory cytokine levels in brain and serum, alter key pathways involved in tissue integrity and blood-brain barrier (BBB) ​​maintenance, confer anxiolytic and anhedonic properties to rats, and enhance BBB protection during inflammatory and stress challenges. This suggests that this class of compounds may be effective in treating psychiatric disorders caused by viral, bacterial or autoimmune encephalitis, and for treating psychiatric symptoms of viral, bacterial and autoimmune meningitis.

[0026] Therefore, the present disclosure provides a method for treating mental disorders caused by viral, bacterial or autoimmune encephalitis and for treating mental symptoms of viral, bacterial and autoimmune encephalitis, the method comprising administering to a patient in need thereof a therapeutically effective amount of (i) a 5-HT 2A 5-HT 2A / D2 receptor ligand, such as a substituted heterocyclic fused γ-carboline, in free, pharmaceutically acceptable salt or prodrug form.

[0027] In another aspect, the present disclosure provides a method for protecting or strengthening the blood-brain barrier, comprising administering to a patient in need thereof a therapeutically effective amount of (i) a 5-HT 2A 5-HT 2A / D2 receptor ligand, such as a substituted heterocyclic fused γ-carboline, in free, pharmaceutically acceptable salt or prodrug form.

[0028] In some embodiments, the present disclosure provides the above methods, wherein such methods further include concurrent administration of a PDE1 inhibitor, such as a compound of Formula II disclosed herein. Such compounds are disclosed in, for example, U.S. Patent No. 9,545,406, the contents of which are incorporated herein by reference in their entirety, and are useful in treating central nervous system diseases, disorders and injuries, as well as as neuroprotectants and / or neuroregenerative agents. Such compounds are further disclosed in, for example, WO 2018 / 049417, the contents of which are incorporated herein by reference in their entirety, and are useful in treating diseases and disorders characterized by neuroinflammation.

[0029] Detailed Description

[0030] Lumiperone is a 5-HT 2ALumiperone is a therapeutic agent that has strong binding to D1 and D2 receptors (Ki = 0.5 nM) and moderate binding to the 5-hydroxytryptamine transporter (SERT). Functionally, receptor binding can generally result in agonist activity, partial agonist activity, or antagonist activity. Lumiperone has been found to have a strong binding to 5-HT 2A Receptors and SERT show potent antagonist activity and mixed agonist / antagonist activity for D1 and D2 receptors (depending on the cell type). In particular, lumepirone shows activity as a mesencephalic / mesocortical selective dopamine receptor protein phosphorylation regulator, consistent with presynaptic D2 receptor partial agonism and postsynaptic D2 receptor antagonism (Ki=32nM) in vivo, with high D1 receptor affinity (Ki=52nM) and inhibition of 5-hydroxytryptamine transporter activity (SERT) (Ki=26-62nM, using different SERT activity assays). Lumiperone also indirectly enhances NMDA- and AMPA-mediated neurotransmission (Titulaer et al., "Lumateperoneincreases glutamate release in the rat medial prefrontal cortex," Eur. Neuropsychopharmacol. 53: S556-S557 (2022)). Lumiperone is approved in the United States as a treatment for schizophrenia and bipolar depression, and is being studied for the treatment of major depressive disorder, agitation in dementia (including Alzheimer's disease), and other psychiatric disorders.

[0031] It has been surprisingly found that lumepirone has the potential to improve pathological levels of inflammation in the brain, microglia and serum, and to maintain BBB integrity after immune injury and stress in rodents. When administered at different time points with a certain dose range, lumepirone reduces key proinflammatory markers elevated by inflammatory agents (e.g., lipopolysaccharide, LPS) or by acute restraint stress. Surprisingly, cytokines IL-1β, IL-6 and TNF-α, which are known to be normalized by lumepirone treatment, are elevated in patients with mental disorders and in human postmortem tissues (including the prefrontal cortex from suicide victims).

[0032] Lumiperone treatment reduced the expression of the Nlrp3 inflammasome, a large multiprotein complex containing NLRP3, a cytosolic sensor involved in innate immunity. Although the inflammasome has no baseline activity, once activated by stress, infection, or other stimuli, the complex is thought to produce active forms of the inflammatory cytokines IL-1b and IL-18. In preclinical studies, Nlrp3-null mutant mice were reported to be protected from the effects of stress on depressive-like behaviors, and Nlrp3 expression was increased in peripheral blood mononuclear cells (PBMCs) from untreated MDD patients.

[0033] The present disclosure shows that under conditions that induce pathological inflammation, lumepirone treatment reduces Nlrp3 transcript levels, which may partially contribute to the antidepressant-like effects of lumepirone. In addition, lumepirone has been shown to have anxiolytic-like effects and reverse anhedonia in rats.

[0034] Stress and inflammation are thought to damage BBB integrity and functionality in many pathological conditions. The BBB regulates the exchange of ions and nutrients between the brain and the blood, while protecting brain tissue from harmful substances. Dysfunctional BBB can lead to chemical exposure and infection, and it has been reported that the BBB may be damaged in people suffering from mental disorders (such as schizophrenia or depression) or neurodegenerative diseases (such as Alzheimer's disease) (a large amount of evidence has been demonstrated that the BBB in these diseases is destroyed).

[0035] The present disclosure provides that after receiving lumepirone 2 hours before measurement, Evidence for increased RNA copy number of hippocampal Cldn5 in mice and confirmed these results in the brains of acutely stressed or LPS-treated mice. Claudins such as Cldn5 are small proteins (20-27 kDa) expressed in tight junctions between brain endothelial cells, and they help maintain BBB integrity. In mice, Cldn5 ablation enhances BBB permeability and allows large proteins up to ∼69 kD (e.g., IL-6) to infiltrate into the brain parenchyma; this result has been associated with depressive-like behaviors and behavioral impairments characteristic of schizophrenia and depression. Therefore, lumepirone-mediated upregulation of Cldn5 gene expression is consistent with the enhanced protein expression observed in mice treated with other chronic antipsychotics or antidepressants. Although chronic but not acute imipramine treatment rescued social avoidance and restored Cldn5 levels altered by social defeat stress, acute lumepirone treatment was surprisingly effective in improving similar behavioral states.

[0036] This finding highlights another potential difference between typical antidepressant treatment and lumepirone treatment. Based on the observed reduction in brain uptake of sodium fluorescein (NaFl) and differences in anti-inflammatory cytokine expression between the central nervous system and the periphery, without being bound by theory, it is believed that Cldn5 may be altered early after lumepirone administration, resulting in the preservation of BBB integrity and limiting the infiltration of large proteins (e.g., IL-6), infectious agents, and other potential pro-inflammatory stimuli into the CNS. In addition, TNF-a / NFk-B signaling increases BBB permeability by reducing tight junction protein expression of Cldn5.

[0037] It has also been reported that typical antidepressants regulate the level of ICAM-1, which is involved in leukocyte brain infiltration and BBB hyperpermeability. It has been confirmed that the level of ICAM-1 (a cell adhesion molecule and a member of the immunoglobulin gene superfamily) increases in the orbitofrontal cortex of patients with depression. The present disclosure shows that in preclinical models, lumepirone sharply reduces Icam1 expression. These findings are also consistent with the literature showing that ICAM1 upregulation is conducive to leukocyte migration through the endothelium and vascular wall to regulate the BBB. In short, the results described herein are revelations that lumepirone regulates a set of processes (repertoire), covering signal transduction networks involving various biological processes, which are related to maintaining BBB integrity and controlling harmful inflammatory states.

[0038] It is also known that increased BBB integrity activates microglia and causes microglial phenotype changes. In the CNS, microglia are an important component of local brain immune responses. It is disclosed herein that in acute inflammatory conditions, lumepirone significantly increases the expression of genes associated with microglial physiological functions and anti-inflammatory phenotypes, and reduces the expression of microglial markers associated with immunoregulation. Surprisingly, it was shown that enriched hippocampal microglia reproduced the anti-inflammatory response observed in whole brain homogenates. One of the genes overexpressed in the hippocampus of mice from LPS treatment is Csf1. This gene encodes a ligand for the microglial receptor CSF1R, which is involved in maintaining microglial viability and immune surveillance. It was found that LPS-induced Csf1 expression increased significantly in the case of co-administration of lumepirone. In addition, the results described herein show that lumepirone upregulates the anti-inflammatory cytokine IL-10, which may increase the inflammation resolution mechanism after abnormal levels of stress and inflammation by affecting microglial function. In conclusion, the data described herein show that the ability of lumepirone to alter gene expression in microglia following inflammatory challenge and to reduce Csf1 gene expression may prevent activation of microglial function following exposure to proinflammatory stimuli.

[0039] Stress and active agents that trigger neuroinflammation are closely related to the etiology of a variety of brain diseases, including neurodegenerative disorders, mental 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 disorders including bipolar disorder and schizophrenia. In addition, viruses such as CMV can trigger psychopathological conditions in part by directly increasing proinflammatory cytokines (including TNF-α and IL-6). Coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), which can cause coronavirus disease 2019 (COVID-19) infection, trigger a hyperimmune response (cytokine storm), which may lead to the onset of psychiatric illness in infected patients, but the exact triggering event (e.g., stress or the virus itself) remains to be elucidated. However, it is worth noting that the SARS-CoV-2 virus crosses the BBB of mice and passes through the olfactory mucosa of humans, which supports the potential pathway / mechanism for the virus to enter brain tissue. Thus, without being bound by theory, it is believed that therapeutic agents with anti-inflammatory benefits, such as lumepirone and its analogs, may provide further benefits by normalizing abnormal neuroinflammatory events and mitigating their effects on brain dysfunction, particularly with respect to maintaining BBB integrity.

[0040] Without being bound by theory, it is believed that disturbance of the BBB may be the basis for the occurrence of various mental disorders, including schizophrenia, autism spectrum disorder (ASD) and affective disorders. Increased permeability of the BBB is obviously a common factor in these diseases, resulting in increased infiltration of peripheral substances into the brain, ultimately leading to neuroinflammation and oxidative stress. The loss of BBB integrity is an early and prominent pathological feature of neuroinflammatory diseases. BBB permeability increases in response to many proinflammatory stimuli, such as lipopolysaccharide, tumor necrosis factor α (TNFα), IL-6, MCP-1 and IL-1β, accompanied by the downregulation of tight junction proteins such as tight junction protein-5 (Cldn5). In response to danger signals, brain endothelial cells are activated, and it is characterized by the upregulation of cell adhesion molecules such as ICAM-1 and VCAM-1, and the downregulation of Claudin-5, thereby promoting leukocytes to enter the CNS and promote immune response. Therefore, measuring the presence, absence or concentration of these different biomarker signals can indicate the presence of neuroinflammation and the destruction of BBB integrity.

[0041] In a specific embodiment, the present disclosure provides a method for treating a psychiatric disorder caused by viral, bacterial or autoimmune encephalitis and treating the psychiatric symptoms of viral, bacterial and autoimmune encephalitis (Method 1), comprising administering to a patient in need thereof a therapeutically effective amount of 5-HT 2A5-HT 2A / D2 receptor ligands, for example, compounds of formula I:

[0042]

[0043] in:

[0044] X is –N(H)-, –N(CH3)- or –O-;

[0045] Y is –C(=O)-, –C(H)(OH)- or –C(H)(OR1)-;

[0046] 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, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C 1-22 Alkoxy (e.g., ethoxy) groups are substituted, 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, wherein such compounds hydrolyze to form residues of natural or unnatural, saturated or unsaturated fatty acids, for example said compounds hydrolyze to form hydroxy compounds on the one hand and to form octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand,

[0047] The compound is optionally in deuterated form,

[0048] In the form of a free base, a pharmaceutically acceptable salt or a prodrug. For example, method 1 may be as follows:

[0049] 1.1. Method 1, wherein X in the compound of formula I is -N(H)-, -N(CH3)- or -O-;

[0050] 1.2. Method 1 or 1.1, wherein X in the compound of formula I is -N(H);

[0051] 1.3. Method 1 or 1.1, wherein X in the compound of formula I is -N(CH3)-;

[0052] 1.4. Method 1 or 1.1, wherein X in the compound of formula I is -O-;

[0053] 1.5. Method 1 or any one of Formulas 1.1-1.4, wherein Y in the compound of Formula I is -C(=O)-, -C(H)(OH)- or -C(H)(OR1)-;

[0054] 1.6. Method 1 or any one of Formulas 1.1-1.4, wherein Y in the compound of Formula I is -C(=O)-;

[0055] 1.7. Method 1 or any one of Formulas 1.1-1.4, wherein Y in the compound of Formula I is -C(H)(OH)-;

[0056] 1.8. Method 1 or any one of Formulas 1.1-1.4, wherein Y in the compound of Formula I is -C(H)(OR1)-;

[0057] 1.9. Any of methods 1 or 1.1-1.5 or 1.8, wherein in the compound of 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, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C 1-22 Alkoxy (e.g., ethoxy) groups are substituted, 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 wherein the compounds are hydrolyzed to form residues of natural or unnatural, saturated or unsaturated fatty acids, for example, the compounds are hydrolyzed to form hydroxy compounds on the one hand and to form octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand; for example, wherein in the compounds of formula I, R1 is -C(O)-C 6-15 Alkyl, for example -C(O)-C9 alkyl; or wherein in the compound of formula I, R1 is -C(O)-C 1-5 Alkyl, for example -C(O)-C3 alkyl;

[0058] 1.10. Any of methods 1 or 1.1-1.5 or 1.7, wherein the compound of formula I is:

[0059]

[0060] 1.11. Any of methods 1 or 1.1-1.5 or 1.7, wherein the compound of formula I is:

[0061]

[0062] 1.12. Any of Methods 1 or 1.1, 1.3, 1.5 or 1.6, wherein the compound of Formula I is lumepirone:

[0063]

[0064] 1.13. Any of method 1 or 1.1-1.12, for example method 1.12, wherein the compound of formula I is in the form of a pharmaceutically acceptable salt, for example a tosylate salt;

[0065] 1.14. Any of method 1 or 1.1-1.12, for example method 1.12, wherein the compound of formula I is in the form of a free base;

[0066] 1.15. Method 1 or any one of 1.1-1.14, wherein the compound of Formula I is in deuterated form, for example, wherein the deuterium:protium ratio of a particular carbon-bonded hydrogen atom is significantly higher than the natural isotope ratio, for example, at least 2 times higher, for example, at least 10 times higher;

[0067] 1.16. Method 1.15, wherein the compound of Formula I is a deuterated form of lumepirone, for example, selected from:

[0068]

[0069] wherein D represents a hydrogen position, having a deuterium incorporation much greater than that found naturally (i.e. much greater than 0.0156%), e.g., greater than 60% or greater than 70% or greater than 80% or greater than 90% or greater than 95% or greater than 96% or greater than 97% or greater than 98% or greater than 99%, in the form of a free base or a pharmaceutically acceptable salt, e.g., a tosylate salt;

[0070] 1.17. Any of the above methods, wherein 5-HT 2A 5-HT 2A / The D2 receptor ligand is a compound of formula I in the form of a free base or a pharmaceutically acceptable salt, such as a tosylate salt, administered in a daily dose equivalent to 1-100 mg of the free base, for example in an amount equivalent to 1-75 mg or 1-60 mg or 1-40 mg or 1-20 mg or 1-10 mg of the free base;

[0071] 1.18. Method 1.17, wherein the method comprises administering once daily a unit dose for oral administration, such as a tablet or capsule, comprising: a compound of formula I in free base or pharmaceutically acceptable salt form, such as tosylate form, in an amount equivalent to 1-100 mg of free base, such as an amount equivalent to 1-75 mg or 1-60 mg or 1-40 mg or 1-30 mg or 1-20 mg or 1-10 mg or 1-5 mg or 40-60 mg or 20-40 mg or 10-20 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 free base; and a pharmaceutically acceptable diluent or carrier;

[0072] 1.19. Method 1.17, wherein the method comprises administering once daily a unit dose for oral transmucosal administration, such as a sublingual or buccal orally disintegrating tablet, wafer or film, comprising: a compound of formula I in free base or pharmaceutically acceptable salt form, such as tosylate form, in an amount equivalent to 0.5-30 mg of free base, such as an amount equivalent to 1-30 mg or 1-20 mg or 1-15 mg or 1-10 mg or 20-30 mg or 10-20 mg, or about 5 mg or about 10 mg or about 15 mg or about 20 mg of free base; and a pharmaceutically acceptable diluent or carrier;

[0073] 1.20. Any of the above methods, wherein the condition being treated is relieved within 1 week, such as within 3 days, such as within 1 day;

[0074] 1.21. Any of the above methods, wherein the method is a method of treating a mental disorder caused by viral, bacterial or autoimmune encephalitis.

[0075] 1.22. Any of the above methods, wherein the method is a method of treating psychiatric symptoms of viral, bacterial or autoimmune encephalitis.

[0076] 1.23. Method 1.21 or 1.22, wherein the encephalitis is viral encephalitis;

[0077] 1.24. Method 1.23, wherein the encephalitis is caused by or suspected to be caused by the following viruses: 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)

[0078] or influenza virus (e.g. influenza A, such as H1N1, H2N2, H3N2, H5N1, H7N7);

[0079] 1.25. Method 1.23 or 1.24, wherein the patient suffers from acute viral encephalitis;

[0080] 1.26. Method 1.21 or 1.22, wherein the encephalitis is bacterial encephalitis;

[0081] 1.27. Method 1.26, wherein the encephalitis is caused or believed to be caused by toxoplasmosis, rickettsia, mycoplasma, Borrelia (e.g., Lyme disease), or malaria;

[0082] 1.28. Method 1.21 or 1.22, wherein the encephalitis is autoimmune encephalitis;

[0083] 1.29. Method 1.28, wherein the encephalitis is caused or believed to be caused by autoantibodies against NMDA receptors, AMPA receptors, voltage-gated potassium channels (VGKC), LGL1 protein, GABA receptors, glycine receptors, glutamate receptors or CASPR2 receptors;

[0084] 1.30. Any of the above methods, wherein the mental disorder and / or mental symptom is depression (e.g., acute depression, MDD depression, bipolar depression), anxiety (e.g., acute anxiety), psychosis (e.g., schizophrenia), post-traumatic stress disorder, anhedonia, memory loss, impaired executive function, difficulty concentrating, epileptic seizures, difficulty sleeping, hallucinations, personality changes, or any combination thereof;

[0085] 1.31. Any of the above methods, wherein the mental disorder and / or mental symptom is depression (e.g., acute depression, MDD depression, bipolar depression);

[0086] 1.32. Any of the above methods, wherein the mental disorder and / or mental symptom is anxiety (e.g., acute anxiety);

[0087] 1.33. Any of the above methods, wherein the mental disorder and / or mental symptom is anhedonia;

[0088] 1.34. Any of the above methods, wherein the patient is diagnosed with suicidal ideation and / or suicidal tendencies;

[0089] 1.35. Any of the above methods, wherein the patient has no previous history of mental disorder or mental symptoms;

[0090] 1.36. Any of the above methods, wherein 5-HT 2A 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 a unit dosage form, or a free combination administered sequentially or simultaneously or within a 24-hour period);

[0091] 1.37. Method 1.36 wherein the anxiolytic or antidepressant is selected from one or more compounds in free base or pharmaceutically acceptable salt form selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and atypical antipsychotics, such as one or more compounds in free base or pharmaceutically acceptable salt form selected from:

[0092] (a) Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (Celexa), escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), fluvoxamine (Luvox), and sertraline (Zoloft, Lustral);

[0093] (b) serotonin-norepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella), tolfenacin (Elamol, Tofacine), and venlafaxine (Effexor);

[0094] (c) Tricyclic antidepressants (TCAs), such as amitriptyline (Elavil, Endep), amitriptyline oxide (Amioxid, Ambivalon, Equilibrin), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), dibenzepin (Noveril, Victoril), dimetacrine (Istonil), doxepin (Prothiaden), doxepin (Adapin, Sinequan) , imipramine (Tofranil), lofepramine (Lomont, Gamanil), melitracen (Dixeran, Melixeran, Trausabun), nitrosazepine (Sintamil), nortriptyline (Pamelor, Aventyl), noxetine (Agedal, Elronon, Nogedal), pipofezine (Azafen / Azaphen), protriptyline (Vivactil), trimipramine (Surmontil);

[0095] (d) Benzodiazepines The invention relates to a class of drugs, for example, selected from 2-keto compounds (e.g., clorazepate, diazepam, flurazepam, halazepam, prazepam); 3-hydroxy compounds (lorazepam, lormetazepam, oxazepam, temazepam); 7-nitro compounds (e.g., clonazepam, flunitrazepam); lunitrazepam, nimetazepam, nitrazepam); triazolo compounds (e.g., adinazolam, alprazolam, estazolam, triazolam); and imidazolo compounds (climazolam, loprazolam, midazolam);

[0096] 1.38. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands, such as compounds of Formula I, are administered intranasally, subcutaneously, intramuscularly, intravenously, orally, sublingually, intraperitoneally or buccally, such as oral fast-dissolving tablets, wafers or films, which dissolve in the mouth for transmucosal absorption;

[0097] 1.39. Any of the above methods, wherein the method further comprises concurrent administration of an antidepressant (e.g., selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof), e.g., by simultaneous, separate or sequential administration;

[0098] 1.40. Any of the above methods, wherein the method further comprises concurrently administering an NMDA receptor antagonist, such as ketamine (e.g., S-ketamine and / or R-ketamine), hydroxynorketamine, memantine, dextromethorphan, dextroallorphan, dextrorphan, amantadine and agmatine, or any combination thereof, such as by simultaneous, separate or sequential administration;

[0099] 1.41. Any of the above methods, wherein the method further comprises concurrently administering an NMDA receptor allosteric modulator, such as an NMDA receptor glycine site modulator, such as rapastinel, nebostinel, apimostinel, D-cycloserine, or any combination thereof, such as by simultaneous, separate or sequential administration;

[0100] 1.42. Any of the above methods, wherein the method provides the patient with a therapeutic or active agent (e.g., 5-HT 2A 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 any additional antidepressant);

[0101] 1.43. Method 1.42, wherein the patient exhibits an acute response to treatment within less than 3 weeks, e.g., less than 2 weeks or less than 1 week or 1-7 days or 1-5 days or 1-3 days or 1-2 days or about 1 day or less than 2 days or less than 1 day (e.g., 12-24 hours, 6-12 hours or 3-6 hours);

[0102] 1.44. Any of the above methods, wherein the patient has not responded to treatment with another antidepressant, has responded inadequately, or has experienced adverse side effects from treatment with another antidepressant, such as any one or more of a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor), or a serotonin receptor antagonist;

[0103] 1.45. Any of the above methods, wherein the mental disorder or symptom is not related to schizophrenia or dementia;

[0104] 1.46. Any of the above methods, wherein the patient does not suffer from (or has not been previously diagnosed with) schizophrenia or dementia;

[0105] 1.47. Any of the above methods, wherein the method protects or strengthens the blood-brain barrier;

[0106] 1.48. Any of the above methods, wherein the patient has elevated levels of pro-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as elevated levels of C-reactive protein (CRP) of TNF-a, IFN-g, IL-1 (IL-1a and / or IL-1b), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, or Csf1, and / or decreased levels of anti-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as TNF-b, IFN-a, IL-4, and IL-10;

[0107] 1.49. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands for 5-HT 2A The activity (agonism and / or antagonism) of the receptor has an IC of less than 250 nM 50 or EC less than 250nM 50 , for example, having an IC 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 the activity (agonism or antagonism) of the receptor 50 or EC 50 ;

[0108] 1.50. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor pairing D2 receptor activity (agonism and / or antagonism) with an IC of less than 250 nM 50 or EC less than 250nM 50 , for example, having an IC 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 the activity (agonism or antagonism) of the receptor 50 or EC 50 ;

[0109] 1.51. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands have an IC less than 250 nM for the activity (agonism and / or antagonism) of D1 receptors 50 or EC less than 250nM 50 , for example, having an IC 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 the activity (agonism or antagonism) of the receptor 50 or EC 50 ;

[0110] 1.52. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands have an IC less than 250 nM for the activity (agonism and / or antagonism) of the serotonin transporter (SERT) 50 or EC less than 250nM 50 , for example, having an IC 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 the activity (agonism or antagonism) of the transporter 50 or EC 50 ;

[0111] 1.53. Any of the above methods, wherein 5-HT 2A 5-HT 2A / The D2 receptor ligand is lumepirone, in free base or pharmaceutically acceptable salt form, optionally in deuterated form;

[0112] 1.54. Any of the above methods, wherein 5-HT 2A 5-HT 2A / the D2 receptor ligand is lumiperone in the form of a tosylate salt (e.g., monotosylate), optionally in a deuterated form, and optionally in a crystalline or amorphous tosylate salt form;

[0113] 1.55. Any of the above methods, wherein 5-HT 2A 5-HT 2A / The D2 receptor ligand is lumepirone, which is a free base or in the form, optionally in a deuterated form;

[0114] 1.56. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligand is administered in the form of a long-acting injectable (LAI) composition, e.g., for intramuscular or subcutaneous injection;

[0115] 1.57. Method 1.56 wherein the dosage of the LAI composition is sufficient to provide a daily dosage equivalent to 1-100 mg of free base, e.g., 1-75 mg or 1-60 mg or 1-40 mg or 1-20 mg or 1-10 mg of free base, released over a period of about 1 week to about 3 months, e.g., about 1 week to about 8 weeks or about 1 week to about 6 weeks or about 1 week to about 4 weeks or about 1 week to about 3 weeks or about 1 week to about 2 weeks;

[0116] 1.58. Method 1.56 or 1.57, wherein the LAI composition comprises a compound of Formula I dissolved, dispersed, suspended or encapsulated in a polymer matrix;

[0117] 1.59. Method 1.58, wherein the polymer matrix comprises one or more biocompatible and biodegradable polymers as defined herein, such as poly(hydroxy carboxylic acids), poly(amino acids), cellulosic polymers, modified cellulosic polymers, polyamides and polyesters;

[0118] 1.60. Method 1.59, wherein the one or more polymers comprise 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(α-cyanoacrylate) such as poly(butyl cyanoacrylate) or poly(2-octyl cyanoacrylate), poly(orthoesters), polycarbonates, polyorthocarbonates, polyamino acids (e.g., poly-γ.-L-alanine, poly-γ.-benzyl-L-glutamate or poly-γ-methyl-L-glutamate) and / or hyaluronate;

[0119] 1.61. Method 1.60, wherein the one or more polymers comprise polyorthoester (POE), polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic-co-glycolic acid);

[0120] 1.62. Method 1.60, wherein the one or more polymers comprises a poly(lactic-glycolic acid) copolymer, such as poly-d,l-lactide-co-glycolide (PLGA), e.g., a PLGA copolymer having a lactide-co-glycolide molar ratio of about 50:50-90:10 or 50:50-85:15 or 50:50-75:25, and / or a molecular weight of 5,000-500,000 Daltons or 5,000-150,000 Daltons or 20,000-200,000 Daltons or 24,000-38,000 Daltons;

[0121] 1.63. Any of the above methods, wherein 5-HT 2A 5-HT 2A / the D2 receptor ligand is administered as a monotherapy, e.g., it is not administered concurrently or in combination with an antidepressant, antipsychotic, or anxiolytic agent;

[0122] 1.64. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands are administered without direct supervision by a healthcare professional (e.g., the compound is self-administered by a patient);

[0123] 1.65. Any of the above methods, wherein the method does not include administering a dose of 5-HT 2A 5-HT 2A Supervision or observation of the patient by a healthcare professional during or after (e.g., within 2 hours after) administration of a D2 receptor ligand;

[0124] 1.66. Any of the above methods, wherein the method does not put the patient at risk for sedation, dissociation, abuse, misuse, or suicidal ideation;

[0125] 1.67. Any of the above methods, wherein the method administers a dose of 5-HT 2A 5-HT 2A / D2 receptor ligand does not cause hypertension (e.g., systolic and / or diastolic hypertension) within 4 hours after the dose, for example, an increase in systolic and / or diastolic blood pressure of greater than 10 mm Hg, or greater than 20 mm Hg, or greater than 30 mm Hg, or greater than 40 mm Hg within 30 minutes to 4 hours after the dose;

[0126] 1.68. Any of the above methods, wherein the method does not result in cognitive decline;

[0127] 1.69. Any of the above methods, wherein the patient has (e.g., has been diagnosed with) or is at risk for aneurysmal vascular disease (e.g., thoracic aortic, abdominal aortic, intracranial or peripheral arterial aneurysm), arteriovenous malformation or cerebral hemorrhage;

[0128] 1.70. Any of the above methods, wherein the patient is concurrently treated with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0129] 1.71. Any of the above methods, wherein the patient is not concurrently treated with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0130] 1.72. Any of the above methods, wherein the patient is unresponsive to or cannot be treated with ketamine (e.g., S-ketamine), for example because ketamine is contraindicated in the patient;

[0131] 1.73. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligand and PDE1 (cyclic nucleoside phosphodiesterase 1) inhibitor are administered to the patient concurrently (e.g., simultaneously, separately or sequentially) in free base or pharmaceutically acceptable salt form;

[0132] 1.74. Method 1.73 wherein the PDE1 inhibitor is a compound of Formula II:

[0133]

[0134] wherein R2 is H, and R3 and R4 together form a tri- or tetra-methylene bridge [preferably wherein the carbons carrying R3 and R4 have the R and S configuration, respectively]; or R2 and R3 are each methyl, and R4 is H; or R2 and R4 are H, and R3 is isopropyl [preferably wherein the carbon carrying R3 has the R configuration];

[0135] R6 is (optionally halogen-substituted)phenylamino or (optionally halogen-substituted)benzylamino;

[0136] R 10 is (optionally halogen-substituted)phenyl, (optionally halogen-substituted)pyridyl (eg 3-fluoropyridin-2-yl), thiadiazolyl (eg 1,2,3-thiadiazol-4-yl) or C 1-6 Alkylcarbonyl (e.g. methylcarbonyl);

[0137] It is in the form of a free base or a pharmaceutically acceptable salt;

[0138] 1.75. Method 1.74, wherein in the compound of formula II, R6 is phenylamino or 4-fluorophenylamino;

[0139] 1.76. Method 1.74, wherein in the compound of formula II, R 10 is 3-fluoropyridin-2-yl or methylcarbonyl;

[0140] 1.77. Method 1.74, wherein in the compound of formula II, R6 is phenylamino or 4-fluorophenylamino, and R 10 is 3-fluoropyridin-2-yl or methylcarbonyl;

[0141] 1.78. Any of methods 1.74-1.77, wherein the compound of formula II is

[0142]

[0143] It is in the form of a free base or a pharmaceutically acceptable salt;

[0144] 1.79 Method 1.77, wherein the compound of formula II is in the form of a monophosphate salt;

[0145] 1.80 Any of methods 1.74-1.79, wherein the compound of formula I is:

[0146]

[0147] It is in the form of a free base or a pharmaceutically acceptable salt, such as a tosylate salt, optionally in deuterated form; and the compound of formula II is:

[0148]

[0149] It is in the form of a free base or a pharmaceutically acceptable salt, such as a monophosphate;

[0150] 1.81 Any of 1.74-1.80, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a compound of Formula II;

[0151] 1.82 Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligand is a compound of formula I in free base or pharmaceutically acceptable salt form, optionally in deuterated form, and wherein the compound is administered in the form of a long-acting injectable (LAI) composition comprising the compound of formula I dissolved or dispersed in or in a pharmaceutically acceptable carrier and a polymer matrix comprising a polymer selected from polyorthoester (POE), polylactic acid, polyglycolic acid, polycitric acid, polymalic acid or poly(lactic-glycolic acid) copolymer;

[0152] 1.83 Method 1.82, wherein the pharmaceutically acceptable carrier comprises water (e.g., an aqueous buffer) and / or an organic solvent (e.g., a water-miscible organic solvent);

[0153] 1.84 Method 1.82 or 1.83, wherein the polymer comprises a polylactic acid and / or a polyglycolic acid polymer;

[0154] 1.85 Method 1.82 or 1.83, wherein the polymer comprises a poly(lactic-glycolic acid) copolymer, such as poly-d,l-lactide-co-glycolide (PLGA), for example, a PLGA copolymer having a lactide-glycolide molar ratio of about 50:50-90:10 or 50:50-85:15 or 50:50-75:25, and / or a molecular weight of 5,000-500,000 Daltons or 5,000-150,000 Daltons or 20,000-200,000 Daltons or 24,000-38,000 Daltons;

[0155] 1.86 Any of 1.82-1.85, wherein the LAI composition is administered by intramuscular or subcutaneous injection, or is formulated for administration by intramuscular or subcutaneous injection;

[0156] 1.87 Method 1 or any one of 1.1-1.86, wherein the patient has no previous history of depression;

[0157] 1.88 Method 1 or any one of 1.1-1.87, wherein the 5-HT 2A 5-HT 2A / D2 receptor ligand, the patient showed evidence of brain damage or encephalopathy on magnetic resonance imaging (MRI);

[0158] 1.89 Method 1 or any one of 1.1-1.88, wherein the 5-HT 2A 5-HT 2A Prior to administration of the HER2 / D2 receptor ligand, the patient tested positive for serum antibodies or antigens against one or more of the following: 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);

[0159] 1.90 Method 1 or any one of 1.1-1.89, wherein the patient tests positive for serum antibodies to autoantibodies to NMDA receptors, AMPA receptors, voltage-gated potassium channels (VGKCs), LGL1 protein, GABA receptors, glycine receptors, glutamate receptors, or CASPR2 receptors;

[0160] 1.91 Any of the above methods, wherein the patient has elevated levels of one or more biomarkers indicative of CNS inflammation, e.g., selected from TNF-a, IFN-g, 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., isolated from blood), urine, CSF, and / or CNS microglia (e.g., isolated from CSF);

[0161] 1.92 Any of the above methods, wherein the patient has altered levels of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity in serum or CSF, such as increased levels of ICAM-1, VCAM-1, E-selectin, P-selectin, or soluble isoforms thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin) or decreased levels of Cldn5, Occludin, and ZO-1;

[0162] 1.93 Any of the above methods, wherein the patient has a decrease in one or more anti-inflammatory biomarker levels indicative of CNS inflammatory dysfunction, such as TNF-β, 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 microglia (e.g., isolated from CSF);

[0163] 1.94 Any of the above methods, wherein 5-HT 2A 5-HT 2AAfter administration of a 5-dT / D2 receptor ligand (e.g., a compound of formula (optionally in deuterated form), the patient has a reduced level of one or more biomarkers indicative of CNS inflammation, such as TNF-α, 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., isolated from blood), urine, CSF, and / or CNS microglia (e.g., isolated from CSF), compared to a baseline before treatment, e.g., within 28 days of initiating treatment;

[0164] 1.95 Method 1.94, wherein the patient has 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, e.g., within 28 days of initiating treatment;

[0165] 1.96 Any of the above methods, wherein 5-HT 2A 5-HT 2A After treatment with a CNS / D2 receptor ligand (e.g., a compound of the formula, optionally in deuterated form), the patient has a favorable change in the level of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity, such as a decrease in the level of ICAM-1, VCAM-1, E-selectin, P-selectin, or a soluble isoform thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), or an increase in the level of Cldn5, occludin, and ZO-1 in serum or CSF, compared to a baseline before treatment, e.g., within 28 days of initiating treatment;

[0166] 1.97 Method 1.96, 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 anti-inflammatory biomarkers indicative of CNS inflammation, e.g., within 28 days of initiating treatment;

[0167] 1.98 Any of the above methods, wherein the 5-HT 2A 5-HT 2AAfter treatment with a D2 receptor ligand (e.g., a compound of the formula, optionally in deuterated form), the patient has an increased level of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, such as TNF-β, 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 microglia (e.g., isolated from CSF), compared to a baseline before treatment, e.g., within 28 days of initiating treatment;

[0168] 1.99 Method 1.98, 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, e.g., within 28 days of initiating treatment;

[0169] 1.100 Any of the above methods, wherein the method further comprises the following steps: 2A 5-HT 2A Before treatment with a D2 receptor ligand (e.g., a compound of the general formula, optionally in deuterated form), and / or after initiation of said treatment, testing one or more body fluids or tissues of the 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, and optionally comparing the results before treatment and after one or more treatments thereof, in order to quantify the effectiveness of the treatment for the patient and / or adjust the treatment regimen;

[0170] 1.101 Method 1.100, wherein the biomarker is selected from one or more of TNF-α, 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, soluble isoforms thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNF-β, IFN-α, IL-4 and IL-10;

[0171] 1.102 Method 1.100 or 1.101, 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 microglia (e.g., isolated from CSF), or a brain biopsy tissue sample;

[0172] 1.103 Any of the above methods, wherein the method further comprises the following steps: 2A 5-HT 2A Before and / or after starting treatment with a D2 receptor ligand (e.g., a compound of the general formula, optionally in deuterated form), non-invasively testing the patient's central nervous system for the presence and / or concentration of one or more biomarkers indicative of CNS inflammation or CNS inflammatory dysfunction, and optionally comparing the pre-treatment and one or more post-treatment results thereof in order to quantify the effectiveness of the treatment in the patient and / or adjust the treatment regimen;

[0173] 1.104 Method 1.103, wherein the biomarker is selected from one or more of TNF-α, 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, soluble isoforms thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNF-β, IFN-α, IL-4 and IL-10;

[0174] 1.105 Method 1.103 or 1.104, wherein the step comprises an imaging method, such as magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI), to assess the presence and / or concentration of the biomarker;

[0175] 1.106 Any of methods 1.100-1.105, wherein the method includes the step of initiating, changing or terminating the treatment regimen based on an observed change in the level of one or more of the biomarkers (e.g., a selected 5-HT 2A 5-HT 2A / D2 receptor ligand, its dosage, its administration route, its administration frequency, its administration form and / or selected 5-HT 2A 5-HT 2A / D2 receptor ligand in combination with any other therapeutic agent).

[0176] In another aspect, the present disclosure provides a 5-HT 2A 5-HT 2A / D2 receptor ligand, such as a compound of formula I, such as lumepirone, in free base or salt form, optionally in deuterated form, for use in treating mental disorders caused by viral, bacterial or autoimmune encephalitis and for treating mental symptoms of viral, bacterial and autoimmune encephalitis, such as for use in any one of method 1, etc.

[0177] In another aspect, the present disclosure provides a 5-HT 2A 5-HT 2A / D2 receptor ligand, such as a compound of formula I, such as lumepirone, in free base or salt form, optionally in deuterated form, for the preparation of a medicament for treating mental disorders caused by viral, bacterial or autoimmune encephalitis and for treating the mental symptoms of viral, bacterial and autoimmune encephalitis, such as for use in any one of method 1, etc.

[0178] In a specific embodiment, the present disclosure provides a method for protecting or strengthening the blood-brain barrier (Method 2), comprising administering a therapeutically effective amount of 5-HT to a patient in need thereof. 2A 5-HT 2A / D2 receptor ligands, such as compounds of formula I:

[0179]

[0180] in:

[0181] X is –N(H)-, –N(CH3)- or –O-;

[0182] Y is –C(=O)-, –C(H)(OH)- or –C(H)(OR1)-;

[0183] 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, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C 1-22 Alkoxy (e.g., ethoxy) groups are substituted, 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, wherein such compounds hydrolyze to form residues of natural or unnatural, saturated or unsaturated fatty acids, for example said compounds hydrolyze to form hydroxy compounds on the one hand and to form octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand,

[0184] The compound is optionally in deuterated form,

[0185] is a free base, a pharmaceutically acceptable salt or a prodrug form. For example, method 2 can be as follows:

[0186] 2.1. Method 2, wherein X in the compound of Formula I is -N(H)-, -N(CH3)- or -O-;

[0187] 2.2. Method 2 or 2.1, wherein X in the compound of formula I is -N(H);

[0188] 2.3. Method 2 or 2.1, wherein X in the compound of formula I is -N(CH3)-;

[0189] 2.4. Method 2 or 2.1, wherein X in the compound of formula I is -O-;

[0190] 2.5. Method 2 or any one of Formulas 2.1-2.4, wherein Y in the compound of Formula I is -C(=O)-, -C(H)(OH)- or -C(H)(OR1)-;

[0191] 2.6. Method 2 or any one of Formulas 1.1-1.4, wherein Y in the compound of Formula I is -C(=O)-;

[0192] 2.7. Method 2 or any one of Formulas 2.1-2.4, wherein Y in the compound of Formula I is -C(H)(OH)-;

[0193] 2.8. Method 2 or any one of Formulas 2.1-2.4, wherein Y in the compound of Formula I is -C(H)(OR1)-;

[0194] 2.9. Any of Methods 2 or 2.2-2.5 or 2.8, wherein in the compound of 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, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C 1-22 Alkoxy (e.g., ethoxy) groups are substituted, 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, wherein such compounds are hydrolyzed to form residues of natural or unnatural, saturated or unsaturated fatty acids, for example, the compounds are hydrolyzed to form hydroxy compounds on the one hand and octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand); for example, wherein in the compound of formula I, R1 is -C(O)-C 6-15 Alkyl, for example -C(O)-C9 alkyl; or wherein in the compound of formula I, R1 is -C(O)-C 1-5Alkyl, for example -C(O)-C3 alkyl;

[0195] 2.10. Any of methods 2 or 2.1-2.5 or 2.7, wherein the compound of formula I is:

[0196]

[0197] 2.11. Any of Methods 2 or 2.1-2.5 or 2.7, wherein the compound of Formula I is:

[0198]

[0199] 2.12. Any of Methods 2 or 2.1, 2.3, 2.5 or 2.6, wherein the compound of Formula I is lumepirone:

[0200]

[0201] 2.13. Any of method 2 or 2.1-2.12, for example method 2.12, wherein the compound of formula I is in the form of a pharmaceutically acceptable salt, for example a tosylate salt;

[0202] 2.14. Any of method 2 or 2.1-2.12, for example method 2.12, wherein the compound of formula I is in the form of a free base;

[0203] 2.15. Any of Method 2 or 2.1-2.14, wherein the compound of Formula I is in deuterated form, e.g., wherein the deuterium:protium ratio of a particular carbon-bonded hydrogen atom is significantly higher than the natural isotope ratio, e.g., at least 2 times higher, e.g., at least 10 times higher;

[0204] 2.16. Method 2.15, wherein the compound of Formula I is a deuterated form of lumepirone, for example selected from:

[0205]

[0206] wherein D represents hydrogen positions having deuterium incorporation much greater than natural (i.e. much greater than 0.0156%), such as greater than 60% or greater than 70% or greater than 80% or greater than 90% or greater than 95% or greater than 96% or greater than 97% or greater than 98% or greater than 99%,

[0207] It is in the form of a free base or a pharmaceutically acceptable salt, such as a tosylate salt;

[0208] 2.17. Any of the above methods, wherein 5-HT 2A 5-HT 2A / The D2 receptor ligand is a compound of formula I in the form of a free base or a pharmaceutically acceptable salt, such as a tosylate salt, administered in a daily dose equivalent to 1-100 mg of the free base, for example in an amount equivalent to 1-75 mg or 1-60 mg or 1-40 mg or 1-20 mg or 1-10 mg of the free base;

[0209] 2.18. Method 2.17, wherein the method comprises administering once daily a unit dose for oral administration, such as a tablet or capsule, comprising a compound of formula I in free base or pharmaceutically acceptable salt form, such as tosylate form, in an amount equivalent to 1-100 mg of free base, such as an amount equivalent to 1-75 mg or 1-60 mg or 1-40 mg or 1-30 mg or 1-20 mg or 1-10 mg or 1-5 mg or 40-60 mg or 20-40 mg or 10-20 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 free base; and a pharmaceutically acceptable diluent or carrier;

[0210] 2.19. Method 2.17, wherein the method comprises administering once daily a unit dose for oral transmucosal administration, such as a sublingual or buccal orally disintegrating tablet, wafer or film, comprising: a compound of formula I in free base or pharmaceutically acceptable salt form, such as tosylate form, in an amount equivalent to 0.5-30 mg of the free base, such as an amount equivalent to 1-30 mg or 1-20 mg or 1-15 mg or 1-10 mg or 20-30 mg or 10-20 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;

[0211] 2.20. Any of the above methods, wherein the patient has a viral, bacterial, or autoimmune encephalitis, such as caused or suspected to be 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), influenza virus (e.g., influenza A, such as H1N1, H2N2, H3N2, H5N1, H7N7), toxoplasmosis, rickettsia, mycoplasma, borrelia (e.g., Lyme disease), malaria, or autoantibodies to NMDA receptors, AMPA receptors, voltage-gated potassium channels (VGKC), LGL1 protein, GABA receptors, glycine receptors, glutamate receptors, or CASPR2 receptors;

[0212] 2.21. Any of the above methods, wherein the patient is diagnosed with suicidal ideation and / or suicidal tendencies;

[0213] 2.22. Any of the above methods, wherein the patient is diagnosed with a psychiatric disorder or psychiatric symptoms, such as depression (e.g., acute depression, MDD depression, bipolar depression), anxiety (e.g., acute anxiety), psychosis (e.g., schizophrenia), post-traumatic stress disorder, anhedonia, memory loss, impaired executive function, difficulty concentrating, seizures, difficulty sleeping, hallucinations, personality changes, or any combination thereof;

[0214] 2.23. Any of the above methods, wherein the patient develops acute psychotic symptoms without a history of mental disorder or psychotic symptoms;

[0215] 2.24. Any of the above methods, wherein the patient is at risk of blood-brain barrier damage or compromise, e.g., due to CNS inflammation, CNS infection (e.g., encephalitis), neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, or due to cerebral trauma (e.g., traumatic brain injury, e.g., concussive injury);

[0216] 2.25. Any of the above methods, wherein the patient has elevated levels of pro-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as elevated levels of C-reactive protein (CRP) of TNF-α, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, or Csf1, and / or decreased levels of anti-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as TNF-β, IFN-α, IL-4, and IL-10;

[0217] 2.26. Any of the above methods, wherein 5-HT 2A 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 a unit dosage form, or a free combination administered sequentially or simultaneously or within a 24-hour period);

[0218] 2.27. Method 2.26, wherein the anxiolytic or antidepressant is selected from one or more compounds in free base or pharmaceutically acceptable salt form selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and atypical antipsychotics, such as one or more compounds in free base or pharmaceutically acceptable salt form selected from:

[0219] (a) Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (Celexa), escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), fluvoxamine (Luvox), and sertraline (Zoloft, Lustral);

[0220] (b) serotonin-norepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella), tolfenacin (Elamol, Tofacine), and venlafaxine (Effexor);

[0221] (c) tricyclic antidepressants (TCAs), such as amitriptyline (Elavil, Endep), amitriptyline oxide (Amioxid, Ambivalon, Equilibrin), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), diphenhydramine (Noveril, Victoril), dimethoprim (Istonil), dosuliprine (Prothiaden), doxepin (Adapin, Sinequan), imipramine (Tofranil), lofepramine (Lomont, Gamanil), melitracen (Dixeran, Melixeran, Trausabun), nitrosazepine (Sintamil), nortriptyline (Pamelor, Aventyl), noxitriptyline (Agedal, Elronon, Nogedal), pipofiazine (Azafen / Azaphen), protriptyline (Vivactil), trimipramine (Surmontil);

[0222] (d) Benzodiazepines Class, for example, selected from 2-keto compounds (e.g., clorazepate, diazepam, flurazepam, halazepam, prazepam); 3-hydroxy compounds (clorazepam, lormetazepam, oxazepam, temazepam); 7-nitro compounds (e.g., clonazepam, flunitrazepam, nimetazepam, nitrazepam); triazolo compounds (e.g., adiazolam, alprazolam, estazolam, triazolam); and imidazolo compounds (clomazolam, loprazolam, midazolam);

[0223] 2.28. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands, such as compounds of Formula I, are administered intranasally, subcutaneously, intramuscularly, intravenously, orally, sublingually, intraperitoneally or buccally, such as oral fast-dissolving tablets, wafers or films, which dissolve in the mouth for transmucosal absorption;

[0224] 2.29. Any of the above methods, wherein the method further comprises concurrent administration of an antidepressant (e.g., selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor), a serotonin receptor antagonist, or any combination thereof), e.g., by simultaneous, separate or sequential administration;

[0225] 2.30. Any of the above methods, wherein the method further comprises concurrently administering an NMDA receptor antagonist, such as ketamine (e.g., S-ketamine and / or R-ketamine), norethisterone, memantine, dextromethorphan, dextroalorphine, dextrorphan, amantadine and agmatine, or any combination thereof, such as by simultaneous, separate or sequential administration;

[0226] 2.31. Any of the above methods, wherein the method further comprises concurrently administering an NMDA receptor allosteric modulator, such as an NMDA receptor glycine site modulator, such as rapatenat, nepotinet, apitinel, D-cycloserine, or any combination thereof, such as by simultaneous, separate or sequential administration;

[0227] 2.32. Any of the above methods, wherein the method provides the patient with a therapeutic or active agent (e.g., 5-HT 2A 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 any additional antidepressant);

[0228] 2.33. Method 2.32, wherein the patient shows an acute response to treatment in less than 3 weeks, e.g., less than 2 weeks or less than 1 week or 1-7 days or 1-5 days or 1-3 days or 1-2 days or about 1 day or less than 2 days or less than 1 day (e.g., 12-24 hours, 6-12 hours or 3-6 hours);

[0229] 2.34. Any of the above methods, wherein the patient is unresponsive or inadequately responsive to treatment with another antidepressant or experiences adverse side effects from treatment with another antidepressant, such as any one or more of a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor or serotonin receptor antagonist);

[0230] 2.35. Any of the above methods, wherein the patient does not suffer from (or has not been previously diagnosed with) schizophrenia or dementia;

[0231] 2.36. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands for 5-HT 2A The activity (agonism and / or antagonism) of the receptor has an IC of less than 250 nM 50 or EC less than 250nM 50 , for example, having an IC 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 the activity (agonism or antagonism) of the receptor 50 or EC 50 ;

[0232] 2.37. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands have an IC less than 250 nM for the activity (agonism and / or antagonism) of D2 receptors 50 or EC less than 250nM 50 , for example, an activity (agonism or antagonism) on the receptor having an IC 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 EC 50 ;

[0233] 2.38. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands have an IC less than 250 nM for the activity (agonism and / or antagonism) of D1 receptors 50 or EC less than 250nM 50, for example, having an IC 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 the activity (agonism or antagonism) of the receptor 50 or EC 50 ;

[0234] 2.39. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands have an IC less than 250 nM for the activity (agonism and / or antagonism) of the serotonin transporter (SERT) 50 or EC less than 250nM 50 , for example, having an IC 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 the activity (agonism or antagonism) of the transporter 50 or EC 50 ;

[0235] 2.40. Any of the above methods, wherein 5-HT 2A 5-HT 2A / The D2 receptor ligand is lumepirone, in free base or pharmaceutically acceptable salt form, optionally in deuterated form;

[0236] 2.41. Any of the above methods, wherein 5-HT 2A 5-HT 2A / the D2 receptor ligand is lumiperone in the form of a tosylate salt (e.g., monotosylate), optionally in a deuterated form, and optionally in a crystalline or amorphous tosylate salt form;

[0237] 2.42. Any of the above methods, wherein 5-HT 2A 5-HT 2A / the D2 receptor ligand is lumepirone, in free base form, optionally in deuterated form;

[0238] 2.43. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligand is administered in the form of a long-acting injectable (LAI) composition, e.g., for intramuscular or subcutaneous injection;

[0239] 2.44. Method 2.43, wherein the dosage of the LAI composition is sufficient to provide a daily dose equivalent to 1-100 mg of the free base, e.g., 1-75 mg or 1-60 mg or 1-40 mg or 1-20 mg or 1-10 mg of the free base, released over a period of about 1 week to about 3 months, e.g., about 1 week to about 8 weeks or about 1 week to about 6 weeks or about 1 week to about 4 weeks or about 1 week to about 3 weeks or about 1 week to about 2 weeks;

[0240] 2.45. 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;

[0241] 2.46. Method 2.45, wherein the polymer matrix comprises one or more biocompatible and biodegradable polymers as defined herein, such as poly(hydroxy carboxylic acids), poly(amino acids), cellulosic polymers, modified cellulosic polymers, polyamides and polyesters;

[0242] 2.47. Method 2.46, wherein the one or more polymers comprise 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(α-cyanoacrylate) such as poly(butyl cyanoacrylate) or poly(2-octylhydroxyacrylate), poly(orthoesters), polycarbonates, polyorthocarbonates, polyamino acids, (e.g., poly-γ.-L-alanine, poly-γ.-benzyl-L-glutamate or poly-γ-methyl-L-glutamate), and / or hyaluronate;

[0243] 2.48. Method 2.46, wherein the one or more polymers comprise polyorthoester (POE), polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic-co-glycolic acid);

[0244] 2.49. Method 2.46, wherein the one or more polymers comprises a poly(lactic-glycolic acid) copolymer, such as poly-d,l-lactide-co-glycolide (PLGA), for example, a PLGA copolymer having a lactide-glycolide molar ratio of about 50:50-90:10 or 50:50-85:15 or 50:50-75:25, and / or a molecular weight of 5,000-500,000 Daltons or 5,000-150,000 Daltons or 20,000-200,000 Daltons or 24,000-38,000 Daltons;

[0245] 2.50. Any of the above methods, wherein 5-HT 2A 5-HT 2A / the D2 receptor ligand is administered as a monotherapy, e.g., it is not administered concurrently or in combination with an antidepressant, antipsychotic, or anxiolytic;

[0246] 2.51. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands are administered without the direct supervision of a healthcare professional (e.g., the compound is self-administered by a patient);

[0247] 2.52. Any of the above methods, wherein the method does not include administering a dose of 5-HT 2A 5-HT 2A Supervision or observation of the patient by a healthcare professional during or after (e.g., within 2 hours after) administration of a D2 receptor ligand;

[0248] 2.53. Any of the above methods, wherein the method does not put the patient at risk for sedation, dissociation, abuse, misuse, or suicidal ideation;

[0249] 2.54. Any of the above methods, wherein the method does not involve administering a dose of 5-HT 2A 5-HT 2A / D2 receptor ligand causes hypertension (e.g., systolic and / or diastolic hypertension) within 4 hours after the dose, for example, an increase in systolic and / or diastolic blood pressure of greater than 10 mmHg, or greater than 20 mmHg, or greater than 30 mmHg, or greater than 40 mmHg within 30 minutes to 4 hours after the dose;

[0250] 2.55. Any of the above methods, wherein the method does not result in cognitive decline;

[0251] 2.56. Any of the above methods, wherein the patient has (e.g., has been diagnosed with) or is at risk for aneurysmal vascular disease (e.g., thoracic aortic, abdominal aortic, intracranial or peripheral arterial aneurysm), arteriovenous malformation or cerebral hemorrhage;

[0252] 2.57. Any of the above methods, wherein the patient is concurrently treated with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0253] 2.58. Any of the above methods, wherein the patient is not concurrently treated with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0254] 2.59. Any of the above methods, wherein the patient is unresponsive to or cannot be treated with ketamine (e.g., S-ketamine), for example because ketamine is contraindicated in the patient;

[0255] 2.60. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligand and PDE1 (cyclic nucleoside phosphodiesterase 1) inhibitor are administered to the patient concurrently (e.g., simultaneously, separately or sequentially) in free base or pharmaceutically acceptable salt form;

[0256] 2.61. Method 2.60 wherein the PDE1 inhibitor is a compound of Formula II:

[0257]

[0258] wherein R2 is H, and R3 and R4 together form a tri- or tetra-methylene bridge [preferably wherein the carbons carrying R3 and R4 have the R and S configuration, respectively]; or R2 and R3 are each methyl, and R4 is H; or R2 and R4 are H, and R3 is isopropyl [preferably wherein the carbon carrying R3 has the R configuration];

[0259] R6 is (optionally halogen-substituted)phenylamino or (optionally halogen-substituted)benzylamino;

[0260] R 10 is (optionally halogen-substituted)phenyl, (optionally halogen-substituted)pyridyl (eg 3-fluoropyridin-2-yl), thiadiazolyl (eg 1,2,3-thiadiazol-4-yl) or C 1-6 Alkylcarbonyl (e.g. methylcarbonyl);

[0261] It is in the form of a free base or a pharmaceutically acceptable salt;

[0262] 2.62. Method 2.61, wherein in the compound of formula II, R6 is phenylamino or 4-fluorophenylamino;

[0263] 2.63. Method 2.61, wherein in the compound of formula II, R 10 is 3-fluoropyridin-2-yl or methylcarbonyl;

[0264] 2.64. Method 2.61, wherein in the compound of formula II, R6 is phenylamino or 4-fluorophenylamino, and R 10 is 3-fluoropyridin-2-yl or methylcarbonyl;

[0265] 2.65. Any of methods 2.61-2.64, wherein the compound of formula II is

[0266]

[0267] It is in the form of a free base or a pharmaceutically acceptable salt.

[0268] 2.66 Method 2.65, wherein the compound of Formula II is in the form of a monophosphate salt;

[0269] 2.67 Any of methods 2.61-2.66 wherein the compound of formula I is:

[0270]

[0271] It is in the form of a free base or a pharmaceutically acceptable salt, such as a tosylate salt, optionally in deuterated form; and the compound of formula II is:

[0272]

[0273] It is in the form of a free base or a pharmaceutically acceptable salt, such as a monophosphate;

[0274] 2.68 Any of Methods 2.61-2.67, comprising administering a pharmaceutical composition comprising therapeutically effective amounts of a compound of Formula I and a compound of Formula II;

[0275] 2.69 Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligand is a compound of formula I in free base or pharmaceutically acceptable salt form, optionally in deuterated form; and wherein the compound is administered in the form of a long-acting injectable (LAI) composition comprising a compound of formula I dissolved or dispersed in or in a pharmaceutically acceptable carrier and a polymer matrix comprising a polymer selected from polyorthoesters (POE), polylactic acid, polyglycolic acid, polycitric acid, polymalic acid or poly(lactic-glycolic acid) copolymer;

[0276] 2.70 Method 2.69, wherein the pharmaceutically acceptable carrier comprises water (e.g., an aqueous buffer) and / or an organic solvent (e.g., an organic solvent miscible with water);

[0277] 2.71 Method 2.69 or 2.70, wherein the polymer comprises a polylactic acid and / or a polyglycolic acid polymer;

[0278] 2.72 Method 2.69 or 2.70, wherein the polymer comprises a poly(lactic-glycolic acid) copolymer, such as poly-d,l-lactide-co-glycolide (PLGA), for example, a PLGA copolymer having a lactide-glycolide molar ratio of about 50:50-90:10 or 50:50-85:15 or 50:50-75:25, and / or a molecular weight of 5,000-500,000 Daltons or 5,000-150,000 Daltons or 20,000-200,000 Daltons or 24,000-38,000 Daltons;

[0279] 2.73 Any of Methods 2.69-2.72, wherein the LAI composition is administered by intramuscular or subcutaneous injection, or is formulated for administration by intramuscular or subcutaneous injection;

[0280] 2.74 Any of method 2 or 2.1-2.74, wherein the patient has no previous history of depression;

[0281] 2.75 Method 2 or any one of 2.1-2.75, wherein the 5-HT 2A 5-HT 2A / D2 receptor ligand, the patient showed evidence of brain damage or encephalopathy on magnetic resonance imaging (MRI);

[0282] 2.76 Method 2 or any of 2.1-2.75, wherein the 5-HT 2A 5-HT 2A Before administration of a D2 receptor ligand, the patient tested positive for serum antibodies or antigens against 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);

[0283] 2.77 Method 2 or any of 2.1-2.76, wherein the patient tests positive for serum antibodies to autoantibodies to NMDA receptors, AMPA receptors, voltage-gated potassium channels (VGKCs), LGL1 protein, GABA receptors, glycine receptors, glutamate receptors, or CASPR2 receptors;

[0284] 2.78 Any of the above methods, wherein the patient has elevated levels of one or more biomarkers indicative of CNS inflammation in blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) (e.g., isolated from blood), urine, CSF and / or CNS microglia (e.g., isolated from CSF), selected from TNF-α, 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;

[0285] 2.79 Any of the above methods, wherein the patient has altered levels of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity in serum or CSF, such as increased levels of ICAM-1, VCAM-1, E-selectin, P-selectin, or soluble isoforms thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), or decreased levels of Cldn5, occludin, and ZO-1;

[0286] 2.80 Any of the above methods, wherein the patient has reduced levels of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, such as TNF-β, 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 microglia (e.g., isolated from CSF);

[0287] 2.81 Any of the above methods, wherein the 5-HT 2A 5-HT 2A After treatment with a D2 receptor ligand (e.g., a compound of the formula, optionally in deuterated form), the patient has a reduced level of one or more biomarkers indicative of CNS inflammation, such as TNF-α, 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., isolated from blood), urine, CSF, and / or CNS microglia (e.g., isolated from CSF), compared to a baseline before treatment, e.g., within 28 days of initiating treatment;

[0288] 2.82 Method 1.94, wherein the patient has at least a 5%, 10%, 15%, 20% or 25%, 30%, 35%, 40%, 45% or 50% reduction in the level of one or more biomarkers indicative of CNS inflammation, e.g., within 28 days of initiating treatment;

[0289] 2.83 Any of the above methods, wherein the 5-HT 2A 5-HT 2AAfter treatment with a CNS / D2 receptor ligand (e.g., a compound of the formula, optionally in deuterated form), the patient has a favorable change in the level of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity in serum or CSF, such as an increase in the level of ICAM-1, VCAM-1, E-selectin, P-selectin, or a soluble isoform thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), or a decrease in the level of Cldn5, occludin, and ZO-1, compared to a baseline before treatment, e.g., within 28 days of initiating treatment;

[0290] 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 anti-inflammatory biomarkers indicative of loss of CNS integrity and / or BBB integrity, e.g., within 28 days of initiating treatment;

[0291] 2.85 Any of the above methods, wherein the 5-HT 2A 5-HT 2A After treatment with a D2 receptor ligand (e.g., a compound of the formula, optionally in deuterated form), the patient has an increased level of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, such as TNF-β, 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 microglia (e.g., isolated from CSF), compared to a baseline before treatment, e.g., within 28 days of initiating treatment;

[0292] 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;

[0293] 2.87 Any of the above methods, wherein the method further comprises initiating the 2A 5-HT 2A / D2 receptor ligand (e.g., a compound of the general formula, optionally in deuterated form) and / or after initiation of said treatment, a step of testing one or more body fluids or tissues of the patient for the presence and / or concentration of a biomarker indicative of CNS inflammation or CNS inflammatory dysfunction, and optionally comparing the pre-treatment and one or more post-treatment results in order to quantify the effectiveness of the treatment for the patient and / or adjust the treatment regimen;

[0294] 2.88 Method 2.87, wherein the biomarker is selected from one or more of TNF-α, 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, soluble isoforms thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNF-β, IFN-α, IL-4 and IL-10;

[0295] 2.89 Method 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 microglia (e.g., isolated from CSF), or a brain biopsy tissue sample;

[0296] 2.90 Any of the above methods, wherein the method further comprises the following steps: 2A 5-HT 2A Before and / or after initiation of treatment with a D2 receptor ligand (e.g., a compound of the general formula, optionally in deuterated form), and / or before and / or after initiation of said treatment, testing the patient's central nervous system for the presence and / or concentration of one or more biomarkers indicative of CNS inflammation or CNS inflammatory dysfunction in a non-invasive manner, and optionally comparing pre-treatment and one or more post-treatment results to quantify the effectiveness of the treatment for the patient and / or adjust the treatment regimen;

[0297] 2.91 Method 2.90, wherein the biomarker is selected from one or more of TNF-α, 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, soluble isoforms thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNF-β, IFN-α, IL-4 and IL-10;

[0298] 2.92 Method 2.90 or 2.91, wherein the step comprises an imaging method, such as magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI), for assessing the presence and / or concentration of the biomarker;

[0299] 2.93 Methods of any of 2.90-2.92, wherein the method comprises the step of initiating, altering or terminating a treatment regimen (e.g., a selected 5-HT inhibitor) based on an observed change in the level of one or more of the biomarkers. 2A 5-HT 2A / D2 receptor ligand, its dosage, its administration route, its administration frequency, its administration form and / or selected 5-HT 2A 5-HT 2A / D2 receptor ligand in combination with any other therapeutic agent).

[0300] In another aspect, the present disclosure provides a 5-HT 2A 5-HT 2A / D2 receptor ligand, such as a compound of formula I, such as lumepirone, in free base or salt form, optionally in deuterated form, for use in protecting or strengthening the blood-brain barrier, such as for use in any of method 2, etc.

[0301] In another aspect, the present disclosure provides a 5-HT 2A 5-HT 2A / D2 receptor ligand, such as a compound of formula I, such as lumepirone, in free base or salt form, optionally in deuterated form, for the preparation of a medicament for protecting or strengthening the blood-brain barrier, such as for use in any one of method 2, etc.

[0302] In a specific embodiment, the present disclosure provides a method for treating a psychiatric disorder in a patient in need thereof (method 3), wherein the patient has elevated levels of pro-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as TNF-α, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, or elevated levels of C-reactive protein (CRP) or Csf1, and / or decreased levels of anti-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as TNF-β, IFN-α, IL-4, and IL-10, the method comprising administering to the patient a therapeutically effective amount of 5-HT 2A 5-HT 2A / D2 receptor ligands, such as compounds of formula I:

[0303]

[0304] in:

[0305] X is –N(H)-, –N(CH3)- or –O-;

[0306] Y is –C(=O)-, –C(H)(OH)- or –C(H)(OR1)-;

[0307] 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, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C 1-22 Alkoxy (e.g., ethoxy) groups are substituted, 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, wherein such compounds hydrolyze to form residues of natural or unnatural, saturated or unsaturated fatty acids, for example said compounds hydrolyze to form hydroxy compounds on the one hand and to form octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand,

[0308] Optionally in deuterated form,

[0309] is a free base, a pharmaceutically acceptable salt or a prodrug form. For example, method 3 can be as follows:

[0310] 3.1. Method 3, wherein X in the compound of formula I is -N(H)-, -N(CH3)- or -O-;

[0311] 3.2. Method 3 or 3.1, wherein X in the compound of formula I is -N(H);

[0312] 3.3. Method 3 or 3.1, wherein X in the compound of formula I is -N(CH3)-;

[0313] 3.4. Method 3 or 3.1, wherein X in the compound of formula I is -O-;

[0314] 3.5. Method 3 or any one of Formulas 3.1-3.4, wherein Y in the compound of Formula I is -C(=O)-, -C(H)(OH)- or -C(H)(OR1)-;

[0315] 3.6. Method 3 or any one of Formulas 3.1-3.4, wherein Y in the compound of Formula I is -C(=O)-;

[0316] 3.7. Method 3 or any one of Formulas 3.1-3.4, wherein Y in the compound of Formula I is -C(H)(OH)-;

[0317] 3.8. Method 3 or any one of Formulas 3.1-3.4, wherein Y in the compound of Formula I is -C(H)(OR1)-;

[0318] 3.9. Any of Methods 3 or 3.1-3.5 or 3.8, wherein in the compound of 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, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C 1-22 Alkoxy (e.g., ethoxy) groups are substituted, 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 wherein the compounds are hydrolyzed to form residues of natural or unnatural, saturated or unsaturated fatty acids, for example, the compounds are hydrolyzed to form hydroxy compounds on the one hand and to form octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand; for example, wherein in the compounds of formula I, R1 is -C(O)-C 6-15 Alkyl, for example -C(O)-C9 alkyl; or wherein in the compound of formula I, R1 is -C(O)-C 1-5 Alkyl, for example -C(O)-C3 alkyl;

[0319] 3.10. Any of Methods 3 or 3.1-3.5 or 3.7, wherein the compound of Formula I is:

[0320]

[0321] 3.11. Any of Methods 3 or 3.1-3.5 or 3.7, wherein the compound of Formula I is:

[0322]

[0323] 3.12. Any of Methods 3 or 3.1, 3.3, 3.5 or 3.6, wherein the compound of Formula I is lumepirone:

[0324]

[0325] 3.13. Any of Method 3 or 3.1-1.12, for example Method 1.12, wherein the compound of Formula I is in the form of a pharmaceutically acceptable salt, for example a tosylate salt;

[0326] 3.14. Any of Method 3 or 3.1-1.12, for example Method 1.12, wherein the compound of Formula I is in free base form;

[0327] 3.15. Any of Methods 3 or 3.1-1.14, wherein the compound of Formula I is in deuterated form, e.g., wherein the deuterium:protium ratio of a particular carbon-bonded hydrogen atom is significantly higher than the natural isotope ratio, e.g., at least 2 times higher, e.g., at least 10 times higher;

[0328] 3.16. Method 3.15, wherein the compound of Formula I is a deuterated form of lumepirone, for example selected from:

[0329]

[0330] wherein D represents a hydrogen position having deuterium incorporation much greater than that of nature (i.e. much greater than 0.0156%), e.g., greater than 60% or greater than 70% or greater than 80% or greater than 90% or greater than 95% or greater than 96% or greater than 97% or greater than 98% or greater than 99%, in free base or pharmaceutically acceptable salt form, e.g., tosylate form;

[0331] 3.17. Any of the above methods, wherein 5-HT 2A 5-HT 2A / The D2 receptor ligand is a compound of formula I in the form of a free base or a pharmaceutically acceptable salt, such as a tosylate salt, administered in a daily dose equivalent to 1-100 mg of the free base, for example in an amount equivalent to 1-75 mg or 1-60 mg or 1-40 mg or 1-20 mg or 1-10 mg of the free base;

[0332] 3.18. Method 3.17, wherein the method comprises administering once daily a unit dose for oral administration, such as a tablet or capsule, comprising: a compound of Formula I in free base or pharmaceutically acceptable salt form, such as tosylate form, in an amount equivalent to 1-100 mg of the free base, such as an amount equivalent to 1-75 mg or 1-60 mg or 1-40 mg or 1-30 mg or 1-20 mg or 1-10 mg or 1-5 mg or 40-60 mg or 20-40 mg or 10-20 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;

[0333] 3.19. Method 3.17, wherein the method comprises administering once daily a unit dose for oral transmucosal administration, such as a sublingual or buccal orally disintegrating tablet, wafer or film, comprising: a compound of Formula I in free base or pharmaceutically acceptable salt form, in an amount equivalent to 0.5-30 mg of the free base, such as 1-30 mg or 1-20 mg or 1-15 mg or 1-10 mg or 20-30 mg or 10-20 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;

[0334] 3.20. Any of the above methods, wherein the condition being treated is relieved within 1 week, such as within 3 days, such as within 1 day;

[0335] 3.21. Any of the above methods, wherein the patient has or is diagnosed with viral, bacterial or autoimmune encephalitis;

[0336] 3.22. Method 3.21, wherein the patient's mental disorder is caused or suspected to be caused by viral, bacterial or autoimmune encephalitis;

[0337] 3.23. Method 3.21 or 3.22, wherein the encephalitis is viral encephalitis;

[0338] 3.24. Method 3.23, wherein the viral encephalitis is caused or suspected to be 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, such as H1N1, H2N2, H3N2, H5N1, H7N7);

[0339] 3.25. Method 3.21, 3.22 or 3.23, wherein the viral encephalitis is acute viral encephalitis;

[0340] 3.26. Method 3.21, wherein the encephalitis is bacterial encephalitis;

[0341] 3.27. Method 3.26 wherein the encephalitis is caused or believed to be caused by toxoplasmosis, rickettsia, mycoplasma, borrelia (eg, Lyme disease), or malaria.

[0342] 3.28. Method 3.21, wherein the encephalitis is autoimmune encephalitis;

[0343] 3.29. Method 3.28, wherein the encephalitis is caused or believed to be caused by autoantibodies against NMDA receptors, AMPA receptors, voltage-gated potassium channels (VGKC), LGL1 protein, GABA receptors, glycine receptors, glutamate receptors or CASPR2 receptors;

[0344] 3.30. Any of methods 3.21-3.29, wherein the patient has no history of psychiatric disorder or psychiatric symptoms prior to diagnosis of encephalitis;

[0345] 3.31. Any of methods 3.21-3.29, wherein prior to the diagnosis of encephalitis, the patient has no history of one or more of the following: depression, anxiety, psychosis, post-traumatic stress disorder, anhedonia, dementia, memory loss, impaired executive function, difficulty concentrating, seizures, difficulty sleeping, hallucinations, or personality changes;

[0346] 3.32. Any of the above methods, wherein the mental disorder is depression (e.g., acute depression, MDD depression, bipolar depression), anxiety (e.g., acute anxiety), psychosis (e.g., schizophrenia), post-traumatic stress disorder, anhedonia, memory loss, impaired executive function, difficulty concentrating, seizures, difficulty sleeping, hallucinations, personality changes, or any combination thereof;

[0347] 3.33. Any of the above methods, wherein the mental disorder is depression (eg, acute depression, MDD depression, bipolar depression);

[0348] 3.34. Any of the above methods, wherein the mental disorder is anxiety (eg, acute anxiety disorder);

[0349] 3.35. Any of the above methods, wherein the mental disorder is anhedonia;

[0350] 3.36. Any of the above methods, wherein the patient is diagnosed with suicidal ideation and / or suicidal tendencies;

[0351] 3.37. Any of the above methods, wherein 5-HT 2A 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 a unit dosage form, or a free combination administered sequentially or simultaneously or within a 24-hour period);

[0352] 3.38. Method 3.37, wherein the anxiolytic or antidepressant is selected from one or more compounds in free base or pharmaceutically acceptable salt form selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and atypical antipsychotics, such as one or more compounds in free base or pharmaceutically acceptable salt form selected from:

[0353] (a) Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (Celexa), escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), fluvoxamine (Luvox), and sertraline (Zoloft, Lustral);

[0354] (b) serotonin-norepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella), tolfenacin (Elamol, Tofacine), and venlafaxine (Effexor);

[0355] (c) tricyclic antidepressants (TCAs), such as amitriptyline (Elavil, Endep), amitriptyline oxide (Amioxid, Ambivalon, Equilibrin), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), diphenhydramine (Noveril, Victoril), dimethoprim (Istonil), dosuliprine (Prothiaden), doxepin (Adapin, Sinequan), imipramine (Tofranil), lofepramine (Lomont, Gamanil), melitracen (Dixeran, Melixeran, Trausabun), nitrosazepine (Sintamil), nortriptyline (Pamelor, Aventyl), noxitriptyline (Agedal, Elronon, Nogedal), pipofiazine (Azafen / Azaphen), protriptyline (Vivactil), trimipramine (Surmontil);

[0356] (d) Benzodiazepines Class, for example, selected from 2-keto compounds (such as clorazepate, diazepam, flurazepam,

[0357] halazepam, prazepam); 3-hydroxy compounds (clorazepam, lormetazepam, oxazepam, temazepam); 7-nitro compounds (e.g., clonazepam, flunitrazepam, nimetazepam, nitrazepam); triazolo compounds (e.g., adizalam, alprazolam, estazolam, triazolam); and imidazolo compounds (clomazolam, loprazolam, midazolam);

[0358] 3.39. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands, such as compounds of Formula I, are administered intranasally, subcutaneously, intramuscularly, intravenously, orally, sublingually, intraperitoneally or buccally, such as oral fast-dissolving tablets, wafers or films, which dissolve in the mouth for transmucosal absorption;

[0359] 3.40. Any of the above methods, wherein the method further comprises concurrently administering an antidepressant (e.g., selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor),

[0360] 3.41. Any of the above methods, wherein the method further comprises simultaneously administering an NMDA receptor antagonist, for example, selected from ketamine (e.g., S-ketamine and / or R-ketamine), norethisterone, memantine, dextromethorphan, dextroalorphine, dextrorphan, amantadine and agmatine or any combination thereof, for example, by simultaneous, separate or sequential administration;

[0361] 3.42. Any of the above methods, wherein the method further comprises concurrently administering an NMDA receptor allosteric modulator, such as an NMDA receptor glycine site modulator, such as rapatenat, nepotinab, apitinab, D-cycloserine, or any combination thereof, such as by simultaneous, separate, or sequential administration;

[0362] 3.43. Any of the above methods, wherein the method provides the patient with one or more therapeutic agents (e.g., 5-HT 2A 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 any other antidepressant);

[0363] 3.44. Method 3.43, wherein the patient shows an acute response to treatment in less than 3 weeks, e.g., less than 2 weeks or less than 1 week or 1-7 days or 1-5 days or 1-3 days or 1-2 days or about 1 day or less than 2 days or less than 1 day (e.g., 12-24 hours, 6-12 hours or 3-6 hours);

[0364] 3.45. Any of the above methods, wherein the patient is unresponsive or inadequately responsive to treatment with another antidepressant, or experiences adverse side effects from treatment with another antidepressant, such as any one or more of a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor), or a serotonin receptor antagonist;

[0365] 3.46. Any of the above methods, wherein the mental disorder is not related to schizophrenia or dementia;

[0366] 3.47. Any of the above methods, wherein the patient does not suffer from (or has not been previously diagnosed with) schizophrenia or dementia;

[0367] 3.48. Any of the above methods, wherein the method protects or strengthens the blood-brain barrier;

[0368] 3.49. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands for 5-HT 2A The activity (agonism and / or antagonism) of the receptor has an IC of less than 250 nM 50 or EC less than 250nM 50 , for example, having an IC 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 the activity (agonism or antagonism) of the receptor 50 or EC 50 ;

[0369] 3.50. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands have an IC less than 250 nM for the activity (agonism and / or antagonism) of D2 receptors 50 or EC less than 250nM 50 , for example, having an IC 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 the activity (agonism or antagonism) of the receptor 50 or EC 50 ;

[0370] 3.51. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands have an IC less than 250 nM for the activity (agonism and / or antagonism) of D1 receptors 50 or EC less than 250nM 50 , for example, having an IC 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 the activity (agonism or antagonism) of the receptor 50 or EC50 ;

[0371] 3.52. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands have an IC less than 250 nM for the activity (agonism and / or antagonism) of the serotonin transporter (SERT) 50 or EC less than 250nM 50 , for example, having an IC 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 the activity (agonism or antagonism) of the transporter 50 or EC 50 ;

[0372] 3.53. Any of the above methods, wherein 5-HT 2A 5-HT 2A / The D2 receptor ligand is lumepirone, in free base or pharmaceutically acceptable salt form, optionally in deuterated form;

[0373] 3.54. Any of the above methods, wherein 5-HT 2A 5-HT 2A / the D2 receptor ligand is lumiperone in the form of a tosylate salt (e.g., monotosylate), optionally in a deuterated form, and optionally in a crystalline or amorphous tosylate salt form;

[0374] 3.55. Any of the above methods, wherein 5-HT 2A 5-HT 2A / the D2 receptor ligand is lumepirone, in free base form, optionally in deuterated form;

[0375] 3.56. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligand is administered in the form of a long-acting injectable (LAI) composition, e.g., for intramuscular or subcutaneous injection;

[0376] 3.57. Method 3.56, wherein the dosage of the LAI composition is sufficient to provide a daily dose equivalent to 1-100 mg of free base, e.g., 1-75 mg or 1-60 mg or 1-40 mg or 1-20 mg or 1-10 mg of free base, released over a period of about 1 week to about 3 months, e.g., about 1 week to about 8 weeks or about 1 week to about 6 weeks or about 1 week to about 4 weeks or about 1 week to about 3 weeks or about 1 week to about 2 weeks;

[0377] 3.58. Method 3.56 or 3.57, wherein the LAI composition comprises a compound of Formula I dissolved, dispersed, suspended or encapsulated in a polymer matrix;

[0378] 3.59. Method 3.58, wherein the polymer matrix comprises one or more biocompatible and biodegradable polymers as defined herein, such as poly(hydroxy carboxylic acids), poly(amino acids), cellulosic polymers, modified cellulosic polymers, polyamides, and polyesters;

[0379] 3.60. Method 3.59, wherein the one or more polymers comprise 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(α-cyanoacrylate) such as poly(butyl cyanoacrylate) or poly(2-octyl hydroxyacrylate), poly(orthoesters), polycarbonates, polyorthocarbonates, polyamino acids (e.g., poly-γ.-L-alanine, poly-γ.-benzyl-L-glutamate or poly-γ-methyl-L-glutamate), and / or hyaluronate;

[0380] 3.61. Method 3.60, wherein the one or more polymers comprise polyorthoester (POE), polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, or poly(lactic-co-glycolic acid);

[0381] 3.62. Method 3.60, wherein the one or more polymers comprises a poly(lactic-glycolic acid) copolymer, such as poly-d,l-lactide-co-glycolide (PLGA), for example, a PLGA copolymer having a lactide-glycolide molar ratio of about 50:50-90:10 or 50:50-85:15 or 50:50-75:25, and / or a molecular weight of 5,000-500,000 Daltons or 5,000-150,000 Daltons or 20,000-200,000 Daltons or 24,000-38,000 Daltons;

[0382] 3.63. Any of the above methods, wherein 5-HT 2A 5-HT 2A / the D2 receptor ligand is administered as a monotherapy, e.g., it is not administered concurrently or in combination with an antidepressant, antipsychotic, or anxiolytic;

[0383] 3.64. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligands are administered without the direct supervision of a healthcare professional (e.g., the compound is self-administered by a patient);

[0384] 3.65. Any of the above methods, wherein the method does not include administering a dose of 5-HT 2A 5-HT 2A Supervision or observation of the patient by a healthcare professional during or after (e.g., within 2 hours after) administration of a D2 receptor ligand;

[0385] 3.66. Any of the above methods, wherein the method does not put the patient at risk for sedation, dissociation, abuse, misuse, or suicidal ideation;

[0386] 3.67. Any of the above methods, wherein the method does not involve administering a dose of 5-HT 2A 5-HT 2A / D2 receptor ligand causes hypertension (e.g., systolic and / or diastolic hypertension) within 4 hours after the dose, for example, an increase in systolic and / or diastolic blood pressure of greater than 10 mm Hg, or greater than 20 mm Hg, or greater than 30 mm Hg, or greater than 40 mm Hg within 30 minutes to 4 hours after the dose;

[0387] 3.68. Any of the above methods, wherein the method does not result in cognitive decline;

[0388] 3.69. Any of the above methods, wherein the patient has (e.g., has been diagnosed with) aneurysmal vascular disease (e.g., thoracic aortic, abdominal aortic, intracranial or peripheral arterial aneurysm), arteriovenous malformation or cerebral hemorrhage, or is at risk for the above diseases;

[0389] 3.70. Any of the above methods, wherein the patient is concurrently treated with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0390] 3.71. Any of the above methods, wherein the patient is not concurrently treated with an oral antidepressant selected from duloxetine, escitalopram, sertraline, or venlafaxine;

[0391] 3.72. Any of the above methods, wherein the patient is unresponsive to or cannot be treated with ketamine (e.g., S-ketamine), for example because ketamine is contraindicated in the patient;

[0392] 3.73. Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligand and PDE1 (cyclic nucleoside phosphodiesterase 1) inhibitor are administered to the patient concurrently (e.g., simultaneously, separately or sequentially) in free base or pharmaceutically acceptable salt form;

[0393] 3.74. Method 3.73 wherein the PDE1 inhibitor is a compound of Formula II:

[0394]

[0395] wherein R2 is H, and R3 and R4 together form a tri- or tetra-methylene bridge [preferably wherein the carbons carrying R3 and R4 have the R and S configuration, respectively]; or R2 and R3 are each methyl, and R4 is H; or R2 and R4 are H, and R3 is isopropyl [preferably wherein the carbon carrying R3 has the R configuration];

[0396] R6 is (optionally halogen-substituted)phenylamino or (optionally halogen-substituted)benzylamino;

[0397] R 10 is (optionally halogen-substituted)phenyl, (optionally halogen-substituted)pyridyl (eg 3-fluoropyridin-2-yl), thiadiazolyl (eg 1,2,3-thiadiazol-4-yl) or C 1-6 Alkylcarbonyl (e.g. methylcarbonyl);

[0398] It is in the form of a free base or a pharmaceutically acceptable salt;

[0399] 3.75. Method 3.74, wherein in the compound of formula II, R6 is phenylamino or 4-fluorophenylamino;

[0400] 3.76. Method 3.74, wherein in the compound of formula II, R 10 is 3-fluoropyridin-2-yl or methylcarbonyl;

[0401] 3.77. Method 3.74, wherein in the compound of formula II, R6 is phenylamino or 4-fluorophenylamino, and R 10 is 3-fluoropyridin-2-yl or methylcarbonyl;

[0402] 3.78. Any of methods 3.74-3.77, wherein the compound of formula II is

[0403]

[0404] It is in the form of a free base or a pharmaceutically acceptable salt;

[0405] 3.79. Method 3.77, wherein the compound of Formula II is in the form of a monophosphate salt;

[0406] 3.80. Any of Methods 3.74-3.79 wherein the compound of Formula I is:

[0407]

[0408] It is in the form of a free base or a pharmaceutically acceptable salt, such as a tosylate salt, optionally in deuterated form; and the compound of formula II is:

[0409]

[0410] It is in the form of a free base or a pharmaceutically acceptable salt, such as a monophosphate;

[0411] 3.81 Any of Methods 3.74-3.80, comprising administering a pharmaceutical composition comprising therapeutically effective amounts of a compound of Formula I and a compound of Formula II;

[0412] 3.82 Any of the above methods, wherein 5-HT 2A 5-HT 2A / D2 receptor ligand is a compound of formula I in free base or pharmaceutically acceptable salt form, optionally in deuterated form; and wherein the compound is administered in the form of a long-acting injectable (LAI) composition comprising a compound of formula I dissolved or dispersed in or in a pharmaceutically acceptable carrier and a polymer matrix comprising a polymer selected from polyorthoester (POE), polylactic acid, polyglycolic acid, polycitric acid, polymalic acid or poly(lactic-glycolic acid) copolymer;

[0413] 3.83 Method 3.82, wherein the pharmaceutically acceptable carrier comprises water (e.g., an aqueous buffer) and / or an organic solvent (e.g., an organic solvent miscible with water);

[0414] 3.84 Method 3.82 or 3.83, wherein the polymer comprises a polylactic acid and / or a polyglycolic acid polymer;

[0415] 3.85 Method 3.82 or 3.83, wherein the polymer comprises a poly(lactic-glycolic acid) copolymer, such as poly-d,l-lactide-co-glycolide (PLGA), such as a PLGA copolymer having a lactide-glycolide molar ratio of about 50:50-90:10 or 50:50-85:15 or 50:50-75:25, and / or a molecular weight of 5,000-500,000 Daltons or 5,000-150,000 Daltons or 20,000-200,000 Daltons or 24,000-38,000 Daltons;

[0416] 3.86 Any of Methods 3.82-3.85, wherein the LAI composition is administered by intramuscular or subcutaneous injection, or is formulated for administration by intramuscular or subcutaneous injection;

[0417] 3.87 Any of method 3 or 3.1-3.86, wherein the patient has no previous history of depression;

[0418] 3.88 Any of Method 3 or 3.1-3.87, wherein the 5-HT 2A 5-HT 2A / D2 receptor ligand, the patient showed evidence of brain damage or encephalopathy on magnetic resonance imaging (MRI);

[0419] 3.89 Any of Method 3 or 3.1-3.88, wherein the 5-HT 2A 5-HT 2A Before administration of a D2 receptor ligand, the patient tested positive for serum antibodies or antigens against 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);

[0420] 3.90 Method 3 or any of 3.1-3.89, wherein the patient tests positive for serum antibodies to autoantibodies to NMDA receptors, AMPA receptors, voltage-gated potassium channels (VGKCs), LGL1 protein, GABA receptors, glycine receptors, glutamate receptors, or CASPR2 receptors;

[0421] 3.91 Any of the above methods, wherein the patient has elevated levels of one or more biomarkers indicative of CNS inflammation, e.g., selected from TNF-α, 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., isolated from blood), urine, CSF, and / or CNS microglia (e.g., isolated from CSF);

[0422] 3.92 Any of the above methods, wherein the patient has altered levels of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity in serum or CSF, such as increased levels of ICAM-1, VCAM-1, E-selectin, P-selectin, or soluble isoforms thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), or decreased levels of Cldn5, occludin, and ZO-1;

[0423] 3.93 Any of the above methods, wherein the patient has reduced levels of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, such as TNF-β, 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 microglia (e.g., isolated from CSF);

[0424] 3.94 Any of the above methods, wherein the 5-HT 2A 5-HT 2A After treatment with a D2 receptor ligand (e.g., a compound of the formula, optionally in deuterated form), the patient has a reduced level of one or more biomarkers indicative of CNS inflammation, such as TNF-α, 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., isolated from blood), urine, CSF, and / or CNS microglia (e.g., isolated from CSF), compared to a baseline before treatment, e.g., within 28 days of initiating treatment;

[0425] 3.95 Method 3.94, wherein the patient has at least a 5%, 10%, 15%, 20% or 25%, 30%, 35%, 40%, 45% or 50% reduction in the level of one or more biomarkers indicative of CNS inflammation, e.g., within 28 days of initiating treatment;

[0426] 3.96 Any of the above methods, wherein 5-HT 2A 5-HT 2A After treatment with a CNS / D2 receptor ligand (e.g., a compound of the formula, optionally in deuterated form), the patient has a favorable change in the level of one or more biomarkers indicative of CNS inflammation and / or loss of BBB integrity in serum or CSF, such as an increase in the level of ICAM-1, VCAM-1, E-selectin, P-selectin, or a soluble isoform thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), or a decrease in the level of Cldn5, occludin, and ZO-1, compared to a baseline before treatment, e.g., within 28 days of initiating treatment;

[0427] 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 initiating treatment;

[0428] 3.98 Any of the above methods, wherein 5-HT 2A 5-HT 2A After treatment with a D2 receptor ligand (e.g., a compound of the formula, optionally in deuterated form), the patient has an increased level of one or more anti-inflammatory biomarkers indicative of CNS inflammatory dysfunction, such as TNF-β, 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 microglia (e.g., isolated from CSF), compared to a baseline before treatment, e.g., within 28 days of initiating treatment;

[0429] 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;

[0430] 3.100 Any of the above methods, wherein the method further comprises the following steps: 2A 5-HT 2A Before and / or after initiation of treatment with a D2 receptor ligand (e.g., a compound of the formula, optionally in deuterated form), and / or testing one or more body fluids or tissues of the patient for the presence and / or concentration of a biomarker indicative of CNS inflammation or CNS inflammatory dysfunction, and optionally comparing pre-treatment and one or more post-treatment results in order to quantify the effectiveness of the treatment for the patient and / or adjust the treatment regimen;

[0431] 3.101 Method 3.100, wherein the biomarker is selected from one or more of TNF-α, 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, soluble isoforms thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNF-β, IFN-α, IL-4 and IL-10;

[0432] 3.102 Method 3.100 or 3.101, 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 microglia (e.g., isolated from CSF), or a brain biopsy tissue sample;

[0433] 3.103 Any of the above methods, wherein the method further comprises the following steps: 2A 5-HT 2A Before and / or after initiation of treatment with a D2 receptor ligand (e.g., a compound of the general formula, optionally in deuterated form), and / or before and / or after initiation of said treatment, non-invasively testing the patient's central nervous system for the presence and / or concentration of one or more biomarkers indicative of CNS inflammation or CNS inflammatory dysfunction, and optionally comparing pre-treatment and one or more post-treatment results to quantify the effectiveness of the treatment for the patient and / or adjust the treatment regimen;

[0434] 3.104 Method 3.103, wherein the biomarker is selected from one or more of TNF-α, 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, soluble isoforms thereof (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), TNF-β, IFN-α, IL-4 and IL-10;

[0435] 3.105 Method 3.103 or 3.104, wherein the step comprises an imaging method, such as magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI), for assessing the presence and / or concentration of the biomarker;

[0436] 3.106 Any of methods 3.100-3.105, wherein the method comprises the step of initiating, changing or terminating a treatment regimen (e.g., a selected 5-HT inhibitor) based on an observed change in the level of one or more of the biomarkers. 2A 5-HT 2A / D2 receptor ligand, its dosage, administration route, administration frequency, administration form and / or selected 5-HT 2A 5-HT 2A / D2 receptor ligand in combination with any other therapeutic agent).

[0437] In another aspect, the present disclosure provides a 5-HT 2A 5-HT 2A / D2 receptor ligand, e.g., a compound of Formula I, e.g., lumepirone, in free base or salt form, optionally in deuterated form, for use in treating a psychotic disorder in a patient in need thereof, wherein the patient has elevated levels of pro-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), e.g., TNF-α, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, or elevated levels of C-reactive protein (CRP) or Csf1, and / or reduced levels of anti-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), e.g., TNF-β, IFN-α, IL-4 and IL-10, e.g., for use in any one of method 3, etc.

[0438] In another aspect, the present disclosure provides a 5-HT 2A 5-HT 2A / D2 receptor ligand, such as a compound of Formula I, such as lumepirone, in free base or salt form, optionally in deuterated form, for the preparation of a medicament for treating a psychotic disorder in a patient in need thereof, wherein the patient has elevated levels of pro-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as TNF-α, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, or elevated levels of C-reactive protein (CRP) or Csf1, and / or reduced levels of anti-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as TNF-β, IFN-α, IL-4 and IL-10, such as for use in any one of method 3, etc.

[0439] In some embodiments described herein, a particularly suitable patient for implementing the disclosed method can be identified by measuring the level of certain biomarkers in the body 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 reasons. Therefore, the patient's psychological symptoms can be particularly attributed to such inflammatory changes, and can particularly benefit from the unique properties and activity of the compounds described herein. Biomarkers indicating CNS inflammation include TNF-α, 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 taken from blood, plasma, serum, peripheral blood mononuclear cells (PBMC) (e.g., separated from blood), urine, cerebrospinal fluid (CSF) and / or samples of microglia separated from CSF to identify or quantify. In particular, changes in certain biomarkers indicate the destruction of blood-brain barrier integrity, such as ICAM-1, VCAM-1, E-selectin, P-selectin, Cldn5, occludin and ZO-1 or its soluble isoforms (e.g., sICAM-1, sVCAM1, sP-selectin, sE-selectin), which can be identified or quantified in serum or CSF. The destruction of the BBB can lead to cell damage and cell lysis, resulting in the presence of membrane-bound tight junction proteins 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 immune cells to infiltrate the CSF. Changes in the levels of any or all of these biomarkers can indicate CNS inflammation and / or BBB damage or BBB integrity loss. Similarly, another class of biomarkers are those associated with anti-inflammatory properties, such as anti-inflammatory cytokines. The reduction in the level of such biomarkers can indicate CNS inflammatory dysfunction, i.e., dysfunction of normal body control of cellular inflammation. Examples of such biomarkers include TNF-β, IFN-α, IL-4, and IL-10, which can also be identified or quantified in samples taken from blood, plasma, serum, peripheral blood mononuclear cells (PBMC) (e.g., isolated from blood), urine, cerebrospinal fluid (CSF), and / or microglia isolated from CSF. In addition to detecting these biomarkers in body fluids and tissues, much work has been done using non-invasive imaging techniques (e.g., MRI, PET) to obtain the same information, particularly in difficult-to-access body compartments such as the CNS.Additional information on methods for measuring such biomarkers and interpreting changes in the levels of these biomarkers can be found in the following references: 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).

[0440] The term "5-HT 2A Receptor ligand refers to a receptor that is at least 5-hydroxytryptamine (5-HT) 2A Compounds that exhibit pharmacological activity against a receptor, for example, compounds that have an IC of less than 250 nM for activity (agonism and / or antagonism) against said receptor 50 or EC less than 250nM 50 In some embodiments, the term refers to a compound that has an IC 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 the activity (agonism or antagonism) of the receptor. 50 or EC 50 of compounds.

[0441] The term "5-HT 2A"D2 receptor ligand" refers to a ligand that is at least 5-hydroxytryptamine (5-HT) 2A Compounds that exhibit physiological activity against D2 receptors and D3 receptors, for example, compounds that have an IC of less than 250 nM for activity (agonism and / or antagonism) against each of said receptors 50 or EC less than 250nM 50 In some embodiments, the term refers to a compound that has an IC 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) on one or both of these receptors. 50 or EC 50 of compounds.

[0442] The terms "treatment" and "treating" should be understood accordingly to include prevention and treatment or amelioration of disease symptoms and / or treatment of the cause of the disease. In specific embodiments, the terms "treatment" and "treating" refer to the prevention or amelioration of disease symptoms.

[0443] The term "patient" may include human or non-human patients.

[0444] Unless otherwise stated or the context is unclear, the following terms have the following meanings as used herein:

[0445] As used herein, "alkyl" is a saturated or unsaturated hydrocarbon moiety, for example, 1-21 carbon atoms in length, which may be straight chain or branched (e.g., n-butyl or tert-butyl), preferably straight chain, unless otherwise specified. For example, "C 1-21 "Alkyl" means an alkyl group having 1 to 21 carbon atoms. In one embodiment, the alkyl group is optionally substituted with one or more hydroxyl groups or C 1-22 In another embodiment, the alkyl group comprises 1-21 carbon atoms, preferably straight chain and optionally saturated or unsaturated, for example R1 can be an alkyl chain comprising 1-21 carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon atoms, for example such that it forms, together with the attached -C(O)-, the residue of a natural or non-natural, saturated or unsaturated fatty acid, for example when cleaved from the compound of formula I.

[0446] 5-HT 2A 5-HT 2AThe / D2 receptor ligand, for example the substituted heterocyclic fused γ-carbolines described herein can be in the form of a free base, a pharmaceutically acceptable salt or a prodrug. Pharmaceutically acceptable salts include, for example, tosylate salts in the case of compounds of formula I. When the dose or amount of a salt is given by weight, for example, milligrams per day or milligrams per unit dose, the dose of the salt is given as the weight of the corresponding free base, unless otherwise indicated.

[0447] In any and all embodiments described herein, 5-HT 2A 5-HT 2A The D2 receptor ligand may also be a SERT ligand, that is, the compound may be a 5-HT 2A / SERT or 5-HT 2A / D2 / SERT receptor ligand.

[0448] In any and all embodiments described herein, 5-HT 2A 5-HT 2A The D2 receptor ligand may be free or substantially free of any opioid receptor activity (e.g., free or substantially free of μ-opioid receptor activity, e.g., having an IC greater than 50 nM, or greater than 100 nM, or greater than 150 nM). 50 ).

[0449] 5-HT 2A 5-HT 2A / D2 receptor ligands may also exist in prodrug form in some cases. Prodrug forms are compounds that are converted into active compounds in vivo. For example, compounds containing hydroxyl or carboxyl substituents can form physiologically hydrolyzable and acceptable esters. As used herein, "physiologically hydrolyzable and acceptable esters" refer to esters that can be hydrolyzed under physiological conditions to produce acids (in the case of compounds with hydroxyl substituents) or alcohols (in the case of compounds with carboxyl substituents), and the acids or alcohols themselves are physiologically tolerable at the dose to be administered. For example, wherein Y of the compound of formula I is -C(H)(OR1), and R1 is -C(O)-C 1-21 Alkyl, such as -C(O)-C3 alkyl or -C(O)-C9 alkyl, which can be hydrolyzed under physiological conditions to form compounds of formula I, wherein on the one hand 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, the term thus includes conventional prodrug forms of the drug. When a prodrug (e.g., a compound of formula (I) wherein R1 is -C(O)-C 1-21 When Y is -C(=O)- or -CH(OH)-, the dosage is calculated based on the amount of the compound of formula (I) in which Y is -C(=O)- or -CH(OH)- in free base form.

[0450] When referring to therapeutic uses, the term "concurrently" refers to the administration of two or more active ingredients to a patient as part of a regimen for treating a disease or condition, whether the two or more active agents are administered at the same or different times or by the same or different routes of administration. The concurrent administration of two or more active ingredients can be performed at different times of the same day, or on different days or at different frequencies.

[0451] When used in relation to therapeutic purposes, the term "simultaneously" means that two or more active ingredients are administered at or about the same time by the same route of administration.

[0452] When referring to therapeutic uses, the term "separately" means that two or more active ingredients are administered simultaneously or about simultaneously by different routes of administration.

[0453] About the use of 5-HT 2A 5-HT 2A Without being bound by theory, it is believed that the combination of these agents may allow for the use of lower doses of both agents to treat depression or other neuropsychiatric disorders described herein, such that the dissociative effects produced by the NMDA receptor antagonist will be minimized while the synergistic antidepressant effect will be maximized.

[0454] The dosage adopted for practicing the present disclosure will of course vary according to, for example, the specific disease or condition being treated, the specific active compound used, the mode of administration and the desired therapy. Unless otherwise indicated, the amount of the active compound used for administration (whether administered in the form of a free base or a salt) refers to or is based on the amount of the compound in the free base form (i.e., the amount is calculated based on the amount of the active part in the free base form, without considering the weight of the counter ion in the case of a salt).

[0455] 5-HT 2A 5-HT 2A The D2 receptor ligand may be administered by any suitable route, including oral, intramuscular, subcutaneous, parenteral, transmucosal or transdermal administration, but oral or transmucosal administration is preferred. 2A 5-HT 2A The / D2 receptor ligand can be administered, for example, in the form of tablets, capsules, wafers, injections (eg, intravenous, intramuscular or subcutaneous injections), or oral rapidly disintegrating tablets, wafers or films for sublingual or buccal administration.

[0456] For the avoidance of doubt, any disclosure of a numerical range, such as an amount "up to X", is intended to include the upper numerical limit X. Thus, a disclosure of "up to 60 mg" is intended to include 60 mg.

[0457] Pharmaceutical compositions containing compounds of the present disclosure can be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.

[0458] The compounds of the present disclosure can be included as long-acting injectable preparations (i.e., depot preparations), for example, by dispersing, dissolving, suspending or encapsulating the compounds of the present invention in a polymer matrix as described herein, so that the compound is continuously released when the polymer degrades over time. The release of the compounds of the present invention from the polymer matrix provides controlled release and / or delayed release and / or sustained release of the compounds, for example, from the drug reservoir composition to the subject, for example, a warm-blooded animal, for example, a human body, to which the drug reservoir is applied. Therefore, the drug reservoir delivers the compounds of the present invention to the subject at a concentration effective for treating a specific disease or medical condition within a sustained time period (e.g., 1 week to 3 months).

[0459] The polymer of the polymer matrix that can be used in the composition of the present invention (e.g., the reservoir composition of the present invention) may include polyesters of hydroxy fatty acids and their derivatives or other agents, such as polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-β.-hydroxybutyric acid, ε.-caprolactone ring-opening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, polylactic acid-polyethylene glycol copolymer or polyglycolic acid-polyethylene glycol copolymer), PEG-PLGA copolymer or block copolymer, polymer of α-cyanoacrylate alkyl ester (e.g., poly(2-cyanoacrylate butyl ester)), polyalkylene oxalate (e.g., polytrimethylene oxalate or polytetramethylene oxalate), polyorthoester, polycarbonate (e.g., polyethylene carbonate or polyethylene propylene carbonate), polyorthocarbonate, polyamino acid (e.g., poly-.γ.-L-alanine, poly-.γ.-benzyl-L-glutamic acid or poly-y-methyl-L-glutamic acid), hyaluronic acid ester, etc., and one or more of these polymers can be used.

[0460] If the polymer is a copolymer, they can be any of random, block and / or graft copolymers. When the above-mentioned α-hydroxycarboxylic acids, hydroxydicarboxylic acids and hydroxytricarboxylic acids have optical activity in their molecules, any of D-isomers, L-isomers and / or DL-isomers can be used. Among them, α-hydroxycarboxylic acid polymers (preferably lactic acid-glycolic acid polymers), their esters, poly-α-cyanoacrylates, etc. can be used, and preferably lactic acid-glycolic acid copolymers (also referred to as poly (lactide-α-glycolide) or poly (lactic acid-co-glycolic acid), and hereinafter referred to as PLGA). Therefore, in one aspect, the polymer that can be used for the polymer matrix is ​​PLGA. As used herein, 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, such as PLGA 50:50, PLGA 85:15, and PLGA 90:10.

[0461] 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, wherein the polymer material should be degraded into a product that is easily processed by the body through a body process, and should not accumulate in the body. The product of biodegradation should also be biocompatible with the body because the polymer matrix is ​​biocompatible with the body. The particularly useful examples of polymer matrix materials include poly (glycolic acid), poly-D, L-lactic acid, poly-L-lactic acid, the aforementioned copolymers, poly (aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone (polydioxanone), poly (orthocarbonate), poly (acetal), poly (lactic acid-caprolactone), polyorthoesters, poly (glycolic acid-caprolactone), polyanhydrides and natural polymers, including albumin, casein and wax, such as glyceryl monostearate and glyceryl distearate, etc. Preferred polymers for practicing this aspect of the disclosure are polylactide, polyglycolide and poly(d,l-lactide-co-glycolide). Preferably the molar ratio of lactide to glycolide in such copolymers is in the range of about 75:25-50:50.

[0462] In the case of polyester polymers, including polylactide, polyglycolide and poly(d,l-lactide-co-glycolide), it is understood that the polymer can have carboxylic acid end groups or carboxylate end groups. Particularly useful are poly(d,l-lactide-co-glycolide) copolymers (PLGA copolymers) having a lactide-glycolide molar ratio of about 50:50-90:10 or 50:50-85:15 or 50:50-75:25, and / or a molecular weight of 5,000-500,000 Daltons or 5,000-150,000 Daltons or 20,000-200,000 Daltons or 24,000-38,000 Daltons.

[0463] Useful PLGA polymers can have a weight average molecular weight of about 5,000-500,000 daltons, preferably about 150,000 daltons. Depending on the degradation rate to be achieved, polymers of different molecular weights can be used. Due to the diffusion mechanism of drug release, the polymer should remain intact until all the drug is released from the polymer matrix and then degraded. When the polymer excipient bioerodes, the drug can also be released from the polymer matrix.

[0464] PLGA can be prepared by any conventional method or can be commercially available. For example, PLGA can be prepared by ring-opening polymerization of cyclic lactide, glycolide, etc. using a suitable catalyst (see EP-0058481B2; Effects of polymerization variables on PLGA properties: molecular weight, composition and chain structure).

[0465] It is believed that PLGA can be biodegraded by degradation of the entire solid polymer composition, which is attributed to the decomposition of hydrolyzable and enzymatically cleavable ester bonds to form lactic acid and glycolic acid under biological conditions (e.g., in the presence of biological enzymes found in water and warm-blooded animals such as human tissues). Lactic acid and glycolic acid are both water-soluble, non-toxic normal metabolites that can be further biodegraded to form carbon dioxide and water. In other words, it is believed that PLGA is degraded by hydrolysis of its ester groups in the presence of water, such as in warm-blooded animals such as humans, producing lactic acid and glycolic acid and generating an acidic microenvironment. Lactic acid and glycolic acid are byproducts of various metabolic pathways in warm-blooded animals (e.g., humans) under normal physiological conditions, and therefore have good tolerance and produce minimal systemic toxicity.

[0466] For long-acting injectable compositions, 5-HT 2A 5-HT 2AThe 5-HT receptor ligand may be dissolved, dispersed or suspended in a polymer matrix and / or further mixed with a pharmaceutically acceptable diluent or carrier. Such a carrier may be aqueous, such as water suitable for injection (e.g., an aqueous buffer), or non-aqueous, such as an organic solvent, or a mixture of water and an organic solvent (e.g., an organic solvent miscible with water). In some embodiments, the 5-HT receptor ligand may be dissolved, dispersed or suspended in a polymer matrix and / or further mixed with a pharmaceutically acceptable diluent or carrier. Such a carrier may be aqueous, such as water suitable for injection (e.g., an aqueous buffer), or non-aqueous, such as an organic solvent, or a mixture of water and an organic solvent (e.g., an organic solvent miscible with water). 2A 5-HT 2A / D2 receptor ligands are encapsulated in microspheres or microparticles suspended or dispersed in a pharmaceutically acceptable diluent or carrier, as described in US9,708,322 and US9,956,227, the contents of each of which are incorporated herein by reference in their entirety. Further information on the preparation of microparticles can be found in US2008 / 0069885, the contents of which are incorporated herein by reference in their entirety. Example

[0467] Drugs and Experimental Design: Lumiperone, also known as ITI-007 or IC200056 tosylate, is a compound of formula I, wherein X is N(CH3) and Y is C=O:

[0468]

[0469] It exists in the form of its tosylate salt. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar depression in adults. Lumiperone provides selective and simultaneous modulation of serotonin, dopamine, and glutamate neurotransmission and is of particular interest in psychiatric disorders.

[0470] Unless otherwise noted, all other reagents were obtained at the highest purity available from Sigma-Aldrich (St. Louis, MO). For most experiments, mice or rats at least 8 weeks old were given an intraperitoneal (IP) injection of lumepirone (0.3, 1, 3, or 8 mg / kg) or its vehicle (v / v: 5% DMSO, 5% Tween 20, 15% polyethylene glycol [PEG] 400, and 75% pure HPLC water). Some rodents were co-treated by subcutaneous (SC) injection of lipopolysaccharide (LPS, 500 μg / kg; Sigma-Aldrich, ref#0127:B8) diluted in 0.9% injectable saline, while control animals received injections of all vehicles matching experimental conditions. In experiments investigating delayed administration of lumepirone, mice (n=4-9 / group) first received a subcutaneous injection of LPS or saline, followed by an IP injection of lumepirone (3 mg / kg) or its vehicle 30 minutes later. In experiments using restraint stress, mice assigned to the restraint stress group received a single injection of lumepirone (3 mg / kg) or its vehicle and were immediately placed in rodent restraint bags. In behavioral experiments, rats received pretreatment with lumepirone (1 mg / kg) or its vehicle on day 1. On day 2, naive rats were given no injection, or injected with saline or LPS (1 mg / kg, SC). On day 3, rats received another injection of lumepirone or saline and were tested the following day (day 4).

[0471] Animals: Adult male C57BL / 6 mice weighing 28-30 g at the time of the experiment were housed in small cages in groups of 4 or 5. Adult male Sprague-Dawley rats weighing 175-200 g upon arrival after transportation were housed in pairs. All animals were housed under standard laboratory housing conditions with a 12-h light / dark cycle and ad libitum access to food and water.

[0472] Tissue collection: Mice were euthanized 2 hours after injection of lumepirone (for co-treatment studies with LPS) or application of restraint stress for sample collection. Rats were euthanized 18 hours after LPS injection for sample collection. Hippocampi from mice and rats were rapidly dissected under RNase-free conditions and placed in 1.5 ml Eppendorf tubes. When appropriate, samples were snap-frozen in liquid nitrogen and then stored at -80°C until further analysis. Trunk blood from mice was collected 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.

[0473] Multiplex analysis: In mouse serum, protein levels of IL-1b, IL-6, IL-10, and TNF-α were measured using the V-Plex Meso Scale Discovery (MSD) Multiplex Spot Assay Mouse Neuroinflammation 1 Panel (Meso Scale Diagnostics, Rockville, MD). All samples were run in duplicate or triplicate according to the manufacturer's instructions and analyzed using MSD Discovery Workbench software (Meso Scale Diagnostics).

[0474] Quantitative real-time PCR: Mouse hippocampal tissue was homogenized with glass beads in 1 mL Trizol reagent using BeadBeater (Biospec Products, Bartlesville, OK). Heavy phase-locked gel tubes were able to perform phase separation after adding 400 μL of chloroform to the sample and centrifuging at 12,000 rpm for 10 minutes at room temperature. RNA was extracted using the Qiagen RNeasy kit (Qiagen, Hilden, Germany). For cDNA synthesis, 2 μg of total RNA was used (SuperScript IV reverse transcriptase; ThermoFisher Scientific, Waltham, MA). The purity and concentration of RNA were measured using a Nanodrop spectrophotometer; the optical density (OD) 260 / 280 and OD 260 / 230 were within 1.8-2.3. In the hippocampus, four key markers of pro-inflammatory and anti-inflammatory cytokines and chemokines (Il1b: ID Mm00434228_m1, Tnfa: ID Mm00443258_m1, Il6: IDMm00446190_m1, and Il10: ID Mm01288386_m1; ThermoFisher Scientific) were initially selected for analysis (n=5-12 / group). In subsequent experiments, transcripts of other inflammatory markers were selected for analysis, including Icam1 (IDMm00516023_m1; cell adhesion molecule involved in immune cell migration), Cldn5 (ID Mm00727012_s1; tight junction protein), colony stimulating factor 1 (Csf1: ID Mm00432686_m1; factor regulating microglial function) and its receptor Csf1r (ID Mm01266652_m1); and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome complex (Nlrp3: Mm00840904_m1). Gapdh (ID Mm99999915_g1) was selected as a housekeeping gene. Each plate (MicroAmp Optical 384-well plate; Applied Biosystems, Waltham, MA and ThermoFisher Scientific) was analyzed using QuantStudio 7 (ThermoFisher Scientific) and loaded with TaqMan Universal Master Mix II without uracil-DNA glycosylation using 100 ng cDNA / well in a 20 μl reaction volume. Total mRNA was measured by qRT-PCR on an ABI Prism 7900HT system using TaqMan Gene Expression Assays.The Ct values ​​of the gene of interest were calibrated to the Ct value of a reference gene (Gapdh).

[0475] NanoString: Mouse neuropathology panel includes 770 genes related to neurotransmission, neuron-glia interaction, neuroplasticity, cell structure integrity, neuroinflammation and metabolism. A total of 13 housekeeping genes were used for expression normalization (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_0 10368.1, Lars: NM_134137.2, Mto1: NM_026658.2, Supt71: 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 a Qiagen micro kit (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 / group, n=5-6 / group) were performed according to the NanoString manufacturer's instructions (NanoString Technologies, Seattle, WA). The calibrated data were converted to log2 scores to represent fold changes. NanoString results (raw and calibrated counts) were exported from RCC files using nSolver software (version 2.6; NanoString Technologies). Complementary Gene Software Analysis Tools Advanced Analysis Software (NanoString Technologies) provides comprehensive free cloud-based data analysis for nCounter data by directly analyzing the raw RCC files generated by NanoString. Advanced analysis software for calibration, calculation of fold changes, P values, identification of enriched pathways and heat maps.

[0476] Microglia enrichment: In male adult rats (8-9 weeks old, n=8-12 / group) pre-treated with LPS and lumiperone or vehicle 1 day before (18 hours), the hippocampus was dissected and placed in 1 mL of medium A solution containing 0.6% glucose and 15mM HEPES. The brain tissue was then processed by a dounce homogenizer and then passed through 16-gauge and 20-gauge needles. 1 mL of medium A was added to wash the cell suspension, which was passed through a 70 mm cell strainer and kept 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. The 75% Percoll cell suspension was then spread below the 25% Percoll solution layer containing phenol red, with a PBS layer above it. The discontinuous Percoll density gradient was layered as follows: 75%, 25%, and 0% isotonic Percoll (PBS) to separate hippocampal microglia. The gradient was then centrifuged at 3,000 rpm for 25 minutes at 4°C in a swinging bucket with minimal acceleration and deceleration and no brakes. After centrifugation, the upper layer containing myelin and debris (interface PBS / 25% Percoll) was removed and the 25% / 75% intercalary cell layer was collected and washed. Pilot experiments compared gene expression in the different fractions and verified the presence of microglia in the intercalary layer. The final pellet was resuspended in 350 μL of buffer RLT from Qiagen microkit (Qiagen) for RNA extraction according to the manufacturer's instructions.

[0477] Restraint Stress Protocol: Acute restraint stress was performed using a special rodent "decapicone" restraint bag (Braintree Scientific, Braintree, MA; ref# MDC-200) in a traditional triangular shape. Mice (n=11-13 / group) were maintained in their restraint bags while placed on a secure surface at room temperature for 2 hours. At the end of the 2-hour stress period, mice were euthanized and whole hippocampal samples were collected. Control, non-stressed mice were left in their home cages in adjacent chambers and euthanized at the same time points as the stressed mice for sample collection.

[0478] BBB permeability assay: Sodium fluorescein (NaFl) permeability assay was performed as previously described (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)) with minor modifications. Mice (n=4-8 / group) were administered lumepirone and given LPS or restraint as described above. Mice received 200 μl 10% NaFl (Catalog No. F6377, MilliporeSigma) IP 45 minutes before tissue collection. Mice were then euthanized by isoflurane overdose and blood was collected by cardiac puncture and allowed to clot while protected from light. Mice were perfused with 15 ml of 1x PBS solution. The brains were then removed and snap frozen, protected from light. Serum was collected from blood samples by centrifugation at 1,500 g for 10 minutes at 4°C. The brain was homogenized in 1×PBS and centrifuged at 10,000 g for 10 minutes at 4°C, and the supernatant was collected for obtaining protein concentration and further analysis by Peirce BCA protein assay. Proteins from serum and tissue homogenates were extracted on ice by trichloroacetic acid precipitation (Catalog No. T6399, MilliporeSigma) and centrifuged at 10,000 g for 10 minutes at 4°C. Samples were run in duplicate on a FITC filter spectrophotometer (EnVision 2105, PerkinElmer, Waltham, MA; Excitation: 485 nm, Emission: 535 nm). The mean fluorescence of sham-operated mice was subtracted from each value before calculation. The tissue homogenate fluorescence readings were first calibrated relative to total protein concentration, and the brain / serum ratio of arbitrary fluorescence units was calculated.

[0479] Behavioral assessments: All behavioral tests were performed in the morning using adult male Sprague-Dawley rats (n=9-11 / group for experiments with LPS and n=13-14 / group for naive rats).

[0480] Novelty Suppressed Feeding Test (NSFT): This test measures the consumption of familiar food in a novel environment and relies on rodents' aversion to eating in a novel environment after a period of food deprivation (Ramaker and Dulawa, "Identifying fast-onset antidepressants using rodent models," Mol. Psychiatry 22:656-665 (2017)). Rats were food deprived overnight and placed in an open field (76.5×76.5×40 cm) with a small number of food pellets (6 pellets in total). 3 ). At the time of testing, rats were exposed to the open field (novelty) for the first time and were allowed to explore under red light for up to 15 minutes. The latency of the animal to approach the food pellet and take its first bite was manually scored. This was followed by a cage feeding test (HCFT) to ensure that the latency measured in the NSFT was not a matter of hunger differences. The cage food intake analysis assessed the amount of food consumed (in grams) within 10 minutes after the end of the entire test period.

[0481] Novelty-induced hypoappetism (NIH): This conflict-based behavioral task assesses the effects of environmental stressors on conditioned approach responses to palatable food rewards (Ramaker and Dulawa, 2017). Rats were habituated to diluted (1:3 milk / water) sweetened condensed milk, which was accessible for 1 hour per day in their home cages for 3 consecutive days. Initially, animals were tested in cages under normal lighting. For testing after drug treatment, drinking latencies were recorded after rats were placed in new clean cages of the same size without bedding and under dim lighting (~50 lux), with white paper under the cage to enhance aversion.

[0482] Open field test (OFT): Rats were placed in an open field box (76.5 × 76.5 × 40 cm) under dim lighting. 3 ) and locomotor activity was measured over a 10-min period using ANY-Maze software (Stoelting Co., Wood Dale, IL).

[0483] Rewarded Sniff Test (also known as Female Urine Sniff Test (FUST)): In this anhedonia-based assay, rats were brought to a well-ventilated testing room under dim lighting. A sterile cotton-tipped applicator was attached to one wall of the home cage for 1 hour to habituate the rats to the new object. For 2 phases of the 5-minute test, the rats were first exposed to a new cotton swab dipped in sterile water as a control, which was removed at the end of 5 minutes; after 45 minutes, another cotton tip pre-dipped in fresh rat urine collected from females of the same strain was attached to the cage wall. Male behavior was video recorded, and the latency to the first sniff of the cotton swab and the total time spent sniffing the cotton swab applicator were determined.

[0484] Statistical analysis: Data are expressed as mean ± SEM. All statistical analyses were performed using GraphPad version 9 or earlier (GraphPad Software, San Diego, CA). The sample size for this experiment was calculated using the expected effect size and variance based on previous data. The Kolmogorov-Smirnov test was used as a normality test. Unpaired t-tests were used bilaterally for comparisons between 2 groups. When normal distribution was not confirmed, the Mann–Whitney U test was used to compare the average rankings of the 2 groups. Multiple group comparisons were performed using one-way ANOVA, followed by Bonferroni post hoc tests or Tukey multiple comparison tests. NanoString nCounter analysis was based on multivariate linear regression with Benjamani-Yekutieli adjustment. Probability values ​​were recorded in each figure, and details about the specific test used were stated in the legend. Outliers were removed using the median absolute deviation (MAD) equation (median plus or minus 2.5 times, MAD method for outlier detection).

[0485] Example 1: Lumiperone normalizes the pro-inflammatory state in a dose-dependent manner

[0486] Specific cytokines in serum or plasma of patients with MDD and other mental disorders are elevated. In this article, the gene and protein expression of a subset of pro-inflammatory cytokines and anti-inflammatory cytokines in response to an inflammatory attack using a single dose of LPS (500 μg / kg) to induce acute brain inflammation in the mouse brain was measured. Samples were collected 2 hours after co-injection of LPS and lumepirone or vehicle. mRNA was isolated and analyzed by qRT-PCR or NanoString Neuropath group. The ability of lumepirone to improve the changes in hippocampal mRNA levels of these cytokines induced by LPS was studied using 3 doses of lumepirone (0.3, 3 and 8 mg / kg, IP). These doses span the effective dose range of lumepirone in rodents to regulate antipsychotic and antidepressant activities (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 relative changes in mRNA levels of each cytokine gene (Il1b, Il6, Tnfa, Il10) calibrated to the control group using the Dct method (n=5-12 / group):

[0487]

[0488] As expected, LPS treatment significantly increased the gene expression of pro-inflammatory cytokines in the hippocampus relative to control mice, but did not significantly alter the gene expression of the anti-inflammatory cytokine Il10, as determined by one-way ANOVA analysis (Effect of LPS treatment on Il1b levels: 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).

[0489] Results showed that when administered concurrently with LPS, lumepirone reduced the LPS-induced increase in hippocampal mRNA levels of the pro-inflammatory genes Il1b, Tnfa, and Il6 in a dose-dependent manner (Il1b: 3 and 8 mg / kg doses, P < .001; Il6: 3 mg / kg doses, P < .001, 8 mg / kg, P < .01; Tnfa: all doses, P < .001). In addition, lumepirone significantly increased hippocampal mRNA levels of the anti-inflammatory cytokine Il10 at doses of 3 and 8 mg / kg when compared to levels observed in animals receiving LPS alone (post hoc comparison of means: P = .004 and P < .001 at 3 and 8 mg / kg lumepirone doses compared to LPS).

[0490] To determine whether lumepirone also reduces the increase in proinflammatory cytokine protein levels in LPS-induced peripheral blood, a dose of 3 mg / kg lumepirone was selected for further analysis based on the data from the above dose-response study in hippocampal tissue. Additional experimental groups receiving separate lumepirone injections were included as additional control groups. Protein concentrations were measured using Multiplex MSD assay V-Plex technology. Results were expressed in pg / mL, except for IL-6, which was measured in ng / mL.

[0491]

[0492]

[0493] When protein levels of inflammatory biomarkers in serum were examined, a similar pattern of results was obtained as observed for gene expression changes in hippocampal tissue. Two-way ANOVA revealed a significant effect of LPS, which increased protein levels of all biomarkers studied (Tukey multiple comparisons to 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).

[0494] It was found that lumaperone treatment reduced serum circulating protein levels of the proinflammatory cytokines IL-1b, TNF-a, and IL-6 compared with mice treated with LPS alone (IL-1b: LPS vs. LPS+Luma, P = .0081; IL-6: LPS vs. LPS+Luma, P < .0001; TNF-a: LPS vs. LPS+Luma, P < .0001). Prior work has shown that LPS, a cell wall component of Gram-negative bacteria, binds to Toll-like receptor 4 (TLR4) and activates nuclear factor kappa B (NFkB) 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)) as well as a mixed gene profile that is not strictly proinflammatory, as it is known to also upregulate IL-10 signaling molecules in primary rodent microglia.

[0495] In contrast to brain tissue, LPS challenge was found to increase IL-10 protein levels in serum. Two-way ANOVA did not reveal any drug effect on IL-10 protein levels in serum (F (1,16) =0.03489, P = .8542), however, if compared only to the control group, lumepirone treatment alone in the absence of LPS induced a significant increase in IL-10. These data suggest that lumepirone increased protein levels of the anti-inflammatory cytokine IL-10 compared to vehicle, while normalizing certain pro-inflammatory cytokines elevated by LPS in serum and brain.

[0496] To gain a deeper understanding of the transcriptional pathways and regulatory mechanisms altered by lumepirone in the setting of elevated inflammation, NanoString nCounter-based analysis was performed after co-injection of LPS (500 μg / kg) and lumepirone (3 mg / kg), with samples 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. When co-injected with LPS, NanoString software analysis confirmed that lumepirone significantly reduced the expression of genes implicated in the inflammatory process, as shown in the following table:

[0497]

[0498]

[0499] Typically, directed global significance scores measure the extent to which a given gene is upregulated or downregulated relative to a given covariate. It is calculated in a manner similar to the unidirected global significance score, but takes into account the sign of the t-statistic. The scores are calculated by nSolver software using the control group as a reference.

[0500] Therefore, in this paper, the directional global significance score measures the extent to which a given gene set is upregulated or downregulated relative to the control group. The results showed that LPS + lumepirone treatment downregulated the expression of gene sets involved in cytokine signaling, inflammatory signaling, innate immune response, and NF-kB pathways. Pathway analysis also recorded an increase in genes related to angiogenesis, epigenetic regulation, and Notch and Wnt pathways in the group injected with lumepirone.

[0501] It was surprisingly found that lumepirone alone altered gene expression in some of these pathways to an extent comparable to treatment with the combination of LPS + lumepirone (ie, similar scores).

[0502] The table below shows the head genes involved in microglial function, neuroprotection, and inflammation found to be altered in the LPS+lumepirone group compared to the LPS group.

[0503]

[0504] As shown in the table above, NanoString software analysis also showed that compared with LPS alone, the LPS+lumepirone combination increased the expression of neuroprotective markers, such as Fos, Egr1, Cldn5, Vegfa and Ngf, while significantly reducing the expression of genes involved in inflammation, such as Casp4, Ccr2, Socs3, Lrg1, Il1b, Osmr, Ly6a, Myd88, Il1r1, Nfkb2, Tnfrsf1 and Ikbkb.

[0505] Lumaperone was found to upregulate homeostatic microglial markers, including Maff, Cx3cr1, Cd36, Trem100, Trem144, and P2ry12, further supporting the potential protective properties of lumaperone in acute inflammatory conditions.

[0506] Next, use Heat maps comparing cytokine-specific gene expression in LPS+Luma versus LPS alone were obtained using Advanced Analysis Software and filters set to P < .04999. Data analysis performed confirmed that lumepirone significantly downregulated genes that promote inflammation (e.g., Osmr, Tnfrsf1a, Tnfrsf11b, Prl, and Il1r1). A Venn diagram based on this analysis revealed some overlap in significantly altered gene expression changes when group comparisons were made (P≤.04999). The results showed that the advanced glycation end products (RAGE) pathway was significantly altered when comparing LPS to the control group; the brain-derived neurotrophic factor (BDNF) signaling pathway was one of the most significantly altered pathways in the LPS+lumepirone versus LPS group; and IL-6 regulation was also one of the head pathways that was altered when comparing lumepirone to LPS. In summary, lumepirone was found to reverse acute inflammatory conditions by normalizing key pathways involved in inflammation while enhancing gene signatures indicative of tissue protection and repair.

[0507] Example 2: Lumiperone reduces LPS-induced pro-inflammatory cytokine mRNA levels in pre-established hippocampus

[0508] Based on these findings, it is desirable to investigate whether delayed administration of lumepirone can alter the established state of elevated inflammation, thereby reestablishing immune system homeostasis. Adult mice first received a subcutaneous injection of LPS injection (500 μg / kg) or vehicle (0.9% saline), and 30 minutes later, mice were IP injected with lumepirone (3 mg / kg) or vehicle (5% DMSO, 5% Tween-20, 15% PEG-400, 75% water). Samples were collected 1.5 hours later (i.e., 2 hours after LPS injection). The results are shown in Table 2A as the relative changes in hippocampal mRNA levels of each cytokine gene (Il1b, Il6, TNFα, Il10) calibrated relative to the control group using the Dct method as in Example 1 (n=4-9 / group):

[0509]

[0510] It was found that LPS significantly increased the hippocampal mRNA levels of Il1b, Il6 and Tnfa (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 delayed injection of lumepirone was found to reduce mRNA levels (Il1b: LPS vs. LPS+Luma, P = .0433; Il6: LPS vs. LPS+Luma, P = .0078; Tnfa: LPS vs. LPS+Luma, P < .0001). These results suggest that lumepirone exhibits similar effects when co-injected with LPS or given 30 minutes after LPS injection. It also showed that lumepirone increased the mRNA level of Il10 in the presence or absence of LPS. Two-way ANOVA analysis of Il10 showed that LPS (F (1,20) =21.31, P = .0002) and lumepirone (F (1,20) =69.02, P < .0001), which confirmed that lumepirone modulated the hippocampal mRNA levels of this anti-inflammatory cytokine.

[0511] Complementary key markers revealed by NanoString analysis were also examined using the same methods as described above.

[0512]

[0513] Significant interactions were found for Cldn5 and Icam1, namely, treatment (LPS) by drug effect (lumepirone). Lumeperone reduced the levels of Icam1 (LPS vs. LPS+Luma, P<.0001)), and co-administration of LPS with lumepirone increased Cldn5 (LPS vs. LPS+Luma, P<.0001). Analysis of Csf1 mRNA levels showed drug-treatment interactions as well as drug effects, with lumepirone reducing Csf1 relative to the LPS group (LPS vs. LPS+Luma, P=.0009). In summary, these results suggest that transcriptional regulation of genes associated with inflammation and tissue repair is initiated when lumepirone is administered with a delay following LPS-induced inflammation.

[0514] Example 3: Lumiperone enhances BBB integrity in the hippocampus

[0515] Systemic inflammation is associated with increased permeability of the BBB, and this has been discussed as a potential factor in the pathophysiology of depression. In this experiment, mice received a single injection of lumepirone (3 mg / kg, IP) at the same time (co-injection) or 30 minutes after (delay) LPS injection. 45 minutes before sample collection, mice received NaFl injection (200 μL 10% solution, IP) (Table 3).

[0516]

[0517] Mice treated with LPS exhibited significantly increased NaFl brain penetration, and this was significantly inhibited in both the lumaperone co-injection group and the lumaperone delayed injection group (Control = normalized to 1, LPS = 1.406, Control vs. LPS: Tukey's multiple comparison test P < .05; LPS + Luma = 0.863, LPS vs. LPS + Luma: P < .01; LPS + Luma (delayed) = 0.652, LPS vs. LPS + Luma (delayed): P < .001 - all units are expressed in arbitrary units normalized to the control group). F (3,21) =11.49, P = .0001. Table 1). These data indicate that lumepirone administered in combination with LPS rescues the integrity of the BBB.

[0518] Example 4: Lumiperone reduces stress-induced inflammation and blood-brain barrier permeability

[0519] To determine whether lumepirone can normalize pathological inflammation in the brain induced by acute stressors, restraint stress, a stressor known to cause increased inflammation, was used. Mice received a single injection of lumepirone (3 mg / kg, IP) or vehicle (5% DMSO, 5% Tween-20, 15% PEG-400, 75% water) and were immediately placed in a rodent restraint bag for 2 hours. Control mice received vehicle treatment and were returned to their cages before sample collection. Protein concentrations were measured using Multiplex MSD assay V-Plex technology, calibrated relative to the control group. Results are expressed in pg / mL.

[0520]

[0521] It was found that acute restraint stress resulted in a significant increase in serum IL-1b, IL-6, and TNF-α levels, while in mice receiving Lumaperone, each of these proteins was significantly reduced to control levels (compared to control, IL-1b: stress versus stress + Luma, Bonferroni multiple comparison test P < .001; IL-6: stress versus stress + Luma, P < .001; TNF-a: stress versus stress + Luma, P = .007). The corresponding data of hippocampal mRNA expression were collected according to the method of Example 1. The results are shown in Table 4B as the relative changes in the mRNA levels of each cytokine gene (Il1b, Il6, Tnfa, Il10) calibrated with the control group using the Dct method:

[0522]

[0523] In the hippocampus of the same mice, acute restraint stress resulted in an increase in Il1b mRNA levels (control = calibrated to zero, P = .007), which was not significantly reduced after lumepirone treatment. At this time, Tnfa and Il6 mRNA levels were not altered by acute restraint stress. Interestingly, both IL-10 serum protein and hippocampal mRNA levels were increased by lumepirone compared with controls (IL-10 protein levels: control vs. stress+Luma, Bonferroni multiple comparison test P = .001; Il10 mRNA levels: control calibrated to zero, stress+Luma, P < .001).

[0524] Serum corticosterone levels and hippocampal Cldn5 mRNA expression (corticosterone was measured using a commercial ELISA kit) were also measured using similar methods as described above.

[0525]

[0526] The data showed that the serum corticosterone level in stressed mice was elevated, and the elevated level was significantly suppressed by Lumaperone (stress vs. stress+Luma: P < .001; F (2,27) =124.2, P < .001). Lumaperone also demonstrated significant elevation of Cldn5 transcripts in stressed animals (Stressed vs. Stress+Luma: P < .001; F (2,36) =11.44,P<.001).

[0527] In the separate groups, acute restraint stress was found not to significantly increase NaFl brain infiltration (Control = normalized to 1, Stress = 1.132). However, Lumaperone alone did significantly reduce NaFl brain infiltration in the Stress + Luma group compared to the Stress group (Stress + Luma = 0.7278; Stress vs. Stress + Luma: unpaired t-test P < .05; t (7) =2.373; see Table 3 above).

[0528] Example 5: Lumaperone reduces anxiety and normalizes LPS-induced anhedonia

[0529] LPS was administered to induce a transient anhedonic state in rats, and reward system-dependent behaviors were measured by using female urine as a rewarding stimulus to investigate whether lumepirone could rescue transient LPS-induced deficits.

[0530] In the pilot study, a dose-response curve was completed with different doses of LPS to select the optimal dose for inducing anhedonic responses in rats. Based on these studies, a SC dose of 1 mg / kg LPS was selected. Rats were first injected with lumepirone (1 mg / kg; IP) or vehicle before treatment. LPS (1 mg / kg; SC) was injected 24 hours later. Then, 24 hours later, rats were injected with lumepirone (1 mg / kg; IP) or vehicle after treatment. Control rats were administered saline instead of LPS, and vehicle was administered instead of lumepirone. FUST (female urine sniff test) was used and the delay of sniffing reward was measured in combination with the time spent sniffing reward to assess anhedonia. The delay in sniffing water was used as a control. The results are shown in the table below (time in seconds), where the MAD method is used to remove outliers:

[0531]

[0532] The results showed that male rats treated with LPS that had been administered with lumepirone showed a reduced delay in sniffing urine-soaked cotton tips when exposed to reward cues (female urine) compared to the LPS group. In summary, it was found that during the 5-minute test, rats treated with lumepirone spent as much time sniffing reward cues as rats in the control group. Importantly, there was no significant difference in the time spent by rats exploring the water-soaked cotton tips used as a control test. Movement in an open field (track length in meters) was also measured as a control. As shown in the following table, regardless of the group, motor activity was also affected:

[0533]

[0534] In the absence of LPS, 2 commonly used tests, the NSFT and the novel environment-induced hypoappetite test (NIH), were also used to test basal levels of anxiety. It is well documented that rodents experience increased stress levels when placed in a new environment (Ramaker and Dulawa, 2017). These two tests take advantage of this feature, measuring the delay of eating in food-deprived rats (NSFT), or the delay of receiving the rewards they are accustomed to before the test (NIH).

[0535] Similar to previous studies, rats were injected with lumepirone (1 mg / kg; IP) on days 1 and 3. Lumaperone was found to reduce the latency to eat in NSFT (Control: 657.8 s, Luma: 507.9 s, Mann–Whitney U test P = .0009, Table 6).

[0536]

[0537] On the contrary, it was found that there was no effect on feeding itself, as shown in the HCFT (which is a control for the NSFT). Similarly, in the NIH test, which measures anxiety in a slightly different environment and does not require food deprivation, it was found that when rats were placed in a new, empty and bright cage that induced stress, lumaperone reduced the delay of drinking reward (i.e. diluted condensed milk, control group: 65.4s, Luma: 30.5s, Mann–Whitney U test P=.0257, Table 2). Similarly, the movement assessed in the open field did not reveal a significant effect of lumaperone between the treatment groups (Table 6).

[0538] In conclusion, these results demonstrate that lumepirone has the potential to reduce anhedonia and lower basal anxiety levels in stressful situations.

[0539] Example 6: Lumiperone acts on rat microglia isolated from the hippocampus after LPS-induced inflammation

[0540] Based on the associations revealed by the above gene ontology analysis, it was desirable to investigate the potential involvement of microglia in the reduction of LPS-induced inflammation mediated by lumepirone administration. Microglia, the resident immune cells of the brain, have emerged as possible effectors of initiating and resolving neuroinflammation in a wide range of conditions and disorders. Therefore, the effects of lumepirone on in vivo inflammatory activity in hippocampal microglia were specifically monitored, thereby examining the time window in which inflammation was detected in enriched preparations of rat brain microglia.

[0541] Exploratory experiments revealed that in the microglial-rich fraction from rat hippocampus, inflammation returned to closer to background levels at +26 hours after LPS dose. Therefore, an earlier time point of +18h after LPS injection was selected to evaluate potential changes indicative of inflammation. Rats were pretreated with the same dose of LPS used for biochemical and RNA-based experiments (500 μg / kg, diluted in 0.9% saline) and received lumepirone (3 mg / kg in vehicle) or vehicle (5% DMSO, 5% Tween-20, 15% PEG-400, 75% water) injection 16 hours later.

[0542] After 2 hours (+18 hours after LPS injection), the hippocampus of both sides of the brain was collected, and the microglia in the enriched fraction were quickly separated by Percoll gradient. RNA was extracted from the obtained reconstructed cell pellet and RT-qPCR was 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) calibrated with the control group using the Dct method (n = 8-12 per group):

[0543]

[0544] The results showed that LPS treatment led to a significant increase in Il1b and Il6 gene expression in isolated hippocampal microglia; these increases were significantly inhibited by lumepirone 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, lumepirone significantly reduced gene expression levels compared with LPS alone (one-way ANOVA, F (2,26) =4.302, P = .02). However, at this time point, Tnfa gene expression was not different from controls, most likely reflecting a different time course of response in isolated microglia compared with that observed in intact tissue.

[0545] Nevertheless, lumepirone administration was found to result in a decrease in Tnfa mRNA levels when compared to microglia isolated from control rats or LPS-treated microglia (Tnfa: one-way ANOVA F (2,20) =3.868, P = .04). LPS showed a trend to increase Csf1r mRNA levels in microglia, whereas lumepirone tended to reduce this response (one-way ANOVA F (2,29) =0.9725, P=.39). This trend parallels the effect of lumepirone treatment observed in whole tissue. Taken together, this data suggests that lumepirone inhibits LPS-induction of a subset of proinflammatory genes expressed in hippocampal microglia.

[0546] Example 7: Post hoc analysis of a phase 3 clinical trial of lumiperone in patients with schizophrenia

[0547] A randomized, double-blind, placebo-controlled Phase 3 clinical trial was conducted on 450 schizophrenia patients aged 18 to 60 years who were experiencing acute exacerbations of psychosis. Patients were included if they experienced acute exacerbations of psychosis, which were defined as a total score of 15 points or higher based on the 40-point Brief Psychiatric Rating Scale, with scores of 4 points or higher on 2 or more positive symptoms, and an acute attack began within 4 weeks of screening. Patients were required to have a score of 4 or more on the Clinical Global Impression-Illness Severity (CGI-S) at screening and baseline, indicating moderate to severe disease severity. The severity of the disease was confirmed by a total score of 70 or more on the Positive and Negative Syndrome Scale (PANSS) at baseline, indicating moderate to extreme symptoms of schizophrenia. A subgroup of these patients experienced comorbid depressive symptoms at baseline (defined as having a Calgary Schizophrenia Depression Scale (CDSS) score greater than 6 at baseline). Full details of the clinical study are reported in Correll et al., JAMA Psychiatry, 77(4):349–358 (2020).

[0548] Patients were randomized 1:1:1 (150 patients per group) to receive 60 mg lumepirone tosylate (42 mg free base), 40 mg lumepirone tosylate (28 mg free base), or placebo once daily for 28 days.

[0549] The primary efficacy endpoint was the mean change in the total score of the Positive and Negative Syndrome Scale (PANSS) relative to placebo from baseline to Day 28. The key secondary efficacy measure was the Clinical Global Impression-Severity of Disease (CGI-S) score. PANSS subscale scores, social function, safety, and tolerability were also assessed. The primary and key secondary efficacy measures were assessed weekly. Safety was assessed by treatment-emergent adverse reactions (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).

[0550] Results from this trial suggest that lumepirone is effective in improving symptoms of schizophrenia and has a favorable safety profile.

[0551] Using stored blood samples from this study, a post hoc analysis of inflammatory biomarkers in PBMCs from patients with schizophrenia and comorbid depression was performed. For patients treated with 60 mg of lumepirone, samples from day 0 and day 28 were analyzed. Day 0 samples were obtained from 20 patients, while day 28 samples were only available from 18 patients. In the selected patients, the mean baseline CDSS was 10.0, and the mean baseline PANSS total score was 88.7.

[0552] Samples were processed using the Ficoll-Paque method to isolate PBMCs according to standard methods. Statistical analysis was performed using a two-tailed paired t-test. C-reactive protein (CRP), serum amyloid A (SAA), soluble ICAM-1, soluble VCAM-1, IL-1β, TNF-α, IL-6, IL-10, IL-2, IL-8, IL-13, and IFN-γ were tested for samples. ICAM-1 and VCAM-1 are expressed by vascular endothelium, macrophages, and lymphocytes. Upon cytokine stimulation, their concentrations increased significantly. ICAM-1 can be induced by IL-1β and TNF. ICAM and VCAM proteins may also be involved in pathogen transport into the CNS.

[0553] The results are shown in the following table (biomarker levels are expressed in ng / mL; some values ​​of N are less than the total number of patients because the biomarker levels of the samples were below the minimum value for quantification):

[0554]

[0555]

[0556] These data show that patients with schizophrenia and comorbid depression have elevated levels of inflammatory biomarkers in their blood cells (PBMCs) at baseline, and these levels are significantly reduced after 28 days of treatment with lumepirone. These results also demonstrate that schizophrenia patients with comorbid depressive symptoms can be pre-identified by measuring inflammatory biomarkers in the blood.

[0557] Interestingly, unlike the measure of depressive symptoms (CDSS), the placebo group did not show significant changes 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, comprising administering a therapeutically effective amount of 5-HT to a patient in need thereof 2A 5-HT 2A / D2 receptor ligand.

2. The method of claim 1, wherein the ligand is a compound of formula I: in: 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 (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, optionally saturated or unsaturated, and optionally substituted by one or more hydroxyl groups or C 1-22 Alkoxy (e.g., ethoxy) groups are substituted, 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, wherein such compounds hydrolyze to form natural or unnatural, saturated or unsaturated fatty acid residues, for example said compounds hydrolyze to form hydroxy compounds on the one hand and to form octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the other hand, The compound is optionally in deuterated form, In the form of free base, pharmaceutically acceptable salt or prodrug.

3. The method of claim 2, wherein X in the compound of formula I is -N(H)-, -N(CH3)- or -O-.

4. The method of claim 3, wherein X in the compound of formula I is -N(CH3)-.

5. The method of claim 3 or 4, wherein Y in the compound of formula I is -C(=O)-.

6. The method of claim 2, wherein the compound of formula I is lumepirone:

7. A method according to claim 6, wherein the compound of formula I is in the form of a free base or a pharmaceutically acceptable salt, such as a tosylate salt.

8. The method of any one of claims 2 to 7, wherein the method comprises administering once daily a unit dose for oral administration, such as a tablet or capsule, comprising: a compound of formula I in free base or pharmaceutically acceptable salt form, such as tosylate form, in an amount equivalent to 1-100 mg of the free base, such as an amount equivalent to 1-75 mg, or 1-60 mg, or 1-40 mg, or 1-30 mg, or 1-20 mg, or 1-10 mg, or 1-5 mg, or 40-60 mg, or 20-40 mg, or 10-20 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.

9. The method of any one of claims 2 to 7, wherein the method comprises administering once daily a unit dose for oral transmucosal administration, such as a sublingual or buccal orally disintegrating tablet, wafer or film, comprising: a compound of formula I in free base or pharmaceutically acceptable salt form, such as tosylate form, in an amount equivalent to 0.5-30 mg of the free base, such as an amount equivalent to 1-30 mg, or 1-20 mg, or 1-15 mg, or 1-10 mg, or 20-30 mg, or 10-20 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.

10. The method of any one of claims 1 to 7, wherein 5-HT 2A 5-HT 2A The / 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 of any one of claims 1-10, wherein the encephalitis is viral encephalitis.

12. The method of claim 11, wherein the encephalitis is caused or suspected to be caused by a virus such as 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, such as H1N1, H2N2, H3N2, H5N1, H7N7).

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

14. The method of claim 13, wherein the encephalitis is caused or believed to be caused by toxoplasmosis, rickettsia, mycoplasma, borrelia (eg, Lyme disease), or malaria.

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

16. The method of claim 15, wherein the encephalitis is caused or believed to be caused by autoantibodies to NMDA receptors, AMPA receptors, voltage-gated potassium channels (VGKCs), LGL1 protein, GABA receptors, glycine receptors, glutamate receptors, or CASPR2 receptors.

17. The method of any one of claims 1-16, wherein the psychiatric disorder and / or psychiatric symptom is depression (e.g., acute depression, MDD depression, bipolar depression), anxiety (e.g., acute anxiety), psychosis (e.g., schizophrenia), post-traumatic stress disorder, anhedonia, memory loss, impaired executive function, difficulty concentrating, seizures, difficulty sleeping, hallucinations, personality changes, or any combination thereof.

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

19. The method of any one of claims 1-18, wherein the patient has elevated levels of pro-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as TNF-α, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, or elevated levels of C-reactive protein (CRP) of Csf1 and / or decreased levels of anti-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as TNF-β, IFN-α, IL-4, and IL-10.

20. The method of any one of claims 1 to 19, wherein 5-HT 2A 5-HT 2A The / D2 receptor ligand or compound of Formula I is administered intranasally, subcutaneously, intramuscularly, intravenously, orally, sublingually, intraperitoneally or buccally, for example as an orally dissolving tablet, wafer or film which dissolves in the mouth for transmucosal absorption.

21. The method of any one of claims 1-20, wherein the patient is unresponsive or inadequately responsive to treatment with another antidepressant, or experiences adverse side effects from treatment with another antidepressant, such as any one or more of a selective serotonin reuptake inhibitor (SSRI), a serotonin reuptake inhibitor (SRI), a tricyclic antidepressant, a monoamine oxidase inhibitor, a norepinephrine reuptake inhibitor (NRI), a dopamine reuptake inhibitor (DRI), SRI / NRI, SRI / DRI, NRI / DRI, SRI / NRI / DRI (triple reuptake inhibitor), or a serotonin receptor antagonist.

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

23. A method for treating a psychiatric disorder in a patient in need thereof, wherein the patient has elevated levels of pro-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as TNF-α, IFN-γ, IL-1 (IL-1α and / or IL-1β), IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, or elevated levels of Csf1 C-reactive protein (CRP) and / or decreased levels of anti-inflammatory cytokines in the CNS (e.g., in the cerebrospinal fluid), such as TNF-β, IFN-α, IL-4, and IL-10, the method comprising administering to the patient a therapeutically effective amount of 5-HT 2A 5-HT 2A / D2 receptor ligand.

Images