SUMMARY  

• If SPRAVATO is used in accordance with approved dosing and administration instructions, withdrawal symptoms are not expected after discontinuation of SPRAVATO given the half-life of 7-12 hours, intermittent dosing regimen, and the lack of accumulation of esketamine levels.^1,2
• There were no withdrawal symptoms observed for up to 4 weeks after cessation of SPRAVATO treatment.^2,3
• During treatment-resistant depression (TRD) clinical trials, potential withdrawal symptoms were assessed using a 20-item Physician Withdrawal Checklist (PWC-20).^1,4
  • A long-term maintenance of effect study found no apparent differences between treatment arms (SPRAVATO + newly initiated daily oral antidepressant [AD] vs AD + placebo [PBO]) for each of the PWC-20 items after cessation of intranasal treatment, and no evidence suggesting a distinct withdrawal syndrome.⁴
  • Findings from an up to 1-year, open-label study evaluating the safety and tolerability of SPRAVATO+AD suggested that drug-specific withdrawal symptoms were unlikely after stopping SPRAVATO.¹
• Careful consideration is advised prior to treatment of individuals with a history of substance abuse disorder. Monitoring for signs of dependence is recommended. Withdrawal symptoms have been reported in individuals with prolonged dependence on ketamine.⁵
• A secondary analysis of the ESCAPE-TRD study, which evaluated the efficacy and safety of SPRAVATO vs quetiapine extended-release (QUE-XR) in patients with TRD, reported 1 (0.3%; 1/334) moderate case of withdrawal syndrome in the SPRAVATO group.⁶
• An analysis of postmarketing safety data (first quarter of 2019 to the second quarter of 2023) evaluating 5132 SPRAVATO-related adverse drug events (ADEs) from the Food and Drug Administration Adverse Event Reporting System (FAERS) database identified 29 cases of withdrawal syndrome among the top 50 ADEs.⁷ Limitations of the FAERS include the inability to infer causality and the level of quality of the information received.⁸

BACKGROUND

No scale has been developed to specifically assess SPRAVATO-related withdrawal symptoms. Instead, the PWC-20 was used in the phase 3 program as it measures some of the potential symptoms reported in literature.² The PWC-20 is a reliable and sensitive instrument used to assess potential benzodiazepine-like withdrawal symptoms with consideration of somatic, mood, cognitive, fatigue, and gastrointestinal factors.^1,9

The PWC-20 has a score range of 0-60 and is comprised of the PWC-depression symptoms (PWC-DS) and PWC-withdrawal symptoms (PWC-WS) subscales that have a range of 0-36 and 0-24, respectively.¹

CLINICAL DATA

Daly et al (2018)⁴ conducted a long-term, double-blind (DB), maintenance of effect study using a randomized withdrawal design to assess the efficacy of flexibly-dosed SPRAVATO+AD vs AD+PBO in delaying relapse of depressive symptoms in patients with TRD who were stable responders and stable remitters after an initial 16 weeks of treatment with SPRAVATO+AD.

After an induction, optimization, and maintenance phase, eligible patients who received ≥1 dose of study medication and had discontinued or completed the study entered a 2-week follow-up phase to assess safety, tolerability, and potential withdrawal symptoms from intranasal study medication discontinuation. It was recommended to continue patients on oral AD during the follow-up phase unless clinically inappropriate; however, the decision was left at the discretion of the investigator.¹⁰

Relative to the maintenance phase endpoint, new or worsened withdrawal symptoms during the follow-up phase (SPRAVATO+AD, n=126; AD+PBO, n=103) were reported on the PWC-20 by <25% in SPRAVATO+AD and AD+PBO groups at week 1 and week 2, with the exception of anxiety-nervousness, for which slightly higher rates were reported (26.7% and 25.8%, respectively) at week 2. The frequency for most withdrawal symptoms was slightly higher (by <5%) in the SPRAVATO+AD group than in the AD+PBO group. Overall, there appeared to be no difference by treatment arm for each of the 20 items, and no clear evidence of withdrawal was observed at either 1 or 2 weeks after cessation of treatment with  SPRAVATO+AD.^4,11

Aluisio et al (2019)¹ conducted a post hoc analysis of the PWC-20 results in patients enrolled in SUSTAIN-2¹² to investigate potential withdrawal symptoms and severe adverse events. SUSTAIN-2 was an open-label, multicenter study primarily evaluating the long-term (up to 1 year of exposure) safety and tolerability of flexibly-dosed SPRAVATO+AD in patients with TRD.¹² PWC-20, PWC-DS, and the PWC-WS were assessed at treatment endpoint, and weeks 1, 2, and 4 of the 4-week follow-up phase (during which the patients did not receive SPRAVATO) for the study population and subgroups. These subgroups were responders (≥50% reduction from baseline in the MADRS total score at day 28) and non-responders (<50% reduction from baseline in the MADRS total score at day 28).

The mean PWC-20 (SD) total score was 7.2 (6.8), 7.5 (6.96), 7.4 (7.1), and 7.2 (6.93) at treatment endpoint, weeks 1, 2, and 4 during the follow-up phase, respectively. The mean total PWC, PWC-DS, and PWC-WS scores are depicted below in Figure: PWC Mean Total and Subscores. PWC-WS accounted for <15% of the total PWC-20 score illustrating a higher prevalence and severity of depression symptoms.

As illustrated in Figure: Individual PWC-20 Symptoms in Responders and Non-responders, non-responders had a higher incidence of depression symptoms than responders. PWC-WS were higher in non-responders to SPRAVATO; apart from discontinuation of SPRAVATO, this may be related to other changes in therapy (ie, discontinuation of current AD and or the initiation of new AD during the follow-up phase).

Of 13 patients (n=307 in the follow-up period) who reported ≥1 serious symptom, 11 patients had ≥1 confounding factor including an underlying medical condition or symptom onset ≥2 weeks after SPRAVATO discontinuation. One patient reported severe diarrhea at the end of treatment, and another reported severe diaphoresis at the end of treatment and week 1 before resolving. Serious adverse events during the follow-up phase were reported in 2.2% of patients (n=357).

McIntyre et al (2024)¹³ conducted a secondary safety and tolerability analysis of the ESCAPE-TRD study, 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. One (0.3%; 1/334) moderate case of withdrawal syndrome was reported in the SPRAVATO group and none in the QUE-XR group.⁶

postmarketing safety data

Chen et al (2024)⁷ conducted an analysis of the FAERS database between the first quarter of 2019 and the second quarter of 2023. A total of 5132 ADEs were reported for SPRAVATO, of which 29 cases of withdrawal syndrome, classified under the system organ class of general disorders and administration site conditions, were identified among the top 50 ADEs (reporting odds ratio [95% confidence interval (CI)], 3.66 [2.54-5.27]; proportional reporting ratio [chi-squared], 3.65 [55.76]; empirical Bayesian geometric mean [EBGM; the lower limit of the 95% CI for the EBGM], 3.65 [2.69]; and information component [IC; the lower limit of the 95% CI for the IC], 1.87 [0.20]).⁷ Limitations of the FAERS database include the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate the incidence rates of the events.⁸ Further well-designed observational studies and long-term risk monitoring are needed to reach definitive conclusions.⁷

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 05 January 2025.