Treatment of schizophrenia disorders using combination therapy

Abstract

The invention relates to the treatment of schizophrenia disorders using combination therapy. The present specification discloses a combination therapy comprising one or more activators of alpha-7 nicotinic acetylcholine receptor activity having 5-HT3 receptor inhibitory activity and one or more activators of 5-HT3 receptor activity for use in the treatment of schizophrenia disorders, and methods of treating schizophrenia disorders by administering a combination therapy comprising one or more activators of alpha-7 nicotinic acetylcholine receptor activity and one or more activators of 5-HT3 receptor activity having 5-HT3 receptor inhibitory activity.

Description

[0001] This application is a divisional application of the application filed on October 21, 2020, with application number 202080089256.8 and invention title "Treatment of Schizophrenic Disorder Using Combination Therapy".

[0002] Schizophrenic disorders are generally considered to be a syndrome involving a breakdown in the relationship between thought, emotion, and behavior, resulting in various impairments in cognition, perception, reality testing, action, feeling, mood, interpersonal relationships, social interaction, and occupational functioning. It can be a group of mental disorders. Schizophrenic disorders are a chronic, severe, and disabling mental disorder affecting 0.5% to 1% of the global population. Both men and women are at equal risk of developing this brain disorder, and it occurs at similar rates across all ethnic groups worldwide. The onset of the illness shows a gender bias, with men typically showing symptoms between their late teens and early twenties, while women typically show symptoms between their mid-twenties and early thirties.

[0003] Schizophrenic disorders affect people differently, and symptoms vary from person to person. Some people may have many symptoms, while others may have only a few. The clinical features of schizophrenic disorders can be clustered into three groups of symptoms: positive symptoms, negative symptoms, and cognitive symptoms. Positive symptoms are categorized as fixed, false emotions or behaviors involving real-life situations, which may be real but are merely manifestations of psychosis, such as delusions, hallucinations, paranoia, thought disorders (disorganized thoughts, speech or behavior, neologism), and motor disorders (clumsiness, incoordination, repetitive movements, dystonia). Negative symptoms are categorized as deficits or reductions in normal mood and behavior, such as affective disorders (unresponsive facial expressions, monotone voice), decreased interest in or lack of pleasure in daily activities (anhedonia, such as depression), lack of motivation (diminished willpower), decreased ability to initiate and maintain planned activities, poverty of speech (alogia), infrequent speech (even when forced to interact), and social withdrawal. Cognitive symptoms are categorized as deficits in mental processes of understanding, judgment, memory, and reasoning, such as problems in selective attention, working memory, executive function, episodic memory, language comprehension, and socio-emotional processing. The disorder is also associated with some quantitative abnormalities in brain structure (e.g., enlarged ventricles and reduced temporal lobe volume), but these abnormalities are not specific to schizophrenic disorders. While positive symptoms in early adulthood are the most prominent clinical feature, cognitive deficits are the core characteristic of the disorder, predating psychotic onset and being the sole best predictor of long-term functional outcomes.

[0004] There is currently no cure for schizophrenic disorder, and individuals diagnosed with this mental illness require long-term treatment. The primary treatment for schizophrenic disorder is antipsychotic medication, usually in combination with psychological and social support. Clinical studies have shown that early treatment with antipsychotic medication can effectively manage psychotic symptoms before serious complications occur and significantly improve the long-term prospects of individuals receiving such treatment. Therefore, antipsychotic medication is considered a key component of the treatment of schizophrenic disorder and is recommended by the National Institute for Health and Care Excellence (NICE), the American Psychiatric Association, and the British Society for Psychopharmacology.

[0005] Currently, all approved antipsychotics work in a relatively similar manner, namely by antagonizing D2 dopamine receptors. Unfortunately, dopaminergic-based antipsychotics are only effective in managing the positive symptoms of schizophrenic sexual disorders. Such drugs have little or no effect on negative or cognitive symptoms, which are the most disabling impairments and have the greatest impact on an individual's quality of life. The ineffectiveness of dopaminergic-based antipsychotics is a driving factor in the adverse social and functional outcomes that impose high personal and social costs on individuals with schizophrenic sexual disorders. Despite considerable recent efforts by the pharmaceutical industry, no novel mechanisms have been approved for addressing the cognitive and negative symptoms associated with schizophrenic sexual disorders, and many have failed late in their development. Therefore, identifying new treatments for schizophrenic sexual disorders is crucial.

[0006] This specification discloses a combination therapy comprising an α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inhibitory activity and a serotonin agonist, for the effective treatment of schizophrenic disorder. The disclosed serotonin agonist may optionally also include α-7 nicotinic acetylcholine receptor agonist activity. Such a combination therapy successfully reduces gastrointestinal side effects to facilitate and enable long-term treatment, which effectively improves the positive, negative, and cognitive symptoms of this mental illness. Overview

[0007] This specification discloses a method for treating schizophrenic disorder by administering a combination therapy comprising one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators.

[0008] This specification discloses a combination therapy for use in the treatment of schizophrenic disorders, the combination therapy comprising one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators.

[0009] This specification discloses the use of combination therapy in the treatment of schizophrenic disorders, the combination therapy comprising one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators.

[0010] This specification discloses the use of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators in the preparation of a medicament for the treatment of schizophrenic disorders.

[0011] This specification discloses a method for treating schizophrenic disorder by administering a combination therapy comprising one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists.

[0012] This specification discloses a combination therapy for use in the treatment of schizophrenic disorders, the combination therapy comprising one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists.

[0013] This specification discloses the use of combination therapy in the treatment of schizophrenic disorders, the combination therapy comprising one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor activators.

[0014] This specification discloses the use of one or more α-7 nicotinic acetylcholine receptor agonists and one or more 5-HT3 receptor activators having 5-HT3 receptor antagonistic activity in the preparation of a medicament for the treatment of schizophrenic disorders.

[0015] This specification discloses a method for treating schizophrenic disorder by administering a combination therapy comprising one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor agonists.

[0016] This specification discloses a combination therapy for use in the treatment of schizophrenic disorders, the combination therapy comprising one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor agonists.

[0017] This specification discloses the use of combination therapy in the treatment of schizophrenic disorders, the combination therapy comprising one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor activators.

[0018] This specification discloses the use of one or more α-7 nicotinic acetylcholine receptor agonists and one or more 5-HT3 receptor activators having 5-HT3 receptor inverse agonist activity in the preparation of a medicament for the treatment of schizophrenic disorders. Detailed description

[0019] Like all its family members, the α-7 nicotinic acetylcholine receptor (α7 nAChR) is considered a cholinergic receptor because it responds to the neurotransmitter acetylcholine. α7 nAChR is a pentapolypeptide composed entirely of α7 subunits [i.e., (α7)5 stoichiometry]. Located in the brain, α7 nAChR is crucial for memory, working memory, learning, and attention.

[0020] α7 nAChR agonists have been developed as potential therapeutic agents for reducing cognitive impairment associated with schizophrenia due to their positive effects on neurocognition. However, to date, all such drug candidates have failed in clinical trials, typically in phase 2 or 3 (e.g., Abbvie, Forum Pharmaceuticals, Roche). While the safety profile of these α7 nAChR agonists is generally favorable, one adverse outcome associated with their use is gastrointestinal (GI) side effects, including reduced intestinal transit and constipation driven by the 5-HT3 receptor antagonistic activity of these α7 nAChR agonists.

[0021] 5-Hydroxytryptamine (5-HT), or serotonin, is a monoamine neurotransmitter that mediates an individual's perception of resources and has various effects on mood, anxiety, sleep, appetite, body temperature, eating behavior, sexual behavior, exercise, and gastrointestinal motility. This neurotransmitter is primarily produced in the enteric nervous system located in the gastrointestinal tract, but it is also found in the central nervous system (CNS), particularly in the raphe nuclei in the brainstem.

[0022] Serotonin's effects are mediated through its serotonin receptor (5-HT receptor). Upon binding to its ligand, the serotonin receptor regulates the release of many neurotransmitters, including glutamate, GABA, dopamine, adrenaline / noradrenaline, and acetylcholine, as well as the release of many hormones, including oxytocin, prolactin, angiotensin, cortisol, adrenocorticotropic hormone (ACTH), and substance P. Serotonin receptors mediate both excitatory and inhibitory neurotransmission, influencing a wide range of biological and neural processes, such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Serotonin receptors are classified into seven families and are found in both the central and peripheral nervous systems.

[0023] Except for the serotonin type 3 (5-HT3) receptor, all other 5-HT receptors are G protein-coupled receptors that activate the intracellular second messenger cascade.

[0024] 5-HT3 receptors belong to the group containing acetylcholine and gamma-aminobutyric acid (GABA). A 5-HT3 receptors belong to the Cys ring superfamily of ligand-gated ion channels (LGICs) that are ligands of glycine receptors, and are therefore structurally and functionally distinct from all other 5-HT receptors. These ion channels are cation-selective and mediate rapid neuronal depolarization and excitation primarily by inward currents of sodium and / or potassium ions. 5-HT3 receptors are found in many regions of the CNS, including the entorhinal cortex, the CA1 region of the hippocampus, the amygdala, the substantia nigra, and the brainstem, as well as in the peripheral nervous system, and mediate a variety of physiological functions. At the cellular level, postsynaptic 5-HT3 receptors have been shown to mediate rapid excitatory synaptic transmission in neocortical interneurons, the amygdala, the hippocampus, and the visual cortex. 5-HT3 receptors are also present in presynaptic nerve endings. 5-HT3 receptors also play an important role in the enteric nervous system.

[0025] Like other ligand-gated ion channels, the functional 5-HT3 receptor forms a pentamer of five pseudo-symmetrically arranged subunits surrounding a central ion conduction pore. Currently, all five 5-HT3 receptor subunits are known (5-HT... 3A To 5-HT 3E The functional channels can consist of five identical 5-HT channels. 3A Subunit composition (homopeptid) or 5-HT3A And four other 5-HT 3B 5-HT 3C 5-HT 3D or 5-HT 3E One of the subunits is a mixture (heteropenic). Each subunit contains an extracellular N-terminal domain with an orthogonal ligand binding site; a transmembrane domain consisting of four interconnected α-helices (M1-M4), in which the extracellular M2-M3 loops participate in gating mechanisms; a large cytoplasmic domain between M3 and M4 involved in receptor transport and regulation; and a short extracellular C-terminus. Although the extracellular domain is the site of action for both agonists and competitive antagonists, the transmembrane domain contains a central ion pore, a receptor gate, and a principle of selective filtering that allows ions to cross the cell membrane.

[0026] In addition to its endogenous ligand serotonin, downstream activities mediated by the 5-HT3 receptor can be modulated by exogenous compounds such as, for example, 5-HT3 receptor agonists, 5-HT3 receptor antagonists, or 5-HT3 receptor inverse agonists. 5-HT3 receptor agonists and inverse agonists have not shown any clinical significance and are mainly used as preclinical agents. On the other hand, 5-HT3 receptor antagonists are effective antiemetics for preventing postoperative or chemotherapy-induced nausea and vomiting, and some are used to treat diarrhea-predominant irritable bowel syndrome. The antiemetic effect appears to be a result of both central and peripheral inhibition of serotonin activity, along with reduced vagal nerve activity and disruption of pathways in the chemoreceptor trigger zone and the nucleus tractus solitarius in the brainstem.

[0027] This specification partially discloses methods for treating schizophrenic disorders. In one embodiment, the method of treating schizophrenic disorders disclosed herein comprises, substantially comprises, or comprises administering a combination therapy, which comprises, substantially comprises, or comprises administering one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators. In one embodiment, the method of treating schizophrenic disorders disclosed herein comprises, substantially comprises, or comprises administering a combination therapy, which comprises, substantially comprises, or comprises administering one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists. In one embodiment, the method of treating schizophrenic disorders disclosed herein comprises, substantially comprises, or comprises administering a combination therapy, which comprises, substantially comprises, or comprises administering one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonistic activity and one or more 5-HT3 receptor agonists. In a preferred embodiment, the method of treating schizophrenic disorders disclosed herein comprises, substantially comprises, or comprises a combination therapy consisting of, substantially comprises, tropisetron and varenicline. In the disclosed embodiments described above, the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity, the 5-HT3 receptor activator, the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity, the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonistic activity, the 5-HT3 receptor agonist, varenicline, and / or tropisetron is a therapeutically effective amount.

[0028] This specification partially discloses combination therapies for use in the treatment of schizophrenic disorders. In one embodiment, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators, for use in the treatment of schizophrenic disorders. In one embodiment, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists, for use in the treatment of schizophrenic disorders. In one embodiment, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonistic activity and one or more 5-HT3 receptor agonists, for use in the treatment of schizophrenic disorders. In a preferred embodiment, the combination therapy comprises, substantially consists of, or consists of tropisetron and varenicline, for use in the treatment of schizophrenia. In the disclosed embodiments described above, the amounts of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity, the 5-HT3 receptor activator, the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity, the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonistic activity, the 5-HT3 receptor agonist, varenicline, and / or tropisetron are therapeutically effective amounts.

[0029] This specification partially discloses combination therapies. A combination therapy includes the use or administration of a first composition and a second composition alone, or the use or administration of a single composition, wherein the first composition comprises, is substantially composed of, or is composed of one or more 5-HT3 receptor activators, the second composition comprises, is substantially composed of, or is composed of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity, and the single composition comprises, is substantially composed of, or is composed of one or more 5-HT3 receptor activators and one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity. In one aspect of this embodiment, the combination therapy includes the use or administration of a first composition and a second composition alone, or the use or administration of a single composition, wherein the first composition comprises, is substantially composed of, or is composed of one or more 5-HT3 receptor agonists, the second composition comprises, is substantially composed of, or is composed of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity, and the single composition comprises, is substantially composed of, or is composed of one or more 5-HT3 receptor agonists and one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity. In another aspect of this embodiment, the combination therapy includes the use or administration of a first composition and a second composition alone, or the use or administration of a single composition, wherein the first composition comprises, is substantially composed of, or is composed of one or more 5-HT3 receptor agonists, the second composition comprises, is substantially composed of, or is composed of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity, and the single composition comprises, is substantially composed of, or is composed of one or more 5-HT3 receptor agonists and one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity. In a preferred embodiment, the combination therapy includes the use or administration of a first composition and a second composition alone, or the use or administration of a single composition, wherein the first composition comprises, is substantially composed of, or is composed of varenicline, the second composition comprises tropisetron, and the single composition comprises, is substantially composed of, or is composed of varenicline and tropisetron. In the disclosed embodiments above, the amounts of the 5-HT3 receptor activity inhibitor, the 5-HT3 receptor activity activator, the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity, the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonistic activity, the 5-HT3 receptor agonist, varenicline, and / or tropisetron are therapeutically effective amounts. In all the disclosed embodiments above, the first composition and the second composition may be used or administered sequentially or simultaneously in any order.

[0030] In one embodiment, the combination therapy disclosed herein may include a single 5-HT3 receptor activator and a single α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity, more than one 5-HT3 receptor activator and a single α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity, a single 5-HT3 receptor activator and more than one α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity, or more than one 5-HT3 receptor activator and more than one α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity. In one aspect of this embodiment, the combination therapy may include 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 5-HT3 receptor activators and a single α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity. In other aspects of this embodiment, the combination therapy may include a single 5-HT3 receptor activator and 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor inhibitory activity. In other aspects of this implementation scheme, the combination therapy may include 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 5-HT3 receptor activators and 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor inhibitory activity.

[0031] In one embodiment, the combination therapy disclosed herein may include a single 5-HT3 receptor agonist and a single α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity, more than one 5-HT3 receptor agonist and a single α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity, a single 5-HT3 receptor agonist and more than one α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity, or more than one 5-HT3 receptor agonist and more than one α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity. In aspects of this embodiment, the combination therapy may include 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 5-HT3 receptor agonists and a single α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity. In other aspects of this embodiment, the combination therapy may include a single 5-HT3 receptor agonist and 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 α-7 nicotinic acetylcholine receptor agonists with 5-HT3 receptor antagonistic activity. In still other aspects of this embodiment, the combination therapy may include 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 5-HT3 receptor agonists and 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 α-7 nicotinic acetylcholine receptor agonists with 5-HT3 receptor antagonistic activity.

[0032] In one embodiment, the combination therapy disclosed herein may include a single 5-HT3 receptor agonist and a single α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity, more than one 5-HT3 receptor agonist and a single α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity, a single 5-HT3 receptor agonist and more than one α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity, or more than one 5-HT3 receptor agonist and more than one α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity. In aspects of this embodiment, the combination therapy may include 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 5-HT3 receptor agonists and a single α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity. In other aspects of this embodiment, the combination therapy may include a single 5-HT3 receptor agonist and 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 α-7 nicotinic acetylcholine receptor agonists with 5-HT3 receptor inverse agonist activity. In still other aspects of this embodiment, the combination therapy may include 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 5-HT3 receptor agonists and 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5 α-7 nicotinic acetylcholine receptor agonists with 5-HT3 receptor inverse agonist activity.

[0033] This specification partially discloses 5-HT3 receptor activators. A 5-HT3 receptor activator is any molecule that initiates, increases, enhances, or otherwise activates the activity of a 5-HT3 receptor. Non-limiting examples of 5-HT3 receptor activators include 5-HT3 receptor agonists.

[0034] This specification partially discloses activators of α-7 nicotinic acetylcholine receptors with 5-HT3 receptor inhibitory activity. An activator of α-7 nicotinic acetylcholine receptors with 5-HT3 receptor inhibitory activity is any molecule that initiates, increases, enhances, or otherwise activates the activity of an α-7 nicotinic acetylcholine receptor, which also decreases, weakens, blocks, or otherwise inhibits the activity of a 5-HT3 receptor. Non-limiting examples of activators of α-7 nicotinic acetylcholine receptors with 5-HT3 receptor inhibitory activity include α-7 nicotinic acetylcholine receptor agonists with 5-HT3 receptor antagonistic activity and α-7 nicotinic acetylcholine receptor agonists with 5-HT3 receptor inverse agonistic activity.

[0035] This specification partially discloses 5-HT3 receptor agonists. A 5-HT3 receptor agonist is a compound that binds to and activates or elicits a biological response from a 5-HT3 receptor. The 5-HT3 receptor agonists disclosed herein can be full agonists, partial agonists, co-agonists, or superagonists. A full 5-HT3 receptor agonist binds to a 5-HT3 receptor and activates it as an agonist capable of eliciting a maximal response from that receptor. A partial 5-HT3 receptor agonist binds to and activates a given 5-HT3 receptor, but elicits only a partial effect on that receptor, even at maximum receptor occupancy, relative to a full agonist. While partial 5-HT3 receptor agonists are agonists, they can act as competitive antagonists in the presence of a full 5-HT3 receptor agonist because they compete with the full agonist for receptor occupancy, resulting in a net reduction in receptor activation compared to that observed with a full agonist alone. 5-HT3 co-agonists act together with other 5-HT3 receptor co-agonists to produce a desired biological response. The 5-HT3 receptor agonist disclosed in this paper can be a super-agonist of the 5-HT3 receptor, capable of producing a greater biological response to the receptor than serotonin.

[0036] The 5-HT3 receptor agonists disclosed herein can be pan-agonists or selective agonists. Pan-agonists bind to and elicit a biological response from any 5-HT3 receptor, regardless of subunit composition. Selective 5-HT3 receptor agonists selectively bind to specific types of 5-HT3 receptors, eliciting a biological response via these specific receptors. For example, selective 5-HT3 agonists may bind only to 5-HT3 homopentapeptides, or only to 5-HT3 heteropentapeptides, or only to 5-HT3 heteropentapeptides composed of certain subunits, such as 5-HT3... 3AC Heteropenic receptor, 5-HT 3AD Heteropenic receptor or 5-HT 3AE Heteropeptidase receptors bind to and elicit biological responses from them.

[0037] The 5-HT3 receptor agonists disclosed herein include, but are not limited to, alcohols with 5-HT3 receptor agonist activity, m-chlorophenyl biguanide (1-(3-chlorophenyl biguanide)), Ibogaine, phenyl biguanide, piperazine with 5-HT3 receptor agonist activity, RS-56812 (N-(1-azabicyclo[2.2.2]octane-3-yl)-2-(1-methylindol-3-yl)-2-oxoacetamide), serotonin (5-HT), SR-57227 (1-(6-chloropyridin-2-yl)piperidine-4-amine), SR-57227A (4-amino-1-(6-chloro-2-pyridinyl)piperidine hydrochloride), tryptamine with 5-HT3 receptor agonist activity, varenicline, volatile gases with 5-HT3 receptor agonist activity, and YM-31636. (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole). Non-limiting examples of alcohols having 5-HT3 receptor agonist activity include butanol, ethanol, and trichloroethanol. Non-limiting examples of piperazines having 5-HT3 receptor agonist activity include benzylpiperazine, m-chlorophenylpiperazine, and quinoperazine. Non-limiting examples of tryptamines having 5-HT3 receptor agonist activity include 2-methyl-5-hydroxytryptamine, α-methyltryptamine, 5-carboxamide tryptamine, N,N -Dimethyl-5-hydroxytryptamine (bufotenin) or 5-hydroxy- N,N,N - Trimethylchrome (bufotenidine). Non-limiting examples of volatile gases with 5-HT3 receptor agonist activity include fluorocarbons, isofluranes, toluene, and trichloroethane.

[0038] This specification partially discloses α-7 nicotinic acetylcholine receptor agonists. An α-7 nicotinic acetylcholine receptor agonist is a compound that binds to and activates or induces a biological response in an α-7 nicotinic acetylcholine receptor. The α-7 nicotinic acetylcholine receptor agonists disclosed herein can be full agonists, partial agonists, co-agonists, or superagonists. A full α-7 nicotinic acetylcholine receptor agonist binds to and activates an α-7 nicotinic acetylcholine receptor as an agonist at the maximal response induced by that receptor. A partial α-7 nicotinic acetylcholine receptor agonist binds to and activates a given α-7 nicotinic acetylcholine receptor, but, relative to a full agonist, induces only a partial effect on that receptor, even at maximum receptor occupancy. Although partial α-7 nicotinic acetylcholine receptor agonists are agonists, they can act as competitive antagonists in the presence of a full α-7 nicotinic acetylcholine receptor agonist because they compete with the full agonist for receptor occupancy, resulting in a net reduction in receptor activation compared to that observed with the full agonist alone. α-7 nicotinic acetylcholine co-agonists act together with other α-7 nicotinic acetylcholine receptor co-agonists to produce the desired biological response. The α-7 nicotinic acetylcholine receptor agonists disclosed herein can be super-potent α-7 nicotinic acetylcholine receptor agonists, capable of producing a biological response at this receptor greater than that of serotonin.

[0039] The α-7 nicotinic acetylcholine receptor agonists disclosed herein can be pan-agonists or selective agonists. Pan-agonists bind to and elicit a biological response from any α-7 nicotinic acetylcholine receptor, regardless of subunit composition. Selective agonists bind selectively to specific types of α-7 nicotinic acetylcholine receptors, eliciting a biological response via these specific receptors. For example, a selective 5-HT3 agonist may bind only to or only to α7 nAChR homopentapeptides and elicit a biological response from them.

[0040] The α-7 nicotinic acetylcholine receptor agonists disclosed herein include, but are not limited to, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide, A-582941, acetylcholine, β-amyloid, neonicotinoid, AR-R17779, Bradanicline, choline, Encenicline, Epiboxidine, GTS-21, ICH-3, nicotine, PHA-543,613, PHA-709829, PNU-282,987, SSR-180,711, TC-1698, Tilorone, Tropisetron, and WAY-317,538.

[0041] This specification partially discloses α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor inhibitory activity. These α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor inhibitory activity are α-7 nicotinic acetylcholine receptor agonists disclosed herein that also bind to 5-HT3 receptors and attenuate, inhibit, or otherwise prevent 5-HT3 receptor-mediated biological responses. Therefore, these α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor inhibitory activity have an affinity for their homologous 5-HT3 receptor but are ineffective against it. However, once bound, they inhibit the function of agonists, inverse agonists, and partial agonists. The α-7 nicotinic acetylcholine receptor activators disclosed herein with 5-HT3 receptor inhibitory activity can mediate their effects by binding to the active orthomeric site on the 5-HT3 receptor or by binding to the allosteric site on the 5-HT3 receptor, or by interacting at unique binding sites that are not normally involved in the biological regulation of 5-HT3 receptor activity. The α-7 nicotinic acetylcholine receptor activators disclosed herein with 5-HT3 receptor inhibitory activity can be reversible or irreversible, depending on the lifetime of the antagonist-receptor complex, which in turn depends on the nature of the antagonist-receptor binding.

[0042] The α-7 nicotinic acetylcholine receptor activators disclosed herein possess 5-HT3 receptor inhibitory activity and can exhibit complete antagonistic activity, partial antagonistic activity, or synergistic antagonistic activity at the 5-HT3 receptor. α-7 nicotinic acetylcholine receptor activators exhibiting complete 5-HT3 receptor antagonistic activity bind to a given 5-HT3 receptor and inhibit the maximal biological response mediated by that receptor. α-7 nicotinic acetylcholine receptor activators exhibiting partial 5-HT3 receptor antagonistic activity bind to a given 5-HT3 receptor and, even at maximum receptor occupancy, attenuate but do not completely inhibit the biological response mediated by that receptor. α-7 nicotinic acetylcholine receptor activators exhibiting complete 5-HT3 receptor synergistic antagonistic activity act synergistically with other 5-HT3 receptor synergistic antagonists to produce a desired blocking effect on the biological response.

[0043] The α-7 nicotinic acetylcholine receptor activators disclosed herein with 5-HT3 receptor antagonistic activity can be either α-7 nicotinic acetylcholine receptor activators exhibiting pan-antagonistic activity against all 5-HT3 receptors or α-7 nicotinic acetylcholine receptor activators exhibiting pan-antagonistic activity against selective 5-HT3 receptors. α-7 nicotinic acetylcholine receptor activators with pan-antagonistic activity bind to any 5-HT3 receptor and attenuate, inhibit, or otherwise prevent biological responses mediated by any 5-HT3 receptor, regardless of subunit composition. α-7 nicotinic acetylcholine receptor activators with selective antagonistic activity bind selectively to specific types of 5-HT3 receptors and attenuate, inhibit, or otherwise prevent biological responses via these specific 5-HT3 receptors. For example, α-7 nicotinic acetylcholine receptor activators with selective 5-HT3 receptor antagonistic activity can interact only with 5-HT3 homopentadienomers, or only with 5-HT3 heteropentadienomers, or only with 5-HT3 heteropentadienomers having specific subunit compositions, such as 5-HT3 homopentadienomers. 3AC Heteropenic receptor, 5-HT 3AD Heteropenic receptor, or 5-HT 3AE Heteropenic receptors bind to and from them attenuate, inhibit, or otherwise prevent biological responses.

[0044] The α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor antagonistic activity disclosed herein include, but are not limited to, α-7 nicotinic acetylcholine receptor activators with antidepressant 5-HT3 receptor antagonistic activity, α-7 nicotinic acetylcholine receptor activators with antiemetic 5-HT3 receptor antagonistic activity, α-7 nicotinic acetylcholine receptor activators with antimalarial 5-HT3 receptor antagonistic activity, α-7 nicotinic acetylcholine receptor activators with antipsychotic 5-HT3 receptor antagonistic activity, and α-7 nicotinic acetylcholine receptor activators with prokinetic 5-HT3 receptor antagonistic activity.

[0045] This specification partially discloses α-7 nicotinic acetylcholine receptor activators with inverse 5-HT3 receptor agonist activity. α-7 nicotinic acetylcholine receptor activators with inverse 5-HT3 receptor agonist activity are compounds that bind to 5-HT3 receptors and reduce, inhibit, or otherwise block the constituent activity of 5-HT3 receptors. Therefore, while molecules with 5-HT3 receptor agonist activity elicit a biological response, molecules with 5-HT3 receptor antagonist activity block the biological response induced by 5-HT3 receptor agonists, and molecules with inverse 5-HT3 receptor agonist activity exert an opposite biological response to 5-HT3 receptor agonists, rather than simply exhibiting a biological response lacking the observed antagonist activity. Activators of α-7 nicotinic acetylcholine receptors with 5-HT3 receptor inverse agonistic activity include, but are not limited to, α-7 nicotinic acetylcholine receptor activators with complete 5-HT3 receptor inverse agonistic activity, α-7 nicotinic acetylcholine receptor activators with partial 5-HT3 receptor inverse agonistic activity, and α-7 nicotinic acetylcholine receptor activators with co-inverse 5-HT3 receptor inverse agonistic activity. Activators of α-7 nicotinic acetylcholine receptors with 5-HT3 receptor inverse agonistic activity include, but are not limited to, α-7 nicotinic acetylcholine receptor activators with pan-inverse 5-HT3 receptor inverse agonistic activity and α-7 nicotinic acetylcholine receptor activators with selective 5-HT3 receptor inverse agonistic activity.

[0046] This specification partially discloses therapeutically effective amounts. Regarding the combination therapies disclosed herein, α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor inhibitory activity, 5-HT3 receptor agonists, α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor antagonistic activity, and α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor inverse agonistic activity, collectively referred to as "activators," are used or administered in a therapeutically effective amount. The therapeutically effective amount of the activator present in the combination therapy is an amount sufficient to treat schizophrenic disorder or condition. In aspects of this implementation, the therapeutically effective amount of the activator present in the combination therapy is an amount sufficient to reduce one or more physiological conditions or symptoms associated with schizophrenic disorder or condition, or an amount sufficient to protect an individual from one or more physiological conditions or symptoms associated with schizophrenic disorder or condition. As used herein, the term “therapeutic effective amount” includes the terms “adequate amount,” “therapeutic adequate amount,” “effective amount,” “effective dose,” or “therapeutic effective dose,” and refers to the minimum amount necessary for the disclosed active agent in the combination therapy disclosed herein to achieve the desired therapeutic effect, and includes an amount sufficient to reduce or suppress one or more physiological conditions or symptoms associated with schizophrenic disorders or symptoms.

[0047] In one aspect of this embodiment, a therapeutically effective amount of the disclosed active agent in the combination therapy reduces or inhibits one or more physiological conditions or symptoms associated with schizophrenia, for example, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In other aspects of this embodiment, an effective amount of the disclosed active agent in the combination therapy reduces or inhibits one or more physiological conditions or symptoms associated with schizophrenia, for example, by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100%. In other aspects of this embodiment, an effective amount of the disclosed active agent present in the combination therapy reduces or inhibits one or more physiological conditions or symptoms associated with schizophrenic disorders or symptoms, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%. In other aspects of this implementation, an effective amount of the disclosed active agent present in the combination therapy reduces or inhibits one or more physiological conditions or symptoms associated with schizophrenic disorders or symptoms for, for example, at least one week, at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.

[0048] In some embodiments, the therapeutically effective dose of the combination therapy comprises about 0.1 mg to about 1,000 mg of an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity and about 0.1 mg to about 1,000 mg of a 5-HT3 receptor agonist. In aspects of these embodiments, the therapeutically effective dose of the combination therapy comprises about 0.25 mg to about 750 mg, about 0.5 mg to about 500 mg, about 0.75 mg to about 250 mg, or about 1 mg to about 250 mg of an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity and about 0.25 mg to about 750 mg, about 0.5 mg to about 500 mg, about 0.75 mg to about 250 mg, or about 1 mg to about 250 mg of a 5-HT3 receptor agonist.

[0049] In some embodiments, the therapeutically effective dose of the combination therapy comprises about 0.1 mg to about 1,000 mg of an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor antagonistic activity and about 0.1 mg to about 1,000 mg of a 5-HT3 receptor agonist. In aspects of these embodiments, the therapeutically effective dose of the combination therapy comprises about 0.25 mg to about 750 mg, about 0.5 mg to about 500 mg, about 0.75 mg to about 250 mg, or about 1 mg to about 250 mg of an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor antagonistic activity and about 0.25 mg to about 750 mg, about 0.5 mg to about 500 mg, about 0.75 mg to about 250 mg, or about 1 mg to about 250 mg of a 5-HT3 receptor agonist.

[0050] In some embodiments, the therapeutically effective dose of the combination therapy comprises about 0.1 mg to about 1,000 mg of an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inverse agonist activity and about 0.1 mg to about 1,000 mg of a 5-HT3 receptor agonist. In aspects of these embodiments, the therapeutically effective dose of the combination therapy comprises about 0.25 mg to about 750 mg, about 0.5 mg to about 500 mg, about 0.75 mg to about 250 mg, or about 1 mg to about 250 mg of an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inverse agonist activity and about 0.25 mg to about 750 mg, about 0.5 mg to about 500 mg, about 0.75 mg to about 250 mg, or about 1 mg to about 250 mg of a 5-HT3 receptor agonist.

[0051] In some embodiments, the therapeutically effective dose of the combination therapy comprises about 1 mg to about 100 mg of tropisetron and about 0.1 mg to about 5 mg of varenicline. In some embodiments, the therapeutically effective dose of the combination therapy comprises about 2 mg to about 75 mg of tropisetron and about 0.25 mg to about 4 mg of varenicline. In some embodiments, the therapeutically effective dose of the combination therapy comprises about 5 mg to about 50 mg of tropisetron and about 0.5 mg to about 2 mg of varenicline.

[0052] In some implementations, the therapeutically effective amount of a combination therapy may be the therapeutically effective amount of one, some, or all of the active agents at their optimal therapeutic levels. The optimal therapeutic level is the amount of active agent that most effectively produces the desired therapeutic effect while remaining within acceptable toxicity levels.

[0053] In some embodiments, the therapeutically effective amount of the combination therapy may be a therapeutically effective amount of one, some, or all of the active agents at a suboptimal therapeutic amount. A suboptimal therapeutic amount is an amount of active agent that is below the optimal therapeutic amount of the active agent but still provides a certain degree of the desired therapeutic effect. In aspects of these embodiments, the suboptimal therapeutic amount of the active agent is, for example, less than 80%, less than 75%, less than 70%, less than 60%, less than 55%, or less than 50% of the optimal therapeutic amount of the active agent. In aspects of these embodiments, the suboptimal therapeutic amount of the active agent is, for example, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, or about 50% to about 80% of the optimal therapeutic amount of the active agent.

[0054] In some embodiments, the therapeutically effective amount of the combination therapy may be a therapeutically effective amount at a non-therapeutic level for one, some, or all of the active agents. A non-therapeutic level is the amount of active agent that provides a therapeutic effect at a suboptimal therapeutic level. In aspects of these embodiments, a non-therapeutic level of the active agent is, for example, less than 80%, less than 75%, less than 70%, less than 60%, less than 55%, or less than 50% of the suboptimal therapeutic level of the active agent. 。 In these embodiments, the non-therapeutic amount of the active agent is, for example, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, or about 50% to about 80% of the second-best therapeutic amount of the active agent.

[0055] In some implementations, the therapeutically effective dose of a combination therapy comprising an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity and a 5-HT3 receptor agonist is such that: 1) the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity is the second-best therapeutic dose when administered alone; 2) the amount of the 5-HT3 receptor agonist is the second-best therapeutic dose when administered alone; or 3) both the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity and the amount of the 5-HT3 receptor agonist are the second-best therapeutic doses when administered alone, respectively. In some aspects of these implementation schemes, the therapeutically effective amount of a combination therapy comprising an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity and a 5-HT3 receptor agonist is such that: 1) the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity is a non-therapeutic amount when administered alone; 2) the amount of the 5-HT3 receptor agonist is a non-therapeutic amount when administered alone; or 3) both the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity and the amount of the 5-HT3 receptor agonist are non-therapeutic amounts when each is administered alone.

[0056] In some implementations, the therapeutically effective dose of combination therapy comprising an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor antagonistic activity and a 5-HT3 receptor agonist is such that: 1) the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor antagonistic activity is the second-best therapeutic dose when administered alone; 2) the amount of the 5-HT3 receptor agonist is the second-best therapeutic dose when administered alone; or 3) both the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor antagonistic activity and the amount of the 5-HT3 receptor agonist are the second-best therapeutic doses when administered alone, respectively. In some aspects of these implementation schemes, the therapeutically effective amount of combination therapy including an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor antagonistic activity and a 5-HT3 receptor agonist is such that: 1) the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor antagonistic activity is the non-therapeutic amount when administered alone; 2) the amount of the 5-HT3 receptor agonist is the non-therapeutic amount when administered alone; or 3) both the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor antagonistic activity and the amount of the 5-HT3 receptor agonist are the non-therapeutic amounts when each is administered alone.

[0057] In some implementations, the therapeutically effective dose of combination therapy comprising an α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity and a 5-HT3 receptor agonist is such that: 1) the amount of the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity is the second-best therapeutic dose when administered alone; 2) the amount of the 5-HT3 receptor agonist is the second-best therapeutic dose when administered alone; or 3) both the amount of the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity and the amount of the 5-HT3 receptor agonist are the second-best therapeutic doses when administered alone, respectively. In some aspects of these implementation schemes, the therapeutically effective dose of combination therapy including an α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity and a 5-HT3 receptor agonist is such that: 1) the amount of the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity is the non-therapeutic dose when administered alone; 2) the amount of the 5-HT3 receptor agonist is the non-therapeutic dose when administered alone; or 3) both the amount of the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor antagonistic activity and the amount of the 5-HT3 receptor agonist are the non-therapeutic doses when each is administered alone.

[0058] In some implementations, the therapeutically effective dose of combination therapy comprising an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inverse agonist activity and a 5-HT3 receptor agonist is such that: 1) the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inverse agonist activity is the second-best therapeutic dose when administered alone; 2) the amount of the 5-HT3 receptor agonist is the second-best therapeutic dose when administered alone; or 3) both the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inverse agonist activity and the amount of the 5-HT3 receptor agonist are the second-best therapeutic doses when administered alone, respectively. In some aspects of these implementation schemes, the therapeutically effective amount of combination therapy including an α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inverse agonist activity and a 5-HT3 receptor agonist is such that: 1) the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inverse agonist activity is the non-therapeutic amount when administered alone; 2) the amount of the 5-HT3 receptor agonist is the non-therapeutic amount when administered alone; or 3) both the amount of the α-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inverse agonist activity and the amount of the 5-HT3 receptor agonist are the non-therapeutic amounts when each is administered alone.

[0059] In some implementations, the therapeutically effective dose of combination therapy comprising an α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity and a 5-HT3 receptor agonist is such that: 1) the amount of the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity is the second-best therapeutic dose when administered alone; 2) the amount of the 5-HT3 receptor agonist is the second-best therapeutic dose when administered alone; or 3) both the amount of the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity and the amount of the 5-HT3 receptor agonist are the second-best therapeutic doses when administered alone, respectively. In some aspects of these implementation schemes, the therapeutically effective dose of combination therapy including an α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity and a 5-HT3 receptor agonist is such that: 1) the amount of the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity is a non-therapeutic dose when administered alone; 2) the amount of the 5-HT3 receptor agonist is a non-therapeutic dose when administered alone; or 3) both the amount of the α-7 nicotinic acetylcholine receptor agonist with 5-HT3 receptor inverse agonist activity and the amount of the 5-HT3 receptor agonist are non-therapeutic doses when administered alone.

[0060] In some embodiments, the therapeutically effective dose of combination therapy including tropisetron and varenicline is a therapeutically effective dose in which: 1) the amount of tropisetron is the second-best therapeutic dose when administered alone, 2) the amount of varenicline is the second-best therapeutic dose when administered alone, or 3) both the amount of tropisetron and the amount of varenicline are the second-best therapeutic doses when administered alone, respectively. In aspects of these embodiments, the therapeutically effective dose of combination therapy including tropisetron and varenicline is a therapeutically effective dose in which: 1) the amount of tropisetron is the non-therapeutic dose when administered alone, 2) the amount of varenicline is the non-therapeutic dose when administered alone, or 3) both the amount of tropisetron and the amount of varenicline are the non-therapeutic doses when administered alone, respectively.

[0061] Those skilled in the art can determine the actual therapeutically effective amount of the disclosed active agent present in the combination therapy disclosed herein, to be used or administered to an individual by considering factors including, but not limited to, the type of schizophrenic disorder or condition, specific physiological conditions or symptoms associated with the schizophrenic disorder or condition, the etiology of the schizophrenic disorder or condition, the severity of the schizophrenic disorder or condition, the expected degree of remission of the schizophrenic disorder or condition, the expected duration of remission of the schizophrenic disorder or condition, the specific active agent used in the combination therapy, the excretion rate of the specific active agent used in the combination therapy, the pharmacodynamics of the specific active agent used in the combination therapy, the nature of other compounds to be included in the combination therapy, the specific route of administration, specific characteristics of the individual, history and risk factors such as, for example, age, weight, general health status, etc., or any combination thereof. Furthermore, in the case of repeated administration of the combination therapy disclosed herein, the actual therapeutically effective amount will also depend on factors including, but not limited to, the frequency of administration, the half-life of the disclosed active agent present in the combination therapy, or any combination thereof. It is known to those skilled in the art that the effective amount of the active agent disclosed herein present in a combination therapy can be inferred from in vitro assays and in vivo administration studies using animal models prior to human administration. Given the varying efficiencies of different routes of administration, a wide range of effective amounts can be expected. For example, oral administration or delivery will generally require higher dose levels than intravenous or intravitreal administration or delivery. These variations in dose levels can be adjusted using optimized standard empirical routes, as is well known to those skilled in the art. The precise therapeutically effective dose level and mode are preferably determined by the attending healthcare professional taking into account the factors described above.

[0062] Administration may be a single dose or cumulative (continuous) and can be readily determined by those skilled in the art. For example, treatment of schizophrenic disorders or conditions may include a single administration of the combination therapy disclosed herein. As a non-limiting example, the combination therapy may be administered to an individual once, for example, as a single injection or deposition. Alternatively, treatment of schizophrenic disorders or conditions may include multiple administrations of the combination therapy disclosed herein over a series of time periods, such as, for example, once daily, every few days, once weekly, once monthly, or once a year. As a non-limiting example, the combination therapy may be administered to an individual once, twice, three times, four times, five times, or six times per year. The timing of administration may vary from person to person, depending on factors such as the severity of the individual's symptoms. For example, the combination therapy may be administered to an individual every three months for an indefinite period or until the individual no longer requires treatment. Those skilled in the art will recognize that the individual's condition can be monitored throughout the treatment process, and the use or administration of the combination therapy disclosed herein can be adjusted accordingly.

[0063] This specification partially discloses schizophrenic disorders. Schizophrenic disorders are a group of mental disorders characterized by a deterioration in the functional interactions between thought, emotion, and behavior, resulting in numerous disturbances in cognition, perception, and mood. Typically, individuals with schizophrenic disorders exhibit a general distortion of reality, significant impairments in language and cognitive function, widespread withdrawal from social interaction, disorganized and fragmented thinking, altered perception, and inappropriate emotional responses.

[0064] The clinical features of schizophrenic disorders can be clustered into three symptom groups: positive symptoms, negative symptoms, and cognitive symptoms. Positive symptoms are categorized as fixed, illusory emotions or behaviors involving manifestations that may be real but are merely psychotic, such as delusions, hallucinations, paranoia, thought disorders (disorganized thoughts, speech or behavior, neologisms), and motor disorders (clumsiness, incoordination, repetitive movements, dystonia) in real-life situations. Negative symptoms are categorized as deficits or reductions in normal emotions and behaviors, such as affective disorders (unresponsive facial expressions, monotone voice), decreased interest in or lack of pleasure in daily activities (anhedonia, such as depression), lack of motivation (diminished willpower), decreased ability to initiate and maintain planned activities, poverty of speech (pénativism), infrequent speech (even when forced to interact), and social withdrawal. Cognitive symptoms are categorized as deficits in mental processes of understanding, judgment, memory, and reasoning, such as problems in selective attention, working memory, executive function, episodic memory, language comprehension, and socioemotional processing.

[0065] Non-limiting examples of schizophrenic disorders include schizophrenia, schizophrenia-like disorders, schizoaffective disorder, and schizotypal personality disorder. Schizophrenia is defined as a condition in which an individual has symptoms of schizophrenia that last for six months or longer. Schizoaffective disorder is defined as a condition in which an individual has symptoms of both schizophrenia and a mood disorder (such as depression or bipolar disorder). Schizophrenia-like disorders are defined as a condition in which an individual has symptoms of schizophrenia but the symptoms last for less than six months. Schizotypal personality disorder is a schizophrenia-like condition characterized by interpersonal deficits and abnormal thought patterns, appearance, and behavior that are not severe enough to meet the clinical criteria for schizophrenia.

[0066] Schizophrenia can be classified into five subtypes based on the type and frequency of positive and negative symptoms: disintegrative, neurotic, paranoid, undifferentiated, and residual. Disintegrative (hebephrenic) schizophrenia is characterized by confused and incoherent thinking; superficial, flat, inappropriate, and / or foolish emotional responses (influences) to situations; and regressive behavior without systematic delusions. Neurotic schizophrenia is characterized by psychomotor disturbances, which may involve stupor, rigidity, agitation, negativity, or bizarre behavior, or alterations within these behaviors; related features include mutism, stereotyped behaviors, and waxy flexibility. Paranoid schizophrenia is characterized by persecutory or grandiose delusions, delusional jealousy, or hallucinations with persecutory or grandiose content. Undifferentiated schizophrenia is characterized by the presence of both positive and negative symptoms of schizophrenia, but does not meet the specific criteria for a paranoid, disintegrative, or neurotic subtype. Residual schizophrenia is characterized by an individual having a previous schizophrenic episode but currently not presenting with any positive symptoms, although negative symptoms may persist.

[0067] In addition to these five symptom subtypes, individuals can also be classified based on other criteria, including susceptibility, initial event, duration, antipsychotic drug resistance, and cognitive symptoms. For example, an individual who begins to experience some psychotic symptoms that may occur in someone who will never develop schizophrenia is classified as extremely high risk of psychosis (UHR) or in an at-risk mental state (ARMS). An individual experiencing their first psychotic symptom or schizophrenia-related episode is classified as having a first episode of psychosis (FEP). An individual with schizophrenia whose positive and negative symptoms are being successfully managed with treatment including antipsychotic medication is classified as having a long-term treatment-responsive schizophrenia. An individual with schizophrenia who develops resistance to antipsychotic medication after initial successful treatment is classified as having treatment-resistant schizophrenia (TRS). An individual with schizophrenia whose positive and negative symptoms are being successfully managed with treatment including antipsychotic medication but who still has cognitive symptoms is classified as having schizophrenia-associated cognitive impairment (CIAS).

[0068] In one embodiment, a method of treating schizophrenic disorder comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators. In another aspect of this embodiment, a method of treating schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators. In another aspect of this embodiment, a method of treating treatment-resistant schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators. In another aspect of this implementation scheme, a method for treating cognitively impaired schizophrenia includes, substantially consists of, or consists of, the administration of a combination therapy comprising, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators.

[0069] In one embodiment, a method of treating schizophrenic disorder comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and a therapeutically effective amount of one or more 5-HT3 receptor activators. In another aspect of this embodiment, a method of treating schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and a therapeutically effective amount of one or more 5-HT3 receptor activators. In another aspect of this embodiment, a method of treating treatment-resistant schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and a therapeutically effective amount of one or more 5-HT3 receptor activators. In other aspects of this embodiment, a method for treating cognitively impaired schizophrenia includes, substantially consists of, or comprises the administration of a combination therapy, which includes, substantially consists of, or comprises a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and a therapeutically effective amount of one or more 5-HT3 receptor activators. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity is the second-best therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity is the non-therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the non-therapeutic amount when administered alone.

[0070] In one embodiment, a method of treating schizophrenic disorder comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists. In another aspect of this embodiment, a method of treating schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists. In another aspect of this embodiment, a method of treating treatment-resistant schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists. In another aspect of this implementation scheme, a method for treating cognitively impaired schizophrenia includes, substantially consists of, or consists of, the administration of a combination therapy comprising, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists.

[0071] In one embodiment, a method of treating schizophrenic disorder comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists. In another aspect of this embodiment, a method of treating schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists. In another aspect of this embodiment, a method of treating treatment-resistant schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists. In other aspects of this embodiment, a method for treating cognitively impaired schizophrenia includes, substantially consists of, or comprises the administration of a combination therapy, which includes, substantially consists of, or comprises a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity is the second-best therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity is the non-therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the non-therapeutic amount when administered alone.

[0072] In one embodiment, a method of treating schizophrenic disorder comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor agonists. In another aspect of this embodiment, a method of treating schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor agonists. In another aspect of this embodiment, a method of treating treatment-resistant schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor agonists. In other aspects of this implementation scheme, the method of treating cognitively impaired schizophrenia includes, substantially includes, or includes the administration of a combination therapy comprising, substantially includes, or includes an α-7 nicotinic acetylcholine receptor agonist having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor agonists.

[0073] In one embodiment, a method of treating schizophrenic disorder comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists. In an aspect of this embodiment, a method of treating schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of an α-7 nicotinic acetylcholine receptor agonist having 5-HT3 receptor inverse agonist activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists. In other aspects of this embodiment, a method of treating treatment-resistant schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of an α-7 nicotinic acetylcholine receptor agonist having 5-HT3 receptor inverse agonist activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists. In other aspects of this embodiment, a method for treating cognitively impaired schizophrenia includes, substantially consists of, or comprises the administration of a combination therapy, which includes, substantially consists of, or comprises a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists. In some embodiments, the therapeutically effective amount of the one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of the one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonistic activity is the amount of the second-best therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonistic activity is the amount of the non-therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the non-therapeutic amount when administered alone.

[0074] In a preferred embodiment, a method of treating schizophrenic disorder comprises, substantially comprises, or comprises administering a combination therapy consisting of, substantially comprises, or comprises varenicline and tropisetron. In an aspect of this embodiment, a method of treating schizophrenia comprises, substantially comprises, or comprises administering a combination therapy consisting of, substantially comprises, or comprises varenicline and tropisetron. In another aspect of this embodiment, a method of treating treatment-resistant schizophrenia comprises, substantially comprises, or comprises administering a combination therapy consisting of, substantially comprises, or comprises varenicline and tropisetron. In yet another aspect of this embodiment, a method of treating cognitively impaired schizophrenia comprises, substantially comprises, or comprises administering a combination therapy consisting of, substantially comprises, or comprises varenicline and tropisetron.

[0075] In a more preferred embodiment, a method of treating schizophrenic disorder comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron. In an aspect of this embodiment, a method of treating schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron. In other aspects of this embodiment, a method of treating treatment-resistant schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron. In yet other aspects of this embodiment, a method of treating cognitively impaired schizophrenia comprises, substantially, or consists of administering a combination therapy comprising, substantially, or consists of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron. In some embodiments, the therapeutically effective amount of tropisetron is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of tropisetron is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective dose of varenicline is the second-best therapeutic dose when administered alone. In some embodiments, the therapeutically effective dose of varenicline is the non-therapeutic dose when administered alone. In some embodiments, the therapeutically effective dose of tropisetron is the second-best therapeutic dose when administered alone, and the therapeutically effective dose of varenicline is the second-best therapeutic dose when administered alone. In some embodiments, the therapeutically effective dose of tropisetron is the non-therapeutic dose when administered alone, and the therapeutically effective dose of varenicline is the non-therapeutic dose when administered alone.

[0076] In one embodiment, the combination therapy comprises, substantially consisting of, or consisting of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators, for use in the treatment of schizophrenic disorder. In another aspect of this embodiment, the combination therapy comprises, substantially consisting of, or consisting of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators, for use in the treatment of schizophrenia. In other aspects of this embodiment, the combination therapy comprises, substantially consisting of, or consisting of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators, for use in the treatment of treatment-resistant schizophrenia. In other aspects of this implementation, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators, for use in the treatment of cognitive impairment associated with schizophrenia.

[0077] In one embodiment, the combination therapy comprises, substantially consisting of, or consisting of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and a therapeutically effective amount of one or more 5-HT3 receptor activators, for use in the treatment of schizophrenic disorder. In another aspect of this embodiment, the combination therapy comprises, substantially consisting of, or consisting of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and a therapeutically effective amount of one or more 5-HT3 receptor activators, for use in the treatment of schizophrenia. In other aspects of this embodiment, the combination therapy comprises, substantially consisting of, or consisting of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and a therapeutically effective amount of one or more 5-HT3 receptor activators, for use in the treatment of treatment-resistant schizophrenia. In other aspects of this embodiment, the combination therapy comprises, substantially consists of, or is composed of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and a therapeutically effective amount of one or more 5-HT3 receptor activators, for use in the treatment of cognitive impairment associated with schizophrenia. In some embodiments, the therapeutically effective amount of the one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of the one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity is the second-best therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity is the non-therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the non-therapeutic amount when administered alone.

[0078] In one embodiment, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists, for use in the treatment of schizophrenic disorder. In another aspect of this embodiment, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists, for use in the treatment of schizophrenia. In other aspects of this embodiment, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists, for use in the treatment of treatment-resistant schizophrenia. In other aspects of this implementation scheme, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and one or more 5-HT3 receptor agonists, for use in the treatment of cognitive impairment associated with schizophrenia.

[0079] In one embodiment, the combination therapy comprises, substantially consisting of, or consisting of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists with 5-HT3 receptor antagonistic activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists, for use in the treatment of schizophrenic disorder. In another aspect of this embodiment, the combination therapy comprises, substantially consisting of, or consisting of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists with 5-HT3 receptor antagonistic activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists, for use in the treatment of schizophrenia. In other aspects of this embodiment, the combination therapy comprises, substantially consisting of, or consisting of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists with 5-HT3 receptor antagonistic activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists, for use in the treatment of treatment-resistant schizophrenia. In other aspects of this embodiment, the combination therapy comprises, substantially consists of, or is composed of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists, for use in the treatment of cognitive impairment associated with schizophrenia. In some embodiments, the therapeutically effective amount of the one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of the one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity is the second-best therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor antagonistic activity is the non-therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the non-therapeutic amount when administered alone.

[0080] In one embodiment, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor agonists, for use in the treatment of schizophrenic disorder. In another aspect of this embodiment, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor agonists, for use in the treatment of schizophrenia. In other aspects of this embodiment, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor agonists, for use in the treatment of treatment-resistant schizophrenia. In other aspects of this implementation, the combination therapy comprises, substantially consists of, or consists of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and one or more 5-HT3 receptor agonists, for use in the treatment of cognitive impairment associated with schizophrenia.

[0081] In one embodiment, the combination therapy comprises, substantially consisting of, or consisting of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists, for use in the treatment of schizophrenic disorder. In another aspect of this embodiment, the combination therapy comprises, substantially consisting of, or consisting of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists, for use in the treatment of schizophrenia. In other aspects of this embodiment, the combination therapy comprises, substantially consisting of, or consisting of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists, for use in the treatment of treatment-resistant schizophrenia. In other aspects of this embodiment, the combination therapy comprises, substantially consists of, or is composed of a therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity and a therapeutically effective amount of one or more 5-HT3 receptor agonists, for use in the treatment of cognitive impairment associated with schizophrenia. In some embodiments, the therapeutically effective amount of the one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of the one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonist activity is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonistic activity is the amount of the second-best therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of one or more α-7 nicotinic acetylcholine receptor agonists having 5-HT3 receptor inverse agonistic activity is the amount of the non-therapeutic amount when administered alone, and the therapeutically effective amount of one or more 5-HT3 receptor agonists is the amount of the non-therapeutic amount when administered alone.

[0082] In a preferred embodiment, the combination therapy comprises, is substantially composed of, or consists of varenicline and tropisetron, for use in the treatment of schizophrenic disorder. In an aspect of this embodiment, the combination therapy comprises, is substantially composed of, or consists of varenicline and tropisetron, for use in the treatment of schizophrenia. In other aspects of this embodiment, the combination therapy comprises, is substantially composed of, or consists of varenicline and tropisetron, for use in the treatment of treatment-resistant schizophrenia. In still other aspects of this embodiment, the combination therapy comprises, is substantially composed of, or consists of varenicline and tropisetron, for use in the treatment of cognitive impairment associated with schizophrenia.

[0083] In a more preferred embodiment, the combination therapy comprises, substantially composed of, or composed of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron, for use in the treatment of schizophrenic disorder. In an aspect of this embodiment, the combination therapy comprises, substantially composed of, or composed of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron, for use in the treatment of schizophrenia. In other aspects of this embodiment, the combination therapy comprises, substantially composed of, or composed of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron, for use in the treatment of treatment-resistant schizophrenia. In yet other aspects of this embodiment, the combination therapy comprises, substantially composed of, or composed of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron, for use in the treatment of cognitive impairment associated with schizophrenia. In some embodiments, the therapeutically effective amount of tropisetron is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of tropisetron is the amount of the non-therapeutic amount when administered alone. In some embodiments, the therapeutically effective amount of varenicline is the amount of the second-best therapeutic amount when administered alone. In some embodiments, the therapeutically effective dose of varenicline is the amount of the non-therapeutic dose when administered alone. In some embodiments, the therapeutically effective dose of tropisetron is the amount of the second-best therapeutic dose when administered alone, and the therapeutically effective dose of varenicline is the amount of the second-best therapeutic dose when administered alone. In some embodiments, the therapeutically effective dose of tropisetron is the amount of the non-therapeutic dose when administered alone, and the therapeutically effective dose of varenicline is the amount of the non-therapeutic dose when administered alone.

[0084] This specification can also be described as follows: 1. A method for treating schizophrenic disorder, the method being carried out by administering a combination therapy comprising one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators.

[0085] 2. The method according to embodiment 1, wherein the one or more α-7 nicotinic acetylcholine receptor activators comprise one or more α-7 nicotinic acetylcholine receptor agonists, one or more α-7 nicotinic acetylcholine receptor positive allosteric modulators, or combinations thereof.

[0086] 3. The method according to embodiment 2, wherein the one or more α-7 nicotinic acetylcholine receptor agonists include α-7 nicotinic acetylcholine receptor full agonists, α-7 nicotinic acetylcholine receptor partial agonists, or α-7 nicotinic acetylcholine receptor co-agonists.

[0087] 4. The method according to embodiment 2 or 3, wherein the one or more α-7 nicotinic acetylcholine receptor agonists include pan-α-7 nicotinic acetylcholine receptor agonists or selective α-7 nicotinic acetylcholine receptor agonists.

[0088] 5. The method according to embodiment 2, wherein the one or more α-7 nicotinic acetylcholine receptor agonists include (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide, A-582941, acetylcholine, β-amyloid, neonicotinoid, AR-R17779, Bradanicline, choline, Encenicline, Epiboxidine, GTS-21, ICH-3, nicotine, PHA-543,613, PHA-709829, PNU-282,987, SSR-180,711, TC-1698, telolonone, tropisetron, WAY-317,538, or any combination thereof.

[0089] 6. The method according to embodiment 2, wherein the one or more positive allosteric modulators of α-7 nicotinic acetylcholine receptor activity include A-867744, AVL-3288, galantamine, ivermectin, nefiracetam, NS-1738, PNU-120,596, or any combination thereof.

[0090] 7. The method according to any one of embodiments 1-6, wherein the 5-HT3 receptor inhibitory activity comprises 5-HT3 receptor antagonistic activity, 5-HT3 receptor inverse agonistic activity, or a combination thereof.

[0091] 8. The method according to embodiment 7, wherein the 5-HT3 receptor antagonistic activity is a complete 5-HT3 receptor antagonistic activity, a partial 5-HT3 receptor antagonistic activity, or a synergistic 5-HT3 receptor antagonistic activity.

[0092] 9. The method according to embodiment 7 or 8, wherein the 5-HT3 receptor antagonistic activity is a pan-antagonistic activity of the 5-HT3 receptor or a selective antagonistic activity of the 5-HT3 receptor.

[0093] 10. The method according to any one of embodiments 7-9, wherein the 5-HT3 receptor antagonistic activity comprises antidepressant 5-HT3 receptor antagonistic activity, antiemetic 5-HT3 receptor antagonistic activity, antimalarial 5-HT3 receptor antagonistic activity, antipsychotic 5-HT3 receptor antagonistic activity, prokinetic 5-HT3 receptor antagonistic activity, or any combination thereof.

[0094] 11. The method according to embodiment 2, wherein the 5-HT3 receptor reverse agonistic activity is a complete 5-HT3 receptor reverse agonistic activity, a partial 5-HT3 receptor reverse agonistic activity, or a 5-HT3 receptor co-reverse agonistic activity.

[0095] 12. The method according to embodiment 2 or 11, wherein the 5-HT3 receptor inverse agonist activity is a pan-inverse agonist activity of the 5-HT3 receptor or a selective inverse agonist activity of the 5-HT3 receptor.

[0096] 13. The method according to any one of embodiments 1-12, wherein the one or more 5-HT3 receptor active activators comprise one or more 5-HT3 receptor agonists.

[0097] 14. The method according to embodiment 13, wherein the one or more 5-HT3 receptor agonists include a 5-HT3 receptor full agonist, a 5-HT3 receptor partial agonist, a 5-HT3 receptor co-agonist, or a 5-HT3 receptor superagonist.

[0098] 15. The method according to embodiment 13 or 14, wherein the one or more 5-HT3 receptor agonists include a pan-5-HT3 receptor agonist or a selective 5-HT3 receptor agonist.

[0099] 16. The method according to any one of embodiments 13-15, wherein the one or more 5-HT3 receptor agonists have α-7 nicotinic acetylcholine receptor agonist activity.

[0100] 17. The method according to any one of embodiments 13-16, wherein the one or more 5-HT3 receptor agonists comprise an alcohol having 5-HT3 receptor agonist activity, m-chlorophenyl biguanide (1-(3-chlorophenyl biguanide)), ibog base, phenyl biguanide, piperazine having 5-HT3 receptor agonist activity, RS-56812 (N-(1-azabicyclo[2.2.2]octane-3-yl)-2-(1-methylindol-3-yl)-2-oxoacetamide), serotonin, SR-57227 (1-(6-chloropyridin-2-yl)piperidine-4-amine), SR-57227A (4-amino-1-(6-chloro-2-pyridyl)piperidine hydrochloride), tryptamine having 5-HT3 receptor agonist activity, varenicline, volatile gases having 5-HT3 receptor agonist activity, and YM-31636. (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole).

[0101] 18. The method according to embodiment 17, wherein the alcohol having 5-HT3 receptor agonist activity includes butanol, ethanol or trichloroethanol.

[0102] 19. The method according to embodiment 17, wherein the piperazine having 5-HT3 receptor agonist activity comprises benzylpiperazine, m-chlorophenylpiperazine, or quinpiperazine.

[0103] 20. The method according to embodiment 17, wherein the tryptamine having 5-HT3 receptor agonist activity comprises 2-methyl-5-hydroxytryptamine, α-methyltryptamine, 5-carboxamide tryptamine, N,N -Dimethyl-5-hydroxytryptamine (toad tannin) or 5-hydroxy- N,N,N - Trimethylchrome (bufotenidin).

[0104] 21. The method according to embodiment 17, wherein the volatile gas having 5-HT3 receptor agonist activity includes fluorocarbons, isofluranes, toluene, or trichloroethane.

[0105] 22. The method according to embodiment 1, wherein the one or more α-7 nicotinic acetylcholine receptor activators are tropisetron, and the one or more 5-HT3 receptor activators are varenicline.

[0106] 23. The method according to any one of embodiments 2-4 and 13-16, wherein the one or more α-7 nicotinic acetylcholine receptor agonists is tropisetron, and the one or more 5-HT3 receptor agonists is varenicline.

[0107] 24. The method according to any one of embodiments 1-23, wherein the one or more α-7 nicotinic acetylcholine receptor activators and the one or more 5-HT3 receptor activators are provided in a therapeutically effective amount.

[0108] 25. The method according to any one of embodiments 2-23, wherein the one or more α-7 nicotinic acetylcholine receptor agonists, the one or more α-7 nicotinic acetylcholine receptor activity positive allosteric modulators and / or the one or more 5-HT3 receptor agonists are provided in a therapeutically effective amount.

[0109] 26. The method according to any one of embodiments 1-25, wherein the combination therapy comprises administering a first composition and a second composition, the first composition comprising one or more α-7 nicotinic acetylcholine receptor activators, and the second composition comprising one or more 5-HT3 receptor activators.

[0110] 27. The method according to any one of embodiments 1-25, wherein the combination therapy comprises administering a single composition comprising one or more α-7 nicotinic acetylcholine receptor activators and one or more 5-HT3 receptor activators.

[0111] 28. The method according to any one of embodiments 2-25, wherein the combination therapy comprises administering a first composition and a second composition, the first composition comprising one or more α-7 nicotinic acetylcholine receptor agonists and / or one or more α-7 nicotinic acetylcholine receptor positive allosteric modulators, and the second composition comprising one or more 5-HT3 receptor agonists.

[0112] 29. The method according to any one of embodiments 2-25, wherein the combination therapy comprises administering a single composition comprising one or more α-7 nicotinic acetylcholine receptor agonists and / or one or more α-7 nicotinic acetylcholine receptor positive allosteric modulators and one or more 5-HT3 receptor agonists.

[0113] 30. A combination therapy comprising one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators, for use in the treatment of schizophrenic disorders.

[0114] 31. The combination therapy according to embodiment 30, wherein the one or more α-7 nicotinic acetylcholine receptor activators comprise one or more α-7 nicotinic acetylcholine receptor agonists, one or more α-7 nicotinic acetylcholine receptor positive allosteric modulators, or combinations thereof.

[0115] 32. The combination therapy according to embodiment 31, wherein the one or more α-7 nicotinic acetylcholine receptor agonists include α-7 nicotinic acetylcholine receptor full agonists, α-7 nicotinic acetylcholine receptor partial agonists, or α-7 nicotinic acetylcholine receptor co-agonists.

[0116] 33. The combination therapy according to embodiment 31 or 32, wherein the one or more α-7 nicotinic acetylcholine receptor agonists include pan-α-7 nicotinic acetylcholine receptor agonists or selective α-7 nicotinic acetylcholine receptor agonists.

[0117] 34. The combination therapy according to embodiment 31, wherein the one or more α-7 nicotinic acetylcholine receptor agonists include (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide, A-582941, acetylcholine, β-amyloid, neonicotinoid, AR-R17779, Bradanicline, choline, Encenicline, Epiboxidine, GTS-21, ICH-3, nicotine, PHA-543,613, PHA-709829, PNU-282,987, SSR-180,711, TC-1698, telotron, tropisetron, WAY-317,538, or any combination thereof.

[0118] 35. The combination therapy according to embodiment 31, wherein the one or more positive allosteric modulators of α-7 nicotinic acetylcholine receptor activity include A-867744, AVL-3288, galantamine, ivermectin, nelfecetan, NS-1738, PNU-120,596, or any combination thereof.

[0119] 36. The combination therapy according to any one of embodiments 30-35, wherein the 5-HT3 receptor inhibitory activity comprises 5-HT3 receptor antagonistic activity, 5-HT3 receptor inverse agonistic activity, or a combination thereof.

[0120] 37. The combination therapy according to embodiment 36, wherein the 5-HT3 receptor antagonistic activity is a complete 5-HT3 receptor antagonistic activity, a partial 5-HT3 receptor antagonistic activity, or a synergistic 5-HT3 receptor antagonistic activity.

[0121] 38. The combination therapy according to embodiment 36 or 37, wherein the 5-HT3 receptor antagonistic activity is a pan-antagonistic activity or a selective antagonistic activity of the 5-HT3 receptor.

[0122] 39. The combination therapy according to any one of embodiments 36-38, wherein the 5-HT3 receptor antagonistic activity comprises antidepressant 5-HT3 receptor antagonistic activity, antiemetic 5-HT3 receptor antagonistic activity, antimalarial 5-HT3 receptor antagonistic activity, antipsychotic 5-HT3 receptor antagonistic activity, prokinetic 5-HT3 receptor antagonistic activity, or any combination thereof.

[0123] 40. The combination therapy according to embodiment 30, wherein the 5-HT3 receptor reverse agonistic activity is a complete 5-HT3 receptor reverse agonistic activity, a partial 5-HT3 receptor reverse agonistic activity, or a synergistic 5-HT3 receptor reverse agonistic activity.

[0124] 41. The combination therapy according to embodiment 30 or 40, wherein the 5-HT3 receptor agonistic activity is a pan-inverse agonistic activity of the 5-HT3 receptor or a selective inverse agonistic activity of the 5-HT3 receptor.

[0125] 42. The combination therapy according to any one of embodiments 30-41, wherein the one or more 5-HT3 receptor activators comprises one or more 5-HT3 receptor agonists.

[0126] 43. The combination therapy according to embodiment 42, wherein the 5-HT3 receptor agonist is a full 5-HT3 receptor agonist, a partial 5-HT3 receptor agonist, a co-agonist of 5-HT3 receptors, or a super-agonist of 5-HT3 receptors.

[0127] 44. The combination therapy according to embodiment 42 or 43, wherein the 5-HT3 receptor agonist is a pan-5-HT3 receptor agonist or a selective 5-HT3 receptor agonist.

[0128] 45. The combination therapy according to any one of embodiments 42-44, wherein the one or more 5-HT3 receptor agonists have α-7 nicotinic acetylcholine receptor agonist activity.

[0129] 46. ​​The combination therapy according to any one of embodiments 42-45, wherein the one or more 5-HT3 receptor agonists are alcohols having 5-HT3 receptor agonist activity, m-chlorophenyl biguanide (1-(3-chlorophenyl biguanide)), ibog base, phenyl biguanide, piperazine having 5-HT3 receptor agonist activity, RS-56812 (N-(1-azabicyclo[2.2.2]octane-3-yl)-2-(1-methylindol-3-yl)-2-oxoacetamide), serotonin, SR-57227 (1-(6-chloropyridin-2-yl)piperidine-4-amine), SR-57227A (4-amino-1-(6-chloro-2-pyridyl)piperidine hydrochloride), tryptamine having 5-HT3 receptor agonist activity, varenicline, volatile gases having 5-HT3 receptor agonist activity, and YM-31636. (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole).

[0130] 47. The combination therapy according to embodiment 46, wherein the alcohol having 5-HT3 receptor agonist activity includes butanol, ethanol, or trichloroethanol.

[0131] 48. The combination therapy according to embodiment 46, wherein the piperazine having 5-HT3 receptor agonist activity includes benzylpiperazine, m-chlorophenylpiperazine, or quinoperazine.

[0132] 49. The combination therapy according to embodiment 46, wherein the tryptamine having 5-HT3 receptor agonist activity includes 2-methyl-5-hydroxytryptamine, α-methyltryptamine, 5-carboxamide tryptamine, N,N -Dimethyl-5-hydroxytryptamine (toad tannin) or 5-hydroxy- N,N,N - Trimethylchrome (bufotenidin).

[0133] 50. The combination therapy according to embodiment 46, wherein the volatile gas having 5-HT3 receptor agonist activity includes halothane, isoflurane, toluene, or trichloroethane.

[0134] 51. The combination therapy according to embodiment 30, wherein one or more α-7 nicotinic acetylcholine receptor activators are tropisetron, and one or more 5-HT3 receptor activators are varenicline.

[0135] 52. The combination therapy according to any one of embodiments 31-33 and 42-45, wherein the one or more α-7 nicotinic acetylcholine receptor agonists is tropisetron, and the one or more 5-HT3 receptor agonists is varenicline.

[0136] 53. The combination therapy according to any one of embodiments 30-52, wherein the one or more α-7 nicotinic acetylcholine receptor activators and the one or more 5-HT3 receptor activators are provided in a therapeutically effective amount.

[0137] 54. The combination therapy according to any one of embodiments 31-52, wherein the one or more α-7 nicotinic acetylcholine receptor agonists, the one or more α-7 nicotinic acetylcholine receptor activity positive allosteric modulators and / or the one or more 5-HT3 receptor agonists are provided in a therapeutically effective amount.

[0138] 55. The combination therapy according to any one of embodiments 30-54, wherein the combination therapy comprises administering a first composition and a second composition, the first composition comprising one or more α-7 nicotinic acetylcholine receptor activators, and the second composition comprising one or more 5-HT3 receptor activators.

[0139] 56. The combination therapy according to any one of embodiments 30-54, wherein the combination therapy comprises administering a single composition comprising one or more α-7 nicotinic acetylcholine receptor activators and one or more 5-HT3 receptor activators.

[0140] 57. The combination therapy according to any one of embodiments 31-54, wherein the combination therapy comprises administering a first composition and a second composition, the first composition comprising one or more α-7 nicotinic acetylcholine receptor agonists and / or one or more α-7 nicotinic acetylcholine receptor positive allosteric modulators, and the second composition comprising one or more 5-HT3 receptor agonists.

[0141] 58. The combination therapy according to any one of embodiments 31-54, wherein the combination therapy comprises administering a single composition comprising one or more α-7 nicotinic acetylcholine receptor agonists and / or one or more positive allosteric modulators of α-7 nicotinic acetylcholine receptor activity and one or more 5-HT3 receptor agonists.

[0142] 59. The method according to any one of embodiments 1-29 or the combination therapy according to any one of embodiments 30-58, wherein the schizophrenic disorder is schizophrenia, schizophrenia-like disorder, schizoaffective disorder or schizotypal personality disorder.

[0143] 60. The method or combination therapy according to implementation plan 59, wherein the schizophrenia is disintegrative schizophrenia, teratogenic schizophrenia, paranoid schizophrenia, undifferentiated schizophrenia, or residual schizophrenia.

[0144] 61. The method or combination therapy according to embodiment 59, wherein the schizophrenia is at very high risk (UHR) or in an at-risk mental state (ARMS) for psychosis, first-episode psychosis, long-term treatment-responsive schizophrenia, treatment-tolerant schizophrenia, or cognitively impaired schizophrenia.

[0145] 62. A method for treating schizophrenic disorder, the method comprising, substantially consisting of, or consisting of administering a combination therapy comprising, substantially consisting of, or consisting of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron.

[0146] 63. A method for treating schizophrenia, the method comprising, substantially consisting of, or consisting of administering a combination therapy comprising, substantially consisting of, or consisting of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron.

[0147] 64. A method for treating treatment-resistant schizophrenia, the method comprising, substantially consisting of, or consisting of administering a combination therapy comprising, substantially consisting of, or consisting of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron.

[0148] 65. A method for treating cognitively impaired schizophrenia, the method comprising, substantially consisting of, or consisting of administering a combination therapy comprising, substantially consisting of, or consisting of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron.

[0149] 66. A combination therapy comprising, substantially consisting of, or consisting of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron, for use in the treatment of schizophrenic disorders.

[0150] 67. A combination therapy comprising, substantially consisting of, or consisting of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron, for use in the treatment of schizophrenia.

[0151] 68. A combination therapy comprising, substantially consisting of, or consisting of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron, for use in the treatment of treatment-resistant schizophrenia.

[0152] 69. A combination therapy comprising, substantially consisting of, or consisting of a therapeutically effective amount of varenicline and a therapeutically effective amount of tropisetron, for use in the treatment of cognitive impairment schizophrenia. Example

[0153] The following non-limiting embodiments are provided for illustrative purposes only to help to provide a more complete understanding of the representative embodiments now contemplated. These embodiments should not be construed as limiting any of the embodiments described in this specification, including those relating to the active agents, combination therapies, or methods or uses disclosed herein for the treatment of schizophrenic disorders.

[0154] Example 1 In Vivo Potency Study This embodiment demonstrates the effectiveness of a combination therapy comprising one or more α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators for use in the treatment of schizophrenic disorders.

[0155] Tropisetron is an activator of the α-7 nicotinic acetylcholine receptor with 5-HT3 receptor inhibitory activity. As an effective antiemetic, tropisetron is primarily used to treat patients with chemotherapy-induced or postoperative nausea and vomiting. Because α-7 nicotinic acetylcholine receptors are located in many cognitively important brain regions (including the hippocampus and frontal cortex), the α-7 nicotinic acetylcholine receptor activity of tropisetron could potentially help modulate brain activity. While some procognitive effects of tropisetron have been observed in patients with schizophrenia, its availability for treating cognitive impairment is not feasible. First, tropisetron is a peripheral, dose-responsive active ingredient, as it is almost entirely absorbed from the gastrointestinal tract. Second, due to the off-target gastrointestinal side effects caused by tropisetron's 5-HT3 receptor inhibitory activity, including reduced intestinal transit and constipation, tropisetron is not suitable for long-term use. Without being bound by any theoretical limitations, the addition of varenicline to counteract peripheral side effects by stimulating 5-HT3 in the GI tract significantly improves the tolerability of tropisetron. Furthermore, varenicline itself possesses α-7 nicotinic acetylcholine receptor activity, which can significantly enhance the therapeutic effect of tropisetron. Therefore, the combined administration of these two compounds will positively impact cognition while minimizing unwanted serotonin-induced gastrointestinal side effects.

[0156] Normal male lister-hooded rats will be used to study latent inhibition in a lever-pressure response reward study based on conditioned inhibition. Animals will initially undergo a two-week treatment and acclimatization period, followed by mild food restriction and initial training in the lever-pressure response. After 10 days of lever training, animals will be tested using a latent inhibition assay. This will be conducted over four consecutive days as follows: Day 1 will include a pre-exposure (PE) or control non-PE phase; Day 2 will include conditioning the animals using a foot-shock conditioning protocol (0.3 mA, 1-second exposure); Day 3 will include baseline re-establishment; and Day 4 will include the testing phase.

[0157] A potential inhibitory effect induced by amphetamine will then be studied. A preclinical potential inhibitory assay will be performed as described in U.S. Provisional Patent Application Serial No. 62 / 820,490, filed March 19, 2019, entitled “Method and Uses of Diagnosing and Recommending Treatment for a Psychotic Disorder” (which is incorporated herein by reference in its entirety), except that the assay will be modified for the animal evaluation discussed herein. In this study, control (NPE) animals will be compared with animals pre-exposed to a foot stimulation conditioned reflex factor (cue) followed by a medium or amphetamine treatment (n=8 per group, 4 groups). This study will confirm the amphetamine dose required to induce the optimal potential inhibitory effect for subsequent testing in combination with novel compounds.

[0158] Following the potential inhibition study induced by amphetamine, a dose-response study using either an α-7 nicotinic acetylcholine receptor activator or a 5-HT3 receptor agonist with 5-HT3 receptor inhibitory activity will be conducted. This 12-week study will test the ability of a single agent to attenuate amphetamine-induced defects in potential inhibition. Based on current pharmacokinetic and clinical data, each active agent will be evaluated at three doses and compared with a mediator control. Each active agent test group will be divided into four treatment groups (n=12) as follows: 1) The α-7 nicotinic acetylcholine receptor activator treatment group with 5-HT3 receptor inhibitory activity includes placebo / placebo animals; placebo / tropisetron dose 1 animals; placebo / tropisetron dose 2 animals; placebo / tropisetron dose 3 animals; and 2) The 5-HT3 receptor agonist treatment group includes placebo / placebo animals; placebo / varenicline dose 1 animals; placebo / varenicline dose 2 animals; placebo / varenicline dose 3 animals.

[0159] Following the dose-response study, a combination therapy study will be conducted using the optimal therapeutic doses of an α-7 nicotinic acetylcholine receptor activator and a 5-HT3 receptor agonist, as determined in the dose-response study. This 6-week study will demonstrate the efficacy of combination therapy using an α-7 nicotinic acetylcholine receptor activator and a 5-HT3 receptor agonist compared to either activator alone. Each treatment group (n=12) will be tested in animals treated with amphetamine at a single dose and compared with an amphetamine plus a vehicle treatment group (n=12), as follows: 1) Alpha-7 nicotinic acetylcholine receptor activator with 5-HT3 receptor inhibitory activity alone treatment group including animals treated with a single optimal therapeutic dose of tropisetron; 2) 5-HT3 receptor agonist alone treatment group including animals treated with a single optimal therapeutic dose of varenicline; 3) Combination therapy treatment group including animals treated with a single optimal therapeutic dose of both tropisetron and varenicline; and 4) Control group including animals treated with amphetamine and a vehicle treatment.

[0160] Example 2 In Vivo Potency Study This embodiment illustrates the efficacy of a combination therapy comprising one or more α-7 nicotinic acetylcholine receptor activators with 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators for use in the treatment of schizophrenic disorders.

[0161] C57BL / 6 mice will be used to study the potential inhibition (LI) conditioned emotional response cessation in a drinking model in mice, as described below, for example, by Bay-Richter et al. 多巴胺增强的潜伏抑制 多巴胺受体缺陷小鼠中D1而非D2受体亚型的性别特异性:对抗精神病药物作用的影响 D-苯丙胺 , Int. J. Neuropsychopharmacol. 12(3): 403-414 (2009); Bay-Richter et al., 以及抗精神病药物对缺乏多巴胺D2受体的小鼠潜伏抑制的影响 氟哌啶醇和氯氮平对潜伏抑制的增强作用在多巴胺D2受体(Drd-2)缺陷小鼠中减弱:抗精神病药物是否通过Drd-2和非Drd-2机制影响学习忽略无关刺激? ​ , Neuropsychopharmacology 38(8): 1512-1520 (2013); O'Callaghan et al., ​ ​ ​ ​, J. Psychopharmacol. 28(10): 973-977 (2014), each of which is incorporated herein by reference in its entirety. Animals will initially undergo a week of treatment and adaptation, during which mice will be restricted to water for 23 hours and have free access to water for one hour each day. From day 1 to day 6, animals will undergo lick training, during which mice will have access to water for 15 minutes in a room and the number of times each animal licks water will be recorded. On day 7 (pre-exposure), mice will be placed in a test room where access to water is withdrawn. One group will receive 20 presentations of a 5-second 85 dB monotone with a 15-second stimulus interval [which, according to previous experiments, produces reduced LI in the control group] (pre-exposure group, PE); the control group of non-pre-exposure (NPE) mice will be placed in a test room where access to water is withdrawn for the same duration but will not receive monotone pre-exposure. On day 8 (conditioned reflex), mice will be placed in a test room where access to water is withdrawn. Two minutes later, two single-tone foot stimulation pairings will be presented. The single tone will last for 5 seconds, followed by a 1-second 0.38 mA foot stimulation and a 2.5-minute interval between tests. After the second stimulation presentation, the mice will remain in the test chamber for 2.5 minutes. On days 16–17 (re-baseline), mice will be placed in the test chamber for 15 minutes with free access to water to re-establish stable licking. Mice that do not complete more than 300 licks will not proceed to the test phase. On day 18 (test), mice will be placed in the test chamber with free access to water. The number of licks per animal will be recorded, as will the time taken to complete 80–90 licks (A) and 90–100 licks (B). After 90 licks, a 5-second 85 dB single tone will be presented until the animal reaches 100 licks or 600 seconds have elapsed. The inhibition ratio (SR) will be calculated using the formula A / (A+B), yielding a scale of 0 to 0.5. A low SR indicates increased inhibition of drinking; a high SR indicates decreased inhibition of drinking. In the PE group, LI was observed to have a higher SR compared to the NPE group.

[0162] In a series of experiments, the cognitive-enhancing doses of tropisetron and varenicline will be established in mice using a standard latent inhibition test for attention (as described above). Animals will be divided into eight groups of 15 animals each (120 mice in total), and two series of experiments will be conducted with 60 animals per experiment. In the first series, the effect of tropisetron on latent inhibition will be assessed at three different doses (Table 1). In the second series, the effect of varenicline on latent inhibition will be assessed at three different doses (Table 2). The results of these experiments will establish the cognitive-enhancing doses of tropisetron and varenicline that enhance low levels of latent inhibition. These results will also allow for the identification of suboptimal doses of tropisetron and / or varenicline. For safety purposes, intestinal motility will also be assessed.

[0163]

[0164]

[0165] In the third series of experiments, the combination of tropisetron and varenicline treatments that enhance the cognitive-promoting effects in latent inhibition will be determined. Animals will be divided into eight groups of 15 animals each (120 mice in total), and two series of experiments will be conducted in 60 animals each using the 18-day latent inhibition regimen described above. In these two series, the effects of tropisetron alone, varenicline alone, and the combination of tropisetron and varenicline treatments on latent inhibition will be evaluated (Table 3). The results of these experiments will determine that the combination of tropisetron and varenicline enhances the cognitive-promoting effects in latent inhibition compared to either drug alone. For safety purposes, intestinal motility will also be evaluated.

[0166]

[0167] In the fourth series of experiments, the reversal of D-amphetamine-induced potential inhibition disruption by combination therapy with tropisetron and varenicline will be evaluated. Animals will be divided into ten groups of 15 animals each (150 mice in total), and two series of experiments will be conducted on 72 animals each using the 18-day potential inhibition regimen described above. In these two series, the effects of tropisetron alone, varenicline alone, and the combination of tropisetron and varenicline on potential inhibition in the presence of D-amphetamine will be evaluated (Table 4). The results of these experiments will determine that the combination of tropisetron and varenicline reverses the disruption of D-amphetamine-induced potential inhibition. For safety purposes, intestinal motility will also be evaluated.

[0168]

[0169] In the fifth series of experiments, the optimal dose of MK801 to produce anomalously sustained latent inhibition will be evaluated. Animals will be divided into eight groups of 15 animals each (120 mice in total), and the latent inhibition protocol described above will be used, except that four single-tone stimulations will be administered to induce low LI (which will then be reversed and enhanced by MK801). The effect of MK801 on latent inhibition will be evaluated at two different doses in the presence of clozapine (Table 5). The results of Experiment 5 will establish the optimal dose of MK801 to produce anomalously sustained latent inhibition before proceeding to Experiment 6.

[0170]

[0171] In the sixth series of experiments, the ability of the combination of tropisetron and varenicline to reverse the abnormally persistent potential inhibitory effect induced by MK801 will be evaluated. Animals will be divided into ten groups of 15 animals each (150 mice in total) and will be treated using the potential inhibitory regimen described above, administered four times with a single-tone stimulation as in Experiment 5 to induce low LI. The effects of tropisetron alone, varenicline alone, and the combination of tropisetron and varenicline on potential inhibition in the presence of MK801 will be evaluated (Table 6). The results of this study will determine whether the combination of tropisetron and varenicline reverses the abnormally persistent potential inhibitory effect induced by MK801. For safety purposes, intestinal motility will also be evaluated.

[0172]

[0173] Finally, it should be understood that although aspects of this specification are emphasized by reference to specific embodiments, those skilled in the art will readily understand that these described embodiments are merely illustrative of the principles of the subject matter disclosed herein. The specific embodiments are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Therefore, it should be understood that the disclosed subject matter is by no means limited to the specific compounds, combinations, articles, devices, methods, schemes, and / or reagents described herein, unless expressly stated otherwise. Furthermore, those skilled in the art will recognize that certain changes, modifications, arrangements, alterations, additions, subtractions, and sub-combinations thereof can be made based on the teachings herein without departing from the spirit of this specification. Therefore, the scope of the invention is not limited by this detailed description. Furthermore, it is intended that the appended claims and the claims introduced herein be construed as encompassing all such changes, modifications, arrangements, alterations, additions, subtractions, and sub-combinations thereof, as they are within their true spirit and scope.

[0174] This document describes certain embodiments of the invention, including the mode known to the inventors as the best mode for carrying out the invention. Of course, variations of these described embodiments will become apparent to those skilled in the art after reading the foregoing description. The inventors contemplate that those skilled in the art may employ such variations as appropriate, and the inventors envision that the invention may be practiced in other ways than specifically described herein. Therefore, the invention includes all modifications and equivalents of the subject matter set forth in the appended claims that are permitted by applicable law. Furthermore, any combination of the above embodiments in all possible variations is covered by the invention unless otherwise stated herein or otherwise clearly contradicted by the context.

[0175] The grouping of alternative embodiments, elements, or steps of the invention should not be construed as limiting. Each member of a group may be mentioned and claimed individually or in combination with other members of a group disclosed herein. It is contemplated that one or more members of a group may be included in or removed from the group for convenience and / or patentability reasons. When any such inclusion or removal occurs, this specification is deemed to contain the group as a modification, thereby achieving the written description of all Markush groups as used in the appended claims.

[0176] Non-substantial modifications to the claimed subject matter that are now known or later designed, as seen by a person skilled in the art, are explicitly contemplated as equivalents within the scope of the claims. Therefore, obvious substitutions now known or later known to a person skilled in the art are defined as being within the scope of the defined elements.

[0177] Unless otherwise specified, all figures used in this specification and claims to represent features, items, quantities, parameters, properties, terms, etc., shall be understood to be modified in all cases by the term “about.” As used herein, the term “about” means that such a qualified feature, item, quantity, parameter, property, or term comprises a range of plus or minus 10% above or below the value of the specified feature, item, quantity, parameter, property, or term. Therefore, unless indicated to the contrary, the numerical parameters shown in this specification and the appended claims are variable approximations. For example, when determining the mass of a given analyte, mass spectrometry equipment may differ slightly, and in the context of the mass of an ion or the mass-to-charge ratio of an ion, the term “about” means + / - 0.50 atomic mass units. At least, and not in an attempt to limit the application of the doctrine of equivalence to the scope of the claims, each numerical indication shall be interpreted at least based on the number of significant figures reported and by the application of common approximation techniques.

[0178] Although the numerical ranges and values ​​listed for the broad scope of the invention are approximate, the numerical ranges and values ​​shown in the specific embodiments are reported as precisely as possible. However, any numerical range or value inherently contains a certain degree of error, which is necessarily caused by the standard deviation found in their respective experimental measurements. The listing of numerical ranges of values ​​herein is merely intended as a shorthand method for individually referring to each individual value falling within the range. Unless otherwise specified herein, the individual values ​​of the numerical ranges are incorporated into this specification as if they were described separately herein.

[0179] The terms "may" or "can" used with respect to embodiments or aspects of embodiments also carry the alternative meanings of "may not" or "cannot." Thus, if this specification discloses that an embodiment or aspect of an embodiment can or can be included as part of the subject matter of the invention, then a negative limitation or exclusion is also expressly indicated, meaning that the embodiment or aspect of an embodiment may not or can not be included as part of the subject matter of the invention. Similarly, the term "optionally" used with respect to embodiments or aspects of embodiments means that such an embodiment or aspect of an embodiment may or may not be included as part of the subject matter of the invention. Whether such a negative limitation or exclusion is used will be based on whether the negative limitation or exclusion is enumerated in the claimed subject matter.

[0180] The terms “a,” “an,” “the,” and similar references used in the context of describing the invention (especially in the context of the following claims) should be interpreted as covering both the singular and plural forms, unless otherwise specified herein or the context clearly contradicts them. Furthermore, sequence indicators used to identify elements—such as, for example, “first,” “second,” “third,” etc.—are used to distinguish these elements and do not indicate or imply a required or limited number of these elements, nor do they indicate a particular location or order of these elements, unless specifically stated otherwise. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all embodiments provided herein, or exemplary language (e.g., “such as”), is intended only to better illustrate the invention and not to limit the scope of the otherwise claimed invention. The language in this specification should not be construed as indicating that any unclaimed element is essential to carrying out the invention.

[0181] When used in the claims, whether submitted or added according to amendments, the open transitional term “comprising,” its variations such as, for example, “comprise” and “comprises,” and its equivalent open transitional phrases such as “including,” “containing,” and “having,” covers all expressly stated elements, limitations, steps, integers, and / or features, alone or in combination with unstated subject matter; named elements, limitations, steps, integers, and / or features are necessary, but other unnamed elements, limitations, steps, integers, and / or features may be added and still form a construction within the scope of the claims. Specific embodiments disclosed herein may also use the closed transitional phrase “consisting of” or “consisting essentially of” (or its variations such as, for example, “consist of,” “consists of,” “consisting essentially of,” and “consists essentially of”) in place of “comprising” or as a modification of “comprising” in the claims. When used in the claims, whether filed or added according to amendments, the closed transition phrase "consisting of..." excludes any elements, limitations, steps, integers, or features not expressly stated in the claims. The closed transition phrase "substantially constitutes..." limits the scope of the claims to the expressly stated elements, limitations, steps, integers, and / or features, and any other elements, limitations, steps, integers, and / or features that do not substantially affect the essential and novel characteristics of the claimed subject matter. Therefore, the open transition phrase "comprising" is defined as encompassing all specifically stated elements, limitations, steps, and / or features, as well as any optional, additional, unstated elements, limitations, steps, and / or features. The closed transition phrase "consisting of..." is defined as including only those elements, limitations, steps, integers, and / or features specifically stated in the claims, while the closed transition phrase "substantially constitutes..." is defined as including only those elements, limitations, steps, integers, and / or features specifically stated in the claims, and those elements, limitations, steps, integers, and / or features that do not substantially affect the essential and novel characteristics of the claimed subject matter. Therefore, the open transition phrase “contains” (and its equivalent open transition phrases) includes, within its meaning, the subject matter for which protection is claimed, as a limitation, the subject matter specifically described by the closed transition phrase “consisting of” or “substantially composed of”.Therefore, the use of the phrase “comprising” in the embodiments described or claimed herein in a clear and unambiguous manner provides a description, implementation, and support for the phrases “substantially constitutes” and “consisting of”.

[0182] All patents, patent publications, and other references cited and identified in this specification are individually and expressly incorporated herein by reference in their entirety for purposes of description and disclosure, such as compositions and methodologies that may be used in connection with the invention as described in such publications. These publications are provided separately with their disclosures prior to the filing date of this application. In this respect, nothing is or should be construed as an admission by virtue of a prior invention or for any other reason prior to such disclosure. All statements regarding dates or the content of these documents are based on information available to the applicant and do not constitute any admission of the accuracy of the dates or content of these documents.

[0183] Finally, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention as solely defined by the claims. Therefore, the invention is not limited to the precise contents shown and described.

Claims

1. The use of one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators in the preparation of a medicament for treating schizophrenic disorders, wherein when said medicament is used, a combination therapy comprising one or more α-7 nicotinic acetylcholine receptor activators having 5-HT3 receptor inhibitory activity and one or more 5-HT3 receptor activators is administered.

2. The use according to claim 1, wherein the one or more α-7 nicotinic acetylcholine receptor activators comprise one or more α-7 nicotinic acetylcholine receptor agonists, one or more α-7 nicotinic acetylcholine receptor positive allosteric modulators, or combinations thereof.

3. The use according to claim 2, wherein the one or more α-7 nicotinic acetylcholine receptor agonists include α-7 nicotinic acetylcholine receptor full agonists, α-7 nicotinic acetylcholine receptor partial agonists, or α-7 nicotinic acetylcholine receptor co-agonists.

4. The use according to claim 2 or 3, wherein the one or more α-7 nicotinic acetylcholine receptor agonists include pan-α-7 nicotinic acetylcholine receptor agonists or selective α-7 nicotinic acetylcholine receptor agonists.

5. The use according to claim 2, wherein the one or more α-7 nicotinic acetylcholine receptor agonists comprise (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide, A-582941, acetylcholine, β-amyloid, neonicotinoid, AR-R17779, Bradanicline, choline, Encenicline, Epiboxidine, GTS-21, ICH-3, nicotine, PHA-543,613, PHA-709829, PNU-282,987, SSR-180,711, TC-1698, telotron, tropisetron, WAY-317,538, or any combination thereof.

6. The use according to claim 2, wherein the one or more positive allosteric modulators of α-7 nicotinic acetylcholine receptor activity include A-867744, AVL-3288, galantamine, ivermectin, nelfecetan, NS-1738, PNU-120,596 or any combination thereof.

7. The use according to any one of claims 1-6, wherein the 5-HT3 receptor inhibitory activity comprises 5-HT3 receptor antagonistic activity, 5-HT3 receptor inverse agonistic activity, or a combination thereof.

8. The use according to claim 7, wherein the 5-HT3 receptor antagonistic activity is a complete 5-HT3 receptor antagonistic activity, a partial 5-HT3 receptor antagonistic activity, or a synergistic 5-HT3 receptor antagonistic activity.

9. The use according to claim 7 or 8, wherein the 5-HT3 receptor antagonistic activity is a pan-antagonistic activity or a selective antagonistic activity of the 5-HT3 receptor.

10. The use according to any one of claims 7-9, wherein the 5-HT3 receptor antagonistic activity comprises antidepressant 5-HT3 receptor antagonistic activity, antiemetic 5-HT3 receptor antagonistic activity, antimalarial 5-HT3 receptor antagonistic activity, antipsychotic 5-HT3 receptor antagonistic activity, prokinetic 5-HT3 receptor antagonistic activity, or any combination thereof.

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