There are dozens of antidepressants on the market, and they work extremely well for a lot of people. But they have little or no effect for as many as half those who try them. Until recently, all doctors could do was keep throwing more drugs at what seemed to be a largely impenetrable target. 

But the newest available treatments—and those on the horizon—are finding success by approaching that target from an entirely different angle.  

The history of antidepressants

Most antidepressants aim for the same target: the monoamine system. They work by raising levels of one or more of the monoamine neurotransmitters in the brain that are involved in mood—serotonin, norepinephrine, and dopamine.

MAOIs, or monoamine oxidase inhibitors, were the first type of antidepressants developed. They have largely been replaced by drugs with fewer side effects.  

SSRIs (selective serotonin reuptake inhibitors), which debuted in the 1980s, work on serotonin. SNRIs (serotonin and norepinephrine reuptake inhibitors) hit serotonin and norepinephrine. Wellbutrin (bupropion)—the only FDA-approved NDRI (norepinephrine and dopamine reuptake inhibitor) for depression—takes aim at norepinephrine and dopamine.

“But they just aren’t fundamentally different from each other and one isn’t any better than another,” says Dr. James Murrough, M.D., Ph.D., director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai in New York City. (Murrough has also consulted and served on advisory boards for several pharmaceutical and biotechnology companies developing treatments for mental disorders.)

What’s more, once a person has tried two different antidepressants, stayed with each one for long enough to feel the effects, and doesn’t get relief, their depression is considered treatment-resistant. 

Even for the people who benefit from these drugs, they’re not perfect pills. Among the problems, SSRIs and SNRIs may take weeks to kick in. They can kill your libido, make orgasm impossible, and may cause a host of other side effects including weight gain, dry mouth, and diarrhea. For all these reasons, it’s critical to find drugs that take a different approach to the problem. 

Homing in on serotonin

In October, the FDA approved gepirone hydrochloride extended release tablets (Exxua) from Fabre-Kramer Pharmaceuticals. Rather than targeting serotonin receptors in general like SSRIs, it shoots for one receptor in particular: the serotonin 1A receptor. 

In clinical trials, the pills eased depression without the sexual side effects that can push some people to quit SSRIs. And there were no adverse effects on weight, blood pressure, heart rate, or liver function. It’s expected to be available in early 2024. 

Ketamine therapy for depression 

Still, not everyone benefits from drugs that work on monoamines. The development of esketamine (Spravato) has helped shift attention beyond these neurotransmitters altogether.

The FDA approved Johnson & Johnson’s drug for treatment-resistant depression in 2019. Esketamine is derived from a pediatric anesthetic called ketamine. Through research pioneered at Yale University, it was discovered that the drug seemed to lift heavy, recalcitrant depression almost immediately. And it did so without working on monoamines.

“Ketamine kind of broke all the rules,” Murrough tells Fortune. “It has no direct effect on the monoamine system or serotonin or anything like that.”

Ketamine affects another neurotransmitter, glutamate, which is known as an excitatory neurotransmitter. Among its many physiological effects that may play a role in depression, ketamine raises levels of glutamate, which may be how it offers such immediate relief from depression. Some people feel better the same day.

It’s a game-changer for some people who are told they need to give traditional antidepressants weeks to do their job only to get no relief and then start the process all over with another similar drug.

But it comes with risks. Ketamine is a sedative and it can cause dissociation—that is, a disconnect from your body, mind, and reality, like a drug trip. It has the potential for abuse, too. Ketamine is also known as the party drug Special K. For these reasons, esketamine can only be administered in a doctor’s office. FDA guidelines recommend patients stay with the doctor for two hours after receiving the dose. It’s taken twice a week for the first month, then once a week for the next month, and tapers down from there.

“Since ketamine has been very effective, moving forward, I’d expect to see compounds that have similar mechanisms of action to ketamine, but have improved safety and adverse effect profiles and reduced abuse liability,” says Melissa Taft Manners, assistant professor in the College of Science and Mathematics at Rowan University in New Jersey.

Products in the works at various pharmaceutical companies aim to make ketamine and other dissociative drugs, such as psychedelics like MDMA, even better antidepressants. Some drugs combine ketamine with other medicines to extend its efficacy and reduce the need for such frequent doctor visits. Other research explores ways to cut the hallucinogenic effects from ketamine and psychedelics while holding onto the antidepressant effects.

New drugs targeting glutamate

Ketamine’s antidepressant effects are part of what prompted researchers to explore other drugs that target glutamate—like the venerable cough suppressant dextromethorphan found in Robitussin and other over-the-counter syrups. Like ketamine, it interacts with glutamate. Now it’s found in Axsome Therapeutics’ Auvelity. Just approved by the FDA last year, this new drugcombines dextromethorphan and bupropion (Wellbutrin). And like esketamine, it works fast. In clinical trials, people felt the effects in about a week.

GABA: The yin to glutamate’s yang

While esketamine was in clinical trials and on its way to FDA approval in 2019, so was brexanolone (Zulresso), the first FDA-approved medication specifically for postpartum depression from Sage Therapeutics.

In pregnancy, levels of the neurosteroid allopregnanolone, a byproduct of the hormone progesterone, run high. After delivery, they plummet. It’s believed that this sudden drop may cause postpartum depression. Brexanalone, an IV form of this pregnancy-related neurosteroid, brings levels back up and relieves depression. Allopregnanolone increases the activity of neurotransmitter GABA.

“Where glutamate excites brain cells, GABA, the main inhibitory transmitter in the brain, tends to quiet them down,” Murrough says.

Just last August, Sage Therapeutics got FDA approval for its pill form of this drug, zuranolone (Zurzuvae), which has shown to ease symptoms of postpartum depression in as little as three  days.

Now scientists from several universities are looking at whether GABA is an effective target for general depression, too.

Antidepressant drugs on the horizon

Antidepressants still in the pipeline take aim at other aspects of our biology that could play a part in depression.

“Many biological processes, receptors, genomic variations, environmental factors, and brain circuits are hypothesized to be a part of the process of depression,” Manners tells Fortune. “If we have a better understanding of what mechanisms underlie disease, we have a better opportunity to identify new targets for treatment.”

Neumora Therapeutics’ Navacaprant is in phase III clinical trials. This drug is a kappa opioid receptor (KOR) antagonist—not to be confused with opioids, such as morphine and fentanyl.

KOR antagonists, in fact, are the focus of research into treatment for depression, anxiety, and substance use disorders. The idea is that these drugs seem to blunt the effects of the stress that can trigger these and many other psychiatric conditions.

These drugs seem to address one of depression’s most troubling symptoms—that loss of motivation and interest in pretty much everything. “They may be particularly effective for impaired motivation and blunted experience of pleasure—anhedonia,” says Dr. John Krystal, a professor of psychiatry at Yale School of Medicine who led the research that confirmed ketamine’s rapid antidepressant effects. (Krystal is a co-inventor on patents related to intranasal ketamine that were licensed to Johnson & Johnson.) “Even among patients who respond overall to standard antidepressants, residual anhedonia can be a problem,” he tells Fortune.

There may be untold other targets for antidepressant drugs. Murrough, for example, is currently conducting research into an anti-seizure drug that, until recently, no one suspected may also relieve depression.

“There’s a lot of reason for excitement right now in the treatment of depression,” Murrough says. “Things are shaking up.”