WO2016061320A2 - Timber therapy for post-traumatic stress disorder - Google Patents

Abstract

The disclosure relates to a therapeutic method based on TIMBER (Trauma Interventions using Mindfulness Based Extinction and/or Reconsolidation). TIMBER is a psychotherapy protocol that consists of 2 parts: a brief version (mini-TIMBER) and an elaborate version (full-TIMBER).

Description

TIMBER THERAPY FOR POST-TRAUMATIC STRESS DISORDER

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 USC § 119(e) to U.S. Provisional Patent Application Serial No. 62/064,000, filed on October 15, 2014, which is hereby

incorporated by reference in its entirety.

FIELD OF THE INVENTION

This disclosure relates generally to the field of psychotherapy, more particularly to psychotherapy of memory disorders such as post-traumatic stress disorder (PTSD).

BACKGROUND

PTSD is a memory disorder in which trauma memories become ingrained into the brain through conditioned learning mediated by the hippocampus, amygdala and prefrontal cortex along with the basal ganglia, brain stem and the hypo-thalamo-pituitary axis. PTSD affects approximately 7.7 million American adults (3.5% of U.S. adults) with a lifetime risk for PTSD at 8.7%. Only 59% or even less of those who have PTSD respond to antidepressants (SSRIs) whereas about 20-30%) patients drop out from the prolonged exposure therapy both of which are currently considered the first line treatments for PTSD. The inadequacy of the existing treatment modalities can be partially explained by the fact that none of the treatment target trauma memories, which are at the core of pathogenesis. Likely exceptions are novel treatments like ketamine which is a trauma- memory modifying agent that is being increasingly shown to improve within a few hours not only the chronic and refractory PTSD symptoms but also its major comorbidities, i.e. treatment-resistant depression. However, therapeutic effects of ketamine are short lasting which can be sustained by combining it with psychotherapy.

It is quite alarming that 50 to 60% of people in the United States are exposed to trauma during their lifetime and an estimated 8% of Americans may have post-traumatic stress disorder (PTSD) at any given time. In recent times, there has been more clarity in understanding PTSD as a memory disorder in which trauma memories become ingrained into the brain through conditioned learning mediated by the hippocampus, amygdala, prefrontal cortex, basal ganglia along with the brain stem and hypo-thalamo-pituitary axis (Shin & Liberzon, 2010). Taking a close look at the origin and maintenance of symptoms and dysfunction in PTSD, one can easily realize that trauma memories (TM) are the core psychopathological entities in PTSD.

Data on treatment of PTSD inform us that over 42% of those receiving treatment for post-traumatic stress disorder (PTSD) receive "minimally adequate treatment. Only 59% or even less of those who have PTSD respond to antidepressants (SSRIs) whereas about 20-30% patients drop out from the prolonged exposure therapy both of which are considered the first lines of pharmacologic and non-pharmacologic treatments respectively for PTSD. The inadequacy of the existing treatment modalities can be partially explained by the fact that none of the treatments target trauma memories, which are at the core of pathogenesis. In clinical settings, extinction-based therapies including the prolonged exposure (PE) therapy which is considered as gold standard for treatment of posttraumatic stress, are effective only in some cases; and of those who do benefit, many show a return of fear due to the problems inherent in using extinction-only based therapy (like Prolonged Exposure/PE therapy), i.e. spontaneous recovery, reinstatement, or renewal which are the three basic properties of extinction mechanism.

Likely exceptions to the existing therapeutics for PTSD are a few medications such as ketamine, propranolol, D-cycloserine that affect trauma memories directly, as shown in preliminary data. Ketamine is a glutamate (NMD A) antagonist and has been shown to influence the trauma memories (TM) and also being increasingly shown to improve within a few hours not only the chronic and refractory PTSD symptoms but also its major comorbidities, i.e. resistant depression and suicidality. One prior study has shown efficacy of ketamine in ameliorating PTSD; however the response has not been sustained enough. Preliminary studies on efficacy of mindfulness based interventions in PTSD has shown some effects but the study designs have significant limitations including lack of a standardized mindfulness intervention protocol that can be reliably replicated in patients suffering from PTSD. So far, in the existing literature, there has been no studies that describes efficacy of a combined approach using both ketamine and mindfulness based cognitive therapy in PTSD.

When trauma/fearful memories are formed, they are initially labile but become progressively consolidated into persistent traces via the synthesis of new proteins. Later retrieval of a consolidated fear memory engages two seemingly opposing mechanisms: reconsolidation and extinction. Reconsolidation is a neurobiological process of updating the existing memory that occurs when memories are recalled into a labile state, integrated with new information in the new learning environment, and consolidated once again. In the process of reconsolidation, a retrieved memory transiently returns to a labile state and requires new protein synthesis to persist further. During this labile state, the memory is amenable to enhancement or disruption. The period of instability or lability, the reconsolidation window, persists for about six hours after retrieval. It is being

increasingly recognized that reconsolidation is not just repetition of the consolidation process; rather it involves somewhat different mechanisms and brain areas.

Reconsolidation occurs in a broad range of learning paradigms (aversive and appetitive conditioning, explicit and implicit memory) and species (from snails to humans).

Fear extinction is a paradigm in which the conditioned stimulus (CS) is repeatedly presented in the absence of the unconditioned stimulus (US)— leads to progressive reduction in the expression of fear, but is not permanent because extinction unlike reconsolidation does not directly modify the existing memory but instead leads to the formation of a new memory (called extinction memory and extinction learning) that suppresses activation of the initial trace. The efficacy of this inhibition, however, is strongly contingent on spatial, sensory, and temporal variables. Specifically, the reemergence of a previously extinguished fear is known to occur, in rodents and humans alike, under three general conditions: (i) renewal, when the CS is presented outside of the extinction context; (ii) reinstatement, when the original US is given unexpectedly; or (iii) spontaneous recovery, when a substantial amount of time has passed. These inherent problems of extinction mechanism explains why patients with PTSD managed with extinction-only based treatments like the prolonged exposure therapy (PE) relapse with time.

These mechanisms have great clinical relevance to PTSD, both in terms of understanding the memory mechanisms as well as treatment. In PTSD, reception of new or surprising information in the context of accessing the trauma memories makes the relatively stable trauma memories labile and thus more prone to changes or updates in a new learning environment. In this situation, two competing processes are evoked: (1) extinction mechanisms initiated by trauma trigger, (2) competing learning engendered when the conditioned response is changed by either using an amnestic agent or by a behavioral protocol that overrides the original trauma memory. These extinction memories involve new learning which is not simply forgetting the old representations but actually updating the existing memories with these information as demonstrated through preliminary studies in rats and humans. From an evolutionary perspective, reconsolidation may serve as an adaptive update mechanism allowing for new information, available at the time of retrieval, to be integrated into the initial memory representation. Numerous studies have demonstrated that blockade of the updating process engaged during retrieval— usually via pharmacological intervention within the reconsolidation window— prevents restorage of the memory and produces amnesia (loss of the specific memory that was reactivated in the presence of the drug or access to it). Thus, in the case of aversive memories (as in PTSD), blocking reconsolidation weakens the emotional impact of a previously fear inducing stimulus by altering the molecular composition of the memory trace. It has been suggested that reconsolidation may serve an adaptive role as a window of opportunity to rewrite emotional memories using pharmacological or behavioral procedures.

The poor therapeutic prognosis for PTSD patients indicates that a broader clinical approach is necessary to develop effective treatment options for PTSD. Research into the underlying pathophysiology and neurobiology of PTSD has implicated dysregulation in multiple neurotransmitter systems including norepinephrine, serotonin, and glutamate as well as the hypothalamic-pituitary axis. The delineation of these chemical, structural, and circuitry abnormalities is of critical importance in the development of effective and rapid treatment of PTSD, but progress in this area will take time. In the interim, it is crucially important to pursue parallel lines of research which focus on clinical treatment using existing classes of psychotropic medications with a theoretical basis for efficacy in PTSD treatment. One of these agents is ketamine, a commonly used anesthetic agent. As a glutamate (NMD A) receptor antagonist, ketamine (K) is being increasingly shown to acutely improve symptoms of chronic and refractory PTSD in addition to symptoms of resistant depression and suicidality which are major comorbidities of PTSD. Although found to be effective in PTSD in one study, the effects of ketamine are not long lasting: this is one of the major limitations of ketamine, both in PTSD and in depression. The therapeutic effects of a single intravenous dose last only a few days (4-7 days). Administration of ketamine needs special expertise and equipment; patients have to be monitored for side effects, some of which could be serious, i.e. psychotic features, mania, increased blood pressure, nausea etc. Also ketamine has abuse liability, if used over prolonged time.

A need exists for more effective treatment of anxiety disorders. In particular, not only should the method provide a long term treatment, it also allows a patient to practice the method in various settings.

SUMMARY OF THE INVENTION

The present invention meets such a need. The method of the present invention pairs a stimulus that previously provoked a deleterious, high-anxiety response with a new learning, thereby generating in the patient a new, more appropriate response to the stimulus to replace the previous disproportionate response. The new learning can be, for example, a new idea, a different perception, a particular physical posture, or any combination thereof. An important technique is instilling the new learning is TIMBER (Trauma Interventions using Mindfulness Based Extinction and/or Reconsolidation).

In one aspect of the invention, a method of treating an anxiety disorder is described by (a) obtaining baseline data indicative the severity of the anxiety disorder prior to treatment; (b) identifying a stimulus that evokes an identifiable reaction indicative of a psychological response to the stimulus in a patient, wherein the stimulus is associated with the anxiety disorder; (c) exposing the stimulus to the patient; (d) having the patient practice an exercise that elicits cognitive mental effort to reduce the severity of the medical disorder, and said exercise is practiced less than 6 hours after the first stimulus is provided; and (e) obtaining after-exercise data indicative of severity of the anxiety disorder after practicing the exercise.

In some embodiments, steps (c) and (d) are repeated until a reduction in the severity of the anxiety disorder is observed. In some embodiments, the anxiety disorder is selected from substance-abuse disorders, mood disorders, panic disorder, agoraphobia, social phobia, specific phobia, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, and movement disorders.

In some embodiments, identifiable reaction is selected from eye response, eye brows response, pupillary change, facial muscle tone, facial color change, movement response in other body parts, change in posture, change of breathing, change in heart rate, perspiration, predominant emotions, and a combination thereof.

In some embodiments, the data indicative of the severity of the medical disorder are assessed on Assessment Scale for Mindfulness Interventions (ASMI), wherein a more severe disorder is given a higher score.

In some embodiments, a reaction score indicative of a psychological response is obtained using a scale of Arousal Response during Trauma Memory Recreation (ART- MR), wherein a more intensive reaction is given a higher score.

In some embodiments, the length of the exposure to the stimulus is adjusted based on the reaction score to minimize prolonged exposure.

In some embodiments, the patient starts practicing the exercise less than 30 minutes after being exposed to the stimulus. In some embodiments, the exercise lasts for a period of about 30-60 minutes. In some embodiments, the exercise comprises a member selected from standardized breathing techniques, focused attentive meditation, yoga and mindfulness meditation.

In some embodiments, the method further includes administering a therapeutically effective amount of a therapeutic agent, wherein said agent is administered less than 20, 15, 10, 5, 4, 3, 2 or 1 hour(s) before the patient is exposed to the stimulus and is selected from antidepressants, arousal modifying agents, and trauma memory modifying agents. In some embodiments, method further includes administering a therapeutically effective amount of a therapeuticagent, said agent selected from ketamine, clonidine, propranolol, and D-cycloserine. In some embodiments, the agent is administered less than 1 hour before the patient is exposed to the stimulus.

In some embodiments, the method further includes exposing the patient to transcranial magnetic stimulation (TMS). Another aspect of the invention provides a method of treating an anxiety disorder, comprising (a) identifying a stimulus that evokes an identifiable reaction indicative of a psychological response to the stimulus in a patient, wherein said first stimulus is associated with the anxiety disorder; (b) administering a therapeutically effective amount of a therapeutic agent, said agent selected from ketamine, clonidine, propranolol, and D- cycloserine; (c) exposing the stimulus to the patient in a window between 30 minutes to 10 hours after administering the agent; and (d) having the patient practice an exercise that elicits cognitive mental effort to reduce the severity of the medical disorder, and said exercise is practiced less than 6 hours after the first stimulus is provided.

Another aspect of the invention provides a method of reducing a patient's score on

ASMI scale.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments of the present invention relates to TIMBER (Trauma Interventions using Mindfulness Based Extinction and/or Reconsolidation) for the treatment of anxiety disorders. TIMBER is a novel mindfulness based cognitive therapy (MBCT) protocol which combines the neurobio logical understanding of PTSD, the fear- learning mechanisms and the principles of controlled exposure therapy. TIMBER interventions can be used alone or in combination with PTSD specific medications like ketamine, propranolol, D-cycloserine (D-CS) to potentiate and sustain the effects of these medications on symptoms of PTSD including the expression of trauma memories.

The articles "a" and "an" as used herein refers to "one or more" or "at least one," unless otherwise indicated. That is, reference to any element or component of the present invention by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element or component is present.

The term "about" as used herein refers to the referenced numeric indication plus or minus 10% of that referenced numeric indication.

As used herein, "anxiety disorder" refers to a disorder characterized by fear, anxiety, addiction, and the like that can be treated with the methods of the invention. An individual who can benefit from the methods of the invention may have a single disorder, or may have a constellation of disorders. The anxiety disorders contemplated in the present invention include, but are not limited to, fear and anxiety disorders, addictive disorders including substance-abuse disorders, and mood disorders. Fear and anxiety disorders include, but are not limited to, panic disorder, agoraphobia, social phobia, specific phobia, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, and movement disorders such as Tourette's syndrome. The disorders contemplated herein are defined in, for example, the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders (4th ed., American Psychiatric Association, Washington D.C., 1994)).

As used herein, a patient is "treated", or subjected to "treatment", when an earnest attempt is made to alleviate a medical disorder or disease. For example, a subject can be treated for a disorder by being exposed to a procedure that is intended to alleviate the disorder, irrespective of whether the treatment actually was successful in alleviating the disorder.

The term "patient" as used herein refers to a human with a medical disorder.

A "therapeutically effective amount" or "therapeutically effective dose" of the therapeutic agent is an amount of the therapeutic agent that, when administered in conjunction with extinction training, results in an improved therapeutic benefit relative to that observed with extinction training in the absence of administering the therapeutic agent.

Efficacy of TIMBER has been studied for treating medical disorders. Based on the limitations of extinction-only therapies, combined extinction and reconsolidation based approaches seem crucial and promising therapies for PTSD because extinction, unlike reconsolidation, does not directly modify the existing memory and so the fear response eventually returns in most cases due to spontaneous recovery, reinstatement, or renewal, the three basic properties of extinction mechanism itself. This explains why extinction- based therapies including the prolonged exposure (PE) do not benefit everyone. Also prolonged exposure therapy could have patient tolerability issues including significant drop outs of patients because its very design is to over-flooding patients by the trauma memories. As outlined in various recent literature on the utility of mindfulness techniques and concepts in trauma therapy, the essential elements in mindfulness are focused attention, compassion, empathy, validation and non-judgmental attitudes which are therapeutic in patients suffering from trauma and their sequlae. These therapeutic elements in mindfulness can be targeted to reappraise the trauma memories. These elements when used in a therapeutic context promote (new) extinction learning by competing with the pre-existing and conditioned trauma memories and this new learning could update/replace the existing trauma memories by the process of reconsolidation.

In TIMBER, the methodology of the behavioral part has been modeled after a successful study in rats and human volunteers. The mindfulness interventions of TIMBER are taken from Yoga and mindfulness based cognitive therapy (Y-MBCT) protocols for mental illness and Standardized Yoga Meditation Program for Stress Reduction (SYMPro- SR) protocol for mental wellness. Both Y-MBCT and SYMPro-SR protocols are adapted from the scriptural description of meditation as described in classic books such as

Visuddhimagga ([Eng. The Path of Purification: the Buddhist encyclopedia on

meditation], Buddhaghosha, circa. 430 CE: English translation by Nyanamoli, 1976).

TIMBER (Trauma. Interventions using the Mindfulness Based

Extinction/Reconsolidation) protocol consists of the mini-TIMBER (shorter version, ideally suited for augmenting the medication effects including that of ketamine in peri- infusion period) and full TIMBER.

The TIMBER protocol proposed for this study will target the 3 principal symptom clusters of PTSD: (1) Hyper-arousal symptoms and its consequences; (2) the intrusive traumatic memories and their unsuccessful avoidance which further intensifies them; and (3) inability to integrate the traumatic experience because of not staying in the moment and inadequate reappraisal and insufficient acceptance of the traumatic experience.

The mini-TIMBER as well as the full-TIMBER have three main components:

1. Middle Way Life Style, to help with the extremes in the life of the patients with PTSD.

2. Integrated & mindful posture (easy sitting posture with two standardized breathing mediations): This is intended for the tuning-in of the participants and for generating body- mind awareness. This is purported tool improve psychosomatic integration aspects in PTSD patients, to be able to stay more in touch with bodily experiences.

3. Staged Meditation Protocols (SMPs: levels- 1, 2 and 3): The SMPs in the TIMBER protocol are the heart of the interventions and use the bottom up model of meditation. The SMPs uses the standardized breathing meditations and concentrative- as well as mindfulness meditations in symptom specific manner to decrease arousal, to bring attention to the present by focused meditation and to reappraise the trauma memories. These employ conscious sensory withdrawal and guided dis-association/detachment (for induction into meditative mode: to decrease intrusive thoughts, to accept

thoughts/experiences as they are, to bring focused attention into practice for inducing further detachment from the traumatic experiences in a mindful way and to decrease identifications with the temporary mental states which include the specific emotions and cognitions associated with the trauma experience. This specific, directed and detached self-visualization that incorporates the mindfulness meditation guided by the five factor philosophy of mental phenomena and their inter-dependent originations helps clients to detach/dis-associate from the trauma experience and see them objectively from the outside as they watch themselves in a traumatic scene and from a more neutral perspective. This dis-association (which is conceptually opposite of dissociation, a major psychopathology in patients with :PTSD) helps patients to reappraise and alter parts of the trauma experiences (including the trauma memories) in order to correct negative emotions, thoughts and memory in order to form an integrated experience in a 'more real' or 'as it is' sense. As observed in the recently finished pilot with PTSD (10 patients), the standardized breathing meditations and reorienting techniques (part of the mini-TIMBER intervention) which are guided by the scores in the Arousal Response to Trauma Memory Reactivation (ART-MR, Pradhan and Gray, 2013, unpublished; Example 3) scale and are applied in a specific window period during their controlled reactivation in the peri-infusion period (with ketamine or normal saline), are able to quickly (within 1-2 minutes or so) decrease the hyper-arousal responses as observed by the change in their emotions, heart rate, blood pressure, pupillary size etc.

As a comprehensive, novel and integrative psychotherapy protocol which is informed not only psychologically but also neurobiologically and spiritually, TIMBER, in addition to its symptom specific mindfulness interventions, incorporates a cognitive behavioral design in which patients suffering from PTSD reassess or retrieves the trauma memories which in turn gets destabilized (made labile) and reinterpreted as safe by presenting an isolated retrieval trial before an extinction/reconsolidation session. The ensuing arousals in response to the therapist assisted triggers are measured by a structured scale, Arousal Response during Trauma Memory Reactivation (ART-MR; Example 3) which measures and targets two specific and key arousal responses, i.e. the heart rate and breathing rate in addition to other cognitive, emotive and behavioral parameters.

During the past 20 years, increased heart rate with trauma stimuli has been one of the most robust autonomic findings from studies of numerous types of traumas. Once controlled arousal is established, patient is gently oriented to the present moment using the mindfulness based cognitive behavioral techniques including the standardized breathing techniques, focused attentive (FA) meditation and mindfulness meditation (Open

Monitoring/OM type). These techniques are used for patient to self-regulate the arousal response and reappraise the trauma memories.

With respect to the techniques and their sequential application, the corner stone of

TIMBER are the Pradhan's standardized meditation protocol (SMPs), as described above in a three tiered intervention (level- 1 till 3), TIMBER first controls the hyperarousal response at level 1 and then achieves the concentrated mental state and induction of detachment at level 2. Finally, at level 3, trauma memories are safely processed and reappraised with respect to the accompanying perceptions, feelings, and thoughts using mindful detachment/disassociation, compassion, and neutrality. Level 1 of TIMBER calls for standardized meditative breathing in sitting posture that controls hyper-arousal symptoms and prepares one for pratyahara / detachment from trauma triggers. Level 2 involves standardized focused meditation that reinforces further detachment and disassociation (very different from the concept of dissociation) and prepares one for directed meta- visualization of self and trauma memories. Level 3 involves detached processing and reappraisal of trauma memories with mindful awareness and bare attention. TIMBER uses therapist-guided and self-exposure formats for controlled exposure to trauma triggers, regulating and reappraising the trauma response using the TIMBER interventions in structured, graded, and individualized manner.

The two parts of TIMBER (mini-TIMBER and full-TIMBER) with different therapeutic purposes:

TIMBER has two parts with different purposes and clinically executed at three levels in sequence, levels- 1 till 3. The first part of TIMBER (mini-TIMBER, level- 1 TIMBER) is designed specifically to rapidly induce remission of the overwhelming arousal and panic symptoms. The second part is the full-TIMBER which is the more elaborate version and consists of levels-2 and 3 interventions in combination with principles of mindfulness based exposure therapy (M-BET). Mini-TIMBER is specifically designed for application in the peri-infusion period (with ketamine) whereas full-TIMBER targets the symptoms and dysfunctions of PTSD in therapist assisted exposure (outpatient office based practice) and controlled self-exposure (home practice) formats without overwhelming the patient. M-BET combines the cue based exposure (extinction mechanism) with mindfulness based interventions (reconsolidation mechanism) and uses therapist guided and self-exposure formats for controlled exposure to trauma triggers and regulate and reappraise the trauma response using the TIMBER interventions in patient- centered, structured, controlled, graded and individualized manner.

The mini-TIMBER sessions because of their ease and quickness of use and standardized methodology are ideal to be combined with medications like ketamine during the peri-infusion period to potentiate their therapeutic effects on trauma memories in the reconsolidation window period (i.e. the first 6-hrs after arousal) whereas the full-TIMBER can be used without medication for maintenance treatment of PTSD to specifically target the PTSD symptoms for relapse prevention. Mini-TIMBER is not only an intervention that acts synergistically with ketamine for overriding the original trauma memory and updates the memory system with the new learning obtained from the mindfulness environment but also primes the patient for the subsequent full-TIMBER (levels 2 and 3) which is used for treatment of PTSD once patients relapse after the initial session of mini-TIMBER. Thus, TIMBER interventions integrate the principles of learning (extinction and reconsolidation) with cognitive behavioral therapy (CBT) and mindfulness meditation to help the patient to self-regulate the arousal response and reappraise the TM, thus inducing new learning. Of note, combined extinction and reconsolidation based approaches seem crucial and promising therapies for PTSD because extinction, unlike reconsolidation, does not directly modify: the existing trauma memory and so the fear response eventually returns in most cases due to the basic properties of extinction mechanism itself. Both mini-TIMBER and full-TIMBER have the potential, at least conceptually as well as in our preliminary study, to be efficacious in maintaining the acute therapeutic effects of ketamine as well as treating ensuing relapses in PTSD. As mentioned before, the TIMBER interventions can be combined with medications like ketamine (data on efficacy available), D-cycloserine, or propranolol that affect fear/trauma memories for more persistent reduction of learned fear, enhancing their effects.

Method of Treating an Anxiety Disorder

An aspect of the invention provides a method of treating an medical disorder, comprising (a) identifying a stimulus that evokes an identifiable reaction indicative of a psychological response to the stimulus in a patient, wherein said first stimulus is associated with the medical disorder; (b) obtaining baseline data indicative the severity of the medical disorder prior to treatment; (c) exposing the stimulus to the patient; (d) having the patient practice an exercise that elicits cognitive mental effort, said exercise designed to reduce the severity of the medical disorder, and said exercise is practiced less than 6 hours after the first stimulus is provided; (e) obtaining after-exercise data indicative of severity of the medical disorder after practicing the exercise; and (f) repeating steps (c) and (d) of until a reduction in the severity of the medical disorder is observed.

Scale and Measurement

The severity of a patient's anxiety disorder at various stages, including before treatment, during each session and after treatment, can be established by various known scales. The baseline data prior to a treatment session serves as a reference point to evaluate the efficacy and the need of additional steps. Both clinician-administered and validated self-report instruments, scales or models can be used. The following non- limiting examples have been used in measuring baseline symptomatology as well as drug actions on aspects such as (1) the overall severity of the disorder, (2) the core symptoms of an anxiety disorder (e.g. PTSD), and (3) depressed mood.

Example 4 provides details on Pradhan Assessment Scale for Mindfulness

Interventions (ASMI©, Pradhan, B.K., 2012; Clinical). This structured and quantitative scale measures the patient's level of mindfulness in 7 domains that is purported to plan and administer the mindfulness interventions in personalized and symptom specific manner.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) includes the revised diagnostic criteria for PTSD. See, American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013.

The Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID-P) is a semi-structured interview that provides probe questions as well as follow-up questions to be asked by the clinician to assist in diagnosis. First et al, Structured Clinical Interview for DSM-IV TR Axis I Disorders, Research Version, Patient Edition (SCID- I/P). New York: New York State Psychiatric Institute, Biometrics Research; 2001. It includes an overview to obtain information about demographics, work, chief complaint, history of present illness, past history, treatment history, and current functioning. The main body of SCID-P includes 9 modules that are designed to diagnose 51 mental illnesses in all.

The SCID-P for DSM-5 is the SCID - Patient version, and is the next edition of the SCID modified to incorporate the new DSM-5 criteria.

The Clinician- Administered PTSD Scale (CAPS) is a structured clinical interview designed to assess the essential features of PTSD as defined by the DSM-IV.

Stimulus and Identifiable Reaction

A stimulus refers to something that generates little if any anxiety in most people but would generate substantial anxiety in a patient experiencing a deleterious, high-anxiety response. The stimulus can be presented in any form relating to the memory of any event or an experience. For example, a patient may be exposed to a stimulus, which is a picture showing the scene of an event. A stimulus may also be a verbal communication that describes a previous event that lead to the anxiety disorder of the patient. Under some circumstances, a patient-initiated recollection of a past event may also be a stimulus. The stimulus triggers arousal to the traumatic memories. The patient is thereafter re-oriented into a new memory-building process using mindfulness-based cognitive behavioral techniques.

The identifiable reaction indicative of a psychological response can be assessed by various established methodologies. Under the scale of "Arousal Response during Trauma Memory Recreation" (ART -MR), the intensity of the reaction can be quantified by scoring the following: eye response, eye brows response, pupillary change, facial muscle tone, facial color change, movement response in other body parts, change in posture, change of breathing, change in heart rate, perspiration, predominant emotions, and a combination thereof. These reactions may be monitored by a medical professional or with the assistance of an instrument. Reactions at different level will be assessed a score and correlate with a particular timeframe.

The ART -MR for evaluating the level or intensity of the identifiable reaction provides multiple benefits. The length and depth of exposing the patient to the stimulus can be adjusted based on the total score. This will ensure that a memory is sufficient reactivated for subsequent memory modification phase. Meanwhile, by monitoring the reaction from the patient, the exposure to the stimulus may be changed to avoid over- flooding the patient with reactivated memory for a prolonged period of time. Further, by comparing the scores at different stages, it helps to determine whether a treatment session is effective and whether additional sessions are needed.

Because the reaction intensity assessed under ART-MR also relates to the length of exposure to the stimulus, the scoring system also provides a guidance to a patient on the timeframe of the memory reactivation stage when the patient practices the present invention at home.

Exercise

In connection with the stimulus exposure step which lays the ground for a patient to reassess or retrieve traumatic memories corresponding to a disorder, the exercise step destabilize the traumatic memories and induce the patient to reinterpret the traumatic memories as safe using at least one mindfulness-based cognitive behavioral technique.

"Exercise" as used herein refers to an activity that promotes the treatment of mental illness, anxiety disorders or emotional disturbances. The exercise can be, for example, a verbal or nonverbal communication, a posture, a physical movement, a breathing pattern or any combination thereof. The exercise may also involve a part or the whole section of known psychotherapy procedures such as extinction training. Other methods of psychotherapy that can be incorporated into the present invention include exposure-based psychotherapy, cognitive psychotherapy, and psycho-dynamically oriented psychotherapy. An exercise may include multiple components which can be practiced

simultaneously or sequentially. For example, a mindfulness-based cognitive behavioral exercise may include standardized breathing techniques, focused attentive meditation, and mindfulness meditation. These individual components can be practiced separately or in combinations. The essential elements in mindfulness are focused attention, compassion, empathy, validation and non-judgmental attitudes. Any of these elements may be incorporated with other techniques such as standard yoga practice.

In some embodiments, a psychotherapy that can be incorporated into the present invention is cognitive behavioral therapy ("CBT"). CBT is a form of psychotherapy that combines cognitive therapy and behavior therapy, and emphasizes the critical role of thinking in causing people to act and feel as they do. Therefore, if an individual is experiencing unwanted feelings and behaviors, CBT teaches that it is important to identify the thinking that is causing the undesirable feelings and/or behaviors and to learn how to replace this deleterious thinking with thoughts that lead to more desirable reactions. There are many approaches to cognitive-behavioral therapy, including Rational Emotive

Behavior Therapy, Rational Behavior Therapy, Rational Living Therapy, Cognitive Therapy, and Dialectic Behavior Therapy. CBT generally begins with a review of a subject's past experiences with similar or different problems, leading to an understanding of the habitual and problematic manner of thinking and behaving that underlies the subject's problem, and culminating in a strategy to develop new ways of thinking, behaving and interacting to manage, alleviate, or eliminate the problem. CBT sessions involving a therapist and a subject typically take between 30 minutes and an hour, and are structured and directive. Typically, each session has a specific agenda. CBT can be used successfully to treat anxiety disorders (e.g., PTSD, agoraphobia, specific phobia, social phobia, substance abuse/addiction, and obsessive-compulsive disorder, depression, chronic pain, insomnia, sexual dysfunction, obesity, and eating disorders).

In some embodiments, the exercise comprises TIMBER. TIMBER can be used as a PTSD specific module and serves as a prototype of the yoga and mindfulness based cognitive therapy models.

In TIMBER, the psycho-physical manifestations of the hyper-arousal episodes and the reappraisal/ modifications of the trauma experiences are addressed by cognitive- emotive restructuring using combined cognitive-behavioral and mindfulness (standardized yoga-meditation) interventions. TIMBER allows destabilization of existing trauma memories (makes them labile) and the formation of new memories that are fear- free, with the expectation that these new memories are permanent. TIMBER interventions are based on the fact that the hyper-arousal response, including the somatic symptoms of PTSD, as well as the flashbacks of the trauma memories, can be targeted by new learning that involves de-conditioning and dis-associating (detaching) the patient from the trauma memories and the psycho-physical manifestations of the hyper-arousal episodes.

TIMBER, in addition to its symptom specific mindfulness interventions, incorporates a standardized cognitive behavioral design in a specific therapeutic window period in which patients suffering from PTSD retrieve the trauma memories. Once controlled arousal of trauma memories is established, the memory becomes destabilized (made labile). Then the patient is gently oriented to the present moment using mindfulness based cognitive behavioral techniques including the standardized breathing meditations, focused attentive (FA) meditation and mindfulness meditation (Open Monitoring/OM type). In TIMBER, the initial traumatic memories are subsequently reinterpreted as safe and patients use these techniques to self-regulate the arousal response and reappraise the trauma memories. Thus, conceptually as well as in its techniques, TIMBER differs from traditional exposure models of therapy where patients are exposed/over-flooded without having the tools to regulate the arousal response or to reappraise them.

TIMBER consists of two types of interventions: a full version and a shorter version. The full version is 45-60 minutes long. It uses standardized yoga mindfulness- based cognitive therapy Y-MBCT protocols and includes mindfulness based exposure therapy (Pradhan, 2014). It is ideally suited for routine practice and graded self-exposure to trauma triggers after an initial phase of therapist-assisted training, which is completed over 2-3 sessions. The ease of performing TIMBER, initially in a therapist-guided setting, and later at home independently, is a major advantage compared to other contemporary psychotherapeutic modalities such as exposure therapy. Unlike prolonged exposure, TIMBER doesn't overwhelm the patient and supports the patient's practice of graded self- exposure. Given that extinction training during the reconsolidation window (about 6 hours) reduces the threat-value of the conditioned stimulus (CS), TIMBER is less likely to re -traumatize the patient as compared to prolonged exposure. TIMBER interventions serve to regulate the arousal response by using mindfulness interventions. These are

standardized techniques involving awareness training directed towards arousal responses, and involve the use of meditative breathing and reappraisal of the aroused state to regulate and deescalate the arousal. These techniques transform the meaning of the CS and make it nonthreatening. Because the new meaning is integrated into the memory through the updating mechanism of reconsolidation, the hallmarks of extinction training, renewal, reinstatement, and spontaneous recovery, will not appear. The result is a more enduring reduction in fear relative to extinction training conducted outside the reconsolidation window.

The shorter, 10 minute version (mini-TIMBER) is used by patients outside of therapy sessions in their daily life. They learn to implement it themselves by practicing it in the therapy sessions as well as at home. They then apply it as needed as a way of handling spontaneous arousals that occur in connection with cues that trigger traumatic memories.

TIMBER can be also be combined with psychopharmacologic treatments for PTSD that include but not limited to antidepressants (selective serotonin reuptake inhibitors [SSRIs], selective serotonin and norepinephrine reuptake inhibitors [SNRIs], norepinephrine and dopamine reuptake inhibitors [NDRIs], mirtazapine etc.), arousal modifying agents like propranolol and clonidine and, trauma memory modifying agents like ketamine and D-cycloserine.

TIMBER is designed for reappraisal and relearning of trauma memories in a targeted way, both during therapist assisted office based treatment sessions as well as during the graded self-exposure sessions at home. Also the tools in TIMBER are used by patients to handle the spontaneous arousal episodes that ensue during day to day life of patients in response to trauma cues. We postulate that, in TIMBER, the bottom-up model of meditation that is used with mindfulness-based exposure therapy, because of its putative effects on trauma memories, dis-associates the cognitive memories of the pre-frontal cortex from the emotional memory network in the amygdala and hippocampal memory network. Thus, TIMBER is specifically designed for amelioration of symptoms in post- traumatic stress disorder (PTSD), including expression of the trauma memories which lie at the core of this devastating disorder.

Objectivity and symptom targeted interventions in the TIMBER therapy are guided by use of two quantitative scales: Assessment Scale for Mindful Interventions and Arousal Response of Trauma Memory Reactivation. The latter scale has been used to estimate quantitatively the biological and clinical correlates of the trauma memory arousal during the retrieval process in the patients suffering from PTSD. In our laboratory, this scale has been used to estimate the level of arousal in patients with PTSD, both during execution of TIMBER sessions as well as during ketamine infusion.

Yoga and mindfulness based treatments have shown to produce the exact opposite effects, i.e. they lower the sympathetic output and enhance the parasympathetic activity. In addition to the autonomic nervous system, the other brain structures playing crucial roles in the arousal response and memory mechanisms in PTSD are the pre-frontal cortex (both dorso-lateral and ventro-medilal areas), amygdala, thalamus, hippocampus and the global attention network of the fronto-parietal cortex. The thalamus, governs the flow of sensory information to cortical processing areas, and through the inhibitory GABAergic neurons, blocks the distribution of these information into the various areas.

As an inhibitory neurotransmitter, GABA plays a key role in the prevention of arousal response: both in normal stress response and in PTSD as well. Interestingly, as compared to physical exercises, Yoga and mindfulness interventions are associated with increased thalamic release of GABA as evidenced from the magnetic resonance spectroscopy scans of patients. In another positron emission tomography study utilizing 1 lC-Raclopride demonstrated a significant increase in dopamine levels during meditation practice. It should be noted that the dopamine system, via the basal ganglia, is believed to participate in regulating the glutamate system, which plays an important role in trauma memories and their expressions. The major neurotransmitters are implicated in both PTSD and in the interventions involving Yoga and mindfulness. Thus, the rationale for use of Yoga and mindfulness based treatments in PTSD is based not only on empirical rationale but also the emerging biological rationale as well. The Yoga and mindfulness

interventions in PTSD can be broadly categorized as two types: (a) non-targeted approaches, which use Yoga and meditation in a general or non-specific way, and (b) targeted approaches, which specifically target the trauma memories, and their expression, e.g. TIMBER.

Efficacy of Yoga has been shown in various studies and includes drops in depression scores, participants showed marked improvements in sleep initiation, disturbed sleep, flashbacks, and anger outbursts. Several subjects used the pranayama to calm themselves when they awoke at night or when they felt "road rage." One interesting finding emerging from these studies is that although practice of the Yogic postures reduced depression, they had no impact on the intrusive or hyper arousal symptoms or anger outbursts of PTSD until other interventions like Yogic breathing were added. Also treatment of depression with Yogic breathing showed decreased levels of Cortisol following treatment and provides further evidence for the utility of combined physical (posture) and meditative aspects of yoga in PTSD. Of note, traditionally Yoga in its entirety consists of eight limbs which includes Yogic (balanced) life style, postures, pranayama and meditation, its 6th and 7th limbs. Thus combined, synergistic and targeted use of many elements of Yoga rather than their isolated or piecemeal use have been found to be more effective.

Yoga and mindfulness based interventions are potentially beneficial, low-risk adjuncts for the treatment of PTSD as well as for depression, stress-related medical illnesses, and substance abuse. Although preliminary and have to be proven in larger studies as well as with respect to their precise mechanisms of action, results of these studies as well as the emerging biological rationale strongly suggest their use in PTSD. However, because Yoga and meditation interventions are quite complex and more often than not uses in non-specific way, these studies are yet to evaluate their independent contributions or what exact role the individual components play in these. One main issue in research is that non-specific and non-standardized use of Yoga and mindfulness interventions can be difficult to evaluate. Thus more standardized and targeted approaches are necessary to ensure not only use of these interventions in more objective and targeted fashion but also for comparing their efficacy across studies or with other treatment modalities. Recognizing these issues as well as the limitations in the utility of only the physical aspects of Yoga, the present invention provides several disorder-specific psychotherapy models that use Yoga in its entirety in targeted and broader ways (that includes all eight limbs) rather than piecemeal and are broadly categorized under Yoga and Mindfulness Based Cognitive Therapy.

The exercise should be practiced within a suitable window after the patient's exposure to the stimulus. Non-limiting examples of the window include less than about 8 hours, 7, hours, 6 hours, 5 hours, 4 hours 3 hours, 2 hours, 100 minutes, 80 minutes, 60 minutes, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes after the exposure to the stimulus.

Each treatment may last from about 20 minutes to about 2 hours, all subranges included. The exercise session may last from about 5 - 100 minutes. In some

embodiments, the exercise is continued for about 45-60 minutes.

Transcranial Magnetic Stimulation (TMS) In PTSD

Transcranial magnetic stimulation (TMS) or repetitive TMS (rTMS) may also be used in conjunction with the above described method. The exact time in length of a patient's exposure to TMS or rTMS may vary, depending upon factors such as the identity, size, and condition of the patient treated. One of ordinary skill in the art will be able to determine the intensity and timeframe of the stimulation without undue

experiments.

Clinical trials done over the last two decades have demonstrated effectiveness of rTMS in PTSD. It has been demonstrated significant improvements in PTSD symptoms after 24-hour mark. In an open trial involving six patients with treatment resistant -PTSD, significant improvement was observed in hostility, insomnia, anxiety and depression as well as a small but significant improvement in core PTSD symptoms. Their results demonstrated that patients who received high frequency (>lHz) rTMS experienced greater improvement in the core PTSD symptoms compared to patients who received low frequency (<1HZ) or sham stimulation, suggesting that neuronal circuitry in the right PFC may be implicated in PTSD. Significant decrease in PTSD symptoms was observed in the high frequency and right PFC group as compared to the left PFC and low frequency group which led authors to propose that the right PFC, after rTMS treatment, possibly inhibits the episodic memory of the left PFC via trans-callosal inhibition. Another randomized control trial using low frequency rTMS to right PFC at 90% motor threshold (MT) for 10 sessions demonstrated significant improvement in the core symptoms of PTSD and depression in 20 veterans as s compared to the controls. These improvements were maintained for 2 months after completion of the TMS course, with a decrease in clinical improvement over time. Efficacy of the low frequency, right PFC rTMS protocols in the treatment of non-PTSD type anxiety disorders supports use of this type of rTMS for PTSD.

Neuroimaging data in patients with PTSD suggests that they have functional abnormalities in the right hemisphere of the brain, which includes the amygdala, the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), ventro-medial pre- frontal cortex (vmPFC) and the hypothalamic pituitary adrenal (HP A) axis (Isserles et al, 2013; Pallanti & Bernardi, 2009). Of note, earlier evidences of involvement of right hemisphere of brain in PTSD were mainly based on clinical parameters rather than neuroimaging. One study that utilized fMRI, suggests the involvement of the right insular cortex and striatum in PTSD (Cisler et al., 2014). Decreased GABAergic functions in bilateral brain areas are found in patients with PTSD and rTMS treatment reversed these but only in the right hemispheric regions and improved the PTSD symptoms (Rossi et al., 2009). The right hemispheric involvement in PTSD has been further demonstrated in clinical studies, which found that that right-sided rTMS is more effective than left-sided treatment (Karsen, Watts, & Holtzheimer, 2014). These authors did not find any difference in terms of clinical outcome with respect to efficacy of high frequency versus low frequency stimulations. Another study (Tillman et al., 2011) showed that rTMS application to the right frontal lobe of patients suffering from PTSD significantly reduced the event related potential (P300: claimed to be a biomarker of trauma response) in response to combat related trauma triggers.

Currently, the only FDA approved indication of rTMS is unipolar depression in which its therapeutic effects are known to be exerted through stimulation of the left PFC in. However, despite these recent advancements in TMS research, it has a long way to go with respect to its precise mechanisms of action, which hopefully could explain many questions including the differential effects with respects to the laterality of the stimulations in different neuropsychiatric disorders. As far as PTSD is concerned, it is possible that rTMS may work by stimulating the prefrontal cortex (PFC), most likely its ventromedial aspects, thereby inhibiting the hyperactive amygdala and the overactive sympathetic system, which might explain its effects in reducing the hyper-arousal symptoms. As evidenced by the animal models of the stress response, it is also possible that changes within the HPA axis, as well as dopaminergic and serotonergic systems of the brain may also be involved. Apart from the putative hypotheses already mentioned, one possible explanation for these differential effects of left or right sided stimulation in rTMS could be due to the differential distribution of the excitatory (glutamatergic) or inhibitory (gamma amino butyric acid: GABAergic) fibers in the cortex in various psychiatric disorders including in PTSD. It is also possible that both low and high frequency rTMS could have different neurophysiological effects. Given these putative neurobio logical mechanisms as well as the clinical and empirical rationale, rTMS can be considered as a viable therapeutic option for PTSD.

TMS or rTMS may be provided before, during or after the patient's exposure to the stimulus. In some embodiments, TMS or rTMS is provided less than about 24 hours, 20 hours, 15 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, and 1 minute before the patient's exposure to the stimulus.

Therapeutic Agent

Pharmaceutical compositions contemplated by the methods of the invention may be formulated and administered to a patient for treatment of the diseases or afflictions disclosed herein as described below.

Administration of a therapeutic agent in conjunction with the method described herein further enhances the efficacy in treating anxiety disorders. The agent may be administered before, during or after the stimulus and exercise steps of the present method. In some embodiments, the agent is administered less than 30 hours before the stimulus step of the present method. Other than non-limiting examples of the timeframe of the administration include less than about 24 hours, 20 hours, 15 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, and 1 minute before the patient's exposure to the stimulus. The methods of the present invention may include the administration of a therapeutic agent. Suitable agents include but are not limited to compounds include antidepressants such as lithium salts, carbamazepine, valproic acid, lysergic acid diethylamide (LSD), p-chlorophenylalanine, p-propyidopacetamide dithiocarbamate derivatives e.g., FLA 63; anti-anxiety drugs, e.g., diazepam; monoamine oxidase (MAO) inhibitors, e.g., iproniazid, clorgyline, phenelzine, tranylcypromine, and isocarboxazid; biogenic amine uptake blockers, e.g., tricyclic antidepressants such as desipramine, imipramine and amitriptyline; atypical antidepressants such as mirtazapine, nefazodone, bupropion; serotonin reuptake inhibitors e.g., fluoxetine, venlafaxine, and duloxetine; antipsychotic drugs such as phenothiazine derivatives (e.g., chlorpromazine (thorazine) and trifluopromazine)), butyrophenones (e.g., haloperidol (Haldol)), thioxanthene derivatives (e.g., chlorprothixene), S and dibenzodiazepines (e.g., clozapine);

benzodiazepines; dopaminergic agonists and antagonists e.g., L-DOPA, cocaine, amphetamine, a-methyl- tyrosine, reserpine, tetrabenazine, benztropine, pargyline;

noradrenergic agonists and antagonists e.g., clonidine, phenoxybenzamine, phentolamine, tropolone.

In certain embodiments, the therapeutic agent is selected from propranolol, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, prazosin, clonidine, carbamazepine, topiramate, Zolpidem, lamotrigine, valproic acid, lithium carbonate, buspirone, risperidone, cyproheptadine, nefazodone, trazodone, amitriptyline, imipramine, phenelzine, or corticosterone, and combinations thereof.

The formulations of the therapeutic agent described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

Pharmaceutical compositions of the therapeutic agent that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for oral, parenteral, topical, pulmonary, intranasal, buccal, ophthalmic, intrathecal or another route of administration. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations. Preferably, the formulations are suitable for oral administration.

The relative amounts of the therapeutic agent, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention may vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) therapeutic agent.

The therapeutically effective dose of the therapeutic agent can be administered using any medically acceptable mode of administration. Although the skilled artisan would contemplate any of the modes of administration known to one of ordinary skill, preferably the pharmacologic agent is administered according to the recommended mode of administration, for example, the mode of administration listed on the package insert of a commercially available agent.

In some embodiments, the patient is treated with ketamine via intravenous or intranasal administration. In some embodiments, the patient is treated intranasally with ketamine, substantially only via the nasal respiratory epithelium, compared to treatment via the nasal olfactory epithelium. In some embodiments, the individual is treated intranasally with ketamine, substantially only via the nasal olfactory epithelium, compared to treatment via the nasal respiratory epithelium. In some embodiments, the individual is treated with a single dose of the therapeutically effective amount of ketamine. In some embodiments, the individual is treated with multiple doses of the therapeutically effective amount of ketamine. In some embodiments, the individual is treated with at least one dose of the therapeutically effective amount of ketamine per week for a period of two or more weeks.

Effective amounts of ketamine in compositions including pharmaceutical formulations, include doses that partially or completely achieve the desired therapeutic, prophylactic, and/or biological effect. In some embodiments, an effective amount of ketamine administered to a subject with PTSD is effective for treating one or more signs or symptoms of PTSD. Specific dosages may be adjusted depending on conditions of disease, i.e., the severity of PTSD, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and

combinations of drugs. Any of the dosage forms described herein containing effective amounts of ketamine, either alone or in combination with one or more active agents, are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.

The dose may be administered as infrequently as weekly or biweekly, or fractionated into smaller doses and administered daily, several times daily, semi-weekly, bi-weekly, quarterly, etc., to maintain an effective dosage level. Preliminary doses can be determined according to animal tests, and the scaling of dosages for human administration can be performed according to art- accepted practices. In certain embodiments, a subject may be administered 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses or more of a ketamine-containing composition described herein. However, other ranges are possible, depending on the subject's response to the treatment Moreover, an initial dose may be the same as, or lower or higher than subsequently administered doses of ketamine. An initial dose may be larger, followed by smaller maintenance doses.

In some embodiments, a dose of ketamine to treat PTSD is approximately 0.001 to approximately 2 mg kg body, 0.01 to approximately 1 mg/kg of body weight, or approximately 0.05 to approximately 0.7 mg/kg of body weight. A subject (e.g., patient) suffering from PTSD may be administered (including self administration) a dose of ketamine of, for example, about 0.01 mg per kg of body weight (mg/kg), about 0.05 mg/kg, 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, or about 3 mg/kg.

In some embodiments, the total dose of ketamine per nasal administration ranges from about 1 to about 250 mg. By way of non-limiting example, ketamine doses of 1 mg, 2 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 1 10 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, and 250 mg are specifically contemplated. In some embodiments, an intranasal or intravenous dose of ketamine for a subject of 80 kg body weight is equal to or greater than about 40 mg, for example, about 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg.

In some embodiments, intranasal administration of 8-32 mg of ketamine, corresponding to 0.13 to 0.53 mg/kg of body weight is contemplated.

Another aspect of the invention provides a method of reducing a patient's score on ASMI scale, comprising (a) obtaining baseline data indicative the severity of a medical disorder prior to treatment; (b) identifying a stimulus that evokes an identifiable reaction indicative of a psychological response to the stimulus in a patient, wherein the stimulus is associated with the anxiety disorder; (c) exposing the patient to the stimulus; (d) having the patient practice an exercise that elicits cognitive mental effort to reduce the severity of the medical disorder, and said exercise is practiced less than 6 hours after the first stimulus is provided; (e) obtaining after-exercise data indicative of severity of the medical disorder after practicing the exercise; and (f) repeating steps (c) and (d) of until a reduction in the severity of the medical disorder is observed.

Details of each step or component of this aspect may reference the above described method of treating an anxiety disorder. The following are provided to summarize the various embodiments.

Non-limiting examples of the anxiety disorder include substance-abuse disorders, mood disorders, panic disorder, agoraphobia, social phobia, specific phobia, posttraumatic stress disorder (PTSD), obsessive-compulsive disorder, and movement disorders.

The identifiable reaction indicative of a psychological response is selected from eye response, eye brows response, pupillary change, facial muscle tone, facial color change, movement response in other body parts, change in posture, change of breathing, change in heart rate, perspiration, predominant emotions, and a combination thereof.

Suitable exercise includes for example standardized breathing techniques, focused attentive meditation, yoga and mindfulness meditation. The length in time of practicing the exercise ranges from about 5 - 80 minutes, all subranges included. In some embodiments, the exercise lasts for about 30 - 60 minutes.

The method may include an additional step of administering agent selected from ketamine, clonidine, propranolol, and D-cycloserine. In some embodiments, the agent is ketamine. In some embodiments, the method further includes a step of exposing the patient to transcranial magnetic stimulation (TMS).

EXAMPLES

Example 1

Primary outcome measures in these studies are the scores on the 2 PTSD specific scales to measure the therapeutic change (Clinician Administered PTSD Scales: CAPS, Dudley et al, 1998 and PTSD Checklist: PCL, Weather et al, 1994). With TIMBER interventions, we have also seen improvements in the secondary outcome measures (but in order to maintain clarity not reported here) like associated depression, anxiety, insomnia, quality of life and somatic symptoms like pain.

I. Efficacy of combined mini-TIMBER (level- 1 TIMBER) and ketamine (single session) in refractory PTSD:

Efficacy of single session of combined ketamine and mini-TIMBER has been examined in a recent pilot study that employed a prospective, placebo controlled, double blind randomized trial design conducted by the index investigators that involved 10 patients suffixing from refractory PTSD. In one arm of this study, the patients (n=5) received ketamine (0.5mg/kg body weight, single infusion over 40 minutes) and mini- TIMBER (TIMBER-K arm). Patients in the other arm (TIMBER-P arm, N=5), received placebo (single infusion of normal saline over 40 minutes) and mini-TIMBER. Subjects' treatment and durations of responses were determined between the two groups. Prior studies on ketamine in PTSD have employed only the change of scores on CAPS and PCL at 25th hour as the response criteria. However, there is no mention about what the minimum duration of response should be in order to consider a patient a 'Responder' in PTSD. The average duration of response to ketamine in depression and PTSD and has ranged from 4-7 days. For this study, we (more stringently) defined 'Responders' as patients who meet all three criteria, from (i) to (iii), i.e. (i) total score reduction from baseline of >20 points in the clinician administered PTSD scale on the second day (25th hour) after the infusion, (ii) total score reduction from baseline of > 10 points in the PTSD check list on the second day (25th hour) after the infusion, and (iii) the duration of response must be sustained for at least 7 days in response to the combined mini-TIMBER and single infusion.

Prior studies on effects of ketamine in treatment resistant depression and PTSD suggest that the peak therapeutic effects of ketamine occur at approximately 24 hours post administration. Also the resolution of the acute sedation and other transient side effects of ketamine are resolved by 24 hours after the end of the infusion. Based upon this data, we selected the change in PTSD severity scores at the 25th hour as the primary endpoint of our study. In this pilot study, although the 25th hour CAPS scores (max scores 136 on 17 items) and PCL scores (maximum scores 85 on 17 items) dropped to below 40 in all 10 patients, only 8 out of 10 patients met the duration criteria for a "Responder' (as defined above). Thus 4 out of 5 patients in the TIMBER-K group and 4 out of 5 patients in the TIMBER-P group met all the three criteria including the duration of response, which ranged from 7-71 days in the TIMBER-K group (n=5) as opposed to 4-20 days in the TIMBER-P group (n=5).

The duration of response in 8 out of these 10 patients in both TIMBER-K and TIMBER-P groups was at least 11 days. As mentioned above, in 1 patient in the TIMBER- K group, the duration of response was 71 days, which is much longer than the usual duration of response of single dose ketamine (4-7 days). These 8 subjects demonstrated strong response to the treatments based on the clinically significant decrease in the PTSD severity scores on CAPS and PCL scales. The CAPS score at 25^th hour post infusion was reduced by 70% and 80% from baseline in the TIMBER-P and TIMBER-K patients, respectively. For PCL the reductions were 58%> and 69%>. The PTSD scale scores reduced further at 8 hours post-infusion and were the lowest at 24 hours post infusion. In addition, compared to the TIMBER-P group, patients in TIMBER-K group showed a more dramatic and robust response beginning 4 hours post-infusion and peaking at 25^th hour on PTSD and depression scales. TIMBER-K group experienced more improvement in associated depression scores and hopelessness (as measured by the scores on the Hamilton

Depression Rating Scale; 17-item, Bech, 1996), greater reduction in the intensity of TM and flash backs in visual, auditory and tactile modalities, as well as more markedly reduced arousal and associated distress during recall of the specifics of the traumatic events. In addition, three out of the five patients in the TIMBER-K group reported impressive reductions in pain and nightmares. There were no clinically significant side effects including cognitive side effects (as measured by the Montreal Cognitive

Assessment: MoCA) in all the patients except mild nausea within 2 hours post-infusion in two patients. Only 1 patient (non-responder, duration of response 4 days, belonged to the TIMBER-P group) dropped out of these 10 patients cohort: this patient had very severe psychosocial stressors and sever ongoing pain and post-operative urinary incontinence from a stab wound as well. Although preliminary, the high retention rates in this study attests to the acceptability by the patient of these interventions in addition to their preliminary efficacy.

II. Efficacy of full-TIMBER (levels 1, 2 and 3) in refractory PTSD

As psychotherapy for PTSD, full-TIMBER has been found to be efficacious for in 4 adolescents and 10 adults with refractory PTSD. The results have been reduction of

CAPS scores by 70% and PCL scores by 75% after 6 sessions of full-TIMBER (individual therapy sessions, 45 minutes each).

Example 2

This study involved four female adolescent patients aged 14-19 years who met DSM-IV criteria for PTSD, and who had no significant non-psychiatric medical conditions, such as thyroid disorders, diabetes, heart conditions, asthma or seizures. PTSD was considered to be treatment refractory based on their lack of response to more than two antidepressant medications in sufficient dosages and duration. A formal Institutional Review Board (IRB) approval was requested and an exemption was granted due to nature of the sample size and interventions. Informed consents were obtained from all participants with a detailed explanation of investigational nature of this protocol. The TIMBER sessions were conducted in between December 2012 and October 2014 and involved 12-sessions of therapist-assisted individual therapy sessions (Full-TIMBER, 60 minutes each) and graded self-exposure to the trauma triggers in daily life situations, followed by regulation of the arousal and reappraisal of the trauma memories by mini- TIMBER interventions (10 minute practice sessions) that the patient mastered during the therapist-assisted and home practice sessions. All therapy sessions were individual 60- minute sessions combined with a standardized home practice design for self-exposure and generalization. Home practice required patients to practice 10-15 minutes twice daily (morning and evening). They were also instructed to use the standardized mini-TIMBER interventions for five minutes as needed to control the arousal during the spontaneous intrusions of the PTSD symptoms during the course of their daily life.

During the application of TIMBER interventions in therapist's office, arousals during cue exposure were handled by the full-TIMBER protocols (mindfulness based exposure therapy and staged meditation protocols for deescalating the arousal symptoms and for inducing detachment) whereas the spontaneous arousal episodes in day to day life situations were handled by the shorter mini-TIMBER protocols. TIMBER interventions, including the breathing meditations and other elements using the bottom up model of meditation, were strategically used in the reconsolidation window (which is usually considered as first 6 hours after retrieval of trauma) to modify the trauma response. Of note, therapist-assisted control of the hyper-arousal state of the patient in the

reconsolidation window served as a mini-session of TIMBER beginning the process of updating the structure of the fear memory. Further transformation of the affective load of the memory was made later using the more elaborate full-TIMBER that includes the elements of the mindfulness based exposure therapy. These meditation interventions were used both during therapist-assisted sessions as well as during in-home sessions and were directed to specifically target the PTSD symptoms affecting the patient. The homework assignments further served to generalize the new learnings beyond the therapist's office.

As shown in Table 1 , the assessment before and after TIMBER interventions was done using PTSD specific rating scales (the PTSD Symptom Check List, PCL; Weathers, Litz, Herman, Huska, & Keane, 1993) as well as semi-structured exploratory interviews. The interviews were used to generate a multi-modal trauma narrative including emotional, cognitive and sensorial information (with tactile, auditory, and visual narratives), which is based on the spontaneous narrative of the patient about the indexed trauma.

Treatment resulted in remission of PTSD symptoms and associated dysfunction as evidenced by reduction in the scores of PTSD Symptom Check List-Civilian version

(PCL-C) as well as in distress and avoidance behavior in daily life. In addition, there were clinically observable improvements in depression, panic symptoms, insomnia and level of general attentiveness. None of the patients required any psycho-tropic medication or any other therapies during this 12-session treatment. The results are shown in Table 1.

Table 1. Results showing efficacy of TIMBER in four adolescents with refractory PTSD.

PCL-C: PTSD Symptom Check List-Civilian version, 17-item (Weathers et al, 1993). The average number of sessions for inducing remission (defined as PCL-C scores

<51; complete remission as PCL-C scores <30; Ballenger, 2001; Doyle & Pollack, 2003) was 4-6 sessions. Currently, all four patients are maintaining in remission and have been doing well in their lives. Of note, there were 100% follow up rates in these four patients and they reported high satisfaction with the TIMBER interventions during course of their treatment.

Example 3

The following example illustrates a scale (Arousal Response during Trauma Memory Reactivation© (ART -MR, Pradhan and Gray, 201.3)) for assessing the intensity of a patient's reaction to stimulus. A stronger reaction is given a higher score.

Patient's Name: Male / Female; Level of Education: ;

Date: Instructions: ART-MR scale requires the rater to carefully observe the patient during the controlled reactivation process. This scale has 11 items, takes about 5 minutes to complete and the scores range from 0 to 55: higher the scores, higher is the level of arousal. The parameters assessed in the ART -MR. scale involve verbal as well as non-verbal responses. In particular, the parameters to observe involve facial expressions and physiological as well as emotional changes in the patient in response to a brief narrative of the index trauma. Depending upon the needs of the clinical situation and patient's preference, the reactivation can be suspended and patient can quickly be reoriented to the present moment by the mmi-TIMBER , a specific mindfulness intervention standardized and used by Dr. Basant Pradhan since 2001 and which has been shown to be effective in studies without causing any observed side effects in the patients.

As can be observed the patient's responses during the controlled reactivation of the traumatic memory, please rate the following factors by encircling the appropriate changes listed below. For all the changes observed, whenever possible, please note the sequence in which the changes occur. Before rating the items in this scale, please indicate the presence or absence of the following two dichotomous items in this patient:

(a) Patient has one or a few very specific memories about an index trauma (involving death or immanent destruction). True False

(b) The trauma is the source of nightmares and flashbacks in which patient relives the trauma or some aspects of it (whether or not patient fully recalls it). True False

On a scale of 0 (none) to 5 (very much without question), please assess the

following items. Eye Response (change in size, movements, open/closed, change in eye contact, downcast):

None or Very much

Little without question

0 1 2 3 4 5

Sequence of change, if any

Eye brows response (e.g. furrowed, frowned, raised, lowered etc.): None or Very much

Little without question

0 1 2 3 4 5

Sequence of change, if any

Pupillary change during arousal widened, contracted, etc.)

None or Very much

Little without question

0 1 2 3 4 5

Sequence of change, if any

Facial muscle tone (e.g. tightened, relaxed, clenched, etc.):

None or Very much

Little without question

0 1 2 3 4 5

Sequence of change, if any

Facial color change (if applicable: reddened, paled, purple, etc.).

None or Very much

Little without question

0 1 2 3 4 5

Sequence of change, if any

Movement response in other body parts (e.g. fidgeting fingers, shaking feet/legs, shrugging shoulders, clenching teeth, biting lips, biting tongue, biting nails, body rigidity)

None or Very much

Little without question 0 1 2-

Sequence of change, if any _

Change in posture (erect, leaning left, leaning right, slouching, leaning back, leaning forward)

None or Very much

Little without question

0- -1-

Sequence of change, if any

Change of breathing (rate increased, rate decreased; any change of breathing location— e.g. high chest, middle chest, belly, etc.)

None or Very much

Little without question

0- -1-

Sequence of change, if any _

Change in heart rate (increased, decreased)

None or Very much

Little without question

0- -1-

Sequence of change, if any _.

Perspiration

None or Very much

Little without question

0- -1-

Sequence of change, if any _.

Predominant emotion(s) during assessment (anger, fear, hatred, sadness, surprise etc.)

None or Very much

Little without question

0 1 2 3 4 5

Sequence of change, if any Strong and involuntary (reflex-like) emotional response either spontaneously with very mild trigger (e.g. eyes welling up with tears or outright crying, changes in breathing, facial color, changes in the pace and tone of voice, a need to stop the narrative because of intense arousal, shaking, sweating, acting as if they were seeing or hearing the event all over again).

Other Questions:

• Duration of reactivation: seconds/minutes

• Time taken to reorient and control the arousal to baseline: _

seconds/minutes

· Any other comments:

Total ART-MR Scores: /55

Example 4

The following example provides a scale (Assessment Scale for Mindfulness Interventions (ASMI©, Pradhan, B.K., 2012; Clinical) for assessing a patient's mental state or severity of the anxiety disorder. A higher score indicates a more severe disorder.

The 18 questions below are self-rated, self-explanatory & usually take less than 10 minutes to complete. Thank you very much for filling this form!

Name: Age: Date: Education:

Even when things are NOT going the way I want, usually I try to be kind and gentle towards myself

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

Usually I'm hard on myself about my own flaws or shortcomings

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

When things are NOT going well for me, I tend to think that difficulties are part of life and almost everyone go through these difficulties

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

Mere are such negative/difficult things about me that I don't want to even think about those

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

Often I compare myself with others and that makes me feel bad about myself

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree) Usually I try too hard in my life but I don 't give myself credit for trying

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

Before criticizing somebody, I tend to imagine how I would feel if I were in their place

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

Usually it is difficult for me to see things from another person 's point of view (0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

While carrying out tasks in my daily life, usually my level of focus/attention is

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

While carrying out tasks, usually my mind wanders into the past/ future rather than staying in present moment

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

In my daily lift, usually I'm quite reactive to situations around me rather than taking them calmly as they come

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

In my daily life, usually I tend to look back and go over the various life situations in a in a calm and detached manner without getting too happy or too upset about them

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

I'm quite aware and quick to notice changes in my body and mind when I'm stressed out (like my heart or breathing or thoughts becoming faster; my muscles getting tense or my voice getting louder)

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

These days my thoughts, feelings and behavior are quite intense and are in the extremes

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

In general, I'm pretty regular with sleeping, eating and the other habits in my daily life

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

I try to use tools (breathing/ relaxation techniques, coping cards etc.) to help myself with the difficulties coming from my nervous / physical symptoms (0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree) 17. Usually it is difficult for me to apply to my daily life the helpful things I learn from the various situations

(0 = Do NOT agree, 1, 2, 3, 4, 5 = Strongly agree)

18. Minutes spent by me daily in practice of the self-help tools (meditation, breathing techniques etc.): 0 = no practice; 1 = less than 15- minutes; 2 =15-30 minutes; 3 = 31-45 minutes; 4= 46-60 minutes; 5= more than 60 minutes)

How easy was it to fill this form? (0 =not easy at all, 1, 2, 3, 4, 5=extremely easy )

Comments if any:

The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

While this subject matter has been disclosed with reference to specific

embodiments, it is apparent that other embodiments and variations can be devised by others skilled in the art without departing from the true spirit and scope of the subject matter described herein. The appended claims include all such embodiments and equivalent variations.

Claims

CLAIMS What is claimed is:

1. A method of treating an anxiety disorder, comprising

(a) obtaining baseline data indicative the severity of the anxiety disorder prior to treatment;

(b) identifying a stimulus that evokes an identifiable reaction indicative of a psychological response to the stimulus in a patient, wherein the stimulus is associated with the anxiety disorder;

(c) exposing the stimulus to the patient;

(d) having the patient practice an exercise that elicits cognitive mental effort to reduce the severity of the medical disorder, and said exercise is practiced less than 6 hours after the first stimulus is provided; and

(e) obtaining after-exercise data indicative of severity of the anxiety disorder after practicing the exercise.

2. The method of claim 1, wherein the anxiety disorder is selected from substance- abuse disorders, mood disorders, panic disorder, agoraphobia, social phobia, specific phobia, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, and movement disorders.

3. The method of claim 1, wherein the anxiety disorder is PTSD.

4. The method of claim 1, wherein the identifiable reaction is selected from eye response, eye brows response, pupillary change, facial muscle tone, facial color change, movement response in other body parts, change in posture, change of breathing, change in heart rate, perspiration, predominant emotions, and a combination thereof.

5. The method of claim 1, wherein the data indicative of the severity of the anxiety disorder is assessed on Assessment Scale for Mindfulness Interventions (ASMI), wherein a more severe disorder is given a higher score.

6. The method of claim 1, wherein a reaction score indicative of a psychological response is obtained using a scale of Arousal Response during Trauma Memory

Recreation (ART -MR), wherein a more intensive reaction is given a higher score.

7. The method of claim 6, wherein the length of the exposure to the stimulus is adjusted based on the reaction score to minimize prolonged exposure.

8. The method of claim 1, wherein the patient starts practicing the exercise less than 10, 20, or 30 minutes after being exposed to the stimulus.

9. The method of claim 1, wherein the exercise lasts for a period of about 30-60 minutes.

10. The method of claim 1, wherein the exercise comprises a member selected from standardized breathing techniques, focused attentive meditation, yoga and mindfulness meditation.

11. The method of claim 1 , wherein the exercise comprises yoga.

12. The method of claim 1, further comprising administering a therapeutically effective amount of a therapeutic agent, wherein said agent is administered less than 20 hours before the patient is exposed to the stimulus and is selected from antidepressants, arousal modifying agents, and trauma memory modifying agents.

13. The method of claim 12, further comprising administering a therapeutically effective amount of a therapeutic agent, said agent selected from ketamine, clonidine, propranolol, and D -cycloserine.

14. The method of claim 12, wherein the agent is ketamine.

15. The method of claim 12, wherein the agent is administered less than 1 hour before the patient is exposed to the stimulus.

16. The method of claim 1, further comprising exposing the patient to transcranial magnetic stimulation (TMS).

17. A method of treating an anxiety disorder, comprising

(a) identifying a stimulus that evokes an identifiable reaction indicative of a psychological response to the stimulus in a patient, wherein said first stimulus is associated with the anxiety disorder;

(b) administering a therapeutically effective amount of a therapeutic agent, said agent selected from ketamine, clonidine, propranolol, and D-cycloserine;

(c) exposing the stimulus to the patient less than 10 hours after administering the agent; and (d) having the patient practice an exercise that elicits cognitive mental effort to reduce the severity of the medical disorder, and said exercise is practiced less than 6 hours after the first stimulus is provided.

18. The method of claim 17, wherein the exercise is selected from standardized breathing techniques, focused attentive meditation, yoga and mindfulness meditation.

19. The method of claim 17, wherein the exercise lasts for about 5-65 minutes.

20. The method of claim 17, wherein the agent is ketamine.

21. The method of claim 17, wherein step (c) is performed less than 1 hour after step (b).

22. A method of reducing a patient's score on ASMI scale, comprising

(a) obtaining baseline data indicative the severity of a anxiety disorder prior to treatment;

(b) identifying a stimulus that evokes an identifiable reaction indicative of a psychological response to the stimulus in a patient, wherein the stimulus is associated with the anxiety disorder;

(c) exposing the patient to the stimulus;

(d) having the patient practice an exercise that elicits cognitive mental effort to reduce the severity of the anxiety disorder, and said exercise is practiced less than 6 hours after the first stimulus is provided;

(e) obtaining after-exercise data indicative of severity of the medical disorder after practicing the exercise; and

(f) repeating steps © and (d) of until a reduction in the severity of the anxiety disorder is observed.

23. The method of claim 21, wherein the anxiety disorder is selected substance-abuse disorders, mood disorders, panic disorder, agoraphobia, social phobia, specific phobia, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, and movement disorders.

24. The method of claim 1, wherein the identifiable reaction is selected from eye response, eye brows response, pupillary change, facial muscle tone, facial color change, movement response in other body parts, change in posture, change of breathing, change in heart rate, perspiration, predominant emotions, and a combination thereof.

25. The method of claim 21, wherein the patient starts practicing the exercise less than 30 minutes after being exposed to the stimulus.

26. The method of claim 21, wherein the exercise lasts for a period of about 30-60 minutes.

27. The method of claim 1, wherein the exercise comprises a member selected from standardized breathing techniques, focused attentive meditation, yoga and mindfulness meditation.

28. The method of claim 1, further comprising administering a therapeutically effective amount of a therapeutic agent, wherein said agent is administered less than 10 hours before the patient is exposed to the stimulus and is selected from ketamine, clonidine, propranolol, and D-cycloserine.

29. The method of claim 27, wherein the agent is ketamine.

30. The method of claim 22, further comprising exposing the patient to transcranial magnetic stimulation (TMS).