The ‘Untreatables’: When Modern Psychiatry Can’t Help

Courtney Walker was first diagnosed with depression more than a decade ago, when she was 12 years old. It started off situational, she thinks — she was reeling from the death of a close family member — but at that point her illness was under control. “I was in therapy and I was on antidepressants, and the symptoms went away,” she recalls. Her depression returned a couple of times over the next decade, but each time she was able to treat her symptoms with therapy. “But nothing compares to how it is now,” she said.

In the past few years, her diagnoses have piled up — general anxiety, mixed-state bipolar — and so have the medications. Right now Courtney is on about 10 medications, and she has no idea how many she’s taken since she was first diagnosed. But despite this, her instability persists. One day she’ll be on a spending spree; the next day she’ll be unable to get out of bed. During one particularly scary incident, she didn’t sleep for two full days. As a result, Courtney has spent more and more time in the hospital. She’s put on suicide watch, then doctors tweak her meds to stabilize her. And that will work for a month or so, then she’s out-of-whack again. Luckily, in spite of all this, Courtney has had enough flexibility to keep her job as a patient care technician at a hospital in Connecticut, and to stay enrolled in community college.

Courtney is one of about 21 million Americans who have a mood disorder — depression, anxiety, or bipolar disorder. Somewhere between 15 and 50 percent of these patients have a treatment-resistant form of the disorder — many can’t hold down jobs, some end up on the street or in jail, and others commit suicide.

Mental health professionals define a treatment-resistant mood disorder as one that isn’t under control after patients have tried two types of medication each taken for its full course of 12 weeks.

Many of these patients who struggle and sometimes never successfully find relief have been dubbed “untreatable.” In recent years, researchers have dedicated a lot of resources towards finding just what makes treatment-resistant patients different from those that respond well to treatment. The answer, they’ve found, lies beyond the current reaches of psychiatry and biology. Slowly, experts are realizing that medicine need to reorient how it treats mental illness in order to help patients in this group to get their lives back.

“As our science gets better, we get better at studying our treatments, and we’re discovering things about their limitations,” Eric Plakun, the associate medical director and director of biopsychosocial advocacy at the Austen Riggs Center in Stockbridge, Massachusetts, told Vocativ.

Often, a patient will receive their first mental health diagnosis from a general physician who isn’t specifically trained in psychiatry, said Mark Rasenick, a neuroscience professor at the University of Illinois. If the treatment this physician prescribes doesn’t work, a patient will typically see a psychiatrist and receive at least a few more rounds of drugs — and, often, a slightly different diagnosis. Patients who find themselves still unable to function with their conditions can seek more extreme treatments, or enter an inpatient facility like Austin Riggs, where Plakun works.

Treatment-resistant disorders are surprisingly common — a study conducted over seven years by the National Institutes of Health and published in 2006 found that about half of depression patients didn’t respond to treatment after two attempts. And for those who tried another round of treatment after two, only one in four will get better. That means, of all depression patients who were diagnosed correctly (meaning they weren’t later diagnosed and effectively treated for a different condition), about 30 percent of people won’t find relief, Rasenick said.

The number of people diagnosed with mood disorders like depression is increasing, and so, too, are the number of people who aren’t responding to treatment. Between medical costs, suicide costs, and issues with employment, these mental illnesses cost the U.S. hundreds of billions of dollars per year (depression alone accounted for $210 billion in 2010).

On an individual level, the costs are even higher. The suicide rate in the U.S. rose by 7 percent between 2010 and 2014. With 13 deaths per 100,000 people, the rate is at a 30-year high, according to a federal study published in April.

There are still consequences for people who never go to that extreme. “The indirect cost is the inability to live your life,” Rasenick said. “Even for people who don’t find resolution and are able to work, a lot of them suffer from presenteeism,” — they can show up to work, he explains, but they can’t really perform their jobs. “That’s very painful,” he says.

Finding a way to help people with these treatment-resistant disorders is an enormous — maybe the greatest — unmet need in psychology said Michael Thase, a professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania. But first scientists need to figure out what makes them different in the first place.

Not so different after all

People with treatment-resistant mood disorders have a few things in common. Many of them have another disorder in addition to depression, anxiety, or bipolar disorder. “One of the things we’re discovering is that most of our patients with treatment-resistant disorders also have on average five other disorders,” Plakun said. That makes it harder to find a treatment that can address all of those, especially if clinicians are limited to drugs that don’t interact negatively with one another. Many, too, experienced trauma or abuse early in life and are coping with post-traumatic stress disorder. Others have borderline or other personality disorders as well.

But that’s about where their similarities end. Despite years of research, no one has been able to find a biomarker, no physiological (or genetic, or chemical) sign that shows why these patients are different than those who respond well to treatment. “In fact there’s nothing particularly different about people with depression on a genetic level,” Plakun said. “When we decoded the human genome, we thought we would find genes for common disorders like depression, but we’re just not finding them.”

Some experts think it’s an issue of diagnosis. Between 1980 and 2000, the clinical definition for these disorders has shifted or loosened to include more people (and more symptoms) than it did in the past, Thase said. More recently, psychologists have quibbled over the parameters through which disorders are diagnosed — in 2013, the director of the National Institute of Mental Health rejected the DSM-5, the recently updated handbook that provides the criteria for diagnosable mental illness in the U.S. Instead, the director kicked off the organization’s Research Domain Criteria, a project in which researchers will continue to look for physiological signs of psychiatric disorders.

Doctors, too, might be hurting patients’ chances of finding a usable treatment. About 80 percent of prescriptions for antidepressants are written by primary care doctors, often without a specific diagnosis — these doctors tend to not listen very carefully and simply write a prescription if someone says they’ve been feeling down, Rasenick says. And though patients don’t usually have negative reactions to those drugs, studies have shown that these drugs are more likely to work on the first try because they have the placebo effect working in their favor — “[Patients] are better off if you get it right the first time,” Rasenick adds.

But Rasenick suspects there’s something else going on, something else that happens in a patient’s brain when a drug doesn’t work to relieve her symptoms. “I’m wondering if there’s a problem with the continued failure that sets you up for failure,” Rasenick said — kind of like an anti-placebo effect. “There’s nothing unique about the people [with treatment-resistant disorders], but as the treatments kept failing, something was altered in such a way that no treatment was going to work.” So far, this is just a hunch — Rasenick has no way to prove this yet, he said, but he thinks there may someday be a way.

Treatments

For patients who have several drugs and still not found relief, doctors will continue to prescribe new cocktails of drugs that might work for a brief period. There are a few last-ditch treatments, such as electroconvulsive therapy (ECT) or magnetic transcranial stimulation. But patients are, understandably, reluctant to undertake these treatments that tend to have higher risks — Courtney, for example, has never seriously considered ECT because her dad has warned her so strongly against it: “He knows someone who did it and it totally screwed him up,” she says. 

To find new treatments, researchers need to discover just how these conditions work in the brain in order to find new pathways through which to combat them. There are a few exciting leads, such as ketamine, a former party drug showing promising results in treating depression. But the pipeline is running dry, Rasenick said, in part because “pharmaceutical companies have picked all the low-hanging fruit.”

Thase anticipates that the next breakthrough discoveries in drugs will only be for a small subset of patients, somewhere around two to four percent, he said. “If there were larger populations [we could treat with a single drug], we would see certain patterns of homogeneity. But we’re not seeing them stand out, so they must be smaller than 10 percent,” Thase said.

But since it’s often their experiences, not physiology, that makes these patients different, some experts expect that old-fashioned talk therapy will be the best way forward for them. “If we want to understand how to treat patients with depression and other treatment-resistent disorders, we have to look beyond medication algorithms,” Plakun said. “Treatment involves relationships. It’s more than tweaking someone’s receptors.”

Until researchers find a major difference between people with treatment-resistant mood disorders and those for whom treatment does work, all clinicians can do is their best to find relief for those patients. “There are conditions that we don’t know how to treat with high confidence, so we keep working and do the things we know can be helpful,” Thase said. “When you tell patient they’re untreatable, they just pack it in. I try not to do that. I simply say there are some people for whom we have no reliable treatments yet.”

Courtney is still holding out hope for a treatment that would stabilize her and allow her to function normally. She works part time and is also enrolled in a local community college, and next semester she has to take chemistry, and she knows she can’t miss class as much as she has been when she’s been hospitalized. She’s optimistic that, sometime soon, her brain will stop changing and she can find a treatment that that is effective and lasts.

If patients like Courtney are willing to keep working, so are their doctors. “I hope they don’t give up on my efforts to try to help them, because I’m not going to give up on them,” Thase said. “We’ll work together until we find something that helps.”