TABLE 4.
Cholinergic receptor modulators and other agents with antidepressant properties in the pipeline.
| Authors | Methodology | Results | Clinical trial phase, trial identifier (if available) |
|---|---|---|---|
| Cholinergic agents | |||
| Davidson et al. (2021) | JNJ-39393406 vs. placebo as add-on, DBRCT, N = 71 MDD patients, 2 weeks | No significant differences between groups in BACS composite score or MADRS total score were reported at week 2. The overall tolerability was good | Phase II, NCT02677207 |
| NLM (2018h) | Ropanicant (SUVN-911), open-label, single-dose study, N = 28 healthy subjects | Primary outcome measure is AUC. Results have not been yet disclosed | Phase I, NCT03551288 |
| NLM (2017e) | SUVN-911 vs. placebo, single/multiple doses, DBRCT, N = 64 healthy male subjects | Primary outcome measures-ECG, vital signs, C-SSRS. Results have not yet been disclosed | Phase I, NCT03155503 |
| Furey and Drevets (2006) | Scopolamine 4 μg/kg i.v. vs. placebo, two DBRCTs, N = 19 MDD/BD patients, repeated sessions 3–5 days apart | Patients who received placebo followed by scopolamine showed no significant change in the main outcomes (MADRS and HAMA scores) during the placebo phase, but significant reductions in both outcomes were observed after scopolamine administration. Patients who received scopolamine first and placebo second also showed significant reductions in depression and anxiety rating scale scores after scopolamine i.v., relative to baseline, and these effects persisted during the placebo phase | Phase N/A |
| Drevets and Furey (2010) | Scopolamine 4 μg/kg i.v. vs. placebo, DBRCT, N = 23 MDD outpatients, repeated sessions 3–5 days apart | MADRS scores decreased by 32% in patients who received first scopolamine (p < 0.001) vs. those who received the placebo first, and improvement was significant at the first evaluation that followed scopolamine administration. Scopolamine administration was associated with drowsiness, blurred vision, dry mouth, lightheadedness, and reduced blood pressure, and no participant dropped out due to side effects | Phase II, NCT00369915 |
| NLM (2017f) | Scopolamine 0.15 mg b.i.d. + naltrexone 1 mg b.i.d. vs. placebo, DBRCT, N = 14 MDD patients, 4 weeks | Unpublished results support a significant change of the MADRS scores from baseline to the end of the study visit (the primary outcome) in favor of the scopolamine and naltrexone group (p = 0.03), and the rate of adverse events in the active group was 25% (mainly nausea) vs. 0% in the placebo group | Phase IV, NCT03386448 |
| NLM (2019c) | Scopolamine i.v. vs. placebo, DBRCT, N = 50 (recruitment target), 2 weeks | The main outcome is the change in HAMD score at 2 weeks. The trial is ongoing | Phase II, NCT04211961 |
| NLM (2012d) | Ketamine + placebo, scopolamine + placebo, and ketamine + scopolamine, DBRCT, N = 0 MDD participants, 4 months | This study was withdrawn due to a lack of funding | Phase N/A, NCT01613820 |
| NLM (2011a) | Scopolamine 4 μg/kg i.v. vs. placebo + ECT, DBRCT, N = 7 MDD patients, 2 weeks | Unpublished results suggest that scopolamine was not significantly superior to placebo in any of the primary outcomes: the change in the HAMD-17 scores was −17.5 vs. −14.0 (scopolamine vs. placebo) at the time of ECT completion (about 2 weeks); the meantime for response for patients receiving ECT was 8.33 vs. 5.0 days, and the mean number of ECT sessions to achieve response/remission was 2.33 vs. 2.5/10 vs. 6.5 (scopolamine vs. placebo) | Phase II, NCT01312844 |
| NLM (2017g) | Scopolamine 0.3 mg/ml or 0.6 mg/ml i.m. vs. placebo + escitalopram 10 mg/day, DBRCT, N = 66 outpatients with severe MDD, 4 weeks | No results of this trial have been yet released | Phase IV, NCT03131050 |
| Other agents | |||
| NLM (2019d) | MAP4343 vs. placebo, DBRCT, N = 110 (estimated), TRD patients, 42 days | The primary outcome measure is HAMD’s total score change. The results of this trial have not yet been disclosed | Phase II, NCT03870776 |
| Frye et al. (2000) | Gabapentin vs. lamotrigine vs. placebo, N = 31 treatment-resistant MDD and BD patients, 6 weeks | Response rates (based on CGI ratings of much or very much improved) were 26% for gabapentin, 52% for lamotrigine, and 23% for placebo. The overall tolerability of gabapentin was good | Phase N/A |
| Arnold et al. (2015) | Pregabalin vs. placebo + SSRI/SNRI, cross-over DBRCT, N = 197 fibromyalgia + depression patients, periods of 2 × 6 week | Pregabalin significantly improved HADS score, both anxiety and depression scale scores, Fibromyalgia Impact Questionnaire total score, but not EuroQoL 5-dimensions scores | Phase N/A |
| Timmers et al. (2018) | JNJ-54175446 vs. placebo, SAD, N = 77 healthy participants | AE were reported in 56% of the participants, and the most frequently reported was headache (18.6%) | Phase I, NCT02475148 |
| NLM (2019d) | JNJ-54175446 vs. placebo, DBRCT, N = 142 (estimated), MDD patients with incomplete response to antidepressants, 8 weeks | The primary outcome measure is MADRS total score change. The trial is ongoing | Phase II, NCT04116606 |
| Brin et al. (2020) | OnabotulinumtoxinA (onabotA) 30 U/50U vs. placebo, DBRCT, N = 255 MDD patients, 24 weeks | Onabot 30U approached significance vs. placebo, according to the MADRS scores change, and reached significance at weeks 3 and 9, with secondary endpoints also reaching significance at several time points. The overall tolerability was good | Phase II, NCT02116361 |
| NLM (2011b) | OnabotA (29–40 U) vs. placebo, DBRCT, N = 30 MDD patients, 6 weeks | Patients were monitored using HAMD-21, and the change in the active drug followed by placebo group was significant vs. placebo followed by active drug (−12.7 vs. −0.4) at 12 weeks (p < 0.001). No SAE were recorded in either group | Phase II, NCT01392963 |
| Finzi and Rosenthal (2014) | OnabotA (29U/40U), vs. placebo, DBRCT, N = 85 MDD patients, 6 weeks | Response rates (based on MADRS scores) at 6 weeks from the injection date were 52% and 15% in the onabotA vs. placebo groups (p < 0.001). The remission rate (also based on MADRS score) was 27% vs. 7% in the onabotA vs. placebo | Phase IV, NCT01556971 |
| NLM (2018i) | OnabotA vs. placebo, DBRCT, N = 58 (estimated), TRD patients, 6 weeks | The main outcome measure is the proportion of patients with improvement of depressive symptoms based on the MADRS scale at 6 weeks after injection. The trial is ongoing | Phase N/A, NCT03484754 |
| NLM (2009b) | OnabotA (20–50 U), open-label, N = 50, MDD and non-depressed individuals, 12 weeks | BDI score change was −14.9 in the MDD group at week 12 vs. −2.7 in the healthy volunteers, while the self-esteem improved by three points on RSES vs. −0.4 in the healthy participants at the endpoint. The quality of life (WHOQOL-BREF) improved in the MDD group with 0.5 points at week 12 compared to baseline, and 0.2 points in the comparator group | Phase IV, NCT01004042 |
| Monti et al. (2019) | PH-10 low-dose/high-dose vs. placebo, DBRCT, N = 30 MDD patients, 9 weeks | HAMD-17 total score change at endpoint vs. baseline showed a trend for difference (p = 0.07), with a greater reduction of depression severity scores for high dose PH10 vs. placebo. The positive effects of PH10 were recorded from week 1 for the high dose (p = 0.03). No SAE were reported, and the overall tolerability was good | Phase IIa |
| Binneman et al. (2008) | CP-316,311 vs. placebo vs. sertraline, DBRCT, N = 167 recurrent MDD patients, 6 weeks | The change from baseline in the HAMD score at the final visit was not significantly different between the investigational product group and placebo group, although sertraline did differentiate itself from the placebo | Phase II, NCT00143091 |
| Zobel et al. (2000) | R121919, open-label, N = 24 MDD patients, 30 days | The drug was safe and well-tolerated within the 30-day observation period. It induced reductions in depression and anxiety scores using clinician-rated and patient-scored instruments (HAMD, BDI, HAMA, CGI, STAI) | Phase IIa |
AE, adverse events; BD, bipolar depression; BDI, Beck Depression Inventory; CGI, Clinical Global Impression; DBRCT, double-blind, randomized controlled trial; ECT, electroconvulsive therapy; HADS, Hospital Anxiety and Depression Scale; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery Asberg Depression Rating Scale; MDD, major depressive disorder; PGI-I, Patient Global Impression of Improvement; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self-Report; RSES, Rosenberg Self-Esteem Scale; SAD, single ascending dose; SAE, severe adverse events; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitors; STAI, State-Trait Anxiety Inventory; TRD, treatment-resistant MDD; WHOQOL-BREF, World Health Organization Quality of Life-BREF.