Esketamin (3) – Spravato®

Adults with treatment-resistant major depression who have not responded to at least two different courses of antidepressant therapy during their current moderate to severe depressive episode

• Hint for a considerable additional benefit
• Overall, the G-BA classifies the certainty of the evidence for the identified additional benefit as ‘hint’.
• mortality
  • By week 32, one person had died in each of the intervention and control arms. Consequently, there is no statistically significant difference between the treatment arms for the endpoint of overall mortality.
• Morbidity – remission and response as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS)
  • For the endpoints of remission and response, statistically significant differences were observed between the treatment arms in favour of esketamine at both week 8 and week 32.
  • There is an effect modification for response at week 32 depending on the class of the patient’s existing antidepressant (SNRI vs. SSRI). A statistically significant advantage of esketamine was observed for patients whose existing antidepressant was an SNRI, but not for those already receiving SSRI treatment.
• Morbidity – Functional remission as measured by the Sheehan Disability Scale (SDS)
  • There was no statistically significant difference between the treatment arms at week 8; however, a statistically significant advantage of esketamine over quetiapine extended-release was observed at week 32.
• Morbidity – General depressive symptoms as measured by the Patient Health Questionnaire 9 (PHQ-9)
  • In the responder analysis (improvement in the PHQ-9 total score of ≥ 5 points), there were statistically significant advantages for esketamine over quetiapine extended-release at both week 8 and week 32.
• Morbidity – General depressive symptoms as measured by the Quality of Life in Depression Scale (QLDS)
  • Statistically significant differences between the treatment arms in favour of esketamine were observed at both week 8 and week 32.
  • A subgroup analysis confirmed the advantage of esketamine at week 8 for those patients already receiving SNRI treatment, but not for those whose existing antidepressant was an SSRI.
• Morbidity – health status as measured by the European Quality of Life Questionnaire 5-Dimensions (EQ-5D)
  • For the health status endpoint, measured as an improvement of ≥ 15 points on the visual analogue scale (VAS) of the EQ-5D, statistically significant advantages for esketamine compared with quetiapine extended-release were observed at both week 8 and week 32.
• Morbidity – Suicidal behaviour as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)
  • No statistically significant differences were observed between the treatment arms at week 8 or week 32 for the endpoint measures of suicidal ideation and suicidal behaviour.
• Health-related quality of life – assessed using the Short Form-36 Health Survey Version 2 (SF-36v2)
  • For the Physical Component Summary (PCS) score of the SF-36v2 (responder analysis for an improvement in the PCS of ≥ 9.4 points), a statistically significant advantage in favour of esketamine was observed between the treatment arms at week 32, but not at week 8.
  • With regard to the mental health summary score (MCS) of the SF-36v2 (responder analysis for an improvement in the MCS of ≥ 9.6 points), there were statistically significant advantages for esketamine compared with quetiapine extended-release at both week 8 and week 32.
  • For the results at week 32, there is an effect modification depending on the class of the patient’s existing antidepressant: statistically significant advantages in favour of esketamine can only be observed when combined with an existing SNRI, but not with an SSRI.
• Side effects – SUEs and therapy discontinuations due to AEs (up to week 32)
  • There is no statistically significant difference between the treatment arms for the endpoint ‘SUEs’, whereas for the endpoint ‘discontinuation due to AEs’, there is a statistically significant advantage for esketamine over quetiapine retard.
• Side effects – Specific side effects (up to week 32)
  • For the endpoints psychiatric disorders (SOC, AEs) as well as disorders of the nervous system (SOC, AEs), the respiratory tract, thoracic cavity and mediastinum (SOC, AEs), nausea (PT, AEs) and vomiting (PT, AEs), statistically significant differences were observed between the treatment arms, with a disadvantage for esketamine.
• Overall assessment
  • Overall, the G-BA concludes that there is considerable additional benefit for esketamine compared with quetiapine extended-release in the treatment of adult patients with treatment-resistant major depression.
  • In the morbidity category, remission and response are of high relevance; these were assessed in the present study using the MADRS. For both remission and response, esketamine showed advantages over quetiapine retard at weeks 8 and 32 respectively.
  • With regard to general depressive symptoms (assessed using the PHQ-9 and the QLDS) and health status (assessed using the visual analogue scale of the EQ-5D), esketamine showed advantages over quetiapine extended-release, in each case when used in combination with an SSRI or SNRI.
  • With regard to functional remission (as measured by the SDS), a difference in favour of esketamine was observed at week 32, but not at week 8.
  • No statistically significant differences were found for the endpoint of suicidality (assessed using the C-SSRS).
  • The analyses of quality of life using the SF-36v2 show an advantage for esketamine over quetiapine extended-release at week 32 (physical total score) and at weeks 8 and 32 (mental total score).
  • With regard to side effects, esketamine showed an advantage in terms of discontinuations due to adverse events. The overall rates of severe adverse events show no statistically significant differences. In detail, specific adverse events reveal disadvantages of esketamine compared with quetiapine extended-release. In summary, esketamine shows advantages in terms of side effects.

Courtesy translation only, please refer to the German original.