Esketamin (2) – Spravato®

• Clinical trials
  • For the benefit assessment of esketamine in adult patients with a moderate to severe episode of major depression as an acute, short-term treatment for the rapid reduction of depressive symptoms which, in the doctor’s judgement, constitute a psychiatric emergency, the pharmaceutical manufacturer has submitted the randomised, controlled Phase III trials SUI3001 and SUI3002 (including a pooled analysis of the two trials), as well as, in support, the Phase II trial SUI2001.
  • Patients with a moderate to severe episode of major depression and current suicidal ideation with intent to act were enrolled in the two RCTs, SUI3001 and SUI3002; from a medical perspective, this indicated the need for acute psychiatric hospitalisation.
  • All participants received antidepressant medication; in addition, they were randomised to receive either esketamine or placebo as an adjunctive treatment, so that the studies compared esketamine plus antidepressant therapy with placebo plus antidepressant therapy.

Adults with a moderate to severe episode of major depression, acute short-term treatment for the rapid reduction of depressive symptoms which, in the clinician’s judgement, constitute a psychiatric emergency

• For adults with a moderate to severe episode of major depression, as acute short-term treatment to rapidly reduce depressive symptoms which, in the clinician’s judgement, constitute a psychiatric emergency, there is a hint of a minor additional benefit.
• The certainty of the evidence is overall classified as a hint.
• mortality
  • By day 90, one person had died in the intervention arm and none in the control arm. Consequently, no advantage or disadvantage of esketamine plus antidepressant therapy compared with placebo plus antidepressant therapy can be identified for the endpoint of all-cause mortality.
• Morbidity – General depressive symptoms – Montgomery-Åsberg Depression Rating Scale (MADRS)
  • Here, an advantage of esketamine plus antidepressant therapy over placebo plus antidepressant therapy is evident in terms of remission and response, both in the responder analysis at day 25 and in the event-time analysis up to day 90.
• Morbidity – General depressive symptoms – Beck Hopelessness Scale (BHS)
  • For the BHS endpoint (analysis of continuous data), no statistically significant differences were observed between the treatment groups, either in the individual studies or in the pooled analysis.
• Morbidity – General depressive symptoms – Quality of Life in Depression Scale (QLDS)
  • For the QLDS, the pooled analysis does indeed show a statistically significant advantage of esketamine plus antidepressant therapy over placebo plus antidepressant therapy at day 25; the 95% confidence interval for the standardised mean difference does not lie entirely outside the non-significant range of −0.2 to 0.2. It cannot therefore be concluded that the effect is clinically relevant.
• Morbidity – Specific depressive symptoms: Suicidal behaviour – Suicide Ideation and Behaviour Assessment Tool (SIBAT)
  • In the pooled analyses of the continuous data, the results do not show any significant difference – neither for the patient-reported measures (self-assessments of risk/protective factors, suicidal thoughts, desire to die, suicidal intent, frequency of suicidal thoughts and probability of suicide) nor for the clinician-assessed modules (overall clinical impression of the frequency of suicidal thoughts, acute suicide risk and long-term suicide risk) in the pooled analyses of continuous data.
• Morbidity – Health status (EQ-5D VAS)
  • For the health status endpoint, measured as an improvement of ≥ 15 points on the EQ-5D visual analogue scale (VAS), the pooled analysis revealed a statistically significant advantage in favour of esketamine plus antidepressant therapy compared with placebo plus antidepressant therapy, both in the responder analysis up to Day 25 and in the time-to-event analysis up to Day 90.
• Health-related quality of life
  • No endpoints were assessed in this category.
• Side effects – overall rates of SUEs and discontinuations due to AEs
  • For the endpoints ‘SAE’ and ‘withdrawal due to AEs’, the pooled analysis showed no statistically significant difference between the treatment groups in either case.
• Side effects – nervous system disorders, psychiatric disorders, gastrointestinal disorders, eye diseases (SOC, AE)
  • The pooled analysis shows a statistically significant disadvantage of esketamine plus antidepressant therapy compared with placebo plus antidepressant therapy across several SOCs (nervous system disorders, psychiatric disorders, gastrointestinal disorders, eye diseases).
• Overall assessment
  • Results on mortality, morbidity and side effects are available from two RCTs and a pooled analysis.
  • For the endpoint ‘general depressive symptoms’, assessed using the MADRS, BHS and QLDS, the pooled analysis shows statistically significant and clinically relevant differences in favour of esketamine exclusively when considering the MADRS.
  • In contrast, for the specific depressive symptom of suicidality (measured using the SIBAT), there is no advantage or disadvantage for esketamine.
  • For the endpoint ‘health status’ (EQ-5D VAS), there is a statistically significant advantage for esketamine.
  • With regard to side effects, there were no statistically significant disadvantages for esketamine in the overall rates, but there were in individual specific adverse events (SOC).
  • For ‘general depressive symptoms’, an overall advantage can be identified, as the MADRS is an established and comprehensive standard for assessing depression.
  • However, when evaluating the present therapeutic indication, it must be taken into account in the overall assessment that no advantage is observed for the specific depressive symptom of suicidality (measured using SIBAT), which would have been significant in this emergency indication.
  • Overall, therefore, only a minor additional benefit can be identified on the basis of the morbidity data.
  • The observed advantage in general health status, as assessed by the EQ-5D VAS, underscores the additional benefit.
  • Disadvantages are evident only in specific AEs, but not in the overall rates; consequently, no relevant disadvantage is assumed in the overall assessment.
  • Overall, there is a minor additional benefit.

Courtesy translation only, please refer to the German original.