Use of SPRAVATO in Patients with Comorbid Anxiety or Obsessive-Compulsive Disorder

SUMMARY

• SPRAVATO nasal spray has not been formally studied in patients with comorbid anxiety or obsessive-compulsive disorders (OCD), although patients with comorbid anxiety disorder could participate in phase 3 clinical trials.^1-7
  • Of note, patients with a current diagnosis of OCD at the time of study entry were excluded from participation.^1-7
• In 2 short-term and 2 long-term phase 3 studies in patients with treatment-resistant depression (TRD), a high percentage of SPRAVATO-treated subjects (62% to 80%) had moderate to severe levels of anxiety symptoms at baseline using self-reported Generalized Anxiety Disorder 7-item Scale (GAD-7) scores.^2-5,8
  • Anxiety symptoms were measured as a secondary endpoint using the GAD-7.^2,3
• In two short-term, double-blind (DB), TRD studies, there were improvements in anxiety symptoms observed in both the SPRAVATO plus newly initiated oral antidepressant (AD; SPRAVATO+oral AD) and placebo(PBO)+oral AD groups.^2,3
  • A post hoc, pooled analysis of the two studies demonstrated greater response rates for depressive symptoms with SPRAVATO+oral AD vs PBO+oral AD, regardless of comorbid anxiety at baseline.^2,3,9
• A post hoc analysis of a 4-week flexible-dose, DB, active-controlled trial (TRANSFORM-2)³ assessed the efficacy and safety of SPRAVATO+oral AD vs PBO+oral AD in patients with TRD with and without comorbid anxiety symptoms or disorder.¹⁰ At day 28, patients in the SPRAVATO+oral AD group, with and without comorbid anxiety symptoms or disorder, demonstrated significant reductions in Montgomery–Åsberg Depression Rating Scale (MADRS) from baseline vs patients in the PBO+oral AD group.
• A retrospective, single-arm, real-world study evaluated the long-term effectiveness and safety of SPRAVATO+oral AD in adults with TRD, including patients with clinically noteworthy anxiety symptoms or anxiety disorders; after ≥100 SPRAVATO sessions, patients demonstrated a reduction in anxiety severity, as assessed by decreases in GAD-7 scores from baseline (16.5) to last assessment (10.5).¹¹ 

BACKGROUND

The GAD-7 is a brief, validated, and self-administered measure of overall anxiety with 7 items scored from 0-3 that yields a total score of 0-21. The GAD-7 was used to measure anxiety in the phase 3 TRD clinical trials.^2,3

The items included in GAD-7 are:

1. Feeling nervous, anxious, or on edge
2. Not being able to stop or control worrying
3. Worrying too much about different things
4. Trouble relaxing
5. Being so restless it is hard to sit still
6. Becoming easily annoyed or irritable
7. Feeling afraid as if something awful might happen

The severity categories for GAD-7 are none (0-4), mild (5-9), moderate (10-14), and severe (15-21).¹²

Clinical TRIAL Data

Post hoc Analyses of Short-term Clinical Trials of TRD

Daly et al (2019)⁹ conducted a post hoc, pooled analysis of two 4-week, double-blind, placebo-controlled studies.^2,3 The objective of the analysis was to evaluate the impact of SPRAVATO in patients with TRD and comorbid anxiety at baseline compared to those without comorbid anxiety. Patients with TRD and comorbid anxiety at baseline were identified based on 3 definitions: 1) presence of anxious depression, based on the Inventory of Depressive Symptomatology – Clinician rating (IDS-C) anxiety subscale (IDS-C_ANX) score ≥8; 2) comorbid anxiety disorder as evaluated on the MINI; and 3) presence of anxious distress, based on a score of ≥2 on at least 2 items of the GAD-7 scale among the following items: item 1 (feeling anxious), 2 (unable to stop worrying), 5 (restlessness), and 7 (being afraid). Response of depressive symptoms was defined as ≥50% improvement in MADRS total score from baseline to day 28.

At baseline, 22.3% (126/564), 14.2% (80/565), and 72.9% (412/565) of patients had anxious depression, comorbid anxiety disorder, or anxious distress, respectively, based on the definitions above. Of those meeting the criteria for comorbid anxiety at baseline (n=430), as assessed by a GAD-7 total score ≥10, 54.7% (129/236) of patients in the SPRAVATO+oral AD group achieved a response to treatment compared with 46.0% (74/161) of patients in the PBO+oral AD group at day 28. For those patients without comorbid anxiety at baseline (GAD-7 total score <10), 71.6% (53/74) of patients treated with SPRAVATO+oral AD achieved a response compared with 42.6% (20/47) of patients treated with PBO+oral AD at day 28. Treatment differences were observed in patients with and without anxiety treated with SPRAVATO+oral AD vs PBO+oral AD, with greater improvement observed in those without comorbid anxiety. (Figure: Response Rates at Day 28 Based on MADRS Total Score in Patients [A] With and [B] Without Comorbid Anxiety at Baseline).

Daly et al (2021)¹⁰ conducted a post hoc analysis of a 4-week flexible-dose, double-blind, active-controlled trial (TRANSFORM-2)³ to assess the efficacy and safety of SPRAVATO+oral AD vs PBO+oral AD in patients with TRD with and without comorbid anxiety symptoms or disorder. Comorbid anxiety was defined as clinically noteworthy anxiety symptoms (GAD‐7 score ≥10) at screening and baseline or comorbid anxiety disorder diagnosis at screening.

• At DB baseline, 72.6% (162/223) of patients had comorbid anxiety symptoms or disorder, with 69.1% (154/223) of patients reporting a GAD-7 total score ≥10 and 13.5% (30/223) meeting criteria for current anxiety disorder on the Mini International Neuropsychiatric Inventory interview (MINI).
  • Patients with comorbid anxiety symptoms or disorder appeared to have more chronic depressive symptoms vs patients without based on a longer mean duration of current depressive episode (SPRAVATO+oral AD group with comorbid anxiety: 122.3 weeks vs without comorbid anxiety: 82.3 weeks; PBO+oral AD group with comorbid anxiety: 130.6 weeks vs without comorbid anxiety: 84.8 weeks) and higher mean MADRS score at baseline (SPRAVATO+oral AD group with comorbid anxiety: 37.4 vs without comorbid anxiety: 36.0; PBO+oral AD with comorbid anxiety: 38.5 vs without comorbid anxiety: 34.1).  
• At day 28, SPRAVATO+oral AD patients with and without comorbid anxiety symptoms or disorder demonstrated significant reductions in MADRS (with comorbid anxiety symptoms or disorder [n=72]: -21.0 [SD:12.51], 95% CI: -23.6 to -18.1 vs without comorbid anxiety symptoms or disorder [n=29]: -22.7 [SD:11.98], 95% CI: -28.4 to      -19.8) from baseline.
  • There was a greater improvement in MADRS score in the SPRAVATO+oral AD group vs PBO+oral AD in both patients with comorbid anxiety (difference of LS mean: with comorbid anxiety [n=144]: -4.2, 95% CI: -8.1 to -0.3; difference of LS mean: patients without comorbid anxiety [n=57]: -7.5, 95% CI: -13.7 to -1.3).
  • Treatment differences between patients with and without comorbid anxiety symptoms or disorder were not statistically significant (difference of LS mean: 3.3, 95% CI: -4.0 to 10.6; P=0.371).
• At day 28, a greater percentage of patients met the response criteria in the SPRAVATO+oral AD vs PBO+oral AD group (patients with comorbid anxiety symptoms or disorder: 65.3% vs 54.2%, respectively; OR=1.59; 95% CI, 0.81 to 3.11 vs patients without: 79.3% vs 46.4%, respectively; OR=4.42, 95% CI, 1.38 to 14.19). In addition, a greater percentage of patients met the remission criteria in the SPRAVATO+oral AD vs PBO+oral AD group (patients with comorbid anxiety symptoms or disorder: 47.2% vs. 33.3%, respectively; OR=1.79; 95% CI: 0.91 to 3.51) vs patients without: 65.5% vs. 25.0%, respectively; OR=5.70; 95% CI: 1.81 to 17.97).
  • The interaction of treatment and comorbid anxiety symptoms or disorder was not statistically significant for response (P=0.136) or remission (P=0.088).
• The most common adverse events reported (>10% of all patients) were anxiety, blurred vision, dissociation, dizziness, dysgeusia, headache, nausea, paresthesia, somnolence, and vertigo, with a higher incidence in the SPRAVATO+oral AD group.
  • Most adverse events in both treatment groups were mild or moderate and resolved on the treatment day.  
  • The incidence of dissociative symptoms, based on CADSS total score >4, was higher in the SPRAVATO+oral AD vs PBO+oral AD group (patients with comorbid anxiety symptoms or disorder: 67.5% vs 12.7%, respectively; P<0.001; patients without: 74.2% vs 6.7%, P<0.001). However, the presence or absence of comorbid anxiety symptoms or disorder appeared to be unrelated to the incidence.  

Real World Study

Ayad et al (2026)¹¹ conducted a retrospective, single‑arm, real‑world study to evaluate the long‑term effectiveness and safety of SPRAVATO+oral antidepressants in adults with TRD, including patients with comorbid anxiety disorders and OCD, treated for ≥100 SPRAVATO sessions from a psychiatric service in the United Arab Emirates.

• A total of 20 patients with TRD were included (male, 50%; mean age, 40 years); 95% (19/20) had ≥1 psychiatric comorbidity, with a mean of 3.1 comorbidities per patient.
  • Generalized anxiety disorder (GAD) was the most common comorbid diagnosis (n=15). Three patients had a comorbid diagnosis of OCD.
• Patients received a mean of 129.3 SPRAVATO sessions (range: 100-202) over a mean treatment duration of 2.5 years; SPRAVATO was initiated at 56 mg and maintained at 84 mg in all patients.
• Depression outcomes were assessed using the Patient Health Questionnaire‑9 (PHQ‑9) scale
  • The median PHQ-9 score decreased from 18.5 prior to the first SPRAVATO session to 11.0 after the last SPRAVATO dose (P=0.0002)
  • Among all patients, 85% (n=17) saw improvements in their depression severity, with remission (PHQ-9 score <5) achieved in 25% (n=5) of patients.
• Anxiety outcomes were assessed using the GAD‑7 scale.
  • Median GAD‑7 total score decreased from baseline from 16.5 (interquartile range, IQR: 11.75-21.25), consistent with clinically noteworthy anxiety symptoms (GAD-7 ≥10), to 10.5 (IQR: 6.62-14.38) at the last assessment.
  • 65% (13/20) of patients demonstrated an improvement in anxiety severity, and 20% (4/20) met criteria for anxiety remission (GAD‑7 score <5) at last assessment.
• Improvements were observed across 6 of 7 individual GAD‑7 items, including nervousness/anxiety, inability to control worry, excessive worry, irritability, restlessness, and fear of negative outcomes.
• Safety outcomes relevant to anxiety included:
  • Dissociative symptoms, assessed using CADSS, were reported in 15% (3/20) of patients shortly after dosing and resolved within 1 hour.
  • Mild sedation (MOAA/S score=4) was reported in 40% (8/20) of patients.
  • The presence of comorbid anxiety symptoms or disorder did not appear to be associated with persistent dissociation or other clinically significant safety findings.
  • The mean brief psychiatric rating scale (BPRS) was 23.9, with 80% (n=16) of patients having a positive BPRS score. Anxiety was observed in 1 patient.

Case Reports and Case Series

Ahmad et al (2025)¹³ described a real‑world case series of five patients with TRD who had failed a full course of transcranial magnetic stimulation (TMS) and were subsequently treated with SPRAVATO plus oral antidepressant therapy. Comorbid anxiety disorders, including GAD, were present in the majority of patients. Response to treatment (≥50% reduction in symptoms) was assessed using the PHQ‑9, Beck Depression Inventory (BDI), and GAD‑7 scales.

After 16 SPRAVATO sessions, all five patients achieved a treatment response (≥50% reduction from baseline) based on PHQ‑9 and BDI scores. Four patients (80%) achieved remission of depressive symptoms based on PHQ‑9 scores, and three patients (60%) achieved remission based on BDI scores. Treatment response based on GAD-7 scores was observed in four patients (80%). GAD-7 scores at baseline, and at the 8th and 16th sessions of SPRAVATO are reported for each patient in the Table: GAD-7 scores.

Matteo et al (2021)¹⁴ described a case report of a 39-year-old male with TRD who presented to the clinic with a major depressive episode. At the time of presentation, the patient was on the following medications: venlafaxine, bupropion, olanzapine, and citelamotrigine. Upon further evaluation, the patient reported intrusive and egodystonic obsessions regarding his wife and the presence of ritualistic intrusive and pervasive doubts regarding his mental health. The patient was diagnosed with TRD with comorbid OCD and enrolled for SPRAVATO treatment. A rapid resolution of depressive symptoms was reported during the induction phase and a significant reduction of OCD symptoms (46.67% reduction, Yale-Brown Obsessive-Compulsive Disorder scale) was reported during the maintenance phase. At the 9^th scheduled dose of SPRAVATO, olanzapine and lamotrigine were discontinued, and residual anxiety symptoms were managed with pregabalin.

Pepe et al (2023)¹⁵ described changes in cognition after 12 weeks of treatment with SPRAVATO in a case series of 8 patients with TRD, including a 50-year-old female patient with comorbid OCD. The patient received SPRAVATO 56 mg twice weekly for the first month followed by 84 mg once weekly over the next 8 weeks, with concomitant sertraline, duloxetine, lithium carbonate, and asenapine.

A reduction in cognitive, depressive, and anxiety symptoms was reported after 3 months of treatment (psychometric assessment scores at baseline vs at 3 months: Digit Symbol Substitution Test [DSST], 45 vs 55; Trail Making Test-B [TMT-B], 90 vs 53; Perceived Deficits Questionnaire for Depression 5-item test [PDQ-D5]; 11 vs 4; MADRS, 36 vs 18; and Hamilton Anxiety Rating Scale [HARS], 19 vs 16). Symptoms of mild dissociation, nausea, and small increases in blood pressure were reported during the 2 hours after SPRAVATO administration and resolved over the course of the observation period. No clinically relevant side effects were reported throughout the treatment period.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 02 March 2026.

Case reports related to comorbid anxiety disorders were excluded from the response.