How does Auvelity (dextromethan) work for depression if it doesn't directly involve serotonin?

How Auvelity Works for Depression Without Directly Targeting Serotonin

Auvelity works through a completely different mechanism than traditional antidepressants by modulating glutamate signaling rather than serotonin, specifically through NMDA receptor antagonism and sigma-1 receptor agonism, which represents a novel therapeutic approach that has demonstrated rapid-onset antidepressant effects. 1

Mechanism of Action

Auvelity contains two active components that work synergistically:

• Dextromethorphan is the primary antidepressant agent that modulates glutamate neurotransmission through uncompetitive antagonism of N-methyl-D-aspartate (NMDA) receptors and agonism of sigma-1 receptors 1
• Bupropion serves primarily to increase the bioavailability of dextromethorphan by inhibiting the CYP2D6 enzyme, which would otherwise rapidly metabolize dextromethorphan 1
• This represents a pharmacokinetic and pharmacodynamic synergy that may account for the rapid onset of action observed in clinical trials 2

Why Glutamate Matters in Depression

The glutamatergic system has emerged as a critical therapeutic target based on convergent evidence:

• A large percentage of adults with major depressive disorder respond insufficiently to conventional monoamine-based antidepressants (including SSRIs and SNRIs), creating the need for mechanistically novel treatments 2
• Glutamatergic signaling dysregulation has been implicated as a potential therapeutic target in depression, similar to how ketamine/esketamine work 2
• The availability of both ketamine/esketamine and dextromethorphan-bupropion validates the relevance of glutamate as a treatment target in major depressive disorder 2

Clinical Evidence of Efficacy

Phase 3 trial data demonstrates that Auvelity produces significant antidepressant effects with notably rapid onset:

• Patients treated with dextromethorphan-bupropion 45-105 mg showed significant reductions in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores compared to placebo 1
• Changes in MADRS scores were observed within two weeks, which is faster than traditional SSRIs that typically require 4-6 weeks 1
• A phase 2 trial comparing dextromethorphan-bupropion to bupropion monotherapy demonstrated significant superiority of the combination, confirming that dextromethorphan adds therapeutic benefit beyond bupropion alone 1
• Remission and response rates were significantly higher with dextromethorphan-bupropion in both studies 1

Long-Term Outcomes

Long-term studies demonstrate sustained efficacy:

• Two open-label studies showed large reductions in MADRS scores maintained through 12 and 15 months of treatment 1
• Remission rates approached 70% in long-term studies, while response rates exceeded 80% 1
• The medication was well-tolerated in both short-term and long-term trials, with most adverse events rated as mild-to-moderate 1

Real-World Usage Patterns

Real-world data from 22,288 patients provides insight into clinical practice:

• Approximately 28.8% of patients initiated Auvelity as monotherapy, while 71.2% used it as add-on therapy 3
• Most commonly, Auvelity was added to an SSRI alone (10.7%) or SNRI alone (6.5%) 3
• Notably, 10.1% of patients were treatment-naïve, suggesting clinicians are comfortable using this non-serotonergic mechanism as first-line therapy in select cases 3
• The majority of patients (83.7%) had previously tried SSRIs, SNRIs, or bupropion, indicating Auvelity often serves as a next-step option after traditional antidepressants 3

Why Non-Serotonergic Mechanisms Are Valid

The historical dominance of serotonin-based treatments does not mean serotonin is the only—or even primary—mechanism in depression:

• The serotonin hypothesis from the 1960s is increasingly questioned, with evidence supporting the involvement of other neurotransmitters including noradrenaline, glutamate, and dopamine 4
• Depression likely involves larger systemic causes such as altered activity in limbic networks and inflammatory processes, not just serotonin deficiency 4
• Historical evidence shows that dual-acting antidepressants (affecting both norepinephrine and serotonin) demonstrated advantages in severe depression compared to selective agents, suggesting multiple neurotransmitter systems are relevant 5

Clinical Implications

Auvelity represents a mechanistically distinct option that may benefit patients who:

• Have failed to respond adequately to serotonin-based antidepressants (SSRIs/SNRIs) 2
• Require rapid onset of antidepressant effects (within 2 weeks rather than 4-6 weeks) 1
• Cannot tolerate the sexual dysfunction commonly associated with SSRIs 5
• May have depression driven more by glutamatergic dysregulation than serotonergic dysfunction 2