TABLE 5.
Neurosteroid analogs and GABA-A receptor modulators with antidepressant properties in the pipeline.
| Authors/Trial sponsor | Methodology | Results | Clinical trial phase, trial identifier (if available) |
|---|---|---|---|
| Kanes et al. (2017a) | Brexanolone (SAGE-547), open-label, N = 4, PPD, 84 h | Mean HAMD and CGI-I scores had favorable evolution; 14 adverse events were reported, but no SAE | Phase II, NCT02285504 |
| Kanes et al. (2017b) | Brexanolone, DBRCT, N = 21, severe PPD, 60 h | HAMD total scores decreased significantly vs placebo at 60 h. Dizziness and somnolence were the most frequently reported adverse events | Phase II, NCT02614547 |
| Meltzer-Brody et al. (2018) | Brexanolone, two DBRCT, N = 138 and 108, severe PPD, 60 h | HAMD scores evolution supported the existence of a significant clinical improvement vs placebo, which persisted up to 30 days. Headache, dizziness, somnolence were the most commonly reported adverse events | Phase III, NCT02942004 |
| Phase III, NCT02942017 | |||
| Gerbasi et al. (2021) | Brexanolone, post-hoc analysis of three trials, N = 299, PPD, 30 days | Brexanolone was superior to placebo after 60 h and 30 days. Higher probability to sustain HAMD-defined remission and CGI-I response vs placebo at day 30 | Phase II, NCT02614547 |
| Phase III, NCT02942004 | |||
| Phase III, NCT02942017 | |||
| Hoffmann et al. (2020) | Zuranolone (SAGE-217), two trials, DBRCT, N = 108 healthy volunteers (72 and 36, respectively), single ascending dose study and multiple ascending dose study | Safety, tolerability, and pharmacokinetics of SAGE-217. Mild and transient sedation was observed. Most adverse events were reported as mild/moderate intensity. No SAE was reported | Phase I |
| Gunduz-Bruce et al. (2019) | Zuranolone, DBRCT, N = 89, MDD, 14 days | HAMD scores improved significantly vs placebo, no SAE was reported. Dizziness, headache, nausea, and somnolence were the most common adverse events | Phase II, NCT03000530 |
| Deligiannidis et al. (2021) | Zuranolone, DBRCT, N = 153, PPD, 45 days | HAMD scores were improved by zuranolone vs placebo from day 3, up to day 45. HAMA and MADRS also improved under zuranolone treatment vs placebo. The overall tolerability of zuranolone was good, with one SAE (confusional state) | Phase III, NCT02978326 |
| National Library of Medicine (2020) | Zuranolone, DBRCT, N = 192, severe PPD, 14 days | HAMD-17 at day 15 is the main outcome measure, the study is ongoing (as of February 2022) | Phase III, NCT04442503 |
| Dichtel et al. (2020) | Ganaxolone (CCD1042) as augmentation strategy, open-label, pilot study, N = 10, MDD with insufficient response, 8 weeks | MADRS scores decreased during 7 weeks, 44% response rate at week 8. Sleep quality, appetite changes, and body weight also improved. Sleepiness, fatigue, and dizziness were the most common adverse events | N/A, NCT02900092 |
| Marinus Pharmaceuticals (2018) | Ganaxolone i.v., N = 58, severe PPD, 34 days | HAMD-17 total score decreased vs placebo at 48 h and the decrease was maintained until day 34. Sedation, dizziness were the most commonly reported adverse events | Phase II, NCT03228394 |
| National Library of Medicine (2021d) | Ganaxolone i.v. 6 h, followed by oral administration 28 days, N = 33, PPD | HAMD-17 scores decreased rapidly at 6 h but did not separate zuranolone from placebo at day 28 | Phase II, NCT03460756 |
| National Library of Medicine (2021e) | PRAX-114 in MDD patients, DBRCT, N = 200 and 125, respectively, 43 days | The change in the HAMD total score at day 15 is the main outcome measure; studies are ongoing (as of February 2022) | Phase II/III, NCT04832425 |
| Phase II, NCT04969510 |
CGI-I, Clinical Global Impression- Improvement; DBRCT, double-blind randomized controlled trial; HAMD-17, Hamilton Depression Rating Scale; MADRS, Montgomery-Asberg Depression Rating Scale; MDD, major depressive disorder; NLM, National Library of Medicine; PPD, post-partum depression; SAE, severe adverse event.