Methods and systems for automated neurocognitive training to extend the alleviation of treatment-resistant psychiatric disorders

Abstract

Described herein is an automated neurocognitive training method and system for extending the alleviation of treatment-resistant psychiatric disorders. An exemplary method includes administering a drug having an antidepressant effect to a patient, and administering a neurocognitive training protocol to the patient during a critical period after administration of the drug. Furthermore, administering the neurocognitive training protocol to the patient includes providing the patient with a plurality of automated neurocognitive training sessions using a computing device. During each of the automated neurocognitive training sessions, a plurality of conditioning sequences are presented to the patient, each conditioning sequence including a respective non-self-related stimulus and a respective self-related stimulus.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 316,098, filed March 3, 2022, and entitled “METHODS AND SYSTEMS FOR AUTOMATED NEUROCOGNITIVE TRAINING TO EXTEND RELIEF OF TREATMENT-RESISTANT MENTAL DISORDERS,” the disclosure of which is expressly incorporated by reference in its entirety herein. Statement regarding federally funded research This invention was made with government support under Grant nos. MH113857 and MH124983 from the National Institutes of Health. The government has certain rights in the invention. [Background technology]

[0002] Depression is a leading cause of disability worldwide, and its disease burden is staggering. Effective treatments have been available for decades, yet remission rates are low, relapse rates are high, disability prevalence rates have remained remarkably consistent, and only 12.7% of patients receive minimally adequate treatment. Suicide, the most tragic outcome of depression, claims one million lives annually worldwide. Suicide rates in the United States have continued to rise in recent years, despite concerted research and clinical efforts to address this tragic need. Eighty percent of those who commit suicide seek medical attention within one year of their death, suggesting that the system as a whole is missing a critical opportunity to engage these patients in effective suicide prevention strategies. Novel and innovative treatments that are accessible, portable, and disseminate are urgently needed to address this public health crisis.

[0003] Depression intervention development is increasingly moving towards leveraging technology to improve patient access, reduce costs, and minimize evasive outcomes through the use of automated computer-based procedures / software. Over the past decade, there has been growing interest in automated “cognitive training” (CT) treatments, designed to directly modulate emotional processing patterns to reduce symptoms. However, while clinical efficacy has shown promise, it is unreliable, especially in acutely depressed patients, and relief typically takes several weeks. At the same time, fast-acting pharmacological agents such as subanesthetic ketamine have been expected to bring about a breakthrough in how depression is managed. Studies have shown that 2 hours after ketamine administration, a 55-80% response rate in depressed patients is achieved. However, because most effects of a single ketamine infusion disappear rapidly (3-7 days), clinical application poses significant challenges in light of concerns regarding the safety and feasibility of repeated administration of ketamine. Furthermore, the majority of depressed patients have expressed a preference for treatments that include a behavioral / learning component (e.g., up to 91% enroll in drug trials). The practical challenges of maintaining drug regimens long term further suggest that a multimodal approach to achieving rapid and sustained relief is needed. Summary of the Invention

[0004] In some embodiments, the technology described herein relates to a method for treating a patient with a psychiatric disorder, comprising: administering a drug having an antidepressant effect to the patient; and administering a neurocognitive training protocol to the patient during a critical period after administration of the drug. The step of administering the neurocognitive training protocol to the patient comprises using a computing device to provide the patient with a plurality of automated neurocognitive training sessions, wherein a plurality of conditioning sequences are presented to the patient during each of the provision of the automated neurocognitive training sessions, and each of the conditioning sequences comprises a respective non-self-related stimulus and a respective self-related stimulus.

[0005] In some embodiments, a first automated neurocognitive training session and a second automated neurocognitive training session are provided to the patient on a first day, and a third automated neurocognitive training session and a fourth automated neurocognitive training session are provided to the patient on a second day. Optionally, a period of time between providing the first and second automated neurocognitive training sessions to the patient is about 20 minutes or more. Optionally, a period of time between providing the third and fourth automated neurocognitive training sessions to the patient is about 20 minutes or more.

[0006] In some embodiments, each of the automated neurocognitive training sessions is between about 15 minutes and about 20 minutes in length.

[0007] In some embodiments, the plurality of automated neurocognitive training sessions is between about 2 sessions and about 14 sessions. Optionally, the plurality of automated neurocognitive training sessions is about 8 sessions.

[0008] In some embodiments, each conditioning sequence further comprises a task, the task being presented to the patient following or in conjunction with the presentation of each set of non-self-relevant and self-relevant stimuli.

[0009] In some embodiments, each non-self-related stimulus and / or each self-related stimulus for each conditioning sequence is an auditory stimulus, hi some embodiments, each non-self-related stimulus and / or each self-related stimulus for each conditioning sequence is a visual stimulus.

[0010] In some implementations, each self-related stimulus for each conditioning sequence includes a sound, picture, or word that is relevant to the patient. Optionally, each non-self-related stimulus for each conditioning sequence includes a sound, picture, or word that is associated with a positive meaning. Optionally, each non-self-related stimulus for each conditioning sequence includes a sound, picture, or word that is associated with a life-affirming meaning.

[0011] In some embodiments, each non-self-related stimulus and each self-related stimulus for each conditioning sequence is included in an n x m matrix including a plurality of visual stimuli. Optionally, administering the neurocognitive training protocol to the patient further includes receiving a selection from the patient to match each non-self-related stimulus with each self-related stimulus for each conditioning sequence.

[0012] In some embodiments, one or more of the plurality of conditioning sequences comprises a subliminal presentation of a non-self-related or self-related stimulus. In some embodiments, one or more of the plurality of conditioning sequences comprises a supercritical presentation of a non-self-related or self-related stimulus.

[0013] In some implementations, a computing device includes a processor and a memory operatively coupled to the processor, the memory having computer-executable instructions stored thereon. Optionally, the memory has stored thereon computer-executable instructions that, when executed by the processor, cause the processor to generate each conditioning sequence.

[0014] In some embodiments, the computing device further includes a display device operably coupled to the processor, and the memory has computer-executable instructions stored thereon that, when executed by the processor, cause the processor to: generate graphical data for each respective conditioning sequence; and display the graphical data on the display device.

[0015] In some embodiments, the critical period is the period during which the drug acutely increases synaptic connections in the brain of the patient.In some embodiments, the critical period is between about 2 hours and about 14 days after administration of the drug.In some embodiments, the critical period is between about 1 day and about 5 days after administration of the drug.

[0016] In some embodiments, the drug is a fast-acting antidepressant. In some embodiments, the fast-acting antidepressant is ketamine. In some embodiments, the drug is brexanolone, zuranolone, rapastinel, scopolamine, or a psychedelic.

[0017] In some embodiments, the psychiatric disorder is depression. In some embodiments, the psychiatric disorder is suicidal behavior.

[0018] In some embodiments, the technology described herein relates to a computer-implemented method for administering a neurocognitive training protocol to a patient with a psychiatric disorder, the patient being administered a drug having an antidepressant effect, and the neurocognitive training protocol being administered during a critical period after administration of the drug to the patient. The computer-implemented method includes providing a plurality of automated neurocognitive training sessions to the patient, wherein during each of the automated neurocognitive training sessions, a plurality of conditioning sequences are presented to the patient, each conditioning sequence including a respective non-self-related stimulus and a respective self-related stimulus.

[0019] In some embodiments, a first automated neurocognitive training session and a second automated neurocognitive training session are provided to the patient on a first day, and a third automated neurocognitive training session and a fourth automated neurocognitive training session are provided to the patient on a second day. Optionally, a period of time between providing the first and second automated neurocognitive training sessions to the patient is about 20 minutes or more. Optionally, a period of time between providing the third and fourth automated neurocognitive training sessions to the patient is about 20 minutes or more.

[0020] In some embodiments, each of the automated neurocognitive training sessions is between about 15 minutes and about 20 minutes in length.

[0021] In some embodiments, the plurality of automated neurocognitive training sessions is between about 2 sessions and about 14 sessions. Optionally, the plurality of automated neurocognitive training sessions is about 8 sessions.

[0022] In some embodiments, each conditioning sequence further comprises a task, the task being presented to the patient following or in conjunction with the presentation of each set of non-self-relevant and self-relevant stimuli.

[0023] In some embodiments, each non-self-related stimulus and / or each self-related stimulus for each conditioning sequence is an auditory stimulus, hi some embodiments, each non-self-related stimulus and / or each self-related stimulus for each conditioning sequence is a visual stimulus.

[0024] In some implementations, each self-related stimulus for each conditioning sequence includes a sound, picture, or word that is relevant to the patient. Optionally, each non-self-related stimulus for each conditioning sequence includes a sound, picture, or word that is associated with a positive meaning. Optionally, each non-self-related stimulus for each conditioning sequence includes a sound, picture, or word that is associated with a life-affirming meaning.

[0025] In some embodiments, each non-self-related stimulus and each self-related stimulus for each conditioning sequence is included in an n x m matrix including a plurality of visual stimuli. Optionally, the computer-implemented method further includes receiving from the patient a selection of matching each non-self-related stimulus with each self-related stimulus for each conditioning sequence.

[0026] In some embodiments, one or more of the plurality of conditioning sequences comprises a subliminal presentation of a non-self-related or self-related stimulus. In some embodiments, one or more of the plurality of conditioning sequences comprises a supercritical presentation of a non-self-related or self-related stimulus.

[0027] In some embodiments, the computer-implemented method further comprises generating each respective conditioning sequence.

[0028] In some embodiments, the computer-implemented method further comprises generating graphical data for each respective conditioning sequence; and causing the graphical data to be displayed on a display device.

[0029] In some embodiments, the critical period is the period during which the drug acutely increases synaptic connections in the brain of the patient.In some embodiments, the critical period is between about 2 hours and about 14 days after administration of the drug.In some embodiments, the critical period is between about 1 day and about 5 days after administration of the drug.

[0030] In some embodiments, the technology described herein relates to a system for administering a neurocognitive training protocol to a patient with a psychiatric disorder, the patient being administered a drug having an antidepressant effect, and the neurocognitive training protocol is administered to the patient at a critical period after the drug is administered. The system includes a processor and a memory operatively coupled to the processor, the memory storing computer executable instructions thereon that, when executed by the processor, cause the processor to: provide a plurality of automated neurocognitive training sessions to the patient, and a plurality of conditioning sequences are presented to the patient during each of the provision of the automated neurocognitive training sessions, each of the conditioning sequences including a respective non-self-related stimulus and a respective self-related stimulus.

[0031] In some embodiments, a first automated neurocognitive training session and a second automated neurocognitive training session are provided to the patient on a first day, and a third automated neurocognitive training session and a fourth automated neurocognitive training session are provided to the patient on a second day. Optionally, a period of time between providing the first and second automated neurocognitive training sessions to the patient is about 20 minutes or more. Optionally, a period of time between providing the third and fourth automated neurocognitive training sessions to the patient is about 20 minutes or more.

[0032] In some embodiments, each of the automated neurocognitive training sessions is between about 15 minutes and about 20 minutes in length.

[0033] In some embodiments, the plurality of automated neurocognitive training sessions is between about 2 sessions and about 14 sessions. Optionally, the plurality of automated neurocognitive training sessions is about 8 sessions.

[0034] In some embodiments, each conditioning sequence further comprises a task, the task being presented to the patient following or in conjunction with the presentation of each set of non-self-relevant and self-relevant stimuli.

[0035] In some embodiments, each non-self-related stimulus and / or each self-related stimulus for each conditioning sequence is an auditory stimulus, hi some embodiments, each non-self-related stimulus and / or each self-related stimulus for each conditioning sequence is a visual stimulus.

[0036] In some implementations, each self-related stimulus for each conditioning sequence includes a sound, picture, or word that is relevant to the patient. Optionally, each non-self-related stimulus for each conditioning sequence includes a sound, picture, or word that is associated with a positive meaning. Optionally, each non-self-related stimulus for each conditioning sequence includes a sound, picture, or word that is associated with a life-affirming meaning.

[0037] In some implementations, each non-self-relevant stimulus and each self-relevant stimulus for each conditioning sequence is included in an n x m matrix that includes a plurality of visual stimuli.

[0038] In some embodiments, one or more of the plurality of conditioning sequences comprises a subliminal presentation of a non-self-related or self-related stimulus. In some embodiments, one or more of the plurality of conditioning sequences comprises a supercritical presentation of a non-self-related or self-related stimulus.

[0039] In some embodiments, the memory further has computer-executable instructions stored thereon that, when executed by the processor, cause the processor to generate the respective conditioning sequences.

[0040] In some embodiments, the memory further stores computer-executable instructions that, when executed by the processor, cause the processor to generate graph data for each conditioning sequence and display the graph data on a display device.

[0041] In some embodiments, the technology described herein relates to a method for treating a patient with a psychiatric disorder, comprising: administering a drug having an antidepressant effect to the patient; and administering a neurocognitive training protocol to the patient during a critical period after the drug administration. The step of administering the neurocognitive training protocol to the patient comprises providing the patient with a plurality of automated neurocognitive training sessions using a computing device. Further, each automated neurocognitive training session comprises: presenting to the patient, using a computing device, an nxm matrix including a plurality of visual stimuli, the plurality of visual stimuli including a first matching pair of non-self-related visual stimuli and self-related visual stimuli; and receiving, using a computing device, a selection by the patient of the first matching pair of non-self-related visual stimuli and self-related visual stimuli.

[0042] In some embodiments, each automated neurocognitive training session further includes presenting, using the computing device, a second matched pair of non-self-related and self-related visual stimuli to the patient, and presenting, using the computing device, a challenge to the patient following or in conjunction with the presentation of the second matched pair of non-self-related and self-related visual stimuli.

[0043] In some embodiments, each automated neurocognitive training session further includes using a computing device to present self-related visual stimuli to the patient, using the computing device to present a challenge to the patient following or in conjunction with the presentation of the self-related stimuli, and using the computing device to present a positive non-self-related visual stimulus after the patient successfully completes the challenge.

[0044] In some embodiments, each of the automated neurocognitive training sessions is between about 15 minutes and about 20 minutes in length.

[0045] In some embodiments, the critical period is the period during which the drug acutely increases synaptic connections in the brain of the patient.In some embodiments, the critical period is between about 2 hours and about 14 days after administration of the drug.In some embodiments, the critical period is between about 1 day and about 5 days after administration of the drug.

[0046] In some embodiments, the technology described herein relates to a computer-implemented method for administering a neurocognitive training protocol to a patient with a psychiatric disorder, the patient being administered a drug having an antidepressant effect, and the neurocognitive training protocol is administered to the patient during a critical period after the drug is administered. The computer-implemented method includes presenting to the patient an nxm matrix including a plurality of visual stimuli, the plurality of visual stimuli including a first matching pair of non-self-related visual stimuli and self-related visual stimuli, and receiving a selection by the patient of the first matching pair of non-self-related visual stimuli and self-related visual stimuli.

[0047] In some embodiments, the technology described herein relates to a system for administering a neurocognitive training protocol to a patient with a psychiatric disorder, the patient being administered a drug having an antidepressant effect, and the neurocognitive training protocol is administered to the patient at a critical period after the drug is administered. The system includes a processor and a memory operatively coupled to the processor, the memory storing computer executable instructions that, when executed by the processor, cause the processor to: present an nxm matrix to the patient, the matrix including a plurality of visual stimuli, the plurality of visual stimuli including a first matching pair of non-self-related visual stimuli and self-related visual stimuli; receive a selection by the patient of the first matching pair of non-self-related visual stimuli and self-related visual stimuli.

[0048] In some embodiments, the technology described herein relates to a method for treating a patient with a psychiatric disorder, comprising: administering to the patient a drug having an antidepressant effect; and administering to the patient a neurocognitive training protocol during a critical period following administration of the drug. The step of administering to the patient the neurocognitive training protocol comprises delivering to the patient, using a computing device, a plurality of automated neurocognitive training sessions, wherein a plurality of conditioning sequences are presented to the patient during each delivery of the automated neurocognitive training sessions.

[0049] In some embodiments, the technology described herein relates to a method for therapeutic association of a patient, comprising administering a neuroplasticity enhancing treatment to the patient; and administering a neurocognitive training protocol to the patient at a critical period after administration of the neuroplasticity enhancing treatment. Administering the neurocognitive training protocol to the patient comprises using a computing device to deliver to the patient one or more conditioning sequences configured to condition the therapeutic association. In some embodiments, the neuroplasticity enhancing treatment is a drug. In other embodiments, the neuroplasticity enhancing treatment is a neuromodulatory intervention.

[0050] It will be appreciated that the subject matter described above may also be embodied as a computer controller, a computer process, a computing system, or an article of manufacture such as a computer readable storage medium.

[0051] Other systems, methods, features and / or advantages will be or may become apparent to one with skill in the art upon examination of the following figures and detailed description, and all such additional systems, methods, features and / or advantages are intended to be included within this description and protected by the accompanying claims. [Brief description of the drawings]

[0052] The components in the drawings are not necessarily to scale relative to each other. Like reference numerals indicate corresponding parts throughout the several views. [Figure 1] FIG. 1 is a flow chart illustrating exemplary operations for treating a subject with a psychiatric disorder according to embodiments described herein. [Diagram 2] FIG. 2 illustrates an example of a conditioning sequence provided during neurocognitive training according to embodiments described herein. [Diagram 3] 3 shows an example of another conditioning sequence provided during neurocognitive training according to embodiments described herein. [Figure 4] 4 shows an example of another conditioning sequence that may be provided during neurocognitive training according to embodiments described herein. [Diagram 5] FIG. 5 illustrates an example of a contingent task (i.e., lexical decision) provided during neurocognitive training. FIG. 5 illustrates an example of a contingent task (i.e., lexical decision) that may be administered during neurocognitive training in accordance with embodiments described herein. [Figure 6]FIG. 6 illustrates another example contingency task (i.e., rapid selection) provided during neurocognitive training according to embodiments described herein. [Figure 7-1] 7A-7C are examples of different conditioning sequences provided during neurocognitive training according to embodiments described herein. Fig. 7A shows an example of a user interface. Fig. 7B shows an example of a pair of self-relevant and non-self-relevant stimuli. Fig. 7C shows an example of a matrix. [Figure 7-2] (As stated above.) [Figure 8] FIG. 8 is an example of a computing device. [Figure 9] Figure 9 is a graph showing depression severity scores (Montgomery-Asberg Depression Rating Scale total score) as a function of days since infusion and treatment assignment in a randomized controlled trial of ketamine and automated self-association training (ASAT) [ketamine + active ASAT, n = 53; ketamine + sham ASAT, n = 50; saline + active ASAT, n = 51]. Line graphs represent mean values ​​and error bars represent standard error of the mean within each time point and treatment group. [Figure 10] Figure 10 shows patient and clinician guesses about treatment allocation as a function of true allocation in Table S1 . [Figure 11-1] Figures 11A-11D are Table S2 showing adverse events. Figure 11A is for ketamine patients and adverse events reported on the day of infusion. Figure 11B is for ketamine patients and adverse events reported after the day of infusion. Figure 11C is for saline patients and adverse events reported on the day of infusion. Figure 11D is for saline patients and adverse events reported after the day of infusion. [Figure 11-2] (As stated above.) [Figure 11-3] (As stated above.) [Figure 11-4] (As stated above.) [Figure 12]Figure 12 shows Table S3, which shows the robustness of the main findings in the text when covariates are included in the model. [Figure 13] FIG. 13 shows depression severity scores (Quick Inventory of Depressive Symptoms Total: Self-reported scale scores) as a function of days since infusion and treatment assignment according to the examples described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] Detailed explanation Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure. As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. As used herein, the term "comprising" and variations thereof are used synonymously with the term "including" and variations thereof and are open-ended and non-limiting terms. As used herein, the term "optionally" or "optionally" means that the subsequently described feature, event or circumstance may or may not occur, and includes instances in which the feature, event or circumstance occurs and instances in which the feature, event or circumstance does not occur. In this specification, ranges may be expressed as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, it includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, the use of the antecedent "about" will be understood to indicate that the particular value forms another aspect. It will be further understood that the endpoints of each range are significant in relation to the other endpoints and independently of the other endpoints. Although embodiments are described for using automated neurocognitive training following intravenous administration of ketamine to prolong the relief of treatment-resistant depression, it will be apparent to one of skill in the art that the embodiments are not limited thereto and are applicable for using automated neurocognitive training following administration of other drugs, compounds, or agents to prolong the relief of treatment-resistant depression or other psychiatric disorders.

[0054] As used herein, the term "about" or "approximately" when referring to a measurable value, such as an amount, percentage, etc., is meant to encompass a variation of ±20%, ±10%, ±5%, or ±1% from the measurable value.

[0055] "Administration" to a subject includes any route of introducing or delivering an agent to a subject. Administration can be by any suitable means for delivering an agent. Administration can be self-administration or administration by another.

[0056] As used herein, the term "subject" is defined to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0057] Referring now to FIG. 1, a flow chart showing example operations for treating subjects (also referred to herein as "patients") with a psychiatric disorder is shown. The methods described herein have advantages over conventional methods, including, but not limited to, overcoming the poor clinical reliability of cognitive training in patients with depression and / or overcoming the rapid loss of effect after a single dose of ketamine. Other advantages of the methods described herein compared to the current standard of care for psychiatric conditions (such as depression) include: 1) rapid onset of beneficial effects (e.g., within one day); 2) efficient, minimizing patient time; 3) sustained effects for at least three months with short-term treatment; 4) fully automated (except for drug administration) and portable, thus scalable and easily deployed in a variety of clinical and non-clinical settings; 5) no resource requirements for administration, minimizing clinician and medical professional time; and 6) effective in treatment-resistant patients who have not previously responded to standard treatments. The methods described herein achieve these advantages by combining delivery of antidepressant medication with delivery of automated neurocognitive training following the protocols described herein. Such automated neurocognitive training leverages Pavlovian conditioning to promote positive implicit self-representation and self-worth. Additionally, the automated neurocognitive training may include tasks to increase patient engagement in the training. In some embodiments described herein, the psychiatric disorder is depression. Optionally, the psychiatric disorder is treatment-resistant depression, i.e., where the patient has not responded to treatment, such as antidepressants or psychotherapy. In other embodiments described herein, the psychiatric disorder is suicidal behavior. It should be understood that depression and suicidal behavior are provided as examples of psychiatric disorders only. The present disclosure contemplates psychiatric disorders other than depression and suicidal behavior, including other treatment-resistant psychiatric disorders.

[0058] In step 102, a drug having antidepressant properties is administered to a patient. As described above, the patient suffers from a psychiatric disorder, e.g., treatment-resistant depression. In some embodiments, the drug is a fast-acting antidepressant. As used herein, a fast-acting antidepressant has a therapeutic onset in a subject (e.g., separation observed between active drug and control conditions in a randomized controlled trial) between about 1 minute and 3 weeks after drug administration. This is in contrast to conventional (e.g., most Food and Drug Administration (FDA) approved) antidepressants, which typically take 4 to 8 weeks to provide a therapeutic effect in a subject. Ketamine is an example of a fast-acting antidepressant. Ketamine is a well-known drug that is commonly used as an anesthetic. Intravenous administration of ketamine has been performed in humans and has shown promise in reducing symptoms of depression and reducing suicidality. It should be understood that ketamine is provided only as an example of a fast-acting antidepressant. The present disclosure contemplates administering to the patient other drugs with antidepressant effects, including, but not limited to, scopolamine and other NMDA receptor antagonists (e.g., Witkin JM, Martin AE, Golani LK, Xu NZ, Smith JL. Rapid-acting antidepressants. Adv Pharmacol. 2019;86:47-96. doi 10.1016 / bs.apha.2019.03.002. Epub 2019 Apr 24. PMID:31378256), brexanolone, or rapastinel. The present disclosure also contemplates administering to the patient other drugs with antidepressant effects, including, but not limited to, zuranolone or psychedelics (e.g., psilocybin, lysergic acid diethylamide, ayahuasca, 3,4-methylenedioxymethamphetamine (MDMA)).

[0059] In step 104, a neurocognitive training protocol is administered to the patient during a critical time period after administration of the drug. As used herein, the critical period refers to a period during which the drug is expected to acutely grow synaptic connections in the brain of the patient. For example, the critical period can optionally be between about 2 hours and about 14 days after administration of the drug. Optionally, the critical period is between about 1 day and about 5 days after administration of the drug. It should be understood that the specific critical periods described above are provided by way of example only and may vary depending on the drug administered to the patient.

[0060] As described herein, administering a neurocognitive training protocol to a patient includes providing a plurality of automated neurocognitive training sessions to the patient using a computing device. The present disclosure contemplates that the computing device may be the computing device shown in FIG. 8. Furthermore, the computing device may be configured to generate content (e.g., including graphical display data) for the automated neurocognitive training sessions. For example, the computing device may be configured to generate content, which may include audio content and / or visual content, for a conditioning sequence (described below). Optionally, the computing device further includes a display device, and the computing device is further configured to generate graphical data for each conditioning sequence and cause the graphical data to be displayed on the display device.

[0061] As described herein, the neurocognitive training protocol includes providing a patient with multiple automated neurocognitive training sessions. The number of sessions can be from about 2 to about 14 sessions, optionally about 8 sessions. For example, in one embodiment described in the Examples below, eight automated neurocognitive training sessions are provided to the patient. The sessions are performed twice a day for four consecutive days. It has been found that eight automated neurocognitive training sessions performed twice a day for four consecutive days during a critical period after drug administration are effective in treating depression. It is understood that the number of sessions, sessions per day, and days are provided by way of example only. The present disclosure contemplates different times of automated neurocognitive training sessions to provide a therapeutic benefit to the patient. This includes performing different sessions per day and on different consecutive or non-consecutive days.

[0062] In one example embodiment, the automated neurocognitive training sessions include a first automated neurocognitive training session and a second automated neurocognitive training session provided to the patient on a first day, and a third automated neurocognitive training session and a fourth automated neurocognitive training session provided to the patient on a second day. The first and second days are different days, and are optionally consecutive or non-consecutive days. Furthermore, the present disclosure contemplates providing additional sessions to the patient on the first and / or second days, or optionally on subsequent days such as the third, fourth, fifth, etc. Optionally, the period between the administration of the automated neurocognitive training sessions on the same day is about 20 minutes or more. The time lapse between sessions (e.g., 20 minutes) is designed to promote "spaced learning," where short-term memory consolidation occurs between sessions, which is believed to promote retention of information based on the neuroscience of learning. It is understood that the 20-minute time lapse between sessions is provided by way of example only. The present disclosure contemplates any length of time between sessions to facilitate such "spaced learning." Additionally, each session of the automated neurocognitive training is less than about 20 minutes long, for example, between about 15 and about 20 minutes long. Feedback has shown that 15-20 minute sessions are efficient and effective, avoiding boredom and reducing fatigue. It should be understood that the 15-20 minute session length is provided by way of example only. The present disclosure contemplates the use of any session length that is likely to be effective while achieving the above objectives.

[0063] During the automated neurocognitive training, multiple conditioning sequences are presented to the patient during each session of the automated neurocognitive training. Optionally, in some embodiments described herein, each conditioning sequence includes a respective non-self-related stimulus and a respective self-related stimulus. Other conditioning sequences include pairings of stimuli (e.g., fearful (phobic) stimuli; currently avoided healthy and / or rewarding activities or scenarios; cues related to future-oriented thinking) with respective positive stimuli for which approach to the stimulus or activity is desired; and pairings of undesirable stimuli (e.g., addiction-related craving cues; cues related to self-harm) with respective negative stimuli for which avoidance of the stimulus or activity is desired. An example of a conditioning sequence is shown in FIG. 2. The conditioning sequence in FIG. 2 includes non-self-related stimuli 202 (or “unconditioned stimuli (US)”) that are associated with positive attributes (i.e., “LOVED” and a photo of a smiling actor in FIG. 2), such as “sweet,” “attractive,” and a photo of a smiling actor, and self-related stimuli 204 (or “conditioned stimuli (CS)”) that are associated with the patient (i.e., “ME” in FIG. 2), such as “me,” “my,” ... patient, and so on. It should be understood that the equal sign shown in FIG. 2 is provided only to illustrate the concept of strengthening the association in the patient’s brain between the non-self-related stimuli 202 and the self-related stimuli 204. An example of another conditioning sequence is shown in FIG. 3. The conditioning sequence in FIG. 3 includes non-self-related stimuli 302 that are random photos of smiling people (i.e., positive attributes), and self-related stimuli 304 that are photos of the subject. Such conditioning is designed to take advantage of Pavlovian conditioning to promote positive implicit self-representations and self-worth. It should be understood that the stimuli shown and described with respect to Figures 2 and 3 are provided by way of example only. For example, the present disclosure contemplates that in some embodiments, the non-self-related stimuli and / or the self-related stimuli are auditory stimuli.Alternatively or additionally, in some embodiments, the non-self-related stimuli and / or the self-related stimuli are visual stimuli. Optionally, the self-related stimuli for each conditioning sequence include sounds, pictures, or words that are relevant to the patient. Optionally, the sound images or words may have a positive meaning, or the sound images or words may have a life-affirming meaning.

[0064] Optionally, in some embodiments, one or more of the plurality of conditioning sequences includes a subliminal presentation of a non-self-related or self-related stimulus. Alternatively or additionally, in some embodiments, one or more of the plurality of conditioning sequences includes a supercritical presentation of a non-self-related or self-related stimulus. This is illustrated in FIG. 4, where a non-self-related stimulus 402 (i.e., the word "good") and a self-related stimulus 404 (i.e., the word "I") are presented in sequence. For example, in some implementations, the non-self-related stimulus 402 and the self-related stimulus 404 are presented subliminal in succession. The subliminal stimulus is below the patient's conscious perception threshold (e.g., 17 milliseconds (ms)). In other embodiments, the non-self-related stimulus 402 and the self-related stimulus 404 are presented in sequence from above the head. The supercritical stimulus is above the patient's conscious perception threshold (e.g., 500 ms presentation). It should be understood that the respective durations of the subliminal and supraliminal presentations shown in Figure 4 are provided by way of example only, and the present disclosure contemplates that the respective durations can be any length below the threshold of awareness (i.e., subliminal) or above the threshold of awareness (i.e., supercritical), for example, subliminal (e.g., about 12 ms stimulation) or supercritical (e.g., >250 ms stimulation).

[0065] Alternatively or additionally, in some embodiments, each conditioning sequence further includes a task, which is presented to the patient following or in association with the presentation of each pair of non-self-related and self-related stimuli. This is shown in FIG. 4, where the patient is prompted to answer whether a random stimulus 406 (i.e., the string "ozgdpyc") begins with a vowel or a non-vowel. The presentation of the task follows the presentation of a pair of stimuli (i.e., a pair of non-self-related and self-related stimuli 402 and 404). In another embodiment, the task, a lexical decision task, begins with the presentation of a non-self-related stimulus (e.g., non-self-related stimulus 402 in FIG. 4), and the subject responds to the non-self-related stimulus to indicate whether the non-self-related stimulus consists of an actual word or a non-word (e.g., a random string of letters). Such a task enhances the patient's engagement in automatic neurocognitive training that promotes both semantic and visual processing of stimuli (e.g., a conditioning sequence designed to leverage Pavlovian conditioning to promote positive implicit self-representations and self-worth). It should be understood that the task described with respect to FIG. 4 is provided as an example only. The present disclosure contemplates presenting other contingency tasks, including, but not limited to, a lexical decision task and a rapid mouse clicking task. As another example, a lexical decision task is shown in FIG. 5. In this task, the patient is prompted to label words and non-words (i.e., random letters of letters). An example of a mouse clicking task is shown in FIG. 6, where the patient is prompted to click / tap on a picture 602 as quickly as possible. The picture 602, which is a self-related stimulus, moves from quadrant to quadrant over time. After the subject clicks / taps, a non-self-related stimulus (not shown in FIG. 6) appears. An example of a non-self-related stimulus is an image of a smiling stranger.

[0066] Alternatively or additionally, in some embodiments, each non-self-related stimulus and each self-related stimulus for each conditioning sequence is included in an nxm matrix containing a plurality of visual stimuli, where n and m are positive integers. This is shown in Figures 7A-7C. In particular, a matrix 710 of visual stimuli is shown in Figure 7C. In this example, the matrix 710 contains 2 rows and 4 columns of visual stimuli (e.g., words and pictures). That is, n=2 and m=4 in Figure 7C. It should be understood that the size of the matrix 710 is provided only as an example and may be other sizes. Prior to presenting the matrix 710, the subject is presented with a matched pair of a plurality of visual stimuli, including at least one pair of non-self-related and self-related stimuli. This is shown in Figure 7B. In particular, "Pair 1" in Figure 7B is a non-self-related stimulus 702a (i.e., a random smiling person picture, which is a positive attribute) and a self-related stimulus 704a (i.e., a picture of the subject). "Pair 2" in FIG. 7B is a non-self-related stimulus 702b (i.e., a life-affirming or life-related photo) and a self-related stimulus 704b (i.e., a photo of a different subject). "Pair 3" does not include a self-related stimulus and is provided to increase the variety and difficulty of the task presentation. During automated neurocognitive training, and as shown in FIG. 7C, subjects are presented with multiple visual stimulus matrices, including a matrix 710, and prompted to respond with a correct selection 720 of matching non-self-related and self-related stimuli (e.g., non-self-related stimulus 702a and self-related stimulus 704a, as shown in FIG. 7B).

[0067] Example Method The treatment methods and computer-implemented methods for implementing neurocognitive training described herein achieve advantages over the prior art by combining the delivery of antidepressants with the delivery of automated neurocognitive training. Specifically, the automated neurocognitive training protocols described herein leverage Pavlovian conditioning to promote positive implicit self-representations and self-worth. Such protocols are designed to produce positive outcomes. Additionally, the automated neurocognitive training may include tasks to increase patient engagement in the training.

[0068] An example of a method for treating a patient with a mental disorder is described herein. The present disclosure contemplates that the logical operations of the method described below can be performed using a computing device (e.g., at least one processor and memory, as described with respect to the computing device of FIG. 8). The method includes administering a drug having an antidepressant effect to the patient, and administering a neurocognitive training protocol to the patient during a critical period after the drug administration. Furthermore, administering the neurocognitive training protocol to the patient includes providing a plurality of automated neurocognitive training sessions to the patient using the computing device. During each of the automated neurocognitive training sessions, a plurality of conditioning sequences are presented to the patient, and each conditioning sequence includes a respective non-self-related stimulus and a respective self-related stimulus.

[0069] An example of a computer-implemented method for administering a neurocognitive training protocol to a patient with a psychiatric disorder is described herein. The present disclosure contemplates that the logical operations of the method described below may be performed using a computing device (e.g., at least one processor and memory, as described with respect to the computing device of FIG. 8). The patient is administered a drug having an antidepressant effect, and the neurocognitive training protocol is implemented at a critical period after the administration of the drug to the patient. The method includes providing a plurality of automated neurocognitive training sessions to the patient. Further, during each of the automated neurocognitive training sessions, a plurality of conditioning sequences are presented to the patient, each of the conditioning sequences including a respective non-self-related stimulus and a respective self-related stimulus.

[0070] Another example method for treating a patient with a psychiatric disorder is described herein. The present disclosure contemplates that the logical operations of the method described below may be performed using a computing device (e.g., at least one processor and memory, as described with respect to the computing device of FIG. 8). The method includes administering a drug having an antidepressant effect to the patient, and administering a neurocognitive training protocol to the patient during a critical period after the drug administration. Furthermore, administering the neurocognitive training protocol to the patient includes providing the patient with a plurality of automated neurocognitive training sessions using the computing device. Each automated neurocognitive training session includes presenting the patient with an nxm matrix including a plurality of visual stimuli, and receiving the patient's selection of a first matching pair of non-self-related visual stimuli and self-related visual stimuli. The plurality of visual stimuli includes a first matching pair of non-self-related visual stimuli and self-related visual stimuli. Moreover, in some embodiments, each automated neurocognitive training session further includes presenting to the patient a second matched pair of non-self-related and self-related visual stimuli, and presenting a challenge to the patient after the presentation of the second matched pair of non-self-related and self-related visual stimuli. Optionally, each automated neurocognitive training session further includes presenting to the patient a self-related visual stimulus, presenting to the patient a challenge after the presentation of the self-related stimulus, and presenting a positive self-related visual stimulus after successful completion of the task by the patient.

[0071] Another example method for treating a patient with a psychiatric disorder is described herein. The present disclosure contemplates that the logical operations of the method described below can be performed using a computing device (e.g., at least one processor and memory as described with respect to the computing device of FIG. 8). The method includes administering a drug having an antidepressant effect to the patient, and administering a neurocognitive training protocol to the patient during a critical period after the drug administration. The step of administering the neurocognitive training protocol to the patient includes using the computing device to deliver a plurality of automated neurocognitive training sessions to the patient, and a plurality of conditioning sequences are presented to the patient during each delivery of the automated neurocognitive training sessions.

[0072] An example of a method for conditioning a therapeutic association in a patient is described herein. The present disclosure contemplates that the logical operations of the method described below may be performed using a computing device (e.g., at least one processor and memory, as described with respect to the computing device of FIG. 8). The method includes administering a neuroplasticity enhancing treatment to the patient, and administering a neurocognitive training protocol to the patient at a critical period after the neuroplasticity enhancing treatment. Administering the neurocognitive training protocol to the patient includes using the computing device to deliver one or more conditioning sequences to the patient configured to condition the therapeutic association. A non-limiting example of a combination of a neuroplasticity enhancing treatment and a neurocognitive training protocol is described below. The present disclosure contemplates that any one of the exemplary neuroplasticity enhancing treatments may be combined and used with any one of the exemplary neurocognitive training protocols to condition the therapeutic association.

[0073] In some embodiments, the neuroplasticity enhancing treatment is a neuromodulatory intervention. Neuromodulatory interventions include non-pharmacological interventions such as transcranial magnetic stimulation, transcranial direct current stimulation, transcranial focused ultrasound, and other neuromodulatory manipulations. Alternatively or additionally, in other embodiments, the neuroplasticity enhancing treatment is a drug. As described herein, the drug may be an antidepressant, and optionally a fast-acting antidepressant such as ketamine. It should be understood that antidepressants are provided as an example only, and other drugs and neuroplasticity enhancing agents may be delivered.

[0074] Further, in some embodiments, the neurocognitive training protocol includes delivery of automated neurocognitive training sessions as described herein, such as multiple conditioning sequences that pair self-related stimuli with non-self-related stimuli. In other embodiments, the neurocognitive training protocol includes delivery of automated neurocognitive training sessions, including, but not limited to, therapeutic pairings targeted at various mental health concerns. Such therapeutic pairings include stimuli for which approach to the stimuli or activities is desired (e.g., feared (phobic) stimuli; currently avoided healthy and / or rewarding activities or scenarios; cues related to future-oriented thinking) and respective positive stimuli. This neurocognitive training can be used to condition approach to feared (phobic) stimuli, currently avoided healthy and rewarding activities or scenarios, or cues related to future-oriented thinking. Alternatively, such therapeutic pairings can include undesired stimuli for which avoidance of stimuli or activities is desired (e.g., craving cues related to addiction; cues related to self-harm) and respective negative stimuli. This neurocognitive training can be used to condition individuals to resist or avoid craving (addiction-related), self-harm-related, or other unwanted cues.

[0075] Examples of Computing Devices It should be understood that the logical operations described herein with respect to the various figures may be implemented (1) as a sequence of computer-implemented acts or program modules (i.e., software) executing on a computing device (e.g., the computing device described in FIG. 8), (2) as interconnected machine logic circuits or circuit modules (i.e., hardware) within a computing device, and / or (3) as a combination of software and hardware in a computing device. Thus, the logical operations discussed herein are not limited to a specific combination of hardware and software. The implementation depends on the performance and other requirements of the computing device. Thus, the logical operations described herein are variously referred to as operations, structural devices, acts, or modules. These operations, structural devices, acts, and modules may be implemented in software, firmware, special purpose digital logic, and any combination thereof. It should also be understood that more or fewer operations may be performed than illustrated in the figures and described herein. Also, these operations may occur in different orders than described herein.

[0076] Referring to FIG. 8, an example of a computing device 800 is shown on which the methods described herein may be implemented. It should be understood that the exemplary computing device 800 is only one example of a suitable computing environment for implementing the methods described herein. Optionally, the computing device 800 may be any known computing system, including, but not limited to, a personal computer, a server, a handheld or laptop device, a multiprocessor system, a microprocessor-based system, a networked personal computer (PC), a minicomputer, a mainframe computer, an embedded system, and / or a distributed computing environment including a plurality of any of the above systems or devices. A distributed computing environment enables remote computing devices connected to a communications network or other data transmission medium to perform a variety of tasks. In a distributed computing environment, program modules, applications, and other data may be stored on local and / or remote computer storage media.

[0077] In its most basic configuration, computing device 800 typically includes at least one processing unit 806 and a system memory 804. Depending on the exact configuration and type of computing device, system memory 804 may be volatile (such as random access memory (RAM)), non-volatile (such as read only memory (ROM), flash memory, etc.), or some combination of the two. This most basic configuration is illustrated in FIG. 8 by dashed line 802. Processing unit 806 may be a standard programmable processor that performs arithmetic and logical operations necessary for operation of computing device 800. Computing device 800 may also include a bus or other communication mechanism for communicating information between various components of computing device 800.

[0078] Computing device 800 may have additional features / functionality. For example, computing device 800 may include additional storage such as removable storage 808 and non-removable storage 810, including but not limited to magnetic or optical disks or tape. Computing device 800 may also include network connections 816 that allow the device to communicate with other devices. Computing device 800 may also have input devices 814, such as a keyboard, mouse, touch screen, etc. Output devices 812, such as a display, speakers, printer, etc. may also be included. Additional devices may be connected to the bus to facilitate data communication between components of computing device 800. All of these devices are well known in the art and need not be described at length here.

[0079] The processing unit 806 may be configured to execute program code encoded on a tangible computer-readable medium. A tangible computer-readable medium refers to any medium capable of providing data that causes the computing device 800 (i.e., a machine) to operate in a specific manner. A variety of computer-readable media may be utilized to provide instructions to the processing unit 806 for execution. Exemplary tangible computer-readable media include, but are not limited to, volatile media, non-volatile media, removable media, and non-removable media implemented in any method or technology for storing information such as computer-readable instructions, data structures, program modules, or other data. The system memory 804, removable storage 808, and non-removable storage 810 are all examples of tangible computer storage media. Exemplary tangible computer readable recording media include, but are not limited to, integrated circuits (e.g., field programmable gate arrays or application specific ICs), hard disks, optical disks, magneto-optical disks, floppy disks, magnetic tape, holographic recording media, solid state devices, RAM, ROM, Electrically Erasable Program Read Only Memory (EEPROM), flash memory or other memory technology, CD-ROM, digital versatile disk (DVD) or other optical storage devices, magnetic cassettes, magnetic tapes, magnetic disk storage devices or other magnetic storage devices.

[0080] In an embodiment, the processing unit 806 may execute program code stored in the system memory 804. For example, a bus may carry data to the system memory 804, from which the processing unit 806 receives and executes the instructions. The data received by the system memory 804 may optionally be stored on the removable storage 808 or on the non-removable storage 810 before or after execution by the processing unit 806.

[0081] It is to be understood that the various techniques described herein may be implemented in connection with hardware or software or, where appropriate, combinations thereof. Thus, the methods and apparatus of the presently disclosed subject matter, or certain aspects or portions thereof, may take the form of program code (i.e., instructions) embodied in a tangible medium, such as a floppy disk, CD-ROM, hard drive, or any other machine-readable storage medium, which when loaded into and executed by a machine, such as a computing device, causes the machine to become an apparatus for implementing the presently disclosed subject matter. In the case of executing program code on a programmable computer, the computing device generally includes a processor, a storage medium readable by the processor (including volatile and non-volatile memory and / or storage elements), at least one input device, and at least one output device. One or more programs may implement or utilize the processes described in connection with the presently disclosed subject matter, for example, through the use of application programming interfaces (APIs), reusable controls, or the like. Such programs may be implemented in a high level procedural or object-oriented programming language to communicate with a computer system. However, the programs may also be implemented in assembly or machine language, if desired. In any case, the language may be a compiled or interpreted language, and combined with hardware implementations. EXAMPLES

[0082] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, are intended to be purely illustrative, and are not intended to limit the disclosure. Efforts have been made to ensure accuracy with respect to numbers (amounts, temperatures, etc.), but some errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is °C or at ambient temperature, and pressure is at or near atmospheric pressure.

[0083] Example 1 A randomized controlled trial has been completed to test whether rapid mood relief during the "window of opportunity" following ketamine infusion can be extended and / or enhanced by reinforcing ("conditioning") a beneficial, positive view of oneself using fully automated neurocognitive training (NT) software. Automated NT is also referred to herein as Automated Self-Association Training (ASAT). A critical gap in previous NT treatment development efforts, which this study fills, was the ability to synergistically initiate NT at a critical clinical window of opportunity (immediately following ketamine infusion) when improved mood and enhanced neuroplasticity are expected, thus consolidating beneficial processing patterns and augmenting and prolonging the rapid mood effects of ketamine.

[0084] The results of this double-blind randomized controlled trial supported the hypothesis. Ketamine rapidly reduced depression scores (compared to saline control infusions) 24 hours after infusion in patients with treatment-resistant depression (i.e., patients who had not previously responded to first-line antidepressants). A brief (2.5 hours total, eight 20-minute sessions over four days) fully automated, computer-based NT intervention or a sham / placebo version of NT was then initiated. The combination of ketamine + active NT (ketamine + active ASAT in Figure 9) produced a stable and sustained reduction in depression compared to saline + NT (saline + active ASAT in Figure 9). In contrast, ketamine + sham NT (ketamine + sham ASAT in Figure 9) produced an initial reduction in depression that decreased linearly over 30 days and was no longer significant by day 12 after infusion. In an ongoing naturalistic follow-up study, the ketamine+NT group demonstrated a sustained effect on self-reported depression 3 months post-infusion (see Example 9).

[0085] Another ongoing randomized controlled trial is testing this synergistic combination (ketamine + computer-based NT) in patients admitted immediately after a suicide attempt to prevent future suicidal ideation, repeated suicide attempts, and completed suicide in this highly at-risk group.

[0086] In summary, a brief synergistic treatment combining ketamine infusions and fully automated cognitive training software provided acute relief to patients with treatment-resistant depression and efficiently extended this relief by exploiting a window of opportunity with a safe, low-cost, portable technology. Intravenous ketamine administration is highly routinely available and widely used in hospital settings as well as specialized community-based clinics worldwide. And the fully automated cognitive training software is highly efficient, straightforward, easy to administer, and feasible in both clinical settings and in patients' homes.

[0087] Example 2 Introduction Depression is one of the most prevalent and costly psychiatric disorders [Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE: Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry.2005;62(6):617-27], with a staggering public burden of disease [Kessler RC: The global burden of anxiety and mood disorders: putting findings from the European Survey of Epidemiology of Mental Disorders (ESEMeD) into perspective. J Clin Psychiatry.2007;68 Suppl 2:10-9]. Although effective treatments have been available for decades, remission rates are low, relapse rates are high, prevalence of the disorder remains significantly consistent or increasing, and only 12.7% of patients receive minimally adequate treatment [Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC: Twelve-month mental health service utilization in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry.2005;62(6):629-40]. In recent years, two breakthrough possibilities have sparked hopes of revolutionizing the clinical management of this disabling condition. First, fast-acting pharmacological agents, particularly intravenous ketamine [Xu Y, Hackett M, Carter G, Loo C, Galvez V, Glozier N, Glue P, Lapidus K, McGirr A, Somogyi AA, Mitchell PB, Rodgers A: Effects of low- and very-low-dose ketamine in patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol.2015; Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB, Treatments APACoRTFoNBa: Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression.Am J Psychiatry.2015;172(10):950-66;Caddy C, Amit BH, McCloud TL, Rendell JM, Furukawa TA, McShane R, Hawton K, Cipriani A: Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev.2015;Sep 23(9):CD011612] have shown promise in dramatically reducing symptoms within 2-24 hours, overcoming poor response to traditional treatments (e.g., 4-6 week delays) that prolong distress, cause non-compliance problems, and fail to address urgent clinical needs (e.g., suicide or other psychiatric crisis). Second, intervention development has increasingly sought to leverage technology to improve patient access, reduce costs, and minimize evasive outcomes through the use of automated, computer-based procedures [Mohr DC, Burns MN, Schueller SM, Clarke G, Klinkman M: Behavioral intervention technologies: an evidence review and recommendations for future research in mental health. Gen Hosp Psychiatry.2013;35(4):332-8]. Over the past decade, there has been growing interest in automated, mechanistic NT treatments designed to directly modulate emotion processing patterns to reduce symptoms [Siegle GJ, Price RB, Jones N, Ghinassi F, Painter T, Thase ME: You gotta try: Pupillary indices of task focus are prognostic of response to neurocognitive interventions for depression. Clin Psychol Sci.2014;2(4):455-71]; however, clinical efficacy, although showing potential, remains unreliable, especially in patients with acute depression. [Mogoase C, David D, Koster EHW: Clinical effectiveness of attentional bias modification procedures: an updated meta-analysis.J Clin Psychol.2014;70:1133-57; Motter JN, Pimontel MA, Rindskopf D, Devanand DP, Doraiswamy PM, Sneed JR: Computerized cognitive training and functional recovery in major depressive disorder: a meta-analysis. J Affect Disord.2016;189:184-91]. The studies described below aim to synergistically combine the benefits of these two approaches.

[0088] The rapidity of ketamine's action is expected to bring about a breakthrough in the treatment of depression, but this expectation has not been realized to date. Its rapidly dissipating effects [Walter M, Li S, Demenescu LR: Multiphasic drug effects of ketamine in the treatment of major depression. Eur Arch Psychiatry Clin Neurosci.2014;264 Suppl 1:S55-65], coupled with substantial concerns about the safety and feasibility of repeated infusions [Schatzberg AF: A word about ketamine. Am J Psychiatry.2014;171(3):262-4; Price RB: From rats to humans: does ketamine enhance resilience to stress? Biol Psychiatry.2016;79(9):e57-9], limit ketamine's clinical impact. Recently, there has been great progress in elucidating the molecular mechanism of action of ketamine. [Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA, Jr., Gould TD: Antidepressant effects of ketamine metabolites independent of NMDAR inhibition. Nature. 2016;533(7604):481-6; Malinow R: Depression: ketamine steps out of the darkness. Nature. 2016;533(7604):477-8] and are developing strategies to extend these effects pharmacologically, but translation into safe and effective novel pharmacology is slow and uncertain. Furthermore, long-term pharmacological interventions are unlikely to be beneficial, feasible or attractive for all patients [Bockting CL, ten Doesschate MC, Spijker J, Spinhoven P, Koeter MW, Schene AH, group Ds: Continuation and maintenance use of antidepressants in recurrent depression.Psychother Psychosom. 2008;77(1):17-26]. A large proportion of patients (e.g., up to 91% of depressed patients enrolled in drug trials [Steidtmann D, Manber R, Arnow BA, Klein DN, Markowitz JC, Rothbaum BO, Thase ME, Kocsis JH: Patient treatment preferences as predictors of response and withdrawal in the treatment of chronic depression. Depress Anxiety. 2012;29(10):896-905]) consistently express a preference for behavioral or combined behavioral-pharmacological treatments [Huijbers MJ, Spinhoven P, van Schaik DJ, Nolen WA, Speckens AE: Patients who prefer pharmacotherapy do as well as those who prefer mindfulness in mindfulness-based cognitive therapy for recurrent depression. J Affect Disord.2016;195:32-; van Schaik DJ, Klijn AF, van Hout HP, van Marwijk HW, Beekman AT, de Haan M, van Dyck R: Patient preferences in the treatment of depressive disorders in primary care. Gen Hosp Psychiatry.2004;26(3):184-9], in part reflecting the belief that such treatment will resolve core problems and introduce new learning that will bring about lasting change [van Schaik DJ, Klijn AF, van Hout HP, van Marwijk HW, Beekman AT, de Haan M, van Dyck R: Patient preferences in the treatment of depressive disorders in primary care. Gen Hosp Psychiatry.2004;26(3):184-9 ]. Pharmacological regimens of antidepressants are difficult to maintain in the long term due to patient discontinuation [Bockting CL, ten Doesschate MC, Spijker J, Spinhoven P, Koeter MW, Schene AH, group Ds: Continuation and maintenance use of antidepressants in recurrent depression.Psychother Psychosom.2008;77(1):17-26], and scarce opportunities for follow-up in community practice [Simon GE, Von Korff M, Rutter CM, Peterson Da: Treatment trajectory and outcomes of managed care patients receiving new antidepressant prescriptions from psychiatrists and primary care physicians. Arch Gen Psychiatry.2001;58:395-401].

[0089] Ketamine is hypothesized to reverse the molecular signature of depression through synaptogenic and neuroplastic effects at the molecular level [Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA, Jr, Gould TD: Antidepressant actions of ketamine metabolites independent of NMDAR inhibition. Nature. 2016;533(7604):481-6 ; Abdallah CG, Sanacora G, Duman RS, Krystal JH: Ketamine and fast-acting antidepressants: a window into the new neurobiology of mood disorder therapeutics. Annu Rev Med.2015;66:509-23; Duman RS, Aghajanian GK, Sanacora G, Krystal JH: Synaptic plasticity and depression: new insights from stress and fast-acting antidepressants. Nat Med 2016;22(3):238-49]. Based on previous studies, it was hypothesized that [Price RB, Duman R.: Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry.2020;25(3):530-43; Wilkinson ST, Holtzheimer PE, Gao S, Kirwin DS, Price RB: Harnessing neuroplasticity to enhance adaptive learning: potential for synergistic physical-behavioral treatment combinations to improve clinical outcomes in depression. 2019;85(6):454-65], these molecular actions may produce corresponding neurocognitive shifts that could extend rapid mood relief during windows of opportunity using behavioral learning-based approaches, e.g., reinforcing adaptive patterns of cognition through neurocognitive training (NT).In this study, we aimed to synergistically initiate NT 1 day after ketamine administration, a critical clinical window for ketamine-induced mood elevation and enhanced plasticity, to consolidate beneficial processing patterns and sustain the rapid mood effects of ketamine.

[0090] Synergistic biobehavioral approaches to psychiatric management (ketamine [Dakwar E, Levin FR, Hart CL, Basaraba CN, Choi CJ, Pavlicova M, Nunes EV: Single infusion of ketamine combined with motivational enhancement therapy for alcohol use disorder: a randomized midazolam-controlled pilot trial. Am J Psychiatry.2020;177:125-33; Dakwar E, Nunes EV, Hart CL, Foltin RW, Mathew SJ, Carpenter KM, Choi CJJ, Basaraba CN, Pavlicova M, Levin FR: Treatment of cocaine dependence with a single infusion of ketamine combined with mindfulness-based behavior modification: a randomized clinical trial. Am J Psychiatry.2019:appiajp201918101123; Wilkinson ST, Rhee TG, Joormann J, Webler R, Ortiz Lopez M, Kitay B, Fasula M, Elder C, Fenton L, Sanacora G: Cognitive behavioral therapy to prolong the antidepressant effects of ketamine in treatment-resistant depression: a randomized clinical trial. Psychother Psychosom. 2021;90(5):318-27] and other "psychoplastic" drugs [Vargas MV, Meyer R, Avanes AA, Rus M, Olson DE: Psychedelics and other tranquilizers for the treatment of psychiatric disorders. Front Psychiatry. 2021;12:727117]), this study was designed to push the boundaries of how fast-acting antidepressants might be used clinically, i.e., as short-term cognitive flexibility enhancers to promote enduring learning that reverses depressive states. Ketamine infusion was used as the first phase of a treatment protocol designed to promote rapid and sustained relief while at the same time leveraging a technology that has the potential to be a low-cost, portable, safe, and readily disseminateable intervention.This is consistent with findings suggesting that behavioral therapy can prevent recurrence of depression even in the absence of continuing care [Bockting CL, ten Doesschate MC, Spijker J, Spinhoven P, Koeter MW, Schene AH, group Ds: Continuation and maintenance antidepressant use in recurrent depression. Psychother Psychosom.2008;77(1):17-26; Bockting CL, Schene AH, Spinhoven P, Koeter MW, Wouters LF, Huyser J, Kamphuis JH: Preventing recurrent depression with cognitive therapy: a randomized controlled trial. J Consult Clin Psychol.2005;73(4):647-57; Hollon SD, Stewart MO, Strunk D: Sustained effects of cognitive behavioral therapy in the treatment of depression and anxiety. 2006;57:285-315; Hollon SD, DeRubeis RJ, Shelton RC, Amsterdam JD, Salomon RM, O'Reardon JP, Lovett ML, Young PR, Haman KL, Freeman BB, Gallop R: Prevention of relapse after cognitive therapy and pharmacotherapy in moderate to severe depression. Arch Gen Psychiatry.2006;62:417-22], and there is preliminary evidence that a brief NT approach may similarly produce durable and clinically meaningful effects [ Siegle GJ, Price RB, Jones N, Ghinassi F, Painter T, Thase ME: You gotta try: Pupillary measures of task focus are prognostic of response to neurocognitive interventions for depression. Clin Psychol Sci.2014;2(4):455-71; Franklin JC, Fox KR, Franklin CR, Kleiman EM, Ribeiro JD, Jaroszewski AC, Hooley JM, Nock MK: A simple mobile app reduces non-suicidal and suicidal self-harm: evidence from three randomized controlled trials.J Consult Clin Psychol.2016;84(6):544-57] _ENREF_8, it was hypothesized that introducing and promoting new learning during the ketamine-induced window of opportunity would provide an efficient route to rapid and sustained relief. In this world-first study, an active / active combination of ketamine + automated neurocognitive training (NT) was compared in a randomized, double-blind, parallel-group design with control conditions that included each intervention component but not the other (i.e., saline + active NT; ketamine + sham NT). This allowed us to directly test the hypothesis of a synergistic effect of ketamine and NT to produce rapid and sustained antidepressant effects.

[0091] Example 3 method Participants To meet the initial recruitment goal of n = 150, we enrolled and randomized n = 154 patients and continued enrollment until we had a final sample that included n = 150 patients who completed at least (1) the infusion day, (2) the 24-hour assessment visit, and (3) ≥ 75% of the targeted cognitive training (active or sham NT) visits. The total N = 154 randomized patients were included in the intent-to-treat analysis reported. Specifically, we studied 154 adult patients (aged 18-60 years) who reported moderate to severe levels of depression [Montgomery-Asberg Depression Rating Scale (MADRS; Montgomery SA, Asberg M: A new depression scale sensitive to change. Br J Psychiatry.1979;134:382-9] score ≥ 25], and lower than normal self-reported self-esteem [i.e., the "Self" subscale of the Cognitive Triad Inventory [Beckham EE, Lieber WR, Watkins JT, Boyer JL, Cook JB: Development of a scale to measure Beck's Cognitive Triad: The Cognitive Triad Inventory. J Consult Clin Psychol.1986;54(4):566-7]. J Clin Psychol.1995;51(5):603-9; Possel P: The Cognitive Triad Inventory (CTI): psychometric properties and factor structure of the German translation.J Behav Ther Exp Psychiatry. 2009;40(2):240-7] and / or Rosenberg Self-Esteem Scale], and having failed at least one adequate trial of an FDA-approved antidepressant in a current depressive episode (Antidepressant Treatment Response Questionnaire; ATRQ [Chandler GM, Iosifescu DV, Pollack MH, Targum SD, Fava M: Study: Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS Neurosci Ther. 2010;16(5):322-5]) were recruited and randomized. Existing depression treatment regimens were required to be stably maintained for at least 4 weeks prior to screening and throughout the study period. See Figure 10, Table S1, and Examples 6-8 below for example characteristics.

[0092] To achieve an initial recruitment goal of a 150-patient sample, the study enrolled and randomized 154 patients and continued enrollment until a fully inclusive sample was achieved with the final goal of 150 patients who completed a minimum of an infusion day, 24-hour assessment visit, and ≥75% of the intended training (active or sham ASAT) visits and were considered assigned to ASAT. All but two participants who exceeded this 75% threshold for ASAT assignment received all eight sessions of the intended ASAT visits as per protocol (N=148 were full protocol completers who received all assigned ASAT sessions). Thus, 96% of randomized participants were fully compliant with all intervention sessions and 97% of the intended ASAT sessions were delivered.

[0093] A three-arm study design was selected to devote all available resources to an active / active treatment (ketamine + ASAT) group compared with two key comparator groups consisting of each intervention component in the absence of the other intervention. The inactive / non-active group (no treatment group) was foreclosed to be more conservative and maximize statistical power for important comparisons. An a priori power analysis was performed based on a primary interest in clinically meaningful, moderate (or larger) effects. A target sample size was selected to provide 80% power to detect moderate effects based on a comparison of 100 ketamine vs. 50 saline in the infusion phase (d ≥ 0.49, r ≥ 0.31, using an alpha of 0.05) and a comparison of 50 patients in each of the ketamine + ASAT, ketamine + sham, and saline + ASAT conditions in the ASAT phase (an effect of d ≥ 0.57 would be detectable with 80% power (using an alpha of 0.05)). These power calculations were conservative because the power of the primary mixed-effects analysis comparing treatment groups was expected to increase as repeated measures were added and to be higher than the power of these simplified single-point controls.

[0094] Assessment timeline An experienced master's level clinical assessor (CRS) administered the pre-specified primary outcome measure, the MADRS, to assess global depression severity during the acute (30-day) study period. This measure was repeated at screening (used only to determine eligibility), at baseline before infusion (-1 h after infusion; the clinical assessor left and was not present for any intervention procedures thereafter), +24 h after infusion (before the first session of active / sham NT), +5 days, +12 days, +21 days, and +30 days. Explicit self-report symptom measures (QIDS-SR [Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB: The 16-item Quick Inventory of Depressive Symptomatology, clinician-rated (QIDS-C), and self-report (QIDS-SR): psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54:573-83]) are still in progress, so these data are not included in this report. This study also envisions including and analysing neurocognitive assessments (e.g., neuroimaging, performance-based) of the effects of ketamine. Adequacy of blinding for both patients and assessors was assessed by self-report using a 0-100 sliding scale (0 = placebo / sham confirmed, 50 = don't know, 100 = ketamine / active confirmed) on day infusion +30 for both infusion and NT allocation.

[0095] Intervention: A randomization table using a permutation of 3 or 6 blocks stratified by (1) biological sex at birth and (2) mild vs. severe treatment resistance (severe treatment resistance = ≥ 3 FDA-approved antidepressant trials during the episode, according to the ATRQ) was created by an independent statistical consultant at the start of the study, administered by the study pharmacist, and communicated the NT allocation (but not the infusion allocation) to one study staff member responsible for the patient at the time of randomization. This staff member was tasked with opening the correct computer program to deliver the NT session to the patient but was not involved in or present during the evaluation of the outcomes. Blinding of all other study personnel was maintained until the completion of the day 30 evaluation of the last patient.

[0096] Participants were randomized 2:1 to receive ketamine (0.5 mg / kg administered over 40 min) or saline (50 ml of 0.9% sodium chloride administered over 40 min). All infusions were performed by blinded certified nurses in a medical hospital affiliated with an ACLS-certified team and monitored by a blinded study physician (RHH), with safety / adverse event monitoring continuing for 4 h after infusion. Adverse events (Figures 11A-11D, Table S2) were mild to moderate, time-limited, and consistent with safety profiles reported in numerous previous studies using identical infusion procedures.

[0097] Cognitive training Building on previous research that used "evaluative conditioning" to influence participants' preferences and "likes," we stated: [De Houwer J, Thomas S, Baeyens F: Associative learning of likes and dislikes: a review of 25 years of research on human evaluative conditioning. Psychol Bull 2001;127(6):853-69; Martijn MV, Roefs A, Huijding J, Jansen A: Increasing body satisfaction in body-concerned women through evaluative conditioning using social cues. Health Psychology 2010;29(5):514-20] Active NT (also referred to herein as active ASAT) was designed to leverage Pavlovian conditioning to promote positive implicit self-representations and self-worth. In eight 15-20 min sessions (two times a day for four consecutive days, with at least 20 min between sessions, starting on the first day after injection and after the 24-h post-injection assessment), participants practiced and strengthened implicit associations between positive attributes [e.g., “sweet”, “attractive”, a picture of a smiling actor; unconditioned stimuli (US)] and self-referential stimuli (e.g., “me”, a picture of the participant’s face; conditioned stimuli (CS)]. Concomitant tasks such as a “lexical decision” task in which participants indicated whether each target was an actual word or a random string of letters, and a high-speed mouse tracking task (clicking on the location of the stimuli as fast as possible) were used to increase task engagement and facilitate both semantic and visual processing of the stimuli. Similar forms of “evaluative conditioning” have been found to alter some measures of implicit self-esteem in healthy participants [ Martijn MV, Roefs A, Huijding J, Jansen A: Socially cued evaluative conditioning enhances body satisfaction in body-conscious women. Health Psychology 2010;29(5):514-20; Dijksterhuis A: Subliminal evaluative conditioning enhances implicit self-esteem. J Pers Soc Psychol.2004;86(2):345-55; Baccus JR, Baldwin MW, Packer DJ: Enhances implicit self-esteem through classical conditioning.Psychol Sci.2004;15(7:498-502], mood reactivity to stress [Dijksterhuis A: Enhancing implicit self-esteem through subliminal evaluative conditioning. J Pers Soc Psychol.2004;86(2):345-55 ], pathological behavior (anxiety avoidance [Clerkin EM, Teachman BA: Training implicit social anxiety associations: an experimental intervention. J Anxiety Disord.2010;24(3:300-8], self-injury [Franklin JC, Fox KR, Franklin CR, Kleiman EM, Ribeiro JD, Jaroszewski AC, Hooley JM, Nock MK: A simple mobile app reduces non-suicidal and suicidal self-injury: evidence from three randomized controlled trials. J Consult Clin Psychol.2016;84(6):544-57 [translate]. The sham NT consisted of exactly the same computerized task, but with neutral USs rather than positive USs and non-self-relevant CSs (words related to "other" and pictures of gender-matched strangers), designed to eliminate the possibility of unintended self-referential or negative / self-induced learning, while providing a reliable "brain training" paradigm that controlled for all non-specific factors and facilitated patient blinding.

[0098] Statistical analysis Intent-to-treat linear mixed-effects regression models were applied, with continuous MADRS score as outcome, days since infusion as a random continuous within-subject effect, and treatment allocation as a fixed between-subject effect. Separate models were designed to test linear patterns based on two hypotheses: (1) during the infusion phase of the intervention (ketamine vs saline), using only pre-infusion and 24-h assessments (collected before active / sham NT started); and (2) during the NT phase of the intervention (saline+NT vs. ketamine+sham vs. ketamine+NT in triplicates), using assessment points from 24 h to day 30. During the infusion phase, symptoms were hypothesized to decrease more rapidly in the ketamine group (compared to the saline group). During the NT phase, symptoms were hypothesized to increase linearly in the ketamine+sham group from 24 h to day 30 (group*time interaction for the saline+NT group). This is consistent with previous studies in which a single infusion of ketamine provided improvement over 1–2 weeks [Xu Y, Hackett M, Carter G, Loo C, Galvez V, Glozier N, Glue P, Lapidus K, McGirr A, Somogyi AA, Mitchell PB, Rodgers A: Efficacy of low- and very-low-dose ketamine in patients with major depression: a systematic review and meta-analysis. Int J Neuropsychopharmacol.2015; Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB, Treatments APACoRTFoNBa: Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry.2015;172(10):950-66; Caddy C, Amit BH, McCloud TL, Rendell JM, Furukawa TA, McShane R, Hawton K, Cipriani A: Ketamine and other glutamate receptor modulators for depression in adults.Cochrane Database Syst Rev.2015;Sep 23(9):CD011612]; and stable (main) effects were observed for the ketamine+active NT group from 24 hours to day 30 (compared with saline+NT). NT phase models used the saline+NT group as the reference group for hypothesis testing and included pre-infusion MADRS score as a covariate. All models included random participant intercepts and slopes to model patient-level trajectories over time and automatically account for missing data (5.1% of all intended observations). Continuous variables were standardized and dichotomous variables were coded 0.5 and -.5 for ease of interpretation. Standardized coefficients (β*) and odds ratios (OR) with 95% profile likelihood confidence intervals are reported. Analyses were performed using R version 3.6.

[0099] For the purposes of descriptive and clinical characterization only, responders (≥50% reduction from pre-infusion MADRS baseline) and remitters (MADRS ≤9 [Hawley CJ, Gale TM, Sivakumaran T, Hertfordshire Neuroscience Research g: Defining remission by MADRS cut-off score: selecting the optimal value. J Affect Disord. 2002;72(2):177-84]) were infused.

[0100] Sensitivity analyses (see Examples 6-8) examined the robustness of findings when including preselected covariates: sex, age, treatment resistance (moderate vs. severe), and concomitant psychotropic medication (dichotomized as "yes" or "no").

[0101] Example 4 result Depression Severity - Infusion Phase Consistent with previous studies, ketamine rapidly reduced MADRS total depression scores 24 hours after infusion (between-group interaction: standardized β=- 1.30, 95% CI: -1.89, -0.70; t=-4.29, df=150, p<.0001; Figure 9). This moderate-to-large linear effect corresponded to a 52% response rate and a 28% remission rate in the ketamine group and a 25% response rate and a 4% remission rate in the saline group [number-need-to-treat (NNT) for response=3.7; NNT for remission=4.2].

[0102] Severity of Depression - NT Phase (ASAT Phase) In an intent-to-treat linear mixed model, depression scores in the ketamine + ASAT group remained stably lower over the 30-day acute phase compared to scores in the saline + ASAT group (β=-0.61, 95% CI=-0.95, -0. 28; t=-3.62 df=148,p=0.0004; Fig. 9), with no corresponding between-group interaction (β=0.009, 95% CI=-0.004, 0.021; t=1.39, df=568, p=0.164; Fig. 9), suggesting a sustained effect over the 30-day period. In contrast, depression scores in the ketamine + sham group showed a linear increasing trend from 24 hours to 30 days, with the effect gradually attenuating after ketamine, and the level of depression scores approaching that of the saline 1 ASAT group (beta = 0.015, 95% CI = 0.003, 0.03; t = 2.35, df = 568, p = 0.019). Although the above intent-to-treat statistical test of linear trajectories over the entire 30-day period was used for statistical hypothesis testing, effect size point estimates were performed using paired post-hoc contrasts at day 30 to further illustrate the clinical impact at this specific time point. These effect size point estimates suggested a small effect for ketamine + ASAT compared with both saline + ASAT (β = -0.38, 95% CI = -0.78, 0.027) and ketamine + sham (β = -0.31, 95% CI = -0.75, 0.13).

[0103] All of the above findings were robustly supported in sensitivity analyses controlling for covariates (see Examples 6-8).

[0104] Adequacy of blinding As shown in Table S1 (Fig. 10), neither patients nor assessors were functionally blinded to the infusion condition (ketamine vs. saline). Thirty-five percent of patients who received saline incorrectly guessed that they had received ketamine, whereas 99% of patients who received ketamine (all but one) correctly guessed that they had received ketamine. In both groups (ketamine and saline), clinician allocation assessments were significantly correlated with the degree of symptom relief (percentage change from baseline in MADRS) at the time blinding was assessed (infusion + 30 days; r's ≥ .46; p's ≤ .001). In contrast, patient allocation assessments were significantly correlated with the degree of symptom relief in the saline group (r = .49; p = .001) but not in the ketamine group (r = .01; p = .95). These patterns suggest that clinicians' correct guesses about allocation may have been influenced uniformly by the degree of clinical improvement, whereas direct knowledge of patients' experiences on other infusion days (e.g., dissociative side effects) likely contributed to correct guesses (independently of clinical improvement).

[0105] In contrast, both patients and assessors were fully blinded to the NT condition. Patients' mean responses in both conditions (active = 54%; sham = 49%; t143 = 1.28; p = .20) were significantly higher than clinicians' responses (active = 55%; sham = 53%; t 147 = 0.60; p = .55), reflecting the “don't know” midpoint on the 0-100% response choice scale.

[0106] Example 5 discussion In this study, cognitive training - a low-cost, fully automated, non-invasive, brief (20 min or less per session, administered over eight sessions), computer-based intervention - successfully extended the rapid antidepressant effect of a single ketamine infusion for at least 30 days. As in previous studies, IV ketamine showed rapid antidepressant effects in patients with treatment-resistant depression. Ketamine infusions also appeared to be successful in opening a clinical window of opportunity, facilitating the efficient uptake of new positive self-representations and preventing relapse of depression over the following month, compared with saline infusions (Figure 9). In contrast, when identical NT was performed without ketamine pretreatment, no beneficial effects on depressive symptoms were observed beyond the nonspecific effects of saline and the comprehensive clinical study context (e.g., repeated depression assessments). A second comparison group, a group that underwent sham NT after ketamine administration, followed the course expected when a single ketamine infusion was administered as a sole treatment, i.e., a rapid decline followed by a gradual return of symptoms over the following weeks. This is the first study to examine the synergistic combination of ketamine and behavioral intervention, including both no-ketamine and no-behavioral controls. Similarly, clinical trials combining various "psychoplastogens" and other brain-targeted approaches (e.g., neuromodulation) with behavioral therapy have almost without exception neglected one or the other of these two important comparators [Wilkinson ST, Holtzheimer PE, Gao S, Kirwin DS, Price RB: Harnessing neuroplasticity to enhance adaptive learning: potential for synergistic physical-behavioral treatment combinations to improve clinical outcomes in depression. 2019;85(6):454-65 ]. The treatment protocol design described herein represents important new evidence hypothesizing a synergistic effect between the acute neuroplasticity-enhancing effects of ketamine and the introduction of protective learning provided by behavioral therapy.

[0107] While this disclosure envisions the possibility that a variety of traditional and non-traditional behavioral therapies may act synergistically with rapid pharmacology, this study focused specifically on NT approaches for practical and scientific reasons. Indeed, NT interventions are mechanistic, portable, and efficiently designed to fit nicely into the short window of opportunity for ketamine (i.e., approximately 1 week). In contrast, a full course of both traditional and computer-assisted cognitive behavioral therapy (CBT) typically requires 12–16 weekly, 1-h sessions, and meta-analyses suggest that the effects of computer-assisted CBT are strongest only when supported by therapist coaching [Andersson G, Cuijpers P: Internet-based and other computer-assisted psychotherapies for adult depression: a meta-analysis. Cogn Behav Ther. 2009;38(4):196-205]. Scientifically, implicit and explicit forms of cognition are distinct entities, and a robust evidence base suggests that implicit cognitions (e.g., implicit self-concept) may be more robust predictors of future behavior than explicit thought contents [Greenwald AG, Poehlman TA, Uhlmann EL, Banaji MR: Understanding and utilizing implicit association testing: III. A meta-analysis of predictive validity. J Pers Soc Psychol. 2009;97(1):17-41]. NT is designed to efficiently and directly target implicit cognitions, resulting in an innovative approach that is efficient yet has the potential to profoundly shape future behaviors and experiences. Furthermore, by targeting unitary, clearly defined, implicit cognitive mechanisms, NT limits the influence of heterogeneous, non-specific factors that are thought to be influential in many traditional behavioral interventions and may make it more difficult to predict and constrain learning that occurs within short time periods (e.g., positive vs. negative therapy session experiences).

[0108] NT specifically targeting implicit self-representations was chosen based on previous research suggesting that targeting this specialized information processing after priming brain plasticity with ketamine may provide optimal synergistic effects. Evidence for rapid plasticity in implicit self-representations after ketamine was supported by two previous studies [Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ, Soleimani L, Charney DS, Foulkes AL, Mathew SJ: Effects of ketamine on explicit and implicit suicidal ideation cognitions: a randomized controlled trial in treatment-resistant depression. Depress Anxiety. 2014;31(4):335-43; Price RB, Nock MK, Charney DS, Mathew SJ: Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66(5):522-6] suggests that ketamine produces the malleability required for information processing in this area. Similarly, prior neuroimaging studies suggest shifts in activity and connectivity in prefrontal and striatal networks following ketamine administration (e.g., increased caudate activation and striatal-mPFC connectivity during face processing [Murrough JW, Collins KA, Fields J, DeWilde KE, Phillips ML, Mathew SJ, Wong E, Tang CY, Charney DS, Iosifescu DV: Ketamine-induced neural regulation of emotion perception in patients with treatment-resistant major depressive disorder. Transl Psychiatry. 2015;5:e509]). The striatum and mPFC are extensively involved in appetitive conditioning in humans and rodents [Martin-Soelch C, Linthicum J, Ernst M: Appetitive conditioning: neural substrates and implications for psychopathology. Neurosci Biobehav Rev.2007;31(3):426-40], these findings may indicate a synergistic correspondence between the neural effects of ketamine and appetitive conditioning paradigms such as those used here.In general, evaluative conditioning techniques have a large and robust literature in healthy controls [Hofmann W, De Houwer J, Perugini M, Baeyens F, Crombez G: Evaluative conditioning in humans: a meta-analysis. Psychol Bull 2010;136(3):390-421], and have previously shown robust and reproducible acute clinical effects in a home (smartphone) delivery modality in clinical samples [Franklin JC, Fox KR, Franklin CR, Kleiman EM, Ribeiro JD, Jaroszewski AC, Hooley JM, Nock MK: A brief mobile app reduces non-suicidal and suicidal self-harm: evidence from three randomized controlled trials. J Consult Clin Psychol.2016;84(6):544-57].The ability to achieve and sustain benefits with a technology that is portable and suitable for dissemination is an important criterion for overcoming formidable barriers to access to treatment, especially for underserved communities [Atdjian S, Vega WA: Disparities in mental health treatment among racial and ethnic minority populations in the United States: Implications for psychiatrists. Psychiatr Serv.2005;56(12):1600-2].Finally, the role of “depressive self-schemas” in creating vulnerability to negative emotions is one of the oldest and best-documented cognitive mechanisms mediating depression. 1730765571837_0 This suggests that this mechanistic target may be of strong clinical relevance.

[0109] Conclusion The global burden of depression is enormous and is expected to continue to increase in the current context of a pandemic. New therapies, especially those that provide efficient relief, are urgently needed. The treatment protocol described herein helps to advance an integrative plasticity-based model of depression and reveals new synergistic therapeutic approaches that provide acute relief and efficiently scale this relief with a safe, low-cost, and portable technology. Alongside fully automated NT, ketamine itself also has properties that make it more suitable for widespread use than many alternatives, including a good safety profile in single injections, current FDA approval and widespread international medical use as a general anesthetic, and a high "name recognition" among patients and clinicians.

[0110] Example 6 Neurocognitive Training Technology Details

[0111] All neurocognitive training (active or sham) was conducted in a private room using E-Prime 2 software (Psychology Software Tools; Pittsburgh PA) and a laptop computer with a Windows operating system. Positive and neutral word lists and pictures were composed from a validated stimulus set used in previous studies.

[0112] Each NT session consisted of three consecutive blocks: (1) a subliminal lexical evaluative conditioning block, (2) a supraliminal lexical evaluative conditioning block, and (3) a pictorial evaluative conditioning block.

[0113] In the subliminal vocabulary assessment conditioning block, 60 trials were presented consecutively in random order. Each trial consisted of a fixation string in the center of the screen ('XXXX', 500 ms) followed by a one-letter probe (active NT: 'I', implicitly representing 'myself': 'A') presented for 17 ms, followed by a positive word (active NT) or a neutral word (sham NT) presented for 17 ms, and finally a probe string of random letters presented until a response was made. The participant's task was to press a key to indicate whether the final random string began with a vowel (left key; 50% of trials) or a consonant (right key; 50% of trials).

[0114] In the supramental vocabulary assessment conditioning block, 60 trials were presented consecutively in random order. Each trial consisted of a fixation string ('XXXX', 500 ms), a single-letter probe (active NT: 'X' or 'I', sham NT: 'X' or 'A') presented for 500 ms, and then either a real word or a random string of letters was presented until a response was made. In the active NT group, random strings were always preceded by the letter 'X', and positive words were always preceded by the letter 'I' (implying 'self'). In the sham NT group, random strings were always preceded by the letter 'X', and negative words were always preceded by the letter 'I'. The participants' task was to press a key to indicate whether the final string was a word (left key: 50% of trials) or a nonword (right key: 50% of trials).

[0115] In the pictorial conditioning block, 480 trials were presented consecutively in random order (with one self-paced break in between). Each trial divided the screen into four quadrants and presented one photographic probe until the participant clicked the mouse in the correct quadrant, after which the first photograph was immediately replaced by a second photograph in the same position and presented for 400 ms. This trial is shown in Figure 3. In the active NT condition, the first (probe) photograph in 33% of trials was one of three digital photographs taken at the screening visit, during which participants were coached to have a neutral facial expression. Headshot photographs were taken at a standardized distance, filling the vertical frame, and at three standardized angles (straight ahead, 45° left, and 45° right). Where the first photograph was a selfie of the participant, the second photograph consisted of a photograph of a happy expression randomly selected from the happy expressions of seven actors of both sexes included in a standardized NimStim image set [Tottenham N, Tanaka JW, Leon AC, McCarry T, Nurse M, Hare TA, Marcus DJ, Westerlund A, Casey BJ, Nelson C: The NimStim facial expression set: judgments by untrained research participants. Psychiatry Res 2009;168(3):242-9]. In the remaining 66% of trials in the active NT condition, the first (probe) picture was from the standardized Karolinska Directed Emotional Faces (KDEF) picture set (Lundqvist, D., Flykt, A., & Ohman, A.; 1998); and the second (replacement) picture was either a second neutral (33% of trials) or an angry (33% of trials) facial expression, randomly selected from standardized angry and neutral facial expressions of seven male and seven female actors from the standardized NimStim picture set. In the sham NT condition, all first (probe) pictures consisted of neutral facial expressions from the standardized Karolinska Directed Emotional Faces (KDEF) picture set (Lundqvist, D., Flykt, A., & Ohman, A.; 1998).The second replacement picture consisted of a second neutral (66% of trials) or angry (33% of trials) facial expression, randomly selected from standardized angry and neutral facial expressions of seven actors of both sexes from the standardized NimStim picture set.

[0116] Example 7 Measurement of covariates At the screening assessment, participants completed a general self-report demographic and medical history form and provided a full list of current medications (including doses and indications). This information was used to quantify the following indicators for use as covariates in sensitivity analyses: age, biological sex assigned at birth (as recorded on birth certificate), and concomitant psychotropic medications. Patients were queried for the date of their last psychotropic medication change to ensure that the period between their last psychotropic medication change and the screening assessment was 4 weeks (equivalent to approximately 6 weeks of stable dosing before the infusion date) and were asked to maintain stable doses of medications and other psychiatric treatments (e.g., psychotherapy) up until the infusion date and throughout the acute study period of 30 days after infusion. Severity of previous treatment resistance to FDA-approved antidepressants was assessed by clinical interviewers using the ATRQ, dichotomized as moderate (<3 trial failures in the current episode) or severe (≥3 trial failures in the current episode), and used to stratify randomization (in addition to sex assignment at birth) and as an additional covariate in sensitivity analyses.

[0117] Example 8 Adequacy of blinding At the final (+30 day) visit, the adequacy of blinding of patients and clinical assessors was assessed for both infusion and NT allocation using a sliding scale of 0–100 (0=definitely placebo / sham, 50=don't know, 100=definitely ketamine / active). As shown in Figure 10, Table S1, neither patients nor assessors were functionally blinded to infusion condition (ketamine vs saline). 35% of patients who received saline incorrectly guessed that they had received ketamine, whereas 99% of patients who received ketamine (all but one) correctly guessed that they had received ketamine. In both groups (ketamine-treated, saline-treated), clinician allocation assessments correlated significantly with the degree of symptom relief (percentage MADRS change from baseline) at the time blinding was assessed (infusion +30 days; r's ≥ .46; p's ≤ .001). In contrast, patients' allocation ratings were significantly correlated with the degree of symptom relief in the saline group (r = .49; p = .001) but not in the ketamine group (r = .01; p = .95). These patterns suggest that clinicians' correct allocation guesses may have been influenced uniformly by the degree of clinical improvement, whereas direct knowledge of patients' experiences on other infusion days (e.g., dissociative side effects) likely contributed to correct guesses (independent of clinical improvement).

[0118] However, both patients and assessors were fully blinded to the NT condition (Figure ​(Figure10; Table S1). The mean responses of patients to both conditions (active=54%; sham=49%; t143=1.28; p=.20) were significantly higher than the mean responses of clinicians (active=55%; sham=53%; t 147 = 0.60; p = .55), reflecting the “don't know” midpoint on the 0-100% response choice scale.

[0119] Few prior ketamine studies have explicitly measured the success of blinding, but given ketamine's specific acute effects on cognition, even when using a psychoactive comparator group (e.g., midazolam), the possibility of inadequate blinding has consistently been cited as a challenge when conducting RCTs of ketamine [Wilkinson ST, Farmer C, Ballard ED, Mathew SJ, Grunebaum MF, Murrough JW, Sos P, Wang G, Gueorguieva R, Zarate CA, Jr: Effects of midazolam versus saline on effect size estimates in a controlled trial of ketamine as a fast-acting antidepressant. Neuropsychopharmacology 2019;44(7):1233-8; Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CM, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ: Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-center randomized controlled trial. Am J Psychiatry 2013;170(10):1134-42]. An inert placebo was chosen because the clinical efficacy of ketamine in depression has already been established in a number of prior studies compared with both inert and psychoactive placebo conditions.) [[Wilkinson ST, Farmer C, Ballard ED, Mathew SJ, Grunebaum MF, Murrough JW, Sos P, Wang G, Gueorguieva R, Zarate CA, Jr: Effects of midazolam versus saline on effect size estimates in a controlled trial of ketamine as a fast-acting antidepressant.Neuropsychopharmacology 2019;44(7:1233-8; Xu Y, Hackett M, Carter G, Loo C, Galvez V, Glozier N, Glue P, Lapidus K, McGirr A, Somogyi AA, Mitchell PB, Rodgers A: Efficacy of low- and very low-dose ketamine in patients with major depression: A systematic review and meta-analysis. Int J Neuropsychopharmacol 2015; Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB, Treatments APACoRTFoNBa: Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression. Am J Psychiatry 2015;172(10):950-66; Caddy C, Amit BH, McCloud TL, Rendell JM, Furukawa TA, McShane R, Hawton K, Cipriani A: Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database Syst Rev 2015;Sep 23(9):CD011612] _ENREF_4, and our design facilitated a clean comparison of the potential synergistic effects of ketamine and NT without introducing potential obscuring or confounding neurocognitive effects (either positive or adverse) from a second psychoactive substance. The fact that we observed a significant response to saline (25% responders at 24 hours, reduction from baseline maintained throughout the 30-day evaluation period - Figure 9) provides reassurance that the saline group successfully controlled for many nonspecific factors that affect outcome in depression treatment trials, including but not limited to expectancy effects. [Dunlop BW, Thase ME, Wun CC, Fayyad R, Guico-Pabia CJ, Musgnung J, Ninan PT: A meta-analysis of factors influencing detection of antidepressant efficacy in clinical trials: the importance of academic sites.Neuropsychopharmacology 2012;37(13):2830-6].

[0120] Example 9 Described below is an analysis of self-report data collected during a one-year naturalistic follow-up study to explore the full extent of the durability of the automated neurocognitive training protocol described in the Examples herein.

[0121] One hundred fifty-four adult patients with treatment-resistant depression receiving stable psychiatric care were randomized to one of three treatment conditions [Price RB, Spotts C, Panny B, Griffo A, Degutis M, Cruz N, et al: A novel, brief, fully automated intervention to prolong the antidepressant effects of a single ketamine infusion: a randomized clinical trial. Am J Psychiatry.2022:appiajp20220216]: A single infusion of ketamine (0.5 mg / kg) was followed by ASAT for 4 days (30–40 min / day). ASAT is a digital therapeutic designed to target self-related implicit thought patterns, leveraging a hypothesized "window" of plasticity following ketamine administration; sham ASAT (identical computer exercises lacking therapeutic and self-related content) was performed after ketamine administration; or active ASAT was performed after saline infusion. Throughout the one-year natural observation period, patients completed the Quick Inventory for Depressive Symptoms (QIDS-SR) [Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, et al: 16-item QIDS (Quick Inventory of Depressive Symptoms), clinician-rated (QIDS-C), and self-report (QIDS-SR): psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54:573-83]) as the primary outcome during follow-up. Questionnaires were collected at the following time points relative to the start of infusion: +30 days, 60 days, 90 days, 120 days, 150 days, 180 days, and 360 days.

[0122] Pre-infusion baseline QIDS-SR score was covaried as a categorical factor in an intention-to-treat hierarchical linear model (with missing values ​​automatically imputed) predicting QIDS-SR total score.

[0123] A significant Timepoint*Group interaction was observed in the full model (standardized F(12,718) = 3.15; p = 0.0002). To elucidate this interaction, given that we have no a priori knowledge of the potential durability of this first-in-the-world intervention approach, we used visual inspection of symptom trajectories to identify data-driven breakpoints at which error bars began to overlap (Figure 13).

[0124] In Figure 13, the blue line represents ketamine + active automated autoassociative training (ASAT), n=53, the orange line represents ketamine + sham ASAT, n=50, and the red line represents saline + active ASAT, n=51. Line graphs represent the mean values, and error bars represent the standard error of the mean within each time point and treatment group. Grey shading indicates the "late" time window, where no significant intergroup differences were observed between the two groups at any time point. Pre-infusion baseline and 1 day post-infusion (immediately after ketamine or saline administration, before active / sham ASAT began) are depicted here for comprehensive visualization, while statistical analysis of the follow-up period focuses on the period from infusion + 30 days onwards (described in the main text). * indicates time points at which there was a significant decrease in the ketamine + active ASAT group versus the saline + active ASAT group, by unpaired t-test.

[0125] To minimize multiple comparisons, paired planned contrasts were used to examine group means during the data-driven "early" (≤90 days) and "late" (≥120 days) time periods. As shown in Figure 13, during the "early" time frame, there was a significant between-group effect for ketamine+ASAT vs. saline+ASAT (β[95% CI]=-0.37[-0.71,-0.04]; SE=0.168; t(144)=-2.21; p=0.0287), whereas there was no corresponding significant effect when ketamine was administered without ASAT (ketamine+sham) compared to saline+ASAT (β=-0.197[-0.54,0.14]; SE=0.172; t(144)=-1.147; p=0.253). In contrast, in the “Late” timeframe, there were no longer any significant differences between groups (Ket+ASAT vs. Saline+ASAT: β = 0.179; SE = 0.168; t(144) = 1.068; p = 0.287; Ket+Sham vs. Saline+ASAT: β = 0.111; SE = 0.170; t(144) = 0.653; p = 0.515).

[0126] This study is the first to show that the rapid effects of ketamine can be made more durable by using a simple, portable digital technology that could be relatively easy to deliver to patients in a variety of settings. A single 40-minute dose of the drug and four days of digital exercise (30-40 minutes per day) produced statistically significant benefits for depression that were sustained for three months, according to new follow-up data.

[0127] Although the present subject matter has been described in language specific to structural features and / or methodological acts, it is to be understood that the subject matter defined in the appended claims is not necessarily limited to the specific features or acts described above. Rather, the specific features and acts described above are disclosed as example forms of implementing the claims.

Claims

1. 1. A method of treating a patient having a psychiatric disorder, comprising: administering to the patient a drug having antidepressant activity; and administering a neurocognitive training protocol to the patient during a critical window of time following drug administration. Including, administering the neurocognitive training protocol to the patient includes delivering, using a computing device, a plurality of automated neurocognitive training sessions to the patient, wherein a plurality of conditioning sequences are presented to the patient during each delivery of the automated neurocognitive training sessions, each conditioning sequence including a respective non-self-related stimulus and a respective self-related stimulus. A method of treating a patient having said psychiatric disorder.

2. providing a first automated neurocognitive training session and a second automated neurocognitive training session to the patient on a first date; A third automated neurocognitive training session and a fourth automated neurocognitive training session are provided to the patient on day 2. Includes. The method of claim 1.

3. 3. The method of claim 2, wherein the period of time between providing the patient with the first and second automated neurocognitive training sessions is about 20 minutes or more.

4. 4. The method of claim 2 or 3, wherein the period of time between providing the patient with the third and fourth automated neurocognitive training sessions is about 20 minutes or more.

5. 5. The method of any one of claims 1 to 4, wherein each of the automated neurocognitive training sessions has a length of between about 15 minutes and about 20 minutes.

6. 2. The method of claim 1, wherein the multiple automated neurocognitive training sessions are between about 2 sessions and about 14 sessions.

7. 2. The method of claim 1, wherein the plurality of automated neurocognitive training sessions is about 8 sessions.

8. 8. The method of claim 1, wherein each conditioning sequence further comprises a task, the task being presented to the patient following or in conjunction with the presentation of each set of non-self-relevant and self-relevant stimuli.

9. 9. The method according to any one of claims 1 to 8, wherein each non-self-relevant stimulus and / or each self-relevant stimulus for each conditioning sequence is an auditory stimulus.

10. 9. The method according to any one of claims 1 to 8, wherein each non-self-relevant stimulus and / or each self-relevant stimulus for each conditioning sequence is a visual stimulus.

11. 9. The method of any one of claims 1 to 8, wherein each self-relevant stimulus for each conditioning sequence consists of a sound, an image, or a word that is relevant to the patient.

12. 12. The method of claim 11, wherein each non-self-associated stimulus for each conditioning sequence comprises a sound, picture, or word associated with a positive meaning.

13. 12. The method of claim 11, wherein each non-self-relevant stimulus for each conditioning sequence consists of a sound, picture, or word associated with a life-affirming meaning.

14. 9. The method of claim 1, wherein each non-self-relevant stimulus and each self-relevant stimulus for each conditioning sequence is included in an nxm matrix of visual stimuli.

15. 15. The method of claim 14, wherein administering the neurocognitive training protocol to the patient further comprises receiving from the patient, for each of the conditioning sequences, a selection that matches each of the non-self-related stimuli and each of the self-related stimuli.

16. 14. The method of any one of claims 1 to 13, wherein one or more of the plurality of conditioning sequences comprises subliminal presentation of a non-self-related or self-related stimulus.

17. 14. The method of any one of claims 1 to 13, wherein one or more of the plurality of conditioning sequences comprises a supercritical presentation of a non-self-relevant or self-relevant stimulus.

18. 18. The method of any one of claims 1 to 17, wherein the computing device comprises a processor and a memory operatively coupled to the processor, the memory having computer-executable instructions stored thereon.

19. 20. The method of claim 18, wherein the memory stores computer-executable instructions that, when executed by the processor, cause the processor to generate respective conditioning sequences.

20. the computing device further comprising a display device operably coupled to the processor, the memory having computer-executable instructions stored thereon that, when executed by the processor, cause the processor to: generating graph data for each conditioning sequence; and Displaying the graph data on a display device. The method of claim 19, further comprising:

21. 21. The method of any one of claims 1 to 20, wherein the critical period is the period during which the drug acutely proliferates synaptic connections in the patient's brain.

22. 22. The method of claim 21, wherein the critical period is between about 2 hours and about 14 days after administration of the agent.

23. 22. The method of claim 21, wherein the critical period is between about 1 day and about 5 days after administration of the drug.

24. 24. The method of any one of claims 1 to 23, wherein the drug is a fast-acting antidepressant.

25. 25. The method of claim 24, wherein the fast-acting antidepressant is ketamine.

26. 24. The method of any one of claims 1 to 23, wherein the drug is brexanolone, zuranolone, rapastinel, scopolamine, or a psychedelic.

27. 27. The method according to any one of claims 1 to 26, wherein the psychiatric disorder is depression.

28. 27. The method of any one of claims 1 to 26, wherein the psychiatric disorder is suicidal behavior.

29. 1. A computer-implemented method for administering a neurocognitive training protocol to a patient with a psychiatric disorder, comprising: the patient is receiving a drug having an antidepressant effect, and the neurocognitive training protocol is administered during a critical period following administration of the drug to the patient; The computer-implemented method comprises: providing a plurality of automated neurocognitive training sessions to the patient, wherein during each of the automated neurocognitive training sessions, a plurality of conditioning sequences are presented to the patient, each conditioning sequence including a respective non-self-related stimulus and a respective self-related stimulus; Including, The computer-implemented method.

30. providing a first automated neurocognitive training session and a second automated neurocognitive training session to the patient on a first date; A third automated neurocognitive training session and a fourth automated neurocognitive training session are provided to the patient on day 2.

30. The computer-implemented method of claim 29, comprising:

31. 31. The computer-implemented method of claim 30, wherein the period of time between providing the patient with the first and second automated neurocognitive training sessions is about 20 minutes or more.

32. 32. The computer-implemented method of claim 30 or 31, wherein the period of time between providing the patient with the third and fourth automated neurocognitive training sessions is about 20 minutes or more.

33. 33. The computer-implemented method of any one of claims 29 to 32, wherein each of the automated neurocognitive training sessions has a length of between about 15 minutes and about 20 minutes.

34. 30. The computer-implemented method of claim 29, wherein the plurality of automated neurocognitive training sessions is between about 2 sessions and about 14 sessions.

35. 30. The computer-implemented method of claim 29, wherein the plurality of automated neurocognitive training sessions is about 8 sessions.

36. 36. The computer-implemented method of claim 29, wherein each conditioning sequence further comprises a task, the task being presented to the patient following or in conjunction with the presentation of each set of non-self-relevant and self-relevant stimuli.

37. 37. The computer-implemented method of any one of claims 29 to 36, wherein each non-self-relevant stimulus and / or each self-relevant stimulus for each conditioning sequence is an auditory stimulus.

38. 37. The computer-implemented method of any one of claims 29 to 36, wherein each non-self-relevant stimulus and / or each self-relevant stimulus for each conditioning sequence is a visual stimulus.

39. 37. The computer-implemented method of any one of claims 29 to 36, wherein each self-relevant stimulus for each conditioning sequence comprises a sound, an image, or a word that is relevant to the patient.

40. 40. The computer-implemented method of claim 39, wherein each non-self-relevant stimulus for each conditioning sequence consists of a sound, picture, or word associated with a positive meaning.

41. 40. The computer-implemented method of claim 39, wherein each non-self-relevant stimulus for each conditioning sequence consists of a sound, picture, or word associated with a life-affirming meaning.

42. 37. The computer-implemented method of any one of claims 29 to 36, wherein each non-self-relevant stimulus and each self-relevant stimulus for each conditioning sequence is included in an n x m matrix of visual stimuli.

43. 43. The computer-implemented method of claim 42, further comprising receiving, for each conditioning sequence, a selection matching each non-self-relevant stimulus with each self-relevant stimulus.

44. 44. The computer-implemented method of any one of claims 29 to 43, wherein one or more of the plurality of conditioning sequences comprises subliminal presentation of a non-self-related stimulus or a self-related stimulus.

45. 44. The computer-implemented method of any one of claims 29 to 43, wherein one or more of the plurality of conditioning sequences comprises a supercritical presentation of a non-self-relevant stimulus or a self-relevant stimulus.

46. The computer-implemented method of any one of claims 29 to 45, further comprising generating each conditioning sequence.

47. generating graph data for each conditioning sequence; displaying the graph data on a display device; 47. The computer-implemented method of claim 46, further comprising:

48. 48. The computer-implemented method of any one of claims 29 to 47, wherein the critical period is a period during which the drug acutely proliferates synaptic connections in the patient's brain.

49. 49. The computer-implemented method of claim 48, wherein the critical period is between about 2 hours and about 14 days after administration of the drug.

50. 49. The computer-implemented method of claim 48, wherein the critical period is between about 1 day and about 5 days after administration of the drug.

51. 1. A system for administering a neurocognitive training protocol to a patient with a psychiatric disorder, comprising: the patient is receiving a drug having an antidepressant effect, and the neurocognitive training protocol is administered during a critical period following administration of the drug to the patient; The system comprises: A processor; and a memory operatively coupled to the processor, the memory being operable, when executed by the processor, to cause the processor to: providing a plurality of automated neurocognitive training sessions to the patient, where during each of the delivery of the automated neurocognitive training sessions, a plurality of conditioning sequences are presented to the patient, each conditioning sequence including a respective non-self-related stimulus and a respective self-related stimulus; and a memory having computer-executable instructions stored thereon to cause the The system.

52. providing a first automated neurocognitive training session and a second automated neurocognitive training session to the patient on a first date; a third automated neurocognitive training session and a fourth automated neurocognitive training session are provided to the patient on the second day.

52. The system of claim 51.

53. 53. The system of claim 52, wherein the period of time between providing the first and second automated neurocognitive training sessions to the patient is greater than or equal to about 20 minutes.

54. 54. The system of claim 52 or 53, wherein the period between the delivery of the third and fourth automated neurocognitive training sessions to the patient is about 20 minutes or more.

55. 55. The system of any one of claims 51-54, wherein each of the automated neurocognitive training sessions has a length of between about 15 minutes and about 20 minutes.

56. 56. The system of claim 55, wherein the plurality of automated neurocognitive training sessions is between about 2 sessions and about 14 sessions.

57. 56. The system of claim 55, wherein the plurality of automated neurocognitive training sessions is about 8 sessions.

58. 58. The system of any one of claims 51 to 57, wherein each conditioning sequence further comprises a task, the task being presented to the patient following or in conjunction with the presentation of each set of non-self-relevant stimuli and self-relevant stimuli.

59. 59. A system according to any one of claims 51 to 58, wherein each non-self-relevant stimulus and / or each self-relevant stimulus for each conditioning sequence is an auditory stimulus.

60. 59. The system of any one of claims 51 to 58, wherein each non-self-relevant stimulus and / or each self-relevant stimulus for each conditioning sequence is a visual stimulus.

61. 59. The system of any one of claims 51 to 58, wherein each self-relevant stimulus for each conditioning sequence comprises a sound, an image, or a word that is relevant to the patient.

62. 62. The system of claim 61, wherein each non-self-relevant stimulus for each conditioning sequence comprises a sound, picture, or word associated with a positive meaning.

63. 62. The system of claim 61, wherein each non-self-relevant stimulus for each conditioning sequence consists of a sound, picture, or word associated with a life-affirming meaning.

64. 64. The system of any one of claims 51 to 63, wherein each non-self-relevant stimulus and each self-relevant stimulus for each conditioning sequence is included in an n x m matrix of visual stimuli.

65. 65. The system of any one of claims 51 to 64, wherein one or more of the plurality of conditioning sequences comprises subliminal presentation of a non-self-related stimulus or a self-related stimulus.

66. 66. The system of any one of claims 51 to 65, wherein one or more of the plurality of conditioning sequences comprises a supercritical presentation of a non-self-relevant stimulus or a self-relevant stimulus.

67. 67. The system of claims 51-66, wherein the memory further has computer-executable instructions stored thereon that, when executed by the processor, cause the processor to generate a respective conditioning sequence.

68. The memory, when executed by the processor, causes the processor to: generating graph data for each conditioning sequence; and Displaying the graph data on a display device.

68. The system of claim 67, further storing computer-executable instructions to cause the system to execute:

69. 1. A method of treating a patient having a psychiatric disorder, comprising: administering to the patient a drug having antidepressant activity; and administering a neurocognitive training protocol to the patient during a critical period following administration of the drug. Including, Administering the neurocognitive training protocol to the patient includes delivering, using a computing device, a plurality of automated neurocognitive training sessions to the patient, wherein each automated neurocognitive training session comprises: presenting, using a computing device, an n x m matrix of visual stimuli to a patient, the plurality of visual stimuli consisting of first matching pairs of non-self-related visual stimuli and self-related visual stimuli; receiving, using a computing device, a selection by the patient of a first matching pair of non-self-related and self-related visual stimuli; using said computing device to deliver a plurality of automated neurocognitive training sessions to the patient; A method of treating a patient having said psychiatric disorder.

70. Each automated neurocognitive training session further: presenting to the patient a second matched pair of non-self-related and self-related visual stimuli using the computing device; and presenting the task to the patient using the computing device following or in conjunction with the presentation of a second matching pair of non-self-related and self-related visual stimuli.

70. The method of claim 69, comprising:

71. Each automated neurocognitive training session further: presenting self-relevant visual stimuli to the patient using a computing device; presenting a task to the patient using a computing device subsequent to or in association with the presentation of the self-relevant stimuli; and using the computing device to present a positive non-self-related visual stimulus following successful completion of the task by the patient.

71. The method of claim 70, comprising:

72. 72. The method of any one of claims 69-71, wherein each of the automated neurocognitive training sessions has a length of between about 15 minutes and about 20 minutes.

73. 72. The method of any one of claims 69 to 71, wherein the critical period is the period during which the drug acutely proliferates synaptic connections in the patient's brain.

74. 74. The method of claim 73, wherein the critical period is between about 2 hours and about 14 days after administration of the drug.

75. 74. The method of claim 73, wherein the critical period is between about 1 day and about 5 days after administration of the agent.

76. 1. A computer-implemented method for administering a neurocognitive training protocol to a patient with a psychiatric disorder, comprising: the patient is receiving a drug having an antidepressant effect, and the neurocognitive training protocol is administered during a critical period following administration of the drug to the patient; The computer-implemented method comprises: presenting to the patient an n x m matrix of visual stimuli, wherein the plurality of visual stimuli comprises a first matching pair of non-self-related visual stimuli and self-related visual stimuli; and Receive the patient's choice of the first matching pair of non-self-relevant and self-relevant visual stimuli. The computer-implemented method comprising:

77. 1. A system for administering a neurocognitive training protocol to a patient with a psychiatric disorder, comprising: the patient is receiving a drug having an antidepressant effect, and the neurocognitive training protocol is administered during a critical period following administration of the drug to the patient; The system comprises: A processor; and a memory operatively coupled to the processor, the memory being operable, when executed by the processor, to cause the processor to: presenting to the patient an n x m matrix of visual stimuli, wherein the plurality of visual stimuli comprises a first matching pair of non-self-related visual stimuli and self-related visual stimuli; and Receive the patient's choice of the first matching pair of non-self-relevant and self-relevant visual stimuli. and a memory having computer-executable instructions stored thereon to cause the The system.

78. 1. A method of treating a patient having a psychiatric disorder, comprising: administering to the patient a drug having antidepressant activity; and administering a neurocognitive training protocol to the patient during a critical window of time following drug administration. Including, administering the neurocognitive training protocol to the patient, the step of administering the neurocognitive training protocol comprising: delivering, using a computing device, a plurality of automated neurocognitive training sessions to the patient, wherein a plurality of conditioning sequences are presented to the patient during the delivery of each of the automated neurocognitive training sessions. A method of treating a patient having said psychiatric disorder.

79. 1. A method for therapeutically related conditioning of a patient, comprising: administering to the patient a treatment that enhances neuroplasticity; and administering a neurocognitive training protocol to the patient during a critical period following administration of the neuroplasticity enhancing treatment. Including, administering a neurocognitive training protocol to the patient includes delivering, using a computing device, one or more conditioning sequences configured to condition a therapeutic association to the patient. A method for therapeutically related conditioning of said patient.

80. 80. The method of claim 79, wherein the neuroplasticity enhancing treatment is a drug or neuromodulatory intervention.

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