SUMMARY

• Currently, there are no prospective, randomized, head-to-head trials comparing the efficacy and safety of SPRAVATO nasal spray and ketamine for treatment-resistant depression (TRD) or for the treatment of depressive symptoms with acute suicidal ideation or behavior (MDSI).
• The efficacy and safety of SPRAVATO for TRD is supported by 3 short-term studies evaluating efficacy and safety, and 2 long-term studies evaluating maintenance of effect and safety up to 1 year, respectively.^1-5
  • In clinical trials, TRD was defined as a Diagnostic and Statistical Manual, fifth edition (DSM-5) diagnosis of major depressive disorder (MDD) in patients who have not responded adequately to at least 2 different antidepressants of adequate dose and duration in the current depressive episode.^1-5
• The efficacy and safety of SPRAVATO for MDSI is supported by 2 identically designed phase 3 studies.^6,7
• Ketamine is not approved by regulatory authorities for depression-related conditions in any formulation, such as intravenous (IV), intramuscular (IM), subcutaneous (SC), or compounded intranasal (IN), oral, or sublingual (SL).⁸
  • A consensus statement from the American Psychiatric Association highlighted that the available data for ketamine in MDD and TRD is lacking, with trials that have relatively small sample sizes and limited data on longer-term efficacy and safety.⁹
• An FDA alert to healthcare professionals in February 2022 about compounded IN ketamine emphasizes that the drug is not the same as the Food and Drug Administration (FDA)-approved SPRAVATO nasal spray.¹⁰
  • Compounded IN ketamine is not FDA approved and there is no data to support dosing conversion between this drug and SPRAVATO. The benefit-risk profile for SPRAVATO has been established while the benefit-risk profile for compounded ketamine nasal spray has not. Compounded drugs should only be used in patients whose medical needs cannot be met by an FDA-approved drug.
• Another FDA alert to patients and healthcare professionals in October 2023 identified potential safety concerns related to the use of compounded ketamine, including oral and SL formulations, available from compounders and telemedicine platforms.¹¹
  • Potential safety concerns included abuse and misuse, psychiatric events, increases in blood pressure, respiratory depression, and lower urinary tract and bladder symptoms. An additional risk was the lack of onsite (i.e., home) monitoring by healthcare professionals.
• A multicenter, observational, prospective cohort study evaluating the effectiveness of IV ketamine and SPRAVATO in 53 adult patients with TRD reported a treatment response rate of 54.0% and 37.0% and depressive symptom remission rate of 38.5% and 18.5%, respectively, at week 4.¹²
• A real-world, retrospective study evaluating the effectiveness and safety of IV ketamine and SPRAVATO in patients with refractory bipolar depression reported that 39.0% of patients achieved a clinical response (≥50% improvement on the Montgomery-Åsberg Depression Rating Scale [MADRS]) and 13.2% of patients achieved remission (MADRS ≤10) during the acute phase. Both treatments led to significant improvements (P<0.001) in mean MADRS and Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) scores.¹³ 
• A retrospective real-world analysis comparing the effectiveness of IV ketamine vs SPRAVATO based on QIDS-SR score in patients with TRD showed that the response (57.4% vs 60.0%) and remission (42.6% vs 26.7) rates were not significantly different between the 2 groups (P>0.05).¹⁴
• A retrospective analysis comparing the trajectory of depression severity, based on MADRS score, between patients treated with up to 8 weeks of IV ketamine and SPRAVATO showed no significant difference between groups.¹⁵
• An analysis based on the Food and Drug Administration Adverse Event Reporting System (FAERS) database found that the odds of renal and urinary disorders were lower with SPRAVATO compared with ketamine, however, the difference was not statistically significant.¹⁶ 
• Both esketamine and ketamine are United States Drug Enforcement Administration (DEA) Schedule III controlled substances (CIII) and may be subject to abuse and diversion.^8,17
  • A phase 1 study compared the abuse potential of esketamine to IV ketamine in recreational polydrug users who had experience with perception-altering drugs and found both of them to have similar subjective “drug liking at the moment” and “take drug again” scores.¹⁸
• Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA).^19-22 However, the precise mechanism of action of esketamine in MDD is unknown. The antidepressant pharmacologic action of esketamine is thought to be similar to ketamine.^19-21,23
• Preclinical studies showed, when compared to racemic ketamine, esketamine had an up to 2- to 3-fold higher affinity for the NMDA receptor, facilitating a lower dose volume via the IN route of administration.^24-26

product labeling

SPRAVATO nasal spray is available only through a restricted program under a REMS (Risk Evaluation and Mitigation Strategy) called the SPRAVATO REMS because of the risks of serious adverse outcomes from sedation, dissociation, respiratory depression, and abuse and misuse.²⁷

Clinical data

Prospective Observational Study

Gutierrez et al (2024)¹² conducted a multicenter, observational, prospective cohort study in real-world settings to evaluate the effectiveness and safety of IV ketamine and SPRAVATO in patients with TRD (N=53). Patients received twice-weekly treatment of IV ketamine (n=26; 0.5 mg/kg over 40 min) or SPRAVATO (n=27; 56 mg initial dose followed by 84 mg for the remaining study period) for 4 weeks. The primary study outcome was improvement on MADRS.

Results

• At week 4, treatment response (≥50 reduction in MADRS total score from baseline) rate was 54.0% for IV ketamine and 37.0% for SPRAVATO. The depressive symptom remission (≤10 MADRS total score after treatment) rate was 38.5% for IV ketamine and 18.5% for SPRAVATO. Clinical results were similar between the per-protocol (PP; only treatment completers) and intention-to-treat analyses. Results from the PP analysis of changes in MADRS and 6-Item Clinician Administered Dissociative Symptom Scale (CADSS-6) from baseline are summarized in Table: Changes in the MADRS, SI, and CADSS-6 Scales After IV Ketamine and SPRAVATO Treatment (Per-Protocol Analysis). Between-group statistical comparisons were not performed.
• Suicidal ideation (SI) was measured using item 10 (Q10) of the MADRS assessment. The SI treatment response (improvement in Q10 score from baseline to treatment endpoint) rate was 46.2% for IV ketamine and 58.8% for SPRAVATO. The SI remission (Q10 score of 0 at treatment endpoint) rate was 30.8% for IV ketamine and 23.5% for SPRAVATO.
• During the treatment period, 88.9% and 81.7% of patients treated with IV ketamine and SPRAVATO, respectively, reported ≥1 side effect. All reported side effects were mild and transient, subsiding 15 to 20 min after administration.
  • Adverse events reported by ≥10% in either the SPRAVATO vs IV ketamine arm, respectively, were anxiety (13.7% vs 18.2%), faintness/light-headedness (35.1% vs 45.5%), sedation/drowsiness (26.7% vs 61.6%), blurred vision (19.1% vs 38.4%), increased blood pressure (25.2% vs 14.1%), and dizziness (37.4% vs 29.3%).

Limitations

• The authors stated that being a multicenter, open-label, observational study, the study design raised concerns regarding interval consistency, variability, interrater reliability, and underreporting of side effects.
• Only MADRS was used to assess psychiatric symptoms, which may have restricted evaluation of symptomatic changes, including changes in the quality of life during the treatment period.
• Patients received ketamine at a flat dose; however, the standard of care practice involved dose optimization. This may have affected the generalizability of the effectiveness and tolerability of IV ketamine.
• Reporting and severity of side effects were based on clinical impressions and patients’ descriptions.

Retrospective Observational Studies

Santucci et al (2024)¹³ conducted a real-world, retrospective study using electronic record and chart review data from patients (N=38) with refractory bipolar depression to evaluate the effectiveness and safety of treatment with IV ketamine (n=19; 0.5 mg/kg over 40 min) and SPRAVATO (n=19; 56/84 mg). The treatment comprised a 4-week initial acute phase with twice weekly doses for up to 4 weeks. In patients who achieved meaningful improvement, treatment was continued for another 4 weeks with weekly doses, followed by tapering to less frequent doses to maintain response or remission (generally every 2-4 weeks). Between-group statistical comparisons were not performed.

Results

• Overall, during the acute phase, 39.0% of patients achieved a clinical response (≥50% improvement on MADRS) and 13.2% of patients achieved remission (MADRS ≤10).
• Mean MADRS score, per 4 treatments, improved from baseline in both the SPRAVATO
  (-7.55; 95% confidence interval [CI], -9.57 to -5.54; P<0.001) and the IV ketamine group (-4.32; 95% CI, -6.40 to -2.23; P<0.001).
• Mean QIDS-SR score, per 4 treatments, improved from baseline in both the SPRAVATO (-4.12; 95% CI, -5.20 to -3.03; P<0.001) and the IV ketamine group (-3.25; 95% CI, -4.72 to -1.77; P<0.001).
• There were 16 hypomania or mania events reported in 13 patients during the maintenance phase. Of these events, 8 were mild episodes (SPRAVATO, n=5; IV ketamine, n=3), resolving without intervention, and 7 were moderate episodes (SPRAVATO, n=5; IV ketamine, n=2). One patient treated with IV ketamine experienced severe mania requiring hospitalization. Two of the 10 patients treated with SPRAVATO were initially diagnosed with unipolar depression, and this was their first hypomanic/manic episode that led to their bipolar diagnosis.
  • Notably, 87.5% of these events occurred in patients on mood stabilizers, antipsychotics, or lithium.

Limitations

• The authors stated that a small sample size and lack of ethnic/racial diversity limited the generalizability of the findings.
• They also noted that the manic and hypomanic symptoms could have been attributed to modifications to the study drugs or other adjunctive therapies.
• Furthermore, the manic and hypomanic events were evaluated retrospectively; possibly, some of the events were not reported if no medical intervention was needed.

Singh et al (2023)¹⁴ conducted a comparative observational study in a real-world setting in patients with TRD (N=62) who had received either up to 6 IV ketamine infusions (0.5 mg/kg; n=47, 76%) or 8 SPRAVATO doses (56 mg/84 mg; n=15, 24%).

Results

• In patients receiving IV ketamine vs SPRAVATO, overall median (interquartile range [IQR]) change and median (IQR) percent change in QIDS-SR score from baseline to last treatment was -8 (range, -13 to -4) vs -10 (range, -13 to -4; P=0.84), and -53 (range, -77 to -25) vs -55 (range, -69 to -24; P=0.65), respectively. No significant difference was observed between the 2 treatment groups.
• Based on QIDS-SR scores, the response (57.4% vs 60.0%) and remission (42.6% vs 26.7%) rates were similar for patients who received IV ketamine vs those who received SPRAVATO (P>0.05). The median number of treatments received to achieve response and remission was significantly lower in patients receiving IV ketamine vs those receiving SPRAVATO (P≤0.01).
• Changes in systolic blood pressure and heart rate from baseline to 40 minutes and to the end of treatment were observed to be higher in patients receiving IV ketamine vs those receiving SPRAVATO (P≤0.04); however, no difference was observed in oxygen saturation and diastolic blood pressure or CADSS scores (P≥0.06 for all).
• A secondary analysis evaluating the antisuicidal properties of IV ketamine and SPRAVATO in 52 patients with suicidality data (IV ketamine, n=37; SPRAVATO, n=15; 81% of 52 patients presented with active or passive suicidality at baseline), reported similar antisuicidal response in both treatment groups, with no interaction between treatment groups and treatment numbers with the improvement in suicidal scores.²⁸

Limitations

• Observational study with a small sample size especially for SPRAVATO group could have affected the statistical analysis.
• The authors suggested there was potential for expectation bias with IV ketamine during counseling of the medications prior to treatment and due to its route of administration, which may have been perceived as a more direct route; these perceptions may have contributed to the faster response compared to SPRAVATO.
• Additionally, not all patients completed the QIDS-SR form at 24 hours post-infusion, at each treatment visit.

Nikayin et al (2022)¹⁵ conducted a comparative retrospective study for all Yale Interventional Psychiatric Service (IPS) patients (n=210) receiving 0.5 mg/kg IV ketamine over 40 min (n=129, 61.4%) or 56 mg or 84 mg SPRAVATO (n=81, 38.6%) between September 2016 and April 2021. Baseline demographics were balanced between groups. Adults with a major depressive episode receiving acute treatment (multiple treatments each ≤7 days apart for up to 8 total treatments) were included in the study.

Results

• With respect to the primary endpoint, no significant difference was found between the treatment groups with an estimated group difference in MADRS by treatment end of 2.15 (95% CI, -0.06 to 4.37; P=0.06). However, differences in secondary endpoints for QIDS-SR scores after 8 treatment sessions, and MADRS and QIDS-SR scores after the first 6 treatments were 1.59 (95% CI, 0.24-2.94; P=0.02), 2.49 (95% CI, 0.01-4.98; P<0.05) and 1.64 (95% CI, 0.08-3.19; P=0.04), respectively, and were all in favor of IV ketamine.
• There were no differences in response (IV ketamine, 37.8% vs SPRAVATO, 36.0%) or remission (29.6% vs. 24.0%, respectively) rates.
• A subgroup analysis showed no differences between IV ketamine and SPRAVATO based on mean SI scores from the MADRS item 10 and QIDS-SR item 12.

Limitations

• The authors stated that these findings should be interpreted with caution given the study limitations, which included patient demographics perhaps not being representative of the general population given the accessibility issues with these treatments and the nonrandomized, unblinded retrospective nature of the analysis.

Post Hoc Analysis of Observational Studies

d'Andrea et al (2024)²⁹ conducted a retrospective, post hoc pooled analysis using data of 311 patients with TRD from real-world studies of IV ketamine (Canadian Rapid Treatment Center of Excellence [CRTCE], Canada) and SPRAVATO (REAL-ESK study, Italy). Depressive symptoms were evaluated using the QIDS-SR score in the IV ketamine group and the MADRS score in the SPRAVATO group.

Results

• In the IV ketamine group (n=171), 106 patients escalated to 0.75 mg/kg infusion twice weekly at the third infusion after receiving initial infusions of 0.5 mg/kg. In the SPRAVATO group (n=140), 69 patients received 84 mg, 66 received 56 mg, and 5 received 28 mg twice weekly.
• The effect sizes of treatment with IV ketamine and SPRAVATO were compared to determine the difference in efficacy between the treatment groups.
• At 1 month, a significant reduction in mean depressive symptoms was observed in both groups (IV ketamine: mean reduction in QIDS-SR scores, P<0.001 and SPRAVATO: mean reduction in MADRS scores, P=0.025).
  • The effect size was larger in the IV ketamine group vs the SPRAVATO group (IV ketamine: Cohen’s d [95% CI], 1.67 [1.37-1.86] vs SPRAVATO: Cohen’s d [95% CI], 1.24 [1.04-1.35]).
• Response at 1 month was significantly higher in the IV ketamine group vs the SPRAVATO group (36% vs 25%; Chi-squared test [χ²], 4.13; P=0.042). Remission at 1 month was similar between the treatment groups (IV ketamine vs SPRAVATO, 13% vs 12%; χ², 0.38; P=0.845).
• The IV ketamine group reported significantly higher treatment-emergent adverse events (AEs) vs the SPRAVATO group, including dissociative symptoms (58% vs 34%, P=0.006), hypertension (45% vs 9%, P<0.001), dizziness (30% vs 6%, P<0.001), and sedation (50% vs 27%, P<0.001). Discontinuations related to AEs and tolerability were similar between the groups.

Limitations

• The study compared contrasting datasets of different investigations with non-uniform time points and different assessment scales; treatment efficacy was determined using the QIDS-SR scale, a self-administered scale, in CRTCE, and the MADRS scale, a clinician-administered scale, in REAL-ESK.
• The study comprised a heterogeneous pool of patients due to the different recruitment processes in the source studies; patients with TRD were recruited from private clinics in CRTCE and from public outpatient clinics in REAL-ESK.

postmarketing safety data

Chiappini et al (2025)¹⁶ conducted an analysis of the FAERS database to evaluate and compare the urological safety profiles of SPRAVATO and ketamine with those of antidepressants and second-generation antipsychotics using a disproportionality analysis.

Results

• Of the 7661 adverse drug reactions (ADRs) identified for SPRAVATO (between 2011 and 2024), 4714 were serious and 140 were related to renal and urinary disorders. Of the 4739 ADRs identified for ketamine (between 1998 and 2024), 4578 were serious and 105 were related to renal and urinary disorders.
• 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 of Urological Adverse Events With SPRAVATO and Ketamine vs Antidepressants and Antipsychotics).

Limitations

• 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.³⁰

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 11 March 2025.

This response excludes meta-analyses and case studies.^31-38