Across 49 European CTIS-authorized Phase II & III depression / major depressive disorder trials, Montgomery–Åsberg Depression Rating Scale (MADRS) endpoints dominate: 30/49 trials (61.2%) measured MADRS in at least one endpoint role and 25/49 (51.0%) used MADRS as a primary endpoint. Secondary endpoint architecture is broader: Clinical Global Impression (CGI) endpoints appear in 22/49 trials (44.9%) as secondary endpoints, followed by safety/tolerability in 17/49 (34.7%), functioning or quality-of-life in 16/49 (32.7%), remission in 14/49 (28.6%), and response in 13/49 (26.5%).
MADRS was measured in 30/49 trials (61.2%). CGI global severity or improvement endpoints followed in 24/49 (49.0%), safety/tolerability/adverse-event endpoints in 22/49 (44.9%), functioning or quality-of-life endpoints in 17/49 (34.7%), response in 16/49 (32.7%), and remission in 14/49 (28.6%).
The endpoint stack is still anchored by clinician-rated depression severity, especially MADRS. CGI, safety, function/QoL, response, and remission appear most often as supporting domains rather than as primary trial-defining measures.
The 49 trials contained 47 primary endpoint records, 165 secondary endpoint records, and 7 exploratory/other endpoint records. MADRS appeared as a primary endpoint in 25/49 trials (51.0%), while CGI was mainly secondary, appearing as a secondary endpoint in 22/49 trials (44.9%) but as primary in only 1/49 (2.0%).
| Endpoint domain | Primary | Secondary | Exploratory/other |
|---|---|---|---|
| MADRS | 25 | 18 | 2 |
| CGI | 1 | 22 | 2 |
| Safety/tolerability/AEs | 4 | 17 | 2 |
| Functioning/QoL/disability | 1 | 16 | 1 |
| Response | 4 | 13 | 1 |
| Remission | 1 | 14 | 0 |
| Anxiety symptoms | 0 | 12 | 0 |
For CTIS/EU submissions, the primary efficacy claim is usually built on MADRS change. The multidimensional benefit profile—global severity, function, response/remission, anxiety, suicidality, and safety—is generally documented in the secondary endpoint layer.
Phase II accounted for 16/49 trials (32.7%) and Phase III for 33/49 (67.3%). MADRS was common in both phases: 9/16 Phase II trials (56.2%) and 21/33 Phase III trials (63.6%). Phase III showed higher use of CGI (19/33, 57.6%), functioning/QoL (15/33, 45.5%), response (12/33, 36.4%), remission (11/33, 33.3%), and safety (16/33, 48.5%).
| Endpoint domain | Phase II | Phase III |
|---|---|---|
| MADRS | 56.2% | 63.6% |
| CGI | 31.2% | 57.6% |
| Safety/tolerability | 37.5% | 48.5% |
| Functioning/QoL | 12.5% | 45.5% |
| Response | 25.0% | 36.4% |
| Remission | 18.8% | 33.3% |
| Neuroimaging/EEG/cognition | 25.0% | 15.2% |
Phase III CTIS submissions look more confirmatory and patient-relevant: they preserve MADRS but add more global severity, functioning, response/remission, and safety endpoints. Phase II retains more exploratory biology and neurocognitive signal work.
MDD / major depression appeared in 38/49 trials (77.6%). Treatment-resistant or refractory depression appeared in 10/49 (20.4%), bipolar depression in 3/49 (6.1%), anhedonia-enriched MDD in 3/49 (6.1%), and unspecified depression in 3/49 (6.1%).
| Subgroup | Most frequent endpoint domains |
|---|---|
| MDD / major depression 38 trials | MADRS 22/38 (57.9%); CGI 19/38 (50.0%); safety 18/38 (47.4%); function/QoL 15/38 (39.5%). |
| Treatment-resistant / refractory depression 10 trials | Safety 9/10 (90.0%); MADRS 9/10 (90.0%); response 6/10 (60.0%); biomarkers 5/10 (50.0%); suicidality 5/10 (50.0%). |
| Bipolar depression 3 trials | MADRS 3/3 (100.0%); anhedonia/SHAPS 2/3 (66.7%); CGI 2/3 (66.7%); safety 1/3 (33.3%). |
Treatment-resistant depression trials show the clearest endpoint expansion: they retain MADRS but add more safety, biomarker, neurocognitive and suicidality measurement. This reflects a more complex risk-benefit package for EU/CTIS submissions in harder-to-treat depression populations.
Small-molecule interventions appeared in 43/49 trials (87.8%), making them the only modality stratum large enough to shape the overall endpoint pattern. Within small-molecule trials, MADRS appeared in 29/43 (67.4%), CGI in 23/43 (53.5%), safety/tolerability in 20/43 (46.5%), functioning/QoL in 16/43 (37.2%), response in 15/43 (34.9%), and remission in 13/43 (30.2%).
The practical benchmark for new European depression submissions is therefore a small-molecule endpoint package anchored by MADRS, supported by CGI, safety, response/remission, and patient-function measures.
Using initial CTIS submission date to first CTIS authorization date, the median interval was 108 days across all 49 trials. Phase II trials had a median of 100.5 days, while Phase III trials had a median of 111 days. Overall, 28/49 trials (57.1%) fell in the 61–120 day interval, 11/49 (22.4%) were authorized within 60 days, and 10/49 (20.4%) took more than 120 days.
For European depression/MDD studies, CTIS endpoint packages should be planned early enough to support a roughly three-to-four-month submission-to-authorization path, especially in Phase III where the endpoint package is broader.
MADRS = Montgomery–Åsberg Depression Rating Scale. CGI = Clinical Global Impression, including CGI-S, CGI-I, and CGI-E. HAMD/HDRS = Hamilton Depression Rating Scale variants. C-SSRS = Columbia-Suicide Severity Rating Scale. BSSI = Beck Scale for Suicide Ideation. SHAPS = Snaith-Hamilton Pleasure Scale. PHQ-9 = Patient Health Questionnaire-9. BDI = Beck Depression Inventory. SDS = Sheehan Disability Scale. CTIS = Clinical Trials Information System.