SUMMARY

• In the clinical trials for SPRAVATO nasal spray, dissociative symptoms and transient perceptual effects, measured by the Clinician Administered Dissociative Symptoms Scale (CADSS), began shortly after the start of SPRAVATO dosing, peaked at 40 minutes, generally resolved by 1.5 hours, and attenuated with repeated dosing.^1-6
• The most common psychological effects of SPRAVATO were perceptual changes (including distortion of time, space and illusions) and dissociative symptoms (including derealization and depersonalization).^2,4,7-9
  • 61%-84% of SPRAVATO-treated patients developed dissociative or perceptual changes compared to 5%-16% of placebo (PBO)-treated patients based on the CADSS total score >4 and change >0.¹
  • Although patients with psychosis were excluded in the phase 3 treatment-resistant depression (TRD) program,^2-6 given its potential to induce dissociative effects, carefully assess patients with psychosis before administering SPRAVATO; treatment should be initiated only if the benefit outweighs the risk.¹
• In an analysis of adverse reactions from phase 2 and phase 3 studies for TRD, of 1709 patients who were treated with SPRAVATO + newly initiated oral antidepressant (AD), the incidence of dissociation was 40.4% (690/1709). Within the double-blind (DB) populations, dissociation was reported in 37.6% (221/587) of patients treated with SPRAVATO+oral AD and 6.2% (30/486) of patients treated with PBO+oral AD.¹⁰ See: Incidence of Dissociation.
  • A post hoc analysis of 2 long-term studies in TRD found that those who experienced an adverse event (AE) of dissociation during the first week of treatment with SPRAVATO+AD were more likely to have dissociation recur during subsequent weeks.¹¹
• Dissociative effects are not required for the AD action of SPRAVATO based on post hoc correlational analyses in TRD.¹²
• Two post hoc analyses of a long-term phase 3 study (SUSTAIN-2) did not find a correlation between clinician-reported AE of dissociation and a specific cut-off on the total CADSS score.^6,13,14
  • There was no universal profile of dissociative symptoms associated with SPRAVATO. However, symptom clusters, including changes in bodily sensations, general perceptual changes, and a general sense of being disconnected from one’s own experience (depersonalization) increased in frequency as the severity of clinicianreported AEs of dissociation increased.¹⁴
• A post hoc analysis of SUSTAIN-2 comparing the efficacy and safety of SPRAVATO nasal spray in younger (18-64 years) vs older (≥65 years) patients with TRD found that the incidences of dissociation occurred in 19.3% vs 16.7% of patients during optimization/maintenance (OP/MA) phase. The incidence of dissociation (CADSS score >4) was similar between both age groups.¹⁵
• A real-world retrospective study in patients with TRD receiving SPRAVATO in outpatient psychiatric setting found that a total of 73% (125/171) of patients experienced dissociation; however, the symptoms resolved within 2 hours in most patients.¹⁶
• The REAL-ESK study, a retrospective, observational study evaluating the safety and effectiveness of SPRAVATO in real-world patients with TRD (N=116) reported dissociative symptoms in 39.7% of patients.¹⁷
• In postmarketing safety data from the Risk Evaluation and Mitigation Strategy (REMS) program from March 5, 2019, to January 5, 2023, dissociative effects were reported in 67.3% of patients and 42.3% of treatment sessions.¹⁸ In an analysis of postmarketing safety data (March 2019 to first quarter 2020) from the Food and Drug Administration Adverse Event Reporting System (FAERS), dissociation was reported (212 cases) as an expected AE with a detected signal.¹⁹
• Clinical judgment should be used for managing severe dissociation that does not resolve by itself during the postadministration monitoring period. See: Management of Dissociative Symptoms.

PRODUCT LABELING

• Because of the risks of serious adverse outcomes resulting from sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program under a REMS called the SPRAVATO REMS.²⁰
  • Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored by a healthcare provider for at least 2 hours (including pulse oximetry) at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.
  • For additional information or questions about the REMS, call 1-855-382-6022 or visit www.SPRAVATOrems.com.
• In studies in patients with major depressive disorder (MDD) and active suicidal ideation with intent, a higher proportion of patients treated with SPRAVATO+AD (84%) reported CADSS total score >4 and change >0 compared with patients treated with PBO+AD (16%).²⁰

BACKGROUND

CADSS

The CADSS is a 23-item scale with excellent inter-rater reliability and internal consistency administered to assess treatment-emergent dissociative symptoms and perceptual changes. It consists of 23 subjective items, divided into 3 components: depersonalization (items 3-7, 20, and 23), derealization (items 1, 2, 8-13, 16-19, and 21) and amnesia (items 14, 15, and 22). Participant’s responses are coded on a 5-point scale (0=not at all, 1=slightly, 2=moderately, 3=considerably, 4=extremely). The total CADSS score ranges from 0 to 92, with a higher score representing a more severe condition and scores between 0 and 4 are considered to be in the normal range.^21,22

CLINICAL DATA

Incidence of Dissociation

In an analysis of adverse reactions from phase 2 and phase 3 studies for TRD, of 1709 patients who were treated with SPRAVATO+AD, the incidence of dissociation was 40.4% (690/1709). Within the DB populations, dissociation was reported in 37.6% (221/587) of patients treated with SPRAVATO+AD and 6.2% (30/486) of patients treated with PBO+AD.¹⁰

• Dissociation included delusional perception, depersonalization/derealization disorder, derealization, diplopia, dissociation, dysesthesia, feeling cold, feeling hot, feeling of body temperature change, hallucination, hallucination – auditory, hallucination – visual, hyperacusis, illusion, ocular discomfort, oral dysesthesia, paresthesia, paresthesia oral, pharyngeal paresthesia, photophobia, time perception altered, tinnitus, vision blurred, and visual impairment.¹
• Across all phase 3 studies in TRD,^2-6 discontinuation of SPRAVATO due to dissociation occurred in 0.4% of patients.²³

In clinical trials in patients with MDD and active suicidal ideation with intent, dissociation was reported as follows:

• ASPIRE-I: 29.2% (33/113) and 3.6% (4/112) of patients treated with SPRAVATO 84 mg plus standard of care (SOC) and with SOC+PBO, respectively.⁷
  • In ASPIRE-I, discontinuation of SPRAVATO+SOC occurred in 4.4% of patients.⁷
• ASPIRE-II: 38.6% (44/114) and 8% (9/113) of patients treated with 84 mg SPRAVATO+SOC and with SOC+PBO, respectively.⁸
  • In ASPIRE-II discontinuation of SPRAVATO+SOC occurred in 2 patients due to dissociation.²⁴

CADSS

TRANSFORM-1 (3001)², TRANSFORM-2 (3002)³, and TRANSFORM-3 (3005)⁴ were 4week, randomized, DB, multinational studies comparing the efficacy and safety of fixed (3001) or flexibly (3002/3005) dosed SPRAVATO+AD vs AD+PBO in adult patients (1864 years; 3001/3002) and ≥65 years (3005) with TRD. Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff.

Dose-related increases in the incidence of dissociative symptoms were observed in TRANSFORM-1 and TRANSFORM-3.^2,4 See Table: Incidence of Dissociation (CADSS Total Score >4 and a Change >0) in Two Double-Blind, Randomized Studies.

Over the course of each study, the peak mean CADSS total score at the 40-minute timepoint in patients treated with SPRAVATO decreased with consecutive doses. See Figure: Mean Total CADSS Score Over Time in TRANSFORM-2.

In the ASPIRE-II study, in patients with MDD and active suicidal ideation with intent, dissociative symptoms measured by the CADSS total score began shortly after SPRAVATO dosing, peaked at the 40-minute postdose assessment, and mostly resolved by 1.5 hours. The highest mean (SD) CADSS total score after the first dose was 15.9 (12.8) in the SPRAVATO +SOC and 1.9 (4.4) in the PBO+SOC group.⁸

Chen et al (2023)²⁶ conducted a randomized, DB, active-controlled, multicenter study in patients with TRD aged 18-64 years in China and the US to evaluate the efficacy and safety of flexibly dosed (56 or 84 mg) SPRAVATO+oral AD (n=126) vs PBO+oral AD (n=126) after 4 weeks of treatment. Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under the supervision of clinical staff. A new open-label oral AD was initiated (duloxetine, escitalopram, sertraline, or venlafaxine extended release).

Dissociation was reported in 59.5% (75/126) of patients in the SPRAVATO group vs 6.3% (8/126) in the PBO group. Treatment-emergent dissociation leading to treatment discontinuation was reported in 1.6% (2/126) of patients treated with SPRAVATO. In both groups, all treatment-related dissociation that occurred on the day of dosing resolved on the same day. Over the course of the study, the peak mean CADSS total score at the 40-minute timepoint in patients treated with SPRAVATO decreased with consecutive doses.²⁷

SUSTAIN-1 (3003)⁵ was a long-term, DB, multicenter, randomized-withdrawal, relapse prevention study to assess the efficacy of flexibly-dosed SPRAVATO+AD compared with an oral AD+PBO in delaying relapse of depressive symptoms in patients with TRD who were stable responders and remitters after an initial 16 weeks of treatment with SPRAVATO+AD. During the induction (IND) phase (initial 4 weeks), patients selfadministered either SPRAVATO or PBO nasal spray 2 times per week. In the OP phase (12 weeks), nasal spray medication was administered weekly for the first 4 weeks; thereafter, in the OP and following MA phase (variable duration), dosing was individualized to once weekly or once every other week based on severity of depression symptoms. 

Mean changes in CADSS total score 40-minute postdose for SPRAVATO+AD patients are as follows:²²

• IND phase – Decreased from 6.7 (day 1) to 2.9 (day 25)
• OP phase – Decreased from 2.9 (week 1) to 2.4 (week 11)
• MA phase – Decreased from 2.7 (week 1) to 2.5 (week 32)

See Figure: Mean Total CADSS Score Over Time in SUSTAIN-1.

SUSTAIN-2 (3004)⁶ was an open-label (OL), multicenter, study to evaluate the long-term (up to 1 year of exposure) safety, tolerability and efficacy of flexibly-dosed SPRAVATO (28, 56 or 84 mg) plus a newly initiated oral AD in patients with TRD. During the IND phase (initial 4 weeks), patients self-administered SPRAVATO+AD 2 times per week. In the OP/MA phase (up to 48 weeks), nasal spray medication was reduced to once weekly for the first 4 weeks, and then individualized to once weekly or once every other week based on severity of depression symptoms.

Mean changes in CADSS total score 40-minute postdose for patients are as follows²²:

• IND phase: Decreased from 6.4 (day 1) to 3.0 (day 25)
• OP/MA phase: Decreased from 2.8 (week 1) to 1.0 (week 48)

SUSTAIN-3 (3008)²⁸ was an open-label extension study to evaluate the long-term safety and efficacy of individualized, intermittently dosed SPRAVATO+oral AD in patients with TRD (N=1148). During the IND phase (initial 4 weeks), patients self-administered a flexible dose of SPRAVATO 2 times per week (starting dose of 28 mg [patients aged ≥65 years], 56 mg, or 84 mg). In the OP/MA phase (variable duration), patients were administered SPRAVATO once weekly, every other week, or every 4 weeks based on severity of depression symptoms.

Dissociation was reported in 25.5% (293/1148) of patients and led to discontinuation of SPRAVATO in 0.4% (5/1148) of patients. The majority of dissociation-related AEs (99.7%) occurred and resolved on the day of dosing across study phases.

ESCAPE-TRD²⁹ was a 32-week, randomized, phase 3b study that evaluated the efficacy and safety of SPRAVATO vs quetiapine extended-release (QUE-XR) in combination with ongoing oral AD (selective serotonin reuptake inhibitor [SSRI] or serotonin norepinephrine reuptake inhibitor [SNRI]) in patients with TRD. In the treatment phase (initial 8 weeks), patients were randomized to receive flexible doses of SPRAVATO+oral AD (28 mg, 56 mg, or 84 mg SPRAVATO) or QUE-XR+oral AD (50 mg on day 1, increasing to 150-300 mg/day QUE-XR); flexible dosing was continued for 24 weeks in the MA phase.³⁰ SPRAVATO was administered 2 times per week during weeks 1-4, once weekly during weeks 5-8, and once weekly or every other week during weeks 9-32.³⁰

Dissociation was reported in 28.1% (94/334) of patients in the SPRAVATO group and 0.6% (2/336) in the QUE-XR group.³⁰ Treatment discontinuation due to dissociation was reported in 0.6% (2/334) of patients in the SPRAVATO group and none in the QUE-XR group.³⁰

Post Hoc Analysis of Tolerability Trends During Postdose Monitoring

Williamson et al (2022)¹¹ conducted a post hoc for the 2 long-term studies^5,6 that characterized the recurrence of AEs for SPRAVATO based on AEs that occurred during the early and later courses of treatment. Incidence, frequency, and severity of the most common AEs (ie, dizziness, dissociation, nausea, vertigo, increased blood pressure, and sedation) were evaluated.¹¹

Results

Dissociation was reported in 16.7% of patients in week 1, (see Table: Rates of Dissociation Recurrence According to Frequency of Dissociation Occurrence in Week 1). Compared with week 1, the dissociation occurrence in week 4 was more closely associated with later recurrence.

The mean severity score was 1.2-1.4 in patients who reported mild-to-moderate levels of dissociation per CADSS (total score ≤14); no obvious difference was reported in the severity of subsequent episodes of dissociation. The mean severity score was 1.3-2.1 in patients with maximum CADSS scores (15-24 and 24-42) across all time frames.¹¹

Post Hoc Analysis of SUSTAIN-2

Ochs-Ross et al (2021)¹⁵ performed a post hoc analysis of the long-term (1-year), openlabel, multicenter, phase 3 SUSTAIN-2 study comparing the efficacy and safety of SPRAVATO nasal spray in younger (18-64 years) vs older (≥65 years) patients with TRD. In younger vs older patients, the incidences of dissociation occurred in 24.0% (150/624) vs 20.6% (32/155) of patients during the IND phase and in 19.3% (92/477) vs 16.7% (21/126) of patients during the OP/MA phase. The greatest mean postdose increase in CADSS total score (at 40 minutes) after the first SPRAVATO dose was higher in younger patients. The incidence of dissociation (CADSS total score >4) was similar between both age groups.

Post Hoc Analysis of ASPIRE Studies

Fua et al (2020)³¹ performed a post hoc analysis of patients with MDD and active suicidal ideation with intent (pooled data from ASPIRE I AND ASPIRE II trials), which found 33.9% of patients (77/227) who had received SPRAVATO+SOC and 5.8% of patients (13/225) who had received PBO+SOC experienced dissociation. Severe dissociation occurred in 4.0% of patients (9/227) who received SPRAVATO+SOC and in no patients who received PBO+SOC. Discontinuations due to dissociation of any severity occurred in 1.3% of patients (3/227) who received SPRAVATO+SOC and in no patients who received PBO+SOC.

Post Hoc Analysis Evaluating the Relationship Between Dissociation and Efficacy

Chen et al (2022)¹² performed a post hoc analysis of patients with TRD (data from TRANSFORM-2 and SUSTAIN-1 studies), which did not find a significant association between the presence of dissociation and efficacy of SPRAVATO. Correlation analyses in TRANSFORM2 showed that there were no significant associations between increases in CADSS total scores after first nasal spray treatment and improvements in depressive symptoms on either day 2 (r=−0.05 [95% confidence interval (CI), -0.23 to 0.14]) or day 28 (r=−0.08 [95% CI, -0.27 to 0.12]), or between increases in CADSS total score after the last nasal spray treatments on day 25 and improvements in depressive symptoms on day 28 (r=−0.16 [95% CI, -0.36 to 0.04]). Similar findings resulted from analyses of the TRANSFORM-1 study.

A mediation analysis of TRANSFORM-2 showed insufficient mediation effects of dissociation on SPRAVATO efficacy on day 1 (least-squares mean difference [LSMD]: -0.45; 95% CI, 1.85 to 0.85) and on day 25 (LSMD: -0.42; 95% CI, -1.95 to 0.94) of treatment. In contrast, SPRAVATO had a significant and direct effect on depressive symptoms on day 1 (LSMD: -3.62; 95% CI, -6.62 to -0.74) and day 25 (LSMD: -4.83; 95% CI, 8.37 to 1.28). Similarly, the mediation analysis for SUSTAIN-1 showed a lack of mediation of dissociation on the time to relapse after SPRAVATO treatment in the MA phase (LSMD: 0.12; 95% CI, -3.22 to 3.45] but a significant effect of SPRAVATO on the time to relapse (LSMD: -2.44; 95% CI, -4.04 to -0.84).

In TRANSFORM-2, mean peak CADSS total scores significantly decreased over time following consecutive SPRAVATO treatments where fewer patients experienced significant dissociation, whereas the AD effect of SPRAVATO was maintained without significant between-group changes in Montgomery and Asberg Depression Rating Scale (MADRS) total scores. The authors suggest further research is needed to understand the N-methyl-Daspartate receptor (NMDAR) antagonist mechanism and pathway that mediates the AD effect relative to the dissociative effects of SPRAVATO.

A similar post hoc analysis of TRANSFORM-1 and TRANSFORM-2 came to the same conclusion, that is, there was no clinically significant positive or negative association between dissociation and AD effect for SPRAVATO.³²

Real-World Retrospective Study

Brendle et al (2022)¹⁶ conducted a retrospective study of real-world treatment outcomes in patients with TRD (N=171) receiving SPRAVATO in an outpatient setting over a period of 2 years. In most patients who experienced dissociation (73%; n=125) the symptoms resolved within 2 hours (99%; n=124/125).

Martinotti et al (2022)¹⁷ conducted a real-world retrospective, observational study (REAL-ESK) in Italy to evaluate the effectiveness of SPRAVATO in 116 patients (female, n=61; mean age [SD], 50 [12] years) with TRD. Dissociative symptoms were reported in 39.7% of patients.

POSTMARKETING SAFETY DATA

REMS Database

REMS patient monitoring forms completed by certified United States (US) healthcare settings and pharmacies from March 5, 2019, to January 5, 2023, identified 34,110 patients who received at least 1 SPRAVATO treatment session and a total of 815,172 treatment sessions.¹⁸ Dissociative effects were reported in 67.3% of patients and 42.3% of treatment sessions. Most reports were nonserious with 99.2% resolving within the postdose monitoring period. There were a total of 1580 serious AEs, of which 4.6% were dissociation.

FAERS

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.¹⁹ A case/noncase study design was utilized in which cases were defined by reports about SPRAVATO, while noncases were represented by AEs recorded for all other drugs in FAERS over the first year of SPRAVATO approval (March 2019 to first quarter 2020). If the proportion of AEs of interest was greater in cases vs noncases, then this was considered a disproportionality signal. AEs were classified into 4 categories, according to their predictability: expected AEs with a detected signal, expected AEs without a signal, disease-related AEs, or unexpected AEs.

Dissociation was reported as an expected AE with a detected signal with 212 reports, a reporting odds ratio (ROR) of 1612.64 (95% CI, 1354.63-1919.79), and a Bayesian information component (IC) of 8.19 (95% CI, 7.96-8.35). The authors noted that the results must be interpreted with caution, partly due to the FAERS database having limitations, including the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate an incidence rate due to a lack of a denominator.¹⁹ Other considerations included: the increasing AE trends for SPRAVATO over the first year were expected due to the low initial SPRAVATO usage following approval, partly due to REMS requirements for certifying treatment centers; in addition, expected AEs such as dissociation are solicited and reported via the REMS at every outpatient SPRAVATO treatment session triggering multiple reports in FAERS.³³

Management of Dissociative Symptoms

Across phase 3 trials of SPRAVATO in TRD (3 short-term trials and 3 long-term trials),^2-6,28 17 patients received a medication for treatment of agitation or anxiety due to dissociation.

• TRANSFORM-1: 3/115 patients treated with SPRAVATO 56 mg + AD and 2/116 patients treated with SPRAVATO 84 mg + AD in the DB phase³⁴
• TRANSFORM-2: 2/115 patients in the DB phase³⁵
• SUSTAIN-2: 1/779 patients in the IND phase and 2/603 patients in the OP/MA phase³⁶
• SUSTAIN-3: 7/1148 patients in the IND and OP/MA phases.²⁸

There were no medications utilized specifically for the management of dissociation. For agitation or anxiety, oral or intramuscular midazolam or another short-acting benzodiazepine was considered.^3,34,36-38 Clinical judgment should be used for managing severe dissociation that does not resolve by itself during the postadministration monitoring period.

In a post hoc analysis of patients with MDD with suicidal ideation (MDSI) (pooled data from the ASPIRE I and ASPIRE II trials; see details from Fua et al [2020]), 1 patient from the SPRAVATO+SOC group received a single dose of diazepam in response to symptoms related to severe dissociation.³¹

Pereira et al (2020)³⁹ describe a case of a 64-year-old female patient whose symptoms of confusion, agitation, and anxiety, due to the dissociation she experienced after SPRAVATO administration, were alleviated while listening to music. Symptoms of dissociation, agitation, and confusion appeared shortly after the first dose and she continued to experience them in subsequent sessions. After the third treatment session, the patient asked to listen to music on her phone to distract her from the dissociative symptoms. Five minutes after listening to music, the patient appeared visibly calmer and was no longer confused or agitated by the dissociation. This strategy was successful in managing her dissociative symptoms during all subsequent visits. The authors suggest music along with other nonpharmacological ways to manage dissociative symptoms, including providing reassurance that patients are safe and adjusting room temperature and lighting, according to patient preference.

Ceban et al (2021)⁴⁰ recommend nonpharmacological approaches such as creating an environment that feels safe and comfortable in a room that is dimly lit with blankets and calming music. If permitted, they also suggest having a trusted family member or friend be present during treatment.

Hauser et al (2024)⁴¹ conducted a retrospective observational study in 37 patients to evaluate the effect of music on adverse events (including dissociation) during treatment with ketamine, which included a small number of patients treated with SPRAVATO (n=6). Multivariate comparisons between the music-listening and non-music-listening treatment sessions found that music worsened the degree of depersonalization (albeit only by a mean difference of +0.6 points) but had no significant effect on the other Dissociation Symptom Scale-IV items (i.e., somatoform dissociation, derealization, and pain perception).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 March 2024. This response contains information limited to the intranasal formulation of esketamine.