Breakthrough antidepressants with fewer side effects could help millions of Americans. Here’s what the future of treatment might look like

There are dozens of antidepressants on the market, and they work extremely well for many people. But they have little or no effect on up to half of 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 treatments available and those on the horizon are finding success by approaching that goal from an entirely different angle.

The history of antidepressants

Most antidepressants target the same target: the monoamine system. They work by raising the levels of one or more monoamine neurotransmitters in the brain that are involved in 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 They have largely been replaced by drugs with fewer side effects.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) affect serotonin and norepinephrine. Wellbutrin (bupropion) is the only FDA-approved NDRI (norepinephrine and dopamine reuptake inhibitor) for depression targeting norepinephrine and dopamine.

But they’re just not fundamentally different from each other, and one isn’t better than the other, says James Murrow, MD, PhD, director of the Depression and Anxiety Discovery and Treatment Center at the Icahn School of Medicine at Mount Sinai. in New York City. (Murrow has also consulted and served on advisory boards for several pharmaceutical and biotech companies developing treatments for mental disorders.)

What’s more, once a person has tried two different antidepressants, stays on each one long enough to feel the effects, and gets no relief, their depression is considered treatment-resistant.

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

Serotonin intake

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

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

Ketamine therapy for depression

However, not everyone benefits from drugs that act on monoamines. The development of esketamine (Spravato) helped shift the focus away from these neurotransmitters.

The FDA approved Johnson & Johnson’s drug for treatment-resistant depression in 2019. Escetamine is derived from a pediatric anesthetic called ketamine. Through research at Yale University, it was found that the drug appears to lift severe, unruly depression almost immediately. And he did it without working on monoamines.

Ketamine kind of broke all the rules, says Murrow 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 increases glutamate levels, which may be how it offers such immediate relief from depression. Some people feel better the same day.

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

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

Because ketamine is so effective, moving forward, I expect to see compounds that have similar mechanisms of action to ketamine, but with improved safety and adverse effect profiles and reduced abuse liability, says Melissa Taft Manners, Ph.D., assistant professor at the College in Science and Mathematics from Rowan University in New Jersey.

Products at various pharmaceutical companies aim to make ketamine and other dissociative drugs, such as psychedelics like MDMA, even better antidepressants. Some medications combine ketamine with other medications to prolong its effectiveness and reduce the need for such frequent doctor visits. Other research is investigating ways to reduce the hallucinogenic effects of ketamine and psychedelics while maintaining antidepressant effects.

New drugs targeting glutamate

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

FUNGUS: Yin to glutamate’s yang

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

In pregnancy, levels of the neurosteroid allopregnanolone, a byproduct of the hormone progesterone, are high. After childbirth, they decline. It is believed that this sudden drop can cause postpartum depression. Brexanalone, an IV form of this pregnancy-related neurosteroid, restores levels and relieves depression. Allopregnanolone increases the activity of the neurotransmitter GABA.

Where glutamate excites brain cells, GABA, the main inhibitory transmitter in the brain, tends to calm them down, says Marrow.

Just last August, Sage Therapeutics received FDA approval for its pill form of this drug, zuranolone (Zurzuvae), which has been shown to relieve symptoms of postpartum depression in just three days.

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

Antidepressants on the horizon

Antidepressants still in the pipeline are targeting other aspects of our biology that might play a role in depression.

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

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

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

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

There may be other undisclosed purposes for antidepressants. For example, Murrow is currently conducting research on an anti-seizure drug that, until recently, no one suspected could alleviate depression.

There is much to be excited about right now in treating depression, says Marrow. Things are shaking.