Auvelity®: Shortening the Onset of Action in Major Depressive Disorder

ashley n. RoDgeRs anD KaRen m. FanCheR, PhaRmD, BCoP

Major depressive disorder (MDD) is a leading cause of disability worldwide, and significantly contributes to the overall global burden of disease.1,2 This disease state is biologically based and can impair a patient’s social, occupational, and everyday functioning.3 The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) requires that a formal diagnosis of major depressive disorder must include five or more symptoms over a two-week period, with at least one of the symptoms of depressed mood or anhedonia. Other symptoms include insomnia, changes in eating habits, loss of interest in daily activities, fatigue, psychomotor changes, sense of worthlessness, impaired ability to concentrate, excessive guilt, and suicidal ideations.4 A patient can be diagnosed with major depression disorder at any time in life depending on differeces in one’s social, personal, or environmental factors. In 2020, 17% of those who struggled with major depressive disorder were between the ages of 18-25 years.5

Currently available medications to treat major depressive disorder center around the mechanism of increasing neurotransmitters within the brain, including serotonin, norepinephrine, and/ or dopamine. A common first line agent class that is used to treat major depressive disorder is the selective serotonin reuptake inhibitors (SSRIs).6 These medications block the serotonin transporter, SERT, from the reuptake of serotonin back into pre-synaptic terminal within the central nervous system (CNS). This results in an increase in the amount of serotonin present within the synaptic cleft, leading to improvement of depression symptoms. Another common medication class used in the treatment of this disease state is serotonin/norepinephrine reuptake inhibitors (SNRIs). These medications work on the serotonin transporter, SERT, and the norepinephrine transporter, NAT, blocking the reuptake of serotonin and norepinephrine into the presynaptic terminal.6 This allows for both serotonin and norepinephrine to be available at increased levels within the synaptic cleft. Other common medications used to treat depression include atypical antidepressants, serotonin modulators, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and N-methyl-D-aspartate (NMDA) receptor antagonists.6

Although the currently available antidepressants have shown efficacy in lessening the symptoms of depression, these medications often take several weeks to produce clinically meaningful effects.2 Not only do these medications take time to reshape the receptors within the brain, but they also have varying effects on patients. Hence, an agent that may work for one patient may not produce the same results in another. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, two-thirds of patients with depression failed to achieve remission of their depression symptoms with the first-line treatment.2 This illustrates that major depression disorder is different for everyone that experiences this disease state. Depending on a patient’s circumstances, waiting six to eight weeks to derive meaningful benefit from a medication may not be feasible.

Within the last two decades, it has been found that subanesthetic doses of the glutamatergic drug ketamine, an NMDA receptor antagonist, had rapid antidepressant effects in treatment resistant patients with depression, leading to an investigation of other agents in this class.1

Accordingly, one agent that has been considered is dextromethorphan. When taken orally in humans, this medication is rapidly metabolized by the CYP2D6 enzyme, making it difficult to achieve potential therapeutic plasma levels of substrate compound.7 To achieve therapeutic plasma concentrations of dextromethorphan, a CYP2D6 inhibitor must be utilized to block the metabolism of this medication. Bupropion, with distinct centrally acting mechanisms of action, was a strong choice as a metabolic inhibitor of dextromethorphan and has potential for pharmacological synergy and clinical use across of neuropsychiatric conditions.7 This led to the creation of dextromethorphan/bupropion, also known as AXS-05 and marketed under the brand name Auvelity®, which was approved by the United States Food and Drug Administration (FDA) for the treatment of major depressive disorder in August 2022.1 With this combination, the aim is to shorten the time it takes to achieve clinical improvement of depression symptoms.

Dextromethorphan-Bupropion (Auvelity®)

This medication has a unique mechanism of action in that it uses bupropion, a common antidepressant and tobacco cessation agent, to block the metabolism of dextromethorphan. This allows dextromethorphan to reach clinically significant plasma levels. Alone, dextromethorphan acts as an uncompetitive NMDA receptor antagonist and a sigma-1 receptor agonist, stimulating the central nervous system.3

As an NMDA receptor antagonist, dextromethorphan blocks the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) from binding to the NMDA receptor, decreasing the release of GABA into the central nervous system. This allows for a decrease in the inhibition of the ex-

Materia Medica

citatory neuron glutamate.8 Dextromethorphan then acts to increase serotonin levels in the brain by acting as a serotonin reuptake inhibitor and sigma-1 agonist to increase serotonin levels in the dorsal raphe of the brain.7 Together, both these medications act as norepinephrine reuptake inhibitors and alpha-4-beta-2 nicotinic (nACh) antagonists.7 Bupropion also acts as a dopamine reuptake inhibitor. Between dextromethorphan and bupropion, these two medications combine the mechanisms of action of distinct antidepressant therapeutic agents into one therapeutic agent.7 After repeat administration of dextromethorphan-bupropion, steady state plasma concentrations of the individual agents are reached within eight days.1

The GEMINI Study

The GEMINI study was a phase 3 trial that assessed the efficacy and safety of dextromethorphan-bupropion compared to placebo in the treatment of patients with MDD.3 This trial was double-blinded and placebo-controlled over a six week period across 40 different centers in the United States from June 2019 – December 2019. Patients were selected for this study based upon their scores on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinician Global Impression-Severity scale (CGI-S). Men and women between the ages of 18-65 that had a total MARDS score of 25 or higher, signifying moderate or greater severity of depression, a CGI-S score of 4 or higher, and a diagnosis of depression according to the DSM-5 criteria without psychotic features were considered to be appropriate candidates for the study.3 As part of the screening process of each patient, an independent assessor confirmed the eligibility and symptom severity of each patient through a clinical review of patient medical history and clinician- and patient-reported outcome measures. Key exclusion criteria for this study included those who had diagnosed bipolar disorder, psychotic disorder, panic disorder, obsessive-compulsive disorder, treatment resistant depression (defined as 2 or more adequate failed antidepressant treat- ments), alcohol/substance use disorder within the last year, clinically significant risk of suicide, and history of seizure disorder.3

Patients were randomly assigned in a 1:1 ratio to receive either dextromethorphan-bupropion (45mg-105 mg) or placebo orally for 6 weeks. The randomization of the treatment was performed by a central interactive web response system.3 Patients received their medication once daily for the first three days, and then twice daily for the remainder of the trial period. Study visits occurred at 1, 2, 3, 4, and 6 weeks after the baseline visit. The primary endpoint for this study was the change from baseline to week 6 in the MARDS total score. The key secondary endpoints included remission, defined as MADRS total score of less than or equal to 10, at week 2, and clinical response, defined as greater than or equal to 50% reduction in MADRS total score at week 6.3

Dextromethorphan-bupropion significantly reduced MADRS total scores compared to placebo at all time points that were accessed.3 The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion and -12.0 points in the placebo group (least squares mean difference of -3.87; 95% CI, -1.39 to -6.36; p = 0.002). Remission, defined as a MADRS total score of less than or equal to 10, was achieved by a significantly greater percentage of patients in the dextromethorphan-bupropion group than in the placebo group at week 2 (16.9% and 7.5% respectively; p = 0.013) and at every time point thereafter. Clinical response, defined as greater than or equal to 50% reduction in MADRS total score at week 6, was achieved by 54% of patients in the dextromethorphan-bupropion group and 34% in the placebo group (p < 0.001). The authors concluded that dextromethorphan-bupropion treatment resulted in early and substantial achievement of remission on the MADRS total score, with statistically significant separation from placebo demonstrated at week 2 and at every subsequent time point.3

Adverse Effects

In the GEMINI trial, the percentage of patients who experienced an adverse event was 61.7% in the dextromethorphan-bupropion group and 45.1% in the placebo group. The most common adverse events in the dextromethorphan-bupropion group included dizziness, nausea, headache, somnolence, and dry mouth.3 Other adverse effects of this medication include excessive sweating and sexual dysfunction.9 The COMET study was a Phase III, multicenter, open-label long-term safety study assessing dextromethorphan-bupropion for up to one year.9 In this study, 876 patients with MDD were included; patients could be rolled over from prior studies of the agent or newly enrolled. Long-term safety in this study was consistent with the results observed in other clinical studies, including GEMINI.9

Administration Considerations

The recommended starting dose is one tablet taken once daily in the morning for three days, then increased to one tablet twice daily (taken at least eight hours apart). Doses may be taken with or without food.1,9 A dosage reduction to one tablet once daily in the morning is recommended for patients with moderate renal impairment, patients who are known to be poor CYP2D6 metabolizers, and when co-administered with strong CYP2D6 inhibitors. Co-administration with strong CYP2B6 inducers should be avoided.9 Due to the risk of serotonin syndrome, dextromethorphan-bupropion should not be administered with a monoamine oxidase inhibitor (MAOI) or within fourteen days of stopping treatment with an MAOI; similarly, and MAOI should not be used within fourteen days of stopping dextromethorphan-bupropion.1

The patient’s baseline blood pressure should be assessed prior to the initiation of dextromethorphan-bupropion and periodically during treatment.9 Patients should also be screened

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