J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://www.jocmr.org

Original Article

Volume 16, Number 2-3, March 2024, pages 46-55

Therapeutic Potential of Buprenorphine in Depression: A Meta-Analysis of Current Evidence

Figure 2. Forest plot for the studies reported MADRS least square mean difference. “+” and “-” signs indicate low and high risk of producing biased results, respectively. LSMD: least square mean difference; CI: confidence interval; SE: standard error; MADRS: Montgomery-Asberg Depression Rating Scale.

Figure 3. Forest plot for the studies reported MADRS. “+” and “-” signs indicate low and high risk of producing biased results, respectively. SD: standard deviation; CI: confidence interval; MADRS: Montgomery-Asberg Depression Rating Scale.

Figure 4. Forest plot for the studies reported HAM-D. “+” and “-” signs indicate low and high risk of producing biased results, respectively. SD: standard deviation; CI: confidence interval; HAM-D: Hamilton Rating Scale for Depression.

Figure 5. Overall risk of bias graph across all included studies. The white area indicated unclear risk of bias.

**Table 1.** Characteristics of Included Studies
Author, year	Study type	Duration and frequency	N	Intervention drug	Assessing psychiatric symptom	Scale(s) used	Mean score change (endline-baseline)	Findings
N: number; MDD: major depressive disorder; BUP: buprenorphine; SAM: samidorphan; HAM-D: Hamilton Rating Scale for Depression; MADRS: Montgomery-Asberg Depression Rating Scale; CGI-S: Clinical Global Impressions-Severity; ANOVA: analysis of variance; SE: standard error; SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin/norepinephrine reuptake inhibitor.
Ehrich et al, 2015 [11]	Randomized placebo-controlled trial	7 days, once daily dosing	45	BUP, SAM and placebo used: 1) BUP/SAM: 8:1 dose-ratio: 2 mg/0.25 mg, 4 mg/0.5 mg; 2) BUP/SAM 1:1 dose-ratio: 4 mg/4 mg, 8 mg/8 mg; 3) placebo	MDD	HAM-D17 and MADRS	HAM-D17 total score (P = 0.032) and MADRS total score (P = 0.054)	Following 7 days of treatment in subjects with MDD, a 1:1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs. placebo in HAM-D17 total score (P = 0.032) and nearly significant improvement in MADRS total score (P = 0.054).
Fava et al., 2016 [19]	Randomized double-blinded, placebo-controlled trial (multicenter)	10 weeks, once daily dosing	142	BUP/SAM at 2 mg/2 mg (the 2/2 dosage group) or 8 mg/8 mg (the 8/8 dosage group) or placebo	MDD	HAM-D, MADRS, and the CGI-S scale	Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (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).	Results of this trial demonstrate clinically meaningful antidepressant effects for the BUP/SAM combination compared with placebo in patients with major depression and an insufficient response to SSRIs or SNRIs. There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance.
Lee et al, 2022 [8]	Randomized placebo-controlled trial (multisite)	8 weeks, once daily dosing	85	0.2 mg of BUP or placebo	Treatment resistant depression	MADRS	No significant differences between the treatment groups in the MADRS trajectories over time (F3,443 = 0.26, P = 0.85).	There were no significant differences between the BUP and placebo groups in MADRS changes over time or adverse effects.
Lin et al, 2019 [17]	Randomized double-blinded, placebo-controlled trial	8 weeks, once daily dosing	31	Low-dose BUP or placebo (0.2 mg/day and increased by 0.2 mg/day each week based on depression severity and tolerability up to a maximum of 1.2 mg/day)	Treatment-resistant MDD	Total score and the dysphoria subscale of the MADRS	No significant group (placebo vs. BUP) difference in improvement of depressive symptoms (with either the total MADRS or dysphoria subscale); the mixed ANOVA on weekly MADRS revealed no significant interaction between group and time (F (8,168) = 0.44, P = 0.898), and no significant group differences (F(1,21) = 0.62, P = 0.439), but there was a significant decrease in MADRS across time independent of group (F(8,168) = 3.46, P < 0.005).	Participants in both the BUP and placebo groups showed similar changes in depressive symptoms
Fava et al, 2018 [20]	Randomized placebo-controlled trial	5 weeks, 6 weeks, once daily dosing	122	BUP/SAM (2 mg/2 mg) + antidepressant or placebo + antidepressant for 5 weeks	MDD	MADRS least square mean difference	No change in MADRS-10 at week 5 versus placebo: -1.8, P = 0.109	MADRS-10 LSMD score indicated BUP was more effective than placebo but was not statistically significant
Zajecka et.al, 2019 [18]	Randomized double-blind placebo- controlled trial	6 weeks, once daily dosing	295	BUP/SAM 2 mg/2 mg or placebo for 6 weeks	MDD	MADRS least square mean difference	Least-squares mean change in MADRS-10 score 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).	MADRS-10 score did not meet the primary end point. Postbaseline improvement in MADRS-10 in the BUP/SAM 2 mg/2 mg group was noted but was not statistically significant.

Table 1. Characteristics of Included Studies

Author, year

Study type

Duration and frequency

Intervention drug

Assessing psychiatric symptom

Scale(s) used

Mean score change (endline-baseline)

Findings

N: number; MDD: major depressive disorder; BUP: buprenorphine; SAM: samidorphan; HAM-D: Hamilton Rating Scale for Depression; MADRS: Montgomery-Asberg Depression Rating Scale; CGI-S: Clinical Global Impressions-Severity; ANOVA: analysis of variance; SE: standard error; SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin/norepinephrine reuptake inhibitor.

Ehrich et al, 2015 [11]

Randomized placebo-controlled trial

7 days, once daily dosing

BUP, SAM and placebo used: 1) BUP/SAM: 8:1 dose-ratio: 2 mg/0.25 mg, 4 mg/0.5 mg; 2) BUP/SAM 1:1 dose-ratio: 4 mg/4 mg, 8 mg/8 mg; 3) placebo

MDD

HAM-D17 and MADRS

HAM-D17 total score (P = 0.032) and MADRS total score (P = 0.054)

Following 7 days of treatment in subjects with MDD, a 1:1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs. placebo in HAM-D17 total score (P = 0.032) and nearly significant improvement in MADRS total score (P = 0.054).

Fava et al., 2016 [19]

Randomized double-blinded, placebo-controlled trial (multicenter)

10 weeks, once daily dosing

142

BUP/SAM at 2 mg/2 mg (the 2/2 dosage group) or 8 mg/8 mg (the 8/8 dosage group) or placebo

MDD

HAM-D, MADRS, and the CGI-S scale

Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (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).

Results of this trial demonstrate clinically meaningful antidepressant effects for the BUP/SAM combination compared with placebo in patients with major depression and an insufficient response to SSRIs or SNRIs. There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance.

Lee et al, 2022 [8]

Randomized placebo-controlled trial (multisite)

8 weeks, once daily dosing

0.2 mg of BUP or placebo

Treatment resistant depression

MADRS

No significant differences between the treatment groups in the MADRS trajectories over time (F3,443 = 0.26, P = 0.85).

There were no significant differences between the BUP and placebo groups in MADRS changes over time or adverse effects.

Lin et al, 2019 [17]

Randomized double-blinded, placebo-controlled trial

8 weeks, once daily dosing

Low-dose BUP or placebo (0.2 mg/day and increased by 0.2 mg/day each week based on depression severity and tolerability up to a maximum of 1.2 mg/day)

Treatment-resistant MDD

Total score and the dysphoria subscale of the MADRS

No significant group (placebo vs. BUP) difference in improvement of depressive symptoms (with either the total MADRS or dysphoria subscale); the mixed ANOVA on weekly MADRS revealed no significant interaction between group and time (F (8,168) = 0.44, P = 0.898), and no significant group differences (F(1,21) = 0.62, P = 0.439), but there was a significant decrease in MADRS across time independent of group (F(8,168) = 3.46, P < 0.005).

Participants in both the BUP and placebo groups showed similar changes in depressive symptoms

Fava et al, 2018 [20]

Randomized placebo-controlled trial

5 weeks, 6 weeks, once daily dosing

122

BUP/SAM (2 mg/2 mg) + antidepressant or placebo + antidepressant for 5 weeks

MDD

MADRS least square mean difference

No change in MADRS-10 at week 5 versus placebo: -1.8, P = 0.109

MADRS-10 LSMD score indicated BUP was more effective than placebo but was not statistically significant

Zajecka et.al, 2019 [18]

Randomized double-blind placebo- controlled trial

6 weeks, once daily dosing

295

BUP/SAM 2 mg/2 mg or placebo for 6 weeks

MDD

MADRS least square mean difference

Least-squares mean change in MADRS-10 score 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).

MADRS-10 score did not meet the primary end point. Postbaseline improvement in MADRS-10 in the BUP/SAM 2 mg/2 mg group was noted but was not statistically significant.