Table 1.
Summary of clinical studies of opioidergic agents in major depressive disorder.
| STUDY | DRUG | DESIGN | PATIENT GROUP | (N) | DOSING REGIME | MAIN OUTCOME | ANTIDEPRESSANT EFFECTS |
|---|---|---|---|---|---|---|---|
| Kline et al. (1977) | β-Endorphin | Single-blind, placebo controlled | MDD (2) BD (1) |
3 | 1.5 −10 mg IV β-Endorphin on two separate occasions | Clinician-rated improvement | -Rapid antidepressant response observed within minutes after first injection but not following repeat dosing. |
| Angst et al. (1979) | β-Endorphin | Open-label | MDD (2) BD (4) |
6 | 10 mg IV β-Endorphin over 5 min | Self-rated visual analogue scales | -Change of depressive symptoms observed in all patients within the first 20–30 min. There was an initial increase of energy and mood and a decrease of anxiety, depression and restlessness. -Changes persisted in general for 2 h but were not maintained. |
| Gerner et al. (1980) | β-Endorphin | Double-blind, placebo-controlled crossover | MDD (7) BD (2) Schizoaffective- depressed (1) |
10 | 1.5 – 11.5 mg IV β-Endorphin over 30–35 min |
Modified Bunney-Hamberg scale | -Significant improvement in depressive symptoms (P = 0.05) after β-endorphin compared with placebo 2–4 hrs after infusion. -Proportion of depressed patients whose condition improved was significantly greater after β-endorphin than placebo (P < 0.025). |
| Pickar et al. (1981) | β-Endorphin | Double-blind, placebo-controlled crossover | MDD | 4 | 4–10 mg IV β-Endorphin over 5 min | -Brief Psychiatric Rating Scale (BPRS) | -No significant difference in ratings between β-Endorphin and placebo. |
| Extein et al. (1981) | Morphine | Open-label | MDD (9), BD (1) | 10 | 5 mg IV Morphine | -Self-rated mood | -Small nonsignificant antidepressant and antianxiety effects in both the depressed and control groups. |
| Methadone | Double-blind, placebo-controlled crossover | MDD (2), BD (4) | 6 | 5 mg IV Methadone | -Self-rated mood and BPRS | -3/6 reported themselves "better" two the "same," and one "worse" 30 min after methadone infusion, whereas all 6 reported themselves the "same" 30 min after saline infusion. -Methadone infusion produced little change according to BPRS. |
|
| Varga et al. (1982) | Codeine | Open-label | MDD | 12 | Oral codeine 90 mg/day to 180 mg/day for 3 weeks monotherapy (4) or added to tricyclic antidepressant (8) | -HAM-D -Zung depression self-rating scale |
-4 depressed patients received codeine alone and none of them improved. -8 patients received codeine in combination with other TCAs and only one of them showed improvement. |
| Emrich et al. (1982) | Buprenorphine | Double-blind, placebo-controlled | MDD | 10 | Sublingual 0.2 mg buprenorphine for 5–8 days | HAM-D | -Significant reduction in HAM-D scores (P < 0.02) during buprenorphine treatment compared with placebo. -50% of the patients responded very strongly to buprenorphine, whereas the other 50% were non responders. |
| Mongan and Callaway (1990) | Buprenorphine | Some subjects open label, others double-blind. | MDD (7) BD (1) |
8 | Sublingual 0.15 – 0.3 mg buprenorphine | Profile of Mood Scale (POMS) | -6/8 demonstrated antidepressant response lasting six hours or longer. |
| Bodkin et al. (1995) | Buprenorphine | Open-label | MDD (TRD) | 10 | Buprenorphine 0.15 mg initiated intranasally or sublingually once daily titrated according to tolerance and clinical benefit, with a maximum daily dosage of 1.8 mg for 4 weeks | HAM-D | -6/7 subjects achieved marked clinical improvement by the end of the trial (3 dropped out). -Mean endpoint HAM-D score was 10.7 (SD = 9.3), representing a 60.7% reduction from baseline (p = 0.006). |
| Nyhuis et al. (2008) | Buprenorphine | Open-label | MDD (TRD) | 6 | Sublingual buprenorphine as monotherapy beginning with 0.4 mg/d increased up to final dosage of 0.8–2.0 mg once daily for 1 week | HAM-D | -HAMD score decreased within 1 week of buprenorphine treatment from an average of 22.8 (range, 17–28) to 6.0 (range, 2–10). -5/ 6 patients reached complete remission. |
| Karp et al. (2014) | Buprenorphine | Open-label | MDD (TRD) | 15 | Titrated dose of sublingual buprenorphine ranged from 0.2 to 1.6 mg/d for 8 weeks | MADRS | -MADRS at baseline was 27.0 (SD = 7.3) and at week 8 was 9.5 (SD = 9.5). -Response at the end of 8 weeks was observed for 8/13 participants (61.54%, 95% CI = 32.3–84.9). |
| Ehrich et al. (2015) | Buprenorphine + Samidorphan (adjunct to antidepressant) | Randomised double-blind placebo-controlled study | MDD (TRD) | 32 | -BUP/SAM 8: 1 dose-ratio (2 mg/0.25 mg for 3 days and 4 mg/0.5 mg for 4 days) (n = 14) -BUP/SAM 1: 1 dose-ratio (4 mg/4 mg for 3 days and 8 mg/8 mg for 4 days) (n = 14) -Placebo (n = 4) |
HAM-D | -Antidepressant effects were greatest in 1:1 ratio group. -For the 1:1 treatment group, the difference in HAM-D from placebo was significant (p = 0.032). |
| Yovell et al. (2016) | Buprenorphine (monotherapy or adjunct to antidepressant) | Randomised double-blind placebo-controlled trial | Severely suicidal patients (average baseline score on the Beck Suicide Ideation scale (BSI), 19.7). | 88 | -Sublingual buprenorphine (initial dosage, 0.1 mg once or twice daily; mean final dosage=0.44 mg/day; n = 57) for 4 weeks -Placebo (n = 31) |
-BSI -BDI |
-Buprenorphine group had a greater reduction in BSSI than placebo at week 2 (mean difference=24.3, 95% CI=28.5, 20.2; p = 0.04) and at the end of week 4 (mean difference=27.1, 95% CI=212.0, 22.3; p = 0.004). - Buprenorphine group had lower BDI scores than the placebo group, although difference did not reach significance (mean difference=26.1, 95% CI=213.2, 1.0; p = 0.09). |
| Fava et al. (2016) | Buprenorphine + Samidorphan (adjunct to antidepressant) | Randomised double-blind placebo-controlled trial | MDD (TRD) | 142 | -BUP/SAM 2 mg/2 mg; (n = 24) -BUP/SAM 8 mg/8 mg (n = 19) -Placebo (n = 98) -4 weeks |
-HAM-D -MADRS -CGI |
-Significantly greater improvements in the 2/2 dosage group across the outcome measures compared with placebo (HAM-D: −2.8, 95% CI=−5.1, −0.6; MADRS: −4.9, 95% CI=−8.2, −1.6; CGI-S: −0.5, 95% CI=−0.9, −0.1). |
| Zajecka et al. (2019) | Buprenorphine + Samidorphan (adjunct to antidepressant) | Phase 3 multicentre randomised, placebo-controlled study conducted at 58 study sites | MDD (TRD) | 295 | -BUP/SAM 2 mg/2 mg (n = 147) -Placebo (n = 148) -6 weeks |
MADRS | -Least-squares mean change in MADRS at end of treatment was − 4.8 (SE 0.67) in the BUP/SAM 2 mg/2 mg group and − 4.6 (SE 0.66) in the placebo group (mean difference −0.3 [SE 0.95], P = 0.782). -There were no differences in MADRS-based response or remission rates. |
| Fava et al. (2020b) | Buprenorphine + Samidorphan (adjunct to antidepressant) | Two phase 3, randomized, double-blind, placebo-controlled studies FORWARD-4 (FW4) FORWARD-5 (FW5) |
MDD (TRD) |
FW4: 168 FW5: 187 |
-BUP/SAM (0.5 mg/0.5 mg) (n = 56) -BUP/SAM (2 mg/2 mg) (n = 56) -Placebo (n = 56) -BUP/SAM (1 mg/1 mg) (n = 62) -BUP/SAM (2 mg/2 mg) (n = 63) -Placebo (n = 62) -6 weeks |
MADRS | -FW5: Adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 6 in MADRS versus placebo: −1.9, P = 0.026). -FW4: Did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: –1.8, P = 0.109). -In pooled analysis, change from baseline on the MADRS in the BUP/SAM 2 mg/2 mg group was greater compared with placebo at all timepoints from week 3 and later, including week 6 (–1.8; P = 0.010; 95% CI: –3.2 to –0.4). |
| Fava et al. (2020a) | CERC-501 (JNJ-67953964) (a kappa selective opioid receptor antagonist) |
Sequential Parallel Comparison Design study | MDD (TRD) | 8 | a) 10 mg/d of CERC-501 for 6 days b) 20 mg/d of CERC-501 for 6 days c) placebo for 3 days followed by 10 mg/d of CERC- 501 for 3 days d) placebo for 3 days followed by 20 mg/d of CERC-501 for 3 days e) placebo for 6 days |
HAMD-6 MADRS |
-Study terminated early due to slow enrolment and sample size limits the ability to draw conclusions. -Weighted mean difference of changes (drug vs placebo) in the HAMD-6 (1.28) and (MADRS) (2.33) were all numerically but not statistically greater for CERC-501 than for placebo. |
| Richards et al. (2016) | AZD2327 (a selective DOR agonist) | Double-blind, parallel group design, placebo-controlled pilot study | Anxious MDD | 22 | -AZD2327 3 mg BD (n = 13) -Placebo (n = 9) -4 weeks |
HAM-D HAM-A |
-Seven (54%) patients responded to active drug and three (33%) responded to placebo. -No significant main drug effect was found on either the HAM-D (p = 0.39) or the HAM-A (p = 0.15). |
| Post et al. (2016) | LY2940094 (a selective NOP receptor antagonist) | Double-blind, parallel group design, placebo-controlled proof-of-concept study | MDD | - LY2940094 (n = 68) -Placebo (n = 61) -8 weeks |
HAM-D | -At Week 8, least-squares mean changes from baseline in HAMD total scores were − 11.4 and − 9.8 for patients in the LY2940094 and placebo treatment groups, respectively. The LS mean difference from placebo was − 1.5 (95% CI − 4.7, 1.7). -The probability that LY2940094 was better than placebo was 82.9%, which was close to, but did not meet, the pre-defined proof-of-concept criterion (88% probability). |