SUMMARY

• The safety and efficacy of SPRAVATO has not been established in pediatric patients.¹
• A randomized double-blind (DB), double-dummy, phase 2b multicenter study compared the efficacy and safety of single fixed doses of SPRAVATO (28 mg, 56 mg, and 84 mg) to a psychoactive comparator, oral midazolam (0.125 mg/kg), in rapidly reducing the symptoms of major depressive disorder (MDD), including suicidal ideation, in pediatric patients (12 to <18 years; N=147) assessed to be at imminent risk for suicide.^{2, 3}
  • Pooled doses (56 and 84 mg) of SPRAVATO plus standard-of-care (SOC) compared to midazolam plus SOC showed statistically significant (P=0.037) and clinically meaningful improvement in depressive symptoms at 24 hours post-first dose (day 2), measured as a change in total Clinician-rated Children’s Depression Rating Scale, Revised (CDRS-R) score from baseline (primary endpoint).³
  • The between-group difference vs midazolam was clinically significant but not statistically significant for each of the 2 higher individual doses of SPRAVATO (P=0.123 for 84 mg; P=0.072 for 56 mg). Due to the testing hierarchy, the 28 mg dose was not formally tested; however, the 84 mg and 56 mg doses showed numerically greater treatment differences vs midazolam than did the 28 mg dose.³
  • At the end of treatment (day 25), all 4 treatment groups, SPRAVATO (28/56/84 mg) plus SOC and midazolam plus SOC, showed continued improvement on the CDRS-R total score; the between-group difference (least squares [LS] mean [95% confidence interval, or CI]) was -7.0 [-12.85, -1.06], -1.0 [-6.72, 4.63], and -6.5 [-12.94,
    -0.10] for SPRAVATO 28 mg, 56 mg, and 84 mg group, respectively.³
  • All 4 treatment groups showed improvement in the severity of suicidality, measured by Clinical Global Impression of Severity of Suicidality-Revised (CGI-SS-R), at 24 hours and at the end of treatment (day 25), though the differences between each SPRAVATO dose group and midazolam were not statistically significant.³
  • The most common adverse events (AEs) observed with SPRAVATO during the treatment phase were dizziness, nausea, dissociation, headache, dysgeusia, and somnolence but no AE-related discontinuation was reported.³
• A case report describes a 17-year-old patient with MDD and comorbid developmental and psychiatric disorders who showed improvement in clinician-measured depressive symptoms (via Montgomery-Åsberg Depression Rating Scale [MADRS]) after treatment with SPRAVATO, but treatment was discontinued due to a lack of clinically relevant sustained change in symptoms.⁴

PRoduct labeling

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. SPRAVATO nasal spray is not approved in pediatric patients.⁵

CLINICAL DATA

Randomized Controlled Trial

Kosik-Gonzalez et al (2023)³ conducted a phase 2b, randomized, DB, double-dummy, psychoactive comparator-controlled, multicenter study to evaluate the efficacy and safety of single fixed doses of SPRAVATO (28 mg, 56 mg, and 84 mg doses) vs midazolam (psychoactive comparator) in rapidly reducing the symptoms of MDD in adolescent patients (12 to <18 years) at imminent risk of suicide. Eligible patients had a MDD diagnosis (per DSM-5 criteria) with current suicidal thinking with intent and were without psychotic features, confirmed by the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID). Patients were required to have a baseline total score ≥58 on the CDRS-R and needed acute psychiatric hospitalization.

The study included a screening phase, a DB treatment phase (days 1-25), and a follow-up phase (days 26-200). A total of 147 patients were randomized (1:1:1:2) to receive DB treatment with either SPRAVATO (28, 56, or 84 mg) or oral midazolam (0.125 mg/kg), each administered twice weekly for 4 weeks. All study medication was self-administered under the direct supervision of the investigator or designee. See Figure: Study Design and Participant Disposition. SOC included initial psychiatric hospitalization (5 days recommended), initiation of 1 of 3 protocol-permitted oral antidepressants (fluoxetine, escitalopram, or sertraline) between day 1 and 7, and treatment with a psychological intervention at least through the initial 8-week follow-up phase (day 81).³

Baseline Characteristics

The treatment groups had similar baseline characteristics. Most patients were White (80.7%) and female (77.9%) with a mean age of 14.9 years across the treatment arms. Mean CDRS-R total score was 76.3 and mean MADRS total score was 39.8. Based on MINI-KID, 80% of patients had a lifetime suicide attempt and 53.8% (based on medical history) had attempted a suicide within the last month. Over 67% of patients had CGI-SS-R scores of 4 (markedly suicidal) and 5 (severely suicidal). An additional 19% were moderately suicidal (score of 3).³

Efficacy

Most patients completed the DB treatment phase (139/147, 94.6%) and entered the
6-month follow-up phase (136/139). The primary endpoint was change in total CDRS-R score for the pooled 56 mg and 84 mg groups from baseline to 24 hours post-first dose (day 2), which was found to be statistically significant over midazolam plus SOC (P=0.037). A between-group comparison was then conducted on the 2 higher individual doses of SPRAVATO vs midazolam, which were found to be clinically significant but not statistically significant (P=0.123 for 84 mg and P=0.072 for 56 mg). Due to the testing hierarchy, the 28 mg dose was not formally tested. See Table: CDRS-R: Change From Baseline to 24 Hours Post-First dose. However, both the 84 mg and 56 mg showed numerically greater treatment differences vs midazolam than did the 28 mg dose. At the end of treatment period (day 25), all 4 treatment groups showed continued improvement on the CDRS-R total score; the between-group difference (LS mean [95% CI]) was -7.0 [-12.85, -1.06],
-1.0 [-6.72, 4.63], and -6.5 [-12.94, -0.10] for SPRAVATO 28 mg, 56 mg, and 84 mg group, respectively.³

There was improvement in the severity of suicidality, assessed by CGI-SS-R total score, in all 4 groups at 4 and 24 hours post first-dose (day 2) and at the end of treatment, but the difference between each SPRAVATO dose and midazolam was not statistically significant.³ See Figure: CGI-SS-R: Frequency Distribution at Baseline, 4 and 24 Hours Post-First Dose and Day 25.

Safety

The most common AEs observed with SPRAVATO during the treatment phase were dizziness, nausea, dissociation, headache, dysgeusia, and somnolence but no AE-related discontinuation was reported. See Table: Most Frequently Reported Adverse Events During the Double-blind Treatment Phase. No deaths were reported during the treatment phase except for 1 female (14 years old) death by suicide in the comparator (midazolam) arm during the follow-up phase (day 193).³

Limitations

Study findings may be limited by the exclusion of participants with select psychiatric comorbidities (eg, psychotic symptoms, bipolar disorder, borderline personality disorder), and small sample size owing to its phase 2b study design.³ The nonsignificant results observed with the individual doses of SPRAVATO and midazolam may have been partially due to the nonspecific benefits of initial hospitalization and comprehensive SOC as well as the use of a psychoactive comparator (vs placebo), which may have dampened signal detection, as has been observed by other studies.⁶

Case Report

Skala et al (2023)⁴ described the case of a 17-year-old female patient who presented to the psychiatric unit with chronic suicidal ideation and was diagnosed with Asperger syndrome, generalized anxiety disorder, and MDD. The patient’s prior medication history included sertraline, fluoxetine, alprazolam, venlafaxine, and quetiapine, with chlorprothixene, lorazepam, and pregabalin as add-on therapy. Due to persistent symptoms of depression and suicidal ideation, she was initiated on SPRAVATO 28 mg twice a week for 4 weeks, followed by 28 mg once a week for 3 weeks, with concomitant psychotherapy.

Improvements in disease severity (decreased Clinical Global Impression Scale [CGI] score from 6 to 4) and functionality (increased Global Assessment of Functioning Scale [GAF] raw score from 8 to 20) were reported over the treatment course. The clinician’s assessment of the patient’s depressive symptoms showed a significant improvement (MADRS, from a raw score of 44 to 30); however, her self-assessed scores remained unchanged (Beck Depression Inventory [BDI-II], from a raw score of 49 to 45; Patient Health Questionnaire [PHQ], from a raw score of 25 to 21). During most treatment sessions, the patient reported dizziness, nausea, and fatigue that lasted 30-60 minutes. Derealization was only reported after the second administration and a slight elevation in blood pressure also only occurred after one treatment session. However, following further clinical observation, the treatment was discontinued due to unsustained effects on depressive mood, anxiety, and general functionality.

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 24 April 2024. Note that the compound search terms are limited to esketamine nasal spray.