The newest antidepressant approved in the United States is an expanded use of esketamine nasal spray (Spravato), which gained FDA approval in 2025 as a standalone treatment for treatment-resistant depression. But several other antidepressants approved since 2022 represent a genuine shift in how depression is treated, moving beyond the serotonin-focused drugs that have dominated for decades.
Why Newer Antidepressants Work Differently
Most antidepressants prescribed today, including SSRIs and SNRIs, work by increasing levels of serotonin or norepinephrine in the brain. These are “modulatory” brain chemicals, and targeting them comes with two well-known limitations: they take weeks to kick in, and they help only a portion of people who try them.
The newer wave of antidepressants targets different brain systems entirely. Some act on glutamate, the brain’s primary excitatory chemical. Others work through GABA, its main inhibitory chemical. Because glutamate and GABA are the two most abundant signaling systems in the brain, drugs that act on them tend to produce faster and, in some cases, stronger effects. Research published in the journal Neuron found that agents targeting these systems directly should be more effective than traditional antidepressants, which could explain both the slow onset and modest results many people experience with older medications.
Spravato: Now Approved as a Standalone Treatment
Esketamine nasal spray was originally approved in 2019 for treatment-resistant depression, but only when combined with an oral antidepressant. The 2025 approval removed that requirement, making it the first time esketamine can be prescribed on its own. This matters for people who haven’t responded to multiple oral medications or who experience intolerable side effects from them.
Esketamine is closely related to ketamine, the anesthetic that researchers discovered has rapid antidepressant effects. It works by blocking a specific type of glutamate receptor, which triggers a cascade that ultimately helps the brain form new synaptic connections, particularly in the prefrontal cortex. Unlike SSRIs, which can take four to six weeks to show results, esketamine can produce noticeable improvement within hours to days. The tradeoff is that it must be administered in a certified healthcare setting because of its potential for sedation and dissociation.
Auvelity: A Faster-Acting Oral Option
Auvelity, approved in 2022, was the first new oral antidepressant mechanism in over 60 years. It combines dextromethorphan (the active ingredient in many cough medicines, but at a different dose and for a different purpose) with bupropion. The dextromethorphan component blocks the same type of glutamate receptor that ketamine targets and also activates sigma-1 receptors, which play a role in nerve cell health. Bupropion is included primarily to slow the breakdown of dextromethorphan in the body so it stays active long enough to work.
Clinical trial data showed that patients experienced meaningful improvement as early as one week after starting treatment, considerably faster than the typical timeline for SSRIs. In the pivotal trial, Auvelity significantly outperformed placebo on standard depression rating scales over six weeks. It’s taken as a pill twice daily, which makes it more convenient than treatments requiring clinic visits.
The retail price sits around $1,186 per fill, which puts it well above generic SSRIs. Insurance coverage varies, and the manufacturer offers savings programs that can reduce the cost by up to $48 per fill.
Exxua: An Antidepressant Without Sexual Side Effects
Exxua (gepirone) was approved in late 2023 after a remarkably long development history. It works on serotonin receptors but in a fundamentally different way than SSRIs. Rather than flooding the brain with serotonin by blocking its reuptake, gepirone directly stimulates a specific serotonin receptor subtype. This targeted approach gives it a side effect profile that sets it apart from nearly every other antidepressant on the market.
Sexual dysfunction is one of the most common reasons people stop taking antidepressants. With SSRIs, rates of sexual side effects run as high as 40% to 70% depending on the study. In Exxua’s clinical trials, sexual side effects were so infrequent they didn’t even meet the threshold for inclusion as an adverse reaction on the drug’s label. Weight gain, another common complaint with many antidepressants, also did not occur at rates higher than placebo. Blood pressure, heart rate, and liver function were similarly unaffected. For people who have cycled through antidepressants and found the side effects worse than the depression itself, Exxua offers a genuinely different option.
Zurzuvae: A 14-Day Course for Postpartum Depression
Zurzuvae (zuranolone), approved in August 2023, is the first oral medication specifically indicated for postpartum depression. Previous treatment for severe postpartum depression required a 60-hour IV infusion in a hospital setting, which made it impractical for most new mothers. Zurzuvae changed that equation dramatically.
The treatment course is unusually short: one pill taken once daily for just 14 days, in the evening with a fatty meal (the fat helps the body absorb the drug). Zurzuvae works on GABA receptors, the same system targeted by benzodiazepines but through a different mechanism. Because hormone fluctuations after childbirth directly affect GABA signaling, this approach addresses one of the biological roots of postpartum depression rather than broadly adjusting serotonin levels.
The 14-day treatment window is a significant departure from traditional antidepressants, which are typically taken for months or years. Clinical trials showed rapid improvement in depressive symptoms, with benefits emerging within days and persisting after the two-week course ended.
How These Drugs Compare at a Glance
- Spravato (2025 expanded approval): Nasal spray for treatment-resistant depression. Works within hours to days. Must be given in a clinical setting. Now approved as a standalone treatment.
- Exxua (2023): Daily oral pill for major depression. No meaningful sexual side effects or weight gain. Works through targeted serotonin receptor activation.
- Zurzuvae (2023): Oral pill for postpartum depression only. Taken for 14 days, then stopped. Works through the GABA system.
- Auvelity (2022): Twice-daily oral pill for major depression. Can work within one week. Acts on the glutamate system, similar in concept to ketamine.
What This Means for Treatment Options
These approvals don’t replace SSRIs, which remain effective for many people and are available as inexpensive generics. But they fill gaps that have existed for decades. If you’ve tried multiple SSRIs without adequate relief, Auvelity or Spravato targets a completely different brain system. If side effects have been your barrier, Exxua removes two of the most common ones. If you’re dealing specifically with postpartum depression, Zurzuvae offers a short, targeted course instead of open-ended treatment.
Cost remains a real barrier. All four of these medications are brand-name drugs without generic equivalents, and monthly costs can reach well over $1,000 without insurance. Coverage decisions by insurers often require documentation that older, cheaper treatments were tried first, a process called step therapy. Manufacturer savings programs and patient assistance programs exist for each, but navigating them takes effort.
The broader picture is that depression treatment is no longer a one-system story. For the first time, clinicians can choose from drugs that work on glutamate, GABA, or serotonin through distinct pathways, matching treatment to individual biology rather than cycling through variations on the same mechanism.