ABOVE: © istock.com, martin barraud

As droughts go, the one plaguing the antidepressant drug development landscape for the past few decades has been noteworthy. Since the advent of serotonin and norepinephrine reuptake inhibitors in the 1980s and 1990s, there has been a dearth of new pharmacological therapies for mood disorders, says psychiatrist Samantha Meltzer-Brody, director of the University of North Carolina’s Perinatal Psychiatry Program. “The same medications largely that were there when I went to medical school a long time ago were still the ones we’ve been using.”

Given this state of affairs, Meltzer-Brody says she had the “most modest” of expectations a few years ago when she got involved in the first clinical trial testing a new drug, SAGE-547, for postpartum depression. Developed by Massachusetts-based Sage Therapeutics, SAGE-547 is a solution of allopregnanolone, a neuroactive metabolite of the sex hormone progesterone, which plays key roles in the...

Progesterone and allopregnanolone levels peak during the third trimester of pregnancy, then crash immediately after delivery. Preclinical data suggested the drop in allopregnanolone could be a trigger for postpartum depression in some women. The company-funded trial involved administering SAGE-547 to a handful of patients with postpartum depression as an intravenous infusion over 48 hours.

The response in the first patient treated with SAGE-547 was dramatic. From being withdrawn and depressed with no appetite before treatment, she began smiling, talking, eating, and interacting, Meltzer-Brody says. “After that first patient, we thought either that’s one heck of a placebo or maybe there’s a signal.” Three more patients were treated, with similar results. Known by the generic name brexanolone, the drug sped through Phase 2 and Phase 3 trials before being approved by the US Food and Drug Administration (FDA) on March 19.

Now marketed by Sage Therapeutics as Zulresso, the therapy is the vanguard of a new wave of antidepressants. Although the path to market hasn’t been straightforward for all drug candidates, these treatments are known for being fast-acting and effective, and have fewer side effects than previous therapies. These improvements are reflected in the price tag: the first of these new antidepressants to reach the market—Zulresso and Janssen Pharmaceuticals’ Spravato (esketamine), approved just two weeks earlier for major depressive disorder—cost up to tens of thousands of dollars for a course of treatment.

But what really sets these new depression-treating drugs apart is the “circuit-driven” approach to their development, says Sage Therapeutics’ chief research officer Jim Doherty. A research focus on basic neuroscience has expanded understanding of how different neural circuits are involved in brain function—and how to target those circuits therapeutically. “The purpose of the brain is as a communication network,” Doherty says. Instead of thinking only in terms of candidate drug molecules and receptors, “we try to think as much as we can at that level [of the whole communication network] to understand what are going to be the circuit-level consequences of our molecules.”

A better understanding of depression

For a long time, the only treatments available for depression were two classes of antidepressants known as tricyclics and monoamine oxidase inhibitors (MAOIs), both of which were discovered in the 1950s. Three decades passed before a new class emerged—the SSRIs, with the first drug Prozac (fluoxetine) launched on the market by pharma giant Eli Lilly in 1988. (See timeline on page 65.) Still the most widely prescribed antidepressants in the world, SSRIs are thought to influence mood by increasing levels of the neurotransmitter serotonin in the brain’s synapses. But their exact mechanism of action is unknown. They’re also ineffective for many people, and even when they help, can require weeks or even months to alleviate patients’ symptoms. Researchers began to ask whether approaches to antidepressant development based on more-recent neuroscience might prove more successful. 

“The exciting thing for a clinician-researcher like me is to be able to see that the field is broadening in the understanding of what’s creating depression,” says Jayashri Kulkarni, psychiatrist and director of the Monash Alfred Psychiatry Research Centre in Melbourne, Australia, who is involved in a clinical trial of esketamine funded by Janssen. “The move in the last ten years has been to look at causes of depression in terms of brain chemistry as well as brain circuitry or brain physiology, and when you do that, you actually come out with some options that are really good” as potential targets for antidepressant drugs. 

Brexanolone, for example, is the product of research on how to modulate the function of the brain’s gamma-aminobutyric acid type A (GABAA) receptors, which normally interact with allopregnanolone and other neuroactive hormones. The drug began life as an epilepsy therapy, but Sage soon realized its potential for treating postpartum depression.

Esketamine, meanwhile, is one of another new class of antidepressants, based on a drug that has been in clinical use for half a century. The general anesthetic and painkiller ketamine is one of the World Health Organization’s essential medicines because of its safety and efficacy in both adults and children.  A couple of decades ago, with growing awareness of the role that the neurotransmitter glutamate and its interactions with the N-methyl-D-aspartate (NMDA) receptor play in mood disorders, researchers began to investigate whether ketamine, which blocks the NMDA receptor, might also be effective in treating depression

After that first patient, we thought either that’s one heck of a placebo or maybe there’s a signal.

 —Samantha Meltzer-Brody, University of North Caro­lina

The first clinical study of ketamine for depression, published in 2000, found significant and rapid improvement in depression symptoms in seven individuals with major depression. A second randomized, placebo-controlled, double-blind crossover study in 2006 confirmed the benefits, and showed that they could be delivered within just two hours of an intravenous infusion, based on patient questionnaires. “You don’t have a suicidal patient sitting around for weeks or months trying to see if the next medication is actually going to work,” says psychiatrist and neuroscientist Ronald Duman, director of the Abraham Ribicoff Research Facilities at Yale University School of Medicine who researches ketamine but wasn’t involved in the 2006 study.

Since that research was published, interest has surged in developing new ketamine-based therapies for depression, and esketamine is the first ketamine-derived product on the market. It’s the s-enantiomer of ketamine—one of two mirror-image molecules that together make up ketamine—and is administered in a nasal spray formulation. The drug was approved by the FDA last March as an add-on therapy for treatment-resistant major depression, but not without some controversy. “The FDA gave Janssen quite a bit of flexibility,” says Todd Gould, a neuropharmacologist at the University of Maryland School of Medicine. “They only met their primary outcome in one of three acute studies.”

A typical course of esketamine involves four weeks of twice-weekly treatments, followed by maintenance doses once every one or two weeks in patients who respond, continuing for up to nine months based on clinical judgement. The choice of nasal delivery was deliberate, says Ella Daly, therapeutic area lead for mood in US Scientific Affairs at Janssen. “Unlike the intravenous formulation, the intranasal route is noninvasive, [and] we felt it would facilitate outpatient access and administration,” Daly says.

However, because esketamine, like ketamine, can have cognitive, dissociative, and even psychedelic side effects, the nasal spray must be administered in a supervised medical setting, and the patient has to remain at the clinic for at least two hours after administration. “Generally [side effects attenuate], though, with repeated dosing, so we see that reducing and being less significant,” Daly says. 

Neither esketamine nor brexanolone are cheap. The list price for Spravato is $590–$885 per treatment session, or up to more than $30,000 for a full nine months of treatment at maximum dosage, while a one-time, 60-hour intravenous  infusion of Zulresso costs around $34,000. But their success has caught the attention of the pharmaceutical industry, which had been moving away from psychiatric drug development due to challenges in translating animal findings into humans, says Duman, who has received fees and grant support from Johnson & Johnson, the parent company of Janssen. “There’s a very renewed interest now because of ketamine and Spravato,” he says. “This is going to help bring big pharma back to the table.”

More new antidepressants on the horizon

Esketamine’s mirror twin, the r-enantiomer of ketamine, is also being investigated as a potential therapeutic molecule. “The preclinical data from our lab and other labs indicates that the r-ketamine is the more potent antidepressant, [but] that remains to be tested in humans,” says Gould. While the s-enantiomer is a more potent antagonist of the NMDA receptor, Gould says that doesn’t necessarily translate to stronger antidepressant effects.

Gould and others are also interested in the metabolites that result from ketamine’s breakdown in the body, after research in animals found that ketamine’s metabolites were not only necessary for its antidepressant effects but could, by themselves, induce ketamine-like responses. One of those metabolites, known as (2R,6R)-hydroxynorketamine and patented by Gould and others, is about to start Phase 1 clinical trials funded by the National Institutes of Health.

At dosages that relieve depression-like symptoms in animals, the compound “does not block the NMDA receptor, it does not produce the side effects of ketamine, and it does not appear to have the potential for addiction or abuse,” says clinical pharmacologist Carlos Zarate, chief of the section on the Neurobiology and Treatment of Mood Disorders at the National Institute of Mental Health who, with colleagues, also has patents for ketamine and its metabolites for the treatment of mood disorders.

Zarate believes that ketamine-based drugs have great potential, especially if the abuse potential and dissociative side effects are reduced. “What we do know is that ketamine, at least in our research, seems to have more-broad therapeutic effects, called pan-therapeutic effects,” Zarate says. “It seems to work very well in anxiety,  [post-traumatic stress disorder] symptoms, anhedonia or lack of pleasure, suicidal thinking, and in fact sometimes even in people who have failed electroconvulsive therapy.”

The drug development pipeline for treatments that, like brexanolone, target the GABA receptor system may also be opening up. Sage Therapeutics is starting Phase 3 trials of another GABAA receptor modulator, called SAGE-217, for adults with major depressive disorder. A recent placebo-controlled Phase 2 study showed that the compound achieved significant improvements in depressive symptoms, without any major safety signals. “That molecule was designed to have the same pharmacology of Zulresso but to have an oral once-a-day pharmacokinetic profile,” Doherty says. The company also has other drugs in early development that target the same NMDA receptor system as ketamine.

It hasn’t all been smooth sailing. Pharmaceutical company Allergan had a high-profile failure of three Phase 3 placebo-controlled clinical trials of its NMDA receptor–targeting drug rapastinel, which did not meet the primary endpoint of preventing relapses of major depression. And both the brexanolone and esketamine Phase 3 trials detected high placebo response rates, a common feature of late-stage trials in depression that can make it difficult to demonstrate that a treatment is achieving a clinical benefit.

In the case of esketamine, one of its Phase 3 trials, carried out in patients aged 65 years and older with treatment-resistant depression, failed to show statistically significant efficacy compared to placebo. “It’s fair to say that studies in the elderly population in depression are more challenging because response rates typically are lower,” Daly says. That study also used a lower starting dose, she notes, adding that an older population may need a longer duration of treatment to show benefit.

Despite the setbacks, there is general agreement that the antidepressant landscape is undergoing a profound change for the better. “It’s going to be the new norm, in that next-generation treatments will be required to have a rapid onset of action unless they’re special or unique in some other therapeutic property,” Zarate says. “Imagine, for every episode of depression you intervene [in] very early, you could significantly reduce the amount of time our patients spend in depression, [are] not able to function, have poor quality of life, and are at risk of suicide.” 


Researchers have been working for decades on new ways to treat depression, but the US market is still dominated by drugs that were developed in the late 1980s and early 1990s.


Iproniazid, the first of the monoamine oxidase inhibitors (MAOIs), is developed, after doctors realize that isoniazid, a tuberculosis drug with a similar structure, has an unexpected euphoric effect on patients. The drug inhibits the monoamine oxidase enzyme, which interacts with several neurotransmitters in the brain, including serotonin. 


Imipramine, the first tricyclic antidepressant, is introduced for medical use. Derived from antihistamine compounds, this drug class blocks the reuptake of serotonin and norepinephrine into presynaptic neurons, thereby increasing extracellular levels of the neurotransmitters in the brain.


Fluoxetine, better known as Prozac, makes its debut on the market as the first selective serotonin reuptake inhibitor (SSRI)—still the class of antidepressants most commonly prescribed today. By reducing the reuptake of serotonin, the drug increases the extracellular concentration of the neurotransmitter.


Bupropion, a type of antidepressant that doesn’t fit into existing drug classes, is approved as a treatment for major depressive disorder. It increases dopamine and norepinephrine levels in the brain by inhibiting the neurotransmitters’ reuptake.


Venlafaxine, the first of the serotonin-norepinephrine reuptake inhibitors (SNRIs), hits the market. Like the SSRIs, these drugs inhibit the reuptake of serotonin, but they additionally do the same for norepinephrine.


Vortioxetine, another atypical antidepressant, is approved. In addition to inhibiting the reuptake of serotonin, vortioxetine acts as an agonist and antagonist of different serotonin receptors, with the net effect of increasing extracellular amounts of serotonin and modulating the release of other, downstream neurotransmitters.


Brexanolone and esketamine, the first of a new wave of drugs born of research into the underlying brain circuitry of depression, are approved and put on the market.

Bianca Nogrady is a freelance science writer based in Sydney, Australia.

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