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 sublingual 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 retrospective real-world analysis comparing the efficacy of IV ketamine vs SPRAVATO based on Quick Inventory of Depressive Symptomatology self-report (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).¹²
• A retrospective analysis comparing the trajectory of depression severity, based on Montgomery-Åsberg Depression Rating Scale (MADRS) score, between patients treated with up to 8 weeks of IV ketamine and SPRAVATO showed no significant difference between groups.¹³
• Both esketamine and ketamine are United States Drug Enforcement Administration (DEA) Schedule III controlled substances (CIII) and may be subject to abuse and diversion.^8,14
  • 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.¹⁵
• Esketamine, the S-enantiomer of racemic ketamine, is a nonselective, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA).^16-19 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.^16-18,20
• 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.^21-23

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.²⁴

Clinical data

Retrospective Observational Studies

Singh et al (2023)¹² 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 Clinician-Administered Dissociative States Scale (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.²⁵

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)¹³ 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 suicidal ideation 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)²⁶ 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 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 adverse events 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.

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 08 April 2024.

This response excludes meta-analyses and case studies.^27-30