Compositions and methods for treating neuropsychiatric disorders

Abstract

To provide compositions for treating brain and / or behavioral health disorders and their associated symptoms.SOLUTION: A therapeutic combination for the treatment of a brain and / or behavioral health disorder or symptom thereof comprises an effective amount of a first agent that targets the adrenergic system and an effective amount of a second agent that targets the renin angiotensin aldosterone system.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the following U.S. provisional applications: 63 / 011,932 filed April 17, 2020, and 63 / 111,156 filed November 9, 2020, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background Brain and behavioral health disorders are the leading cause of disability worldwide. Brain and behavioral health disorders include all major disorders within the specialties of neurology, psychiatry, and psychology. Anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis are 10 cardinal symptoms caused by brain and behavioral health disorders. Individually, these symptoms are the disabling features of these disorders and cause loss of function.

[0003] All 10 cardinal symptoms of brain and behavioral health disorders are difficult to treat because most, if not all, people with brain and behavioral disorders suffer from multiple causes of these symptoms. In clinical practice, the causes of symptoms can be neurological, psychiatric, and / or psychological factors. However, patients seek independent treatment for their symptoms. Anxiety, depression, and psychosis are typically treated by psychiatrists. Headaches, pain, and cognitive difficulties are often treated by neurologists. Irritability, apathy, insomnia, and fatigue are often treated by psychologists or primary care physicians. Anxiety is an example of a symptom that is disabling, difficult to treat, and multifactorial. Somatic anxiety (hypersensitivity to stimuli) is an example of a neurological cause of anxiety and is often associated with migraines. Excessive shyness is an example of a psychological cause of anxiety and is often associated with social phobia. Excessive worry is an example of a psychiatric cause of anxiety and is often associated with generalized anxiety disorder or obsessive-compulsive disorder.

[0004] Despite the fact that the 10 fundamental disabling symptoms of brain and behavioral health disorders (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis) are multifactorial in clinical practice, current FDA-approved treatments typically target each component of the disorder. For example, selective serotonin reuptake inhibitors ("SSRIs"), the first-line treatment for anxiety disorders, were specifically designed to target the serotonergic mechanisms of anxiety. The effectiveness of these medications alone has proven limited. Cognitive behavioral therapy is specifically designed to address the psychological components of anxiety. Patients who receive both medication and cognitive behavioral therapy are predicted to have better outcomes than patients who receive treatments targeting either one alone. Even with cognitive behavioral therapy and medication, treatment success remains limited, suggesting that the neurological underpinnings of anxiety remain untreated in the majority of patients seeking anxiety relief.

[0005] Current treatments are not designed to address the multifactorial nature associated with the most disabling symptoms of brain and behavioral health disorders. Thus, new treatments that address brain and behavioral health disorders and their symptoms are urgently needed. Summary of the Invention

[0006] overview As described below, the present invention features compositions and methods for treating brain and / or behavioral health disorders and their associated symptoms.

[0007] The present invention provides novel combination therapies that include an agent that targets the adrenergic system (e.g., anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil) and an agent that targets the renin-angiotensin-aldosterone system (RAAS) (e.g., candesartan, telmisartan). While such agents are individually approved by the FDA for the treatment of cardiovascular disease, they have not previously been combined or used to treat brain and / or behavioral health disorders. In one embodiment, the present invention provides a combination therapy featuring a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan. Without being bound by theory, the combinations provided herein induce a novel, synergistic balancing effect on total cerebral blood flow through modulation of stress-induced hormones in both the body and the brain.

[0008] These combinations are effective in treating brain and / or behavioral health disorders and their associated symptoms, including, but not limited to, anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis.

[0009] In one aspect, the invention features a therapeutic combination for treating brain and / or behavioral health disorders or symptoms thereof, the combination including an effective amount of a first agent that targets the adrenergic system and an effective amount of a second agent that targets the renin-angiotensin-aldosterone system.

[0010] In another aspect, the invention features a therapeutic combination for treating an anxiety disorder, comprising effective amounts of a first and a second agent, wherein the first agent is verapamil and the second agent is telmisartan, and the first and second agents are provided in sustained release formulations.

[0011] In another aspect, the invention features a method for treating a subject having a brain or behavioral health disorder, the method including administering to the subject a combination therapy including a first agent that targets the adrenergic system and a second agent that targets the renin-angiotensin-aldosterone system, thereby treating the brain or behavioral health disorder.

[0012] In another aspect, the invention features a method for treating an anxiety disorder, comprising administering to a subject a therapeutic combination containing effective amounts of a first and a second agent. The first agent is verapamil and the second agent is telmisartan. The first and second agents are provided in sustained-release formulations.

[0013] In another aspect, the invention features a method for increasing a subject's progress along Maslow's hierarchy of needs. The method includes administering to the subject therapeutically effective amounts of a first agent and a second agent. The first agent modifies metabolism and / or blood flow associated with the adrenergic system, and the second agent modifies metabolism and / or blood flow associated with the brain renin-angiotensin-aldosterone system, thereby increasing the subject's progress along Maslow's hierarchy of needs. The increased progress is relative to a reference.

[0014] In one aspect, the present invention features a pharmaceutical composition comprising effective amounts of a first and a second agent and a pharmaceutically acceptable excipient. The first agent is selected from one or more of anipamil, davapamil, falipamil, gallopamil, tiapamil, and verapamil, and the second agent is selected from one or more of telmisartan and candesartan. In one embodiment, the pharmaceutical composition further comprises magnesium oxide.

[0015] In another aspect, the invention features a therapeutic combination kit containing a therapeutic combination containing a first and a second agent. The first agent is selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and the second agent is selected from one or more of telmisartan and candesartan. The kit also contains instructions for using the combination to treat brain and / or behavioral health disorders or symptoms thereof.

[0016] In any of the above aspects, the first agent has calcium channel blocking activity and the second agent has angiotensin II receptor blocking activity. In any of the above aspects, the first agent is selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil. In any of the above aspects, the first agent is verapamil. In any of the above aspects, the second agent is telmisartan or candesartan. In any of the above aspects, the second agent is telmisartan. In any of the above aspects, the second agent is candesartan.

[0017] In any of the foregoing aspects, the combination is labeled for treating a brain and / or behavioral health disorder. In any of the foregoing aspects, the combination is labeled for treating a symptom of a brain and / or behavioral health disorder selected from one or more of anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain, and psychosis.

[0018] In any of the above aspects, the effective amount of the first agent is about 120 mg to about 720 mg, and the effective amount of the second agent is about 45 mg to about 180 mg. In any of the above aspects, the effective amount of the first agent is about 288 mg, and the effective amount of the second agent is about 96 mg.

[0019] In any of the above aspects, the mass ratio of the first agent to the second agent is about 2:1 to about 5:1. In any of the above aspects, the mass ratio of the first agent to the second agent is about 2:1. In any of the above aspects, the amount of the first agent is about 1 to about 4 times the amount of the second agent. In any of the above aspects, the amount of the first agent is about 1 to about 4 times the amount of the second agent.

[0020] In any of the above aspects, the agents are formulated together or separately.

[0021] In any of the preceding aspects, the combination therapy is administered once daily. In any of the preceding aspects, the combination therapy is administered twice daily.

[0022] In any of the above aspects, the agents are administered simultaneously. In any of the above aspects, the agents are administered sequentially.

[0023] In any of the above aspects, administration is associated with the modification of cerebral metabolism or cerebral blood flow.In some embodiments, cerebral blood flow is modified in one or more of the telencephalon, diencephalon and mesencephalon.In some embodiments, the modification of regional cerebral blood flow is associated with the establishment of hemodynamic balance in certain brain regions.

[0024] In any of the foregoing aspects, the method improves a primary outcome selected from one or more of cognitive functioning, life satisfaction, the subject's sense of meaning and purpose, the subject's sense of emotional or instrumental support, friendships, and life satisfaction.

[0025] In any of the preceding aspects, the therapeutic combination further comprises magnesium oxide. In any of the preceding aspects, the therapeutic combination comprises at least about 150 mg of magnesium oxide. In any of the preceding aspects, the method further comprises administering magnesium oxide to the subject. In embodiments, at least about 150 mg of magnesium oxide is administered to the subject daily.

[0026] Other features and advantages of aspects of the present disclosure will become apparent from the detailed description and claims.

[0027] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which this invention belongs. The following references provide those skilled in the art with general definitions of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds., Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms are assigned the following meanings unless otherwise specified:

[0028] "Agent" means any small molecule chemical compound. Exemplary agents include, but are not limited to, anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil.

[0029] "Ameliorate" means to reduce, suppress, attenuate, diminish, arrest, or stabilize the onset or progression of a disease.

[0030] "Alteration" refers to a positive or negative change. As used herein, alteration includes a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% change. The change can be an improvement or a decrease. The amount measured can be the amount of regional cerebral blood flow. The amount measured can be a quantitative assessment of the magnitude of a disease symptom (e.g., anxiety, apathy, cognitive difficulty, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), or psychosis). In some embodiments, the alteration is a reduction in symptoms associated with a brain and / or behavioral health disorder. In some embodiments, the alteration is an improvement in function associated with treating a brain and / or behavioral health disorder.

[0031] "Ameliorate" means to reduce, suppress, attenuate, diminish, arrest, or stabilize the onset or progression of a disease.

[0032] By "analog" is meant a molecule that is not identical to the molecule of interest, but has similar functional and / or structural characteristics. In some embodiments, the analog is an agent that targets the adrenergic system. In some embodiments, the analog is an agent that targets the renin-angiotensin-aldosterone system.

[0033] "Anipamil" has the following structure: TIFF2025128289000001.tif49128 or a pharmaceutically acceptable salt thereof. In some embodiments, anipamil has calcium channel blocking activity.

[0034] "Candesartan" has the following structure: TIFF2025128289000002.tif34128 or a pharmaceutically acceptable salt thereof. In some embodiments, candesartan has angiotensin II receptor blocking activity.

[0035] " Brain metabolism " refers to the rate of metabolism in the brain or its region. Brain metabolism can be measured using any of a variety of methods available to practitioners, including, but not limited to, X-ray computed tomography (CT), positron emission tomography (PET), near-infrared spectroscopy (NIRS), magnetic resonance imaging (MRI), and the methods provided herein. In some embodiments, the improvement of metabolism in a brain region is associated with an increase in blood flow to that region. Cerebral blood flow can be measured using any of a variety of methods available to practitioners, including, but not limited to, single-photon emission computed tomography (SPECT), positron emission tomography (PET), functional MRI (fMRI), arterial spin labeling (ASL) MRI, transcranial Doppler ultrasound imaging (i.e., ultrasound), phase contrast MRI, and near-infrared spectroscopy (NIRS).

[0036] In this disclosure, "comprises," "comprising," "containing," "having," and the like can have the meaning assigned to them in U.S. patent law and can mean "includes," "including," and the like; "consisting essentially of" or "consisting essentially of" likewise have the meaning assigned to them in U.S. patent law, and the term is open-ended, allowing for the existence of things other than what is described, but excluding prior art aspects, so long as the basic or novel characteristics of what is described are not altered by the existence of things other than what is described. An aspect designated as "comprising" a particular component or element is also contemplated in some aspects as "consisting of" or "consisting essentially of" the particular component or element.

[0037] By "consisting essentially of," it is meant that the composition contains only the recited components, along with normal impurities present in commercially available materials, and any other additives present at levels that do not affect the practice of the present disclosure, for example, less than 5% by weight, or less than 1% by weight, or even less than 0.5% by weight.

[0038] By "reduction" is meant a negative modification.

[0039] "Devapamil" has the following structure: TIFF2025128289000003.tif37128 or a pharmaceutically acceptable salt thereof. In one embodiment, devapamil has calcium channel blocking activity.

[0040] "Disease" refers to any condition or disorder that impairs or interferes with the normal function of cells, tissues, or organs. In embodiments, the disease or disorder is a neuropsychiatric disorder, examples of which include brain and / or behavioral health disorders and their symptoms. Non-limiting examples of brain and behavioral health disorders include affective disorders, anxiety disorders, neurodegenerative disorders, neurodevelopmental disorders, psychotic disorders, personality disorders, migraine disorders, and somatoform disorders. Examples of affective disorders include bipolar disorder, cyclothymia, depression, dysphoria, generalized anxiety disorder, major depressive disorder, obsessive-compulsive disorder, postpartum depression, posttraumatic stress disorder (PTSD), phobias, and seasonal affective disorder. Examples of anxiety disorders include panic disorder, social anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder, and specific phobia. Examples of neurodegenerative disorders include Alzheimer's disease and Parkinson's disease. Examples of neurodevelopmental disorders include autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and learning disabilities. Examples of psychotic disorders include schizophrenia, schizoaffective disorder, and major depression with psychosis. Examples of personality disorders include paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, antisocial personality disorder, emotionally unstable personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and obsessive-compulsive personality disorder. Examples of migraine-related disorders include migraine with aura, migraine without aura, headache-free migraine, and basilar artery migraine. Examples of somatoform disorders include somatization disorder, hypochondriasis, conversion disorder, body dysmorphic disorder, and chronic pain. The symptom associated with the disease is selected from one or more of the "10 basic symptoms" associated with brain and behavioral health disorders, including but not limited to anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain) and psychosis.In some embodiments, the disease is associated with altered regional cerebral blood flow compared with reference (e.g., blood flow present in healthy control brain).The disease can be the brain or behavioral health disorder defined above.

[0041] "Effective amount" refers to the amount of an agent sufficient to treat a disease or disorder. In one embodiment, an effective amount of the combination therapy described herein is sufficient to treat brain and / or behavioral disorders or their symptoms, or to improve primary outcomes (e.g., cognitive function, life satisfaction, a subject's sense of meaning and purpose, a subject's sense of emotional or instrumental support, peer relationships, and life satisfaction).

[0042] "Falipamil" has the following structure: TIFF2025128289000004.tif40128 or a pharmaceutically acceptable salt thereof. In some embodiments, falipamil has calcium channel blocking activity.

[0043] "Gallopamil" has the following structure: TIFF2025128289000005.tif45128 or a pharmaceutically acceptable salt thereof. In some embodiments, gallopamil has calcium channel blocking activity.

[0044] "Hemodynamic equilibrium" refers to a state of balance in terms of relative blood flow rates between corresponding regions of the brain. In embodiments, hemodynamic equilibrium is associated with approximately equal relative blood flow rates and / or metabolic activity between regions.

[0045] "Enhance" means a positive alteration.

[0046] As used herein, "obtaining" in "obtaining an agent" includes synthesizing, purchasing, or otherwise obtaining the agent.

[0047] As used herein, the terms "prevent," "preventing," "prevention," "prophylactic treatment," and the like refer to reducing the probability of developing a disorder or condition in a subject who does not have the disorder or condition but is at risk of or susceptible to developing the disorder or condition.

[0048] By "decrease" is meant a negative alteration.

[0049] "Subject" means a mammal. Non-limiting examples of mammals include a human, or a non-human mammal, such as a cow, horse, dog, sheep, cat, or rodent.

[0050] "Reference" refers to a standard or control condition. In one embodiment, the effect of an agent on a cell is compared with the effect of the agent on a control cell. In an embodiment, the reference is a healthy subject. In an embodiment, the clinical characteristics of a subject with a brain or behavioral disorder are compared with reference clinical characteristics present in a healthy subject. A healthy subject is a subject that does not have the disorder or condition of interest. In some embodiments, the reference is an untreated patient, or a subject before treatment, or a subject before modification during treatment.

[0051] "Brain region" refers to a portion of the brain. In embodiments, the portion of the brain includes one or more of the telencephalon, diencephalon, and mesencephalon. The region may include all three of the telencephalon, diencephalon, and mesencephalon.

[0052] "Co-administration" means administration at the same time.

[0053] "Sequential administration" means administration at different times. For example, one or more agents are sequentially administered when the administration interval is several minutes, several hours, or several days. For example, in sequential administration, a first agent is administered 15 minutes, 30 minutes, 45 minutes, or 60 minutes before the administration of one or more additional agents. In another example of sequential administration, a first agent is administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, or 24 hours before the administration of a second agent. In yet another example of sequential administration, a first agent is administered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days before the administration of a second agent.

[0054] "Telmisartan" has the following structure: TIFF2025128289000006.tif28128 or a pharmaceutically acceptable salt thereof. In some embodiments, telmisartan has angiotensin II receptor blocking activity.

[0055] "Therapeutic agent" refers to a substance that has the potential to affect the function of an organism. Such compounds are, for example, naturally occurring, semi-synthetic, or synthetic agents. For example, the agent is a drug that targets a specific function of an organism. Therapeutic agents can reduce, suppress, attenuate, reduce, stop, or stabilize the onset or progression of a disease, disorder, or condition. Therapeutic agents are associated with altering regional cerebral blood flow in a subject. Non-limiting examples of therapeutic agents described herein include anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil, as well as derivatives, analogs, and functional equivalents of such agents. In embodiments, a therapeutic combination is characterized by a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan.

[0056] "Effective amount" refers to the amount of agent required to reduce or ameliorate the symptoms of a disease compared to a reference. For the therapeutic treatment of a disease, the effective amount of an active compound (e.g., anipamil, candesartan, davapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil) used to implement the present invention varies depending on the mode of administration, the age, weight, and general health of the subject. Ultimately, the attending physician or veterinarian will determine the appropriate amount and administration schedule. Such an amount is referred to as an "effective" amount. The symptoms are selected from one or more of the "10 cardinal symptoms" associated with brain and behavioral health disorders: anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis. In some embodiments, the therapeutically effective amount is the amount of agent or combination of agents required.

[0057] It is understood that ranges provided herein are shorthand for all of the values ​​within that range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0058] "Tiapamil" has the following structure: TIFF2025128289000007.tif41128 or a pharmaceutically acceptable salt thereof. In some embodiments, tiapamil has calcium channel blocking activity.

[0059] As used herein, the terms "treat," "treating," "treatment," and the like refer to the reduction or amelioration of a disease and / or its associated symptoms. It will be understood that, although not excluded, treatment of a disorder or condition does not require that the disorder, condition, or its associated symptoms be completely eliminated.

[0060] "Verapamil" has the following structure: TIFF2025128289000008.tif20128 or a pharmaceutically acceptable salt thereof. In some embodiments, verapamil has calcium channel blocking activity.

[0061] As used herein, unless specifically stated or clear from the context, the term "or" is understood to be inclusive. Unless specifically stated or clear from the context, the terms "a," "an," and "the" are understood to be singular or plural.

[0062] Unless specifically stated or clear from the context, as used herein, the term "about" is understood to mean within the normal tolerance range in the art, for example, within 2 standard deviations of the mean value. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein are modified by the term about.

[0063] The recitation of a list of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment of a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0064] Any composition or method provided herein can be combined with one or more of any of the other compositions and methods provided herein. Throughout this application, where various mechanisms of action, hypotheses, or theories are described, these are not intended to be limiting. [The present invention 1001] A therapeutic combination for the treatment of brain and / or behavioral health disorders or symptoms thereof, comprising an effective amount of a first agent that targets the adrenergic system and an effective amount of a second agent that targets the renin-angiotensin-aldosterone system. [The present invention 1002] 1001. A therapeutic combination of the present invention wherein a first agent has calcium channel blocking activity and a second agent has angiotensin II receptor blocking activity. [The present invention 1003] The therapeutic combination of invention 1001 or invention 1002, wherein the first agent is selected from the group consisting of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil. [The present invention 1004] The therapeutic combination of any of claims 1001 to 1003, wherein the second agent is telmisartan or candesartan. [The present invention 1005] The therapeutic combination of any of claims 1001-1004, labeled for the treatment of a brain and / or behavioral health disorder. [The present invention 1006] The therapeutic combination of any of claims 1001-1005, labeled for the treatment of a symptom of a brain and / or behavioral health disorder selected from the group consisting of anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain, and psychosis. [The present invention 1007] The therapeutic combination of any of claims 1001 to 1006, wherein the first agent is verapamil. [The present invention 1008] The therapeutic combination of any of claims 1001 to 1007, wherein the second agent is telmisartan. [The present invention 1009] A therapeutic combination for the treatment of anxiety disorders comprising effective amounts of a first and a second agent, wherein the first agent is verapamil and the second agent is telmisartan, and wherein the first and second agents are provided in sustained release formulations. [The present invention 1010] The therapeutic combination of any of claims 1001 to 1009, wherein the effective amount of the first agent is about 120 mg to about 720 mg, and the effective amount of the second agent is about 45 mg to about 180 mg. [The present invention 1011] The therapeutic combination of any of claims 1001 to 1010, wherein the effective amount of the first agent is about 288 mg and the effective amount of the second agent is about 96 mg. [The present invention 1012] The therapeutic combination of any of claims 1001 to 1011, wherein the mass ratio of the first agent to the second agent is from about 2:1 to about 5:1. [The present invention 1013] The therapeutic combination of any of claims 1001 to 1012, wherein the mass ratio of the first agent to the second agent is about 2:1. [The present invention 1014] The therapeutic combination of any of claims 1001 to 1013, wherein the amount of the first agent is about 1 to about 4 times the amount of the second agent. [The present invention 1015] The therapeutic combination of any of claims 1001 to 1014, wherein the amount of the first agent is about twice the amount of the second agent. [The present invention 1016] The therapeutic combination of any of claims 1001 to 1015, wherein said agents are formulated together or separately. [The present invention 1017] administering to the subject a combination therapy comprising a first agent that targets the adrenergic system and a second agent that targets the renin-angiotensin-aldosterone system, thereby treating a brain or behavioral health disorder. 10. A method for treating a subject having a brain or behavioral health disorder, comprising: [The present invention 1018] The method of claim 1017, wherein the first agent has calcium channel blocking activity and the second agent has angiotensin II receptor blocking activity. [The present invention 1019] The method of claim 1017 or claim 1018, wherein the first agent is selected from the group consisting of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil. [The present invention 1020] The method of any of claims 1017 to 1019, wherein the second agent is telmisartan or candesartan. [The present invention 1021] The method of any one of claims 1017 to 1020, wherein the first agent is verapamil. [The present invention 1022] The method of any of claims 1017 to 1021, wherein the second agent is telmisartan. [The present invention 1023] A method for treating an anxiety disorder, comprising administering to a subject a therapeutic combination comprising effective amounts of a first and a second agent, wherein the first agent is verapamil and the second agent is telmisartan, and the first and second agents are provided in sustained release formulations. [The present invention 1024] The method of any one of inventions 1017 to 1023, wherein the effective amount of the first agent is about 120 mg to about 720 mg, and the effective amount of the second agent is about 45 mg to about 180 mg. [The present invention 1025] The method of any one of claims 1017 to 1024, wherein the effective amount of the first agent is about 288 mg and the effective amount of the second agent is about 96 mg. [The present invention 1026] 1026. The method of any one of claims 1017 to 1025, wherein the mass ratio of the first agent to the second agent is about 2:1 to about 5:1. [The present invention 1027] 1027. The method of any one of claims 1017 to 1026, wherein the mass ratio of the first agent to the second agent is about 2:1. [The present invention 1028] 1028. The method of any one of claims 1017 to 1027, wherein the amount of the first agent is about 1 to about 4 times the amount of the second agent. [The present invention 1029] 1029. The method of any one of claims 1017 to 1028, wherein the amount of the first agent is about 1 to about 4 times the amount of the second agent. [The present invention 1030] 1029. The method of any of claims 1017 to 1029, wherein the combination therapy is administered once daily. [The present invention 1031] The method of any of claims 1017 to 1030, wherein the combination therapy is administered twice daily. [The present invention 1032] 1032. The method of any one of claims 1017 to 1031, wherein said agents are administered simultaneously. [The present invention 1033] 1033. The method of any one of claims 1017 to 1032, wherein the agents are administered sequentially. [The present invention 1034] 1034. The method of any of claims 1017 to 1033, wherein said administering is associated with an alteration in cerebral metabolism or cerebral blood flow. [This invention 1035] The method of claim 1034, wherein cerebral blood flow is altered in one or more of the telencephalon, diencephalon, and mesencephalon. [The present invention 1036] The method of claim 1034 or claim 1035, wherein the modification of regional cerebral blood flow is associated with the establishment of hemodynamic equilibrium in a region of the brain. [This invention 1037] Any of the methods of claims 1017 to 1036, wherein the primary outcome selected from the group consisting of cognitive function, life satisfaction, the subject's sense of meaning and purpose, the subject's sense of emotional or instrumental support, peer relationships, and life satisfaction is improved. [The present invention 1038] administering to a subject therapeutically effective amounts of a first agent and a second agent, wherein the first agent modifies metabolism and / or blood flow associated with the adrenergic system and the second agent modifies metabolism and / or blood flow associated with the brain renin-angiotensin-aldosterone system; thereby increasing the subject's progress along Maslow's hierarchy of needs, wherein the increased progress is relative to a reference. [This invention 1039] The method of claim 1038, wherein the first agent is selected from the group consisting of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil. [The present invention 1040] The method of claim 1038 or claim 1039, wherein the second agent is selected from one or more of telmisartan and candesartan. [The present invention 1041] The method of any one of claims 1038 to 1040, wherein the first agent is verapamil. [The present invention 1042] The method of any of claims 1038 to 1041, wherein the second agent is telmisartan. [This invention 1043] The therapeutic combination of any one of claims 1001 to 1016, further comprising magnesium oxide. [This invention 1044] A therapeutic combination of the present invention 1043 comprising at least about 150 mg of magnesium oxide. [This invention 1045] The method of any one of claims 1017 to 1042, further comprising the step of administering magnesium oxide to a subject. [The present invention 1046] The method of claim 1045, wherein at least about 150 mg of magnesium oxide is administered to the subject daily. [This invention 1047] A pharmaceutical composition comprising effective amounts of a first and a second agent and a pharmaceutically acceptable excipient, wherein the first agent is selected from the group consisting of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and the second agent is selected from one or more of telmisartan and candesartan. [This invention 1048] The pharmaceutical composition of claim 1047, wherein the first and second agents are provided in a sustained release formulation. [This invention 1049] The pharmaceutical composition of invention 1047 or invention 1048, further comprising magnesium oxide. [The present invention 1050] a therapeutic combination comprising a first and a second agent, wherein the first agent is selected from the group consisting of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and the second agent is selected from one or more of telmisartan and candesartan; Instructions for use of the combination for the treatment of brain and / or behavioral health disorders or symptoms thereof. Includes a kit. [Brief explanation of the drawings]

[0065] [Figure 1A]1A-1J are graphs illustrating the difference in symptoms in 76 patients before and after combination therapy with telmisartan and verapamil. The combination therapy included either 120 mg or 180 mg of verapamil twice daily along with either 40 mg or 80 mg of telmisartan twice daily. FIG. 1A is a graph showing lower overall symptomatology in patients with versus without combination therapy. [Figure 1B] Figures 1A-1J are graphs illustrating the difference in symptoms in 76 patients before and after combination therapy with telmisartan and verapamil. The combination therapy included either 120 mg or 180 mg of verapamil twice daily along with either 40 mg or 80 mg of telmisartan twice daily. Figure 1B is a graph showing lower self-reported anxiety in patients with versus without combination therapy. [Figure 1C] Figures 1A-1J are graphs illustrating the difference in symptoms in 76 patients before and after combination therapy with telmisartan and verapamil. The combination therapy included either 40 mg or 80 mg of telmisartan twice daily, along with either 120 mg or 180 mg of verapamil twice daily. Figure 1C is a graph showing lower self-reported depression in patients with versus without combination therapy. [Figure 1D] Figures 1A-1J are graphs illustrating the difference in symptoms in 76 patients before and after combination therapy with telmisartan and verapamil. The combination therapy included either 120 mg or 180 mg of verapamil twice daily along with either 40 mg or 80 mg of telmisartan twice daily. Figure 1D is a graph showing lower self-reported irritability in patients with versus without combination therapy. [Figure 1E]Figures 1A-1J are graphs illustrating the difference in symptoms in 76 patients before and after combination therapy with telmisartan and verapamil. The combination therapy included either 120 mg or 180 mg of verapamil twice daily along with either 40 mg or 80 mg of telmisartan twice daily. Figure 1E is a graph showing lower self-reported apathy in patients with versus without combination therapy. [Figure 1F] Figures 1A-1J are graphs illustrating the difference in symptoms in 76 patients before and after combination therapy with telmisartan and verapamil. The combination therapy included either 120 mg or 180 mg of verapamil twice daily along with either 40 mg or 80 mg of telmisartan twice daily. Figure 1F is a graph showing lower self-reported fatigue in patients with versus without combination therapy. [Figure 1G] Figures 1A-1J are graphs illustrating the difference in symptoms in 76 patients before and after combination therapy with telmisartan and verapamil. The combination therapy included either 120 mg or 180 mg of verapamil twice daily along with either 40 mg or 80 mg of telmisartan twice daily. Figure 1G is a graph showing lower self-reported bodily pain in patients with versus without combination therapy. [Figure 1H] Figures 1A-1J are graphs illustrating the difference in symptoms in 76 patients before and after combination therapy with telmisartan and verapamil. The combination therapy included either 120 mg or 180 mg of verapamil twice daily along with either 40 mg or 80 mg of telmisartan twice daily. Figure 1H is a graph showing milder self-reported insomnia severity in patients with versus without combination therapy. [Figure 1I]Figures 1A-1J are graphs illustrating the difference in symptoms in 76 patients before and after combination therapy with telmisartan and verapamil. The combination therapy included either 120 mg or 180 mg of verapamil twice daily along with either 40 mg or 80 mg of telmisartan twice daily. Figure 1I is a graph showing the reduction in self-reported headaches in patients with versus without combination therapy. [Figure 1J] Figures 1A-1J are graphs illustrating the difference in symptoms in 76 patients before and after combination therapy with telmisartan and verapamil. The combination therapy included either 40 mg or 80 mg of telmisartan twice daily, along with either 120 mg or 180 mg of verapamil twice daily. Figure 1J is a graph showing the reduction in self-reported cognitive difficulties in patients with versus without combination therapy. [Figure 2A] Figures 2A-2F illustrate the differences in standardized psychosocial outcomes between patients with versus without combination therapy. Figure 2A is a graph showing higher overall life satisfaction in patients with versus without combination therapy. [Figure 2B] Figures 2A-2F illustrate the differences in standardized psychosocial outcomes between patients with versus without combination therapy. Figure 2B is a graph showing the greater significance and purpose in patients with versus without combination therapy. [Figure 2C] Figures 2A-2F illustrate the differences in standardized psychosocial outcomes between patients with versus without combination therapy. Figure 2C is a graph showing higher emotional support in patients with versus without combination therapy treatment. [Figure 2D] Figures 2A-2F illustrate the differences in standardized psychosocial outcomes between patients with versus without combination therapy. Figure 2D is a graph showing higher instrumental support in patients with versus without combination therapy treatment. [Figure 2E]Figures 2A-2F illustrate the differences in standardized psychosocial outcomes between patients with versus without combination therapy. Figure 2E is a graph showing higher peer relationships in patients with versus without combination therapy treatment. [Figure 2F] Figures 2A-2F illustrate the differences in standardized psychosocial outcomes between patients with versus without combination therapy. Figure 2F is a graph showing lower feelings of loneliness in patients with versus without combination therapy. [Figure 3A] Figures 3A and 3B illustrate the difference in outcomes between patients receiving combination treatment and patients receiving telmisartan alone: ​​Figure 3A is a graph showing the difference in life satisfaction, as measured by the NIH Toolbox, between patients receiving combination therapy and patients receiving telmisartan alone. [Figure 3B] Figures 3A and 3B illustrate the difference in outcomes between patients receiving combination treatment and patients receiving telmisartan alone. Figure 3B is a graph showing the difference in anger (hostility) measured by the NIH Toolbox between patients receiving combination therapy and patients receiving telmisartan alone. [Figure 4A] Figures 4A and 4B illustrate the difference in outcomes between patients receiving combination treatment and those receiving verapamil alone. Figure 4A is a graph showing the difference in self-efficacy, as measured by the NIH Toolbox, between patients receiving combination therapy and those receiving telmisartan alone. [Figure 4B] Figures 4A and 4B illustrate the difference in outcomes between patients receiving combination treatment and patients receiving verapamil alone. Figure 4B is a graph showing the difference in anger (aggression) measured by the NIH Toolbox between patients receiving combination therapy and patients receiving verapamil alone. [Figure 5]Figure 5 is a diagram illustrating the proposed mechanism of action of a composition containing verapamil and telmisartan. The diagram illustrates the developing brain before the telencephalon, diencephalon, and midbrain develop into cortical, subcortical, and brainstem structures. [Figure 6] FIG. 6 is a schematic diagram illustrating how a composition containing verapamil and telmisartan is hypothesized to enable the gradual balancing of cerebral blood flow as a patient makes psychosocial progress along Maslow's hierarchy of needs. [Figure 7] 7 shows the bidirectional change in Weber lateralization in patients who started, stopped, or changed the administration of a composition containing verapamil and telmisartan. Of those who had a change in treatment, 83% (15 / 18) had a change in Weber lateralization. Of those who did not have a change in treatment, 20% (1 / 5) reported a change in Weber lateralization. This difference in change in Weber lateralization between patients who had a change in treatment and those who did not was statistically significant (p=0.006). [Figure 8] Figure 8 is a plot showing the bidirectional effect of a composition containing verapamil and telmisartan on patients' blood pressure. For 29 patients with hypertension, the pre- to post-increase within the normal range was statistically significant (p=0.0001). For 11 patients with hypotension, the pre- to post-increase within the normal range was statistically significant (p=0.001). For 29 patients with normal blood pressure, the pre- to post-increase was not statistically significant (p=0.553). [Figure 9]Figure 9 shows a proposed method by which a composition of the present invention, comprising a first agent selected from one or more of anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, can affect the dynamic changes caused by psychological stress. Depending on the structural composition of the brain, particularly in situations of brain energy demand / supply mismatch, psychological stress may cause the body to respond through dynamic adaptations of adrenaline and angiotensin. These adaptations cause changes in brain functional connectivity, which selectively modulate metabolic demand in vulnerable brain regions. In the presence of the composition, the dynamic changes in functional connectivity caused by psychological stress are regulated, resulting in a reduction in neuropsychiatric symptoms. DETAILED DESCRIPTION OF THE INVENTION

[0066] Detailed Description The present invention features compositions and methods that are useful for the treatment of brain and / or behavioral health disorders and their associated symptoms.

[0067] The present invention is based, at least in part, on the discovery that combination therapy including an agent targeting the adrenergic system (e.g., verapamil or other compounds with calcium channel blocking activity) and an agent targeting the renin-angiotensin-aldosterone system (RAAS) (e.g., telmisartan) effectively treated brain and / or behavioral health disorders and significantly reduced associated symptoms. Given this surprising discovery, those skilled in the art will understand that any agent targeting the RAAS (e.g., telmisartan, candesartan) can be combined with any agent targeting the adrenergic system (e.g., anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil) for the treatment of brain and / or behavioral health disorders and their associated symptoms. Specifically, as reported in detail below, verapamil and telmisartan were effective in reducing or eliminating anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, and chronic pain. Importantly, verapamil and telmisartan not only reduced such symptoms in treated subjects, but also produced a number of positive changes in such subjects, including an increase in overall life satisfaction and meaning and purpose. Without being bound by theory, it is likely that the combination of verapamil and telmisartan simultaneously targeted stress-induced hormones in both the body and the brain that collectively affect brain function.

[0068] Brain and behavioral disorders Collectively, brain and behavioral disorders are the leading cause of disability worldwide. In clinical practice, patients have multiple comorbid diagnoses, making it difficult for most patients, physicians, and families to achieve comprehensive recovery across the spectrum of so many different symptoms. Treating patients with multiple comorbidities requires separate, individual treatments for each disorder, which increases complexity, increases costs, and reduces the safety of care.

[0069] Brain and behavioral health disorders, at least in part because they have multiple components, pose significant psychosocial challenges that negatively impact patients' quality of life, yet current treatments are designed to treat only a single (e.g., neurological) component.

[0070] Brain and behavioral health disorders represent a clinically diverse group of disorders, yet abnormal functional connectivity represents a shared common pathological framework. Regardless of the disorder, two independent systems—the adrenergic system and the brain renin-angiotensin-aldosterone system—directly influence functional connectivity. In these disorders, abnormalities in one network tend to disrupt the function of related networks. For example, anxiety disorders and chronic pain can each be classified together as reactive disorders characterized by atypical connectivity between sensorimotor and salience networks. Indeed, successful symptom treatment for many brain and behavioral disorders has been shown to be associated with normalization of atypical patterns of regional cerebral blood flow.

[0071] Non-limiting examples of brain and behavioral health disorders include affective disorders, anxiety disorders, neurodegenerative disorders, neurodevelopmental disorders, psychotic disorders, personality disorders, migraine disorders, and somatosensory somatoform disorders. Examples of affective disorders include bipolar disorder, cyclothymic disorder, depression, dysphoria, generalized anxiety disorder, major depressive disorder, obsessive-compulsive disorder, postpartum depression, posttraumatic stress disorder (PTSD), phobias, and seasonal affective disorder. Examples of anxiety disorders include panic disorder, social anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder, and specific phobias. Examples of neurodegenerative disorders include Alzheimer's disease and Parkinson's disease. Examples of neurodevelopmental disorders include autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and learning disabilities. Examples of psychotic disorders include schizophrenia, schizoaffective disorder, and major depression with psychosis. Examples of personality disorders include paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, antisocial personality disorder, emotionally unstable personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and obsessive-compulsive personality disorder. Examples of somatosensory disorders include chronic pain, and migraine-related disorders include migraine with aura, migraine without aura, headache-free migraine, and basilar artery migraine. Examples of somatoform disorders include somatization disorder, hypochondriasis, conversion disorder, body dysmorphic disorder, and chronic pain. Disease-related symptoms are selected from one or more of the "10 basic symptoms" associated with brain and behavioral health disorders, including, but not limited to, anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis.Such symptoms may be measured using any of a variety of methods available to practitioners, non-limiting examples of which are presented in Brenes, "Anxiety, Depression, and Quality of Life in Primary Care Patients," Primary Care Companion J Clin Psychiatry, 9:437-443 (2007) and Julian, "Measures of Anxiety," Arthritis Care Res, 63:1-11 (2011).

[0072] Current treatments for the disorders listed above are not designed to address the functional connectivity abnormalities closely associated with the disorders. Selective serotonin reuptake inhibitors ("SSRIs") have limited effectiveness against anxiety. Even cognitive behavioral therapy and pharmacotherapy have limited success in treatment. Because SSRIs do not treat symptoms caused by common anxiety comorbidities such as ADHD, the disability caused by the comorbidity remains untreated in the majority of patients seeking anxiety relief. For patients with ADHD, stimulants are ineffective against and often exacerbate comorbid mood disorders. Because symptoms caused by psychiatric comorbidities are often the most disabling, these represent a significant treatment gap. Furthermore, current managed treatment options, specifically benzodiazepines, stimulants, and opiates, are dangerous due to the exacerbation of comorbid mood disorders, addiction, and fatal overdose.

[0073] Combination therapy Certain existing medications that affect the adrenergic system and the brain renin-angiotensin-aldosterone system, which have not previously been used in combination, can be combined to produce novel, synergistic changes in cerebral blood flow that lead to desirable clinical outcomes. Combination treatments of the present invention include, for example, administering to a subject a combination of two or more agents selected from previously FDA-approved cardiovascular medications. The present invention features combinations containing verapamil and telmisartan, combinations containing verapamil and candesartan, and candesartan and / or telmisartan combined with one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil.

[0074] Individually, agents are selected to target the renin-angiotensin-aldosterone system and the adrenergic system. Telmisartan and candesartan block angiotensin II receptors, and therefore, individually or in combination, balance the magnitude of the angiotensin response. Without wishing to be bound by theory, anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil affect norepinephrine output from the midbrain, and therefore, individually or in combination, balance the magnitude of the adrenergic response. Because both the adrenergic system and the brain RAAS interact to modulate functional connectivity, combinations of agents that independently target each system can produce synergistic effects and lead to novel therapeutic effects.

[0075] Presented herein is a novel treatment that alleviates the psychiatric, psychological, and neurological components of disorders manifested as one or more of the 10 basic neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis), regardless of the underlying diagnosis. Without being bound by theory, compositions and / or dosage forms of the present invention containing therapeutic combinations (e.g., verapamil and telmisartan, verapamil and candesartan, and candesartan and / or telmisartan combined with one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil) simultaneously target stress-induced hormones in different regions of the brain. The combination of agents described herein simultaneously targeting both adrenergic and brain RAAS, with a positive multi-way network effect, has not previously been attempted or studied.

[0076] Administration of compositions and dosage forms of the present invention to a subject containing a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, delivered simultaneously or sequentially as a combination treatment, is useful for treating brain and / or behavioral disorders and their associated symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis). Over time, the combination treatment results in positive psychosocial outcomes that correlate with significant improvements in overall quality of life. For example, the composition has been associated with achieving patient improvement along Maslow's hierarchy of needs, a comprehensive health care outcome that not only reflects overall symptoms but also reflects impacts on broad social determinants of health. In some embodiments, the therapeutic combinations described herein positively impact the well-being of treated subjects (e.g., improved cognitive function, improved life satisfaction, improved meaning and purpose, improved emotional support, improved instrumental support, improved peer relationships, improved life satisfaction).

[0077] Pharmacological effects Without being bound by theory, the pharmacological effects of a composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil and a second agent selected from one or more of candesartan and telmisartan are related to the physiology of the adrenergic system and the brain renin-angiotensin-aldosterone system (RAAS). When humans sense danger, these two independent bodily systems alter the intrinsic functional connectivity of the brain.

[0078] The adrenergic system, also known as the sympathetic / parasympathetic nervous system, influences functional connectivity through signaling by a neurotransmitter known as norepinephrine (also known as "adrenaline"). When norepinephrine is produced in the adrenal gland, it travels to the brain, where it binds to beta receptors. When beta receptors bind with norepinephrine, changes such as pupil dilation, decreased pain sensation, and increased alertness occur.

[0079] The brain renin-angiotensin-aldosterone system, also known as the brain RAAS system, influences functional connectivity through a neurotransmitter known as angiotensin. When angiotensin precursors are produced in the kidneys, they travel through the lungs to the brain, where they bind to angiotensin receptors. When brain angiotensin receptors bind to angiotensin, they alter the coupling between arterioles and astrocytes, a process known as neurovascular coupling, which causes local changes in cerebral blood flow.

[0080] Without being bound by a specific mechanism of action, when the adrenergic system and the brain RAAS system are activated, functional connectivity in the brain changes. This change in connectivity is an evolutionarily conserved stress response system that helps the brain adapt to metabolic demands. If chronically maintained, this can cause a state of functional connectivity imbalance that can be harmful. Several factors, including the built environment, social determinants of health, and individual differences, can promote chronic imbalance. These factors can be particularly problematic for patients with brain and / or behavioral health disorders. Without being bound by theory, a composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan can rebalance the functional connectivity changes associated with brain and / or behavioral health disorders.

[0081] Without wishing to be bound by theory, the combination treatment involves administering to a subject a composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan. Such a combination acts on a central functional network common to multiple neuropsychiatric disorders. Without wishing to be bound by theory, the unique combination of angiotensin II receptor blockade and simultaneous adrenergic blockade results in a rebalancing of cerebral blood flow distribution, particularly in the diencephalon, a brain region important for social and emotional awareness. In other words, by affecting the functional network involved in emotion (midbrain) while simultaneously affecting the functional network involved in cognition (telencephalon), the functional network involved in social cognition (diencephalon) is balanced. This hypothesis is based on the observation of significant social changes in patients receiving the combination therapy. For example, bidirectional changes in social and dressing behavior were observed in patients receiving the combination treatment. Specifically, introverted patients showed more extroversion during combined treatment, and extroverted patients showed more introversion during combined treatment. The results of the study described in the examples provided herein showed an improvement in social satisfaction in patients receiving combined treatment. The hypothesis that combined treatment produces a balancing effect on functional brain networks is further supported by the analysis of results from the Weber test, which was performed as part of a routine visit to measure sensorineural function, which is affected by lateralization of the brain's auditory functional network. Patients who began combined treatment in the clinic or who switched from monotherapy to combined treatment showed a shift in Weber test lateralization between visits. Shifts in Weber test lateralization do not occur with standard treatment. Shifts in Weber test lateralization do not occur when patients receive individual components of combined treatment. Notably, these shifts, like the changes in social outcomes, were bidirectional, so some patients shifted to the right and others shifted to the left.

[0082] Although not wishing to be bound by theory, the novel bidirectional outcomes associated with the composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan suggest that the combined treatment may play a modulatory role in the brain regions related to the auditory network and / or other functional brain networks.Since changes in auditory function have been correlated with clinical improvements in social function, the therapeutic combination described herein may affect not only auditory function, but also interoceptive / exteroceptive awareness and social communication skills that rely on auditory function. Indeed, the auditory cortex is directly involved in networks for emotional processing and communication (Disability and poor quality of life associated with comorbid anxiety disorders and physical conditions. Sareen J, Jacobi F, Cox BJ, Belik SL, Clara I, Stein MB. Arch Intern Med. 2006 Oct 23;166(19):2109-16. doi:10.1001 / archinte.166.19.2109).

[0083] The compositions of the present invention modulate adrenergic and angiotensin function A composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, comprises one component for adrenergic modulation and one component for brain RAAS.No drug has been designed that simultaneously targets both systems.This is a significant treatment gap, as both of these systems interact when patients with brain and / or behavioral disorders experience distressing, often untreatable symptoms.

[0084] Adrenergic and angiotensin systems affect different functional brain networks Without being bound by theory, the effect of a composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan depends in part on the relative density of adrenergic receptors and angiotensin receptors in each of the three phylogenetic levels of the brain.The midbrain is the oldest level of the brain, located at the base of the brain, just above the spinal cord.The telencephalon is the most recently evolved level of the brain, located at the top of the brain.Between these levels is the diencephalon.Without being bound by theory, each level of the brain contains a brain region rich in receptors that are involved in several networks that contribute to different neurological processes.

[0085] Because beta receptors (which bind to norepinephrine) are more densely located in the midbrain than in the telencephalon, the effects of norepinephrine are strongest in brain networks that rely on midbrain regions such as the brainstem. Because angiotensin receptors (which bind to angiotensin) are more densely located in the telencephalon than in the midbrain, the effects of angiotensin are strongest in brain networks that rely on telencephalic regions such as the prefrontal cortex. Because the midbrain network has extensive connections with bodily organs, clinically, modulation of the adrenergic system affects neuropsychiatric symptoms (e.g., insomnia, fatigue, apathy, pain, and anxiety). Because the telencephalic network has extensive connections with brain regions involved in sensory processing, modulation of the angiotensin system affects various neuropsychiatric symptoms (e.g., cognitive impairment, headache, and aura).

[0086] Each functional brain network spans various regions of the older and younger brain. Important functional brain networks involved in brain and / or behavioral health disorders include, among others, the default mode network, the salience network, the somatosensory network, the visual network, the auditory network, and the limbic network. Some of these brain networks rely heavily on younger brain regions. For example, the default mode network cooperates with regions located primarily in the telencephalon (the highest phylogenetic level). Meanwhile, the salience network cooperates with regions in the midbrain (the lowest phylogenetic level).

[0087] Table 1. Functional brain network regions organized by phylogenetic level TIFF2025128289000009.tif165163

[0088] The therapeutic combination of the present invention normalizes functional connectivity throughout the brain In one embodiment, a composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, achieves a multi-way network effect, as the balancing of lower brain networks influences the balancing of higher networks, and vice versa. The composition comprises at least two components for blocking two different stress-related systems (the adrenergic system and the brain RAAS). Each of these systems may play an important role in shifting brain functional connectivity as needed. Without being bound by theory, anipamil, devapamil, falipamil, gallopamil, tiapamil, verapamil, and combinations thereof interact with beta receptors in the midbrain (FIG. 5). Without being bound by theory, telmisartan and candesartan interact with angiotensin receptors in the telencephalon (FIG. 5).

[0089] As detailed in the Examples below, a composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, produced clinical effects suggesting modulation of functional connectivity throughout the brain. Due to the unique multi-way network effect achieved by this synergy, the clinical effects of the composition included not only normalization of emotional symptoms, but also social and cognitive symptoms. Without being bound by theory, because these functions arise from three different layers (the diencephalon, the midbrain, and the telencephalon), a composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan alters connectivity at all three levels. The multi-way network effect of the composition allows patients to make rapid psychosocial progress (Figure 6) and further improves whole-brain connectivity (Safety Needs Mediate Stressful Events Induced Mental Disorders. Zheng Z, Gu S, Lei Y, Lu S, Wang W, Li Y, Wang F. Neural Plast. 2016;2016:8058093. doi:10.1155 / 2016 / 8058093. Epub 2016 Sep 21). Without being bound by theory, overall symptom improvement attributable to all three phylogenetic levels does not occur when either agent is administered alone. Overall symptom improvement attributable to all three phylogenetic levels does not occur with known standard of care treatments.

[0090] Preventing brain and / or behavioral health and medical disorders The multi-way network effect of the composition described herein, comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, suggests that treatment with the composition may treat disorders that affect different parts of the brain at different times throughout life (e.g., panic disorder). Many neuropsychiatric disorders that are amenable to preventive treatment are characterized by imbalances in multiple functional brain networks, suggesting that these disorders are promising candidates for preventive treatment with the combination therapies described herein. For example, chronic pain disorders, which, if left untreated, become more refractory to treatment throughout life, are characterized by abnormalities in the visual network, salience network, and default mode network, which may be detectable before the onset of significant disability. Neurodevelopmental disorders, such as ADHD, autism spectrum disorder, and learning disabilities, which, if left untreated, become more refractory to treatment throughout life, are characterized by alterations in multiple networks. Psychotic disorders such as schizophrenia, which become more refractory to treatment throughout life if left untreated, are characterized by functional abnormalities in multiple brain networks.Anxiety disorders, which become more refractory to treatment throughout life if left untreated, exhibit multi-way network effects with some specific differences depending on the disorder.A composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, is a promising preventative treatment for these conditions because it can improve overall brain functional connectivity despite individual differences in network imbalances between disorders.Currently, there is no available treatment to prevent neuropsychiatric disorders, which will worsen throughout life if left untreated.No research has been conducted on the use of such compositions to prevent neuropsychiatric diseases or disability.

[0091] A composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, can be used to prevent the risk of neurodegenerative diseases that begin in middle age.The composition can cumulatively normalize cerebral metabolism, which may be dysregulated in preclinical neurodegenerative disease states.Different neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and frontotemporal lobar degeneration, are characterized by imbalances in different brain networks due to abnormal cerebral metabolism.Currently, there is no available treatment that can normalize cerebral metabolism in patients at risk of neurodegenerative diseases.The use of such a composition has not been studied for the prevention or treatment of neurodegenerative diseases.

[0092] A composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan can normalize brain connectivity throughout the brain, and therefore the composition can be used for certain indications beyond the boundaries of neuropsychiatry (i.e., cancer, autoimmunity, autonomic nervous system, among others). Because brain connectivity affects immune system health, dysregulation of functional connectivity can affect the risk of medical disorders. Specifically, medical disorders that manifest prominently around developmental windows (such as the age of 25, when the brain finishes myelination) are candidates for novel brain-based preventative treatments, including treatment with the composition.

[0093] Pharmaceutical Compositions The present disclosure provides a pharmaceutical composition comprising an effective amount of a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and an effective amount of a second agent selected from one or more of candesartan and telmisartan. Such combinations may be formulated together or separately and administered simultaneously or sequentially. When administered in combination, the first and second agents are useful for treating brain and / or behavioral health disorders (e.g., panic disorder). In some embodiments, the combination therapy is administered to treat one or more of the 10 basic neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis).

[0094] In some embodiments, the compositions of the present invention contain a first agent selected from one or more of anipamil, davapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan for use in combination treatment. In some embodiments, the first agent is verapamil, and the second agent is telmisartan and / or candesartan. In some cases, the first agent is selected to affect beta receptors in the midbrain, and the second agent is selected to interact with angiotensin receptors in the telencephalon. The agents may be selected such that the first agent affects the adrenergic system and the second agent affects the brain renin-angiotensin-aldosterone system. In some embodiments, the compositions are associated with modulation of both adrenergic and angiotensin function.

[0095] In certain embodiments, the compositions of the invention can prevent, inhibit, hinder, or reduce by at least 10%, 25%, 50%, 75%, or even 100% one or more of anxiety, migraine, depression, cognitive difficulties, anger, apathy, fatigue, physical pain, psychosis, and insomnia manifested in individuals suffering from disorders having one or more psychiatric, psychological, and / or neurological components.

[0096] Pharmaceutically acceptable salts of anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil, or combinations thereof, are contemplated herein for the treatment of one or more of the ten cardinal neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, somatic pain, and psychosis). The term "pharmaceutically acceptable salt" also refers to a salt prepared by contacting an agent (e.g., anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, or verapamil) with a pharmaceutically acceptable inorganic or organic base when the agent has an acidic functional group (e.g., a carboxylic acid functional group). Suitable bases include hydroxides of alkali metals, such as sodium, potassium, and lithium; hydroxides of alkaline earth metals, such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-(2-hydroxy-lower alkylamine), bis-(2-hydroxy-lower alkylamine), or tri- N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines such as N,N-dimethyl-N-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, etc., but are not limited thereto.The term "pharmaceutically acceptable salt" also refers to a salt prepared by contacting an agent (e.g., anipamil, candesartan, debapamil, falipamil, gallopamil, telmisartan, tiapamil, or verapamil) with a pharmaceutically acceptable inorganic or organic acid when the agent has a basic functional group (e.g., an amino functional group). Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0097] The compositions of the present invention may contain a salt of magnesium, optionally magnesium oxide (MgO).

[0098] Pharmaceutical treatments For therapeutic use, a composition comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan can be administered systemically. Preferred administration routes include, for example, oral administration or subcutaneous, intravenous, intraperitoneal, intramuscular, or intradermal injection, which provides a continuous, sustained level of drug in the patient. Treatment of human patients or other animals is carried out using a therapeutically effective amount of the therapeutic agent identified herein (e.g., for the treatment of panic disorder) in a physiologically acceptable carrier. Anipamil, devapamil, falipamil, gallopamil, tiapamil, and / or verapamil can be formulated in combination with candesartan and / or telmisartan using a pharmaceutically acceptable buffer, such as saline. Suitable carriers and their formulations are described, for example, in Remington's Pharmaceutical Sciences by E.W. Martin. The amount of the therapeutic agent administered varies depending on the mode of administration, the patient's age and weight, and the clinical symptoms of brain and / or behavioral health disorders. In some embodiments, the clinical symptoms are the 10 basic neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis). Generally, the amount is within the range used for other agents used in the treatment of brain and / or behavioral health disorders. In some embodiments, a composition comprising verapamil and telmisartan, verapamil and candesartan, or candesartan and / or telmisartan combined with one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil is administered at a dosage effective to reduce one or more of the 10 basic neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis).The efficacy of administration can be determined by methods known to those skilled in the art or using any assay (e.g., behavioral assessment, neuropsychological test, etc.) that measures one or more of the 10 neuropsychiatric symptoms. For example, in some embodiments of the present disclosure, the efficacy of treatment can be measured by patient self-report of symptoms and / or via the NIH Toolbox test. Efficacy can also be measured in disease-specific standard outcome measures, such as measures that assess not only symptoms and function, but also overall life satisfaction or quality of life.

[0099] Formulation of Pharmaceutical Compositions A composition containing a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, may be administered to a subject for the treatment of brain and / or behavioral health disorders (e.g., panic disorder) by any suitable means that results in a concentration of the therapeutic agent, in combination with other components, effective to ameliorate, reduce, or stabilize one or more of the ten cardinal neuropsychiatric symptoms. In some embodiments, the combination treats one or more of the ten cardinal neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis). The composition may contain a magnesium salt, optionally magnesium oxide (MgO). The composition may be contained in any suitable amount within any suitable carrier material, generally present in an amount of 1 to 95% by weight of the total weight of the composition. Composition can be provided in a dosage form suitable for oral administration.In some embodiments, composition can be provided in a dosage form suitable for parenteral administration (for example, subcutaneous, intravenous, intramuscular or intraperitoneal).Pharmaceutical composition can be formulated according to conventional pharmaceutical practice (for example, see Remington: The Science and Practice of Pharmacy (20th ed.), ed.AR Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York).

[0100] The dosage for humans can be determined by extrapolating from the amounts of anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, verapamil, or a combination thereof used in mice. Dosages may be determined based on the dosages for effective treatment of the disorders for which each agent is indicated in humans. The dosage (optionally, daily dosage) of one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, individually or collectively, can be about 120 mg to about 480 mg, about 250 mg to about 360 mg, about 200 mg to about 500 mg, about 250 mg to about 350 mg, about 120 mg to about 720 mg, or about 288 mg. The dosage of the second agent can be about 80 mg to about 400 mg, about 45 mg to about 180 mg, about 80 mg to about 320 mg, about 45 mg to about 150 mg, about 90 mg to about 200 mg, or about 96 mg. In some embodiments, the dosage of the second agent is greater than 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, or 150 mg. The dosages of the first agent or a component thereof and the second agent or a component thereof may be contained in one or more dosage forms.

[0101] In some embodiments, the daily dosage of either the first or second agent is administered more than once daily, for example, in some embodiments, a daily dose (e.g., 80 mg) is delivered in two 40 mg doses per day.

[0102] The first agent and the second agent may be administered to a subject (optionally as a single dosage form) in a dosage ratio (mass:mass) of the first agent (e.g., anipamil, devapamil, falipamil, gallopamil, tiapamil, verapamil, or a combination thereof) to the second agent (e.g., candesartan, telmisartan, or a combination thereof) of about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1. In some embodiments, the dosage ratio of the first agent (e.g., anipamil, devapamil, falipamil, gallopamil, tiapamil, verapamil, or a combination thereof) to the second agent (e.g., candesartan, telmisartan, or a combination thereof) is less than about 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1. The first agent (e.g., anipamil, devapamil, falipamil, gallopamil, tiapamil, verapamil, or a combination thereof) may be administered to a subject at a daily dosage that is about two or three times the daily dosage of the second agent (e.g., candesartan, telmisartan, or a combination thereof) administered to the subject. In some embodiments, the dosage of a first agent (e.g., anipamil, devapamil, falipamil, gallopamil, tiapamil, verapamil, or a combination thereof), a second agent (e.g., candesartan, telmisartan, or a combination thereof), or a component thereof (e.g., anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, verapamil, or a combination thereof) is determined by an individual. Individually or in combination, the dose may vary from about 0.1 mg compound / kg body weight to about 2 mg compound / kg body weight; or from about 0.5 mg / kg body weight to about 2 mg / kg body weight, or from about 1.0 mg / kg body weight to about 2 mg / kg body weight; or from about 1.5 mg / kg body weight to about 2 mg / kg body weight; or from about 0.1 mg / kg body weight to about 1.5 mg / kg body weight; or from about 0.10 mg / kg body weight to about 1.0 mg / kg body weight; or from about 0.10 mg / kg body weight to about 0.5 mg / kg body weight.In other embodiments, the dose may be about 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, or 3.0 mg / kg body weight. In other embodiments, it is contemplated that the dose may range from about 0.2 mg compound / kg body weight to about 2 mg compound / kg body weight. Of course, the dosage may be adjusted upward or downward depending on the results of initial clinical trials and the needs of a particular patient, as is routine in such treatment protocols.

[0103] In embodiments, the dosage (optionally, daily dosage) of the magnesium salt (e.g., MgO) is about or at least about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 500 mg. In embodiments, the dosage (optionally, daily dosage) of the magnesium salt (e.g., MgO) does not exceed about 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg.

[0104] Pharmaceutical compositions according to aspects of the present disclosure may be formulated to release the active compound (e.g., anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil, or a combination thereof) substantially immediately upon administration or at any predetermined time or period after administration. The latter type of composition is generally known as a controlled-release formulation, and includes: (i) formulations that induce a substantially constant concentration of drug in the body over an extended period of time; (ii) formulations that induce a substantially constant concentration of drug in the body over an extended period of time after a predetermined lag time; (iii) formulations that sustain action over a predetermined period of time by maintaining a relatively constant effective level in the body, while minimizing undesirable side effects associated with fluctuations in plasma levels of the active substance (sawtooth kinetics); (iv) formulations that localize action, for example, by spatially positioning the controlled-release composition near the intended target cells (e.g., brain cells); (v) formulations that allow convenient dosing, such as once or twice daily, e.g., orally; and (vi) formulations that target calcium channels and angiotensin receptors by using carriers or chemical derivatives to deliver therapeutic agents to specific cell types (e.g., brain cells). For some applications, controlled-release formulations maintain therapeutic plasma levels, eliminating the need for frequent daily administration.

[0105] Any of a number of strategies can be pursued to achieve controlled release, in which the rate of release exceeds the rate of metabolism of the compound. In one example, controlled release is achieved by appropriate selection of various formulation parameters and ingredients, including, for example, various types of controlled-release compositions and coatings. Thus, a therapeutic agent is formulated with appropriate excipients into a pharmaceutical composition that releases the therapeutic agent in a controlled manner upon administration. Examples include single- or multiple-unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, molecular complexes, nanoparticles, patches, and liposomes.

[0106] Parenteral Compositions Pharmaceutical compositions can be administered parenterally by injection, infusion, or implantation (subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional non-toxic pharmaceutically acceptable carriers and adjuvants. The formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulation. Formulations can be found in Remington: The Science and Practice of Pharmacy (supra).

[0107] Compositions for parenteral use may be provided in unit dosage form (e.g., single-dose ampoules) or in vials containing several doses, to which appropriate preservatives may be added (see below). The compositions may be in the form of a solution, suspension, emulsion, injection device, or delivery device for implantation, or may be presented as a dry powder to be reconstituted with water or other suitable vehicle before use. In addition to an active agent that reduces or alleviates one or more of the 10 cardinal neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis), the composition may include suitable parenterally acceptable carriers and / or excipients. The active therapeutic agent may be incorporated into microspheres, microcapsules, nanoparticles, liposomes, etc. for controlled release. Additionally, the composition may include suspending agents, solubilizing agents, stabilizing agents, pH adjusters, osmotic adjusters, and / or dispersing agents.

[0108] As noted above, pharmaceutical compositions according to embodiments of the present disclosure may be in a form suitable for sterile injection. To prepare such compositions, one or more of anipamil, candesartan, davapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil are dissolved or suspended in a parenterally acceptable liquid vehicle. Acceptable vehicles and solvents that may be used include water, water adjusted to an appropriate pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride and glucose solutions. Aqueous formulations may also contain one or more preservatives (e.g., methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, or n-propyl p-hydroxybenzoate). If one of the compounds is poorly soluble in water or has low solubility, a solubility enhancer or solubilizer may be added, or the solvent may contain 10-60% w / w propylene glycol, etc.

[0109] Controlled-Release Parenteral Compositions Controlled-release parenteral compositions can be in the form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, or emulsions. Alternatively, the active drug can be incorporated into biocompatible carriers, liposomes, nanoparticles, implants, or infusion devices.

[0110] Materials for use in preparing microspheres and / or microcapsules are, for example, biodegradable / bioerodible polymers such as polygalactin, poly-(isobutylcyanoacrylate), poly(2-hydroxyethyl-L-glutamine), and poly(lactic acid). Biocompatible carriers that can be used when formulating controlled-release parenteral formulations are carbohydrates (e.g., dextran), proteins (e.g., albumin), lipoproteins, or antibodies. Materials for use in implants can be non-biodegradable (e.g., polydimethylsiloxane) or biodegradable (e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid), or poly(orthoesters), or combinations thereof).

[0111] Solid dosage forms for oral use Formulations for oral use include tablets containing the active ingredient (e.g., one or more of anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil) mixed with non-toxic pharmaceutically acceptable excipients. Such formulations are known to those skilled in the art. Excipients can be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch such as potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives such as microcrystalline cellulose, starch such as potato starch, croscarmellose sodium, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0112] In some embodiments, the tablets are uncoated, while in other embodiments, they are coated. Tablets can optionally be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. The coating can be adapted to release the active drug in a predetermined pattern (e.g., to achieve a controlled-release formulation) or to prevent release of the active drug until after passage through the stomach (enteric coating). In some embodiments, the coating is a sugar coating, a film coating (e.g., based on hydroxypropylmethylcellulose, methylcellulose, methylhydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycol, and / or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and / or ethylcellulose). Additionally, a time-delay material, such as glyceryl monostearate or glyceryl distearate, can be utilized.

[0113] The solid tablet composition, in some embodiments, comprises a coating adapted to protect the composition from undesired chemical changes (e.g., chemical degradation prior to release of the first and / or second agent). In some embodiments, the coating is applied to the solid dosage form in a manner similar to that described in the Encyclopedia of Pharmaceutical Technology (supra).

[0114] One or more of anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil are mixed together or compartmentalized in a tablet. In one example, the first agent (e.g., one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil) is contained inside the tablet, and the second agent (e.g., one or more of candesartan and telmisartan) is contained outside, so that a substantial portion of the second agent is released before the release of the first agent. In some embodiments, the second agent (e.g., one or more of candesartan and telmisartan) is contained inside the tablet, and the first agent (e.g., one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil) is contained outside.

[0115] Formulations for oral use include chewable tablets or hard gelatin capsules in which the active ingredient (i.e., anipamil, candesartan, devapamil, falipamil, gallopamil, telmisartan, tiapamil, and verapamil, or combinations thereof) is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.In some embodiments, powders and granules are prepared using the ingredients described above for tablets and capsules in a conventional manner, for example, using a mixer, a fluidized bed device, or a spray dryer.

[0116] Controlled-Release Oral Dosage Forms Controlled-release compositions (e.g., for oral use) containing a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, can be constructed to release the agent by controlling the dissolution and / or diffusion of the active substance. For example, immediate-release formulations of verapamil and telmisartan are commercially available, and sustained-release versions of verapamil are also commercially available. Verapamil sustained-release (ER) formulations release the drug over 12 or 24 hours. Controlled release by dissolution or diffusion can be achieved by appropriate coating of tablets, capsules, pellets, or granules of the compound, or by incorporating the composition containing the first and / or second agent into a suitable matrix. Controlled-release coatings, in some embodiments, include one or more of the coating materials described above and / or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled-release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax, and stearyl alcohol, Carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbons.

[0117] In some embodiments, the controlled-release compositions containing two agents described herein (e.g., one or more of verapamil, anipamil, devapamil, falipamil, gallopamil, and tiapamil and one or more of telmisartan and candesartan) are in the form of a floating tablet or capsule (i.e., a tablet or capsule that floats on top of the gastric contents for a period of time upon oral administration). Floating tablets of the compositions can be prepared by granulating a mixture of the agent or one or more of its components with excipients and 20-75% w / w of a hydrocolloid, such as hydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxypropylmethylcellulose. The resulting granules can then be compressed into a tablet. Upon contact with gastric fluid, the tablet forms a substantially water-impermeable gel barrier around its surface. This gel barrier helps maintain a density of less than 1, thereby allowing the tablet to remain suspended in gastric fluid.

[0118] An embodiment of the present disclosure provides a method for treating one or more of the ten cardinal neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, bodily pain, and psychosis), comprising administering to a subject (e.g., a mammal such as a human) a therapeutically effective amount of a pharmaceutical composition comprising a first agent (e.g., one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil) and a second agent (e.g., one or more of candesartan and telmisartan). Accordingly, one embodiment is a method for treating a subject suffering from or susceptible to a disease or disorder that causes one or more of the ten cardinal neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, bodily pain, and psychosis). The method includes administering a combination of a first agent and a second agent to a subject in a therapeutic amount sufficient to treat the disease, condition, disorder, or symptom thereof, under conditions such that the disease, condition, disorder, or symptom thereof is treated. Therapeutic methods include prophylactic treatment. In some embodiments, the subject is a mammal, particularly a human, suffering from, having, being susceptible to, or at risk for a disease or disorder that causes one or more of the 10 cardinal neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulty, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis).

[0119] Identification of a subject in need of such treatment can depend on the judgment of the subject or a medical professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

[0120] Combination therapy Optionally, the first agent (e.g., one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil) and / or the second agent (e.g., one or more of candesartan and telmisartan) can be administered in conjunction with any other standard anti-anxiety, anti-migraine, anti-depression, anti-cognitive difficulty, anti-anger, anti-apathy, anti-fatigue, anti-pain, anti-psychotic, or anti-insomnia therapy, e.g., cognitive behavioral therapy, sedatives, etc.; such methods are known to those skilled in the art and are described in Remington's Pharmaceutical Sciences by E.W. Martin. Optionally, the first agent (e.g., one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil) and / or the second agent (e.g., one or more of candesartan and telmisartan) are administered in combination with any conventional anti-anxiety therapy, including, but not limited to, anxiolytics and / or sedatives, antipsychotics, mood stabilizers, anticonvulsants, antihistamines, and antidepressants.

[0121] The compositions of the present invention can be administered to a subject to treat neuropsychological conditions. Neuropsychological conditions can be brain and / or behavioral disorders. Non-limiting examples of brain and behavioral health disorders include emotional disorders, anxiety disorders, neurodegenerative disorders, neurodevelopmental disorders, psychotic disorders, personality disorders, migraine disorders, and somatoform disorders. Examples of emotional disorders include bipolar disorder, cyclothymia, depression, dysphoria, generalized anxiety disorder, major depressive disorder, obsessive-compulsive disorder, postpartum depression, posttraumatic stress disorder (PTSD), phobias, and seasonal affective disorder. Examples of anxiety disorders include panic disorder, social anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder, and specific phobias. Examples of neurodegenerative disorders include Alzheimer's disease and Parkinson's disease. Examples of neurodevelopmental disorders include autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and learning disabilities. Examples of psychotic disorders include schizophrenia, schizoaffective disorder, and major depression with psychosis. Examples of personality disorders include paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, antisocial personality disorder, emotionally unstable personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and obsessive-compulsive personality disorder. Examples of migraine-related disorders include migraine with aura, migraine without aura, headache-free migraine, and basilar artery migraine. Examples of somatoform disorders include somatization disorder, hypochondriasis, conversion disorder, body dysmorphic disorder, and chronic pain. The symptoms associated with the disease may be selected from one or more of the "ten cardinal symptoms" associated with brain and behavioral health disorders: anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis. Administration of a composition or dosage form of the invention to a subject may reduce or ameliorate one or more of the symptoms associated with brain and / or behavioral disorders.

[0122] The composition of the present invention can be administered to subject in an amount sufficient to modify the regional cerebral blood flow in subject.Cerebral region can include one or more of telencephalon, diencephalon and mesencephalon.The composition of the present invention can be administered to subject in an amount sufficient to create hemodynamic balance in the functional brain network that cooperates in a region of telencephalon, diencephalon and mesencephalon of subject.

[0123] Patient Selection for Treatment The present disclosure provides for the selection of patients who are likely to benefit from treatment with the therapeutic combinations described herein.Such patients are selected as having brain or behavioral health disorders or their symptoms (for example, anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis).Patients with brain or behavioral health disorders or their symptoms are selected for therapy with a combination therapy comprising a first agent selected from one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan.

[0124] Without being bound by theory, patients with the greatest energy supply / demand mismatch may benefit the most from the compositions of the present disclosure. Patients with an energy supply / demand mismatch may show the greatest change in functional connectivity before and after combined treatment. When considering energy in a binary manner (high vs. low), four energy demand / supply phenotypes emerge: high demand / high supply (low risk of neuropsychiatric symptomatology), high demand / low supply (high risk of neuropsychiatric symptomatology), low demand / high supply (low risk of neuropsychiatric symptomatology), and low demand / low supply (low risk of neuropsychiatric symptomatology).

[0125] Kit or Pharmaceutical System The compositions of the present invention can be assembled into kits or pharmaceutical systems for treating brain or behavioral health disorders or their symptoms (e.g., anxiety, migraine, depression, cognitive difficulties, anger, apathy, fatigue, pain, psychosis, or insomnia). The kits or pharmaceutical systems include a carrier, such as a box, carton, tube, or the like, into which one or more container means, such as a vial, tube, ampoule, bottle, or the like, are sealed. The kits or pharmaceutical systems can also include instructions for use of the agents of the presently disclosed embodiments. In some embodiments, the kits include a first agent (e.g., one or more of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil) and a second agent (e.g., one or more of candesartan and telmisartan).

[0126] The practice of embodiments of the present disclosure will utilize, unless otherwise indicated, conventional techniques of molecular biology (e.g., recombinant technology), microbiology, cell biology, biochemistry, and immunology, which are well within the skill of those in the art. Such techniques are fully explained in such references as "Molecular Cloning: A Laboratory Manual, second edition (Sambrook, 1989); "Oligonucleotide Synthesis" (Gait, 1984); "Animal Cell Culture" (Freshney, 1987); "Methods in Enzymology"; "Handbook of Experimental Immunology" (Weir, 1996); "Gene Transfer Vectors for Mammalian Cells" (Miller and Calos, 1987); "Current Protocols in Molecular Biology" (Ausubel, 1987); "PCR: The Polymerase Chain Reaction" (Mullis, 1994); and "Current Protocols in Immunology" (Coligan, 1991). These techniques are applicable to the production of the polynucleotides and polypeptides of the invention and therefore may be considered in making and practicing the invention. Particularly useful techniques for specific embodiments are described in the following sections.

[0127] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the assay, screening, and treatment methods of the present invention, and are not intended to limit the scope of what the inventors regard as their invention. [Example]

[0128] Example 1: Novel clinical efficacy of combined treatment with verapamil and telmisartan - a retrospective observational cohort study A study was completed to measure the novel clinical effects of a composition containing verapamil and telmisartan for the treatment of neuropsychiatric symptomatology in adults. The specific objectives of this study were to describe (1) the magnitude of the novel clinical effect on symptomatology; (2) the magnitude of the novel clinical effect on psychosocial outcomes; and (3) any unique clinical effects resulting from the combination treatment but not from monotherapy treatment. For the primary analysis, results were compared between treatment and no treatment for all patients.

[0129] Symptoms with vs. without combined treatment Patients receiving the combined treatment showed dramatic reductions in overall symptomatology, measured by the sum of 10 basic disabling symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, bodily pain, and psychosis), and in 9 / 10 of the individual symptoms, including anxiety, depression, irritability, apathy, fatigue, bodily pain, insomnia, headache, and cognitive difficulties, compared with patients not receiving the combined treatment. All p-values ​​were less than 0.001. All effect sizes were medium to large, except for small effect sizes for depression, insomnia, and headache. Some effect sizes, such as those for overall symptomatology, anxiety, and apathy, were significantly large (>1.0) (Figures 1A-1J).

[0130] Standardized psychosocial outcomes with and without treatment Patients receiving the combined treatment showed significant improvements compared with non-treatment patients on 6 / 10 standardized measures of psychosocial well-being, including general life satisfaction, meaning and purpose, emotional support, instrumental support, peer relationships, and loneliness. All p-values ​​were less than 0.1. All effect sizes, except for meaning and purpose, were medium to large (Figures 2A–2F).

[0131] Uniqueness of combination treatments compared to individual monotherapies Outcomes from the combination therapy were significantly different from those from monotherapy with twice-daily telmisartan or verapamil alone. Compared with the telmisartan-only group, patients receiving the combination treatment demonstrated significantly improved outcome scores for the NIH Toolbox items of general life satisfaction (p<0.01) and anger [hostility] (p<0.04) (Figures 3A-3B).

[0132] Compared to the verapamil group, patients receiving the combination treatment had significantly different scores on the NIH Toolbox items of self-efficacy (p<0.05) and anger [aggression] (p<0.06) (Figures 4A-4B).

[0133] Example 2: Observational Cohort Study of a Novel Combination Treatment, a Composition Containing Verapamil and Telmisartan, for Neuropsychiatric Symptoms in Adults An observational cohort study was completed to evaluate the safety and efficacy of a composition containing verapamil and telmisartan for the treatment of neuropsychiatric symptoms in adults. The specific objectives of this study were (1) to measure the safety of the combined treatment; (2) to compare the efficacy of the combined treatment in patients with different symptoms and disorders; and (3) to use physiological parameters (Weber test) to test whether the mechanism of action of the combined treatment results in normalization of functional connectivity in the auditory functional network. For the primary analysis, the results were compared before and after treatment in the same patients.

[0134] Demographics A total of 102 patients received the combination therapy and consented to the CEDAR study (protocol number: CEDAR2017, originally approved by the Aspire IRB on April 11, 2017). Demographic details, as well as information regarding handedness, primary diagnosis, existing medications, and the presence of cardiovascular diagnoses, can be found in Table 2.

[0135] Table 2: Baseline demographics TIFF2025128289000010.tif163167

[0136] Self-reported neuropsychiatric symptomatology Patients receiving combination treatment demonstrated significant reductions in symptom totals for 8 of the 10 cardinal disabling symptoms (excluding fatigue and psychosis); the greatest effects were seen for apathy, anxiety, cognitive difficulties, and overall neuropsychiatric impairment (see Table 3).

[0137] Among patients with high anxiety (≥7) at baseline, those receiving combination treatment showed significant reductions in symptom totals for 9 of 10 cardinal disabling symptoms. Effect sizes were large for anxiety, irritability, apathy, and global neuropsychiatric disability, medium for depression, insomnia, and cognitive difficulties, and small for all remaining symptoms (fatigue, pain, and headache) (see Table 4). Among patients with moderate anxiety (≥4) at baseline, effect sizes were medium for anxiety, apathy, cognitive difficulties, and global neuropsychiatric disability, and small for all remaining symptoms except psychosis (see Table 5).

[0138] Among patients with severe cognitive difficulties (≥7) at baseline, effect sizes were large for apathy, cognitive difficulties, and global neuropsychiatric impairment, medium for anxiety, depression, and irritability, and small for anxiety, bodily pain, and insomnia (see Table 6). Among patients with moderate cognitive difficulties (≥4) at baseline, effect sizes were large for cognitive difficulties, medium for anxiety, depression, irritability, apathy, and global neuropsychiatric impairment, and small for fatigue and insomnia (see Table 7).

[0139] Table 3. Effect of combined treatment on self-reported neuropsychiatric symptoms (last observation mean follow-up was 8.9 months) TIFF2025128289000011.tif67170

[0140] Table 4. Self-reported symptom totals before and after combined treatment in patients with severe anxiety at baseline TIFF2025128289000012.tif61167

[0141] Table 5. Self-reported symptomatology before and after combined treatment in patients with moderate anxiety at baseline TIFF2025128289000013.tif61167

[0142] Table 6. Self-reported symptom totals before and after combined treatment in patients with severe cognitive impairment at baseline TIFF2025128289000014.tif61167

[0143] Table 7. Self-reported symptomatology before and after combined treatment in patients with moderate cognitive impairment at baseline TIFF2025128289000015.tif61167

[0144] NIH Toolbox Standardized Outcome Items The NIH Toolbox items showed a significant improvement in general life satisfaction and a marginally significant improvement in social satisfaction (Table 8). Outcomes with smaller sample sizes, such as processing speed (n=17) and Dimensional Change Card Sort (n=18), did not show significant changes from pre- to post-treatment (see Table 8).

[0145] Table 8: NIH Toolbox Standardized Outcome Items TIFF2025128289000016.tif34170

[0146] Weber's lateralization indicates bidirectional changes in sensorineural function observations The Weber test is a common clinical examination technique that physicians can use to identify sensorineural hearing loss. The Weber test utilizes a tuning fork placed centrally above the forehead and asks the patient to report whether sound is lateralized to the left or right. In patients with sensorineural hearing loss, sound is lateralized to the stronger side. Patients with neuropsychiatric disorders (e.g., brain and / or behavioral health disorders) without sensorineural hearing loss frequently report left or right lateralization when tested with the Weber test. This lateralization may in fact be due to the fact that auditory functional networks can be left-, right-, or bilaterally dominant (Asymmetries of the planum temporale and Heschl's gyrus: relationship to language lateralization. Dorsaint-Pierre R, Penhune VB, Watkins KE, Neelin P, Lerch JP, Bouffard M, Zatorre RJ. Brain. 2006 May; 129(Pt 5):1164-76. doi:10.1093 / brain / awl055. Epub 2006 Mar 14).

[0147] Figure 7 shows changes in Weber lateralization in patients who initiated, discontinued, or changed the administration of a composition containing verapamil and telmisartan. These changes were not present between visits in which the administration of the composition remained stable. Notably, some patients had Weber results corrected to the left, while others had Weber results corrected to the right.

[0148] Weber test results were available for a total of 23 patients both before and after treatment (see Table 9). Of the 18 patients who had a treatment change, 15 showed a change in lateralization, whereas of the 5 patients who did not have a treatment change, only 1 showed a change in lateralization. This difference was statistically significant (p<0.006).

[0149] Table 9. Weber Lateralization in Patients with vs. without Combined Treatment TIFF2025128289000017.tif40128

[0150] Bidirectional changes in blood pressure In patients with baseline hypertension, administration of a composition containing verapamil and telmisartan was associated with a decrease to normal levels. In patients with baseline hypotension, administration was associated with an increase to normal levels. In patients with baseline normal blood pressure, treatment was not associated with significant changes. The bidirectional changes suggest modulation of functional connectivity in midbrain regions mediating autonomic balance (Figure 8).

[0151] Significant differences in social outcomes in patients receiving combination therapy compared with patients receiving monotherapy Chi-square analyses were performed to compare the proportion of patients who reported significant social changes between those receiving the combination therapy and those receiving the monotherapy (Table 10). At each visit, patients were systematically assessed with self-report questions that reveal basic human needs related to belonging and love. Results showed that patients receiving the combination therapy were significantly more likely to report social momentum, new social contacts, clothing, and changes in appearance. Without being bound by theory, these social changes result from alterations in functional brain networks related to social cognition, which rely heavily on the diencephalic and telencephalic brain regions.

[0152] Table 10. Percentage of patients receiving combination therapy who reported significant social changes compared with patients receiving monotherapy. TIFF2025128289000018.tif40170 * Monotherapy refers to telmisartan alone or verapamil alone.

[0153] Consideration A human clinical study using a combination of verapamil and telmisartan to treat neuropsychiatric indications (e.g., brain and / or behavioral health disorders) has been completed. This observational study was motivated by the clinical impression of notable symptom improvement in patients with several common neuropsychiatric comorbidities who were incidentally treated with the combination therapy for approximately one year as part of clinical practice to achieve more complete relief. This study was designed to empirically test, within the limitations of an observational study design, the safety and efficacy of the combination treatment when delivered in the context of routine neuropsychiatric care. The majority of patients received the intensified combination treatment relative to standard therapy.

[0154] In 102 patients, neither systolic nor diastolic blood pressure was significantly different after combination treatment, despite significant improvements in apathy, anxiety, cognitive difficulties, and overall neuropsychiatric impairment (e.g., cerebral and / or behavioral health impairment). The rate of adverse medical symptoms did not change significantly before and after treatment. The adverse symptom profile of the combination treatment was similar to the established adverse symptom profile of telmisartan and verapamil. Standardized testing showed significant improvements in overall life satisfaction before and after treatment.

[0155] Observational studies can provide similar estimates of effect size compared with randomized controlled trials (Development and reliability testing of a cross-cutting symptom assessment for DSM-5. American Journal of Psychiatry, 170(1), 59-70. Narrow, WE, Clarke, DE, Kuramoto, SJ, Kraemer, HC, Kupfer, DJ, Greiner, L., & Regier, DA (2013). DSM-5 field trials in the United States and Canada, Part III). This study has several strengths that support the accuracy of the observed effect size. These include the large sample size, the longitudinal design that allows for analysis of time effects, the long follow-up period, the inclusion of patients with multiple comorbidities (which more accurately resembles real-world clinical practice), the inclusion of objective measures such as vital signs, and the NIH Toolbox of measures. Another strength of this study was the number of different analyses performed to test for association or causation according to the Bradford-Hill criteria. In order for a factor to be considered causal or associated, the following criteria should be observed: robustness, concordance, specificity, temporality, biological gradient, plausibility, consistency, experimentation, similarity, and reversibility.

[0156] Without wishing to be bound by theory, the combination treatment acts on central pathways common to multiple neuropsychiatric disorders (e.g., brain and / or behavioral health disorders). Without wishing to be bound by theory, the unique combination of angiotensin II receptor blockade and simultaneous adrenergic blockade results in a more balanced distribution of cerebral blood flow, particularly in the diencephalon, a brain region important for social and emotional awareness. In other words, by simultaneously influencing emotion (midbrain) and cognition (telencephalon), this synergistic effect can result in improved social cognition (diencephalon). This hypothesis is based on the observation of significant social changes in patients receiving combination therapy. For example, changes in social and dressing behavior were observed in patients receiving combination treatment. Research results showed improved social satisfaction in patients receiving combination treatment. This is further supported by analysis of results from a Weber test conducted as part of a routine clinic visit, which measures lateralization of the brain's auditory functional network. In clinic, patients who started combination treatment or were changed from monotherapy to combination treatment showed a shift in Weber test lateralization between visits that did not occur with standard of care medications.

[0157] Without wishing to be bound by theory, compositions containing verapamil and telmisartan may exert a modulatory effect on brain regions related to the auditory functional network. These changes in auditory function correlated with clinical improvements in social function, suggesting that the composition may affect not only auditory function but also interoceptive / exteroceptive awareness and social communication, which rely on auditory functionality. In fact, the auditory cortex is directly involved in the network for emotional processing (Disability and poor quality of life associated with comorbid anxiety disorders and physical conditions. Sareen J, Jacobi F, Cox BJ, Belik SL, Clara I, Stein MB. Arch Intern Med. 2006 Oct 23;166(19):2109-16. doi:10.1001 / archinte.166.19.2109).

[0158] Example Methods The following methods were used in Example 1.

[0159] Data and Combination Therapies Data for this study were selected from the Comparative Effectiveness Dementia and Alzheimer's Registry (CEDAR) project. The CEDAR project is a real-world, IRB-approved observational study for patients seeking treatment for neurological, psychological, or psychiatric conditions at a community-based neuropsychiatric specialty clinic in Broward County, FL. Patients received usual care, including medication adjustments and routine cognitive-behavioral therapy for neurological, psychiatric, and psychological comorbidities. No treatment changes were made as a result of participation in the observational study. Only patients who consented to the CEDAR project were included in this study.

[0160] Combination therapy included either 120 mg or 180 mg of verapamil twice daily and either 40 mg or 80 mg of telmisartan twice daily. Control groups used for comparison received neither verapamil nor telmisartan, or only telmisartan, or only verapamil.

[0161] Demographics Data from a total of 76 patients who consented to the Comparative Efficacy Dementia Alzheimer's Disease Registry (CEDAR) study were analyzed. The mean age, sex, ethnicity, and education from each treatment group are provided in Table 11.

[0162] (Table 11) TIFF2025128289000019.tif255151 Results are based on two-sided tests: for each significant pair, the key of the category with the smaller column proportion is represented in the category with the larger column proportion. Significance level for capital letters (A, B, C): .05 a. This category is not used in the comparison because the column percentage is equal to 0 or 1. b. This category will not be used in the comparison because the sum of the case weights is less than 2. c. The test is adjusted for all pairwise comparisons in the rows of each innermost subtable using the Bonferroni correction.

[0163] (Table 11) Continued TIFF2025128289000020.tif255157The results are based on two-sided tests. For each significant pair, the key of the category with the smaller column proportion is represented in the category with the larger column proportion. Significance level for capital letters (A, B, C): .05 a. This category is not used in the comparison because the column percentage is equal to 0 or 1. b. This category will not be used in the comparison because the sum of the case weights is less than 2. c. The test is adjusted for all pairwise comparisons in the rows of each innermost subtable using the Bonferroni correction.

[0164] Diagnostic and Medical Complexity Clinical diagnosis was made by a behavioral neurology fellowship-trained neurologist using an independent medical record review of a complete neurological history and examination, a self-reported psychosocial assessment adapted for neuropsychiatric populations based on Maslow's hierarchy of needs, and the DSM-V psychiatric interview. Medical complexity was assessed using a composite score summarizing positive affirmations (1 point each) to a series of questions about past medical history, surgical history, and family history.

[0165] Symptoms and disability The National Institutes of Health (NIH) Toolbox was used to collect primary outcomes in cognitive, affective, and psychosocial domains. These items were chosen because they are specifically designed to provide a valid longitudinal assessment of neuropsychiatric symptoms in community-based populations of children, adults, and older adults.

[0166] Primary outcomes included standardized self-report items for treated and untreated patients. Fully adjusted T-scores for the NIH Toolbox Pattern Comparison Processing Speed ​​and Dimensional Change Card Sorting tests were the primary cognitive outcomes. The NIH Toolbox Negative Affect composite score and the NIH Toolbox Psychological Well-Being composite score were the primary affective and psychosocial outcomes. The Negative Affect composite score measures the individual components of fear, anger, and sadness. The Psychological Well-Being composite score measures the individual components of positive affect, general life satisfaction, meaning and purpose, perceived stress, self-efficacy, emotional support, instrumental support, loneliness, hostility, perceived rejection, and perceived hostility. The mean symptom severity scale of 10 basic symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis), measured individually on a 0–10 scale and aggregated onto a 0–100 scale to measure self-reported symptom severity, as well as difficulties reported by patients during the course of clinical care on a 0–10 scale, were also used as primary outcomes.

[0167] Exploratory outcomes measured psychosocial gains, including changes in social support, social behavior, relationships, occupational status, and housing situation, and were measured by self-report using the total number of self-reported positive and negative psychosocial events over the course of treatment.

[0168] The medical safety of the procedure was assessed through a measure of medical symptomatology assessed by a self-report scale of the total number of positively reported symptoms before and after the procedure, using patient self-report on a systems review battery given at each visit as part of routine care and asking specific questions about each body system. Blood pressure and pulse and medication adherence data were collected from clinical assessments performed as part of routine care.

[0169] statistics To measure the overall effect of combination treatment with and without treatment, within-group comparisons of means were performed for patients in the following treatment groups: no treatment, monotherapy (verapamil only or telmisartan only), and combination therapy (verapamil + telmisartan). Because data consisted of multiple repeated visits where patients were either on or off medication, the mean value of all visits where patients were not on medication was used to measure the "no treatment" outcome for patients. The mean value of all visits where patients were on medication was used to measure the "on treatment" outcome. Effect sizes were calculated using Cohen's methodology and quantified using standard ranges to designate treatment effects as small (0.2-0.5), medium (0.5-0.8), or large (>0.8).

[0170] To measure the specific effects of the individual components of the combination treatment compared with the combined treatment, a between-group post hoc analysis of variance was performed for patients in the following treatment groups: no treatment, treatment with verapamil only, treatment with telmisartan only, and treatment with the combined therapy (verapamil + telmisartan).

[0171] The following methods were used in Example 2.

[0172] Patient population Data for this study were selected from the Neuro Well Free Not-for-Profit Corporation's Comparative Effectiveness Dementia Alzheimer's Disease Registry (CEDAR) project. The CEDAR project is a real-world, IRB-approved observational study for patients seeking treatment for neurological, psychological, or psychiatric conditions at a community-based neuropsychiatry specialty clinic in Broward County, FL. The clinic accepts all major health insurance plans and includes people of all ages and diagnoses. Patients received their usual course of care, including medication adjustments for neurological, psychiatric, and psychological comorbidities and routine cognitive-behavioral therapy. No treatment changes were made as a result of participation in the observational study. Only patients who consented to the CEDAR project were included in this study.

[0173] Demographics and Diagnostics Demographic details, medical history, and examination were collected at the first visit as part of a comprehensive initial neuropsychiatric evaluation. A comprehensive psychosocial assessment modeled on Maslow's hierarchy of needs was administered to all patients at baseline. Clinical diagnoses were made by a behavioral neurology fellowship-trained neurologist using a psychiatric interview based on DSM-V.

[0174] safety Vital signs were measured using systolic blood pressure, diastolic blood pressure, and pulse measurements collected as part of routine care. Adverse events were measured using a 10-point System Review Inventory covering constitutional, HEENT, respiratory, gastrointestinal, genitourinary, cutaneous, musculoskeletal, endocrine, neurological, and psychiatric symptoms. One point was given for each symptom reported, for a total possible score of 93.

[0175] To calculate the rate of adverse events with combination therapy, the percentage of people who reported "yes" to one of the symptoms during the first month of treatment was calculated for each symptom.

[0176] Effectiveness Symptom severity was measured via a self-reported symptom severity scale administered at each visit as part of routine care. Symptoms included anxiety, depression, irritability, apathy, fatigue, bodily pain, insomnia, headache, psychosis, and cognitive impairment, which were retrieved from medical records. In addition to individual scores ranging from 0 to 10 for each symptom, a total score ranging from 0 to 100 was calculated.

[0177] National Institute of Health Toolbox measures were used to collect self-reported symptom severity as well as composite-level outcomes in cognitive, affective, and psychosocial domains. These items were chosen because they were specifically designed to provide valid longitudinal assessments of neuropsychiatric symptoms in community-based populations of children, adults, and older adults. Specifically, the NIH Toolbox measures Pattern Comparison Processing Speed ​​and Dimensional Change Card Sorting, General Life Satisfaction, Meaning and Purpose, and Social Well-Being were used.

[0178] Visit and Treatment Group Assignment All patients were assigned a baseline visit and two follow-up visits. The baseline visit was assigned as the most recent visit before the patient started the treatment of interest. The first follow-up visit was the most recent visit within approximately one month of the start of medication. The final follow-up visit was the time of the last observation while receiving the treatment of interest. Three different treatments were compared: before and after telmisartan, before and after verapamil, and before and after combined treatment.

[0179] Medication compliance Medication compliance was confirmed by review of medical records, including pharmacy administration records and physician notes.

[0180] Weber's Lateralization The Weber test was administered to patients at the initial and / or follow-up visits as part of routine care, depending on the availability of time in the clinic. Weber lateralization was used for this study as a surrogate for normalization of functional connectivity in the auditory functional network.

[0181] statistics Paired t-tests were used to measure the significance of changes between pre- and post-treatment. Effect sizes were calculated using Cohen's methodology and quantified using a standard range to designate treatment effects as small (0.2-0.5), medium (0.5-0.8), or large (≥0.8). Furthermore, paired t-tests were used to compare outcomes between different doses of combination therapy. Subgroup analyses were performed for individuals with moderate baseline clinical anxiety (≥4), severe baseline clinical anxiety (≥7), moderate baseline clinical cognitive impairment (≥4), and severe baseline cognitive impairment (≥7). In another sensitivity analysis, all patient visits, rather than only pre- and post-visits, were used to calculate mean symptom severity without and with medication. Chi-square analyses were performed to test the association between medication change and Weber lateralization. Treatment groups were categorized as those with and without change in combination therapy. Lateralization was assessed as left, left central, central, right central, and right. Data analysis was performed using STATA (Stata / IC 16.1).

[0182] Other Aspects From the foregoing description, it will be apparent that variations and modifications can be made to the invention described herein to adapt it to various usages and conditions, and such embodiments still fall within the scope of the following claims.

[0183] The recitation of a list of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or subcombination) of the listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0184] All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each individual patent and publication was specifically and individually indicated to be incorporated by reference.

Claims

1. 1. A pharmaceutical composition for use in a method of reducing symptoms of an affective or personality disorder in a subject, comprising a first agent selected from the group consisting of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and a second agent which is telmisartan or candesartan, The method includes administering to a subject having an affective or personality disorder an effective amount of the first agent and an effective amount of the second agent; The pharmaceutical composition, wherein the symptom is selected from the group consisting of apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, and pain.

2. 10. The pharmaceutical composition of claim 1, wherein the first agent is verapamil and the second agent is telmisartan.

3. 10. The pharmaceutical composition of claim 1, wherein the effective amount of the first agent is from about 120 mg to about 720 mg and the effective amount of the second agent is from about 45 mg to about 180 mg.

4. 2. The pharmaceutical composition of claim 1, wherein the first agent comprises 120 to 360 mg of verapamil and the second agent comprises 40 to 180 mg of telmisartan.

5. 10. The pharmaceutical composition of claim 1, wherein the method further comprises administering to the subject an effective amount of magnesium oxide.

6. 10. The pharmaceutical composition of claim 1, wherein the first agent and the second agent are administered once or twice daily.

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