SUMMARY  

• No clinically notable changes in mean body weight from baseline were observed in the SPRAVATO nasal spray short-term, phase 2 and 3 clinical trials.^1,2 Of note, all patients in the phase 3 programs simultaneously received an oral antidepressant (AD), as well as nasal spray medication during the treatment phase(s) of the studies.^3-9
• In the long-term, maintenance-of-effect study (SUSTAIN-1) and the open-label, longterm safety study (SUSTAIN-2) of patients with treatment-resistant depression (TRD), mean body weight changes remained stable through the induction, optimization, and maintenance phases during SPRAVATO treatment.¹
• In the ESCAPE-TRD study, treatment-emergent increased weight was reported in 2.7% (9/334) and 12.5% (42/336) of patients treated with SPRAVATO and quetiapine extended-release (QUE-XR), respectively,¹⁰ and treatment-emergent decreased weight in 2.1% (7/334) and 0% (0/336) of patients treated with SPRAVATO and QUE-XR, respectively.¹¹
  • A secondary analysis of the ESCAPE-TRD study reported a clinically significant weight increase (≥7% increase in body weight from baseline) in 10.5% (34/324) vs 25.9% (82/317) of patients in the SPRAVATO vs QUE-XR groups, respectively, and a clinically significant weight decrease (≥7% decrease in body weight from baseline) in 8.6% (28/324) vs 3.5% (11/317) of patients, respectively.¹² 
• Eight reports of weight increase appeared in an analysis of postmarketing safety data from the Food and Drug Administration Adverse Event Reporting System (FAERS).¹³

CLINICAL DATA

SUSTAIN-1 and SUSTAIN-2 Studies

In the double-blind maintenance phase of SUSTAIN-1, after an initial 16 weeks of treatment with SPRAVATO + a newly initiated oral AD, the mean changes in body weight were similar between the SPRAVATO + AD and AD + placebo (PBO) nasal spray (0.3 kg and 1 kg, respectively) groups. The proportion of patients with a clinically meaningful (≥7%) increase or decrease in body weight at the end of the double-blind maintenance phase was similar between SPRAVATO + AD and AD + PBO.¹

In SUSTAIN-2, the mean change from baseline of the induction phase to week 48 of the optimization/maintenance phase was 0.44 kg (standard deviation, 5.83).¹

The incidence of treatment-emergent abnormal weight changes is presented in Table: Incidence of Treatment-Emergent Abnormal Weight Changes at Endpoints of SUSTAIN-1 and SUSTAIN-2 Relative to Baseline.

ESCAPE-TRD Study

The ESCAPE-TRD study was a 32-week, randomized, phase 3b study that evaluated the efficacy and safety of SPRAVATO vs QUE-XR in the treatment of patients with TRD. Increased weight was reported in 2.7% (9/334) and 12.5% (42/336) of patients treated with SPRAVATO and QUE-XR, respectively,¹⁰ and decreased weight in 2.1% (7/334) and 0% (0/336) of patients, respectively.¹¹ Discontinuation due to increased weight was reported in 0% (0/334) of patients treated with SPRAVATO vs 1.8% (6/336) of patients treated with QUE-XR.¹⁰ No patients in either group discontinued due to decreased weight.¹¹

In a secondary safety and tolerability analysis of the ESCAPE-TRD study, McIntyre et al (2024)¹⁵ reported clinically significant weight change (defined as a ≥7% increase or ≥7% decrease in body weight from baseline) following treatment with SPRAVATO vs QUE-XR. Please see Table: Clinically Significant Weight Changes in ESCAPE-TRD.

Postmarketing Safety Data

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.¹³ A case/non-case study design was utilized, in which cases were defined by reports about SPRAVATO, while non-cases were represented by adverse events (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 non-cases, 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.

Of the 2274 SPRAVATO-related AEs, there were 8 reports of weight increase, with a reporting odds ratio of 0.98 (95% confidence interval [CI], 0.49-1.96), and a Bayesian information component of -0.03 (95% CI, -1.24 to 0.77). Therefore, no safety signal was detected.¹³ 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.

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 13 December 2024.