This prospective case series (n=8) examined repeated intranasal esketamine for people with treatment-resistant obsessive-compulsive disorder and comorbid major depressive disorder, and found clear improvement in depression and a smaller, more variable reduction in obsessive-compulsive symptoms. Depression improved earlier than OCD symptoms, and half of the participants met response criteria for each condition.
Background
Patients with obsessive–compulsive disorder (OCD) and comorbid major depressive disorder (MDD) represent a severe subgroup with increased treatment resistance, greater functional impairment, and limited therapeutic options. Intranasal esketamine is a rapidly acting treatment for resistant depression, with emerging interest in potential anti-obsessional effects. However, prospective data in this comorbid population remain lacking.
Methods
We present eight adult cases (mean age 47.3 ± 8.8 years) with treatment-resistant OCD (TR-OCD) and comorbid MDD treated at Bellvitge University Hospital. All patients had failed at least two adequate SSRI trials, clomipramine, cognitive-behavioral therapy with exposure and response prevention, and at least one pharmacological augmentation strategy. Intranasal esketamine (56–84 mg/session) was administered according to the standard antidepressant protocol over 12 weeks. Response was defined as ≥ 35% reduction in Y-BOCS and ≥ 50% reduction in MADRS.
Results
Depressive symptoms improved substantially, with MADRS scores decreasing by 48.8% at Week 12 (p = 0.0026). Obsessive-compulsive symptoms showed a more modest and heterogeneous reduction, with a 30.3% decrease in Y-BOCS scores (p = 0.0037). Four of the eight participants (50.0%) achieved depression response, including two (25.0%) remissions, and four of the eight participants (50.0%) met OCD response criteria. Depressive symptoms improved earlier, whereas OCD symptoms followed a slower and more variable trajectory.
Conclusions
Repeated intranasal esketamine may offer a therapeutic window for patients with severe TR-OCD and comorbid MDD. These preliminary findings support further controlled studies to clarify its role, optimal administration, and integration with psychotherapy.
Papers cited by this study that are also in Blossom
Martinotti, G., Pettorruso, M. · Brain Sciences (2021)
Mcintyre, R. S., Rosenblat, J. D., Nemeroff, C. B. et al. · American Journal of Psychiatry (2021)
Obsessive-compulsive disorder (OCD) is a chronic and disabling condition that can remain severe despite established first-line treatments such as high-dose selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioural therapy with exposure and response prevention (ERP). The paper notes that a substantial subgroup develops treatment-resistant OCD (TR-OCD), and that comorbid major depressive disorder (MDD) is common and associated with greater severity, functional burden, and more complicated treatment trajectories. The authors frame this as a clinically important gap because current serotonergic and dopaminergic strategies often have limited efficacy in these highly refractory patients. The article also highlights growing interest in glutamatergic mechanisms, including ketamine and esketamine, as potential interventions for both depression and OCD. While intranasal esketamine is established for treatment-resistant depression, prospective data in patients with TR-OCD and comorbid MDD were lacking. The study therefore aimed to examine whether repeated intranasal esketamine augmentation was associated with change in depressive and obsessive-compulsive symptoms in this severe comorbid population, using a prospective case-series design at a specialist OCD referral centre.
López-Rodríguez and colleagues conducted a prospective observational case series at Bellvitge University Hospital. The study was explicitly described as descriptive and hypothesis-generating rather than a controlled efficacy trial. Eight adults with severe TR-OCD and comorbid MDD were included; the extracted text indicates that all had failed at least two adequate SSRI trials, clomipramine, CBT with ERP, and at least one pharmacological augmentation strategy. The paper also states that, descriptively, the sample corresponded to severe treatment resistance consistent with levels 3-4 in the Pallanti-Quercioli framework. Participants received intranasal esketamine as augmentation to their existing medication regimen. Doses ranged from 56 mg to 84 mg per session, following the approved antidepressant protocol for treatment-resistant depression. The induction phase involved two sessions per week for about four weeks, followed by weekly sessions up to Week 12, with minor adjustments made according to clinical evolution and clinician judgement. Concomitant medications, including SSRIs and antipsychotics, were continued throughout. Although all patients had previously received CBT including ERP, psychotherapy was not standardised, protocolised, or experimentally manipulated during the study period. The main outcomes were depression severity measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) and obsessive-compulsive severity measured with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Response was defined in advance as a reduction of at least 50% in MADRS for depression and at least 35% in Y-BOCS for OCD; remission for depression was defined as a MADRS score of 10 or below. Baseline and Week 12 scores were compared using paired two-sided t-tests, and the authors reported mean change, 95% confidence intervals, p-values, and within-subject effect sizes (Cohen’s dz). They also undertook non-parametric sensitivity analyses using Wilcoxon signed-rank tests.
At 12 weeks, both depressive and obsessive-compulsive symptoms improved, but the pattern differed by symptom domain. MADRS scores fell by 48.8% overall, with the change reported as statistically significant (p = 0.0026). Four of the eight participants (50%) met the predefined depression response criterion, and two participants (25%) achieved depression remission. Obsessive-compulsive symptoms also improved, though more modestly and with greater variability across individuals. Y-BOCS scores decreased by 30.3% at Week 12 (p = 0.0037), and four of the eight participants (50%) met the OCD response criterion. The authors report that depressive symptoms tended to improve earlier, whereas OCD symptoms improved more slowly and in a more heterogeneous fashion. Safety findings were limited but reassuring in this small series. The discussion states that repeated intranasal esketamine was generally well tolerated, with no serious adverse events and only transient, manageable side effects. The extracted text does not provide a detailed adverse-event table or additional numerical safety results.
The authors interpret this case series as preliminary evidence that repeated intranasal esketamine augmentation may help both depressive and obsessive-compulsive symptoms in a highly refractory group with TR-OCD and comorbid MDD. They emphasise that the antidepressant response appeared earlier and more consistently than the antiobsessional response, which they describe as slower and more heterogeneous. In their view, this temporal dissociation may mean that short early follow-up periods could underestimate any obsessive-compulsive benefit. They place the depression findings in line with the broader esketamine literature in treatment-resistant depression, including real-world data suggesting that clinically meaningful responses can emerge later in treatment rather than only at the earliest sessions. For OCD, they note that earlier ketamine/esketamine studies have been small, methodologically heterogeneous, and mostly based on single-session intravenous approaches, so their prospective intranasal series extends a still-limited evidence base. They also suggest, cautiously, that the different time courses for depression and OCD might reflect partially overlapping but distinct mechanisms, consistent with glutamatergic involvement in both disorders. The authors are careful not to overstate efficacy. They note that the sample was selected for very high baseline severity, so regression to the mean may explain some improvement, and that without a control group, randomisation, or blinded assessment it is impossible to separate treatment effects from natural fluctuation, expectancy, or repeated clinical contact. They also mention that the high baseline symptom burden leaves more room for percentage improvement while still leaving substantial residual illness. Additional limitations include the very small sample, observational design, 12-week follow-up, and the fact that concomitant psychotherapy was not standardised or measured, making it difficult to judge the interaction between esketamine and ERP. The authors conclude that larger controlled studies are needed to clarify efficacy, optimal treatment parameters, durability of benefit, and the role of concurrent psychotherapy in refractory OCD-MDD presentations.
The authors conclude that repeated intranasal esketamine augmentation was associated with improvement in both depressive and obsessive-compulsive symptoms in this small prospective series, with depression improving earlier and OCD improving more slowly and variably. They state that these findings are preliminary and should be interpreted cautiously because of the small sample, observational design, and absence of a control condition. They call for controlled prospective studies to determine efficacy, dosing and treatment schedules, and how esketamine might be integrated with psychotherapy.
The limited efficacy of purely serotonergic and dopaminergic strategies in a subset of patients with OCD and MDD has increased interest in glutamatergic dysfunction as a shared pathophysiological and therapeutic target. In OCD, converging evidence implicates glutamatergic abnormalities within cortico-striato-thalamo-cortical circuits involved in intrusive thoughts, compulsivity, inhibitory control, and maladaptive habit formation. Consistent with this framework, recent evidence syntheses suggest that glutamatergic agents may have therapeutic potential across obsessive-compulsive and related disorders, particularly OCD, although heterogeneity remains substantial and findings should be interpreted cautiously. Glutamate-related mechanisms may also be relevant to treatment processes: neuroimaging data suggest an association between glutamatergic measures, fear extinction, and CBT outcome in OCD, pediatric work has linked glutamatergic abnormalities to CBT response, and d-cycloserine augmentation of exposure-based CBT has been explored as a strategy to enhance learning-based treatment effects in anxiety, OCD, and related disorders. Against this background, ketamine and esketamine have emerged as particularly relevant glutamate-modulating interventions. Intranasal esketamine has demonstrated efficacy and safety in treatment-resistant depression (TRD) and has become an important addition to the therapeutic armamentarium for refractory depressive disorders. The broader TRD literature further strengthens the rationale for considering esketamine in severe OCD-MDD comorbidity. International expert synthesis has positioned ketamine and esketamine as mechanistically novel options in TRD, and more recent review work has summarized both the clinical data and the mechanistic framework supporting their use. Importantly, newer real- world and observational studies provide a richer context for interpreting outcomes. Olivola et al. reported that baseline mentalization and emotionalcognitive rigidity may shape response to esketamine in TRD, a potentially relevant observation in OCD, where rigidity and cognitive inflexibility are clinically prominent., in data from the REAL-ESK Study Group, showed that clinically meaningful response trajectories may extend into the mid-and long-term course, including later responders, which is especially relevant when different symptom domains may improve at different rates. In addition, Sarasso et al. suggested that esketamine's therapeutic action may extend beyond conventional symptom counts to experiential and phenomenological dimensions such as disembodiment and affective resonance, broadening the conceptual framework through which its clinical effects may be understood. Within OCD specifically, interest in ketamine-and esketamine-based approaches has grown steadily. Systematic reviews suggest preliminary antiobsessional effects of ketamine, but also emphasize the small samples, heterogeneous methodologies, and predominance of single-session intravenous studies in the available literature. More recently, a retrospective chart review reported preliminary improvement in obsessivecompulsive symptoms with esketamine augmentation in treatment-resistant OCD. However, prospective evidence remains extremely limited, and, to our knowledge, no prior prospective case series has specifically examined repeated intranasal esketamine augmentation in patients with TR-OCD and comorbid MDD. To address this gap, we conducted a prospective case series at Bellvitge University Hospital, a specialized referral center with a dedicated OCD Unit. Eight adult patients with severe TR-OCD and comorbid MDD, all of whom had failed at least two adequate SSRI trials, CBT with
This study was designed as a prospective observational case series. Owing to its descriptive and hypothesis-generating nature, it should not be interpreted as a controlled efficacy study.
The Psychiatry Department at Bellvitge University Hospital is a recognized According to the Pallanti-Quercioli proposal, treatment resistance in OCD can be descriptively staged on the basis of illness severity, prior treatment failures, and degree of refractoriness. In our sample, all patients fulfilled criteria consistent with severe treatment-resistant illness, corresponding descriptively to levels 3-4 of this framework. In this framework, levels 3-4 typically correspond to severe treatmentresistant OCD, characterized by persistent symptoms despite multiple adequate pharmacological trials and structured CBT with exposure and response prevention, generally associated with Y-BOCS scores in the severe range (≥24).
Eligible patients initiated intranasal esketamine augmentation to their preexisting psychopharmacological regimen, with doses ranging from 56 to 84 mg per session according to the approved antidepressant 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 minor adjustments based on clinical evolution and clinician judgment. Concomitant medications, including SSRIs and antipsychotics, were maintained throughout the observation period. All patients had previously undergone CBT including ERP as part of their treatment-resistant status. However, structured psychotherapy was not prospectively standardized, protocolized, or experimentally manipulated during the study period. Therefore, the possible contribution of concomitant. Figureshows the study timeline, including assessment points and session frequency.
For OCD, response was defined a priori as a ≥35% reduction from baseline Y-BOCS, in line with commonly used criteria for clinically meaningful treatment response in OCD studies. For depression, response was defined as a ≥50% reduction from baseline MADRS, and remission as a MADRS total score ≤10 at endpoint.
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). Non-parametric sensitivity analyses were conducted using Wilcoxon signed-
To our knowledge, this is the first prospective case series to specifically examine repeated intranasal esketamine augmentation in patients with severe treatment-resistant obsessive-compulsive disorder (TR-OCD) and comorbid major depressive disorder (MDD). In this highly refractory sample, repeated intranasal esketamine was associated with clinically meaningful improvement in both depressive and obsessive-compulsive symptoms over 12 weeks, although the temporal pattern differed across symptom domains. Depressive symptoms improved earlier and more consistently, whereas antiobsessional effects appeared more gradual and heterogeneous. This pattern is clinically relevant because it suggests that symptom domains may not respond in parallel and that short early observation periods may underestimate possible anti-obsessional benefit. The antidepressant findings are broadly consistent with the established literature on esketamine in treatment-resistant depression and with more recent real-world data suggesting that response trajectories may extend beyond the earliest treatment window. In this respect, our results may be read in line with the REAL-ESK data, which indicate that some patients derive clinically meaningful benefit only after more sustained treatment exposure. This is particularly relevant in OCD-MDD emotional-cognitive rigidity may influence esketamine outcomes. Although these variables were not assessed in our study, they may be especially pertinent to OCD and could partly account for the slower and less homogeneous anti-obsessional response observed here. At the same time, the present findings should not be interpreted as proof of a specific anti-obsessional effect independent of nonspecific improvement. Because participants were selected on the basis of high baseline severity, regression to the mean is a plausible contributor to part of the observed score reduction. In the absence of a control group, randomization, or blinded assessment, we cannot formally disentangle true treatment-related change from natural fluctuation, expectancy effects, or the impact of repeated clinical contact. Accordingly, the present data should be interpreted as preliminary clinical observations rather than confirmatory efficacy evidence. Baseline severity may also help explain the response pattern. Patients entering treatment with very high symptom scores have more statistical room for percentage improvement and may therefore be more likely to meet response criteria, while still remaining far from remission thresholds. This may be especially relevant in our sample, which was deliberately enriched for severe OCD and severe depressive symptoms. Thus, the relatively robust response rates should be interpreted alongside the still substantial endpoint burden in several patients, particularly for OCD symptoms. In our series, four of the eight participants (50.0%) met MADRS response criteria, two of the eight (25.0%) achieved MADRS remission, and four of the eight (50.0%) met the predefined OCD response criterion. These figures compare favorably with prior exploratory work in OCD-spectrum esketamine treatment, while remaining broadly consistent with the notion that benefit is heterogeneous and still incompletely characterized in this population. Our observations also extend earlier reports summarized in the ketamine/esketamine literature for OCD, which has so far been dominated by small studies, single-dose intravenous designs, and isolated case-based evidence. In particular, the case report by Marcatili et al. The slower and more variable reduction in obsessive-compulsive symptoms, compared with the more rapid antidepressant effect, also supports a more nuanced dual-action hypothesis. Rather than assuming a uniform effect across symptom domains, our findings suggest that esketamine may influence depressive and obsessive-compulsive dimensions through partially overlapping but temporally distinct mechanisms. This interpretation is conceptually compatible with prior work implicating glutamatergic dysfunction in both mood disorders and OCD, including cortico-striatothalamo-cortical circuitry relevant to compulsivity, and with the broader suggestion that esketamine's clinical effects may extend beyond mood symptoms alone. From a practical standpoint, this raises the possibility that sustained treatment exposure and perhaps combination with structured psychotherapy such as ERP may be necessary to obtain fuller anti-obsessional benefit. Repeated intranasal esketamine was generally well tolerated in this sample. No serious adverse events were observed, and overall side effects were transient and manageable, suggesting that this approach is feasible in specialized psychiatric settings with appropriate monitoring. However, tolerability and feasibility should not be conflated with efficacy, and larger controlled studies will be needed before any firm clinical role can be assigned to intranasal esketamine in refractory OCD-MDD presentations. Several limitations must be emphasized. The small sample size, observational design, and absence of randomization substantially restrict generalizability and preclude causal inference. The lack of a control condition limits interpretation of the observed changes and prevents formal separation of treatment effects from regression to the mean or nonspecific therapeutic factors. Follow-up was limited to 12 weeks, precluding conclusions about maintenance effects, relapse prevention, or the durability of anti-obsessional benefit. In addition, concomitant psychotherapy was not prospectively standardized or systematically quantified, which is particularly important in OCD and limits conclusions regarding the interaction between esketamine and behavioral treatment.
This prospective case series provides preliminary clinical data suggesting that repeated intranasal esketamine augmentation may be associated with improvement in both depressive and obsessive-compulsive symptoms in a subgroup of patients with severe TR-OCD and comorbid MDD. Depressive symptoms appeared to improve earlier, whereas obsessive-compulsive symptoms showed a slower and more heterogeneous trajectory. These findings help inform the ongoing evaluation of administration routes, dosing schedules, and treatment integration strategies for highly refractory OCD-MDD presentations, but they should be interpreted cautiously given the small sample, observational design, and lack of a control condition. Controlled prospective studies are needed to clarify efficacy, optimal treatment parameters, and the role of concurrent psychotherapy.
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