The problem is these drugs only work for about half of people

Illustration: Simone Noronha

If you or someone you know need help, consider calling the National Suicide Prevention Lifeline at 1–800–273-TALK (8255) for English, 1–888–628–9454 for Spanish.

“Some people say ketamine makes them feel like a marshmallow.”

That’s how the ketamine clinic’s therapist explained it to me through my computer screen during our initial meeting. I’d already asked several people what ketamine would feel like, and each time I got a slightly different answer. But the overall consensus was that I’d feel floaty, that I might see things, and that I might feel relaxed or unnerved. My greatest fear was having a panic attack during the experience. “We can always give you something for that,” the therapist assured me.

My recent path to ketamine treatment was at least 20 years in the making. I could no longer remember what it felt like not to be depressed, and not reflexively jump to the worst possible outcome of any scenario. I could not remember what it felt like to want to exist. The isolation and tragedy of the pandemic — saying goodbye to my unconscious grandmother over a screen, living through my own Covid-19 infection after taking every possible precaution, being thrust back into the role of full-time caregiver to a toddler and kindergartener while my career shriveled — all clamped down around me, and I feared I’d leave my girls without a mother. I decided I needed to find a new treatment.

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Celexa, Lexapro, Elavil, and Cymbalta are just a few medications I’ve unsuccessfully tried in the past to quell the harpies inside my brain. As I grew older, my depression spawned anxiety and panic attacks. Becoming a mother maxed out the volume on all of it. And yet psychiatrists continued to write out prescriptions for the same types of pills. “These don’t work,” I’d protest. “We have to keep trying different ones,” they’d respond.

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Nearly all antidepressants work in line with what’s called the monoamine hypothesis of depression, which emerged in the 1950s. The hypothesis asserts that depression is caused by low levels of chemical messengers in the brain called monoamine neurotransmitters, which include serotonin, dopamine, and noradrenaline. The idea is simple: Increase levels of these neurotransmitters in the brain and reverse depression.

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The drugs prescribed to do that fall into several categories, including the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and the older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). They all affect one or more of the monoamine neurotransmitters. These drugs cause monoamines to remain in the synaptic cleft — the space between neurons — for longer, and their success at treating depression is thought to be related to a variety of effects such as the birth of new neurons in a part of the brain called the hippocampus (an area responsible for learning, memory, and emotion) and the increased production of proteins such as brain-derived neurotrophic factor (BDNF), which is known to build neural connections. These processes take time and may account for the lag typically associated with antidepressants. It can take anywhere from weeks to months to alleviate depression symptoms.

The problem is these drugs only work for about half of people.

A 2019 review published in the journal Neuron argues that by narrowly focusing on these neurotransmitters and their role in depression for the past several decades, scientists missed opportunities to identify other neurobiological causes of depression and, therefore, potential new treatments. The authors say “there had long been clues” that changes in the brain, beyond the monoamine neurotransmitters, were relevant to depression. For example, increased BDNF can be caused by signaling outside of the monoamine pathways. In fact, while antidepressants can increase this growth factor, it is likely more of a subtle change, as opposed to the large shift required to alleviate depression (which can be achieved by other treatments such as electroconvulsive therapy).

It’s no surprise then that typical antidepressants fail for many people. One of the most widely cited and largest studies on the effectiveness of common antidepressants, the STAR*D trial, showed that more than half of people treated with several different antidepressants still had persistent symptoms. “And a big proportion of them relapsed; clearly those antidepressant medications weren’t working as well as we thought they were,” says Robert McClure, MD, a psychiatrist and associate professor in the department of psychiatry at the University of North Carolina School of Medicine.

When these drugs were approved by the U.S. Food and Drug Administration (FDA) they were based on data showing efficacy, he says. “But when these studies were repeated and done in a more scientific way and not in the context of, you know, a pharmaceutical company having an agenda to try and get the treatment FDA approved, we discovered that these treatments are not as effective as we thought they were.”

Beyond the monoamine hypothesis

Depression treatments beyond the conventional drugs that target monoamine neurotransmitters include ketamine and psychedelics. Ketamine is not technically a psychedelic but an anesthetic, although it can cause hallucinatory and dissociative effects. There may also be overlap in the way they affect the brain, according to Carlene MacMillan, MD, psychiatrist and CEO and co-founder of Brooklyn Minds.

Drugs like ketamine can rapidly trigger neuroplasticity, the recreation and strengthening of connections between neurons, and the way the brain rewires itself. And they suppress the brain’s default mode network (DMN), areas thought to be associated with introspection and mind-wandering. When this nexus is quieted, “the more pre-conscious, emotional, and primitive parts of the brain can take center stage during the experience,” says MacMillan. “It is in this space that we see new connections and shifts in perspective occurring.”

An alternative way of thinking about psychedelics is described in the book How to Change Your Mind by Michael Pollan. Here, the brain is compared to a snowy hill covered in sled tracks. In this analogy, the sleds are thoughts. Over time, certain sled paths become well-worn, making it difficult to take any other route. These deep grooves signify the most traveled neural pathways, which happen to pass through the DMN. Psychedelics act like a fresh coat of snow, erasing the previous grooves. This allows for travel (or thoughts) in new directions and the creation of new pathways.

The fresh coat of snow metaphor was also used by my clinic’s therapist in describing the effects of ketamine; the drug allows for new neural connections and different ways of thinking in the brain. “Try not to approach it with fear, but curiosity,” she explained.

A game-changer

Ketamine is not a new drug. Developed in the 1960s, it rapidly became prevalent during the Vietnam war as an anesthetic. “You could administer ketamine during surgery and people would be completely unaware of what’s going on. And that’s done basically by shutting down the cerebral cortex,” explains McClure.

But it wasn’t until several decades later that scientists wondered if the drug might also be an effective antidepressant. Unlike the drugs that target monoamines, ketamine works through a different type of neurotransmitter called glutamate. The specific proteins on neurons that recognize and are affected by glutamate include the N-Methyl-d-aspartate (NMDA) receptor. Agents like ketamine that blunt the activity of this NMDA receptor seemed to improve rodents’ stress responses. Then researchers at Yale University found that ketamine quelled major depression symptoms in people. In 2006, ketamine was discovered to do the same for those with treatment-resistant depression, people who had already (and unsuccessfully) tried over six antidepressants. It was also effective at silencing suicidal ideation.

“This was a huge game-changer,” says McClure. “There had been no new pharmacological agents for depression in many, many years.”

Ketamine worked faster, too. “Anyone who has taken an oral antidepressant, like a serotonergic agent, knows that it’s going to take six weeks before it starts working,” says McClure. “Whereas if you use ketamine people can experience improvement in 24–48 hours.”

But because ketamine isn’t new and, therefore, patentable and monetizable, pharmaceutical companies scrambled to develop other drugs that mimicked ketamine’s blockade of the NMDA receptor. In 2019, the nasal spray esketamine, or Spravato, was approved by the FDA.

“Ketamine provided us an unprecedented opportunity to study the brain rapidly switching from severe depression to improved mood within hours.”

“Response rates vary but are generally between 50 and 80% for people receiving ketamine [intravenous] infusions,” says MacMillan. Compared to traditional antidepressants, Spravato also works better. “A general range of response rate for esketamine after a month of intranasal treatments is 53–69%.”

McClure points out there have been no large head-to-head comparison trials so it’s difficult to say if one works better. Intravenous dosing is easier to tailor to the patient, although the nasal spray is more likely to be covered by insurance companies as intravenous ketamine is still considered “experimental.”

Not a cure, but a tool

Some experts view ketamine as a tool to unravel the biological causes of depression and, perhaps someday, cure it. “Ketamine provided us an unprecedented opportunity to study the brain rapidly switching from severe depression to improved mood within hours,” says Chadi Abdallah, MD, associate professor of psychiatry and chair in the neuropsychiatry of military post-traumatic stress syndrome in the department of psychiatry and behavioral sciences at Baylor College of Medicine.

Exactly what ketamine does to the brain is still under investigation. But most scientists agree that it has to do with glutamate, the most abundant neurotransmitter in the brain, and the strengthening of connections between neurons in areas implicated in depression. MacMillan likes to think of ketamine as fertilizing a garden. “Ketamine very quickly increases the activity of the neurotransmitter glutamate in the frontal part of the brain that is underactive in depression. This leads to new connections forming between neurons in that area and causing old ones to regrow.”

Synaptic loss caused by depression may disrupt certain brain networks that ketamine can restore, at least temporarily.

At Vanderbilt University, Lisa Monteggia, PhD, professor of pharmacology and director of the Vanderbilt Brain Institute, and her lab are meticulously mapping out what happens when ketamine binds to the NMDA receptor and blocks its activity. According to Monteggia, these receptors are positioned to dramatically affect signaling between neurons because they lie right at the synapse where communication takes place. “That’s why you trigger these antidepressant effects, you’re at the right place to impact rapid neurotransmission changes.”

Her lab found that when ketamine dampens activity at these receptors, a flurry of events occurs, including a new, unconventional type of signaling, or plasticity, at the synapse through a different glutamate receptor called AMPA; this effect is called potentiation. “This potentiation is the antidepressant effect.”

But ketamine is not a cure. Rather, it’s a window. “We’re revealing it, not fixing it,” explains Monteggia of the antidepressant effect. Unfortunately, the antidepressant effects of ketamine on the brain are temporary. The new connections are short-lived with symptoms returning in around 10–14 days.

“We’re using ketamine, if you will, sort of like a rosetta stone to understand what is a rapid antidepressant effect,” says Monteggia, who stresses that depression is multifaceted and involves multiple genes, environmental factors, and brain circuits going awry. “It’s difficult to believe ketamine can come in and fix all these different circuits, but it may be able to sort of mask it because you just triggered this potentiation.”

Figuring out how to maintain these new synaptic connections is the challenge.

Clues may come from other areas of depression research. “It is thought that abnormally high inflammation in depression is causing the brain connection loss in the first place and subsequently the removal of ketamine-induced connections,” says Abdallah. He and his colleagues recently published a study that found that giving rapamycin, an anti-inflammatory drug, to people prior to intravenous ketamine, prolonged the antidepressant effects; at two weeks, remission rates were higher in the pre-treatment group.

Rapamycin may have protected new connections by reducing inflammation, but it does other things too that could potentially explain the findings. For example, it can increase autophagy, “the process through which cells remove toxic materials and dead elements in tissues,” says Abdallah. In other words, it helps to clear the neurons of any junk, which may also help to preserve new synapses.

It’s still too soon to tell whether this strategy or other efforts may preserve ketamine’s effects. McClure thinks inflammation and microbiome research may yield insight into depression and treatment. At UNC, he says they’re interested in biological markers or biomarkers, which are measurable features of a patient, such as particular protein levels, to explore other possible ways ketamine works. If reliable biomarkers can be teased out, they could offer insight into who is more likely to respond to particular treatments, like ketamine. “I think psychiatrists would really like to have predictors, either clinical characteristics or biomarkers, that we can use to predict who’s going to respond to which treatment.”

Most ketamine studies examine what happens after one infusion, but clinical protocols call for biweekly infusions for at least a month followed by maintenance ketamine treatments spaced farther apart. After the initiation series, the time between these booster treatments will largely be determined by the patient’s responsiveness. McClure says that a few studies found that continued ketamine treatment is necessary for continued remission. “This is not surprising since we know maintenance antidepressant treatment is necessary in patients with recurrent major depressive disorder in order to prevent relapse,” he says.

Ketamine has certainly offered me new experiences. I’ve been in the womb or a singular point in space; I’ve seen swirling mandalas, felt time collapse, become the ocean, felt the boundaries of my body dissolve.

But neurobiology is only part of the puzzle. People with depression may benefit from psychotherapy either alongside or following ketamine treatment. Therapy with an experienced provider can help people make sense of the experience and apply newly gained insights to their lives; it is also recommended following psychedelic treatments. “Having therapy shortly after can take advantage of this window [of increased neuroplasticity] to spark changes in perspective,” says MacMillan. While lessening of depression symptoms is the hope for many, McClure cautions that change, even the good kind, can be stressful.

What’s next?

Like other drugs, ketamine will work wonders for some people and do nothing for others (about 30% will not respond). And some people, like me, will fall somewhere in between. After eight sessions, I cannot say I’m no longer depressed, although I think the treatments would work better without the extreme stress and rigidity of a pandemic. But both my husband and therapist say they’ve noticed improvements, even if I remain somewhat skeptical.

Ketamine has certainly offered me new experiences. I’ve been in the womb or a singular point in space; I’ve seen swirling mandalas, felt time collapse, become the ocean, felt the boundaries of my body dissolve. I felt a connection to something beyond myself. I felt ecstasy that consumed me and a chasm of grief so deep and wide it frightened me. Throughout it all, there was the feeling I was on the precipice of a revelation.

But ketamine isn’t the end of the line. Scientists like Monteggia are busy mapping out the molecular pathway and synaptic effects of many treatments including psychedelics, transcranial magnetic stimulation therapy, and electroconvulsive therapy. Both MacMillan and McClure say that these treatments are also effective for many, but it’s crucial you find the right provider.

For Monteggia, synaptic potentiation is the critical element. The more drugs or treatments scientists can find to evoke it, the more potential options for treatments. When ketamine doesn’t work for people Monteggia says, “Perhaps they have some sort of synaptic abnormality through this pathway. Perhaps they may respond to another type of drug that triggers this potentiation” via a separate route. “There are so many different reasons they may not respond and so we have to appreciate that complexity. If we can think about treatment advances for those individuals that would be a real benefit.”

I don’t know if my brain will rewire or if the new synapses will degrade over time. I do know that I will never forget my many ketamine incarnations. In the book The Noonday Demon, Andrew Solomon, PhD, professor of clinical psychology at Columbia University Medical Center, writes, “You don’t think in depression that you’ve put on a grey veil and are seeing the world through the haze of a bad mood. You think that the veil has been taken away, the veil of happiness, and that now you’re seeing truly.”

I’d offer up that if depression makes you think you see everything the way it truly is, ketamine shows you, even if just for a little while, everything that could be.

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