Adjunctive D-cycloserine augmentation of transcranial magnetic stimulation (TMS) therapy for obsessive-compulsive disorder

Abstract

Adjunctive D-cycloserine (DCS) augmentation of transcranial magnetic stimulation (TMS) therapy for obsessive-compulsive disorder (OCD) is provided. Also provided are combination therapies and methods of treatment that include intermittent or continuous theta burst stimulation, high or low frequency stimulation, or a combination thereof, in conjunction with D-cycloserine (DCS) to treat OCD in a patient and / or to improve and / or alleviate and / or reduce the frequency of one or more symptoms of OCD, including cognitive function, and common co-morbidities such as depression.

Description

[Technical field]

[0001] The present invention relates generally to methods of treating obsessive-compulsive disorder (OCD), and more particularly to adjunctive D-cycloserine (DCS) augmentation of transcranial magnetic stimulation (TMS) therapy for obsessive-compulsive disorder (OCD), including theta burst stimulation (TBS) or high or low frequency stimulation, or a combination thereof. [Background technology]

[0002] Obsessive-compulsive disorder (OCD) is a significant cause of global disability characterized by recurrent intrusive thoughts (obsessions) and ritualistic behaviors (compulsions). Its prevalence in the general population is approximately 3%. 1、2 This is especially true for those under 50. 3 It is considered one of the leading causes of overall disability, and its proportion of overall disability-adjusted life years has been increasing over the past 25 years. 3 OCD imposes significant direct and indirect costs on society. 4 .

[0003] For 40-60% of patients, their symptoms do not improve significantly despite evidence-based drug or psychological therapy. 5 Therefore, there is a need for methods of treating OCD in patients where previous treatment methods have been unsuccessful or not well tolerated.

[0004] In addition to the core symptoms of OCD, there are other important features of OCD that need to be considered. An under-recognized association with OCD is suicidal ideation and behavior. In cross-sectional samples, up to 28% of patients reported current suicidal ideation and behavior. 6~8 , the lifetime suicide attempt rate is 9-27%. 6~8 A prospective study with a short follow-up period of 4 years reported suicide attempts in 5% of patients and death by suicide in 0.9% of patients. 9 , cross-sectional samples give a false impression of the severity of the risk.

[0005] Moreover, these clinical features of OCD are accompanied by cognitive impairments that have several consequences. Neuropsychological tests in OCD demonstrate impairments in several cognitive domains, especially those involving executive functions, extra-dimensional shifts, working memory, and spatial memory. 10~12 These are generally considered poor prognostic factors. 13 , which are not improved by existing treatments 14 These represent major challenges in the treatment needed for OCD.

[0006] As an alternative to conventional treatments for non-responders, abnormalities in cortico-striato-cortical circuits are being targeted using non-invasive brain stimulation. In particular, non-invasive repetitive transcranial magnetic stimulation (rTMS) of brain regions implicated in OCD has emerged as a treatment option for individuals who have not benefited from or tolerated pharmacotherapy. Clinical response rates with rTMS in OCD are approximately 45% compared to 18% with sham stimulation. 15 .

[0007] Thus, methods to enhance rTMS for OCD are needed, as rTMS produces poor treatment outcomes.

[0008] Synaptic plasticity is believed to be the mechanism by which rTMS produces improvements in OCD symptoms. Specifically, pharmacological studies have shown that theta burst protocols, rTMS protocols, and TBS-induced plasticity are N-methyl-D-aspartate receptor (NMDAR) dependent. 16 NDMAR agonists have been used as adjuncts to exposure and response prevention therapy, but adequately powered trials have not found evidence of clinical benefit from this form of psychotherapy. 17~20 This may be because the mechanism of treatment does not directly target synaptic plasticity and / or the cortico-striato-cortical circuit. Pairing an adjunctive NMDAR agonist in combination with rTMS targeting the cortico-striato-cortical circuit may improve the efficacy of rTMS in OCD.

[0009] This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present invention. Summary of the Invention [Means for solving the problem]

[0010] It is an object of the present invention to provide adjunctive D-cycloserine (DCS) augmentation of transcranial magnetic stimulation (TMS) therapy for obsessive-compulsive disorder. In one aspect of the present invention, a method of treating obsessive-compulsive disorder (OCD) in a patient and / or improving and / or alleviating and / or reducing the frequency of one or more symptoms of OCD is provided, comprising administering to the patient a low dose of D-cycloserine and subjecting the patient to either intermittent or continuous theta burst stimulation (TBS), or high or low frequency stimulation, or a combination thereof.

[0011] In another aspect of the invention, a method is provided for reducing suicidal ideation and risk associated with obsessive-compulsive disorder (OCD), comprising administering to a patient a low dose of D-cycloserine and subjecting the patient to either intermittent or continuous theta burst stimulation (TBS), or high or low frequency stimulation, or a combination thereof.

[0012] In another aspect of the invention, a method of reducing cognitive impairment associated with obsessive-compulsive disorder (OCD) is provided, comprising administering to a patient a low dose of D-cycloserine and subjecting the patient to either intermittent or continuous theta burst stimulation (TBS), or high or low frequency stimulation, or a combination thereof.

[0013] In another aspect of the invention, methods are provided for using D-cycloserine as a transcranial magnetic stimulation adjunct, optionally in conjunction with theta burst stimulation (TBS), or high or low frequency stimulation, or a combination thereof.

[0014] These and other features of the present invention will become more apparent in the following detailed description, in which reference is made to the accompanying drawings. [Brief description of the drawings]

[0015] [Figure 1] Motor cortex TMS plasticity data from a randomized placebo-controlled crossover study (n=20) examining changes in stimulus-response curve slope, an indicator of changes in neuronal recruitment, following single and spaced repeated iTBS. The data indicate that in the iTBS+placebo condition, changes in stimulus-response curve slope following a single iTBS are transient and do not augment with repeated iTBS, whereas when delivered with DCS, changes in stimulus-response curve slope following a single iTBS are stable and augment with spaced repeated iTBS. Slopes are normalized to baseline stimulus-response curve slopes. Error bars indicate standard error of the mean. [Diagram 2] Data are presented from a double-blind placebo and sham-controlled randomized controlled trial in patients with moderate to severe OCD. This is a four-arm design, involving iTBS+placebo, iTBS+DCS (100mg), sham iTBS+DCS (100mg) and sham iTBS+placebo. As per pre-planned analysis, sham iTBS+DCS and sham iTBS+placebo are pooled. The iTBS+DCS group shows significantly greater improvement in YBOCS score (OCD Symptom Severity Score) compared to both iTBS+placebo and pooled sham groups. iTBS+DCS vs. iTBS+placebo *p<0.05 **p<0.01; iTBS+DCS vs. sham iTBS pooled ##p<0.01, ###p<0.001. Error bars indicate standard error of the mean. [Diagram 3]Data from a double-blind placebo and sham-controlled randomized controlled study in moderate to severe OCD patients as shown in Figure 1. The iTBS+DCS group showed significantly greater improvement compared to the sham-iTBS group as measured by the Clinical Global Impression-Improvement scale (CGI-I), while the iTBS+placebo group showed no improvement. iTBS+DCS vs. Sham-iTBS pooled. **p<0.01. Error bars indicate standard error of the mean. [Figure 4] Data from a double-blind placebo and sham-controlled randomized controlled study in moderate to severe OCD patients as shown in Figure 1. The iTBS+DCS group showed significantly greater improvement in depression (MADRS) scores compared to the sham iTBS group, while the iTBS+placebo group showed no improvement. iTBS+DCS vs. sham iTBS pooled. **p<0.01. Error bars indicate standard error of the mean. [Diagram 5] Data from a double-blind placebo- and sham-controlled randomized controlled trial in moderate to severe OCD patients are shown in Figure 1. The Wisconsin Card Sorting Task captures executive function changes that have been consistently implicated in OCD, namely perseverative error rates. A two-way repeated measures ANOVA indicated a significant group x time interaction (F(2,10)=12.97, p=0.0017) where participants in the iTBS+DCS treatment, but not those in the iTBS+placebo or sham iTBS treatment, showed a significant decrease in perseverative error rates. Error bars indicate standard error of the mean. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Targeted neurostimulation therapies, such as TBS and other TMS protocols, involve delivering trains of stimuli to drive activity-dependent changes in the brain called synaptic plasticity. The efficacy of TBS depends on plasticity mechanisms and N-methyl-D-aspartate receptors. 16 However, there are several lines of evidence indicating that TMS-related plasticity is impaired in neuropsychiatric disorders. 21~23 , OCD is associated with consistent changes in cortical excitability as determined by TMS.24~29 Responsiveness to TBS, or high or low frequency stimulation, or a combination of both, may be improved by improving TMS-related plasticity in OCD patients.

[0017] Thus, one embodiment of the present invention provides an adjunct therapy to TBS and other TMS protocols to increase TMS-associated plasticity, optionally including increased microstructural changes including neurite density, changes in function and branching, and changes in neurometabolite concentrations.

[0018] Thus, in one embodiment, TBS, or high or low frequency stimulation, or a combination thereof. 30 Improvement of TMS-related plasticity by combining with adjunctive therapy is used in methods of treating OCD in a patient and / or methods of improving and / or alleviating and / or reducing the frequency of one or more symptoms of OCD, including obsessions and compulsions.

[0019] In one embodiment, improving TMS-related plasticity by TBS, or high or low frequency stimulation, or a combination thereof, in combination with adjunctive therapy, is used in a method of treating common comorbidities of OCD, including depression, and / or improving and / or alleviating and / or reducing the frequency of one or more symptoms of those comorbidities. One or more symptoms of depression include feelings of sadness, tearfulness, hopelessness, irritability, loss of purpose / lack of pleasure, memory loss, flat affect, sleep disorders, fatigue, loss of appetite and weight loss, and / or feelings of worthlessness.

[0020] In one embodiment, improving TMS-associated plasticity by TBS, or high or low frequency stimulation, or a combination thereof, in combination with adjunctive therapy is used in a method of improving or restoring cognitive flexibility, executive function, and / or working memory in an OCD patient and / or a method of improving or reversing or partially reversing cognitive impairment in an OCD patient.

[0021] In one embodiment, improving TMS-related plasticity by combining TBS, or high or low frequency stimulation, or a combination thereof, with adjunctive therapy is used in a method to reduce the risk of suicide or suicidal ideation in an OCD patient. In some embodiments, the patient has a history of suicide attempts.

[0022] Suitable TBS protocols are known in the art and include protocols with evidence of efficacy from sham-controlled comparisons. iTBS stimulation frequency is either constant for currently available technology (2 second train of 3 pulse 50 Hz bursts at 5 Hz, trains every 10 seconds) or continuous for cTBS (3 pulse 50 Hz bursts continuously at 5 Hz). The total number of pulses per treatment and treatment intensity can vary. The number of pulses per treatment is about 600 to about 1800. In some embodiments, each treatment includes 600 pulses. In other embodiments, each treatment includes 1200 pulses. In yet other embodiments, each treatment includes 1800 pulses. Intensity can vary from about 80% to about 120% of motor threshold. In a preferred embodiment, the intensity is about 80% to 90% of motor threshold (rMT).

[0023] Suitable high-frequency stimulation protocols are known in the art and include protocols with sham-controlled evidence of efficacy. High-frequency stimulation protocols include trains of about 40 pulses at 5 Hz or higher, with impulse train intervals of about 10-30 seconds. Intensity may vary from about 80% to about 120% of motor threshold. In a preferred embodiment, intensity is about 100% to 120% of resting motor threshold.

[0024] Suitable high-frequency stimulation protocols are known in the art and include protocols with sham-controlled evidence of efficacy. Low-frequency stimulation protocols include pulse trains at about 1 Hz ranging from 300 to 2400 pulses. Intensity can vary from about 80% to about 120% of motor threshold. In a preferred embodiment, the intensity is about 100% to 120% of resting motor threshold.

[0025] In some embodiments, one iTBS treatment is administered daily, while in other embodiments, multiple iTBS treatments are administered daily, optionally between 2 and 10 treatments daily.

[0026] In some embodiments, iTBS, cTBS and other TMS protocols are delivered over 1-52 weeks of treatment, hi some embodiments, iTBS continues to be provided after the course of acute treatment to prevent relapse.

[0027] Synaptic plasticity associated with TBS, or high-frequency or low-frequency stimulation, or a combination of both, has been shown to mediate the activation of ionotropic glutamate receptors, which play a key role in plasticity. 32 , which requires NMDAR signaling 16、31 Upon glutamate binding, this tetrameric receptor can initiate membrane depolarization and, through calcium signaling, initiate intracellular messenger cascades, gene expression, and protein synthesis, altering the strength of synaptic connections. 33 Cell surface expression of NMDARs is itself dynamically regulated, providing a secondary mechanism for long-term regulation of synaptic strength in a manner specific to acute and chronic stress. 34、35 Thus, in one embodiment of the present invention, the adjunctive therapy of TBS, or high or low frequency stimulation, or a combination thereof, is to increase TMS-related plasticity through NMDAR signaling. 16、31

[0028] In one embodiment, TBS, or high or low frequency stimulation, or a combination thereof, in combination with an NMDAR agonist or partial agonist is used in a method for reducing the risk of suicide or suicidal ideation in an OCD patient. In some embodiments, the patient has a history of suicide attempts.

[0029] In some embodiments of the invention, using an NMDAR agonist or partial agonist as adjunctive therapy to TBS, or high or low frequency stimulation, or a combination thereof, the NMDAR agonist or partial agonist is provided immediately prior to or concurrently with each treatment.

[0030] D-Cycloserine (DCS) is a partial NMDAR agonist that preferentially binds to the glycine site of the NR2C NMDAR subunit 36、37 .

[0031] In one embodiment, TBS, or high or low frequency stimulation, or a combination thereof, in combination with D-cycloserine (DCS) is used in a method of treating OCD in a patient and / or to ameliorate and / or alleviate and / or reduce the frequency of one or more symptoms of OCD.

[0032] In one embodiment, TBS, or high or low frequency stimulation, or a combination thereof, in combination with D-cycloserine (DCS) is used in a method to improve global cognitive function and / or improve / ameliorate specific cognitive deficits in working memory or executive function / cognitive control in OCD patients.

[0033] In one embodiment, TBS, or high or low frequency stimulation, or a combination thereof, in combination with D-cycloserine (DCS) is used in a method to reduce the risk of suicide or suicidal ideation in an OCD patient. In some embodiments, the patient has a history of suicide attempts.

[0034] Thus, one embodiment of the present invention provides D-cycloserine (DCS) as an adjunct therapy to TBS, or high or low frequency stimulation, or a combination thereof, to increase TMS-related plasticity.

[0035] In an embodiment of the present invention, DCS is provided as a daily dose immediately before or simultaneously with daily TBS, or high or low frequency stimulation, or a combination thereof, for 1-52 weeks. In some embodiments, DCS is provided less than 15 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, about 120 minutes, or about 360 minutes before iTBS treatment. Optionally, the timing of TBS, or high or low frequency stimulation, or a combination thereof, treatment depends on the plasma level of DCS. Thus, in some embodiments, the plasma level of DCS must be above a minimum threshold before the start of iTBS or cTBS treatment. Optionally, the minimum threshold is 10 μg / mL.

[0036] In some embodiments, the methods of the present invention include low dose D-cycloserine (DCS). Low dose D-cycloserine (DCS) includes a dose of DCS ranging from about 1 to 250 mg. In a preferred embodiment, the dose ranges from about 50 mg to about 150 mg of DCS. The appropriate dose of D-cycloserine may be based on the patient's weight or may result in a plasma concentration of 1 to 30 μg / mL. Optionally, the plasma concentration of D-cycloserine is assessed prior to treatment with TBS, or high or low frequency stimulation, or a combination thereof.

[0037] In some embodiments, D-cycloserine is provided as a pharma- ceutically acceptable salt of D-cycloserine, a pharma- ceutically acceptable ester of D-cycloserine, an alkylated D-cycloserine, or a pharma- ceutically acceptable precursor of D-cycloserine.

[0038] In some embodiments, D-cycloserine is provided as a pharmaceutical composition, which may include a pharma- ceutically acceptable carrier or diluent.

[0039] Pharmaceutical compositions containing D-cycloserine can be administered to a patient by any one or combination of several routes, including oral, intravenous, transmucosal (e.g., nasal, intravaginal, etc.), pulmonary, transdermal, intraocular, buccal, sublingual, intraperitoneal, intrathecal, or intramuscular. In some embodiments, the pharmaceutical compositions are formulated for rapid absorption and distribution.

[0040] Oral, sublingual or buccal pharmaceutical formulations are preferred, such as tablets, capsules, sprinkle formulations and oral suspensions. In some embodiments, solid compositions for oral administration may contain suitable carriers or excipients, such as cornstarch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginic acid, or controlled slow release materials. Disintegrants that can be used include, without limitation, microcrystalline cellulose, cornstarch, sodium starch glycolate and alginic acid. Tablet binders that can be used include, without limitation, acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (povidone), hydroxypropylmethylcellulose, sucrose, starch, and ethylcellulose. EXAMPLES

[0041] D-Cycloserine stabilizes motor plasticity after a single or spaced repeated treatment following transcranial magnetic TBS.

[0042] We completed a randomized, double-blind, placebo-controlled, crossover study in healthy participants to evaluate whether the NMDA-R partial agonist, D-cycloserine, could enhance TMS motor plasticity following single and spaced TBS treatments.

[0043] Methods: A randomized, double-blind, placebo-controlled crossover study in healthy participants (n=20) was conducted (NCT05081986). Participants completed the study in two separate experimental sessions. In these experiments, TMS intermittent theta burst stimulation (iTBS) was used to stimulate the motor cortex twice, with a 1-hour interval between interventions. In random order, this was supplemented with placebo or D-cycloserine (100 mg), then reversed at least 1 week later.

[0044] Neuronavigation software (ANT Neuro, Germany) was used to register participants' surface anatomical markers to template magnetic resonance brain images, allowing neuronavigation and reliable targeting throughout the experiment. Transcranial magnetic stimulation involved a MagPro X100 system (MagVenture, Denmark) with a Cool-B70 figure-of-eight coil. The iTBS protocol consisted of 20 trains of bursts of 3 pulses at 50 Hz repeated at 5 Hz with an 8 s impulse train interval at 80% RMT.

[0045] Stimulus-response curves were characterized by sampling motor evoked potentials (MEPs) from the first dorsal interosseous muscle using CED Signal (Cambridge, UK) before and after iTBS. Stimulus-response curves (SRCs) were obtained by delivering TMS pulses at 0.25 Hz and randomly varying the stimulation intensity between 100 and 150% of the resting motor threshold (RMT). A total of 10 pulses were delivered for each stimulation intensity. Stimulus-response curves (SRCs) were characterized at baseline, +30 and +60 min after the first iTBS, then +30 and +60 min after the second iTBS.

[0046] Using MATLAB® with custom written scripts as previously described 123EMG data were analyzed offline. Mean-corrected peak-to-peak amplitudes in a 100 ms window before the TMS pulse were isolated. EMG traces were examined individually before inclusion in the analysis. For analysis, we determined changes in recruitment curves by characterizing the slope of the SRC sigmoidal function. For graphical representation, these were normalized by the slope of the baseline SRC.

[0047] Results: Referring to Figure 1, after the first iTBS in the placebo condition, the SRC shifts transiently at +30 min, then returns to baseline at +60 min. In the DCS condition, the initial SRC shift at +30 min remains stable at +60 min. A second iTBS delivered 60 min after the first SRC produced no change in the placebo condition, but a further shift in the SRC slope at +30 min in the DCS condition persisted at +60 min.

[0048] Conclusions: NMDA-R agonist activity leads to lasting synaptic plasticity as measured by stimulus-response curves following single and spaced repeated iTBS interventions. EXAMPLES

[0049] Combining DCS with iTBS enhances clinical outcomes in OCD.

[0050] The efficacy of 100 mg DCS as an adjunct strategy to iTBS was examined in a randomized, double-blind, 4-week study with both placebo- and sham-controlled arms with a 1-month follow-up after treatment. The study was a double-blind, randomized, placebo- and sham-controlled study with a 1-month follow-up after treatment, registered with clinicaltrials.gov and conducted in accordance with Good Clinical Practice standards.

[0051] Reductions in OCD and depressive symptoms in iTBS+DCS participants from baseline to completion of the double-blind treatment phase will be compared to iTBS+placebo and sham-iTBS treatment participants.

[0052] Participants were randomized 2:2:1:1 to one of four conditions: 1) real stimulation iTBS+DCS, 2) real stimulation iTBS+placebo, 3) sham iTBS+DCS, or 4) sham iTBS+placebo. In this study, we utilized a MagPro X100 (MagVenture, Denmark) TMS device in combination with a Cool D-B80A / P coil capable of delivering sham and real stimulation. Participants received either daily iTBS+cycloserine, iTBS+placebo, sham iTBS+cycloserine, or sham iTBS+placebo once every weekday for 4 weeks (20 rTMS sessions). Prior to the first treatment, the motor threshold (MT) of each subject would first be determined using established methods of neuronavigation-directed TMS over the primary motor cortex. A short stimulation procedure called motor threshold testing was performed to determine the appropriate intensity of rTMS. The RMT was defined as the minimum stimulation intensity required to elicit involuntary movement of the contralateral extensor hallucis longus in at least 5 out of 10 trials.

[0053] The iTBS protocol included 50 Hz bursts repeated at 5 Hz; 2 s on and 8 s off; 600 pulses per session delivered at 80% rMT. 38 This was the stimulation intensity utilized in our pilot exercise physiology data. MPFC was targeted by advancing the coil 4 cm anterior to the extensor hallucis longus motor cortical representation.

[0054] DCS was a placebo control repackaged into 100 mg capsules. Capsules were taken orally 2 hours before each treatment. 39 .

[0055] Participants received daily TMS (Monday to Friday) in combination with an oral placebo control oral compound for four weeks.

[0056] Participants were assessed by clinicians at baseline, 2 weeks, and 4 weeks. Self-report measures were obtained weekly during the double-blind phase. Long-term follow-up for real-stimulation iTBS-treated participants was scheduled for 1 month after the end of treatment. To mitigate unblinding of sham-treated participants, non-responders (≥30% improvement on YBOCS) were offered 4 weeks of open-label treatment.

[0057] The primary efficacy outcome was clinician-rated change in OCD symptoms using the YBOCS after 4 weeks of treatment. Secondary efficacy outcomes at 4 weeks included assessment of clinical response (≥30% reduction in YBOCS score), improvement in Clinical Global Impressions and depressive symptoms MADRS, and efficacy over the 1-month follow-up phase.

[0058] Results: With reference to FIG. 2, there is a clinically meaningful statistical separation in the YBOCS scale of OCD symptoms in favor of the iTBS+DCS group compared to both the iTBS+placebo and sham-iTBS groups. These effects were seen during the acute treatment period and persisted over one month. With reference to FIG. 3, these improvements were paralleled by greater overall improvement in the iTBS+DCS group as measured by the Clinician-rated Clinical Global Impressions Scale. With reference to FIG. 4, depressive symptoms as measured by the MADRS improved significantly more in the iTBS+DCS group.

[0059] Conclusions: Adjunctive DCS combined with iTBS improves OCD symptoms, depression symptoms, and global functioning compared with iTBS + placebo and sham-iTBS.

[0060] Example 3: Combining DCS with iTBS reduces OCD-related cognitive impairment.

[0061] The efficacy of 100 mg DCS as an adjunct strategy to iTBS to reduce OCD-related cognitive impairment and / or improve cognition in OCD was tested in a randomized, double-blind, 4-week study described in the Examples above.

[0062] Participants completed the Wisconsin Card Sorting Task at baseline and after 4 weeks of treatment. Planned objectives were to measure executive function, cognitive flexibility, and perseverative error rates as an index of cognitive control.

[0063] Results: Referring to FIG. 5, the group treated with iTBS+DCS showed a decrease in perseverative error rate, and the slope of this relationship was significantly different compared to the change in perseverative error rate in the iTBS+placebo and sham groups.

[0064] Conclusions: Adjunctive DCS combined with iTBS improves executive function and cognitive control in OCD compared with iTBS + placebo and sham-iTBS.

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[0066] While the present invention has been described with reference to certain specific embodiments, various modifications thereof will be apparent to those skilled in the art without departing from the spirit and scope of the invention. All such modifications as would be apparent to those skilled in the art are intended to be included within the scope of the following claims.

Claims

1. A therapeutic agent for obsessive-compulsive disorder (OCD), for use in the use of optionally intermittent or continuous theta burst stimulation, high-frequency or low-frequency stimulation, and combinations thereof, to augment transcranial magnetic stimulation (TMS) therapy for OCD, the therapeutic agent for obsessive-compulsive disorder (OCD) comprising an effective amount of supplemental D-cycloserine or a pharmaceutically acceptable ester of D-cycloserine, or an alkylated D-cycloserine, or a pharmaceutically acceptable precursor of D-cycloserine, to improve and / or alleviate and / or reduce the frequency of one or more symptoms of OCD.

2. An OCD treatment and / or OCD improvement and / or OCD relief and / or OCD frequency reducer for use in administering to a patient transcranial magnetic stimulation, optionally intermittent or continuous theta burst stimulation, high frequency or low frequency stimulation, or combinations thereof, the OCD treatment and / or OCD improvement and / or OCD relief and / or OCD frequency reducer comprising a low dose of 1 to 250 mg of D-cycloserine.

3. The OCD therapeutic agent and / or OCD ameliorating agent and / or OCD alleviating agent and / or OCD frequency reducing agent according to claim 2, wherein the low dose is a dose of D-cycloserine sufficient to achieve a plasma D-cycloserine concentration of 1 to 30 μg / mL.

4. The OCD therapeutic agent and / or OCD improving agent and / or OCD alleviating agent and / or OCD frequency reducing agent according to claim 2, wherein the patient is subjected to intermittent or continuous theta burst stimulation, high-frequency or low-frequency stimulation, or a combination thereof when the plasma D-cycloserine concentration is 1 to 30 μg / mL.

5. A transcranial magnetic stimulation adjunct containing D-cycloserine or an N-methyl-D-aspartate receptor agonist or a partial N-methyl-D-aspartate receptor agonist as an active ingredient, which improves symptoms of OCD including obsessions and compulsions and is used when optionally using intermittent or continuous theta burst stimulation, high-frequency or low-frequency stimulation, and combinations thereof.

6. An OCD therapeutic agent and / or OCD improving agent and / or OCD alleviating agent and / or OCD frequency reducing agent, comprising D-cycloserine formulated to achieve a peak plasma level of 1 to 30 μg / mL within 6 hours to support adjunctive use in the treatment of OCD using transcranial magnetic stimulation, optionally intermittent or continuous theta burst stimulation, high-frequency or low-frequency stimulation, and combinations thereof.

7. An agent for improving OCD cognitive impairment, including executive function and cognitive control, for use in patients receiving transcranial magnetic stimulation, optionally intermittent or continuous theta burst stimulation, high-frequency or low-frequency stimulation, and combinations thereof, the agent comprising a low dose of D-cycloserine.

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