Is combining dextromethorphan with bupropion more effective in treating depression than bupropion alone?

Is combining dextromethorphan with bupropion more effective in treating depression than bupropion alone?

Comment by InpharmD Researcher

A phase 2 study found the combination of dextromethorphan and bupropion formulated into a single product to be more effective than bupropion alone for improving major depressive disorders for up to 6 weeks. However, the follow-up phase 3 study compared dextromethorphan/bupropion to placebo, limiting further comparisons. Long-term safety and efficacy associated with this combination remain unexamined.

PubMed: dextromethorphan bupropion depression= 12 results (3 relevant)

Background

A 2019 review article discusses the pharmacological synergism of dextromethorphan/bupropion oral antidepressant agent. The antidepressant activity of dextromethorphan focuses on the combined activity on N-methyl-D-aspartate (NMDA) receptor, serotonin transporter (SERT), and norepinephrine transporter (NET). Bupropion exerts activity on the NET transporter and can also block the reuptake of dopamine, increasing its availability. Dextromethorphan is also rapidly metabolized by CYP2D6 enzymes after oral administration. Bupropion serves as an inhibitor of CYP2D6, allowing for longer maintenance of dextromethorphan therapeutic ranges, which would theoretically prolong antidepressant activity. [1]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is combining dextromethorphan with bupropion more effective in treating depression than bupropion alone?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-2 for your response.

Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial
Design	Randomized, double-blind, active-controlled phase 2 trial N= 80
Objective	To assess the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder
Study Groups	Dextromethorphan-bupropion (n= 43) Bupropion (n= 37)
Inclusion Criteria	Aged 18 to 65 years, confirmed diagnosis of major depressive disorder based on the DSM-5 criteria, current major depressive episode of moderate or greater severity (defined as a score ≥ 25 on the Montgomery-Åsberg Depression Rating Scale [MADRS] and a score ≥ 4 on the Clinical Global Impressions severity scale [CGI-S])
Exclusion Criteria	Bipolar disorder, panic disorder, obsessive-compulsive disorder, treatment-resistant depression (defined as having had at least two failed adequate antidepressant treatments in the current major depressive episode), a substance use disorder within the past year, a lifetime history of psychotic disorder, a clinically significant risk of suicide, a history of seizure disorder
Methods	After discontinuing previous antidepressants, eligible patients were randomly assigned (1:1) to receive either dextromethorphan- bupropion (45 mg/105 mg tablet) or bupropion (105 mg tablet) once daily for the first 3 days and twice daily thereafter for a total of six-week active treatment. All patients tracked their mood daily by completing a daily visual analog mood scale and were followed up regularly during the study period. Adherence to medications was measured with tablet counting and assessment of plasma concentrations of bupropion at the end of the study.
Duration	Enrollment: May 2018 to December 2018 Follow-up: 7 weeks
Outcome Measures	Primary: change from baseline to week 6 in the MADRS total score (0-60; higher = more severe depression) Secondary: clinical response (defined as a reduction ≥ 50% from baseline in MADRS total score); remission (defined as a MADRS total score ≤ 10); score on the Clinical Global Impressions improvement scale (CGI-I; scores range from 1 [very much improved] to 7 [very much worse]); safety
Baseline Characteristics		Dextromethorphan-bupropion (n= 43)	Bupropion (n= 37)
	Age, years	37.3	37.7
	Female	58.1%	70.3%
	Race White Black or African American Asian	69.8% 27.9% 2.3%	54.1% 37.8% 0
	Depression scale MADRS total score CGI-S score	31.8 4.4	32.2 4.5
Results	Endpoint	Dextromethorphan-bupropion (n= 43)	Bupropion (n= 37)	Between-group difference; p-value
	MADRS total score Overall Week 2 Week 6	-13.7 ± 0.6 -12.5 ± 1.4 -17.3 ± 1.4	-8.8 ± 0.7 -7.8 ± 1.5 -12.1 ± 1.5	-4.9; < 0.001 -4.7; 0.024 -5.2; 0.013
	Remission Week 2 Week 6	25.6% 46.5%	2.7% 16.2%	22.9%; 0.004 30.3%; 0.004
	Clinical response Week 2 Week 6	37.2% 60.5%	27.0% 40.5%	10.2%; not significant 19.9%; not significant
	Overall change of CGI-S score	-1.6 ± 0.1	-1.0 ± 0.1	-0.5; < 0.001
Adverse Events	Common Adverse Events: dextromethorphan-bupropion vs. bupropion- any adverse events (72.9% vs. 64.6%), dizziness (20.8% vs. 4.2%), nausea (16.7% vs. 12.5%), dry mouth (10.4% vs. 8.3%), decreased appetite (10.4% vs. 8.3%), anxiety (10.4% vs. 2.1%)
	Severe Adverse Events: 6.3% vs. 2.1%
	Percentage that Discontinued due to Adverse Events: 12.5% for both groups
Study Author Conclusions	In patients with major depression, dextromethorphan-bupropion (AXS-05) significantly improved depressive symptoms compared with bupropion and was generally well tolerated.
InpharmD Researcher Critique	Results from a phase 2 trial are exploratory and require further confirmation in a larger size phase 3 trial. Exclusion of patients with other psychologic comorbidities and concomitant treatments may limit the generalizability of the study findings.

References:
[1] Tabuteau H, Jones A, Anderson A, Jacobson M, Iosifescu DV. Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial. Am J Psychiatry. 2022;179(7):490-499. doi:10.1176/appi.ajp.21080800

Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI)
Design	Double-blind, phase 3 trial N= 327
Objective	To evaluate the efficacy and safety of dextromethorphan-bupropion (AXS-05), an oral N-methyl-D-aspartate (NMDA) receptor antagonist and σ1 receptor agonist, in the treatment of major depressive disorder (MDD)
Study Groups	Dextromethorphan-bupropion (n= 163) Placebo (n= 164)
Inclusion Criteria	Age 18 to 65 years, primary diagnosis of MDD based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Editions (DSM-5), experience major depressive episode of at least 4 weeks in duration, Montgomery-Asberg Depression Rating Scale (MADRS) score 25 or higher, Clinical Global Impression-Severity (CGI-S) scale of 4 or higher
Exclusion Criteria	Bipolar disorder, psychotic disorder, panic disorder, obsessive-compulsive disorder, treatment-resistant depression (2 or greater failed attempts at antidepressant treatment in the current major depressive episode), alcohol/substance use disorder within the past year, clinically significant risk of suicide, history of seizure disorder
Methods	Patients were randomized (1:1) to receive either dextromethorphan-bupropion (45 mg to 105 mg) or a placebo orally for 6 weeks. Treatment was received once daily for 3 days, then twice daily thereafter. Patients were followed up to 6 weeks for efficacy and 7 weeks for safety (1 week after the last study dose).
Duration	Enrollment: June 2019 to December 2019 Follow-up: 7 weeks
Outcome Measures	Primary: change from baseline to week 6 in MARDS total score (0 to 60, higher score indicates more severe depression) Secondary: change in MADRS total score at week 1 and week 2, achieving remission (MADRS total score of 10 or less at week 2), clinical response (50% or greater reduction in MADRS total score at week 6), safety
Baseline Characteristics		Dextromethorphan-bupropion (n= 156)	Placebo (n= 162)
	Age, years	42.1	41.2
	Female	60.9%	72.2%
	Race White Black or African American Asian Multiple Other	53.8% 37.2% 5.8% 1.9% 1.3%	56.8% 33.3% 4.9% 1.2% 3.7%
	Body mass index, kg/m²	29.3	29.3
	MADRS total score	33.6	33.2
	CGI-S score	4.6	4.6
Results	Endpoint*	Dextromethorphan-bupropion (n= 156)	Placebo (n= 162)	Least-squares mean difference (95% confidence interval [CI]; p-value)
	Change in MARDS total score from baseline to week 6	-15.9	-12.0	-3.87 (-1.39 to -6.36; p= 0.002)
	Change in MARDS total score from baseline to: Week 1 Week 2	-7.2 -11.1	-5.0 -7.7	-2.2 (-0.6 to -3.9; p= 0.007) -3.4 (-1.4 to -5.5; p< 0.001)
	Patients that achieved remission at week 6	39.5%	17.3%	22.2 (11.17 to 32.7; p< 0.001)
	Clinical response at week 6	54.0%	34.0%	20.0% (8.4% to 31.6%; p< 0.001)
	*Efficacy analyses were performed on the modified intent-to-treat population, which consisted of all patients who were randomized, received at least 1 dose of study medication, and had at least 1 post-baseline efficacy assessment.
Adverse Events	General adverse events were reported in 61.7% of the dextromethorphan-bupropion group versus 45.1% in the placebo group. The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. One serious event (pancreatitis) occurred in the dextromethorphan-bupropion group. Discontinuation due to adverse events occurred in 6.2% of the dextromethorphan-bupropion group versus 0.6% in the placebo group. Withdrawal after discontinuing treatment was not observed.
Study Author Conclusions	In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation and was generally well tolerated.
InpharmD Researcher Critique	The definitions for achieving remission or clinical response are based on short-term treatment, which may not reflect other definitions of clinically effective response. Safety outcomes were limited to one week after treatment discontinuation.

References:
[1] Iosifescu DV, Jones A, O'Gorman C, et al. Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder: A Phase 3 Randomized Clinical Trial (GEMINI). J Clin Psychiatry. 2022;83(4):21m14345. Published 2022 May 30. doi:10.4088/JCP.21m14345