WO2011038124A2

WO2011038124A2 - Systems and methods for treating depression, including the use of neurobehavioral tasks

Info

Publication number: WO2011038124A2
Application number: PCT/US2010/050010
Authority: WO
Inventors: Diego A. Pizzagalli
Original assignee: Harvard University
Current assignee: Harvard University
Priority date: 2009-09-24
Filing date: 2010-09-23
Publication date: 2011-03-31
Anticipated expiration: 2012-03-24
Also published as: WO2011038124A3

Abstract

The present invention generally relates to systems and method for treating depression, including clinical depression. In one aspect, a subject is engaged in a neurobehavioral task. In some cases, an antidepressant treatment may also be applied to the subject. The neurobehavioral task may be one which tests the ability of the subject to respond to negative feedback and/or commission of an error, and/or to monitor conflicting information or stimuli. For instance, the neurobehavioral task may involve providing a subject with information that is inherently conflicting. In certain embodiments, such treatments may be effective because the neurobehavioral tasks may boost the potential success for treating the depression, e.g., by stimulating the rostral anterior cingulate cortex ("ACC"), and/or by increasing functional or structural connectivity between the ACC and other prefrontal cortex regions, including, but not limited to, the dorsolateral prefrontal cortex. Other aspects of the present invention are directed to systems and methods for implementing such techniques, analyzing such techniques, promotion of such techniques, and the like.

Description

SYSTEMS AND METHODS FOR TREATING DEPRESSION,

INCULDING THE USE OF NEUROBEHAVIORAL TASKS

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Patent Application Serial

No. 61/245,640, filed September 24, 2009, entitled "Systems and Methods for Treating Depression, Including the Use of Neurobehavioral Tasks," by Pizzagalli, incorporated herein by reference.

FIELD OF INVENTION

The present invention generally relates to systems and method for treating depression, including clinical depression.

BACKGROUND

Depression is a common, recurrent, and disabling disorder. Epidemiological studies show that depressive disorders are the leading cause of years lost to disability, resulting in an annual global loss of 13 million years worldwide, 1.5 million of those in the U.S. alone where the lifetime prevalence of depression is 17%. Despite the availability of a variety of antidepressant treatments, up to 34% of patients fail to respond, 46% fail to achieve full remission, and 50% will relapse. Accordingly, improvements in increasing the likelihood of response to treatment would have vast implications for individuals and society. These benefits would include a decrease in personal suffering and suicide risk; improvements in functioning and quality of life; and a reduction in healthcare costs.

SUMMARY OF THE INVENTION

The present invention generally relates to systems and method for treating depression, including clinical depression. The subject matter of the present invention involves, in some cases, interrelated products, alternative solutions to a particular problem, and/or a plurality of different uses of one or more systems and/or articles.

In one aspect, the present invention is directed to a method of treating a subject diagnosed with or suspected of having depression. According to one set of

embodiments, the method includes acts of engaging the subject diagnosed with depression in a neurobehavioral task, and applying antidepressant treatment to the subject. In another set of embodiments, the method includes acts of engaging the subject diagnosed with depression in a neurobehavioral task, and after engaging the subject in the neurobehavioral task, assessing the effectiveness of the treatment by assessing a degree of depression in the subject.

The method, in accordance with yet another set of embodiments, includes acts of engaging the subject in a first neurobehavioral task, engaging the subject in a second neurobehavioral task, where the second neurobehavioral task occurs after the first neurobehavioral task, and assessing a degree of depression in the subject.

In one aspect, the present invention is directed to a method of treating a subject suspected of having depression. In one set of embodiments, the method includes acts of engaging the subject in a neurobehavioral task for at least three sessions, and assessing a degree of depression in the subject. The method, in another set of embodiments, includes acts of engaging the subject in a first, second, and third neurobehavioral tasks, where the first, second, and third neurobehavioral tasks each occur within a 7-day period, and assessing a degree of depression in the subject.

In still another aspect, the present invention is generally directed to a computer- implemented method. According to one set of embodiments, the method includes an act of operating a computer to engage a subject in a neurobehavioral task and assess a degree of depression in the subject.

The present invention, in yet another aspect, is directed to an article. In one set of embodiments, the article includes a machine-readable medium having a program stored thereon. In one embodiment, the program comprises instructions for, when executed, causing a computer to perform acts of engaging a subject in a neurobehavioral task, and assessing a degree of depression in the subject.

Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention. In cases where the present specification and a document incorporated by reference include conflicting and/or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and/or inconsistent disclosure with respect to each other, then the document having the later effective date shall control. DETAILED DESCRIPTION

The present invention generally relates to systems and method for treating depression, including clinical depression. In one aspect, a subject is engaged in a neurobehavioral task. In some cases, an antidepressant treatment may also be applied to the subject. The neurobehavioral task may be one which tests the ability of the subject to respond to negative feedback and/or commission of an error, and/or to monitor conflicting information or stimuli. For instance, the neurobehavioral task may involve providing a subject with information that is inherently conflicting. In certain

embodiments, such treatments may be effective because the neurobehavioral tasks may boost the potential success for treating the depression, e.g., by stimulating the rostral anterior cingulate cortex ("ACC") and/or by increasing functional or structural connectivity between the ACC and other prefrontal cortex regions, including, but not limited to, the dorsolateral prefrontal cortex. Other aspects of the present invention are directed to systems and methods for implementing such techniques, analyzing such techniques, promotion of such techniques, and the like.

Certain aspects of the invention are directed to the treatment of depression in human subjects, including clinical depression such as major depressive disorder (MDD). Without wishing to be bound by any theory, it is believed that the anterior cingulate cortex ("ACC"), including the rostral ACC, is involved with regulating emotion and mood, including depression. For instance, the anterior cingulate cortex is involved with various cognitive functions, such as reward anticipation, decision-making, action monitoring, and emotion. Accordingly, in some aspects, by engaging the subject in a task, such as a neurobehavioral task, that affects the state or condition of the anterior cingulate cortex, including the rostral ACC, the subject may be able to respond more effectively to antidepressant treatment. Thus, in certain cases, the subject is transformed from a first state to a second state in which the subject is able to respond more effectively to antidepressant treatment.

Such engagement may increase the response of the subject to antidepressant treatment over time, in certain embodiments, even without the use of feedback (e.g., via EEG-based feedback) techniques or the like. Thus, the engagement may, in some embodiments, transform the subject from one exhibiting a first level of responsiveness to antidepressant treatment (e.g., no responsiveness) to one which exhibits relatively more responsiveness to the antidepressant treatment. In certain cases, the neurobehavioral task may itself have some antidepressant effects on subjects; thus, in some cases, a subject may be treated for depression by engaging the subject in a neurobehavioral task. In one set of embodiments, the subject is treated for depression by exclusively engaging the subject in a neurobehavioral task.

In some cases, the neurobehavioral task involves monitoring and correction of behavioral performance by the subject, and/or monitoring of competing information by the subject. For instance, in certain embodiments, the neurobehavioral task involves providing a subject with information that is inherently conflicting; to respond correctly to the task, the subject may suppress some information while acting on other information. For example, the neurobehavioral task may exhibit two "channels" of information, and the subject must respond to the first channel of information while ignoring or mentally suppressing the other channel. Thus, as a specific non-limiting example, in the Stroop Task, words spelling one color but printed or displayed in a different color are presented to the subject (e.g., the word "red" may be displayed in blue); the first channel of information is the word itself, while the second channel of information is the color of the word. The subject may be required, as part of the neurobehavioral task, to name the color the word is printed or displayed in while ignoring the written word. Due to the competing channels of information, such tasks are often error-prone. Other examples of suitable neurobehavioral tasks are discussed herein.

Without wishing to be bound by any theory, it is believed that such tasks, due to competing channels of information, require the subject to use the frontocingulate brain pathway to effectively suppress incorrect channels of information and/or modulate behavior adaptively in order to perform the neurobehavioral tasks. Thus, in one set of embodiments, the neurobehavioral task is a task that, in general, targets the

frontocingulate brain pathways. For instance, the task may be one which has been shown to result in brain activity in the frontocingulate portion of the brain of a subject when the task is given to the subject, in at least a substantial percentage of normal subjects. Surprisingly the use of a neurobehavioral task, which ordinarily does not require sophisticated monitoring or feedback systems as EEG-based systems, may be able to produce a significant improvement in the response of subjects to antidepressant treatment. Examples of neurobehavioral tasks that incorporates the ability of the subject to respond to negative feedback and/or adjust behavior after committing errors is the Eriksen Flanker Task, which generally involves identifying a central stimulus flanked by similar or different stimuli, for example, identifying whether the central arrow in the pattern "> > < > >" is pointing to the left or right, or whether the central letter in the string of letters HHSHH is an "H" or "S", etc. Other non-limiting examples include the Stroop Task (identifying words printed in one color but reciting a different color), the Counting Stroop Task (counting the number of times words identifying a number are shown, where the identified number may not be equal to the number of times it appears, e.g., "one one one"), the Emotional Counting Stroop (counting the number of times words having emotional content appear), the Directional Stroop Task (identifying words based on their physical location, which can be inconsistent with their meaning, e.g., "left" on the right side of the page), the Simon Task (making spatial responses, i.e., pressing a left or right key, depending on a given stimulus, where a given stimulus presented to the right of a fixation cross would require pressing a left key), the A-X

Continuous Performance Test (identifying a letter, e.g. "X," only if certain conditions are met, for instance, being preceded by an "A"), the Go/NoGo Task (responding to certain targets ("Go") but ignoring distracters ("NoGo") in a list of words), or the Emotional Go/NoGo Task (responding to certain emotions, presented as words, pictures, faces, etc., (e.g., happy, angry, sad, etc.), while ignoring other emotions (e.g., neutral, happy, etc.) in a suitable display of words, pictures, faces, etc.). These and other, similar tasks are known by those of ordinary skill in the art and can be applied to a subject without undue effort, e.g., by a person or a computer, for instance, self-administered by the subject. For instance, for the Stoop Task, a computer may randomly select a color and a color name from suitable lists (optionally discarding cases where the colors are identical), display the color name in the selected color to the subject, await input from the subject regarding the color of the text, and score the results accordingly. Similar processes may be used for the other tests described above, e.g., random selection from appropriate lists.

Accordingly, in some aspects of the present invention, the subject is engaged in a neurobehavioral task. The neurobehavioral task, in some embodiments, includes tasks in which the ability of the subject to respond to negative feedback and/or commission of an error is provided to the subject. Such neurobehavioral tasks have not generally been previously recognized clinically as being useful as treatments for depression. Thus, in one set of embodiments, a subject may engage in neurobehavioral tasks to treat depression and/or to increase the likelihood of responding favorably to a different type of antidepressant treatment, including, but not limited to, pharmacological treatment, depression counseling or psychotherapy, electroconvulsive therapy, electroshock therapy, vagal stimulation, deep brain stimulation, epidural cortical stimulation, or transcranial stimulation, sleep deprivation, light therapy, or other treatments disclosed herein. In some cases, the neurobehavioral task may be administered prior to, concurrently, and/or subsequent to the other antidepressant treatment. Furthermore, in some (but not all) cases, a clinically accepted antidepressant treatment may also be given to the subject, e.g., as discussed below.

In one set of embodiments, the subject is engaged in the neurobehavioral task for a period of time sufficient to statistically increase the subject's accuracy in perform the task over time (e.g., over the course of treatment). For example, the accuracy of the subject may increase by at least about 5%, at least about 7.5%, at least about 10%, at least about 12.5%, etc. As discussed, such tasks may stimulate the ACC or cause an increase in ACC function, including the rostral ACC, which may synergistically improve the effectiveness of antidepressant treatments given to the subject.

In some cases, more than one session may be necessary. For example, multiple sessions may be necessary before the subject shows a statistical increase in accuracy and/or more efficient performance, including, but not limited to, faster performance while maintaining a similar level of accuracy. Thus, the subject may be given the neurobehavioral task over multiple sessions, e.g., over two, three, four, five, six, ten, fifteen, or more sessions, where the sessions generally occur on different days. For instance, the sessions may be given to the subject after one or several hours, e.g., after 4 or 6 hours, or daily, weekly, monthly, etc. In some cases, multiple sessions may be given within a week, e.g., two, three, four, five, six, ten, fifteen, or more sessions. The tasks may be given to the subject by the same therapist or different therapist, or in some cases, the tasks may be self-administered or administered by a computer, depending on the task. In some cases, the subject may be engaged in more than one neurobehavioral task, and the tasks may be given at the same time (e.g., in the same session), or at different times or sessions. For example, the subject may be engaged in a first neurobehavioral task at a first session and a second neurobehavioral task at a second session, and/or more than one neurobehavioral task may be given to the subject in a given session.

In certain aspects, the subject may also be assessed to determine the degree of depression exhibited by the subject. The assessment may occur before and/or after a neurobehavioral task. The assessment may be used, for instance, to determine that the subject exhibits fewer symptoms and/or severity of depression, e.g., by being

transformed from a subject exhibiting depression to a subject exhibiting a milder form of depression (including no depression).

Any of a wide variety of suitable depression tests may be used, and many are commercially available or otherwise readily obtainable. Such tests may be useful, e.g., for determining progress of subject in responding to antidepressant treatment and/or the effects of the neurobehavioral task. The assessment may be performed by a therapist or other professional, or in some cases, the assessment may be self-administered (e.g., by having the subject use a computer, the WWW, and/or the Internet to present a depression assessment questionnaire). In some cases, the computer may also be one which engages the subject in the neurobehavioral task.

Non-limiting examples of depression tests include the Hamilton Rating Scale for Depression test, the Montgomery- Asberg Depression Rating Scale test, the Beck Depression Inventory test, the Zung Self-Rating Depression Scale test, the Wechsler Depression Rating Scale test, the Raskin Depression Rating Scale test, the Depressive Symptomatology test, or the Quick Inventory of Depressive Symptomatology test. Many of these tests involve a series of questions presented to the subject, and the answers by the subject are used to rate the severity of the subject's depression. For example, the questions may include questions relating to mood, insomnia, agitation, anxiety, weight loss, fatigue, concentration, lack of energy, appetite, feelings of hopelessness and irritability, cognitions such as guilt or feelings of being punished, pessimistic or suicidal thoughts, or the like.

As previously described, certain embodiments of the invention may be implemented on a computer, and/or implemented using the WWW or the Internet. In some cases, the embodiments may be implemented using hardware, software or a combination thereof. When implemented in software, the software code can be executed on any suitable processor or collection of processors, whether provided in a single computer or distributed among multiple computers. For example, in one set of embodiments, a computer is used to engage a subject in a neurobehavioral task, and/or assess a degree of depression in the subject, e.g., as described herein. As specific examples, the program may be implement using the WWW or the Internet, and the subject uses a web browser to access the program, e.g., for the neurobehavioral task and/or assessment of depression.

Also, the various methods or processes outlined herein may be coded as software that is executable on one or more processors that employ any one of a variety of operating systems or platforms. Additionally, such software may be written using any of a number of suitable programming languages and/or conventional programming or scripting tools, and also may be compiled as executable machine language code.

The invention, in some cases, may be embodied as a computer readable medium (or multiple computer readable media) (e.g., a computer memory, one or more floppy discs, compact discs, optical discs, magnetic tapes, flash drives, hard disks, CDs, DVDs, Blu-ray Discs, etc., or any other optical and/or magnetic storage media) encoded with one or more programs that, when executed on one or more computers or other processors, perform methods that implement the various embodiments of the invention discussed above. When loaded by a computer or other suitable machine (e.g., a general- purpose computer or a specific machine), the program, when executed, may be used to engage a subject in a neurobehavioral task, and/or assess a degree of depression in the subject. The computer readable medium or media can be transportable, such that the program or programs stored thereon can be loaded onto one or more different computers or other processors to implement various aspects of the present invention as discussed above.

The terms "program" or "software" are used herein in a generic sense to refer to any type of computer code or set of computer-executable instructions that can be employed to program a computer or other processor to implement various aspects of the present invention as discussed above. Additionally, it should be appreciated that according some embodiments, one or more computer programs that when executed perform methods of the present invention need not reside on a single computer or processor, but may be distributed in a modular fashion amongst a number of different computers or processors to implement various aspects of the present invention.

Computer-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices. Generally, program modules include routines, programs, objects, components, data structures, etc. that perform particular tasks or implement particular abstract data types. Typically the functionality of the program modules may be combined or distributed as desired in various embodiments.

Some aspects of the invention involve applying antidepressant treatment to the subject, and in certain embodiments, more than one antidepressant treatment may be given to the subject, and in any suitable order, e.g., sequentially, simultaneously, etc. For instance, the antidepressant treatment may be given to the subject during (or before or after) a neurobehavioral task, or the antidepressant treatment may be applied to the subject on a regime that has some degree of overlap in time with the neurobehavioral task. For example, the antidepressant treatment may occur over several days, weeks, months, etc., and the subject may engage the neurobehavioral task in multiple sessions over several days, weeks, months, etc., where there may be at least some overlap in time of the two.

In some cases, the response of a subject to treatment may be determined using systems and methods such as those taught in U.S. Patent Application Serial No.

12/225,943, filed October 2, 2008, entitled "Systems and Methods for Predicting Effectiveness in the Treatment of Psychiatric Disorders, Including Depression," by Pizzagalli, incorporated herein by reference in its entirety.

The antidepressant treatment may be any treatment generally clinically accepted as a form of depression treatment. For example, in one set of embodiments, the antidepressant treatment may include depression counseling or psychotherapy, e.g., by a licensed professional or other competent therapist. In some embodiments, the antidepressant treatment may include electroconvulsive therapy, electroshock therapy, vagal stimulation, deep brain stimulation, epidural cortical stimulation, or transcranial stimulation. In some cases, such therapies involve the creation of electrically-induced seizures in anesthetized subjects for therapeutic effect. In still another set of embodiments, the antidepressant treatment may include sleep modification, including sleep disruption or sleep deprivation. In still another set of embodiments, the subject may be exposed to increased or decreased light levels as an antidepressant treatment, e.g., for a portion of a day, or on a predictable schedule (e.g., at certain times every day). In yet another set of embodiments, the subject may be exposed to acupuncture as an antidepressant treatment.

In yet another set of embodiments, the antidepressant treatment includes the application of antidepressant medication. Many such medications are readily available commercially. Non-limiting examples of antidepressant medications include monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants, or other substances such as St. John's wort, SAMe (S-adenosylmethionine), or omega-3 fatty acids. Examples of MAOIs include, but are not limited to, benmoxin, hydralazine, hydrazine, iproclozide, iproniazid, isocarboxazid, mebanazine, metfendrazine, monomethylhydrazine, nialamide, phenelzine, pheniprazine, phenoxypropazine, phenylhydrazine, pivalylbenzhydrazine, procarbazine, safrazine, tranylcypromine, befloxatone, brofaromine, cimoxatone, clorgyline, curcumin, harmine, harmaline, tetrahydroharmine, methylene blue, minaprine, moclobemide, pirlindole, toloxatone, tyrima, catechin, desmethoxyyangonin, epicatechin, hydroxytyrosol, lazabemide, pargyline, piperine, rasagiline, or selegiline. Non-limiting examples of TCAs include amitriptyline, butriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, trimipramine, desipramine, nortriptyline, protriptyline, dibenzepin, iprindole, melitracen, nitroxazepine, amineptine, opipramol, or tianeptine. Examples of TeCAs include, but are not limited to, amoxapine, maprotiline, mianserin, mirtazapine, or setiptiline. Non-limiting examples of SSRIs include citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or zimelidine. Non-limiting examples of SNRIs include venlafaxine, desvenlafaxine, duloxetine, milnacipran, tramadol, sibutramine, or bicifadine. Non-limiting examples of atypical antidepressant include wellbutrin. Such antidepressant medications may be applied with a suitable pharmaceutically acceptable carrier.

As used herein, the term "pharmaceutically acceptable" is given its ordinary meaning. Pharmaceutically acceptable compositions are generally compatible with other materials of the formulation and are not generally deleterious to the subject. Any of the compositions of the present invention may be administered to the subject in a therapeutically effective dose. A "therapeutically effective" or an "effective" as used herein means that amount necessary to delay the onset of, inhibit the progression of, halt altogether the onset or progression of, diagnose a particular condition being treated, or otherwise achieve a medically desirable result. In administering the antidepressant medication to a subject, dosing amounts, dosing schedules, routes of administration, and the like may be selected so as to affect known activities of the antidepressant

medications. The dosage may be given in some cases at the maximum amount while avoiding or minimizing any potentially detrimental side effects within the subject. The dose delivered may also depend on conditions associated with the subject, and can vary from subject to subject in some cases. For example, the age, sex, weight, size, environment, physical conditions, or current state of health of the subject may also influence the dose required.

Any medically acceptable method may be used to administer the antidepressant medication to the subject. The administration may be localized (i.e., to a particular region, physiological system, tissue, organ, or cell type) or systemic, depending on the condition to be treated. For example, the composition may be administered orally, vaginally, rectally, buccally, pulmonary, topically, nasally, transdermally, through parenteral injection or implantation, via surgical administration, or any other method of administration. Examples of parenteral modalities that can be used with the invention include intravenous, intradermal, subcutaneous, intracavity, intramuscular,

intraperitoneal, epidural, or intrathecal. Examples of implantation modalities include any implantable or injectable drug delivery system. Oral administration may be preferred in some embodiments because of the convenience to the subject as well as the dosing schedule. Antidepressant medications suitable for oral administration may be presented as discrete units such as hard or soft capsules, pills, cachettes, tablets, troches, or lozenges, each containing a predetermined amount of the active compound.

Administration of the antidepressant medication may also include oral dosage forms, bolus injections, transdermal patches or subcutaneous implants. Other delivery systems include time-release, delayed release, sustained release, or controlled release delivery systems. Administration of the antidepressant medication can be alone, or in combination with other antidepressant medications and/or other antidepressant treatments.

In certain embodiments of the invention, an antidepressant medication can be combined with a suitable pharmaceutically acceptable carrier, for example, as incorporated into a liposome, incorporated into a polymer release system, or suspended in a liquid, e.g., in a dissolved form or a colloidal form. In general, pharmaceutically acceptable carriers suitable for use in the invention are well-known to those of ordinary skill in the art. As used herein, a "pharmaceutically acceptable carrier" refers to a nontoxic material that does not significantly interfere with the effectiveness of the biological activity of the antidepressant medication to be administered, but is used as a formulation ingredient, for example, to stabilize or protect the active compound(s) within the composition before use. The term "carrier" denotes an organic or inorganic ingredient, which may be natural or synthetic, with which one or more antidepressant medication are combined. The carrier may be either soluble or insoluble, depending on the application. Examples of well-known carriers include glass, polystyrene, polypropylene,

polyethylene, dextran, nylon, amylase, natural and modified cellulose, polyacrylamide, agarose and magnetite. The nature of the carrier can be either soluble or insoluble. Those skilled in the art will know of other suitable carriers, or will be able to ascertain such, using only routine experimentation.

In some embodiments, the pharmaceutically acceptable carrier may include formulation ingredients such as salts, carriers, buffering agents, emulsifiers, diluents, excipients, chelating agents, fillers, drying agents, antioxidants, antimicrobials, preservatives, binding agents, bulking agents, silicas, solubilizers, or stabilizers. For example, if the formulation is a liquid, the carrier may be a solvent, partial solvent, or non-solvent, and may be aqueous or organically based. Examples of suitable

formulation ingredients include diluents such as calcium carbonate, sodium carbonate, lactose, kaolin, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch, gelatin or acacia; lubricating agents such as magnesium stearate, stearic acid, or talc; time-delay materials such as glycerol monostearate or glycerol distearate; suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone; dispersing or wetting agents such as lecithin or other naturally-occurring phosphatides; thickening agents such as cetyl alcohol or beeswax; buffering agents such as acetic acid and salts thereof, citric acid and salts thereof, boric acid and salts thereof, or phosphoric acid and salts thereof; or preservatives such as benzalkonium chloride, chlorobutanol, parabens, or thimerosol. The antidepressant medication may be formulated into preparations in solid, semi-solid, liquid or gaseous forms such as tablets, capsules, elixirs, powders, granules, ointments, solutions, depositories, inhalants or injectables. Those of ordinary skill in the art will know of other suitable formulation ingredients, or will be able to ascertain such, using only routine experimentation.

Preparations include sterile aqueous or nonaqueous solutions, suspensions and emulsions, which can be isotonic with the blood of the subject in certain embodiments. Examples of nonaqueous solvents are polypropylene glycol, polyethylene glycol, vegetable oil such as olive oil, sesame oil, coconut oil, arachis oil, peanut oil, mineral oil, injectable organic esters such as ethyl oleate, or fixed oils including synthetic mono or di-glycerides. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, 1,3-butandiol, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents and inert gases and the like. Those of skill in the art can readily determine the various parameters for preparing and formulating the compositions of the invention without resort to undue experimentation.

In some embodiments, the antidepressant medication may be present as a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salts" includes salts of the antidepressant medication, prepared in combination with, for example, acids or bases, depending on the particular compounds found within the antidepressant medication and the treatment modality desired. Pharmaceutically acceptable salts can be prepared as alkaline metal salts, such as lithium, sodium, or potassium salts; or as alkaline earth salts, such as beryllium, magnesium or calcium salts. Examples of suitable bases that may be used to form salts include ammonium, or mineral bases such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and the like. Examples of suitable acids that may be used to form salts include inorganic or mineral acids such as hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric, carbonic, monohydrogencarbonic, phosphoric,

monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, phosphorous acids and the like. Other suitable acids include organic acids, for example, acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic, galacturonic, salicylic, formic, naphthalene-2-sulfonic, and the like. Still other suitable acids include amino acids such as arginate, aspartate, glutamate, and the like.

U.S. Patent Application Serial No. 12/225,943, filed October 2, 2008, entitled "Systems and Methods for Predicting Effectiveness in the Treatment of Psychiatric Disorders, Including Depression," by Pizzagalli, is incorporated herein by reference in its entirety. Also incorporated herein by reference in its entirety is U.S. Provisional Patent Application Serial No. 61/245,640, filed September 24, 2009, entitled "Systems and Methods for Treating Depression, Including the Use of Neurobehavioral Tasks," by Pizzagalli.

While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.

All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.

The indefinite articles "a" and "an," as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean "at least one."

The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases.

Multiple elements listed with "and/or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and/or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and/or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, "or" or "and/or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e. "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and/or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of and

"consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

What is claimed is:

Claims

1. A method of treating a subject diagnosed with depression, the method

comprising:

engaging the subject diagnosed with depression in a neurobehavioral task; and

applying antidepressant treatment to the subject.

2. The method of claim 1 , wherein the neurobehavioral task is not itself a treatment for depression.

3. The method of any one of claims 1 or 2, wherein the task is an Eriksen Flanker Task.

4. The method of any one of claims 1 or 2, wherein the task is a Stroop Task.

5. The method of any one of claims 1 or 2, wherein the task is a Counting Stroop Task.

6. The method of any one of claims 1 or 2, wherein the task is an Emotional

Counting Stroop Task.

7. The method of any one of claims 1 or 2, wherein the task is an A-X Continuous Performance Test.

8. The method of any one of claims 1 or 2, wherein the task is an Emotional

Go/NoGo Task.

9. The method of any one of claims 1 or 2, wherein the task is a Simon Task.

10. The method of any previous claim, wherein the subject engages the

neurobehavioral task over multiple sessions. The method of any previous claim, wherein the neurobehavioral task causes an increase in rostral ACC function.

The method of any previous claim, wherein the neurobehavioral task causes increased functional or structural connectivity between the ACC and a separate prefrontal cortex region.

The method of any previous claim, wherein the neurobehavioral task causes increased functional or structural connectivity between the ACC and the dorsolateral prefrontal cortex.

The method of any previous claim, wherein the subject has major depressive disorder.

The method of any previous claim, wherein the act of engaging the subject in the neurobehavioral task comprises at least three sessions.

The method of any previous claim, further comprising, after engaging the subject in the neurobehavioral task, assessing the effectiveness of the treatment by assessing a degree of depression in the subject.

The method of claim 16, wherein assessing a degree of depression in the subject comprises engaging the subject in a Hamilton Rating Scale for Depression test.

18. The method of any one of claims 16 or 17, wherein assessing a degree of

depression in the subject comprises engaging the subject in a Montgomery- Asberg Depression Rating Scale test.

19. The method of any one of claims 16-18, wherein assessing a degree of depression in the subject comprises engaging the subject in a Beck Depression Inventory test.

20. The method of any one of claims 16-19, wherein assessing a degree of depression in the subject comprises engaging the subject in a Zung Self-Rating Depression Scale test.

21. The method of any one of claims 16-20, wherein assessing a degree of depression in the subject comprises engaging the subject in a Wechsler Depression Rating Scale test.

The method of any one of claims 16-21, wherein assessing a degree of depression in the subject comprises engaging the subject in a Raskin Depression Rating Scale test.

The method of any one of claims 16-22, wherein assessing a degree of depression in the subject comprises engaging the subject in a Depressive Symptomatology test.

24. The method of any one of claims 16-23, wherein assessing a degree of depression in the subject comprises engaging the subject in a Quick Inventory of Depressive Symptomatology test.

25. The method of any previous claim, wherein assessing a degree of depression in the subject is performed by the subject.

26. The method of any previous claim, further comprising applying antidepressant treatment to the subject.

27. The method of claim 26, wherein the antidepressant treatment includes

antidepressant medication.

28. The method of any one of claims 26 or 27, wherein the antidepressant treatment includes psychotherapy.

The method of any one of claims 26-28, wherein the antidepressant treatment includes electroshock therapy.

The method of any one of claims 26-29, wherein the antidepressant treatment includes sleep modification.

The method of any one of claims 26-30, wherein the antidepressant treatment includes sleep deprivation.

The method of any one of claims 26-31, wherein the antidepressant treatment includes transcranial stimulation.

The method of any one of claims 26-32, wherein the antidepressant treatment includes vagal stimulation.

The method of any one of claims 26-33, wherein the antidepressant treatment includes deep brain stimulation.

The method of any one of claims 26-34, wherein the antidepressant treatment includes epidural cortical stimulation.

The method of any one of claims 26-35, wherein the antidepressant treatment includes light therapy.

The method of any one of claims 26-36, wherein the antidepressant treatment is applied after engaging the subject in a neurobehavioral task.

38. The method of any one of claims 26-36, wherein the antidepressant treatment is applied prior to engaging the subject in a neurobehavioral task.

The method of any one of claims 26-36, wherein the antidepressant treatment is applied simultaneously with engaging the subject diagnosed with depression in a neurobehavioral task.

The method of any one of claims 26-36, wherein engaging the subject in the neurobehavioral task and applying the antidepressant treatment to the subject at least partially overlap in time.

The method of any previous claim, wherein the neurobehavioral task comprises presenting inherently conflicting information to the subject.

The method of any previous claim, wherein the subject is transformed from a subject exhibiting depression to a subject exhibiting a milder form of depression.

The method of any previous claim, wherein the neurobehavioral task comprises behavioral adjustments after committing errors.

The method of any previous claim, wherein the neurobehavioral task comprises behavioral adjustments after receiving feedback about task performance.

The method of any previous claim, wherein the subject is diagnosed with clinical depression.

A method of treating a subject diagnosed with depression, the method

comprising:

engaging the subject diagnosed with depression in a neurobehavioral task; and

after engaging the subject in the neurobehavioral task, assessing the effectiveness of the treatment by assessing a degree of depression in the subject.

The method of claim 46, wherein the neurobehavioral task is not itself a treatment for depression.

48. The method of any one of claims 46 or 47, wherein the subject is diagnosed with clinical depression.

49. The method of any one of claims 46-48, wherein the task is selected from the group consisting of an Eriksen Flanker Task, a Stroop Task, a Counting Stroop Task, an Emotional Counting Stroop Task, a Simon Task, an A-X Continuous Performance Test, an Emotional Go/NoGo Task, and a Simon Task.

50. The method of any one of claims 46-49, wherein the subject engages the

neurobehavioral task over multiple sessions.

51. The method of any one of claims 46-50, wherein the neurobehavioral task causes an increase in rostral ACC function.

52. The method of any one of claims 46-51, wherein the neurobehavioral task causes increased functional or structural connectivity between the ACC and a separate prefrontal cortex region.

53. The method of any one of claims 46-52, wherein the neurobehavioral task causes increased functional or structural connectivity between the ACC and the dorsolateral prefrontal cortex.

54. The method of any one of claims 46-53, wherein assessing a degree of depression in the subject comprises engaging the subject in a test selected from the group consisting of a Hamilton Rating Scale for Depression test, a Montgomery- Asberg Depression Rating Scale test, a Beck Depression Inventory test, a Zung Self- Rating Depression Scale test, a Wechsler Depression Rating Scale test, a Raskin Depression Rating Scale test, a Depressive Symptomatology test, and a Quick Inventory of Depressive Symptomatology test.

The method of any one of claims 46-54, wherein the antidepressant treatment includes a treatment selected from the group consisting of antidepressant medication, psychotherapy, electroshock therapy, sleep modification, vagal stimulation, deep brain stimulation, epidural cortical stimulation, transcranial stimulation, sleep deprivation, and light therapy.

The method of any one of claims 46-55, wherein the neurobehavioral task comprises presenting inherently conflicting information to the subject.

The method of any one of claims 46-56, wherein the neurobehavioral task comprises behavioral adjustments after committing errors.

The method of any one of claims 46-57, wherein the neurobehavioral task comprises behavioral adjustments after receiving feedback about task

performance.

A method of treating a subject suspected of having depression, the method comprising:

engaging the subject in a neurobehavioral task for at least three sessions; and

assessing a degree of depression in the subject.

The method of claim 59, wherein the neurobehavioral task is not itself a treatment for depression.

61. The method of any one of claims 59 or 60, wherein the subject engages the

neurobehavioral task over multiple sessions.

62. The method of any one of claims 59-61, wherein the neurobehavioral task causes an increase in rostral ACC function.

63. The method of any one of claims 59-62, wherein the neurobehavioral task causes increased functional or structural connectivity between the ACC and a separate prefrontal cortex region.

64. The method of any one of claims 59-63, wherein the neurobehavioral task causes increased functional or structural connectivity between the ACC and the dorsolateral prefrontal cortex.

65. The method of any one of claims 59-64, wherein the subject is suspected of having major depressive disorder.

66. The method of any one of claims 59-65, wherein the accuracy of the subject increases by at least about 5%.

The method of any one of claims 59-66, wherein the accuracy of the subject increases by at least about 10%.

The method of any one of claims 59-67, further comprising applying

antidepressant treatment to the subject.

69. The method of any one of claims 59-68, wherein the subject is suspected of having clinical depression.

70. A method of treating a subject suspected of having depression, the method

comprising:

engaging the subject in a first neurobehavioral task;

engaging the subject in a second neurobehavioral task, the second neurobehavioral task occurring after the first neurobehavioral task; and

assessing a degree of depression in the subject.

71. The method of claim 70, wherein the neurobehavioral task is not itself a

treatment for depression.

The method of any one of claims 70 or 71, wherein the subject engages the neurobehavioral task over multiple sessions.

The method of any one of claims 70-72, wherein the neurobehavioral task causes an increase in rostral ACC function.

The method of any one of claims 70-73, wherein the neurobehavioral task causes increased functional or structural connectivity between the ACC and a separate prefrontal cortex region.

The method of any one of claims 70-74, wherein the neurobehavioral task causes increased functional or structural connectivity between the ACC and the dorsolateral prefrontal cortex.

The method of any one of claims 70-75, wherein the subject is suspected of having major depressive disorder.

The method of any one of claims 70-76, wherein the accuracy of the subject increases by at least about 5%.

The method of any one of claims 70-77, wherein the accuracy of the subject increases by at least about 10%.

The method of any one of claims 70-78, wherein the second neurobehavioral task occurs at least about a day after the first neurobehavioral task.

The method of any one of claims 70-79, wherein the second neurobehavioral task occurs at least about a week after the first neurobehavioral task.

The method of any one of claims 70-80, further comprising applying

antidepressant treatment to the subject.

The method of any one of claims 70-81, wherein the second neurobehavioral task occurs at least about 1 hour after the first neurobehavioral task.

The method of any one of claims 70-82, wherein the subject is suspected of having clinical depression.

engaging the subject in a first, second, and third neurobehavioral tasks, the first, second, and third neurobehavioral tasks each occurring within a 7-day period; and

assessing a degree of depression in the subject.

The method of claim 84, wherein the subject is suspected of having clinical depression.

An article, comprising:

a machine-readable medium having a program stored thereon, which program comprises instructions for, when executed, causing a computer to perform acts of:

engaging a subject in a neurobehavioral task; and

assessing a degree of depression in the subject.

The article of claim 86, wherein the program comprises instructions for determining accuracy of the subject in the neurobehavioral task.

88. The article of any one of claims 86 or 87, wherein the program comprises

instructions for determining reaction time of the subject in the neurobehavioral task. A computer-implemented method, comprising an act of operating a computer to engage a subject in a neurobehavioral task, and assess a degree of depression in the subject.