Compositions and methods for alleviating depression or improving cognition

Abstract

This application describes compositions of receptor inhibitors, including antipsychotic agents, for example haloperidol, and methods of use for alleviating clinical depression, improving cognition and / or treating other syndromes, conditions or diseases for which anti-depressant agents are prescribed. Furthermore, this application describes compositions and methods to induce supersensitivity in dopamine D2 and other receptors involved in depression and / or cognition as a means of alleviating clinical depression or improving cognition.

Description

RELATED APPLICATIONS[0001]The present application is a divisional of co-pending U.S. patent application Ser. No. 12 / 863,513 filed on Jul. 19, 2010, which is a National Stage of International Application No. PCT / CA2009 / 000145, filed Feb. 5, 2009, which claims the benefit of priority of U.S. Provisional Patent Application No. 61 / 026,279, filed Feb. 5, 2008, the contents of each of which are herein incorporated by reference.FIELD OF THE APPLICATION[0002]The present application relates to compositions of receptor inhibitors, including dopamine receptor inhibitors such as haloperidol, and methods for alleviating clinical depression, improving cognition and / or alleviating depression-related symptoms in other conditions, diseases or syndromes. Furthermore, this application relates to methods of use of compositions of receptor inhibitors, including dopamine receptor inhibitors, to promote supersensitivity in receptor states associated with depression and / or cognition as a means of alleviati...

AI Technical Summary

Benefits of technology

[0065]Due to the relatively high number of adverse reactions associated with the currently approved antidepressants, the fact that a large number of clinically depressed individuals remain refractory to currently available therapies, and that the effects of therapies wane over time, there is a need for new approaches to treat clinical depression. Furthermore, there is a need for new approaches to treat depression-associated symptoms of other conditions, syndromes or diseases for which anti-depression agents are sometimes used. Described herein are novel compositions and methods for the treatment of clinical depression, cognition and / or other conditions, syndromes or diseases for which anti-depressant agents are prescribed, which are expected to result in improved efficacy and more ready acceptance by depressed patients or individuals with diminished cognition. The present application is based on the principle that a low level of post-synaptic receptor supersensitivity, as controlled by the level of receptors in the functional or “high affinity” state, can simultaneously mediate the two processes of antidepressant and pro-cognitive action.

[0072]The low dosage of dopamine D2 receptor inhibitor, which avoids any Parkinsonism or extrapyramidal motor reactions, optionally in combination with the intermittent dosing, is a unique design that results in dopamine D2 receptor supersensitivity. The dopamine supersensitivity is mediated by the dopamine D2 receptor inhibitor induction of an increase in the proportion of dopamine D2 receptors that are in the high-affinity state, or D2High. The method of the present application is applicable to haloperidol and other antipsychotic agents and other receptors associated with depression, cognition and / or other conditions, syndromes or diseases for which anti-depressant agents are prescribed.

Problems solved by technology

Some individuals experience a combination of both the threat of harm accompanied by physical harm.

The symptoms unlike other types of syndromes persist, and may last more than six months resulting in significant impairment in social, family and work relationships.

The second is that the person's response involved intense fear, or helplessness.

Pharmacological strategies have reduced PTSD symptoms but have not been successful in eliminating them.

These include antidepressants such as selective serotonin reuptake inhibitors (SSRI's) such as citalopram, escitalopram, fluvoxamine, paroxetine and sertraline, and tricyclic antidepressants (TCA's), which are associated with less efficacy and increased side-effects.

While none of these agents are curative, many such as the TCAs have unwanted side effects.

Anorexia nervosa, can involve neurobiological, psychological, and sociological components, and can lead to death in certain circumstances.

Pharmacological methods have included SSRIs or other antidepressant medications but these have not been found to be generally effective for either treating anorexia (Claudino A M., et al.

Additional neural circuits superimposed on this system have the potential to override the homeostatic signals, resulting in either gluttony or anorexia at the extremes.

Oct. 30[Epub ahead of print], 2008); however, to date significant strides have not been made in the treatment of these individuals.

Currently-available drugs for treating depression have delayed onset of action, poor efficacy, anticholinergic effects at therapeutic doses, cardiotoxicity, convulsions and the clinical risk of overdosing.

In particular, side effects of SSRI's include nausea, diarrhoea, headaches and sexual dysfunction such as loss of libido, failure to reach orgasm and erectile problems.

Side effects of TCA's include dry mouth, blurred vision, drowsiness, dizziness, tremors, sexual problems, skin rash, and weight gain or loss.

MAOI's are of particular concern because there are potentially fatal interactions between this class of medication and certain foods (those containing tyramine).

Furthermore, a large number of clinically depressed individuals remain refractory to currently-available therapies and the effects of therapies wane over time.

However, the doses of these antipsychotics are generally lower in treating depression, and it is likely that the antipsychotics are actually only removing the element of anxiety within the clinical depression as opposed to treating true clinical depression (M. M. Katz et al., Depression & Anxiety 4: 257-267, 1996-97).

However, amisulpride has not been approved for depression.

These data suggest that not all antipsychotics or doses will be useful for inhibiting depressive symptoms.

In addition, it is known that there are fundamental differences between antipsychotics based on their differing affinities for the dopamine D2 receptor.

A review of atypical antipsychotics for enhancing antidepressant action in major depression revealed that while small clinical studies appeared to show some improvement, large well-controlled clinical studies failed to show effectiveness of atypical antipsychotics in reducing major depressive disorder when used with antidepressant agents (Shelton R C et al.

While each of the compounds and medications listed above may improve one or two of the components of cognition, there is no single compound that improves all aspects and components of cognition.

Moreover, each of these compounds has adverse effects.