Composition and method for treatment of neuropsychiatric disorders

Abstract

The present invention relates to a composition and method for combinative therapy, capable of temporarily regulating inherent dysfunctional neural processes and reducing symptoms and/or signs of neuropsychiatric disorders including, but not limited to, psychostimulant use disorder (PUD) and other substance-related additive disorders, post-traumatic stress disorder (PTSD) and other trauma- and stress-related disorders, and levodopa-induced dyskinesia (LID) and other types of dyskinesias. The present specification shows specific examples of a dosage form.

Description

CLAIM OF PRIORITY[0001]This application claims priority to U.S. provisional patent Application No. 62 / 108,616, filed on Jan. 28, 2015, the disclosure of which is incorporated herein by reference in its entirety for all purposes.UNITED STATES GOVERNMENT FUNDING AND RIGHTS[0002]The present invention was produced in part using funds from the United States Federal Government under NIH Grant Nos.: R01 DA012768 entitled “Cocaine Withdrawal: A Window of Treatment Opportunity”; R01DA14323 entitled “Medication Development for Methamphetamine Abuse”; NS42124 entitled “Presynaptic Mechanisms and Parkinson's Treatment”; and RC2 DA028905 entitled “Novel Ondansetron Formulation for Combination Treatment of Psychostimulant Abuse.” Accordingly, the Federal Government has certain rights to the present invention.BACKGROUND OF THE INVENTION1. Field of the Invention[0003]The present invention relates to combination therapy compositions and methods that can temporally modulate underlying dysfunctional n...

AI Technical Summary

Benefits of technology

[0027]It is an object of the present invention to provide combination therapy compositions and methods, which may, by temporally modulating the underlying dysfunctional neural processes, reduce symptoms and / or signs of neuropsychiatric disorders, including, but not limited to, psychostimulant use disorder (PUD) and other substance-related and addictive disorders, post-traumatic stress disorder (PTSD) and other trauma- and stressor-related disorders, and levodopa-induced dyskinesia (LID) and other types of dyskinesia.

Problems solved by technology

Despite a high unmet need for effective treatment of psychostimulant use disorder (PUD), more than 20 drugs tested in clinical studies to date have shown only limited efficacy, and no drug is approved by the FDA for this indication.

Drugs that are currently used for PUD patients are typically limited to the treatment of comorbid psychiatric conditions.

Meanwhile, various psychoactive drugs have been used “off-label” (i.e., without FDA approval) to treat PUD, but the effectiveness thereof has not been strictly tested.

While the combination therapy method, whereby a 5HT2, 5-HT3 or NK-1 receptor antagonist is administered to animals after the fixed delay of 3.5 hrs. after administration of a DA agonist, was well established in animal models of PUD (see Lee et al., 2012 supra), the utility of these treatments in humans were limited by their strict dependence on the obligatory dosing regimen (i.e., agonist followed 3.5 h later by antagonist) that forces patients to administer the two drugs at the respective prescribed time points in order to obtain any therapeutic benefits.

This lack of practical means to ensure treatment compliance is especially problematic for PUD and other psychiatric patients, who, because of their primary or comorbid psychiatric diagnoses, are typically unwilling or unable to adhere to prescribed treatment plans.

Thus, successful use of the combination therapy in these patients is typically limited to monitored settings such as inpatient or residential treatment facilities, and attempts to treat PUD patients in an outpatient setting will lead to failure to meet the treatment objective of reduced illicit drug use.

However, its propensity to induce levodopa-induced dyskinesia (LID) and associated efficacy loss continue to limit its usefulness in the long-term management of PD patients.

These fluctuations, in turn, induce dysfunctional synaptic alterations in the basal ganglia and other brain areas.

Unfortunately, these “sustained” levodopa approaches have not been as effective as originally expected.

Maintenance of drug concentrations within the effective therapeutic range for extended periods of time is expected to frequently lead to increased incidences of night-time side effects such as nightmares, sleep disturbances, etc.

These considerations suggest that numerous factors, including individual differences in drug metabolism, ability to adhere to prescribed dosing regimen, and / or therapy noncompliance due to increasing LID or other side effects may potentially lead to variability in the duration of the sustained levodopa levels—thus limiting the utility of “sustained” treatments as an “anti-LID” strategy.

Recently, deep brain stimulation (DBS) has been also increasingly utilized, although, in addition to its invasive nature and risks for short- and long-term post-operative complications, it is yet to be systematically determined whether this procedure directly modifies critical neurobiological alterations underlying LID or only indirectly does so by allowing for reduced levodopa doses, secondary LID expression blockade and / or slowing down PD progression.

Although benzodiazepines, atypical antipsychotics, anticonvulsants have been also examined, these agents have not shown consistent efficacy, and are not currently on the recommended drug list in the aforementioned guideline.

Images