Table 1.
Summary of key published clinical trials of novel targets for TRD.Abbreviations: intravenous (IV), oral (PO), double-blinded randomized controlled trial (DB-RCT), open label (OL).
| Target (Novel Pathway) |
Route | Study Type (n) | Summarized Trial Results |
|---|---|---|---|
| Infliximab (inflammation) | IV | DB-RCT (n=60) | Trial showed no difference between placebo and infliximab in the primary outcome (17-item HDRS); however, when patients were stratified based on the levels of their inflammatory state (based on [hsCRP]>5mg/L), a significant anti-depressant effect was shown as 62% of TRD patients obtained >50% reduction in HAM-D scores versus only 33% in the placebo group [41]. |
| Creatine (bioenergetics) |
PO | OL (n=10) | Trial showed significant improvement in depression scores at weeks 1, 2, 3 and 4 in seven out of the ten TRD patients [113]. |
| PO | OL (n=5) | Kodo et al. studied five female adolescents with TRD using 4g of creatine in addition to fluoxetine (which they were already taking) and observed improved depression score and a significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up (31) P MRS brain scan [114]. | |
| SAMe (bioenergetics) | PO | DB-RCT (n=73) | Trial showed significant improvement in depression scores after a 6-week trial of adjunctive oral SAMe (target dose: 800 mg/twice daily) with a NNT of seven [119]. |
| Ketamine (glutamate/ NMDA) |
IV | DB-RCT (n=18) | Zarate et al. (2006) showed that patients receiving IV infusion of ketamine hydrochloride (0.5 mg/kg) on 2 test days, a week apart showed significant improvement in depression ratings compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week [136]. |
| IV | DB-RCT (n=73) | TRD patients were randomly assigned to receive a single IV infusion of ketamine or midazolam in a 2:1 ratio. The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS). After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points. The likelihood of response at 24 hours was greater with ketamine than with midazolam with response rates of 64% and 28%, respectively [137]. | |
| IV | OL (n=24) | TRD patients underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. The overall response rate at study end was 70.8%. There was a large mean decrease in MARDS score at 2 hours after the first ketamine infusion (18.9 +/- 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific) [139]. | |
| Riluzole (glutamate) | PO | OL (n=19) | Riluzole (100-200mg/day oral) was used as a monotherapy for six weeks after a one-week drug free period. Significant improvement in depression scores occurred during weeks 3 through 6 for all patients [145]. |
| PO | OL (n=10) | Riluzole was used as an augmenting agent for 6-12 weeks showing significant improvement in depression scores at the end of the first week of treatment, which persisted for the 12-week duration of the study [146]. | |
| EPO | IV | DB-RCT (n=40) | TRD patients were randomized to eight weekly EPO (Eprex; 40 000 IU) or saline infusion. Patients were assessed at baseline and at weeks 5, 9, and 14 for improvement in depressive symptoms and cognition. Hamilton depression rating scores and remission rates showed no effects of EPO over saline at week 9; however, EPO improved the BDI and WHOQOL-BREF scores, and this was maintained at follow-up week 14. As well, EPO enhanced verbal recall and recognition, which was sustained at follow-up [131]. |
| CP-101,606 (glutamate) | IV | DB-RCT (n=30) | Intravenous CP-101,606 was usedas an adjunct to paroxetine versus paroxetine alone for four weeks. Significant improvement was found in depression scales with seventy-eight percent of CP-101,606-treated responders maintaining response status for at least 1 week after the infusion [147]. |
| AZD6765 (glutamate) | IV | DB-RCT (n=22) | A single infusion of AZD6765 (150 mg) on 2 test days 1 week apart was associated with rapid but short-lived improvement in depression scores versus infusion of placebo [173]. |
| Buprenorphine (opioid) | PO | OL (n=10) | Buprenorphinewas tolerated by 7/10 participants for whom significant improvement in depression scales was shown within the first week and persisted for the duration of the trial (four to six weeks) [161]. |
| Target (Novel Pathway) |
Route | Study Type (n) | Summarized Trial Results |
| Metyrapone (HPA axis) | PO | DB-RCT (n=63) |
Inpatients with TRD received augmentation of nefazodone or fluvoxamine for 3 weeks with placebo versus 1 g of metyrapone once daily. The metyrapone group showed a significant improvement in depression scores compared with the placebo group [84]. |
| Biperiden (muscarinic) | PO | OL (n=10) | Trial showed significant improvement in depression scores for TRD inpatients given an average dose of 12mg biperiden per day for thirty days [164]. |
| Scopolamine (muscarinic) | IV | DB-RCT (n=18) | Sample included both bipolar and unipolar treatment refractory depression. Trial showed a rapid and robust improvement in depression scores with intravenous administration of scopolamine versus placebo [167]. |
| IV | DB-RCT (n=23) | This trial was a replication of the above trial except was exclusive for unipolar TRD. Trial showed a similar rapid and robust improvement in depression scores with intravenous administration of scopolamine versus placebo [168] | |
| Mecamylamine (nicotinic) | PO | DB-RCT (n=23) | Trial used mecamylamine as an augmenter of SSRIs for treatment of TRD, significantly improving depression scores compared to SSRI therapy alone during an 8-week trail [171] |
| Varenicline (nicotinic) | PO | OL (n=18) | Adult smokers with TRD were givenvarenicline, another nicotinic antagonist, as an adjunct to conventional therapy, lowering depression scores and facilitate smoking cessation [170, 172]. |