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: U.S. Provisional Application No. 63 / 011,932, filed April 17, 2020, and U.S. Provisional Application No. 63 / 111,156, filed November 9, 2020, the entire contents of which are hereby incorporated by reference.

Background Art

[0002] Background Worldwide, brain and behavioral health disorders are the leading cause of disability. Brain and behavioral health disorders include all of the major disorders belonging to the specialties of neurology, psychiatry, and psychology. Anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis are the ten basic symptoms caused by brain and behavioral health disorders. These symptoms, individually, are the disabling characteristics of these disorders and they cause loss of function.

[0003] The ten basic disabling symptoms of brain and behavioral health disorders are all difficult to treat because most, if not all, people with brain and behavioral disorders suffer from multiple causes of these symptoms. In actual clinical practice, the causes of the symptoms can be due to 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 disabling, difficult-to-treat, and multifactorial symptom. Physical 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] In actual clinical practice, despite the fact that the ten basic 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, the treatments currently approved by the FDA typically target one component of the disorder at a time. For example, selective serotonin reuptake inhibitors ("SSRI"), the first-line treatment for anxiety disorders, are specifically designed to target the serotonergic mechanism of anxiety. The effectiveness of these pharmacotherapies has been found to be limited alone. Cognitive behavioral therapy is specifically designed to address the psychological components of anxiety. Patients who receive both pharmacotherapy and cognitive behavioral therapy are predicted to have better outcomes than those who receive treatment targeting either one alone. Even with cognitive behavioral therapy and pharmacotherapy, treatment success remains limited, suggesting that the neurological basis of anxiety remains untreated in the majority of patients seeking anxiety relief.

[0005] Current treatments are not designed to address the multifactorial characteristics associated with the most disabling symptoms of brain and behavioral health disorders. Thus, there is an urgent need for new treatments to address brain and behavioral health disorders and their symptoms. SUMMARY OF THE INVENTION

[0006] Summary 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 a novel combination therapy comprising an agent that targets the adrenergic system (e.g., anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil) and an agent that targets the renin-angiotensin-aldosterone system (RAAS) (e.g., candesartan, telmisartan). Such agents have been individually approved by the FDA for the treatment of cardiovascular disease, but have not been previously combined or used for the treatment of brain and / or behavioral health disorders. In one aspect, the present invention features a combination therapy comprising a first agent selected from one or more of anipamil, depamil, faripamil, 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 elicit a novel synergistic equilibration effect on global cerebral blood flow through modulation of stress-induced hormones in both the body and the brain.

[0008] These combinations are effective in the treatment of 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 a health disorder of the brain and / or behavior or symptoms thereof. The combination contains 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, containing effective amounts of a first and a second agent. The first agent is verapamil and the second agent is telmisartan, and the first and second agents are provided in a sustained release formulation.

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

[0012] In another aspect, the invention features a method for treating an anxiety disorder, including administering to the 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 a sustained release formulation.

[0013] In another aspect, the invention features a method for increasing the progress of a subject along the Maslow hierarchy of needs. The method includes administering to the subject a therapeutically effective amount of a first 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 progress of the subject along the Maslow hierarchy of needs. The increase in progress is referenced to a control.

[0014] In one aspect, the present invention features a pharmaceutical composition containing an effective amount of a first and a second agent and a pharmaceutically acceptable excipient. The first agent is selected from one or more of anipamil, deparamil, faripamil, gallopamil, tiapamil, and verapamil, and the second agent is selected from one or more of telmisartan and candesartan. In an embodiment, the pharmaceutical composition further contains magnesium oxide.

[0015] In another aspect, the present invention features a kit containing a therapeutic combination containing a first and a second agent. The first agent is selected from one or more of anipamil, deparamil, faripamil, gallopamil, tiapamil, and verapamil, and the second agent is selected from one or more of telmisartan and candesartan. The kit also contains instructions for the use of the combination for the treatment of brain and / or behavioral health disorders or their symptoms.

[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, deparamil, faripamil, 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 above aspects, the combination is labeled for the treatment of brain and / or behavioral health disorders. In any of the above aspects, the combination is labeled for the treatment of symptoms of brain and / or behavioral health disorders selected from one or more of anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain, and psychosis.

[0018] In any of the foregoing situations, 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. In any of the foregoing situations, 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 foregoing situations, the mass ratio of the first agent to the second agent is from about 2:1 to about 5:1. In any of the foregoing situations, the mass ratio of the first agent to the second agent is about 2:1. In any of the foregoing situations, the amount of the first agent is about 1 to about 4 times the amount of the second agent. In any of the foregoing situations, the amount of the first agent is about 1 to about 4 times the amount of the second agent.

[0020] In any of the foregoing situations, the agents are formulated together or separately.

[0021] In any of the foregoing situations, the combination therapeutic is administered once a day. In any of the foregoing situations, the combination therapeutic is administered twice a day.

[0022] In any of the foregoing situations, the agents are administered simultaneously. In any of the foregoing situations, the agents are administered sequentially.

[0023] In any of the foregoing situations, the administration is related to a modification in cerebral metabolism or cerebral blood flow. In an aspect, the cerebral blood flow is modified in one or more of the telencephalon, diencephalon, and midbrain. In an aspect, the modification of the regional cerebral blood flow is associated with the establishment of a hemodynamic equilibrium in a region of the brain.

[0024] In any of the foregoing situations, the method improves one or more primary outcomes selected from cognitive function, 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 foregoing situations, the therapeutic combination further contains magnesium oxide. In any of the foregoing situations, the therapeutic combination contains at least about 150 mg of magnesium oxide. In any of the foregoing situations, the method further includes a step of administering magnesium oxide to a subject. In an embodiment, 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 the claims.

[0027] Definitions Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. The following references provide one of ordinary skill 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 have the meanings ascribed to them below, unless otherwise specified.

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

[0029] "Relieving" means reducing, suppressing, weakening, diminishing, halting, or stabilizing the onset or progression of a disease.

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

[0031] "Relieving" means reducing, suppressing, weakening, diminishing, halting, or stabilizing the onset or progression of a disease.

[0032] "Analog" means 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" means a compound having the following structure: TIFF0007697110000001.tif49128 or a pharmaceutically acceptable salt thereof. In some embodiments, anipamil has calcium channel blocking activity.

[0034] "Candesartan" means a compound having the following structure: It means a compound having TIFF0007697110000002.tif34128 or a pharmaceutically acceptable salt thereof. In some embodiments, candesartan has angiotensin II receptor blocking activity.

[0035] "Brain metabolism" means the rate of metabolism in the brain or its regions. Brain metabolism can be measured using any of a variety of methods available to practitioners, including, by way of non-limiting example, X-ray computed tomography (CT), positron emission tomography (PET), near-infrared spectroscopy (NIRS), magnetic resonance imaging (MRI), and the methods provided herein. In an embodiment, an improvement in metabolism in a region of the brain 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, by way of non-limiting example, single photon emission computed tomography (SPECT), positron emission tomography (PET), functional MRI (fMRI), arterial spin labeling (ASL) MRI, transcranial Doppler ultrasonography (i.e., sonography), phase contrast MRI, and near-infrared spectroscopy (NIRS).

[0036] In the present disclosure, terms such as "comprises," "comprising," "contains," and "has" can have the meanings assigned to them in United States patent law and can mean "includes," "including," etc.; "consisting essentially of" or "consisting essentially" likewise has the meaning assigned in United States patent law, and this term is non-limiting and allows for the presence of elements other than those described, provided that the basic or novel features of what is described are not changed by the presence of elements other than those described, excluding aspects of the prior art. Embodiments specified as "comprising" a particular component or element are, in some embodiments, also contemplated as "consisting of" or "consisting essentially of" the particular component or element.

[0037] "Consisting essentially of" means that a component contains only the recited components, together with normal impurities present in commercially available materials and other optional additives present at levels that do not affect the practice of the present disclosure, e.g., at levels less than 5 wt% or less than 1 wt% or even less than 0.5 wt%.

[0038] "Decrease" means a negative modification.

[0039] "Debafamil" means a compound having the following structure: TIFF0007697110000003.tif37128 or a pharmaceutically acceptable salt thereof. In one embodiment, debafamil has calcium channel blocking activity.

[0040] "Disease" means any condition or disorder that impairs or interferes with the normal function of cells, tissues, or organs. In some embodiments, the disease or disorder is a neuropsychiatric disorder, examples of which include disorders of brain and / or behavioral health and their symptoms. Non-limiting examples of disorders of brain and behavioral health include mood disorders, anxiety disorders, neurodegenerative disorders, neurodevelopmental disorders, psychotic disorders, personality disorders, headache disorders, and somatic symptom disorders. Examples of mood disorders include bipolar disorder, cyclothymia, depression, irritability, generalized anxiety disorder, major depressive disorder, obsessive-compulsive disorder, postpartum depression, post-traumatic stress disorder (PTSD), phobias, and seasonal affective disorder. Examples of anxiety disorders include panic disorder, social anxiety disorder, post-traumatic 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 disorders. Examples of psychotic disorders include schizophrenia, schizoaffective disorder, and major depressive disorder with psychosis. Examples of personality disorders include paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, antisocial personality disorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and obsessive-compulsive personality disorder. Examples of headache-related disorders include migraine with aura, migraine without aura, acephalgic migraine, and basilar migraine. Examples of somatic symptom disorders include somatic symptom disorder, illness anxiety disorder, conversion disorder, body dysmorphic disorder, and chronic pain. Symptoms associated with the disease include, but are not limited to, anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis, and are selected from one or more of the "10 basic symptoms" associated with disorders of brain and behavioral health. In some embodiments, the disease is associated with altered regional cerebral blood flow compared to a reference (e.g., blood flow present in a healthy control brain). The disease can be a disorder of brain or behavioral health as defined above.

[0041] "Effective amount" means an amount of an agent sufficient to treat a disease or disorder. In one aspect, the effective amount of the combination therapies described herein is sufficient to treat a brain and / or behavioral disorder or symptoms thereof, or to effect an improvement in a primary outcome (e.g., cognitive function, life satisfaction, subject's sense of meaning and purpose, subject's sense of emotional or instrumental support, friendships, and improvement in life satisfaction).

[0042] "Falipamil" means a compound having the following structure: TIFF0007697110000004.tif40128 or a pharmaceutically acceptable salt thereof. In some aspects, falipamil has calcium channel blocking activity.

[0043] "Gallopamil" means a compound having the following structure: TIFF0007697110000005.tif45128 or a pharmaceutically acceptable salt thereof. In some aspects, gallopamil has calcium channel blocking activity.

[0044] "Hemodynamic balance" means a state of balance with respect to the relative blood flow velocities between corresponding regions of the brain. In an aspect, hemodynamic balance is associated with approximately equal relative blood flow velocities and / or metabolic activities between regions.

[0045] "Improve" means a positive modification.

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

[0047] As used herein, terms such as "prevent," "preventing," "prevention," "preventive treatment," etc., 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 developing it or is predisposed to developing it.

[0048] "To lower" means a negative modification.

[0049] "Subject" means a mammal. Non-limiting examples of mammals include humans, or non-human mammals such as cows, horses, dogs, sheep, cats, or rodents.

[0050] "Reference" means a standard or control condition. In one aspect, the effect of an agent on cells is compared to the effect of that agent on control cells. In an aspect, the reference is a healthy subject. In an aspect, the clinical features of a subject having a disorder of the brain or behavior are compared to reference clinical features present in a healthy subject. A healthy subject is a subject that does not have the disorder or condition of interest. In some aspects, the reference is an untreated patient, or a subject before treatment, or a subject before modification during treatment.

[0051] "Region of the brain" means a part of the brain. In an aspect, a part of the brain contains one or more of the telencephalon, diencephalon, and mesencephalon. The region may contain all three of the telencephalon, diencephalon, and mesencephalon.

[0052] "Concurrent administration" means administering at the same time.

[0053] "Sequential administration" means administering at separate times. For example, one or more agents are administered sequentially when the dosing intervals are in minutes, hours, or days. For example, in sequential administration, the 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, the 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 the second agent. In yet another example of sequential administration, the first agent is administered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days before the administration of the second agent.

[0054] "Telmisartan" means the following structure: It means a compound having TIFF0007697110000006.tif28128 or a pharmaceutically acceptable salt thereof. In some embodiments, telmisartan has angiotensin II receptor blocking activity.

[0055] "Therapeutic agent" means a substance that has the potential to affect the functions 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. A therapeutic agent can reduce, suppress, weaken, reduce, stop, or stabilize the onset or progression of a disease, disorder, or condition. A therapeutic agent is associated with the modification of regional cerebral blood flow in a subject. Non-limiting examples of therapeutic agents described herein include anipamil, candesartan, devapamil, faripamil, gallopamil, telmisartan, tiapamil, and verapamil, as well as derivatives, analogs, and functional equivalents of such agents. In an embodiment, a therapeutic combination is characterized by a first agent selected from one or more of anipamil, devapamil, faripamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan.

[0056] "Effective amount" means the amount of an agent required to reduce or alleviate the symptoms of a disease as compared to a reference. For the therapeutic treatment of a disease, the effective amount of the active compounds (e.g., anipamil, candesartan, devapamil, faripamil, gallopamil, telmisartan, tiapamil, and verapamil) used to practice 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 determines the appropriate amount and dosing schedule. Such an amount is referred to as an "effective" amount. The symptoms are selected from one or more of the "10 basic symptoms" associated with brain and behavioral health disorders: anxiety, apathy, cognitive difficulty, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis. In an embodiment, a therapeutically effective amount is the amount of the agent or combination of agents required.

[0057] The ranges provided in this specification are to be understood as shorthand for all values within those ranges. For example, a range of 1 - 50 includes any number, combination of numbers, or sub - range derived 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" refers to the following structure: a compound having TIFF0007697110000007.tif41128 or a pharmaceutically acceptable salt thereof. In some embodiments, tiapamil has calcium channel blocking activity.

[0059] As used herein, the terms "treating", "treatment", "treat", etc. refer to the reduction or alleviation of a disease and / or related symptoms. It will be understood that treatment of a disorder or condition, while not excluding, does not necessarily require complete elimination of the disorder, condition, or their related symptoms.

[0060] "Verapamil" refers to the following structure: an agent having TIFF0007697110000008.tif20128 or a pharmaceutically acceptable salt thereof. In some embodiments, verapamil has calcium channel blocking activity.

[0061] Unless specifically stated otherwise or otherwise apparent from the context, as used herein, the term "or" is to be understood as inclusive. Unless specifically stated otherwise or otherwise apparent from the context, the terms "a", "an", and "the" are to be understood as being either singular or plural.

[0062] Unless otherwise specified or apparent from the context, as used herein, the term "about" is understood to be within the normal tolerance in the art, for example within 2 standard deviations of the mean value. About can be understood to be 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 apparent 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 the definition of that variable as any single group, or combination of the listed groups. The recitation of aspects for a variable or aspect herein includes that aspect as any single aspect, or in combination with any other aspect 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, when various mechanisms of action, hypotheses, or theories are described, these are not intended to be limiting. [Invention 1001] A therapeutic combination for the treatment of a brain and / or behavioral health disorder 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. [Invention 1002] The therapeutic combination of Invention 1001, wherein the first agent has calcium channel blocking activity and the second agent has angiotensin II receptor blocking activity. [Invention 1003] The therapeutic combination of Invention 1001 or Invention 1002, wherein the first agent is selected from the group consisting of anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil. [Invention 1004] A therapeutic combination according to any one of inventions 1001 to 1003, wherein the second agent is telmisartan or candesartan. [Invention 1005] A therapeutic combination according to any one of inventions 1001 to 1004, which is labeled for the treatment of brain and / or behavioral health disorders. [Invention 1006] A therapeutic combination according to any one of inventions 1001 to 1005, which is labeled for the treatment of symptoms of brain and / or behavioral health disorders selected from the group consisting of anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, pain, and psychosis. [Invention 1007] A therapeutic combination according to any one of inventions 1001 to 1006, wherein the first agent is verapamil. [Invention 1008] A therapeutic combination according to any one of inventions 1001 to 1007, wherein the second agent is telmisartan. [Invention 1009] A therapeutic combination for the treatment of an anxiety disorder, comprising effective amounts of a first and a second agent, wherein the first agent is verapamil, the second agent is telmisartan, and the first and second agents are provided as sustained-release formulations. [Invention 1010] A therapeutic combination according to any one of inventions 1001 to 1009, 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. [Invention 1011] A therapeutic combination according to any one of inventions 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. [Invention 1012] A therapeutic combination according to any one of inventions 1001 to 1011, wherein the mass ratio of the first agent to the second agent is from about 2:1 to about 5:1. [Invention 1013] A therapeutic combination according to any one of inventions 1001 to 1012, wherein the mass ratio of the first agent to the second agent is about 2:1. [The present invention 1014] Any of the therapeutic combinations of the present inventions 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] Any of the therapeutic combinations of the present inventions 1001 to 1014, wherein the amount of the first agent is about 2 times the amount of the second agent. [The present invention 1016] Any of the therapeutic combinations of the present inventions 1001 to 1015, wherein the agents are formulated together or separately. [The present invention 1017] A step of administering to a subject in need of combination therapy comprising a first agent targeting the adrenergic system and a second agent targeting the renin - angiotensin - aldosterone system, thereby treating a brain or behavioral health disorder. A method for treating a subject having a brain or behavioral health disorder, comprising the step of [The present invention 1018] The method of the present invention 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 the present invention 1017 or the present invention 1018, wherein the first agent is selected from the group consisting of anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil. [The present invention 1020] The method of any of the present inventions 1017 to 1019, wherein the second agent is telmisartan or candesartan. [The present invention 1021] The method of any of the present inventions 1017 to 1020, wherein the first agent is verapamil. [The present invention 1022] The method of any of the present inventions 1017 to 1021, wherein the second agent is telmisartan. [The present invention 1023] A method for treating an anxiety disorder, comprising the step of administering to a subject a therapeutic combination comprising an effective amount of a first agent and a second agent, wherein the first agent is verapamil, the second agent is telmisartan, and the first and second agents are provided in sustained release formulations. [Inventive concept 1024] The method according to any one of inventive concepts 1017 to 1023, 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. [Inventive concept 1025] The method according to any one of inventive concepts 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. [Inventive concept 1026] The method according to any one of inventive concepts 1017 to 1025, wherein the mass ratio of the first agent to the second agent is from about 2:1 to about 5:1. [Inventive concept 1027] The method according to any one of inventive concepts 1017 to 1026, wherein the mass ratio of the first agent to the second agent is about 2:1. [Inventive concept 1028] The method according to any one of inventive concepts 1017 to 1027, wherein the amount of the first agent is about 1 to about 4 times the amount of the second agent. [Inventive concept 1029] The method according to any one of inventive concepts 1017 to 1028, wherein the amount of the first agent is about 1 to about 4 times the amount of the second agent. [Inventive concept 1030] The method according to any one of inventive concepts 1017 to 1029, wherein the combination therapy is administered once a day. [Inventive concept 1031] The method according to any one of inventive concepts 1017 to 1030, wherein the combination therapy is administered twice a day. [Inventive concept 1032] The method according to any one of inventive concepts 1017 to 1031, wherein the agents are administered simultaneously. [Inventive concept 1033] The method according to any one of inventive concepts 1017 to 1032, wherein the agents are administered sequentially. [Inventive concept 1034] Any method of the invention from 1017 to 1033, wherein the administration is associated with a modification in brain metabolism or cerebral blood flow. [Invention 1035] The method of invention 1034, wherein cerebral blood flow is modified in one or more of the telencephalon, diencephalon, and midbrain. [Invention 1036] The method of invention 1034 or invention 1035, wherein the modification of regional cerebral blood flow is associated with the establishment of a hemodynamic balance in a region of the brain. [Invention 1037] Any method of the invention from 1017 to 1036, wherein a major 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, friendship, and life satisfaction is improved. [Invention 1038] A step of administering a therapeutically effective amount of a first agent and a second agent to a subject, 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 Including, thereby increasing the progress of the subject along the Maslow's hierarchy of needs, and the increase in the progress is based on a reference, a method of increasing the progress of the subject along the Maslow's hierarchy of needs. [Invention 1039] The method of invention 1038, wherein the first agent is selected from the group consisting of anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil. [Invention 1040] The method of invention 1038 or invention 1039, wherein the second agent is selected from one or more of telmisartan and candesartan. [Invention 1041] Any method of the invention from 1038 to 1040, wherein the first agent is verapamil. [Invention 1042] Any method of the invention from 1038 to 1041, wherein the second agent is telmisartan. [Invention 1043] A therapeutic combination according to any one of 1001 to 1016 of the present invention, further comprising magnesium oxide. [Invention 1044] A therapeutic combination according to Invention 1043, comprising at least about 150 mg of magnesium oxide. [Invention 1045] A method according to any one of 1017 to 1042 of the present invention, further comprising the step of administering magnesium oxide to a subject. [Invention 1046] A method according to Invention 1045, wherein at least about 150 mg of magnesium oxide is administered to the subject daily. [Invention 1047] A pharmaceutical composition comprising an effective amount of a first and a second agent and a pharmaceutically acceptable excipient, wherein the first agent is selected from the group consisting of anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil, and the second agent is selected from one or more of telmisartan and candesartan. [Invention 1048] A pharmaceutical composition according to Invention 1047, wherein the first and second agents are provided as sustained release formulations. [Invention 1049] A pharmaceutical composition according to Invention 1047 or Invention 1048, further comprising magnesium oxide. [Invention 1050] A therapeutic combination comprising a therapeutic combination comprising a first and a second agent, wherein the first agent is selected from the group consisting of anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil, and the second agent is selected from one or more of telmisartan and candesartan, and instructions for the use of the combination for the treatment of brain and / or behavioral health disorders or their symptoms and a kit.

Brief Description of the Drawings

[0065]

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Mode for Carrying Out the Invention

[0066] Detailed Description The present invention features compositions and methods useful for treating brain and / or behavioral health disorders and their related symptoms.

[0067] The present invention is based, at least in part, on the discovery that combination therapies comprising an agent targeting the adrenergic system (e.g., verapamil or other compounds having calcium channel blocking activity) and an agent targeting the renin - angiotensin - aldosterone system (RAAS) (e.g., telmisartan) effectively treat brain and / or behavioral health disorders and significantly reduce associated symptoms. In view of this surprising discovery, one of ordinary skill 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, faripamil, 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 the treated subjects, but also produced a number of positive changes in such subjects, including improvements in overall life satisfaction and sense of meaning and purpose. Without being bound by theory, the combination of verapamil and telmisartan likely simultaneously targets stress - induced hormones in both the body and the brain that collectively affect brain function.

[0068] Brain and behavioral disorders Collectively, worldwide, brain and behavioral disorders are the leading cause of disability. In actual clinical practice, patients have multiple comorbid diagnoses, and achieving comprehensive recovery across the entire spectrum of a very wide range of different symptoms is difficult for most patients, physicians, and families. Treating patients with multiple comorbidities requires separate individual treatments for each disorder, which increases complexity, raises costs, and reduces the safety of care.

[0069] Brain and behavioral health disorders, at least in part, have multiple components and thus present significant psychosocial challenges that negatively impact a patient's quality of life. However, current treatments are designed to address only a single (e.g., neurological) component.

[0070] Brain and behavioral health disorders are a clinically diverse group of disorders, but 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 affect 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 be grouped together as reactive disorders characterized by atypical connectivity between the sensorimotor network and the salience network, respectively. Indeed, treatment success for symptoms of 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 mood disorders, anxiety disorders, neurodegenerative disorders, neurodevelopmental disorders, psychotic disorders, personality disorders, migraine disorders, and somatic body-expression disorders. Examples of mood disorders include bipolar disorder, cyclothymia, depression, irritability, generalized anxiety disorder, major depressive disorder, obsessive-compulsive disorder, postpartum depression, post-traumatic stress disorder (PTSD), phobias, and seasonal affective disorder. Examples of anxiety disorders include panic disorder, social anxiety disorder, post-traumatic 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 disorders. 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, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and obsessive-compulsive personality disorder. Examples of somatic disorders include chronic pain, and migraine-related disorders include migraine with aura, migraine without aura, acephalgic migraine, and basilar artery migraine. Examples of body-expression disorders include somatic symptom disorder, hypochondriasis, conversion disorder, body dysmorphic disorder, and chronic pain. Symptoms associated with the disease include, but are not limited to, anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis, and are selected from one or more of the "10 basic symptoms" associated with brain and behavioral health disorders.Such symptoms are 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", Prim 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 coupling abnormalities that are closely related to the disorders. Selective serotonin reuptake inhibitors ("SSRIs") have limited effectiveness against anxiety. Even with cognitive behavioral therapy and pharmacotherapy, treatment success remains limited. Since SSRIs do not treat symptoms caused by common comorbidities such as ADHD, in the majority of patients seeking anxiety relief, the disability due to comorbidities remains untreated. For patients with ADHD, stimulants are not effective against the comorbid mood disorder and can often worsen it. Symptoms caused by psychiatric comorbidities are often the most disabling, so these represent a significant treatment gap. Furthermore, currently managed treatment options, specifically benzodiazepines, stimulants, and opioids, are dangerous due to the exacerbation, intoxication, and lethal overdose of the comorbid mood disorder.

[0073] Combination therapy It is possible to combine certain existing medicaments that affect the adrenergic system and the brain renin-angiotensin-aldosterone system, which have not been previously used in combination, in order to cause novel synergistic changes in cerebral blood flow leading to a desirable clinical outcome. The combination treatment of the present invention includes, for example, the step of administering a combination of two or more agents selected from previously FDA-approved cardiovascular drug therapies. 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, deparamil, faripamil, gallopamil, tiapamil, and verapamil.

[0074] Individually, the agents are selected to target the renin-angiotensin-aldosterone system and the adrenergic system. Telmisartan and candesartan block the angiotensin 2 receptor and, individually or in combination, balance the intensity of the angiotensin response. Without wishing to be bound by theory, anipamil, deparamil, faripamil, gallopamil, tiapamil, and verapamil affect the output of norepinephrine from the midbrain and, individually or in combination, balance the intensity of the adrenergic response. Since both the adrenergic system and the brain RAAS interact to modulate functional coupling, combinations of agents that target each system independently cause a synergistic effect and result in a novel treatment effect.

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

[0076] The administration to a subject of a composition and dosage form of the present invention containing a first agent selected from one or more of amipamil, depamamil, faripamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, which are co-administered or sequentially administered as a combination treatment, is useful for the treatment of brain and / or behavioral disorders and their related symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis). The combination treatment results in positive psychosocial outcomes that correlate over time with a significant improvement in the overall scale of quality of life. For example, the composition is associated with the achievement of improvement in patients along the Maslow's hierarchy of needs, which is a comprehensive outcome in healthcare that reflects not only the overall symptoms but also the impact on a wide range of social determinants of health. In some embodiments, the therapeutic combinations described herein positively affect the well-being of the treated subject (e.g., improvement in cognitive function, improvement in life satisfaction, improvement in meaning and purpose, improvement in emotional support, improvement in instrumental support, improvement in friendships, improvement in 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 amipamil, depamamil, faripamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan relate to the physiology of the adrenergic and brain renin-angiotensin-aldosterone system (RAAS). When a human perceives danger, two independent body systems change the intrinsic functional couplings in the brain.

[0078] The adrenergic system, which is also known as the sympathetic / parasympathetic nervous system, affects functional connectivity via signal transduction by a neurotransmitter known as norepinephrine (also known as "adrenaline"). When norepinephrine is produced in the adrenal glands, it travels to the brain and binds to β-receptors there. When the β-receptors bind norepinephrine, changes such as pupil dilation, decreased pain sensation, and increased arousal occur.

[0079] The brain renin-angiotensin-aldosterone system, which is also known as the brain RAAS system, affects functional connectivity via a neurotransmitter known as angiotensin. When the angiotensin precursor is produced in the kidneys, it travels to the brain through the lungs and binds to angiotensin receptors there. When the brain angiotensin receptors bind angiotensin, changes occur in the coupling of arterioles and astrocytes, a process known as neurovascular coupling, which causes local changes in cerebral blood flow.

[0080] Although not restricted by a specific mechanism of action, when the adrenergic system and the brain RAAS system are activated, the functional connectivity of the brain changes. This change in connectivity is an evolutionarily conserved stress response system that helps the brain adapt to metabolic demands. When maintained chronically, this can cause an imbalance in functional connectivity that can be harmful. Several factors, including the built environment, social determinants of health, and individual differences, can promote chronic dysregulation. 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, depamil, faripamil, gallopamil, tiapamil, and verapamil and a second agent selected from one or more of candesartan and telmisartan can rebalance changes in functional connectivity associated with brain and / or behavioral health disorders.

[0081] Although not 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 amipamil, depamir, faripamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan. Such combinations act on central functional networks common to multiple neuropsychiatric disorders. Without being bound by theory, the unique combination of angiotensin II receptor blockade and concurrent adrenergic blockade results in rebalancing of the distribution of cerebral blood flow, particularly in the diencephalon, which is a brain region important for social and emotional awareness. In other words, by affecting the functional network related to emotion (midbrain) and at the same time affecting the functional network related to cognition (telencephalon), the functional network related to social cognition (diencephalon) is balanced. This hypothesis is based on findings of significant social changes in patients receiving combination therapy. For example, in patients receiving combination treatment, bidirectional changes in social behavior and dressing behavior were observed. Specifically, introverted patients showed more extroversion during combination treatment, and extroverted patients showed more introversion during combination treatment. The results of the studies described in the examples provided herein showed improvement in social satisfaction in patients receiving combination treatment. The hypothesis that combination treatment results in a balancing effect in functional brain networks is further supported by analysis of results from the Weber test, which is part of regular clinic visits that measures sensory function affected by lateralization of the brain's auditory functional network. At the clinic, patients who initiated combination treatment or who changed from monotherapy to combination treatment showed a shift in the lateralization of the Weber test between visits. A shift in the lateralization of the Weber test does not occur with standard therapeutic agents. A shift in the Weber lateralization does not occur when the patient receives the individual components of the combination treatment. Notably, these shifts are bidirectional, like the changes in social outcomes, and thus there were patients who shifted to the right and patients who shifted to the left.

[0082] While not wishing to be bound by theory, a novel bi - directional outcome associated with a composition comprising a first agent selected from one or more of amipamil, depamipil, faripamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan, suggests that combination treatment may exert a regulatory function in brain regions associated with the auditory network and / or other functional brain networks. Since changes in auditory function correlated with clinical improvement in social function, the therapeutic combinations described herein may affect not only auditory function, but also interoceptive / exteroceptive awareness and social communication skills that rely on auditory functionality. 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 composition of the present invention modulates adrenergic and angiotensin functions A composition comprising a first agent selected from one or more of amipamil, depamipil, faripamil, 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 the brain RAAS. No agent has been designed to target both systems simultaneously. This represents a significant treatment gap since both of these systems interact when patients with brain and / or behavioral disorders experience symptoms that are often untreatable and cause suffering.

[0084] The adrenergic and angiotensin systems affect different functional brain networks Although not bound by theory, the effect of a composition comprising a first agent selected from one or more of amipamil, depamil, faripamil, 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 and angiotensin receptors at each of 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. Although not bound by theory, each level of the brain contains receptor-rich brain regions involved in several networks that contribute to different neurological processes.

[0085] Since β-receptors (which bind norepinephrine) are located at higher density 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. Since angiotensin receptors (which bind angiotensin) are located at higher density in the telencephalon than in the midbrain, the effects of angiotensin are strongest in brain networks that rely on telencephalon regions such as the prefrontal cortex. Since midbrain networks have extensive connections with body organs, clinically, modulation of the adrenergic system affects neuropsychiatric symptoms (e.g., insomnia, fatigue, apathy, pain, anxiety). Since telencephalon networks have extensive connections with brain regions for sensory processing, modulation of the angiotensin system affects various neuropsychiatric symptoms (e.g., cognitive impairment, headache, aura).

[0086] The brain networks for each function span various regions of the older and newer brains. 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 newer brain regions. For example, the default mode network is coordinated in regions mainly located within the telencephalon (the highest phylogenetic level). On the other hand, the salience network is coordinated in regions within the midbrain (the lowest phylogenetic level).

[0087] (Table 1) Functional brain network regions organized by phylogenetic level TIFF0007697110000009.tif165163

[0088] The therapeutic combination of the present invention normalizes the functional connectivity of the whole brain In an aspect, a composition comprising a first agent selected from one or more of anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil and a second agent selected from one or more of candesartan and telmisartan achieves a multi-network effect because the equilibration in the lower brain network affects the equilibration in the higher network 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 can play an important role in shifting the functional connectivity of the brain, if necessary. Without being bound by theory, anipamil, depamil, faripamil, gallopamil, tiapamil, verapamil, and combinations thereof interact with β-receptors in the midbrain (Figure 5). Without being bound by theory, telmisartan and candesartan interact with angiotensin receptors in the telencephalon (Figure 5).

[0089] A composition comprising a first agent selected from one or more of aniperamil, depamil, faripamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan has shown clinical effects suggesting regulation of functional connectivity throughout the brain, as detailed in the following examples. The clinical effects of the composition included normalization of emotional symptoms, as well as social and cognitive symptoms, due to the unique multi-network effect achieved by this synergistic action. Without being bound by theory, since these functions arise from three different layers (diencephalon, midbrain, and telencephalon), a composition comprising a first agent selected from one or more of aniperamil, depamil, faripamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan modifies connectivity at all three levels. The multi-network effect of the composition enables patients to achieve 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, the improvement of overall symptoms attributable to all three phylogenetic levels does not occur when either agent is administered alone. The improvement of overall symptoms attributable to all three phylogenetic levels does not occur with known standard treatment regimens.

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

[0091] A composition comprising a first agent selected from one or more of aniperamil, deperamil, faripamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan can be used for preventing the risk of neurodegenerative diseases starting in middle age. The composition can cumulatively normalize brain metabolism that can become dysregulated in the preclinical neurodegenerative disease state. 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 brain metabolism. Currently, there is no available treatment that can normalize brain metabolism in patients at risk of neurodegenerative diseases. The use of such a composition has not been studied with respect to the prevention or treatment of neurodegenerative diseases.

[0092] A composition comprising a first agent selected from one or more of aniperamil, deperamil, faripamil, gallopamil, tiapamil, and verapamil, and a second agent selected from one or more of candesartan and telmisartan can normalize the intracerebral connections throughout the brain, so the composition can be used for certain indications (i.e., especially cancer, autoimmunity, autonomic nervous system) beyond the boundaries of psychosomatic medicine. Since intracerebral connections affect the health of the immune system, dysregulation of functional connections can affect the risk of medical disorders. Specifically, medical disorders that appear prominently near developmental windows (such as age 25 when the brain finishes myelination) are candidates for new brain-based preventive treatments, including treatment with the composition.

[0093] Pharmaceutical composition The present disclosure provides a pharmaceutical composition comprising an effective amount of a first agent selected from one or more of anipamil, dexpamil, faripamil, 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 formulated and administered simultaneously or sequentially. The first and second agents, when administered in combination, are useful for the treatment of brain and / or behavioral health disorders (e.g., panic disorder). In some embodiments, the combination therapy is administered to treat one or more of 10 basic neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis).

[0094] In an embodiment, the composition of the invention contains a first agent selected from one or more of anipamil, dexpamil, faripamil, gallopamil, tiapamil, and verapamil and a second agent selected from one or more of candesartan and telmisartan for use in combination treatment. In an embodiment, the first agent is verapamil and the second agent is telmisartan and / or candesartan. In some cases, the first agent is selected to affect β - 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 an embodiment, the composition is related to the modulation of both adrenergic activation and angiotensin function.

[0095] In certain embodiments, the compositions of the present invention prevent, inhibit, impede, 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 that manifest in an individual suffering from a disorder having one or more psychiatric, psychological, and / or neurological components.

[0096] Pharmaceutically acceptable salts of anipamil, candesartan, devapamil, faripamil, gallopamil, telmisartan, tiapamil, and verapamil, or combinations thereof, are contemplated herein for the treatment of one or more of the 10 basic neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis). The term "pharmaceutically acceptable salt" also refers to salts prepared by contacting an agent (e.g., anipamil, candesartan, devapamil, faripamil, 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 monoalkylamines, dialkylamines, or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-(2-hydroxy-lower alkylamine), bis-(2-hydroxy-lower alkylamine), or tris-(2-hydroxy-lower alkylamine), e.g., mono-(2-hydroxyethyl)-amine, bis-(2-hydroxyethyl)-amine, or tris-(2-hydroxyethyl)-amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy-lower alkyl)-amine, e.g., 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 salts prepared by contacting an agent (e.g., anipamil, candesartan, devapamil, faripamil, gallopamil, telmisartan, thiapamil, 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, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0097] The composition of the present invention can contain a salt of magnesium and optionally magnesium oxide (MgO).

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

[0099] Formulation of the pharmaceutical composition Administration of a composition containing a first agent selected from one or more of anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil and a second agent selected from one or more of candesartan and telmisartan, in combination with other components, can be administered to a subject for the treatment of a brain and / or behavioral health disorder (e.g., panic disorder) by any suitable means that results in a concentration of a therapeutic agent effective to relieve, reduce, or stabilize one or more of the 10 basic neuropsychiatric symptoms. In some embodiments, the combination treats one or more of the 10 basic neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulty, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis). The composition can contain a salt of magnesium, optionally magnesium oxide (MgO). The composition can generally be contained in any suitable amount in any suitable carrier substance present in an amount of 1 to 95% by weight of the total weight of the composition. The composition can be provided in a dosage form suitable for oral administration. In some embodiments, the composition can be provided in a dosage form suitable for parenteral (e.g., subcutaneous, intravenous, intramuscular, or intraperitoneal) administration routes. The pharmaceutical composition can be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988 - 1999, Marcel Dekker, New York).

[0100] The dosage in humans can be initially determined by extrapolation from the amount of anipamil, candesartan, devapamil, faripamil, gallopamil, telmisartan, thiapamil, verapamil, or combinations thereof used in mice. The dosage may be determined based on the dosage for effective treatment of the disorder for which the individual agent is indicated in humans. The dosage of one or more of anipamil, devapamil, faripamil, gallopamil, thiapamil, and verapamil (optionally, the daily dosage) can be, individually or collectively, 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 more than 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, or 150 mg. The dosage of the first agent or its components and the second agent or its components 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 a day. For example, in some embodiments, a daily dosage (e.g., 80 mg) is delivered in two 40 mg doses per day.

[0102] The first agent and the second agent can be administered to a subject (optionally, as a single dosage form) at a dosage ratio (mass:mass) of about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1, or at least about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1, of the first agent (e.g., anipamil, deparamil, faripamil, gallopamil, tiapamil, verapamil, or a combination thereof) and the second agent (e.g., candesartan, telmisartan, or a combination thereof). In some embodiments, the dosage ratio of the first agent (e.g., anipamil, deparamil, faripamil, gallopamil, tiapamil, verapamil, or a combination thereof) and the second agent (e.g., candesartan, telmisartan, or a combination thereof) is lower than about 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1. The first agent (e.g., anipamil, deparamil, faripamil, gallopamil, tiapamil, verapamil, or a combination thereof) can be administered to the subject at a daily dosage that is about 2 or 3 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 the first agent (e.g., anipamil, deparamil, faripamil, gallopamil, tiapamil, verapamil, or a combination thereof), the second agent (e.g., candesartan, telmisartan, or a combination thereof), or components thereof (e.g., anipamil, candesartan, deparamil, faripamil, gallopamil, telmisartan, tiapamil, verapamil, or a combination thereof) can vary individually or in combination 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, this dosage can 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 dosage can range from about 0.2 mg compound / Kg body weight to about 2 mg compound / Kg body weight. Of course, the dosage can be adjusted up or down depending on the results of the initial clinical trials and the needs of the particular patient, as is routinely done in such treatment protocols.

[0103] In an embodiment, the dosage (optionally, the daily dosage) of the magnesium salt (e.g., MgO) is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 500 mg, or at least about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 500 mg. In an embodiment, the dosage (optionally, the 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 can be formulated to release an active compound (e.g., anipamil, candesartan, devapamil, faripamil, gallopamil, telmisartan, thiapamil, and verapamil, or combinations 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, which includes: (i) a formulation that causes a substantially constant concentration of the drug in the body over a long period of time; (ii) a formulation that causes a substantially constant concentration of the drug in the body over a long period of time after a predetermined delay time; (iii) a formulation that sustains its 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 the plasma level of the active substance (sawtooth kinetic pattern); (iv) a formulation that localizes its action, for example, by the spatial placement of a controlled release composition near the intended target cells (e.g., brain cells); (v) a formulation that enables convenient dosing such that the dose is administered once or twice a day, for example, orally; and (vi) a formulation that targets calcium channels and angiotensin receptors by using a carrier or chemical derivative to deliver a therapeutic agent to a specific cell type (e.g., brain cells). For some applications, the controlled release formulation obviates the need for frequent administration during the day to maintain therapeutic levels of plasma levels.

[0105] To obtain controlled release where the rate of release exceeds the rate of metabolism of the compound, any of a number of strategies can be pursued. In one example, controlled release is obtained by appropriate selection of various formulation parameters and components, including, for example, various types of controlled release compositions and coatings. Thus, the 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 unit or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, molecular complexes, nanoparticles, patches, and liposomes.

[0106] Parenteral composition A pharmaceutical composition is a dosage form, formulation, or can be administered parenterally by injection, infusion, or implantation (subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) via a suitable delivery device or implant, 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. Formulation can be found in Remington: The Science and Practice of Pharmacy (supra).

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

[0108] As shown above, a pharmaceutical composition according to an aspect of the present disclosure can be in a form suitable for sterile injection. To prepare such a composition, one or more of anipamil, candesartan, depamil, faripamil, gallopamil, telmisartan, thiapamil, and verapamil are dissolved or suspended in a parenterally acceptable liquid medium. Acceptable media and solvents that can be used include water, water adjusted to an appropriate pH by the addition of an appropriate amount of hydrochloric acid, sodium hydroxide, or an appropriate buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride and glucose solutions. Aqueous formulations can 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 solubilizing enhancer or solubilizer may be added, or the solvent may contain 10 - 60% w / w of propylene glycol or the like.

[0109] Controlled-release parenteral composition A controlled-release parenteral composition can be in the form of an aqueous suspension, microspheres, microcapsules, magnetic microspheres, an oil solution, an oil suspension, or an emulsion. Alternatively, the active drug can be incorporated into a biocompatible carrier, liposomes, nanoparticles, an implant, or an infusion device.

[0110] Materials for use in the preparation of microspheres and / or microcapsules are biodegradable / biodegradable polymers such as, for example, polygalactine, poly-(isobutyl cyanoacrylate), 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(orthoester), or combinations thereof).

[0111] Solid dosage forms for oral use Formulations for oral use include tablets containing an active ingredient (e.g., one or more of anipamil, candesartan, devapamil, faripamil, 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 bulking agents (e.g., sucrose, sorbitol, sugar, mannitol, crystalline cellulose, starch, e.g., potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives, e.g., crystalline cellulose, starch, e.g., potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, crystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, or polyethylene glycol); and lubricants, flow promoters, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hardened vegetable oil, or talc). Other pharmaceutically acceptable excipients can be coloring agents, flavoring agents, plasticizers, humectants, buffering agents, etc.

[0112] The tablets are, in some embodiments, uncoated and, in other embodiments, coated. The tablets may optionally be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a longer lasting effect. The coating may also be adapted to release the active drug in a predetermined pattern (e.g., to achieve a controlled release formulation) or to not release the active drug until after passing through the stomach (enteric coating). The coating is, in some embodiments, a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymer, polyethylene glycol, and / or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and / or ethylcellulose). Further, a time delay material such as, for example, glyceryl monostearate or glyceryl distearate may be utilized.

[0113] The solid tablet composition, in some embodiments, includes a coating adapted to protect the composition from unwanted chemical changes (e.g., chemical decomposition 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 those described in Encyclopedia of Pharmaceutical Technology (supra).

[0114] One or more of anipamil, candesartan, devapamil, faripamil, gallopamil, telmisartan, tiapamil, and verapamil are mixed together or compartmentalized within a tablet. In one example, a first agent (e.g., one or more of anipamil, devapamil, faripamil, gallopamil, tiapamil, and verapamil) is contained inside the tablet such that a substantial portion of the second agent is released before the release of the first agent, and a second agent (e.g., one or more of candesartan and telmisartan) is contained outside. In some embodiments, a second agent (e.g., one or more of candesartan and telmisartan) is contained inside the tablet and a first agent (e.g., one or more of anipamil, devapamil, faripamil, 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, faripamil, gallopamil, telmisartan, tiapamil, and verapamil, or combinations thereof) is mixed with an inert solid diluent (e.g., potato starch, lactose, crystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium, e.g., peanut oil, liquid paraffin, or olive oil. Powders and granules are prepared in a conventional manner in some embodiments using the aforementioned ingredients for tablets and capsules, for example, using a mixer, a fluid bed apparatus, or a spray dryer.

[0116] Controlled-release oral dosage form A controlled-release composition of a first agent selected from one or more of anipamil, dexpamil, faripamil, gallopamil, tiapamil, and verapamil (for example, for oral use), and a second agent selected from one or more of candesartan and telmisartan can be constructed to release the agents by controlling the dissolution and / or diffusion of the active substances. For example, immediate-release formulations of verapamil and telmisartan are commercially available, and a sustained-release version of verapamil is also commercially available. The verapamil sustained-release (ER) formulation releases the drug over 12 or 24 hours. Release control 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 agents into an appropriate matrix. In some embodiments, the release control coating includes one or more of the above coating substances, and / or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxy methacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycol. In a release control matrix formulation, the matrix material can include, for example, hydrated methyl cellulose, carnauba wax, and stearyl alcohol, carbopol 934, silicon, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbon.

[0117] The controlled-release composition containing two agents described in this specification (for example, one or more of verapamil, anipamil, devapamil, faripamil, gallopamil, thiapamil, and one or more of telmisartan and candesartan) is, in some embodiments, 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 certain period of time upon oral administration). The floating tablet of the composition can be prepared by granulating one or more of the agents or its components with an excipient and 20 - 75% w / w of a hydrocolloid, such as hydroxyethyl cellulose, hydroxypropyl cellulose, or hydroxypropyl methyl cellulose. The resulting granules can then be compressed into tablets. When contacted with gastric juice, the tablets form a substantially water-impermeable gel barrier around their surface. This gel barrier helps to maintain a density of less than 1, thereby enabling the tablets to continue to float in the gastric juice.

[0118] Aspects of the present disclosure provide a method of treating one or more of ten basic neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulty, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis) comprising administering to a subject (e.g., a mammal such as a human) in a therapeutically effective amount a pharmaceutical composition comprising a first agent (e.g., one or more of anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil) and a second agent (e.g., one or more of candesartan and telmisartan). Thus, one aspect is a method of treating a subject afflicted with, or susceptible to, a disease or disorder that causes one or more of the ten basic neuropsychiatric symptoms (i.e., anxiety, apathy, cognitive difficulty, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis). The method comprises administering to the subject, under conditions such that the disease, condition, disorder, or symptoms thereof are treated, a combination of the first agent and the second agent in a therapeutically sufficient amount to treat the disease, condition, disorder, or symptoms thereof. The methods of treatment include prophylactic treatment. In some aspects, the subject is a mammal, specifically a human, afflicted with, having, susceptible to, or at risk of a disease or disorder that causes one or more of the ten basic 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 be by the judgment of the subject or a healthcare provider and can be subjective (e.g., an opinion) or objective (e.g., measurable by a test or diagnostic method).

[0120] Combination therapy Optionally, a first agent (e.g., one or more of anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil) and / or a second agent (e.g., one or more of candesartan and telmisartan) can be administered together with any other standard anti-anxiety treatment, anti-migraine treatment, antidepressant treatment, anti-cognitive difficulty treatment, anti-anger treatment, anti-apathy treatment, anti-fatigue treatment, anti-pain treatment, antipsychotic treatment, or anti-insomnia therapy, such as 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, depamil, faripamil, 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 anti-anxiety and / or sedative agents, antipsychotic agents, mood stabilizers, anti-seizure agents, antihistamine agents, and antidepressant agents.

[0121] The composition of the present invention can be administered to a subject for treating a neuropsychological condition. The neuropsychological condition can be a disorder of the brain and / or behavior. Non-limiting examples of brain and behavioral health disorders include mood disorders, anxiety disorders, neurodegenerative disorders, neurodevelopmental disorders, psychotic disorders, personality disorders, migraine disorders, and somatic symptom disorders. Examples of mood disorders include bipolar disorder, cyclothymia, depression, irritability, generalized anxiety disorder, major depressive disorder, obsessive-compulsive disorder, postpartum depression, post-traumatic stress disorder (PTSD), phobias, and seasonal affective disorder. Examples of anxiety disorders include panic disorder, social anxiety disorder, post-traumatic 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 disorders. 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, borderline 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, acephalgic migraine, and basilar artery migraine. Examples of somatic symptom disorders include somatic symptom disorder, illness anxiety disorder, conversion disorder, body dysmorphic disorder, and chronic pain. The symptoms associated with the disease can be selected from one or more of the "10 basic symptoms" associated with brain and behavioral health disorders: anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis. Administration of the composition or dosage form of the present invention to a subject can reduce or alleviate one or more of the symptoms associated with a disorder of the brain and / or behavior.

[0122] The composition of the present invention can be administered to a subject in an amount sufficient to modify local cerebral blood flow in the subject. The brain region can include one or more of the telencephalon, diencephalon, and mesencephalon. The composition of the present invention can be administered to a subject in an amount sufficient to bring about a hemodynamic balance in a functional intracerebral network that coordinates in certain regions of the subject's telencephalon, diencephalon, and mesencephalon.

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

[0124] Without being bound by theory, patients with the greatest energy supply / demand mismatch can obtain the greatest benefit from the compositions of the present disclosure. Patients with an energy supply / demand mismatch may exhibit the greatest change in functional connectivity before and after combination treatment. When considering energy dichotomously (high vs. low), four energy demand / supply phenotypes emerge. The four types are high demand / high supply (low risk of neuropsychiatric symptoms), high demand / low supply (high risk of neuropsychiatric symptoms), low demand / high supply (low risk of neuropsychiatric symptoms), and low demand / low supply (low risk of neuropsychiatric symptoms).

[0125] Kit or pharmaceutical system The composition of the present invention can be assembled into a kit or a pharmaceutical system 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 kit or pharmaceutical system includes one or more container means, e.g., vials, tubes, ampoules, bottles, etc., sealed therein, and a means of transportation, e.g., boxes, cartons, tubes, etc. The kit or pharmaceutical system can also include the relevant instructions for use of the agent of the aspects of the present disclosure. In some aspects, the kit includes a first agent (e.g., one or more of anipamil, depamil, faripamil, gallopamil, tiapamil, and verapamil) and a second agent (e.g., one or more of candesartan and telmisartan).

[0126] The practice of aspects of the present disclosure, unless otherwise indicated, utilizes conventional techniques of molecular biology (e.g., recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are well within the level of those of ordinary skill in the art. Such techniques are fully described in references such 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);" "Current Protocols in Immunology" (Coligan, 1991). These techniques are applicable to the production of the polynucleotides and polypeptides of the present invention and can thus be considered in the making and practicing of the present invention. Particularly useful techniques for specific embodiments are described in the following sections.

[0127] The following examples are set forth to provide a complete disclosure and description of how to make and use the assays, 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 Effects of Combination Treatment with Verapamil and Telmisartan - A Retrospective Observational Cohort Study A study to measure the novel clinical effects of a composition containing verapamil and telmisartan for the treatment of the overall symptoms of the mental and nervous systems in adults has been completed. The specific objectives of this study were: (1) the magnitude of the novel clinical effects on the overall symptoms; (2) the magnitude of the novel clinical effects on the psychosocial outcomes; and (3) to describe the unique clinical effects that result from the combination treatment but not from the monotherapy treatment. For the main analysis, the results with treatment versus without treatment were compared in all patients.

[0129] Overall symptoms with versus without combination treatment Patients who received combination treatment showed a dramatic reduction in the overall overall symptoms measured by the total of 10 basic disabling symptoms (i.e., anxiety, apathy, cognitive difficulties, depression, fatigue, headache, insomnia, irritability, physical pain, and psychosis), as well as 9 / 10 of the individual symptoms including anxiety, depression, irritability, apathy, fatigue, physical pain, insomnia, headache, and cognitive difficulties, compared to patients who did not receive it. All p-values were less than 0.001. Except for the small effect sizes for depression, insomnia, and headache, all effect sizes were medium to large. Some effect sizes, such as those for the overall overall symptoms, anxiety, and apathy, were significantly large (greater than 1.0) (Figures 1A - 1J).

[0130] Standardized psychosocial outcomes with and without treatment Patients who received combination treatment showed a significant improvement in 6 / 10 of the standardized items of psychosocial health, including general life satisfaction, meaning and purpose, emotional support, instrumental support, friendship, and loneliness, compared to patients who did not receive it. 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 treatment compared to individual monotherapies The outcomes from the combination therapy were significantly different from those from monotherapy with telmisartan twice daily alone or verapamil alone. Compared with the telmisartan-only group, patients who received the combination treatment showed significantly improved outcome scores for the NIH Toolbox items of overall life satisfaction (p<0.01) and anger [hostility] (p<0.04) (Figures 3A - 3B).

[0132] Compared with the verapamil group, patients who received the combination treatment showed significantly different scores for the NIH Toolbox items of self-efficacy (p<0.05) and anger [aggressiveness] (p<0.06) (Figures 4A - 4B).

[0133] Example 2: Observational cohort study of a novel combination treatment, a composition containing verapamil and telmisartan, for the overall symptoms of the psychoneurological system 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 the overall symptoms of the psychoneurological system in adults. The specific objectives of this study were: (1) to measure the safety of the combination treatment; (2) to compare the efficacy of the combination treatment for patients with different symptoms and different disorders; and (3) to use physiological items (Weber test) to test whether the mechanism of action of the treatment combination results in normalization of functional connectivity in the auditory functional network. For the main analysis, 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 trial (Implementation Plan Number: CEDAR2017, first approved by Aspire IRB on April 11, 2017). Details of the demographics, as well as information regarding handedness, primary diagnosis, existing drug therapy, and the presence of cardiovascular diagnosis, can be found in Table 2.

[0135] (Table 2) Baseline demographics TIFF0007697110000010.tif163167

[0136] Self-reported comprehensive symptoms of the mental and nervous system Patients who received the combination treatment showed a significant reduction in comprehensive symptoms for 8 out of 10 basic disabling symptoms (excluding fatigue and psychosis); the greatest effects were seen for apathy, anxiety, cognitive difficulties, and overall mental and neurological disability (see Table 3).

[0137] Among patients who had high anxiety (≥7) at baseline, patients who received the combination treatment showed a significant reduction in comprehensive symptoms for 9 out of 10 basic disabling symptoms. The effect sizes were large for anxiety, irritability, apathy, and overall mental and neurological disability, medium for depression, insomnia, and cognitive difficulties, and small for all remaining symptoms (fatigue, pain, and headache) (see Table 4). Among patients who had moderate anxiety (≥4) at baseline, the effect sizes were medium for anxiety, apathy, cognitive impairment, and overall mental and neurological disability, and small for all remaining symptoms other than psychosis (see Table 5).

[0138] Among patients who had high cognitive difficulties (≥7) at baseline, the effect sizes were large for apathy, cognitive difficulties, and overall mental and neurological disability, medium for anxiety, depression, and irritability, and small for anxiety, physical pain, and insomnia (see Table 6). Among patients who had moderate cognitive difficulties (≥4) at baseline, the effect sizes were large for cognitive difficulties, medium for anxiety, depression, irritability, apathy, and overall mental and neurological disability, and small for fatigue and insomnia (see Table 7).

[0139] (Table 3) Effect of combination treatment on self-reported comprehensive symptoms of the mental and nervous system (the final observation mean follow-up period was 8.9 months) TIFF0007697110000011.tif67170

[0140] (Table 4) Self-reported comprehensive symptoms before and after combined treatment in patients with severe anxiety at baseline TIFF0007697110000012.tif61167

[0141] (Table 5) Self-reported comprehensive symptoms before and after combined treatment in patients with moderate anxiety at baseline TIFF0007697110000013.tif61167

[0142] (Table 6) Self-reported comprehensive symptoms before and after combined treatment in patients with severe cognitive impairment at baseline TIFF0007697110000014.tif61167

[0143] (Table 7) Self-reported comprehensive symptoms before and after combined treatment in patients with moderate cognitive impairment at baseline TIFF0007697110000015.tif61167

[0144] NIH Toolbox standardized outcome items The NIH Toolbox items showed a significant improvement in overall life satisfaction and a barely significant improvement in social satisfaction (Table 8). Outcomes with fewer cases, such as processing speed (n = 17) and Dimensional Change Card Sort (n = 18), did not show significant changes before and after treatment (see Table 8).

[0145] (Table 8) NIH Toolbox standardized outcome items TIFF0007697110000016.tif34170

[0146] Lateralization of Weber showing bidirectional changes in the observation of sensory function The Weber test is a common clinical examination technique that can be used by physicians to identify sensorineural hearing loss. The Weber test utilizes a tuning fork placed at the center above the forehead and asks the patient to report whether the sound lateralizes to the left or to the right. In patients with sensorineural hearing loss, the sound lateralizes to the stronger side. Patients with psychoneurological disorders (e.g., brain and / or behavioral health impairments) without sensorineural hearing loss frequently report lateralization to the left or right when tested by the Weber test. This lateralization may actually be due to the fact that the auditory functional network can be left-dominant, right-dominant, or bilateral 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 the changes in Weber lateralization in patients who initiated, discontinued, or changed the administration of a composition containing verapamil and telmisartan. These changes did not exist between visits when the composition administration remained stable. Notably, there were patients in whom the Weber result was corrected to the left and patients in whom the Weber result was corrected to the right.

[0148] For a total of 23 patients, Weber test results were available 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 had no 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 and without combination treatment TIFF0007697110000017.tif40128

[0150] Bidirectional change in blood pressure In patients who had hypertension at baseline, administration of the composition containing verapamil and telmisartan was associated with a decrease to normal levels. In patients who had hypotension at baseline, administration was associated with an increase to normal levels. In patients who had normal blood pressure at baseline, treatment was not associated with a significant change. The bidirectional change suggests regulation of functional connectivity in the mesencephalic region that mediates autonomic balance (Figure 8).

[0151] Significant differences in social outcomes in patients receiving combination therapy compared to patients receiving monotherapy To compare the proportion of those reporting significant social changes between patients receiving combination therapy and patients receiving monotherapy, a chi-square analysis was performed (Table 10). At each visit, patients were systematically assessed by self-report questions that revealed basic human desires regarding belonging and love. The results showed that patients receiving combination therapy were significantly more likely to report changes in social momentum, new social contacts, clothing, and appearance. Although not bound by theory, these social changes result from changes in the functional brain networks associated with social cognition that rely heavily on the diencephalic and telencephalic brain regions.

[0152] (Table 10) Comparison of the proportion of patients receiving combination therapy reporting significant social changes with patients receiving monotherapy TIFF0007697110000018.tif40170 * Monotherapy refers to only telmisartan or only verapamil.

[0153] Discussion Clinical studies in humans have been completed using a combination of verapamil and telmisartan to treat indications of the mental and nervous systems (e.g., brain and / or behavioral health disorders). This observational study was motivated by the clinical impression of notable symptom improvement in patients with some common mental and nervous system comorbidities who were incidentally treated with combination therapy for approximately one year as part of real-world clinical practice to achieve more complete remission. This study was designed to empirically test the safety and efficacy of combination treatment when delivered in the context of routine mental and nervous care, within the limits of an observational study design. Most patients received combination treatment intensified relative to standard therapy.

[0154] In 102 patients, despite significant improvement in apathy, anxiety, cognitive difficulties, and overall neuropsychological disability (e.g., brain and / or behavioral health disability) after combination treatment, neither systolic nor diastolic blood pressure was significantly different. The proportion of adverse medical syndromes did not change significantly before and after treatment. The adverse symptom profile of combination treatment was similar to the established adverse symptom profiles of telmisartan and verapamil. Standardized tests showed a significant improvement in overall life satisfaction before and after.

[0155] Observational studies can provide estimates of effect sizes similar to those from randomized comparative trials (Development and reliability testing of a cross-cutting symptom assessment for DSM-5. American Journal of Psychiatry, 170(1), 59-70. Narrow, W. E., Clarke, D. E., Kuramoto, S. J., Kraemer, H. C., Kupfer, D. J., Greiner, L., & Regier, D. A. (2013). DSM-5 field trials in the United States and Canada, Part III). This study included several strengths that supported the accuracy of the observed effect sizes. These included a large number of cases, a longitudinal study design that allowed for the analysis of temporal effects, a long follow-up period, inclusion of patients with multiple comorbidities (more accurately similar to real-world clinical settings), inclusion of objective items such as vital signs, and NIH Toolbox items. Another strength of this study was the number of different analyses conducted to test whether associations were causal or merely related, according to the Bradford Hill criteria. To consider a factor causal or related, the following criteria should be observed: strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, analogy, and reversibility.

[0156] Although not bound by theory, the combination treatment acts on central pathways common to multiple neuropsychiatric disorders (e.g., brain and / or behavioral health disorders). Without being bound by theory, the unique combination of angiotensin II receptor blockade and concurrent adrenergic blockade results in a more balanced distribution of cerebral blood flow, particularly in the diencephalon, which is a brain region important for social and emotional awareness. In other words, by affecting emotion (midbrain) and cognition (telencephalon) simultaneously, this synergistic effect can result in improved social cognition (diencephalon). This hypothesis is based on findings of significant social changes in patients receiving combination therapy. For example, changes in social and grooming behavior were observed in patients receiving combination treatment. The results of the study showed an improvement in social satisfaction in patients receiving combination treatment. This is further supported by analysis of results from the Weber test, which was performed as part of regular clinic visits to measure the lateralization of the brain's auditory functional network. At the clinic, patients who initiated combination treatment or who changed from monotherapy to combination treatment showed a shift in lateralization on the Weber test between visits. A shift in lateralization on the Weber test does not occur with standard therapeutic agents.

[0157] Although not bound by theory, a composition containing verapamil and telmisartan can perform a regulatory function in brain regions related to the auditory function network. Since these changes in auditory function correlated with clinical improvement in social function, the composition can affect not only auditory function, but also interoceptive / exteroceptive awareness and social communication that relies on auditory functionality. Indeed, the auditory cortex is directly involved in networks 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] Methods of the Examples The following method was used in Example 1.

[0159] Data and combination therapy 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 the course of usual care, including adjustment of drug therapy and routine cognitive behavioral therapy for neurological, psychiatric, and psychological comorbidities. As a result of participation in the observational study, treatment was not changed. Only patients who consented to the CEDAR project were included in this study.

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

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

[0162] (Table 11) TIFF0007697110000019.tif255151Results are based on two-sided tests. For each significant pair, the key of the category with the smaller column percentage is presented in the category with the larger column percentage. Significance levels 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 is not used in the comparison because the total of the case weights is less than 2. c. The tests are adjusted for all pairwise comparisons in the rows of the innermost sub-tables using the Bonferroni correction.

[0163] (Table 11) continued TIFF0007697110000020.tif255157Results are based on two-sided tests. For each significant pair, the key of the category with the smaller column percentage is presented in the category with the larger column percentage. Significance levels 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 is not used in the comparison because the total of the case weights is less than 2. c. The tests are adjusted for all pairwise comparisons in the rows of each of the innermost sub-tables using the Bonferroni correction.

[0164] Diagnosis and Medical Complexity Clinical diagnosis was performed by a neurologist who had received behavioral neurology fellowship training using a complete neurological history and re-review of independent clinical records of examinations, self-reported psychosocial assessments adapted to the psychoneurological population based on Maslow's hierarchy of needs, and DSM-V psychiatric interviews. Medical complexity was evaluated using a composite score that summarized positive affirmatives (1 point each) to a series of questions regarding past medical history, surgical history, and family history.

[0165] General Symptoms and Disability The National Institute of Health (NIH) Toolbox was used to collect primary outcomes in the cognitive, emotional, and psychosocial domains. These items were selected because they were specifically designed to provide a valid longitudinal assessment of psychoneurological symptoms in community-based populations of children, adults, and older adults.

[0166] The primary outcomes included standardized self-report items for patients with and without treatment. The fully adjusted T-scores of the Pattern Comparison Processing Speed of the NIH Toolbox and the test of dimensional change card sorting were the primary cognitive outcomes. The Negative Affect composite score of the NIH Toolbox and the Psychological Well-Being composite score of the NIH Toolbox were the primary emotional 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. To measure the severity of self-reported symptoms, the average symptom severity scale of 10 basic symptoms (i.e., anxiety, apathy, cognitive difficulty, depression, fatigue, headache, insomnia, irritability, pain (e.g., physical pain), and psychosis), individually measured from 0 to 10 and aggregated on a scale of 0 to 100, as well as the difficulty on a scale of 0 to 10 reported by patients during the clinical care process, were also used as primary outcomes.

[0167] The exploratory outcomes measured psychosocial improvement, including changes in social support, social behavior, relationships, occupational status, and living situation, and were measured by self-report during the treatment process using the total number of self-reported positive and negative psychosocial events.

[0168] The medical safety of the treatment was assessed through the measurement of overall medical symptoms, as determined by the self-report scale of the total number of symptoms reported positively before and after treatment, using the patient's self-report for a systematic review battery that specifically asks about each body system, one by one, given at each visit as part of routine care. Data on blood pressure, pulse, and medication compliance were collected from clinical assessments conducted as part of routine care.

[0169] Statistics To measure the overall effect of the combination treatment with and without treatment, the following intragroup comparisons of the means were performed for patients in the treatment groups: no treatment, monotherapy (verapamil only or telmisartan only), and combination therapy (verapamil + telmisartan). Since the data consisted of multiple repeated hospital visits where the patient had or had not received therapy with any of the drug therapies, the mean of all hospital visits where the patient had not received drug therapy was used to measure the "no treatment" outcome for the patient. The mean of all hospital visits where the patient had received drug therapy was used to measure the "treatment" outcome. The effect size was calculated using Cohen's methodology and quantified using the standard range designating the effect of treatment as small (0.2 - 0.5), medium (0.5 - 0.8), or large (greater than 0.8).

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

[0171] The following method was used in Example 2.

[0172] Patient population Data for this study were selected from the Comparative Effectiveness Dementia Alzheimer's Registry (CEDAR) project of the neuro well FREE Not for Profit Corporation. 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. This clinic accepts all major health insurances and people of all diagnoses of all ages. Patients received the usual course of care, including medication adjustments for neurological, psychiatric, and psychological comorbidities and routine cognitive behavioral therapy. As a result of participation in the observational study, treatment was not changed. Only patients who consented to the CEDAR project were included in this study.

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

[0174] Safety Vital signs were measured using the measurement of systolic blood pressure, diastolic blood pressure, and pulse collected as part of routine care. Adverse events were measured using a 10-point system review inventory covering constitutional, HEENT, respiratory, gastrointestinal, genitourinary, skin, musculoskeletal, endocrine, neurological, and psychiatric symptoms. One point was given for each symptom reported as present, and the possible total score was 93.

[0175] To calculate the rate of adverse events when receiving combination therapy, the percentage of people who answered "present" for one of the symptoms at the 1-month mark of treatment was calculated for each symptom.

[0176] Effectiveness The severity of symptoms 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, physical pain, insomnia, headache, psychosis, and cognitive ability impairment, which were retrieved from medical records. In addition to individual scores in the range of 0 - 10 for each symptom, a total score in the range of (0 - 100) was calculated.

[0177] In addition to self-reported symptom severity, the National Institute of Health Toolbox measurements were used to collect composite level outcomes in the cognitive domain, emotional domain, and psychosocial domain. These items were selected because they are specifically designed to provide a valid longitudinal assessment of neuropsychiatric symptoms in community-based populations of children, adults, and older adults. Specifically, measurements were taken using the NIH Toolbox's pattern comparison processing speed and dimensional change card sorting, general life satisfaction, meaning and purpose, and social satisfaction tests.

[0178] Clinic Visits and Treatment Group Assignment All patients were assigned a baseline clinic visit and two follow-up clinic visits. The baseline clinic visit was assigned as the most recent visit before the patient initiated the treatment of interest. The first follow-up clinic visit was the most recent visit within approximately one month of the start of drug therapy. The last follow-up clinic visit was the time point of the last observation while the patient was receiving the treatment of interest. Three different treatments: before and after telmisartan, before and after verapamil, and before and after combination treatment were compared.

[0179] Medication Adherence Medication adherence was confirmed by reexamining medical records including pharmacy administration records and physician notes.

[0180] Weber's Lateralization The Weber test was administered to patients at their 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 proxy for normalization of functional connectivity in the auditory functional network.

[0181] Statistics To measure the significance of changes before and after treatment, a paired t-test was used. The effect size was calculated using Cohen's methodology and quantified using the standard range that designates the treatment effect as small (0.2 - 0.5), medium (0.5 - 0.8), or large (0.8 and above). Additionally, a paired t-test was used to compare outcomes between different dosage combination therapies. Subgroup analysis was performed on individuals who had moderate baseline clinical anxiety (4 or more), severe baseline clinical anxiety (7 or more), moderate baseline clinical cognitive impairment (4 or more), and severe baseline cognitive impairment (7 or more). In another sensitivity analysis, all patient visits, not just before and after, were used to calculate the mean symptom severity with and without drug therapy. To test the association between drug therapy change and Weber lateralization, a chi-square analysis was performed. The treatment groups were classified as having a change or no change in combination therapy. Lateralization was evaluated as left, left central, central, right central, and right. Data analysis was performed using STATA (Stata / IC 16.1).

[0182] Other aspects From the above description, it will be apparent that the present invention described herein can be varied and modified to suit various usage methods and conditions. Such aspects are also within the scope of the following claims.

[0183] The recitation of elements in any definition of a variable herein includes the definition of that variable as any single element, or combination (or sub-combination) of the recited elements. The recitation of an aspect herein includes that aspect as any single aspect, or in combination with any other aspect or portion thereof.

[0184] All patents and publications referred to herein are incorporated herein 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 improving psychosocial health in a human in need thereof comprising a calcium channel blocker (CCB) selected from the group consisting of anipamil, devapamil, falipamil, gallopamil, tiapamil, and verapamil, and / or an angiotensin II receptor blocker (ARB) selected from the group consisting of telmisartan and candesartan, the method comprising: orally administering an effective amount of a CCB; and Administer an effective amount of an ARB orally Including, The person's psychosocial health in need of improvement is characterized by a need for improvement in three or more psychosocial health factors selected from the group consisting of: (i) meaning and purpose, (ii) emotional support, (iii) instrumental support, (iv) peer relationships, and (v) loneliness; and the human does not have a neurodegenerative disorder; Pharmaceutical compositions.

2. 2. The pharmaceutical composition of claim 1, wherein the ARB is telmisartan.

3. 2. The pharmaceutical composition of claim 1, wherein the effective amount of the CCB is from about 120 mg to about 720 mg and the effective amount of the ARB is from about 45 mg to about 180 mg.

4. 2. The pharmaceutical composition of claim 1, wherein (i) the CCB is verapamil, (ii) the effective amount of the CCB is 120-360 mg, (iii) the ARB is telmisartan, and (iv) the effective amount of the ARB is 40-180 mg.

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

6. 2. The pharmaceutical composition of claim 1, wherein an effective amount of the CCB is administered once or twice daily and an effective amount of the ARB is administered once or twice daily.

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