Illustration: Chris Kindred

'Side Effects May Include': The Search for an Antidepressant That Works

It's hard to find the right medication for depression when doctors still don't understand the science behind it.

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Jun 14 2017, 4:00pm

Illustration: Chris Kindred

TV commercials for prescription drugs follow a familiar pattern. After extolling the lifesaving virtues of the particular drug, the commercial rattles off a laundry list of potential side effects. Often, these side effects ironically sound worse than the ailment the drug is designed to treat.

Antidepressants are particularly prone to this phenomenon.

Nausea. Diarrhea. Constipation. Headaches. Difficulty sleeping. Weight loss. Weight gain. Suicidal thoughts. Worsening depression. Even the inability to orgasm. There are dozens of different kinds of antidepressants on the market, each with a slightly different impact and list of possible side effects.

Different drugs vary in dosage and no single antidepressant is effective for everyone, meaning many people with mental illness spend months or years trying drug after drug and getting no relief (but plenty of unpleasant side effects). For nearly 40 percent of people, according to one meta-analysis, none of the drugs work at all.

"I need these drugs to live, but they're pretty shitty," said Emily McCombs, a writer and editor who has written candidly about her experience with depression. "My experience with antidepressants has been that there's always a trade-off. You can be happy, but you have to be happy and gain weight, or happy but you can't have orgasms, or happy and have a tremor. There's always some kind of weird side effect."

These medications do provide relief for millions of people, and have undoubtedly saved lives—McCombs told me when she is on a medication that works, the difference is night and day. But they're far from perfect, and considering that nearly 20 percent of all US adults have some form of mental illness, you'd think we'd have a better treatment option by now. Why is it so hard to make an antidepressant that doesn't suck?

"I need these drugs to live, but they're pretty shitty"

"Understanding mental health and how it relates to our environment, our genes, and our brain, is probably the most complex health problem we have," said Dr. Leanne Williams, a professor of psychiatry and behavioral neuroscience at Stanford University. "Up until now, we haven't had the tools to deal with that complexity."

When you take a look at the history of antidepressants, it's not all that surprising that our options for treating depression fall short. Our first antidepressants were discovered completely by accident, and weren't even designed to treat mental illness.

In 1952, while testing out iproniazid, a tuberculosis treatment, researchers began to notice patients getting some unexpected side effects: they were happier. Patients were gleeful, joyful even, despite suffering from a painful and sometimes deadly disease.

"[Patients were] dancing in the halls, though there were holes in their lungs," one study author noted at the time.

Gradually, doctors began to realize that this tuberculosis treatment might be useful for mental illnesses, even though they didn't really understand what caused depression and anxiety. Though iproniazid continued to be marketed as a tuberculosis treatment, doctors began using it to treat depression, too.

Iproniazid is a monoamine oxidase inhibitor, or MAOI, which means it disrupts an enzyme in the brain called monoamine oxidase. This enzyme is kind of like your brain's janitor, going through, sweeping up excess neurotransmitters like serotonin and dopamine. But on MAOIs, this process is disrupted, amounting to higher levels of serotonin and dopamine in the brain. Because this drug worked for depression, doctors figured the illness must have something to do with chemicals in the brain.

"The idea was: antidepressants treat depression, therefore depression is caused by some kind of abnormality that antidepressants treat," said Eva Redei, a professor and researcher in psychiatry at Northwestern University. "But that's kind of circular logic."

MAOIs paved the way for selective serotonin reuptake inhibitors, or SSRIs, which were developed in the 70s and 80s and are now the most commonly prescribed antidepressants in America. Prozac, Zoloft, and Lexapro are all SSRIs, which work by limiting the reabsorption of serotonin to increase the amount of that mood-affecting hormone in the brain.

The common explanation for all of this, popularized by iconic commercials, is that depression and anxiety disorders are caused by a "chemical imbalance in the brain." But the truth is, we don't know if that's always true.

There's still some debate in the field as to whether a chemical imbalance has any role, and if antidepressants can ever work. An oft-cited meta-analysis of clinical trials published in 2008 showed that, except in extreme cases, antidepressants are no more effective than a placebo.

"I think it's unlikely we will find that there's an underlying chemical cause for depression and anxiety; we've been trying to find one for 50 years," said Dr. Joanna Moncrieff, a psychiatrist and researcher at University College London, who is critical of antidepressants. "I don't think there's nothing we can do, but we need a completely different approach."

Other meta-analyses have found contradictory results, showing that antidepressants can be effective, though not always. The fact that we don't know for sure is frustrating for doctors and patients alike.

In fact, depression and anxiety are catch-all terms for many different experiences. The spectrum of mental illness experience can depend on brain chemicals, perhaps, but also genetics, stress hormones, life experience, and possibly even our microbiome—the unique community of bacteria that live in and on the human body. Redei said there could really be as many as 200 variations of depression.

It's sort of like how we use cancer to describe many different diseases. Leukemia isn't the same as breast cancer, but they're still both cancer. Only, with depression and anxiety, we don't really have any more nuanced terms, and we use a one-size-fits-all treatment strategy.

Depression and anxiety are catch-all terms for many different experiences

Therapy also plays a role in treating mental illness, and there are lot of different options that have different impacts, such as cognitive behavioral therapy. But not everyone has access to therapy, and many Americans simply describe their symptoms to a general practitioner and end up going home with a prescription for an antidepressant. As much as 80 percent of antidepressant prescriptions are written by GPs. It's our standard protocol.

This variety of experiences is part of the reason we have so many different antidepressants, and why there's no single option that works for everyone.

"Even though antidepressants are often described as being the same thing, like SSRIs for example, each one is doing something a little different and affect different systems of the brain to different degrees," Williams said. "That might be a small difference—like 3 or 4 percent difference—but that can have an enormous impact on an individual."

If we ever want to find better treatment options and streamline the search for a good fit, we need to better understand how the kinds of depression differ, and how medication impacts them. Luckily, we're slowly beginning to do this.

A study published in December 2016 in Nature Medicine used fMRI scans to identify different areas of the brain that were linked with different symptoms of depression. These different neural circuits directly correlated with four subcategories of depression reported by the 1,000 people in the study, when charted along two axes: how anxious the person was, and how anhedonic they were (anhedonia is the inability to feel pleasure):

Anxiety related connectivity chart. Image: Nature Medicine

It was one of the first glimpses we've had at possible biological subcategories of depression, and the first step toward a more personalized approach to treatment. In fact the researchers found that people with one subtype of depression were three times as likely as those in the other subtypes to respond to transcranial magnetic stimulation, or TMS. TMS is a non-invasive treatment that uses magnetic pulses to stimulate the areas of the brain associated with mood, and has shown success for patients with depression who haven't been able to get relief from other treatment.

The better we can understand the different kinds of depression and anxiety, and what parts of the brain they impact, the better we'll be able to match a patient with the right treatment. Those treatments could vary from a particular SSRI, therapy, TMS, or emerging treatments such as psychedelic drugs and medical cannabis.

"The most important predictor of what is going to benefit someone is this combination of brain systems, genes, and symptoms together—integrating that information," said Williams.

We may be on the cusp of a mental health revolution

Williams is currently researching what she calls "neuroscience-informed precision mental health," that takes all of this information and uses it to predict which treatment option is best for an individual patient. In one trial, Williams and her team were able to predict with 80 percent accuracy whether an antidepressant would be effective based on brain scans and personal history.

At this point it's still a highly specialized field, but Williams said we may be on the cusp of a mental health revolution, allowing each patient to get precise, personalized care that works, and doesn't suck. It's something McCombs said would be a huge improvement over the current system, and would allow a lot more people to stop suffering.

"It's a lot of steps that you have to take in order to feel better and it's easy to forget, when you're depressed, that you can feel better," McCombs said. "When I'm on an antidepressant that's working, I go from being depressed to feeling like myself again. It feels like a window opening on a spring day. It's like coming back into my body. It's a return to who I am, and it feels amazing."

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