TABLE 3.
Monoaminergic modulators with antidepressant properties in the pipeline.
| Authors/Trial sponsor | Methodology | Results | Clinical trial phase, trial identifier (if available) | |
|---|---|---|---|---|
| Mi et al. (2021) | Ansofaxine (LY03005), DBRCT, N = 255, MDD, 6 weeks | HAMD-17 total score changes at week 6 were significant vs placebo. The overall tolerability was good | Phase II, NCT03785652 | |
| Luye Pharma (2021), NLM (2021a) | Ansofaxine, DBRCT, N = 58, MDD, 8 weeks | MADRS total score, HAMD-17 total score, CGI, HAMA, HAMD-17 Anxiety/Somatization factor, Cognitive Impairment factor, Blocking factor, MADRS Anhedonia factor, SDS total score—all were statistically significant improved vs placebo at week 8. No SAE occurred during this trial. Nausea, vomiting, headache, and drowsiness were the most commonly reported adverse events | Phase III, NCT04853407 | |
| Ball et al. (2016) | Edivoxetine (LY2216684) adjunctive to the ongoing antidepressant regimen, three DBRCT, N = 701, 689, and 449, MDD with partial response to SSRI, 8 weeks | The mean outcome was the mean change from baseline to week 8 in the MADRS total score. This outcome was not reached by any of these three trials. Most of the secondary objectives were not reached, either | Phase III, NCT01173601 Phase III, NCT01187407 Phase III, NCT01185340 | |
| Oakes et al. (2015) | Edivoxetine, N = 1249, MDD, 8 weeks open-label (edivoxetine + SSRI) + open-label 12 weeks stabilization period + DBRCT 24 weeks | No significant difference between edivoxetine and placebo was detected at the end of the trial (evaluated by MADRS total score) | Phase III, NCT01299272 | |
| Ball et al. (2014) | Edivoxetine /placebo adjunctive to SSRI, DBRCT, N = 131, MDD partial responsive to SSRI, 10 weeks | No significant differences in efficacy between groups at the end of the trial, based on the MADRS total score | Phase II, NCT00840034 | |
| Pangallo et al. (2011) | Edivoxetine, DBRCT, N = 495, MDD, 10 weeks | MADRS scores were improved significantly by edivoxetine vs placebo at week 10. Higher rates of response and remission were higher with edivoxetine. SDS scores also were significantly improved vs placebo | Phase II/III, NCT00795821 | |
| Ball et al. (2015) | Edivoxetine as adjunctive to SSRI, open-label, N = 328, MDD with partial response to SSRI, 54 weeks | The study discontinuation rate due to adverse events was 17%, 13 SAE (1 death). Most commonly reported adverse events: nausea, hyperhidrosis, constipation, headache, dry mouth, dizziness, vomiting, insomnia, upper respiratory tract infection. Mean MADRS score improvements were −17.0 at week 54 | Phase III, NCT01155661 | |
| Davidson et al. (2016) | MIN-117 vs placebo vs paroxetine, DBRCT, N = 84, moderate-to-severe MDD, 6 weeks | MADRS total score was improved by MIN-117 vs placebo at week 6. Remission with MIN-117 was achieved by 24% of patients (2.5 mg investigational product). The overall tolerability was good | Phase II, EudraCT 2015-000306-18 | |
| National Library of Medicine (2018) | MIN-117, DBRCT, N = 360, adult MDD patients, 6 weeks | No significant differences between active drug and placebo were detected by MADRS, HAMA, and CGI-S scores evolution | Phase II, NCT03446846 | |
| Carhart-Harris et al. (2021) | Psilocybin vs escitalopram, DBRCT, N = 59, moderate-to-severe MDD, 6 weeks | QIDS-SR scores at week 6 were not significantly changed vs placebo. Response rate 70% (psilocybin) vs 48% (placebo) | Phase II, NCT03429075 | |
| Griffiths et al. (2016) | Psilocybin, DBRCT, cross-over trial, N = 51 cancer patients + depression + anxiety, 5 weeks + 6 months follow-up | GRID-HAMD-17 and HAM-A scores were decreased by high-dose psilocybin. Quality of life, life meaning, and optimism scores improved, and death anxiety decreased under psilocybin treatment. At 6 months these changes persisted, 80% of these patients presented clinically significant decreases in depressed mood and anxiety scores | Phase II, NCT00465595 | |
| Ross et al. (2016) | Psilocybin vs niacin + psychotherapy, DBRCT, N = 29 patients with cancer-related anxiety and depression, 7 weeks, cross-over design | Rapid and sustained improvements in anxiety and depression before crossover, plus decreases in cancer-related demoralization and hopelessness, improvements in spiritual well-being, and quality of life. At the follow-up visit (6.5 months) consistent anxiolytic and antidepressant effects were present in the psilocybin group | Phase I, NCT00957359 | |
| Carhart-Harris et al. (2016) | Psilocybin + psychological support, open-label, N = 12, moderate-to-severe, treatment-resistant MDD, 3 months | The mean self-rated intensity of psilocybin effects was dose-related, and the drug was well tolerated by all patients. Depressive symptoms were markedly reduced at 1 week and 3 months compared to baseline, after high-dose treatment. Anhedonia and anxiety were markedly improved, also | Phase II, ISRCTN14426797 | |
| Davis et al. (2021) | Psilocybin, DBRCT, N = 24, MDD + psychotherapy, 4 weeks | The mean GRID-HAMD scores were significantly lower in the immediate treatment group, and the QIDS-SR scores reflected a rapid decrease in mean depression score after the first session, which remained significant up to week 4. In the overall sample, 71% of the participants had week 1 and week 4 clinically significant responses to the intervention. The remission rate was 58% at week 1 and 54% at week 4 | Phase II, NCT03181529 | |
| COMPASS, (2021) | Psilocybin + psychological support, DBRCT, N = 233, treatment-resistant MDD, 4 weeks | The high dose drug (25 mg) induced a significant decrease in MADRS scores vs inactive dose after day 1, and these improvements persisted after week 3, but the difference between the low dose (10 mg) group and the control group was not significant | Phase IIb, NCT03775200 | |
| Fava et al. (2018) | Cariprazine (low doses/high doses) adjunctive to antidepressant, DBRCT, N = 231, treatment-resistant MDD, 19 weeks | No differences were reported on any measures between low doses of cariprazine and placebo, and higher doses led to numerically greater mean change in MADRS and CGI-I scores. MADRS response and remission rates were higher vs placebo, but without reaching statistical significance. The overall tolerability was good | Phase II, NCT00854100 | |
| Durgam et al. (2016) | Cariprazine (low doses/high doses) adjunctive to antidepressants, DBRCT, N = 269, treatment-resistant MDD, 8 weeks | Reductions in MADRS total score at week 8 were significantly greater for the high dose of cariprazine vs placebo, but not for the low dose. Treatment-emergent adverse events most commonly reported were akathisia, insomnia, and nausea | Phase II, NCT01469377 | |
| Earley et al. (2018) | Cariprazine adjunctive to antidepressants, DBRCT, N = 530, 8 weeks | Cariprazine did not significantly improve MADRS total score or SDS score vs placebo. A nonsignificant decrease in depressive symptoms was, however, recorded in the cariprazine-treated patients vs placebo group. Cariprazine improved significantly CGI-I score vs placebo, and a significantly higher proportion of patients achieved MADRS response with cariprazine vs placebo (but not significant). The overall tolerability of cariprazine was good | Phase III, NCT01715805 | |
| Fava et al., 2019 | Pimavanserin as an adjunctive agent, DBRCT, N = 207, MDD with inadequate response to SSRI/SNRI, 10 weeks | Pimavanserin + ongoing SSRI/SNRI treatment significantly improved depressive symptoms (reflected in HAMD-17 total score change). Dry mouth, nausea, and headache were the most common adverse events in pimavanserin-treated patients. In patients with anxious depression, the response rate was 55.2 vs 22.4% (pimavanserin vs placebo) and the remission rate was 24.1 vs 5.3% (pimavanserin vs placebo), among patients with a baseline Anxiety/Somatization factor ≥7 | Phase II, NCT03018340 | |
| National Library of Medicine (2019a) | Pimavanserin as adjunctive agent DBRCT, N = 298, MDD with inadequate response to antidepressant treatment, 5 weeks | Recruitment incomplete due to COVID-19-related problems. A 9-point HAMD total score decline at week 5 for pimavanserin treatment was reported vs 8.1 points for placebo (p = 0.295). A CGI-S change at week 5 of −1.4 vs −1.1 (pimavanserin vs placebo) was also reported. Response and remission rates were 31.1 and 18.2% vs 30.9 and 16.8% (pimavanserin vs placebo) | Phase III, NCT03968159 | |
| National Library of Medicine (2019b) | Pimavanserin as an adjunctive agent, N = 236, MDD and inadequate response to antidepressant treatment, 52 weeks | The trial was prematurely terminated “for business reasons and not due to safety concerns” | Phase III, NCT04000009 | |
| Loebel et al. (2022) | SEP-4199, DBRCT, N = 289/337 patients, BD type I, 6 weeks | Endpoint improvement in MADRS total score was observed on both the primary analysis (N = 289 participants) for SEP-4199 200 mg/day and 400 mg/day and the secondary, full ITT, analysis (N = 337 participants) for both regimens. Median increases in prolactin were +83.6 μg/L for the 200 mg/day dosage, +95.2 μg/L for 400 mg/day | Phase II, NCT03543410 | |
| National Library of Medicine (2021b) | SEP-4199, DBRCT, N = 522 (estimated), BD type I, 6 weeks | The trial is ongoing | Phase III, NCT05169710 | |
BD, bipolar depression; CGI-I, Clinical Global Impression-Improvement; CGI-S, Clinical Global Improvement-Severity; DBRCT, double-blind randomized controlled trial; HAMA, Hamilton Anxiety Rating Scale; HAMD-17, Hamilton Depression Rating Scale; MADRS, Montgomery-Asberg Depression Rating Scale; QIDS-SR, Quick Inventory of Depressive Symptomatology - Self-rated; MDD, major depressive disorder; NLM, National Library of Medicine; SAE, severe adverse event; SDS, Sheehan Disability Scale; SNRI, Serotonin and norepinephrine reuptake inhibitor; SSRI, Selective serotonin reuptake inhibitor.