Intranasal Esketamine Augmentation in Treatment-Resistant Obsessive–Compulsive Disorder with Comorbid Treatment-Resistant Depression: A Six-Month Case Report

Abstract

Background: Evidence for repeated intranasal esketamine in obsessive–compulsive disorder (OCD) remains preliminary, particularly when OCD co-occurs with treatment-resistant depression (TRD). Methods: We report a 58-year-old woman treated with intranasal esketamine in routine clinical care for TRD; change in obsessive–compulsive symptoms was followed as a secondary observational outcome. Her history aligned with the eligibility framework of a 2026 prospective intranasal esketamine series: primary Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) OCD, baseline Yale–Brown Obsessive Compulsive Scale (Y-BOCS) score of 33, a comorbid major depressive episode with a Montgomery–Åsberg Depression Rating Scale (MADRS) score of 38, sequential inadequate response to two high-dose selective serotonin reuptake inhibitor (SSRI) trials, clomipramine 250 mg/day for 6 months, eight cognitive-behavioral therapy (CBT) sessions incorporating exposure and response prevention (ERP), and brexpiprazole augmentation. The CBT/ERP course was time-limited and did not overlap with esketamine. Esketamine was administered at 56 mg initially and 84 mg thereafter, twice weekly for 4 weeks, weekly in month 2, and every 2 weeks during months 3–6. Results: MADRS/Y-BOCS scores were 23/18 at month 1, 19/15 at month 3, and 17/14 at month 6, corresponding to reductions of 55.3% and 57.6%. The OCD response threshold was met from month 1 and the depression response threshold from month 3. Adverse effects were transient and required no medical intervention or treatment discontinuation. Conclusions: During 6 months of routine-care intranasal esketamine augmentation for TRD, obsessive–compulsive improvement accompanied antidepressant improvement. The observation is hypothesis-generating and cannot distinguish a direct anti-obsessional effect from improvement related to depression, ongoing oral treatment, repeated clinical contact, or other nonspecific factors.

1. Introduction

Obsessive–compulsive disorder (OCD) is a chronic and disabling condition associated with intrusive thoughts, images, or urges and repetitive behaviors or mental acts that can consume substantial time and impair family, social, occupational, and recreational functioning [1,2]. High-dose selective serotonin reuptake inhibitors (SSRIs), clomipramine, and cognitive-behavioral therapy (CBT) incorporating exposure and response prevention (ERP) are established treatments [2,3,4]. Nevertheless, a clinically important subgroup remains markedly symptomatic after sequential evidence-based interventions. This subgroup is especially difficult to manage when severe OCD co-occurs with a major depressive episode, because depressive hopelessness, anhedonia, cognitive rigidity, anxiety, and reduced motivation can intensify impairment and complicate both pharmacological management and engagement in ERP.

Treatment outcome in OCD is dimensional rather than binary. In the present report, partial response denotes a clinically discernible improvement with substantial residual symptoms; full response denotes a larger clinically meaningful reduction that may still fall short of minimal symptoms; remission denotes absent or minimal symptoms; relapse denotes a clinically important return of symptoms after response or remission; resistance denotes persistence despite adequately delivered evidence-based treatments; and refractoriness denotes a more advanced degree of resistance after failure of multiple pharmacological and psychotherapeutic steps [4,5]. These states should not be used interchangeably. A patient may improve without remitting, and an apparent failure may reflect insufficient dose exposure, premature discontinuation, poor adherence, unrecognized comorbidity, diagnostic overlap between obsessions and depressive rumination, or inadequately delivered behavioral treatment rather than true biological nonresponse.

The definition of treatment-resistant OCD (TR-OCD) is therefore methodologically complex. Published criteria differ in the number of required serotonergic trials, whether clomipramine must be tested separately, the dose and duration considered adequate, how adherence is established, whether antipsychotic or other pharmacological augmentation is required, and the intensity, fidelity, and completion of ERP [4,5,6]. Some definitions emphasize a minimum percentage reduction on the Yale–Brown Obsessive Compulsive Scale (Y-BOCS), whereas others emphasize the sequence of prior interventions and persistent functional impairment. Transparent reporting of each treatment component is consequently more informative than applying the label TR-OCD without a patient-level treatment history.

The Pallanti–Quercioli framework was developed to organize this heterogeneity by distinguishing response, remission, relapse, resistance, and refractoriness and by staging nonresponse along a continuum of progressively broader treatment failure [5]. In practical terms, movement toward the higher levels reflects persistence of clinically significant symptoms after multiple serotonin-reuptake inhibitor strategies and additional interventions such as clomipramine, pharmacological augmentation, and CBT/ERP. Thus, a descriptive placement around levels 3–4 indicates advanced multimodal resistance rather than failure of a single antidepressant trial. Because the adequacy of each component still matters, retrospective staging should remain cautious when session frequency, homework adherence, ERP fidelity, or exact medication exposure cannot be fully reconstructed.

For direct comparability, the present report uses the published eligibility framework of the 2026 prospective case series of repeated intranasal esketamine as an external descriptive comparator [7]. That framework required a primary Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) OCD diagnosis, baseline Y-BOCS ≥ 24, a co-occurring major depressive episode with Montgomery–Åsberg Depression Rating Scale (MADRS) ≥ 35, inadequate response to at least two adequate SSRI trials, previous clomipramine treatment, CBT including ERP, and at least one pharmacological augmentation strategy. The resulting clinical profile was described as severe TR-OCD and aligned descriptively with Pallanti–Quercioli levels 3–4 [5,7]. Applying the same criterion-level framework allows readers to judge comparability with the available prospective evidence, but it does not imply that all definitions of resistance are equivalent or that a time-limited ERP course is identical to a fully protocolized and adequately dosed behavioral intervention.

Clinical complexity increases further when severe OCD co-occurs with treatment-resistant depression (TRD). Glutamatergic abnormalities within cortico-striato-thalamo-cortical circuits provide a mechanistic rationale for examining N-methyl-D-aspartate receptor modulation in OCD, while ketamine-related synaptic plasticity mechanisms have generated substantial interest in mood disorders [8,9,10]. Intranasal esketamine has demonstrated antidepressant efficacy in TRD when administered under supervised protocols in conjunction with ongoing oral antidepressant treatment [11,12,13]. An antidepressant indication, however, does not establish an anti-obsessional indication. In a patient with both disorders, improvement in mood, anxiety, motivation, cognitive flexibility, or treatment engagement may secondarily reduce the intensity or functional impact of obsessions even in the absence of a direct OCD-specific pharmacological effect.

The early OCD literature provides a possible but inconsistent rapid signal. A case report described rapid resolution of obsessions after a single intravenous ketamine infusion [14]. In an open-label study, short-term mean improvement was modest and no categorical OCD responders were identified [15]. Two complex patients with histories of major depressive disorder developed delayed dysphoria, anxiety, and suicidal thinking after ketamine [16]. Conversely, a randomized crossover proof-of-concept trial reported a 1-week OCD response in 50% of participants who received ketamine in the first treatment phase [17]. These observations suggested that glutamatergic modulation might affect obsessive–compulsive symptoms in selected patients, but they also demonstrated marked variability, limited durability, and a need for careful safety monitoring.

Subsequent studies attempted to extend or reproduce the acute signal through exposure-based CBT after intravenous ketamine, intranasal ketamine combined with intensive CBT, repeated intravenous dosing, intramuscular administration, oral maintenance, and treatment in adolescents [18,19,20,21,22,23,24,25]. An intranasal ketamine feasibility study was stopped early after two completers because of poor nasal tolerability and low enrollment [20], whereas repeated intravenous treatment produced clinically relevant benefit in only a minority of patients [21]. More recent route-diverse work has reported dose-related Y-BOCS reductions after intramuscular ketamine, possible maintenance of gains during an oral extension, and acceptable short-term tolerability but limited persistence in a small adolescent series [23,24,25]. Taken together, these findings are difficult to integrate because the samples are small, formulations and routes differ, dosing schedules are heterogeneous, comorbidity is variable, and response definitions are not uniform.

Esketamine-specific evidence is even more limited. Case reports have described parallel improvement in depressive and obsessive–compulsive symptoms during intranasal esketamine, including treatment courses combined with psychotherapy [26,27]. A retrospective review of eight patients treated predominantly with subcutaneous esketamine found full response in 25% and partial response in 50% at 1 week, but the uncontrolled design and route heterogeneity restrict interpretation [28]. The most directly comparable prospective dataset enrolled eight adults who fulfilled the operational severe TR-OCD framework and received repeated 56–84 mg intranasal esketamine over 12 weeks [7]. Mean MADRS and Y-BOCS reductions were 48.8% and 30.3%, respectively; 50% met the predefined ≥50% MADRS response criterion and 50% met the ≥35% Y-BOCS response criterion. Depressive improvement tended to emerge earlier, whereas OCD improvement was slower and more variable. Recent reviews therefore characterize the overall signal as promising but preliminary and heterogeneous [29,30,31,32].

Racemic ketamine and esketamine, and the routes by which they are delivered, should not be treated as clinically interchangeable. Racemic ketamine contains both R- and S-enantiomers and has most often been studied intravenously in OCD, whereas esketamine is the S-enantiomer and, in the present case, was administered intranasally through a supervised medical device within a TRD regimen. Formulation, bioavailability, dose exposure, administration schedule, monitoring requirements, concomitant treatment, and patient selection differ across intravenous, intramuscular, subcutaneous, oral, and intranasal approaches [7,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32]. Evidence obtained with one molecule or route cannot therefore be assumed to establish efficacy or tolerability for another, and antidepressant response cannot be assumed to represent a direct anti-obsessional effect.

Against this background, we describe the 6-month course of a woman with severe OCD and comorbid TRD who received intranasal esketamine augmentation in routine clinical care for TRD. Change in OCD severity was a secondary, partly unexpected observational outcome rather than the primary indication for treatment. The aims are to provide a detailed de-identified chronology, clarify how the pretreatment history relates to an operational TR-OCD framework, report repeated MADRS and Y-BOCS measurements and tolerability through maintenance treatment, and distinguish the observed temporal association from causal evidence.

2. Detailed Case Description

2.1. Patient Information and Diagnostic Context

A 58-year-old woman had a more than 10-year history of a primary OCD diagnosis established by the treating psychiatric team according to DSM-5 criteria. The available de-identified clinical record documented the treating team’s diagnosis but did not specify use of a structured diagnostic interview. Her illness was characterized predominantly by intrusive and repetitive health-related obsessions concerning herself and close family members. The thoughts were experienced as persistent, distressing, and difficult to disengage from. Over time, they became pervasive and time-consuming and were associated with progressive family, social, and recreational impairment. The available record did not contain a sufficiently detailed symptom-dimension inventory to quantify checking, reassurance seeking, avoidance, mental rituals, or level of insight; these documentation limits are considered in the Discussion. She had no relevant medical comorbidities and no history of substance use disorder.

Against this background, she developed a severe major depressive episode characterized by hopelessness, anhedonia, social withdrawal, and declining quality of life. At baseline, the Y-BOCS score was 33 and the MADRS score was 38, exceeding the severity thresholds used in the 2026 prospective series (Y-BOCS ≥ 24 and MADRS ≥ 35) [7]. The treating team classified the depressive episode as TRD [11]. The record did not provide a separate standardized measure of global functioning or quality of life, but the narrative history documented clinically meaningful impairment across several domains. Calendar dates are reported relative to the first intranasal esketamine administration (T0) to reduce re-identification risk. This approach preserves the documented treatment sequence and all confirmed target-dose intervals while avoiding unnecessary disclosure of exact dates.

2.2. Pretreatment Course and Resistance Staging

Before T0, pharmacological treatment proceeded sequentially. At an earlier pre-T0 stage, paroxetine was administered at the target dose of 60 mg/day for 2 months with consistently maintained adherence. It produced a partial but clinically insufficient overall response: symptom intensity decreased modestly, but clinically significant obsessions and associated functional impairment persisted and remission was not achieved. This distinction is important because the trial was not classified as complete absence of change; it was considered inadequate because substantial symptoms and disability remained despite target-dose exposure.

Sertraline was subsequently titrated from 100 mg/day to 200 mg/day. The 200 mg/day target dose was maintained for the final 2 months of the trial without meaningful improvement in either obsessive–compulsive or depressive symptoms. The final pre-T0 antidepressant trial was clomipramine (Anafranil), titrated to 250 mg/day and continued for 6 months, again without clinically meaningful remission. Intranasal esketamine was initiated only after these sequential high-dose trials had proved insufficient. The de-identified record preserved the treatment order, target doses, confirmed target-dose intervals, and clinical outcomes, but it did not permit reliable reconstruction of every titration date or the complete calendar duration of the earlier SSRI courses.

During the pre-esketamine period, clonazepam had initially been prescribed at 0.5 mg three times daily. During the final 2 months before T0, the regimen was changed to an oral solution (2.5 mg/mL), administered as five drops as needed for anxiety or agitation. Brexpiprazole 1 mg/day was also used as a pharmacological augmentation strategy for at least 2 months and was discontinued because of extrapyramidal symptoms. No neuromodulation strategy had been implemented before esketamine initiation. These interventions are included in the timeline because they influence the operational staging and because the response observed after T0 cannot be interpreted without acknowledging the broader longitudinal treatment context.

The patient also attended eight sessions of CBT incorporating ERP before T0. Treatment was discontinued after the eighth session because no clinically meaningful reduction in overall obsessive–compulsive symptom burden or associated functional impairment was observed. The exact inter-session frequency, session duration, therapist qualifications, homework adherence, exposure targets, and fidelity to a manualized ERP protocol were not retained in the available de-identified documentation. Accordingly, this time-limited course should not be equated with a fully characterized, protocolized adequate ERP trial. It was nevertheless the complete documented ERP-containing treatment attempt and met the categorical prior CBT/ERP component used in the 2026 comparator series [7]. The record confirms that CBT/ERP occurred during the broader pharmacological treatment course before T0, but it does not allow precise reconstruction of its overlap with each individual oral medication trial. ERP was not delivered concurrently with esketamine.

Taken together, the primary DSM-5 OCD diagnosis, baseline Y-BOCS 33, comorbid major depressive episode with MADRS 38, two high-dose SSRI trials, clomipramine, brexpiprazole augmentation, and prior CBT/ERP attempt aligned the patient with all published components of the 2026 severe TR-OCD eligibility framework [7]. The profile was descriptively compatible with Pallanti–Quercioli levels 3–4 [5,7]. This operational alignment is used to facilitate comparison, not to resolve the broader definitional debate. In particular, the limited duration and incomplete process documentation of the ERP course restrict how confidently refractoriness can be inferred. The consolidated clinical chronology and its operational relevance are presented in Table 1.

Table 1. De-identified clinical timeline and operational evidence for the severe treatment-resistant obsessive–compulsive disorder (TR-OCD) framework.

Relative Period	Clinical Phase	Treatment Details, Outcome, and Operational Relevance
>10 years before T0	OCD course	Primary DSM-5 OCD with predominantly health-related obsessions concerning the patient and close family members; progressive family, social, and recreational impairment.
Earlier pre-T0; 2 months at target dose	First high-dose SSRI trial	Paroxetine 60 mg/day for 2 months with consistently maintained adherence; partial but clinically insufficient response, persistent clinically significant obsessions and functional impairment, and no remission.
Subsequent pre-T0; final 2 months at target dose	Second high-dose SSRI trial	Sertraline titrated from 100 mg/day to 200 mg/day and maintained at 200 mg/day for the final 2 months; no meaningful improvement in obsessive–compulsive or depressive symptoms.
Approximately 6 months before T0 through T0	Final pre-T0 antidepressant trial	Clomipramine (Anafranil) titrated to 250 mg/day and continued for 6 months without clinically meaningful remission; esketamine was initiated after this trial.
During the pre-T0 course	CBT/ERP attempt	Eight CBT sessions incorporating ERP were discontinued for lack of clinically meaningful benefit. Exact spacing, session duration, homework adherence, exposure targets, and manual fidelity were not retained. ERP did not continue after T0.
During the pre-T0 course	Augmentation and anxiolytic treatment	Brexpiprazole 1 mg/day for at least 2 months was stopped because of extrapyramidal symptoms. Clonazepam was initially 0.5 mg three times daily and later oral solution 2.5 mg/mL, five drops as needed. No prior neuromodulation.
T0 (Day 1; index date)	Baseline and first esketamine administration	Y-BOCS 33 and MADRS 38. The pretreatment history aligned operationally with the 2026 severe TR-OCD framework and descriptively with Pallanti–Quercioli levels 3–4. Esketamine 56 mg was administered for TRD in routine clinical care; OCD change was secondary.
Weeks 1–4 after T0	Induction	Esketamine was increased to 84 mg from the second session because of good tolerability and administered twice weekly under specialist and hemodynamic monitoring.
Month 1 (T1)	First outcome assessment	MADRS 23 (−39.5%) and Y-BOCS 18 (−45.5%); the descriptive OCD response threshold was met.
Month 2	Continuation	Esketamine 84 mg once weekly; no scheduled MADRS/Y-BOCS assessment.
Month 3 (T2)	Maintenance and outcome assessment	Esketamine 84 mg every 2 weeks; MADRS 19 (−50.0%) and Y-BOCS 15 (−54.5%); both descriptive response thresholds were met.
Months 3–6; Month 6 (T3)	Maintenance and final reported follow-up	Esketamine 84 mg every 2 weeks. At month 6, MADRS 17 (−55.3%) and Y-BOCS 14 (−57.6%). Transient session-related adverse effects required no medical intervention or discontinuation.

Note: Abbreviations: CBT, cognitive-behavioral therapy; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ERP, exposure and response prevention; MADRS, Montgomery–Åsberg Depression Rating Scale; OCD, obsessive–compulsive disorder; SSRI, selective serotonin reuptake inhibitor; T0, first intranasal esketamine administration; T1, month 1; T2, month 3; T3, month 6; TRD, treatment-resistant depression; TR-OCD, treatment-resistant obsessive–compulsive disorder; Y-BOCS, Yale–Brown Obsessive Compulsive Scale. Calendar dates are expressed relative to T0 to reduce re-identification risk. The table combines chronology with criterion-level evidence. The eight-session ERP-containing course is reported as documented and is not equated with a fully characterized, protocolized adequate ERP trial.

2.3. Clinical Methods, Esketamine Intervention, and Ethical Oversight

At T0, intranasal esketamine was initiated in routine clinical care as augmentation for TRD under specialist supervision. The intervention was not undertaken as a protocol designed to test efficacy in OCD; change in obsessive–compulsive symptoms was followed as a secondary observational outcome. The first administration was 56 mg using two devices. The dose was increased to 84 mg using three devices from the second session because of good tolerability. Esketamine was administered twice weekly for the first 4 weeks, 84 mg once weekly during month 2, and 84 mg once every 2 weeks from month 3 through month 6, with continued clinical and hemodynamic monitoring. This schedule was consistent with repeated-dose intranasal esketamine strategies used for TRD [12,13].

Esketamine was not the only therapeutic exposure during follow-up. Ongoing oral treatment and regular specialist clinical contact continued while esketamine was added. No antidepressant switch or treatment discontinuation was recorded during the 6-month observation period, and no CBT or ERP was delivered concurrently with esketamine. The available retrospective record did not permit reliable dose-by-dose reconstruction of the oral regimen or actual as-needed clonazepam use across every visit during the full follow-up. The continued background treatment, repeated clinical contact, and incomplete granularity of the concomitant-medication record are therefore treated as potential confounders rather than being attributed to esketamine.

Depressive symptoms were measured with the MADRS [33], and obsessive–compulsive symptom severity was measured with the Y-BOCS [34,35]. Assessments were completed at baseline (T0), 1 month (T1), 3 months (T2), and 6 months (T3) as part of routine clinical care. The available record did not establish assessor independence or confirm that the same clinician completed every rating. For descriptive comparison with the 2026 prospective series, OCD response was defined as a ≥35% reduction from baseline Y-BOCS, depression response as a ≥50% reduction from baseline MADRS, and depression remission as MADRS ≤ 10 [7]. These thresholds were applied retrospectively for descriptive comparability and were not prespecified within a controlled study designed to test an OCD indication.

Clinical monitoring included specialist observation and hemodynamic assessment during treatment sessions. The report documented transient dissociation, sedation, nausea, dizziness, mild blood pressure elevation, and transient tachycardia, with no serious adverse event, clinically significant hemodynamic instability, medical intervention, or treatment discontinuation. A structured adverse-event instrument and quantitative session-level vital-sign dataset were not preserved in the available de-identified material. Consequently, tolerability can be described clinically but the frequency, intensity, duration, and dose relationship of individual events cannot be analyzed quantitatively.

The clinical observation and reporting were conducted in accordance with the Declaration of Helsinki and approved by the Internal Review Board of the University of L’Aquila (protocol code 06/2022; approval date: 6 February 2022). Written informed consent for participation was obtained from the patient. Separate written informed consent was also obtained for publication of the de-identified clinical information presented in this case report. Exact calendar dates were replaced by relative time points to reduce re-identification risk without changing the confirmed sequence or duration of treatment exposures.

2.4. Outcomes and Tolerability

At baseline, MADRS and Y-BOCS scores were 38 and 33, respectively. At month 1, the scores were 23 and 18, representing reductions of 39.5% and 45.5%. At month 3, the scores were 19 and 15, representing reductions of 50.0% and 54.5%. At month 6, the scores were 17 and 14, corresponding to reductions of 55.3% and 57.6%. The patient therefore met thedescriptive OCD response thresholdfrom month 1 onward and the depression response threshold from month 3 onward. MADRS remission was not achieved at any reported follow-up. The complete longitudinal scale trajectory and descriptive response classification are shown in Table 2.

Table 2. Longitudinal Montgomery–Åsberg Depression Rating Scale (MADRS) and Yale–Brown Obsessive Compulsive Scale (Y-BOCS) scores and descriptive response classification during 6 months of intranasal esketamine treatment.

Time Point	MADRS	Y-BOCS	Response Classification
T0 (baseline)	38 (baseline)	33 (baseline)	Baseline
T1 (1 month)	23 (−39.5%)	18 (−45.5%)	MADRS response: no; OCD response: yes
T2 (3 months)	19 (−50.0%)	15 (−54.5%)	MADRS response: yes; OCD response: yes
T3 (6 months)	17 (−55.3%)	14 (−57.6%)	MADRS response: yes; OCD response: yes

Abbreviations: MADRS, Montgomery–Åsberg Depression Rating Scale; OCD, obsessive–compulsive disorder; T0, baseline; T1, month 1; T2, month 3; T3, month 6; Y-BOCS, Yale–Brown Obsessive Compulsive Scale. Response thresholds, aligned descriptively with the 2026 prospective series [7], were ≥50% MADRS reduction for depression and ≥35% Y-BOCS reduction for OCD; MADRS remission required a score ≤ 10.

Both symptom domains improved substantially by the first scheduled follow-up and improved further during the continuation and maintenance phases, despite progressively less frequent esketamine administration. However, the four assessment points do not establish the exact week-by-week onset, whether change in one symptom domain preceded the other, or whether depressive improvement mediated the change in obsessive–compulsive symptoms. Threshold crossing should also not be interpreted as a biological event: MADRS and Y-BOCS changed continuously, whereas the response labels are categorical summaries applied for comparison with the prospective series. The trajectory is clinically meaningful, but no inferential statistical interpretation is possible in a single uncontrolled case.

No serious adverse events, clinically significant hemodynamic instability, or treatment discontinuations were reported. The transient dissociation, sedation, nausea, dizziness, mild blood pressure elevation, and transient tachycardia resolved without medical intervention. No standardized functional scale, clinician- or patient-rated global impression, quality-of-life measure, or formal patient-perspective statement was available. The absence of these complementary outcomes limits the ability to determine how closely symptom-score changes corresponded to broader recovery in everyday functioning.

3. Discussion

The principal observation of this case report is a substantial parallel reduction in depressive and obsessive–compulsive symptom severity during 6 months of repeated intranasal esketamine administered in routine clinical care for TRD. MADRS and Y-BOCS scores decreased by 55.3% and 57.6% from baseline, respectively, without treatment discontinuation. The OCD response threshold was met from month 1 and the depression response threshold from month 3. Importantly, esketamine was prescribed for TRD, and the change in OCD symptoms was a secondary, partly unexpected observational outcome. The contribution of the report is therefore the duration and granularity of follow-up under a specific intranasal regimen, not proof that esketamine is efficacious for TR-OCD.

The trajectory is broadly compatible with earlier esketamine case reports and extends the observation window of the recent 12-week prospective series [7,26,27]. In that series, mean depressive improvement was larger and tended to emerge earlier than obsessive–compulsive improvement. The present patient showed substantial reductions on both scales by month 1, followed by further improvement during weekly and then every-2-week dosing. This pattern may suggest persistence of benefit while dosing frequency was reduced, but it does not identify a minimum effective schedule or demonstrate that maintenance dosing caused continued improvement. Between-report differences may reflect individual variability, baseline depressive burden, OCD symptom dimensions, background treatment, expectancy, rating frequency, or chance rather than a true difference in pharmacological response.

The wider clinical literature remains heterogeneous. Early intravenous studies ranged from rapid case-level improvement to modest mean change without categorical responders, and the crossover trial provided only short-term proof-of-concept evidence [14,15,17]. Attempts to extend benefit with CBT, repeated dosing, or alternative routes have produced mixed results and have often been limited by very small samples, open-label designs, incomplete maintenance data, or tolerability and recruitment difficulties [18,19,20,21,22,23,24,25]. Esketamine reports and small series add a clinically interesting signal, particularly in patients with comorbid depression, but do not resolve whether improvement is specific to OCD, secondary to antidepressant effects, or restricted to selected phenotypes [7,26,27,28]. The current case therefore adds longitudinal detail to a preliminary literature rather than changing the level of evidence.

The distinction between racemic ketamine and esketamine is central to interpretation. Most OCD-specific evidence derives from intravenous racemic ketamine, whereas this patient received the S-enantiomer through a medically supervised intranasal device within a TRD treatment pathway. These interventions should not be considered interchangeable. Enantiomeric composition, route-dependent bioavailability, dose exposure, administration schedule, monitoring, concomitant oral treatment, and patient selection differ substantially. The poor acceptability observed in an earlier intranasal ketamine feasibility study cannot be assumed to predict the tolerability of supervised intranasal esketamine, just as antidepressant efficacy of intranasal esketamine in TRD cannot be assumed to establish a direct anti-obsessional action [12,13,20]. The present observation also cannot be extrapolated to intravenous, intramuscular, subcutaneous, or oral administration, or to patients with OCD without comorbid depression.

The resistance classification is informative but requires nuance. The patient had a primary OCD diagnosis, severe baseline symptoms, two high-dose SSRI trials, a 6-month clomipramine trial, brexpiprazole augmentation, and a prior CBT course incorporating ERP. This history aligned with the components of the 2026 operational framework and was descriptively compatible with Pallanti–Quercioli levels 3–4 [5,7]. However, the eight-session CBT/ERP course was time-limited, and its frequency, homework adherence, exposure targets, therapist qualifications, and manual fidelity were not available. It therefore supports operational comparison with the published series but should not be presented as equivalent to a fully documented, adequately dosed ERP protocol. This qualification is particularly important because resistance and refractoriness are not interchangeable labels and because insufficient behavioral treatment can mimic pharmacological refractoriness [4,5,6].

Causality cannot be established. The Y-BOCS improvement may reflect a direct anti-obsessional effect, an indirect consequence of reduced depressive or anxiety burden, improved motivation and engagement, or a combination of these processes. OCD and depression share dimensions of repetitive negative thinking, and the four available MADRS/Y-BOCS time points cannot separate these pathways. Glutamatergic modulation and downstream synaptic plasticity provide a biologically plausible framework [8,9,10], but biological plausibility does not establish that the observed clinical change was mediated by an OCD-specific mechanism. The fact that the categorical OCD threshold was crossed before the categorical depression threshold also cannot prove independence, because both continuous scales had already improved substantially at month 1 and no intermediate ratings were available.

The potential confounding effects of ongoing oral treatment and repeated clinical contact deserve explicit consideration. Background pharmacotherapy may have contributed delayed, additive, or synergistic effects even without a recorded antidepressant switch. Repeated specialist visits may improve adherence, provide support and reassurance, increase expectancy, facilitate behavioral activation, and create more opportunities to identify and manage symptoms or adverse effects. The structured treatment environment itself may reduce uncertainty and increase perceived safety. Natural fluctuation, regression toward the mean after a severe baseline assessment, and nonspecific effects of close monitoring are additional alternatives. These factors do not negate the observed improvement, but they prevent attribution of the trajectory to esketamine alone.

The clinical implications are therefore limited but potentially useful. First, systematic measurement of both depressive and obsessive–compulsive symptoms may reveal changes that would otherwise be overlooked when esketamine is prescribed for TRD in a patient with comorbid OCD. Second, the divergent indications should remain clear: monitoring an unexpected OCD improvement is not equivalent to prescribing esketamine as an established OCD treatment. Third, future studies should stabilize and fully document concomitant medication, collect frequent early ratings, characterize OCD dimensions and insight, and include functional and patient-reported outcomes. Given hypotheses regarding ketamine-related plasticity, controlled work could also examine whether carefully timed, adequately delivered ERP enhances durability, while distinguishing such combined treatment from pharmacological monotherapy [18,19].

Tolerability in this case was consistent with commonly described acute effects during supervised intranasal esketamine: dissociation, sedation, nausea, dizziness, mild blood pressure elevation, and transient tachycardia were self-limited and required no intervention. Nevertheless, the broader ketamine literature includes delayed dysphoria, anxiety, and suicidal thinking in rare complex cases, as well as dose-related dissociative and cardiovascular effects in controlled work [16,23]. Careful screening, pre- and post-dose monitoring, and post-administration observation remain essential. Because no structured adverse-event instrument or quantitative vital-sign dataset was available, this case supports only a descriptive statement of tolerability and cannot define incidence, severity distribution, or comparative safety.

Strengths include a clearly identified primary article type, criterion-level reporting of the pretreatment history, a de-identified relative timeline, repeated validated MADRS and Y-BOCS assessments, use of the same descriptive response thresholds as the most comparable prospective series, an explicit dosing schedule, 6-month follow-up, and transparent recognition that OCD improvement was secondary to treatment prescribed for TRD. Limitations include the single-case design; absence of a control condition, randomization, blinding, or independent ratings; lack of a documented structured diagnostic interview; limited characterization of OCD symptom dimensions and insight; incomplete detail on ERP delivery and on the exact oral regimen during follow-up; potential confounding by ongoing pharmacotherapy and repeated clinical contact; absence of biomarkers, functional scales, global impression measures, and a formal patient perspective; and lack of structured adverse-event and quantitative vital-sign data. Exact calendar dates were replaced with relative time points to reduce re-identification risk. These limitations make the report hypothesis-generating and restrict both causal inference and generalizability.

4. Conclusions

In this patient with severe OCD operationally aligned with the eligibility framework of the 2026 prospective series and comorbid TRD, routine-care intranasal esketamine augmentation was temporally associated with substantial, parallel reductions in MADRS and Y-BOCS scores that persisted through 6 months. Obsessive–compulsive improvement was a secondary observational outcome, and the case does not establish a direct anti-obsessional effect, demonstrate efficacy, or support interchangeability between intranasal esketamine and racemic ketamine delivered by other routes. Prospective controlled studies should use explicit TR-OCD definitions, fully characterize prior and concurrent ERP, stabilize and document background pharmacotherapy, employ blinded repeated ratings and functional outcomes, and collect structured safety data to determine whether any OCD-specific benefit is independent of antidepressant response.