The next generation of antidepressants: Are they effective?

By Samar Mahmoud, PhD | Medically reviewed by Kevin Kennedy, MD
Published October 5, 2022

Key Takeaways

  • The FDA approved extended-release dextromethorphan-bupropion, the first oral NMDA receptor antagonist, for the treatment of major depressive disorder (MDD) in August 2022.

  • While traditional antidepressants take 2 to 4 weeks to show effect, dextromethorphan-bupropion has demonstrated efficacy within a week of treatment initiation.

  • The FDA also approved brexanolone and esketamine in 2019, which modulate GABA receptors and glutamate activity, respectively.

A new breed of antidepressants has the potential to change the way depression is treated and provide hope for patients with treatment-resistant depression.

These FDA-approved medications include dextromethorphan-bupropion (Auvelity), brexanolone (Zulresso), and esketamine (Spravato). All three offer unique benefits over previous medications for depression.

Mechanism of action

Dextromethorphan-bupropion is the first oral N-methyl D-aspartate (NMDA) receptor antagonist to be approved for the treatment of MDD.[]

It was granted Breakthrough Therapy designation by the FDA in March 2019 based on preliminary clinical results for its potential to benefit MDD patients. In August 2022, the FDA approved extended-release tablets for the treatment of MDD in adults.

Dextromethorphan-bupropion combines two drugs—dextromethorphan, an uncompetitive antagonist of the NMDA receptor (also referred to as a sigma-1 receptor agonist), and bupropion, an established antidepressant. Inhibition of the NMDA receptor is thought to affect glutamate signaling in the central nervous system.

However, the use of dextromethorphan has been limited in human subjects because the drug is metabolized rapidly by the cytochrome P450 system resulting in decreased drug plasma levels. To circumvent this, dextromethorphan-bupropion contains bupropion, which increases the plasma concentration of dextromethorphan by preventing it from being metabolized by the liver.

Clinical trial efficacy

In a double-blind, phase 3 trial, patients with a DSM-5 diagnosis of MDD were randomized to receive either placebo or oral dextromethorphan-bupropion (45 mg–105 mg tablet) given twice daily for 6 weeks.[]

Investigators observed significant improvements in depressive symptoms in patients receiving the treatment compared with placebo as early as 1 week post-treatment initiation.

The combination of dextromethorphan and bupropion was also well-tolerated in general.

“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Clinical Trials Network and Institute Executive Director and consultant to Auvelity manufacturer Axsome Therapeutics Maurizio Fava, MD, said in a press release.

“Nearly two-thirds of patients treated with currently available antidepressants do not adequately respond, and those that do may not achieve clinically meaningful responses for up to 6 to 8 weeks," Dr. Fava continued.

"Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition."

Maurizio Fava, MD

Comparison with older drugs

While dextromethorphan-bupropion modulates glutamate signaling, patients diagnosed with MDD have traditionally been treated with selective serotonin reuptake inhibitors (SSRIs), which increase serotonin levels in the brain by inhibiting the process of serotonin reuptake.[]

SSRIs, which are considered safer and better-tolerated than older types of antidepressants, include fluoxetine (Prozac), sertraline (Zoloft), and escitalopram (Lexapro).

A significant advantage of dextromethorphan-bupropion has over traditional SSRIs is that it's demonstrated positive changes in depressive symptoms within 1 week of treatment initiation. This is in stark contrast to SSRIs and serotonin-norepinephrine reuptake inhibitors, which typically take anywhere from 2 to 4 weeks to show effect.[]

Other new drugs for MDD

While the majority of people respond favorably to standard antidepressants, at least 30% of individuals have treatment-resistant depression.[] These patients have tried at least two different kinds of antidepressants but continue to experience symptoms of depression.

Over the past 20 years, scientists have made significant strides in our understanding of the biology of depression.

This information has been critical in the development of novel antidepressants with new therapeutic targets beyond a small subset of neurotransmitters.

The FDA approved brexanolone in 2019. It’s the first drug to be marketed for treatment of postpartum depression, and is thought to modulate GABA receptors, which aid in mood regulation.

Unlike other antidepressants, brexanolone is an IV drug that patients must receive at a healthcare facility over the course of 60 hours. However, it works quickly and may begin to decrease postpartum depressive symptoms as soon as the end of the treatment.

The FDA also approved esketamine, a prescription nasal spray, in 2019.

Esketamine functions by modulating glutamate activity in the brain, and improvements have been seen in patients within 24–48 hours or days after starting esketamine treatment.

While esketamine may be a good option for patients with treatment-resistant depression as well as those who experience suicidal thoughts, it may only provide temporary relief from symptoms. Because of this, clinicians recommend taking rapid-onset drugs in combination with traditional antidepressants.

What this means for you

In the past two decades, our understanding of the biology of depression has expanded, leading scientists to pursue new drug targets. The FDA recently approved Auvelity, a novel drug combination that’s been shown to be effective in treating MDD in as little as 1 week, unlike traditional antidepressants that take 2 to 8 weeks to work. The FDA also recently approved Zulresso and Spravato, antidepressants with the potential to expand the range of medications used in the treatment of depression.

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