One of the main reasons I started this blog is because I bring a background to psychiatric practice that’s different from most. I spent two years working in a medical ICU, then four and a half years as a Certified Specialist in Poison Information at the West Virginia Poison Center, handling thousands of overdose and toxic exposure cases. It’s through that lens—now as a psychiatric mental health nurse practitioner—that I view the risks and benefits of the medications I prescribe. I know what these drugs look like on both ends: the lifesaving and the life-threatening. And when I see a concerning trend taking shape in psychiatry, I feel a responsibility to speak up—not just for patients, but for the providers treating them.
For over 70 years, we’ve treated depression by targeting the same basic neurotransmitters: serotonin, norepinephrine, and dopamine. The 1950s brought us monoamine oxidase inhibitors (MAOIs), followed by tricyclic antidepressants (TCAs). Then, in 1987, Prozac changed the landscape entirely, ushering in the SSRI era (An Overview of SSRIs with a Detailed Look at Mechanism of Action) with safer and more tolerable medications. Since then, nearly every new antidepressant has been some variation on that same monoamine model.
Today, SSRIs and SNRIs remain the first-line options. But many patients—especially those with severe or chronic symptoms—don’t get full relief. In my practice, most patients I see on intake have already tried multiple first-line treatments. Two SSRIs, an SNRI, maybe bupropion or mirtazapine added in. Trazodone for sleep. Often, there’s been an attempt at augmentation with antipsychotics like Abilify or Seroquel. Not every case is that complex, but enough of them are that it raises real concerns about how we manage treatment-resistant depression (TRD).
TRD doesn’t have a universally accepted definition, but it’s generally understood as depression that doesn’t respond after at least two adequate antidepressant trials. And we know from the STAR*D trial that each new medication tried after the first two has diminishing returns—remission rates drop significantly with every subsequent step (PubMed link).
Fortunately, we’re entering a new era—one that moves beyond serotonin and begins to target glutamate, the brain’s primary excitatory neurotransmitter. The goal here isn’t just symptom reduction, but actual neuroplasticity and long-term recovery. As of 2025, we have three FDA-authorized options that do this:
- Transcranial Magnetic Stimulation (TMS) – FDA-cleared, done in-office, well-tolerated by many patients.
- Spravato (intranasal esketamine) – FDA-approved, often used as augmentation, requires REMS enrollment and in-clinic administration.
- Auvelity – The first and only oral NMDA receptor antagonist approved for major depressive disorder.
Of the three, Auvelity is by far the easiest to administer—taken at home, no in-office monitoring, and often faster-acting than traditional antidepressants. It combines dextromethorphan (DXM) and bupropion in a fixed-dose formulation. DXM was FDA-approved in 1958 as a cough suppressant but has since shown promise in treating depression due to its multiple mechanisms: NMDA antagonism (boosting glutamate), serotonin reuptake inhibition, sigma-1 receptor agonism (similar to Luvox), and AMPA receptor effects. It also increases brain-derived neurotrophic factor (BDNF), supporting neuroplasticity.
The problem is that DXM is metabolized very quickly—its half-life is around 4 hours—so on its own, it doesn’t stick around long enough to do much for mood. That’s where bupropion comes in. By inhibiting CYP2D6, bupropion slows DXM’s metabolism and extends its therapeutic effect. But here’s the critical point: the bupropion in Auvelity is a proprietary formulation. It’s structurally closest to sustained-release bupropion, but it is not identical to any formulation currently available on the market.
Despite this, insurance companies—especially Medicaid programs like West Virginia’s—are requiring patients to try the individual components separately before authorizing Auvelity. On the surface, that may seem like a reasonable cost-containment strategy. But as someone who has managed thousands of overdose cases, I can tell you: this is dangerous.
I’ve never prescribed DXM and bupropion separately—and I never will. I’ve inherited patients who have tried it. None have succeeded. The DXM wears off too fast. The bupropion dose isn’t right. Patients become overstimulated, develop tremors or tachycardia, or feel so uncomfortable they stop one or both meds. Sometimes they’re left without any antidepressant coverage at all—and in patients with severe depression, that’s a serious clinical risk.
Let’s be honest: DIY drug combinations aren’t always bad. In fact, it’s common practice in psychiatry. We often prescribe sertraline and buspirone instead of Viibryd. We pair olanzapine and fluoxetine as an alternative to Symbyax. Those combinations are safe, straightforward, and well understood. But Auvelity cannot be safely replicated this way. DXM and bupropion have complex pharmacology, abuse potential, and narrow dosing tolerances. Prescribing them separately is not the same—and doing so outside of a fixed-dose formulation creates real, documented risks.
Both medications have histories of misuse. DXM, especially in higher doses, is widely abused for its dissociative effects. Bupropion has been misused for stimulant-like effects and is one of the most common agents involved in overdose presentations. But when combined as Auvelity, the abuse potential has been studied—and found to be nonexistent. In human abuse liability testing, Auvelity showed no meaningful abuse potential (PubMed link).
I want to be clear: this post is not about championing an expensive medication or launching a war with insurance companies. I understand cost concerns. I understand step therapy. But requiring providers to cobble together two risky drugs in hopes of mimicking a drug specifically designed to be taken as a single unit—that crosses a line.
This isn’t theoretical for me. I’ve managed bupropion overdoses. I’ve seen what happens with recreational DXM use. I’ve worked both ends of the spectrum—first as a toxicology specialist, now as a psychiatric provider. And I’ve already written about this from the bupropion angle in my post: My Complicated Relationship with Wellbutrin
The point here isn’t to make a sales pitch. It’s to educate—to give context to a clinical decision that’s increasingly being questioned or denied by payors. Because while pharmacy benefit managers may treat DXM and bupropion as interchangeable parts, those of us who know better must do better.
For patients battling treatment-resistant depression, we can’t afford shortcuts that compromise safety. If a patient is a candidate for Auvelity, they deserve the real thing—not a DIY version that has never been tested, studied, or proven safe.
We owe them that much.
This post was written by Richard Gray, PMHNP-BC. The above information is for educational/entertainment purposes and is not intended to be treated as medical advice. If you have questions about a medication you are taking, discuss these questions with your medical provider