2026 ECNP Congress

PS03-3083

Dual-SSRI combinations in ultra-resistant obsessive–compulsive disorder: a real-world observational pilot study

Sara Cicali — A. Cuomo, C. Libri, M.B. Rescalli, F. Castaldo, A.N. Piscopello, F. Martorelli, A. Santangelo, M. Pinzi, A. Fagiolini · University of Siena, Department of Molecular and Developmental Medicine, Siena, Italy

2026 ECNP Congress

Introduction

Obsessive – compulsive disorder (OCD) is a chronic and disabling condition for which selective serotonin reuptake inhibitors (SSRIs) represent first-line treatment. In treatment-resistant cases, strategies such as clomipramine switching and antipsychotic augmentation are commonly adopted; however, a clinically relevant subgroup remains refractory, defining ultra-resistant OCD. In this setting, therapeutic options are extremely limited, and no systematic clinical data are currently available on dual-SSRI strategies. Combining SSRIs may provide a pharmacologically plausible approach through enhanced serotonergic modulation, but its clinical utility remains largely unexplored. This study aimed to descriptively evaluate clinical outcomes and tolerability of dual-SSRI combinations in ultra-resistant OCD in a real-world setting.

Methods

This naturalistic observational study included patients with ultra-resistant OCD, defined as non-response to at least three adequate SSRI trials, clomipramine, and at least one antipsychotic augmentation. Patients were treated with dual-SSRI combinations consisting of sertraline plus either citalopram or fluoxetine. Assessments were conducted at baseline (T0), 4 weeks (T1), and 8 weeks (T2). The primary outcome was change in Yale–Brown Obsessive Compulsive Scale (Y-BOCS) total score (absolute and percentage variation). Clinical response was defined as ≥35% reduction in Y-BOCS and CGI-I ≤2. Secondary outcomes included longitudinal changes in Y-BOCS subscores, CGI-I distribution, and tolerability assessed through FIBSER and adverse event monitoring. All analyses were descriptive due to the small sample size.

Results

Ten patients with long-standing, highly treatment-refractory OCD were included, with high baseline severity (mean Y-BOCS 30.6 ± 4.7). A progressive reduction in symptom severity was observed over time: T1 : 26.1 ± 4.8 and T2 : 20.1 ± 2.8 corresponding to a mean reduction of 33.8% at 8 weeks. No patients met response criteria at T1, whereas 6/10 (60.0%) were responders at T2, suggesting a delayed and time-dependent treatment effect. CGI-I ≤2 was observed in 70.0% of patients at T2. Both obsessive and compulsive dimensions improved in parallel. Descriptively, both combination strategies showed similar trajectories. The fluoxetine-based combination showed a numerically higher responder rate compared to the citalopram-based strategy (75.0% vs 50.0%), while mean percentage reduction was comparable (33.7% vs 33.9%). These differences should be interpreted cautiously given baseline heterogeneity. Tolerability was overall acceptable. Mild adverse events were reported in 50.0% of patients, including gastrointestinal symptoms, sedation, activation/insomnia, sexual dysfunction, and appetite/weight changes. No serious adverse events, hospitalizations, or treatment discontinuations were observed. Importantly, no cases of serotonin syndrome requiring treatment were observed. Body weight remained overall stable.

Conclusions

In this small real-world sample, dual-SSRI combinations showed a progressive, time-dependent signal of clinical improvement in ultra-resistant OCD, emerging after the first month of treatment and associated with an overall manageable tolerability profile. These findings are preliminary and hypothesis-generating, and suggest that dual-SSRI strategies may represent a potential option in carefully selected ultra-resistant patients within specialist settings. Further controlled studies are warranted.

References

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