Intranasal Esketamine Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder with Comorbid Major Depressive Disorder: A Case Series of Eight Patients

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To our knowledge, no published case series has focused on intranasal esketamine in patients with both treatment-resistant obsessive–compulsive disorder (TR‑OCD) and comorbid major depression (MD). Methods: We present eight adult cases at Bellvitge University Hospital who met criteria for TR‑OCD with comorbid MD and received intranasal esketamine augmentation between summer 2023 and 2024. Eligibility required inadequate response to at least two adequate SSRI trials, clomipramine plus one pharmacological augmentation strategy, Y‑BOCS ≥24, and MADRS ≥35. Esketamine was administered intranasally at 56–84 mg per session according to standard protocol for 12 weeks. Response for OCD was defined as ≥35% reduction from baseline Y‑BOCS; depression response as ≥50% reduction from baseline MADRS; depression remission as MADRS ≤10 at endpoint. Results: The mean MADRS score decreased from 37.5±3.8 at baseline to 19.8±13.3 at Week 12 (t(7)=4.55, p=0.0026), reflecting a 48.8% improvement. Y‑BOCS scores declined from 30.1±4.8 to 21.3±8.0 (t(7)=4.16, p=0.0042), a 30.4% reduction. Four participants (50.0%) achieved depression response, of whom two (25.0%) achieved remission; three participants (37.5%) met the OCD response criterion. Conclusions: Esketamine augmentation may exert dual efficacy in reducing both depressive and obsessive–compulsive symptoms in TR‑OCD with comorbid MD. Prospective controlled trials are warranted to confirm these preliminary findings, refine dosing and frequency, and evaluate the role of concurrent psychotherapy in sustaining gains. Obsessive–compulsive disorder Treatment-resistant Major depressive disorder Comorbidity Intranasal esketamine augmentation Figures Figure 1 Introduction Obsessive–compulsive disorder (OCD) is a chronic and disabling condition characterized by persistent, intrusive obsessions and compulsive behaviors that markedly impair daily functioning [ 1 ]. Despite the availability of established first‑line treatments—namely high‑dose selective serotonin reuptake inhibitors (SSRIs), and cognitive‑behavioral therapy (CBT) with exposure and response prevention (ERP)—approximately 40–60% of patients do not achieve sufficient symptom relief after an initial SSRI trial, and an additional 30–40% continue to be symptomatic despite further treatment, thereby meeting criteria for treatment‑resistant OCD (TR‑OCD) [ 2 , 3 ]. Functional impairment resulting from OCD increases significantly when patients suffer from comorbid Major Depression (MD), a quite common clinical situation. This comorbidity, the most frequent among patients with OCD, exacerbates symptom severity, delays functional recovery, and increases the risk of suicide [ 4 ]. Traditional augmentation strategies against OCD, such as the addition of low‑dose antipsychotics, have provided only modest improvements in these challenging cases [ 5 ]. The limited efficacy of serotonergic- and dopaminergic-based pharmacotherapies in some individuals with OCD and MDD suggests the involvement of additional neurotransmitter systems in their neurobiology and treatment. In this sense, recent research has increasingly implicated glutamatergic dysfunction in the pathophysiology of both OCD and MD [ 6 , 7 ]. Alterations in N‑methyl‑D‑aspartate (NMDA) receptor activity appear to contribute significantly to these disorders, as well as to their response to treatment (reviewed in [ 8 ]). Ketamine, an NMDA receptor antagonist, has demonstrated rapid and robust antidepressant effects [ 9 ] and may also modulate the cortico‑striato‑thalamo‑cortical circuits that underlie obsessive–compulsive symptoms [ 10 ]. Although the potential antidepressive benefits of intravenous (IV) ketamine have been studied extensively, its invasive administration limits broader clinical application. In contrast, intranasal esketamine offers a less invasive alternative and has already shown efficacy in treatment‑resistant depression [ 11 ]. A retrospective chart review has also recently reported promising anti‑obsessional effects following a single‑dose of subcutaneous or IV esketamine infusion in patients with OCD [ 12 ]. In this sense, investigations in pediatric populations [ 13 ] and recent literature reviews [ 14 ] have underscored the therapeutic potential of targeting the glutamatergic system in OCD. Neuroimaging data suggest that glutamatergic modulation may facilitate fear extinction and enhance CBT outcomes in OCD [ 15 ] and augmentation of exposure‑based CBT with d‑cycloserine (a partial agonist of NMDA glutamate receptors) has been explored as a potential tool to improve outcomes in OCD and related disorders [ 16 ]. To address the gap in evidence regarding the use of intranasal esketamine in patients with TR‑OCD and comorbid major depression, we conducted a prospective case series at Bellvitge University Hospital, a specialized referral center with a dedicated OCD Unit. Eight adult patients, all of whom had failed to respond to at least two adequate trials of SSRIs, CBT, clomipramine and an augmentation strategy with atypical antipsychotics and exhibited a Montgomery–Åsberg Depression Rating Scale (MADRS) [ 17 ] score of ≥ 35 and a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) [ 18 , 19 ] ≥ 24 (considered the threshold for severe major depression and severe OCD), were enrolled between summer 2023 and 2024. Patients received intranasal esketamine at doses ranging from 56 to 84 mg per session according to the approved usual antidepressant protocol. We evaluated their baseline clinical characteristics, as well as 12-week changes in obsessive–compulsive and depressive symptom severity, and overall treatment tolerability. The aim of this study is to generate preliminary data that may inform future controlled trials on optimal dosing regimens in this complex, comorbid population. Patients and methods (*Clinical trial number: not applicable.) Study setting and participants The Psychiatry Department at Bellvitge University Hospital is a recognized referral center in Catalonia for the diagnosis and treatment of adult OCD, evaluating approximately 300 new patients per year from across Catalonia and other regions of Spain. We consecutively recruited eight adult patients between July 2023 and August 2024 who met all the following criteria: Primary DSM-5 diagnosis of OCD with a baseline Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) total score ≥ 24. Co-occurring major depressive episode with a Montgomery–Åsberg Depression Rating Scale (MADRS) score ≥ 35. Inadequate response to at least two adequate trials of selective serotonin reuptake inhibitors (SSRIs), cognitive–behavioral therapy (CBT) including exposure and response prevention (ERP), and clomipramine, plus at least one pharmacological augmentation strategy (e.g., low-dose antipsychotic). Treatment protocol Eligible patients initiated intranasal esketamine augmentation to their existing psychopharmacological regimen, with doses ranging from 56 to 84 mg per session according to the approved treatment protocol for treatment-resistant depression. The induction phase consisted of two sessions per week for approximately four weeks, followed by once-weekly sessions until Week 12, with adjustments based on symptom evolution and clinician judgment. Concomitant medications, including SSRIs and antipsychotics, were maintained throughout the study. Assessments and data collection Demographic information, OCD resistance level according to the Pallanti–Quercioli proposal, total number of intranasal esketamine sessions, and adverse events recorded by clinicians were collected for each patient. Symptom severity and clinical status were evaluated at baseline, Week 1, Week 4, Week 8, and Week 12 (or last observation if dropout occurred) using: Y-BOCS: to assess OCD severity. Y-BOCS Symptom Checklist: to characterize obsessive–compulsive symptom dimensions. MADRS: to evaluate depressive symptom severity. Clinical Global Impression–Severity (CGI-S): to rate global illness severity. Detailed demographic and baseline clinical characteristics of the sample are presented in Table 1 . Response and remission criteria For OCD, response was defined as a ≥ 35% reduction from baseline Y-BOCS. For depression, response was defined as a ≥ 50% reduction from baseline MADRS, and remission as a MADRS total score ≤ 10 at endpoint. Statistical analysis Primary analyses compared baseline versus Week 12 scores for MADRS and Y‑BOCS using two‑sided paired t‑tests. We report mean change (points), 95% confidence intervals, p‑values, and within‑subject effect sizes (Cohen’s dz and Hedges’ gav). Non‑parametric sensitivity analyses used Wilcoxon signed‑rank tests. Statistical significance was set at two‑sided p < 0.05. No multiplicity correction was applied given the exploratory design and n = 8. Ethics statement The study was conducted in accordance with the Declaration of Helsinki and was approved by the Clinical Research Ethics Committee of Bellvitge University Hospital. All participants provided written informed consent prior to participation. Table 1 Baseline demographic, clinical, and treatment characteristics of the study sample (n = 8). Values are presented as individual patient data. Abbreviations: BZD = Benzodiazepine; CBT-ERP = Cognitive Behavioral Therapy with Exposure and Response Prevention; DLP = Dyslipidemia; ESK = Esketamine; GAD = Generalized Anxiety Disorder; HT = Hypertension; IBS = Irritable Bowel Syndrome; IN-ESK = Intranasal Esketamine; MADRS = Montgomery–Åsberg Depression Rating Scale; OCD = Obsessive-Compulsive Disorder; PTSD = Post-Traumatic Stress Disorder; SSRI = Selective Serotonin Reuptake Inhibitor; TCA = Tricyclic Antidepressant; Y-BOCS = Yale-Brown Obsessive-Compulsive Scale. Id Sex Age Main OCD symptoms Pallanti Severity Index/resistance level Comorbidities (Medical / Psych) MADRS wk0 YBOCS wk0 CGI wk0 Past Augmentations Duration of Illness (years) Total Sessions Final Esketamine Dose (mg) MADRS wk12 YBOCS wk12 CGI wk12 1 M 49 Contamination 3 Hypertension / Social Anxiety Disorder, MDD 35 24 5 SSRI + Antipsychotic, CBT-ERP 7 12 84 4 16 2 2 F 37 Moral (Scrupulosity) 3 Fibromyalgia / Generalized Anxiety Disorder, MDD 35 28 4 SSRI + TCA, CBT-ERP 10 10 84 5 12 1 3 M 47 Checking 4 MDD 35 32 6 SSRI + BZD, CBT-ERP 4 8 56 20 30 5 4 M 59 Contamination 4 Hypothyroidism / Panic Disorder, MDD 40 36 7 Clomipramine + Antipsychotic, CBT-ERP 8 12 84 22 18 2 5 F 44 Moral (Scrupulosity) 3 IBS / PTSD, MDD 40 28 4 SSRI + Antipsychotic, CBT-ERP 6 6 56 16 16 2 6 F 36 Checking 4 MDD 35 34 6 SSRI + TCA + BZD, CBT-ERP 9 11 84 30 32 6 7 M 60 Checking 4 HT, DLP, MDD 45 35 7 SSRI, CBT-ERP 5 9 56 45 30 7 8 F 46 Contamination 3 Epilepsy, fibromyalgia, MDD 35 24 5 SSRI + Lithium, CBT-ERP 10 5 56 16 14 3 Results Symptom severity and treatment response were assessed at baseline, Week 1, Week 4, Week 8, and Week 12 (or last observation if dropout occurred) using the Y-BOCS, Y-BOCS Symptom Checklist, MADRS, and CGI-S. For OCD, response was defined as a ≥ 35% reduction from baseline Y-BOCS. For depression, response was defined as a ≥ 50% reduction from baseline MADRS, and remission as a MADRS score ≤ 10 at endpoint. Temporal pattern of improvement Clinically, depressive symptoms tended to improve rapidly, with most MADRS reduction observed within the first four weeks and sustained thereafter. In contrast, OCD symptoms generally showed slower and more heterogeneous change: minor reductions were often noted by Week 4, with more consistent improvement emerging between Weeks 8 and 12 in responders. Statistical outcomes From baseline to Week 12, MADRS decreased from 37.5 ± 3.78 to 19.75 ± 13.32 (mean change 17.75, 95% CI 8.53–26.97; t(7) = 4.55, p = 0.0026; Cohen’s dz = 1.61). Y-BOCS decreased from 30.13 ± 4.79 to 21.25 ± 8.00 (mean change 8.88, 95% CI 3.83–13.92; t(7) = 4.16, p = 0.0042; Cohen’s dz = 1.47). Mean percentage improvements were 48.8% (MADRS) and 30.4% (Y-BOCS). Wilcoxon signed-rank tests corroborated these results (MADRS p = 0.018; Y-BOCS p = 0.0078). CGI-S decreased from 5.50 ± 1.20 at baseline to 3.50 ± 2.20 at Week 12 (mean change − 2.00, 95% CI − 3.41 to − 0.59; t(7) = 3.35, p = 0.012; Cohen’s dz = 1.18). Response rates Four of eight participants (50.0%) met MADRS response criteria, and two of these (25.0%) achieved remission. Three of eight participants (37.5%) met the OCD response criterion. Wilson 95% CIs were [0.215, 0.785] for MADRS response, [0.071, 0.591] for MADRS remission, and [0.137, 0.694] for Y-BOCS response. Figure 1 depicts individual trajectories and group means for MADRS and Y-BOCS. The earlier, steeper slope in MADRS curves reflects the more rapid antidepressant effect, while Y-BOCS curves illustrate the slower onset of OCD symptom improvement. Tolerability and adverse events No severe adverse events were documented. Four participants (50%) reported transient dissociative experiences, typically subsiding spontaneously within 20–30 minutes. One (12.5%) experienced moderate nausea. None withdrew because of adverse events. Discussion To our knowledge, this is the first study to systematically investigate repeated intranasal esketamine augmentation in patients with treatment-resistant obsessive–compulsive disorder (OCD) and comorbid major depression. The results indicate that repeated intranasal esketamine was associated with clinically meaningful reductions in obsessive–compulsive and depressive symptoms for five of the eight participants. The observed 48.8% mean reduction in depressive symptoms aligns with prior reports of esketamine's antidepressant efficacy in treatment-resistant depression [ 5 ]. Importantly, 50% of participants exceeded the 50% response threshold on MADRS, suggesting a robust clinical effect. The 30.4% average reduction in obsessive–compulsive symptoms, with 37.5% of patients reaching clinical response levels (≥ 35% Y-BOCS reduction), provides preliminary support for esketamine’s anti-obsessional potential. Notably, individual trajectories revealed that improvement in OCD symptoms was more variable and occurred more gradually compared to the more rapid and consistent antidepressant effects. These findings suggest a promising dual effect of intranasal esketamine, though further randomized controlled trials are needed to establish long-term efficacy, optimal treatment regimens, and durability of response. These findings extend earlier single-dose subcutaneous or intravenous esketamine studies [ 12 ] by demonstrating potential benefits of a repeated intranasal protocol in a patient cohort with pronounced depressive symptoms. This study provides an incremental step toward clarifying how the administration route and dosing schedule might be optimized for individuals with refractory OCD and major depression. Furthermore, our findings provide further evidence that dysregulation of glutamatergic transmission is central to the neurobiological underpinnings of both obsessive-compulsive disorder and major depressive disorder. As discussed earlier in this paper, previous work has documented alterations in glutamate signalling associated with these conditions [ 6 , 7 ]. The rapid and significant improvements observed in MADRS scores, and the more gradual yet clinically relevant reductions in Y-BOCS scores, are consistent with the hypothesis that modulating glutamatergic activity can alleviate symptoms across these disorders, albeit with different response timelines. Future studies employing neuroimaging and biomarker assessments will be critical to further elucidate these mechanisms and to optimize glutamate-targeted interventions. Differences in OCD symptom dimensions or other clinical factors may influence treatment trajectories, and future investigations would benefit from detailed characterization of individual symptom profiles. Furthermore, the potential effects of structured exposure and response prevention (ERP) therapy in combination with intranasal esketamine were not assessed in our protocol and might constitute a useful and novel strategy. Esketamine could potentially enhance response to ERP in OCD patients with comorbid MDD, since depression often interferes with the motivation to engage in exposure tasks [ 2 , 4 ]. Trials integrating pharmacologic strategies with established psychotherapeutic interventions could help clarify the degree of synergy between these approaches and whether this combination could accelerate or potentiate the anti-obsessional effect observed over the longer term. Our preliminary results suggest that depressive symptoms may respond earlier and more robustly to repeated intranasal esketamine than obsessive-compulsive symptoms. Esketamine’s rapid antidepressant properties could facilitate greater adherence and reduce patient dropout, possibly by improving factors such as anhedonia or hopelessness. Further research is warranted to determine whether faster reduction in depressive symptoms translates to sustained long-term improvements and whether dosing schedules can be optimized to target both obsessive-compulsive and depressive dimensions effectively. Repeated intranasal esketamine was generally well tolerated in this sample. No serious adverse events were reported, and overall side effects were manageable, indicating that this approach could feasibly be implemented in specialized psychiatric settings. Future investigations should consider clinical, neurobiological, or other biomarkers of response to optimize patient selection and inform personalized treatment plans. A more precise understanding of which patients are most likely to benefit may lead to improved outcomes in complex presentations of OCD and major depression. Several limitations must be noted. The small sample size, observational design, and absence of randomization restrict the generalizability of the findings and preclude definitive conclusions regarding causality. Moreover, the lack of a control condition makes it difficult to ascertain whether the observed effects are attributable to esketamine itself or to nonspecific factors such as increased clinical contact. The focus on relatively short-term outcomes (12 weeks) does not clarify the durability of symptom improvement or the potential need for maintenance dosing. Finally, we did not track adjunctive psychotherapies, limiting conclusions about the interplay between pharmacological and behavioral interventions. Future research should involve larger randomized prospective trials to replicate and expand upon these preliminary observations, explore extended or maintenance dosing regimens, and identify predictors of positive response in refractory OCD with comorbid major depression. Incorporating evidence-based OCD interventions (e.g., ERP) into study protocols would help disentangle medication-specific effects from those of concurrent psychotherapy. The use of validated measures of functional outcomes and quality of life would further enrich assessments of real-world clinical impact. Continued efforts in this area may advance treatment strategies for the considerable subgroup of patients who experience persistent and impairing obsessive-compulsive symptoms alongside major depressive disorder. Conclusions This case series provides preliminary evidence that repeated intranasal esketamine augmentation (56–84 mg/session) can produce clinically meaningful improvement in both depressive and obsessive–compulsive symptoms in patients with severe, treatment-resistant OCD comorbid with major depression. The antidepressant effect appeared rapidly, whereas the anti-obsessional effect emerged more gradually, underscoring the importance of sustained treatment and tailored follow-up. These findings address a notable gap in the current literature, which has been dominated by intravenous ketamine studies, and suggest that intranasal administration could be a viable, more accessible alternative. Robust prospective research—including randomized controlled trials and integration with structured ERP—is needed to optimize treatment protocols, identify predictors of response, and clarify the role of intranasal esketamine in the long-term management of refractory OCD–MDD. Abbreviations BZD Benzodiazepine CBT-ERP Cognitive–behavioral therapy with exposure and response prevention CGI-S Clinical Global Impression–Severity DLP Dyslipidemia HTN Hypertension IBS Irritable bowel syndrome MADRS Montgomery–Åsberg Depression Rating Scale MDD Major depressive disorder NMDA N-methyl-D-aspartate OCD Obsessive–compulsive disorder SSRI Selective serotonin reuptake inhibitor TCA Tricyclic antidepressant TR-OCD Treatment-resistant obsessive–compulsive disorder Y-BOCS Yale–Brown Obsessive Compulsive Scale Declarations Ethics approval and consent to participate The Bellvitge University Hospital Ethics Committee approved the study. All participants provided written informed consent prior to inclusion. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Funding No external funding was received for this work. Author Contribution SL-R and PA conceptualized the study; SL-R collected and interpreted clinical data, and drafted the initial manuscript. CS, ER, JMM, MU, and PA contributed to the clinical management patients, interpretation of findings, and manuscript reviews. PA provided critical revisions for intellectual content. All authors read and approved the final manuscript. Acknowledgement We thank the clinical and nursing teams of the Interventional Psychiatry and Neuromodulation Unit of the Bellvitge University Hospital for their support during patient assessment and intranasal esketamine administration. We are also grateful to the hospital pharmacy for logistical assistance with medication preparation and dispensing. Data Availability All data generated or analyzed during this study are included in this published article. 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Cite Share Download PDF Status: Published Journal Publication published 26 Apr, 2026 Read the published version in BMC Psychiatry → Version 1 posted Editorial decision: Revision requested 04 Mar, 2026 Reviews received at journal 01 Mar, 2026 Reviewers agreed at journal 01 Mar, 2026 Reviews received at journal 20 Sep, 2025 Reviewers agreed at journal 17 Sep, 2025 Reviewers agreed at journal 17 Sep, 2025 Reviewers invited by journal 17 Sep, 2025 Editor assigned by journal 15 Sep, 2025 Editor invited by journal 28 Aug, 2025 Submission checks completed at journal 28 Aug, 2025 First submitted to journal 28 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7417012","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":520683839,"identity":"340f2843-083b-4777-8bd6-b4694ee5d70e","order_by":0,"name":"Sergi 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15:27:43","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":70751,"visible":true,"origin":"","legend":"","description":"","filename":"68abd2325c964f6787093edc099e95231structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7417012/v1/7aa5a93fad9469bed4a9bd06.xml"},{"id":92274768,"identity":"dc6a070f-63a1-4a8b-8638-b53c28d4c49f","added_by":"auto","created_at":"2025-09-26 15:27:37","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":77489,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7417012/v1/bac84209b48f5fce2db0f92b.html"},{"id":92274766,"identity":"115aca1b-5ea5-4e4b-8d35-e9a736eb4ecd","added_by":"auto","created_at":"2025-09-26 15:27:37","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":258360,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in depressive and obsessive–compulsive symptoms over time. (A) Individual and mean Montgomery–Åsberg Depression Rating Scale (MADRS) scores. (B) Individual and mean Yale–Brown Obsessive Compulsive Scale (Y-BOCS) scores. Each colored line represents one participant (n = 8); the thick black line represents the sample mean at each timepoint. Depressive symptoms showed rapid improvement within the first month, whereas OCD symptom reduction was more gradual and heterogeneous, with more consistent gains emerging between Weeks 8 and 12.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7417012/v1/35b0a90f8c856f6ee7b240c0.jpeg"},{"id":107928068,"identity":"60e7dc70-26d5-4c9b-9772-a55e3c9d47fd","added_by":"auto","created_at":"2026-04-27 16:07:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":498009,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7417012/v1/dc842fe7-c393-46ca-9ea1-1c77342b6cfe.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Intranasal Esketamine Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder with Comorbid Major Depressive Disorder: A Case Series of Eight Patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eObsessive\u0026ndash;compulsive disorder (OCD) is a chronic and disabling condition characterized by persistent, intrusive obsessions and compulsive behaviors that markedly impair daily functioning [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite the availability of established first‑line treatments\u0026mdash;namely high‑dose selective serotonin reuptake inhibitors (SSRIs), and cognitive‑behavioral therapy (CBT) with exposure and response prevention (ERP)\u0026mdash;approximately 40\u0026ndash;60% of patients do not achieve sufficient symptom relief after an initial SSRI trial, and an additional 30\u0026ndash;40% continue to be symptomatic despite further treatment, thereby meeting criteria for treatment‑resistant OCD (TR‑OCD) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Functional impairment resulting from OCD increases significantly when patients suffer from comorbid Major Depression (MD), a quite common clinical situation. This comorbidity, the most frequent among patients with OCD, exacerbates symptom severity, delays functional recovery, and increases the risk of suicide [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Traditional augmentation strategies against OCD, such as the addition of low‑dose antipsychotics, have provided only modest improvements in these challenging cases [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe limited efficacy of serotonergic- and dopaminergic-based pharmacotherapies in some individuals with OCD and MDD suggests the involvement of additional neurotransmitter systems in their neurobiology and treatment. In this sense, recent research has increasingly implicated glutamatergic dysfunction in the pathophysiology of both OCD and MD [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Alterations in N‑methyl‑D‑aspartate (NMDA) receptor activity appear to contribute significantly to these disorders, as well as to their response to treatment (reviewed in [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]). Ketamine, an NMDA receptor antagonist, has demonstrated rapid and robust antidepressant effects [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and may also modulate the cortico‑striato‑thalamo‑cortical circuits that underlie obsessive\u0026ndash;compulsive symptoms [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although the potential antidepressive benefits of intravenous (IV) ketamine have been studied extensively, its invasive administration limits broader clinical application. In contrast, intranasal esketamine offers a less invasive alternative and has already shown efficacy in treatment‑resistant depression [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A retrospective chart review has also recently reported promising anti‑obsessional effects following a single‑dose of subcutaneous or IV esketamine infusion in patients with OCD [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In this sense, investigations in pediatric populations [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and recent literature reviews [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] have underscored the therapeutic potential of targeting the glutamatergic system in OCD. Neuroimaging data suggest that glutamatergic modulation may facilitate fear extinction and enhance CBT outcomes in OCD [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and augmentation of exposure‑based CBT with d‑cycloserine (a partial agonist of NMDA glutamate receptors) has been explored as a potential tool to improve outcomes in OCD and related disorders [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTo address the gap in evidence regarding the use of intranasal esketamine in patients with TR‑OCD and comorbid major depression, we conducted a prospective case series at Bellvitge University Hospital, a specialized referral center with a dedicated OCD Unit. Eight adult patients, all of whom had failed to respond to at least two adequate trials of SSRIs, CBT, clomipramine and an augmentation strategy with atypical antipsychotics and exhibited a Montgomery\u0026ndash;\u0026Aring;sberg Depression Rating Scale (MADRS) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] score of \u0026ge;\u0026thinsp;35 and a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u0026thinsp;\u0026ge;\u0026thinsp;24 (considered the threshold for severe major depression and severe OCD), were enrolled between summer 2023 and 2024. Patients received intranasal esketamine at doses ranging from 56 to 84 mg per session according to the approved usual antidepressant protocol. We evaluated their baseline clinical characteristics, as well as 12-week changes in obsessive\u0026ndash;compulsive and depressive symptom severity, and overall treatment tolerability. The aim of this study is to generate preliminary data that may inform future controlled trials on optimal dosing regimens in this complex, comorbid population.\u003c/p\u003e"},{"header":"Patients and methods (*Clinical trial number: not applicable.)","content":"\u003cp\u003eStudy setting and participants\u003c/p\u003e\u003cp\u003eThe Psychiatry Department at Bellvitge University Hospital is a recognized referral center in Catalonia for the diagnosis and treatment of adult OCD, evaluating approximately 300 new patients per year from across Catalonia and other regions of Spain. We consecutively recruited eight adult patients between July 2023 and August 2024 who met all the following criteria:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003ePrimary DSM-5 diagnosis of OCD with a baseline Yale\u0026ndash;Brown Obsessive\u0026ndash;Compulsive Scale (Y-BOCS) total score\u0026thinsp;\u0026ge;\u0026thinsp;24.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eCo-occurring major depressive episode with a Montgomery\u0026ndash;\u0026Aring;sberg Depression Rating Scale (MADRS) score\u0026thinsp;\u0026ge;\u0026thinsp;35.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eInadequate response to at least two adequate trials of selective serotonin reuptake inhibitors (SSRIs), cognitive\u0026ndash;behavioral therapy (CBT) including exposure and response prevention (ERP), and clomipramine, plus at least one pharmacological augmentation strategy (e.g., low-dose antipsychotic).\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eTreatment protocol\u003c/p\u003e\u003cp\u003eEligible patients initiated intranasal esketamine augmentation to their existing psychopharmacological regimen, with doses ranging from 56 to 84 mg per session according to the approved treatment protocol for treatment-resistant depression. The induction phase consisted of two sessions per week for approximately four weeks, followed by once-weekly sessions until Week 12, with adjustments based on symptom evolution and clinician judgment. Concomitant medications, including SSRIs and antipsychotics, were maintained throughout the study.\u003c/p\u003e\u003cp\u003eAssessments and data collection\u003c/p\u003e\u003cp\u003eDemographic information, OCD resistance level according to the Pallanti\u0026ndash;Quercioli proposal, total number of intranasal esketamine sessions, and adverse events recorded by clinicians were collected for each patient. Symptom severity and clinical status were evaluated at baseline, Week 1, Week 4, Week 8, and Week 12 (or last observation if dropout occurred) using:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eY-BOCS: to assess OCD severity.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eY-BOCS Symptom Checklist: to characterize obsessive\u0026ndash;compulsive symptom dimensions.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMADRS: to evaluate depressive symptom severity.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eClinical Global Impression\u0026ndash;Severity (CGI-S): to rate global illness severity.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eDetailed demographic and baseline clinical characteristics of the sample are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eResponse and remission criteria\u003c/p\u003e\u003cp\u003eFor OCD, response was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;35% reduction from baseline Y-BOCS. For depression, response was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;50% reduction from baseline MADRS, and remission as a MADRS total score\u0026thinsp;\u0026le;\u0026thinsp;10 at endpoint.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003ePrimary analyses compared baseline versus Week 12 scores for MADRS and Y‑BOCS using two‑sided paired t‑tests. We report mean change (points), 95% confidence intervals, p‑values, and within‑subject effect sizes (Cohen\u0026rsquo;s dz and Hedges\u0026rsquo; gav). Non‑parametric sensitivity analyses used Wilcoxon signed‑rank tests. Statistical significance was set at two‑sided p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. No multiplicity correction was applied given the exploratory design and n\u0026thinsp;=\u0026thinsp;8.\u003c/p\u003e\u003cp\u003eEthics statement\u003c/p\u003e\u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki and was approved by the Clinical Research Ethics Committee of Bellvitge University Hospital. All participants provided written informed consent prior to participation.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eBaseline demographic, clinical, and treatment characteristics of the study sample (n\u0026thinsp;=\u0026thinsp;8). Values are presented as individual patient data.\u003c/b\u003e Abbreviations: BZD\u0026thinsp;=\u0026thinsp;Benzodiazepine; CBT-ERP\u0026thinsp;=\u0026thinsp;Cognitive Behavioral Therapy with Exposure and Response Prevention; DLP\u0026thinsp;=\u0026thinsp;Dyslipidemia; ESK\u0026thinsp;=\u0026thinsp;Esketamine; GAD\u0026thinsp;=\u0026thinsp;Generalized Anxiety Disorder; HT\u0026thinsp;=\u0026thinsp;Hypertension; IBS\u0026thinsp;=\u0026thinsp;Irritable Bowel Syndrome; IN-ESK\u0026thinsp;=\u0026thinsp;Intranasal Esketamine; MADRS\u0026thinsp;=\u0026thinsp;Montgomery\u0026ndash;\u0026Aring;sberg Depression Rating Scale; OCD\u0026thinsp;=\u0026thinsp;Obsessive-Compulsive Disorder; PTSD\u0026thinsp;=\u0026thinsp;Post-Traumatic Stress Disorder; SSRI\u0026thinsp;=\u0026thinsp;Selective Serotonin Reuptake Inhibitor; TCA\u0026thinsp;=\u0026thinsp;Tricyclic Antidepressant; Y-BOCS\u0026thinsp;=\u0026thinsp;Yale-Brown Obsessive-Compulsive Scale.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"16\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eId\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMain OCD symptoms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePallanti Severity Index/resistance level\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eComorbidities (Medical / Psych)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMADRS wk0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eYBOCS wk0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCGI wk0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePast Augmentations\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eDuration of Illness (years)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eTotal Sessions\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003eFinal Esketamine Dose (mg)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c14\"\u003e\u003cp\u003eMADRS wk12\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c15\"\u003e\u003cp\u003eYBOCS wk12\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c16\"\u003e\u003cp\u003eCGI wk12\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eContamination\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHypertension / Social Anxiety Disorder, MDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSSRI\u0026thinsp;+\u0026thinsp;Antipsychotic, CBT-ERP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMoral (Scrupulosity)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFibromyalgia / Generalized Anxiety Disorder, MDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSSRI\u0026thinsp;+\u0026thinsp;TCA, CBT-ERP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eChecking\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSSRI\u0026thinsp;+\u0026thinsp;BZD, CBT-ERP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eContamination\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHypothyroidism / Panic Disorder, MDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eClomipramine\u0026thinsp;+\u0026thinsp;Antipsychotic, CBT-ERP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMoral (Scrupulosity)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIBS / PTSD, MDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSSRI\u0026thinsp;+\u0026thinsp;Antipsychotic, CBT-ERP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eChecking\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSSRI\u0026thinsp;+\u0026thinsp;TCA\u0026thinsp;+\u0026thinsp;BZD, CBT-ERP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eChecking\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHT, DLP, MDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSSRI, CBT-ERP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eContamination\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eEpilepsy, fibromyalgia, MDD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSSRI\u0026thinsp;+\u0026thinsp;Lithium, CBT-ERP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c15\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c16\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eSymptom severity and treatment response were assessed at baseline, Week 1, Week 4, Week 8, and Week 12 (or last observation if dropout occurred) using the Y-BOCS, Y-BOCS Symptom Checklist, MADRS, and CGI-S.\u003c/p\u003e\u003cp\u003eFor OCD, response was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;35% reduction from baseline Y-BOCS. For depression, response was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;50% reduction from baseline MADRS, and remission as a MADRS score\u0026thinsp;\u0026le;\u0026thinsp;10 at endpoint.\u003c/p\u003e\u003cp\u003eTemporal pattern of improvement\u003c/p\u003e\u003cp\u003eClinically, depressive symptoms tended to improve rapidly, with most MADRS reduction observed within the first four weeks and sustained thereafter. In contrast, OCD symptoms generally showed slower and more heterogeneous change: minor reductions were often noted by Week 4, with more consistent improvement emerging between Weeks 8 and 12 in responders.\u003c/p\u003e\u003cp\u003eStatistical outcomes\u003c/p\u003e\u003cp\u003eFrom baseline to Week 12, MADRS decreased from 37.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.78 to 19.75\u0026thinsp;\u0026plusmn;\u0026thinsp;13.32 (mean change 17.75, 95% CI 8.53\u0026ndash;26.97; t(7)\u0026thinsp;=\u0026thinsp;4.55, p\u0026thinsp;=\u0026thinsp;0.0026; Cohen\u0026rsquo;s dz\u0026thinsp;=\u0026thinsp;1.61).\u003c/p\u003e\u003cp\u003eY-BOCS decreased from 30.13\u0026thinsp;\u0026plusmn;\u0026thinsp;4.79 to 21.25\u0026thinsp;\u0026plusmn;\u0026thinsp;8.00 (mean change 8.88, 95% CI 3.83\u0026ndash;13.92; t(7)\u0026thinsp;=\u0026thinsp;4.16, p\u0026thinsp;=\u0026thinsp;0.0042; Cohen\u0026rsquo;s dz\u0026thinsp;=\u0026thinsp;1.47).\u003c/p\u003e\u003cp\u003eMean percentage improvements were 48.8% (MADRS) and 30.4% (Y-BOCS). Wilcoxon signed-rank tests corroborated these results (MADRS p\u0026thinsp;=\u0026thinsp;0.018; Y-BOCS p\u0026thinsp;=\u0026thinsp;0.0078).\u003c/p\u003e\u003cp\u003eCGI-S decreased from 5.50\u0026thinsp;\u0026plusmn;\u0026thinsp;1.20 at baseline to 3.50\u0026thinsp;\u0026plusmn;\u0026thinsp;2.20 at Week 12 (mean change \u0026minus;\u0026thinsp;2.00, 95% CI \u0026minus;\u0026thinsp;3.41 to \u0026minus;\u0026thinsp;0.59; t(7)\u0026thinsp;=\u0026thinsp;3.35, p\u0026thinsp;=\u0026thinsp;0.012; Cohen\u0026rsquo;s dz\u0026thinsp;=\u0026thinsp;1.18).\u003c/p\u003e\u003cp\u003eResponse rates\u003c/p\u003e\u003cp\u003eFour of eight participants (50.0%) met MADRS response criteria, and two of these (25.0%) achieved remission. Three of eight participants (37.5%) met the OCD response criterion. Wilson 95% CIs were [0.215, 0.785] for MADRS response, [0.071, 0.591] for MADRS remission, and [0.137, 0.694] for Y-BOCS response. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e depicts individual trajectories and group means for MADRS and Y-BOCS. The earlier, steeper slope in MADRS curves reflects the more rapid antidepressant effect, while Y-BOCS curves illustrate the slower onset of OCD symptom improvement.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTolerability and adverse events\u003c/p\u003e\u003cp\u003eNo severe adverse events were documented. Four participants (50%) reported transient dissociative experiences, typically subsiding spontaneously within 20\u0026ndash;30 minutes. One (12.5%) experienced moderate nausea. None withdrew because of adverse events.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first study to systematically investigate repeated intranasal esketamine augmentation in patients with treatment-resistant obsessive\u0026ndash;compulsive disorder (OCD) and comorbid major depression. The results indicate that repeated intranasal esketamine was associated with clinically meaningful reductions in obsessive\u0026ndash;compulsive and depressive symptoms for five of the eight participants. The observed 48.8% mean reduction in depressive symptoms aligns with prior reports of esketamine's antidepressant efficacy in treatment-resistant depression [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Importantly, 50% of participants exceeded the 50% response threshold on MADRS, suggesting a robust clinical effect.\u003c/p\u003e\u003cp\u003eThe 30.4% average reduction in obsessive\u0026ndash;compulsive symptoms, with 37.5% of patients reaching clinical response levels (\u0026ge;\u0026thinsp;35% Y-BOCS reduction), provides preliminary support for esketamine\u0026rsquo;s anti-obsessional potential. Notably, individual trajectories revealed that improvement in OCD symptoms was more variable and occurred more gradually compared to the more rapid and consistent antidepressant effects.\u003c/p\u003e\u003cp\u003eThese findings suggest a promising dual effect of intranasal esketamine, though further randomized controlled trials are needed to establish long-term efficacy, optimal treatment regimens, and durability of response. These findings extend earlier single-dose subcutaneous or intravenous esketamine studies [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] by demonstrating potential benefits of a repeated intranasal protocol in a patient cohort with pronounced depressive symptoms. This study provides an incremental step toward clarifying how the administration route and dosing schedule might be optimized for individuals with refractory OCD and major depression.\u003c/p\u003e\u003cp\u003eFurthermore, our findings provide further evidence that dysregulation of glutamatergic transmission is central to the neurobiological underpinnings of both obsessive-compulsive disorder and major depressive disorder. As discussed earlier in this paper, previous work has documented alterations in glutamate signalling associated with these conditions [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The rapid and significant improvements observed in MADRS scores, and the more gradual yet clinically relevant reductions in Y-BOCS scores, are consistent with the hypothesis that modulating glutamatergic activity can alleviate symptoms across these disorders, albeit with different response timelines. Future studies employing neuroimaging and biomarker assessments will be critical to further elucidate these mechanisms and to optimize glutamate-targeted interventions.\u003c/p\u003e\u003cp\u003eDifferences in OCD symptom dimensions or other clinical factors may influence treatment trajectories, and future investigations would benefit from detailed characterization of individual symptom profiles. Furthermore, the potential effects of structured exposure and response prevention (ERP) therapy in combination with intranasal esketamine were not assessed in our protocol and might constitute a useful and novel strategy. Esketamine could potentially enhance response to ERP in OCD patients with comorbid MDD, since depression often interferes with the motivation to engage in exposure tasks [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Trials integrating pharmacologic strategies with established psychotherapeutic interventions could help clarify the degree of synergy between these approaches and whether this combination could accelerate or potentiate the anti-obsessional effect observed over the longer term. Our preliminary results suggest that depressive symptoms may respond earlier and more robustly to repeated intranasal esketamine than obsessive-compulsive symptoms. Esketamine\u0026rsquo;s rapid antidepressant properties could facilitate greater adherence and reduce patient dropout, possibly by improving factors such as anhedonia or hopelessness. Further research is warranted to determine whether faster reduction in depressive symptoms translates to sustained long-term improvements and whether dosing schedules can be optimized to target both obsessive-compulsive and depressive dimensions effectively.\u003c/p\u003e\u003cp\u003eRepeated intranasal esketamine was generally well tolerated in this sample. No serious adverse events were reported, and overall side effects were manageable, indicating that this approach could feasibly be implemented in specialized psychiatric settings. Future investigations should consider clinical, neurobiological, or other biomarkers of response to optimize patient selection and inform personalized treatment plans. A more precise understanding of which patients are most likely to benefit may lead to improved outcomes in complex presentations of OCD and major depression.\u003c/p\u003e\u003cp\u003eSeveral limitations must be noted. The small sample size, observational design, and absence of randomization restrict the generalizability of the findings and preclude definitive conclusions regarding causality. Moreover, the lack of a control condition makes it difficult to ascertain whether the observed effects are attributable to esketamine itself or to nonspecific factors such as increased clinical contact. The focus on relatively short-term outcomes (12 weeks) does not clarify the durability of symptom improvement or the potential need for maintenance dosing. Finally, we did not track adjunctive psychotherapies, limiting conclusions about the interplay between pharmacological and behavioral interventions.\u003c/p\u003e\u003cp\u003eFuture research should involve larger randomized prospective trials to replicate and expand upon these preliminary observations, explore extended or maintenance dosing regimens, and identify predictors of positive response in refractory OCD with comorbid major depression. Incorporating evidence-based OCD interventions (e.g., ERP) into study protocols would help disentangle medication-specific effects from those of concurrent psychotherapy. The use of validated measures of functional outcomes and quality of life would further enrich assessments of real-world clinical impact. Continued efforts in this area may advance treatment strategies for the considerable subgroup of patients who experience persistent and impairing obsessive-compulsive symptoms alongside major depressive disorder.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis case series provides preliminary evidence that repeated intranasal esketamine augmentation (56\u0026ndash;84 mg/session) can produce clinically meaningful improvement in both depressive and obsessive\u0026ndash;compulsive symptoms in patients with severe, treatment-resistant OCD comorbid with major depression. The antidepressant effect appeared rapidly, whereas the anti-obsessional effect emerged more gradually, underscoring the importance of sustained treatment and tailored follow-up. These findings address a notable gap in the current literature, which has been dominated by intravenous ketamine studies, and suggest that intranasal administration could be a viable, more accessible alternative. Robust prospective research\u0026mdash;including randomized controlled trials and integration with structured ERP\u0026mdash;is needed to optimize treatment protocols, identify predictors of response, and clarify the role of intranasal esketamine in the long-term management of refractory OCD\u0026ndash;MDD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBZD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBenzodiazepine\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCBT-ERP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCognitive\u0026ndash;behavioral therapy with exposure and response prevention\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCGI-S\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eClinical Global Impression\u0026ndash;Severity\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDLP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDyslipidemia\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHTN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIBS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIrritable bowel syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMADRS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMontgomery\u0026ndash;\u0026Aring;sberg Depression Rating Scale\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMDD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMajor depressive disorder\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNMDA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eN-methyl-D-aspartate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOCD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eObsessive\u0026ndash;compulsive disorder\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSSRI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSelective serotonin reuptake inhibitor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTCA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTricyclic antidepressant\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTR-OCD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTreatment-resistant obsessive\u0026ndash;compulsive disorder\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eY-BOCS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eYale\u0026ndash;Brown Obsessive Compulsive Scale\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003e The Bellvitge University Hospital Ethics Committee approved the study. All participants provided written informed consent prior to inclusion.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eNo external funding was received for this work.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSL-R and PA conceptualized the study; SL-R collected and interpreted clinical data, and drafted the initial manuscript. CS, ER, JMM, MU, and PA contributed to the clinical management patients, interpretation of findings, and manuscript reviews. PA provided critical revisions for intellectual content. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank the clinical and nursing teams of the Interventional Psychiatry and Neuromodulation Unit of the Bellvitge University Hospital for their support during patient assessment and intranasal esketamine administration. We are also grateful to the hospital pharmacy for logistical assistance with medication preparation and dispensing.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analyzed during this study are included in this published article. No additional datasets are available.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStein DJ, Craske MA, Rothbaum BO, et al. Obsessive-compulsive disorder. Nat Rev Dis Primers. 2019;5(1):52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBloch MH, Landeros-Weisenberger A, Rosario MC, Pittenger C, Leckman JF. Meta-analysis of the symptom structure of obsessive-compulsive disorder. Am J Psychiatry. 2008;165(12):1532\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePallanti S, Quercioli L. Treatment-refractory obsessive-compulsive disorder: methodological issues, operational definitions and therapeutic lines. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(3):400\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRuscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15(1):53\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThe Expert Consensus Panel for Obsessive-Compulsive Disorder. Treatment of obsessive-compulsive disorder. J Clin Psychiatry. 1997;58(Suppl 4):2\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHenter ID, Park LT, Zarate CA Jr. Novel glutamatergic modulators for the treatment of mood disorders: current status. CNS Drugs. 2021;35(5):527\u0026ndash;43. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s40263-021-00816-x\u003c/span\u003e\u003cspan address=\"10.1007/s40263-021-00816-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePittenger C, Bloch MH, Williams K. Glutamate abnormalities in obsessive compulsive disorder: neurobiology, pathophysiology, and treatment. Pharmacol Ther. 2011;132(3):314\u0026ndash;32. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.pharmthera.2011.09.006\u003c/span\u003e\u003cspan address=\"10.1016/j.pharmthera.2011.09.006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCoelho DRA, Yang C, Suriaga A, et al. Glutamatergic Medications for Obsessive-Compulsive and Related Disorders: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025;8(1):e2452963.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBandeira ID, Lins-Silva DH, Cavenaghi VB, et al. Ketamine in the Treatment of Obsessive-Compulsive Disorder: A Systematic Review. Harv Rev Psychiatry. 2022;30(2):135\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFerguson AA, Khan AI, Abuzainah B, et al. Clinical Effectiveness of NMDA Receptor Antagonists in Adult OCD Treatment: A Systematic Review. Cureus. 2023;15(4):e37833.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDaly EJ, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018;75(2):139\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlves-Pereira R, Fontenelle LF, do Ros\u0026aacute;rio MC, et al. Esketamine Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder: A Retrospective Chart Review. Clin Neuropharmacol. 2024;47(1):17\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eO\u0026rsquo;Neill J, Piacentini JC, Chang S, et al. Glutamate in pediatric obsessive-compulsive disorder and response to cognitive-behavioral therapy: A randomized clinical trial. Neuropsychopharmacology. 2017;42:2414\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMartinotti G, Chiappini S, Pettorruso M, et al. Therapeutic Potentials of Ketamine and Esketamine in OCD, SUD, and ED: A Review of the Current Literature. Brain Sci. 2021;11(7):856.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGim\u0026eacute;nez M, Cano M, Mart\u0026iacute;nez-Zalaca\u0026iacute;n I, et al. Is glutamate associated with fear extinction and cognitive behavioral therapy outcome in OCD? A pilot study. Eur Arch Psychiatry Clin Neurosci. 2019;270:1003\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMataix-Cols D, Fern\u0026aacute;ndez de la Cruz L, Monzani B, et al. d-Cycloserine augmentation of exposure-based CBT for anxiety, obsessive-compulsive, and posttraumatic stress disorders: A systematic review and meta-analysis of individual participant data. JAMA Psychiatry. 2017;74(5):501\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMontgomery SA, \u0026Aring;sberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR, Charney DS. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989;46(11):1006\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR, Charney DS. The Yale-Brown Obsessive Compulsive Scale. II Validity Arch Gen Psychiatry. 1989;46(11):1012\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Obsessive–compulsive disorder, Treatment-resistant, Major depressive disorder, Comorbidity, Intranasal esketamine, augmentation","lastPublishedDoi":"10.21203/rs.3.rs-7417012/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7417012/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Intranasal esketamine has gained attention as a rapidly acting intervention for treatment-resistant depression, and there is growing interest in its potential anti-obsessional effects. To our knowledge, no published case series has focused on intranasal esketamine in patients with both treatment-resistant obsessive–compulsive disorder (TR‑OCD) and comorbid major depression (MD).\u003cbr\u003e\n\u003cstrong\u003eMethods:\u003c/strong\u003e We present eight adult cases at Bellvitge University Hospital who met criteria for TR‑OCD with comorbid MD and received intranasal esketamine augmentation between summer 2023 and 2024. Eligibility required inadequate response to at least two adequate SSRI trials, clomipramine plus one pharmacological augmentation strategy, Y‑BOCS ≥24, and MADRS ≥35. Esketamine was administered intranasally at 56–84 mg per session according to standard protocol for 12 weeks. Response for OCD was defined as ≥35% reduction from baseline Y‑BOCS; depression response as ≥50% reduction from baseline MADRS; depression remission as MADRS ≤10 at endpoint.\u003cbr\u003e\n\u003cstrong\u003eResults: \u003c/strong\u003eThe mean MADRS score decreased from 37.5±3.8 at baseline to 19.8±13.3 at Week 12 (t(7)=4.55, p=0.0026), reflecting a 48.8% improvement. Y‑BOCS scores declined from 30.1±4.8 to 21.3±8.0 (t(7)=4.16, p=0.0042), a 30.4% reduction. Four participants (50.0%) achieved depression response, of whom two (25.0%) achieved remission; three participants (37.5%) met the OCD response criterion.\u003cbr\u003e\n\u003cstrong\u003eConclusions:\u003c/strong\u003e Esketamine augmentation may exert dual efficacy in reducing both depressive and obsessive–compulsive symptoms in TR‑OCD with comorbid MD. Prospective controlled trials are warranted to confirm these preliminary findings, refine dosing and frequency, and evaluate the role of concurrent psychotherapy in sustaining gains.\u003c/p\u003e","manuscriptTitle":"Intranasal Esketamine Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder with Comorbid Major Depressive Disorder: A Case Series of Eight Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-26 15:05:47","doi":"10.21203/rs.3.rs-7417012/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-04T19:48:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-02T02:51:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196297948759082121151934173534891979105","date":"2026-03-01T22:15:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-20T17:30:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"172142520057264984983370569828906320065","date":"2025-09-17T18:39:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"21727056996534964884177059025101060263","date":"2025-09-17T16:20:19+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-17T16:18:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-15T15:57:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-28T18:38:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-28T17:14:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2025-08-28T17:12:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"90b3910c-4602-40f7-bf6d-6e07eb05f5cc","owner":[],"postedDate":"September 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T16:04:59+00:00","versionOfRecord":{"articleIdentity":"rs-7417012","link":"https://doi.org/10.1186/s12888-026-08119-5","journal":{"identity":"bmc-psychiatry","isVorOnly":false,"title":"BMC Psychiatry"},"publishedOn":"2026-04-26 15:58:45","publishedOnDateReadable":"April 26th, 2026"},"versionCreatedAt":"2025-09-26 15:05:47","video":"","vorDoi":"10.1186/s12888-026-08119-5","vorDoiUrl":"https://doi.org/10.1186/s12888-026-08119-5","workflowStages":[]},"version":"v1","identity":"rs-7417012","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7417012","identity":"rs-7417012","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}