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Geoffrey Attardo first tried Prozac to treat his depression when he was doing postdoctoral research at Yale School of Public Health and was feeling the pressures of a new job in academia. Soon after he started, the colors around him seemed brighter, he had enough motivation to begin exercising more, and he felt hopeful for the first time in a long while. But about five months into the treatment, colors started dulling again and his energy waned. Increasing the dose didn’t help.

He eventually switched to a similar antidepressant called Zoloft and has been on it for about 20 years, though it makes him emotionally numb and never completely got rid of the depression. “It takes the edge off and keeps you from completely breaking down,” he said, “but it’s not really a great way to live.”

Then this year, Attardo, who is 49, tried a new treatment for depression — ketamine — a drug long used as an anesthetic and that works through a different pathway in the brain than the traditional drugs he’d taken. A few days after one of his first ketamine infusions, he found himself awake at 9 a.m., a time he usually slept long past, with much more energy than usual.

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Patient responses like Attardo’s, after years of unsuccessful treatment with standard drugs, are spurring a gradual — and, some would say, overdue — shift in psychiatry toward a new way of thinking about depression, its causes, and therapies. The profession’s long embrace of the “monoamine hypothesis” — the idea that depression primarily results from abnormal levels of neurotransmitter chemicals in the brain and that drugs can restore the proper balance — is giving way to a more complex understanding and alternative treatments, from ketamine to psychedelics to magnetic stimulation.

The stubbornly high, and steadily increasing, rate of suicides in the U.S. is one factor driving the shift. In April, the National Institute of Mental Health (NIMH) awarded eight grants to test new ways to reduce suicidal thoughts and behaviors in a fast-acting manner, including ketamine and using magnets to activate parts of the brain.

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Overall, an unofficial estimate shows the agency’s funding for research involving novel antidepressants roughly doubled from $34.3 million in the 2007 fiscal year to $68.5 million in FY 2020, based on a search of the National Institutes of Health RePORTER database. A search for “transcranial magnetic stimulation” for depression reveals an estimated ninefold increase to $21.4 million over the same period.

Claudia López Lloreda / STAT Source: NIH RePORTER database.

Nolan Williams, a psychiatrist and neurologist at Stanford University, received one of the new grants as well as another from the NIMH to study magnetic stimulation in treatment-resistant depression. He said there is a push in the field to to think beyond the typical view of depression, and consider new treatments. “We’re enhancing [the monoamine] view to have a multilevel understanding of the problem,” he said. “It’s about incorporating it into a deeper, more dynamic understanding [of depression].”

NIMH Director Joshua Gordon told STAT the agency recognizes that new treatments for depression are needed and that it is funding research to explore the underlying biology beyond the monoamine hypothesis. When it comes to understanding depression, “there are fewer and fewer questions of importance with regard to the monoamine systems,” he said. He noted that in addition to federal funding, many startups and small companies are pursuing new treatments for depression.

Currently, almost all patients with depression are first treated with medications called selective serotonin reuptake inhibitors, a class of drugs that includes both Zoloft and Prozac. They increase the amount of the neurotransmitter serotonin in the brain, which controls mood, emotions, and cognition. Serotonin and two other neurotransmitters targeted by some antidepressants, norepinephrine and dopamine, are called monoamines because they contain one chemical group called an amine.

“The entire thinking of the approach to treating depression is pretty much confined in that little box,” said Lisa Harding, a psychiatrist at the Yale School of Medicine.

The monoamine hypothesis came about by serendipity. In the 1960s, doctors found that certain drugs, like iproniazid that was used to treat tuberculosis, had an unintended side effect: They messed with the levels of monoamine neurotransmitters and affected patients’ mood. The explanation for mental health disorders had previously eluded psychiatrists, so they were overjoyed to have a lead to follow.

“The theories arose because of the actions of the drugs,” said Phil Cowen, professor of psychopharmacology at University of Oxford who studies depression. “In retrospect, it’s simplistic, but there wasn’t really much else to go on.”

Claudia López Lloreda / STAT Source: NIH RePORTER database.

Soon, clinicians realized that some observations didn’t mesh with the hypothesis. Antidepressant drugs took weeks to improve the symptoms of depression, suggesting that the drugs may not be working through neurotransmitters exclusively. Then, psychiatrists found that many people, like Attardo, did not respond to monoamine antidepressants. About 1 out of every 3 patients with depression is diagnosed with treatment-resistant depression, meaning at least two antidepressants failed to improve their symptoms.

Even with these contradictions, doctors faithfully stuck by the hypothesis as the central dogma. “The field got stuck in a cul-de-sac of just looking at [the same drugs],” said Cowen.

Then a study done by researchers at Yale University in 2000 found that ketamine rapidly improved depression symptoms in seven patients. Although it was a small study, it opened the door for researchers to explore other potential treatments for depression.

“We’ve now got a completely different option for the treatment-resistant group,” said Susannah Murphy, researcher at the University of Oxford who studies how to improve treatments for depression. The finding emboldened researchers to explore other drug targets and develop different therapies, she added: “It put a lot more confidence back in new treatments.”

Researchers are now exploring those new treatments and, in parallel, are seeking to advance the biological understanding of mental health disorders. In 2019, the FDA approved Spravato, a nasal spray of a version of ketamine called esketamine, for the treatment of adults with treatment-resistant depression. Studies have found that ketamine works through receptors for another neurotransmitter, glutamate, which is also dysregulated in depression. Glutamate and its receptors underlie a process called synaptic plasticity, in which brain connections strengthen or weaken. This supports the idea that changes in synaptic plasticity underlie depression and by targeting glutamate, ketamine could be reversing those changes.

Along with ketamine, other psychedelics, like psilocybin, have emerged as candidates for treatment-resistant depression. A small study published in the New England Journal of Medicine in April showed that psilocybin was as effective as a common antidepressant drug.

The psychedelic market is seen as so potentially lucrative that half a dozen companies in that space have gone public this year. Cybin, which has a psilocybin formulation in a Phase 2 clinical trial for major depression, started selling shares on the New York Stock Exchange last week, and five other psychedelics companies are already listed on the Nasdaq.

Psychedelics like psilocybin mostly activate receptors for serotonin, similar to the typical antidepressants. But studies show that psilocybin also can change levels of glutamate, suggesting it, too, involves synaptic plasticity.

Many clinicians and researchers say the field should move beyond a focus on neurotransmitters and look at activating entire neural circuits in the brain, networks of interconnected neurons that perform specific functions. “There’s not one neurotransmitter, not one neural site where things go wrong, it’s some system-level dysfunction in the brain,” said Cowen. A recent study analyzed patients with depression who underwent deep brain stimulation, in which electrodes are implanted to pass current through specific brain areas, or transcranial magnetic stimulation, which is a noninvasive form of stimulation. By looking at whether patients’ symptoms improved or worsened, researchers identified a brain circuit that includes the dorsolateral prefrontal cortex, an area that controls emotion processing and is impaired in patients with depression, that could be targeted to treat depression.

Understanding and treating depression could even go beyond the brain, as immune molecules such as cytokines that control inflammation could also be considered potential treatment targets. One analysis found that patients with depression had different levels of neuroinflammatory molecules in the blood. Other clues come from observing patients treated with medications that target inflammation for other conditions. Such studies found that patients treated with drugs that suppress immune activity, like those that target the molecule IL-6, had reduced depressive symptoms.

While the paradigms surrounding psychiatry seem to be shifting, new drugs and treatments still have a long road to approval and widespread use. The drug development pipeline has been particularly fruitless for psychiatry, which has a 6.2% likelihood of getting a drug from Phase 1 clinical trials to approval, as compared to infectious diseases treatments that have about 20% likelihood of approval.

Even if new treatments are approved, patients could encounter obstacles in accessing them, especially populations that already have poor access to mental health care due to high rates of poverty and lack of insurance, experts say. Many of the novel therapies are technically challenging to administer and require specialized facilities with trained professional staff. And many psychedelics are still classified as Schedule I drugs, as illegal as street drugs like heroin. Some, like ketamine, can be abused, and the long-term effects of chronic use of psychedelics are not clear, said Gerard Sanacora, psychiatrist and director of the Yale Depression Research Program.

A number of states have moved to relax laws governing use of psychedelics. In November 2020, Oregon became the first state to decriminalize possession and legalize therapeutic use of psilocybin, the active ingredient in magic mushrooms, and California may soon be next. In March of this year, a law decriminalizing magic mushrooms, ayahuasca, and mescaline went into effect in Washington, D.C. Recently, Rep. Alexandria Ocasio-Cortez (D-N.Y.) proposed an amendment to allow research into the therapeutic potential of Schedule I drugs like psilocybin and ecstasy.

The research and law changes are giving many patients a reason for optimism. Attardo is eager to try psilocybin, which data suggest could have a longer-lasting therapeutic effect than ketamine, whose benefits last just a few days for him. Just knowing that his depression can disappear, like when he is taking ketamine or during those first few months on Prozac, gives him hope: “I’m not trapped forever.”

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