Dissociation with Intranasal Esketamine (Spravato)
Definition and Clinical Presentation
Dissociation is the most common psychological adverse effect of intranasal esketamine, occurring in 61–84% of treated patients and manifesting as perceptual disturbances including distortion of time and space, illusions, derealization, and depersonalization. 1
The FDA label specifically describes these effects as "dissociative or perceptual changes" that are measured using the Clinician-Administered Dissociative States Scale during clinical monitoring. 1
In real-world clinical practice, one case series documented dissociation occurring approximately 20 minutes after esketamine administration. 2
Onset and Duration
Dissociative symptoms typically begin within 20–40 minutes of intranasal administration, based on clinical observations and the required 2-hour monitoring period. 1, 2
The dissociative effects are time-limited and resolve within the mandatory 2-hour post-administration observation period in the vast majority of patients, as evidenced by the FDA requirement that patients must be monitored until "clinically stable and ready to leave the healthcare setting." 1
The transient nature of these symptoms is reflected in the safety data showing that dissociation was reported as a treatment-emergent adverse event in 24.3% of patients in controlled trials, but did not result in high discontinuation rates. 3
Mandatory Management Protocol (FDA-Required)
All patients receiving esketamine must be monitored by a healthcare provider for at least 2 hours at each treatment session specifically because of dissociation risk, followed by an assessment to determine clinical stability before discharge. 1
Specific Management Steps:
Pre-administration counseling: Instruct patients not to engage in potentially hazardous activities (driving, operating machinery) until the next day after a restful sleep. 1
During-administration monitoring: Continuous observation by healthcare personnel throughout the 2-hour period using standardized assessment tools (Modified Observer's Assessment of Alertness/Sedation scale and Clinician-Administered Dissociative States Scale). 1
Post-administration assessment: Document that dissociative symptoms have resolved and the patient has returned to baseline mental status before allowing departure. 1
REMS program requirement: Esketamine is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program specifically because of dissociation risk (along with sedation, respiratory depression, and abuse potential). 1
Special Considerations for Patient Selection
Carefully assess patients with psychosis before administering esketamine; treatment should be initiated only if the benefit outweighs the risk, given the potential for dissociative effects to exacerbate psychotic symptoms. 1
The presence of dissociative symptoms does not typically require treatment discontinuation—in clinical trials, dissociation was common (24.3%) but was generally well-tolerated and self-limited. 3
In one case series, dissociation occurred with every administration but did not prevent successful treatment outcomes, including resolution of suicidal ideation. 2
Clinical Context
The high incidence of dissociation (61–84% by structured assessment, 24.3% reported as adverse event) represents a predictable pharmacologic effect of NMDA receptor antagonism rather than an idiosyncratic reaction. 1, 3 This distinction is important for patient counseling—dissociation should be framed as an expected, transient experience that will be monitored and managed during the mandatory observation period, not as a dangerous complication requiring treatment cessation.