How to Monitor Response and Adverse Effects After Onfasprodil Infusion
How should clinicians monitor early antidepressant response and infusion-related adverse effects after intravenous onfasprodil in treatment-resistant depression?
Rapid-acting antidepressant treatments require clinicians to assess both near-term benefit and short-lived but clinically relevant neurobehavioral adverse effects. This guide applies to patients receiving intravenous onfasprodil under conditions similar to those studied and focuses on the timing and measures reported in the trial.
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Administer the infusion using the studied format
In the trial, all study treatments were given as 40-minute intravenous infusions at the site. Monitoring should be organized around the infusion start time because both antidepressant assessments and adverse-effect timing in the article were anchored to that point.
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Assess depressive symptoms at 24 hours
Measure change from baseline in MADRS total score 24 hours after the first infusion, which was the study's primary end point. At that time point, both pooled onfasprodil dose groups separated from placebo, with adjusted mean differences of -8.25 for 0.16 mg/kg and -5.71 for 0.32 mg/kg.
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Repeat symptom assessment at 48 hours
Reassess MADRS 48 hours after the first infusion to determine whether early benefit is maintained. In the study, statistically significant reductions versus placebo persisted at 48 hours for both pooled onfasprodil groups.
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Reevaluate sustained benefit after repeated dosing
After the repeated-dose phase, reassess depressive symptoms at 6 weeks. In this trial, only 2 regimens showed statistically significant benefit versus placebo at Week 6 on MMRM analysis: 0.16 mg/kg biweekly with an adjusted mean difference of -6.46 and 0.32 mg/kg weekly with an adjusted mean difference of -5.42.
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Track dissociative symptoms with structured scales
Monitor dissociative effects with the Clinical-Administered Dissociative States Scale and the Dissociative Experiences Scale, as done throughout the study. CADSS elevations with onfasprodil extended from the end of the first infusion up to 24 hours for 0.16 mg/kg regimens and up to 48 hours for 0.32 mg/kg regimens, while DES scores were generally low and stable except for higher values in the 0.32 mg/kg biweekly group from baseline to 24 hours.
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Watch closely for early neurobehavioral adverse events
Expect adverse effects to occur during or soon after infusion rather than later in the course. In onfasprodil-treated patients, dissociation and amnesia began 0 to 0.7 hours after infusion start, the maximum time to onset of significant adverse events was 4.4 hours, and all treatment-emergent adverse events of interest resolved within hours, with a maximum time to resolution of 9.2 hours after onset.
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Focus surveillance on the most common adverse effects
Pay particular attention to dizziness, amnesia, somnolence, and feeling abnormal, which were the most common treatment-emergent adverse events reported in the onfasprodil groups. Dissociation occurred in 23.8% of pooled 0.16 mg/kg patients and 26.3% of pooled 0.32 mg/kg patients, and short periods of amnesia were reported in 10 onfasprodil-treated patients.
Clinical Considerations
- The ketamine comparison was exploratory because the study was not formally powered for all between-group comparisons.
- Ketamine dosing in the trial differed from more customary practice, limiting interpretation of relative tolerability and efficacy against ketamine.
- Most adverse events were mild and resolved within hours, but serious adverse events occurred in 5 patients overall and 4 patients discontinued treatment because of adverse events.
- The sustained efficacy signal at Week 6 was regimen-specific rather than uniform across all onfasprodil dosing schedules.
Bottom Line
After onfasprodil infusion, clinicians should check MADRS response at 24 and 48 hours and monitor closely during the first several hours for dizziness, amnesia, somnolence, and dissociation, which in this study generally began early and resolved within hours.
