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SPRAVATO® (esketamine)

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Adverse Event of SPRAVATO - Urinary Disorders

Last Updated: 10/09/2026

Summary

In clinical trials of SPRAVATO, a higher rate of lower urinary tract symptoms (pollakiuria [abnormally frequent urination], dysuria, micturition urgency, nocturia, and cystitis) were reported in SPRAVATO-treated patients than in placebo.¹ No cases of treatment-related interstitial cystitis were observed in long-term trials (up to 6.5 years) of SPRAVATO.²^,³
- In a pooled analysis of short-term treatment-resistant depression (TRD) studies (TRANSFORM-1 and 2),⁴^,⁵ pollakiuria occurred in 3% of patients treated with SPRAVATO + oral antidepressant (AD; n=11/346) vs 0.5% of patients treated with placebo + oral AD (n=1/222).¹
- In a pooled analysis of short-term major depressive disorder with acute suicidal ideation or behavior studies (ASPIRE-I AND II),⁶^,⁷ pollakiuria (including micturition urgency) occurred in 2% of patients treated with SPRAVATO + oral AD (n=5/227) vs 1% of patients treated with placebo (n=2/225).¹
Real world studies in TRD:
- In a retrospective analysis of safety data collected from 93 patients receiving racemic ketamine subcutaneous (SC) injection or SPRAVATO from 2021 to 2023 for TRD, 29% (n=27) reported problems passing urine at least once between sessions using the Ketamine Side Effect Tool (KSET). In a limited follow-up dataset, problems passing urine were reported in 3 of 45 assessments at 0-6 months and 2 of 7 assessments at 7-12 months post-baseline. No clinically significant changes in BPIC-SS (Bladder Pain/Interstitial Cystitis Symptom Score, defined as total score of ≥19 indicating moderate-to-severe bladder pain) were reported.⁸
- In a retrospective analysis of real-world clinical practice in France (ESKALE study) in 157 patients with moderate to severe TRD who were treated with SPRAVATO, adverse events (AEs) related to renal and urinary disorders were reported in 1 patient (0.6%).⁹
Postmarketing safety data:
- An analysis of the Risk Evaluation and Mitigation Strategy (REMS) program and Janssen Global Medical Safety (GMS) database (US source only) from 05 March 2019 to 05 January 2024 evaluated safety data collected from 1,486,213 outpatient treatment sessions. Two events of cystitis were reported, and both were considered nonserious.¹⁰
- A disproportionality analysis based on the Food and Drug Administration Adverse Event Reporting System (FAERS) database evaluated the urological safety profiles of SPRAVATO and ketamine compared to those of antidepressants (ADs; selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs]) and second-generation antipsychotics (SGAs). The odds of renal and urinary disorders were comparable between SPRAVATO and ketamine and SPRAVATO and SGAs, but were observed to be significantly higher when compared to ADs.¹¹
- An analysis of the FAERS database from the first quarter of 2019 to the fourth quarter of 2023 evaluating 14,606 SPRAVATO-related AEs reported 159 (1.1%) cases related to renal and urinary disorders. The analysis identified 5 cases of interstitial cystitis among the top 50 AEs. Limitations of the database prohibit the inference of causality due to incomplete information in reporting.¹²

PRODUCT LABELING

Monitor for urinary tract and bladder symptoms during the course of treatment with SPRAVATO and refer to an appropriate healthcare provider as clinically warranted.¹³

CLINICAL DATA

Additional study-specific data on AEs related to renal and urinary disorders from phase 3 clinical trials are provided in the table below.

Study/Study Design	Rates of Urinary Disorders
Short-term Clinical Trials in TRD
Ochs-Ross et al (2020) (TRANSFORM-3)¹⁴ conducted a 4-week, randomized, DB, active-controlled, multicenter study in elderly patients (≥65 years) with TRD which assessed the efficacy, safety, and tolerability of flexible doses of SPRAVATO plus a newly initiated oral AD compared with a newly initiated oral AD plus PBO. Study Treatment Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. A new OL oral AD was initiated. Study Groups 28, 56, or 84 mg SPRAVATO + oral AD (n=72); SPRAVATO was started on day 1 at 28 mg Oral AD + PBO (n=65)	UTIs SPRAVATO + oral AD: 8.3% (n=6/72) Oral AD + PBO: 1.5% (n=1/65)
Long-term Clinical Trials in TRD
Wajs et al (2020) (SUSTAIN-2)² conducted an 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. Study Treatment During the induction phase (initial 4 weeks), patients self-administered either SPRAVATO or PBO 2 times per week. In the optimization and maintenance phases (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. A new OL oral AD was initiated. Study Groups 28, 56, or 84 mg SPRAVATO + oral AD (n=802); SPRAVATO was started on day 1 at 28 mg for patients ≥65 years and 56 mg for all other patients.	A total of 136 patients (17%) reported TEAEs related to renal and urinary disorders. Most were considered mild to moderate in severity and resolved within 2 weeks. Cystitis SPRAVATO + oral AD: 0.6% (n=5/802; all cases resolved while continuing SPRAVATO treatment) Bacterial Cystitis SPRAVATO + oral AD: 0.1% (n=1/802) 4/136 patients had 6 serious TEAEs (pyelonephritis, acute pyelonephritis, and tubulointerstitial nephritis, UTI); however, none resulted in discontinuation, and none were due to esketamine according to investigators. 1 patient experienced urinary retention, which led to temporary discontinuation of treatment but was restarted 4 days later after it resolved. This was assessed by investigators as doubtfully related to SPRAVATO. Another patient had moderate pollakiuria, which required a dose reduction from 84 mg to 56 mg and resolved within 5 days (assessed as probably drug-related). There was another who discontinued due to urinary incontinence. No cases of interstitial or ulcerative cystitis occurred during the study.
Zaki et al (2023) (SUSTAIN-3)³ conducted an OLE study to evaluate the long-term (up to 6.5 years) safety and efficacy of individualized, intermittently-dosed SPRAVATO plus a newly initiated oral AD in patients with TRD. Study Treatment During the induction phase (initial 4 weeks), patients self-administered a flexible dose of SPRAVATO 2 times per week. In the optimization/maintenance phase (variable duration), patients were administered SPRAVATO weekly, every other week, or every 4 weeks based on the assessment of CGI-S rating and tolerability. Study Groups Starting SPRAVATO dose of 28 mg (patients aged ≥65 years), 56 mg, or 84 mg (N=1148): induction phase, n=458; optimization/ maintenance phase, n=1110 (690 directly enrolled; 420 continued from the induction phase).	UTIs SPRAVATO + oral AD: 15.8% (n=181/1148) There were no cases of treatment-related interstitial or ulcerative cystitis. Other renal disorder-related AEs (≥1%) included dysuria (3.0%), cystitis (2.4%), pollakiuria (2.4%), nephrolithiasis (1.7%), micturition urgency (1.5%), urinary incontinence (1.5%), and hematuria (1.3%).
Reif et al (2023)¹⁵ conducted an OL, 32-week, randomized, phase 3b study that evaluated the efficacy and safety of SPRAVATO vs QUE-XR in combination with ongoing oral AD (SSRI or SNRI) for the treatment of patients with TRD. Study Treatment¹⁶ In the initial treatment phase (8 weeks) patients were randomized to receive flexible doses of SPRAVATO + oral AD or QUE-XR + oral AD; flexible dosing was continued for 24 weeks in the maintenance phase. 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. Study Groups¹⁶ SPRAVATO 56 mg on day 1, then 56 mg or 84 mg from day 4 + oral AD (patients aged 65 to ≤74 years or adults of Japanese ancestry started on 28 mg on day 1, then 28 mg, 56 mg, or 84 mg on day 4) (n=334) QUE-XR 50 mg on day 1, increasing to 150-300 mg/day + oral AD (n=336)	Renal and Urinary Disorders (Nephrolithiasis)¹⁷ SPRAVATO + oral AD: 1/334 (0.3%) QUE-XR + oral AD: 0/336 (0.0%) Severity Analysis of Treatment-Emergent Cystitis (a TEAE of Special Interest)¹⁷ SPRAVATO + oral AD: 1 (0.3%) mild case of cystitis, 1 (0.3%) moderate case of pollakiuria, and no cases of dysuria QUE-XR + oral AD: 2 (0.6%) moderate cases of cystitis, and 1 (0.3%) mild case each of pollakiuria and dysuria
Abbreviations: AD, antidepressant; AE, adverse event; CGI-S, Clinical Global Impression-Severity Scale; DB, double-blind; OL, open-label; OLE, open-label extension; PBO, placebo nasal spray; QUE-XR, quetiapine extended release; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TEAE, treatment-emergent adverse event; TRD, treatment-resistant depression; UTI, urinary tract infection.

Real-world Studies in TRD

Bayes et al (2024)⁸ conducted a real-world, multicenter, retrospective study in Australia in 93 patients receiving either racemic SC ketamine (n=74) or SPRAVATO (n=19) for TRD from 2021 to 2023. Problems passing urine at least once between treatment sessions were reported in 29% of patients (n=27/93) using the KSET. Problems passing urine were reported in 3 of 45 assessments at 0-6 months and 2 of 7 assessments at 7-12 months post-baseline. When comparing between formulations, 28.4% of patients (n=21/74) receiving racemic ketamine and 31.6% of patients receiving SPRAVATO (n=6/19) reported problems passing urine, respectively.¹⁸ Additionally, patients completed BPIC-SS and urinalysis at baseline and follow-up. No patients scored ≥19 on the BPIC-SS, the threshold for moderate-to-severe bladder pain, across the follow-up periods. Among the 29 urinalysis tests that were normal at baseline, one was abnormal at ≤6 months. One patient had abnormal urinalysis findings during the 7-12 month follow-up period across a total of 7 tests.

Samalin et al (2024)⁹ conducted a real-world, multicenter, retrospective study in France (ESKALE study) in adult (≥18 years old) patients (N=157) with moderate to severe TRD (defined as nonresponsive to ≥2 oral ADs) who initiated SPRAVATO from October 2019 to July 2021. Data was collected over 12 months following SPRAVATO initiation, up to June 2022. During the study period, 1 patient (0.6%) reported AEs related to renal and urinary disorders.

postmarketing safety data

Sanacora et al (2025)¹⁰ conducted an analysis of the REMS program and Janssen Global Medical Safety (GMS) database (US source only) between 05 March 2019 and 05 January 2024. There was a total of 1,486,213 outpatient treatment sessions among 58,483 patients who had at least 1 SPRAVATO treatment session. Two events of nonserious cystitis were reported.

Chiappini et al (2025)¹¹ conducted an analysis of the FAERS database to evaluate the urological safety profiles of SPRAVATO and ketamine with those of ADs (SSRIs, SNRIs, and TCAs) and SGAs.

Of the 7661 AEs identified for SPRAVATO (between 2011 and 2024), 140 were related to renal and urinary disorders, including lower urinary tract symptoms (n=68 cases; comprising pollakiuria, micturition urgency, urinary incontinence, and dysuria), nephrolithiasis (n=16), bladder conditions (n=19 cases; comprising bladder pain, bladder disorder, and interstitial cystitis), urinary tract obstruction (n=19), and nonurological conditions (n=24 cases; comprising renal impairment, acute kidney injury, and renal failure).

Of the 4739 AEs identified for ketamine (between 1998-2024), 105 were related to renal and urinary disorders. The following lists some of the more frequently reported events (≥20 cases): nonurological conditions (n=133 cases; acute kidney injury, renal failure, and renal infarct were among the most frequently reported), nephrolithiasis (n=90), urinary tract disorder (n=50), urinary tract obstruction (n=49 cases; comprising hydronephrosis, urinary retention, and ureteric stenosis), lower urinary tract symptoms (n=42 cases; comprising urinary incontinence, dysuria, lower urinary tract symptoms, and pollakiuria), hematuria (n=26), and conditions involving the bladder (n=20 cases; comprising hypertonic bladder and ulcerative cystitis).

The odds of renal and urinary disorders were lower with SPRAVATO when compared with ketamine but the difference was not statistically significant (see Table: Disproportionality Assessments Related to Renal and Urinary Disorders With SPRAVATO vs Ketamine, Antidepressants, and Antipsychotics). The odds of these AEs were higher with SPRAVATO when compared to SSRIs, SNRIs, and TCAs.

Disproportionality Assessments Related to Renal and Urinary Disorders With SPRAVATO vs Ketamine, Antidepressants, and Antipsychotics¹¹

SPRAVATO vs Treatment Group	Odds of Renal and Urinary Disorders ROR (95% CI)	Odds of Renal and Urinary Disorders (Serious Cases) ROR (95% CI)
Ketamine	0.82 (0.06 to -0.45)	0.79 (0.02 to -0.49)
Antipsychotics
SGAs^a	1.13 (0.30 to -0.04)	0.85 (0.01 to -0.33)
Antidepressants
SSRIs^b	2.05 (0.9 to 0.5)	1.9 (0.82 to 0.45)
SNRIs^c	1.63 (0.7 to 0.3)	1.46 (0.57 to 0.19)
TCAs^d	2.7 (1.2 to 0.8)	2.47 (1.14 to 0.67)
Abbreviations: CI, confidence interval; ROR, relative odds ratio; SGA, second generation antipsychotic; SNRI, serotonin noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. ^aDrugs evaluated were quetiapine, aripiprazole, olanzapine, and risperidone. ^bDrugs evaluated were citalopram, escitalopram, paroxetine, fluoxetine, and sertraline. ^cDrugs evaluated were duloxetine and venlafaxine. ^dDrugs evaluated were amitriptyline and clomipramine. Note: ROR <1 indicated lower odds of renal and urinary disorders compared with the reference group; ROR >1 indicated higher odds of renal and urinary disorders compared with the reference group.

Limitations of the FAERS database include inability to infer causality; passive reporting; limitations in the quality of the information received; and inability to stratify data using specific drugs, dose regimens, or administration routes, which may make direct comparison difficult. AEs associated with some formulations of ketamine may also be underreported due to its use outside healthcare supervision.¹⁹

Liu et al (2024)¹² conducted an analysis of the FAERS database between the first quarter of 2019 and the fourth quarter of 2023. A total of 14,606 AEs were reported for SPRAVATO, of which 159 (1.1%) cases were related to renal and urinary disorders. The analysis identified interstitial cystitis (5 cases) among the top 50 AEs (reporting odds ratio, 17.14 [95% confidence interval (CI): 7.10-41.37]; proportional reporting ratio, 17.12 [95% CI: 7.10-41.32]; and empirical Bayes geometric mean [EBGM], 16.96 [the lower limit of the 90% CI for the EBGM: 7.02]). 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.¹⁹

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 15 September 2026. Studies with less than 30 patients were excluded.

References

Show

1	Center for Drug Evaluation and Research. Other Review. NDA 211243 - SPRAVATO (esketamine) - Reference ID: 4398871. 2019- [cited 2024 February 25]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211243Orig1s000OtherR.pdf
2	Wajs E, Aluisio L, Holder R, et al. Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3).
3	Zaki N, Chen L (Nancy), Lane R, et al. Safety and efficacy with esketamine in treatment-resistant depression: long-term extension study. Int J Neuropsychopharmacol. 2025;28(6):pyaf027.
4	Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616-630.
5	Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438.
6	Fu DJ, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m13191.
7	Ionescu DF, Fu DJ, Qiu X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24(1):22-31.
8	Bayes A, Cao TV, Barreiros AR, et al. Safety outcomes of ketamine for treatment-resistant depression in clinical settings and development of the ketamine side effect tool-revised (KSET-R). Psychiatry Res. 2025;344:116334.
9	Samalin L, Mekaoui L, Rothärmel M, et al. Use of esketamine nasal spray in patients with treatment-resistant depression in routine practice: a real-world French study. Dépress Anxiety. 2024;(1):7262794.
10	Sanacora G, Ahmed M, Brown B, et al. Real-World Safety of Esketamine Nasal Spray: A Comprehensive Analysis Almost 5 Years After First Approval. Am J Psychiatry. 2025;182(10):913-921.
11	Chiappini S, Guirguis A, Schifano N, et al. Comparative safety of prescribed esketamine and ketamine in relation to renal and urinary disorders: a pharmacovigilance perspective. Prog Neuro-Psychopharmacol Biol Psychiatry. 2025;136:111213.
12	Liu R, Liu C, Feng D, et al. Pharmacovigilance of esketamine nasal spray: an analysis of the FDA adverse event reporting system database. Front Pharmacol. 2024;15:1414703.
13	SPRAVATO (esketamine) nasal spray [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf
14	Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121-141.
15	Reif A, Bitter I, Buyze J, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med. 2023;389(14):1298-1309.
16	Reif A, Bitter I, Buyze J, et al. Supplement to: Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med. 2023;389(14):1298-1309.
17	McIntyre RS, Bitter I, Buyze J. Supplement to: Safety and tolerability of esketamine nasal spray versus quetiapine extended release in patients with treatment resistant depression. Eur Neuropsychopharmacol. 2024;85:58-65.
18	Bayes A, Cao TV, Barreiros AR, et al. Safety outcomes of ketamine for treatment-resistant depression in clinical settings and development of the ketamine side effect tool-revised (KSET-R). Psychiatry Res. 2025;344 (suppl):116334.
19	FDA Adverse Event Reporting System (FAERS) Public Dashboard. Available via: https://www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard

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