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At a growing number of research centers across the country, scientists are scanning brains of patients with depression, drawing their blood, asking about their symptoms, and then scouring that data for patterns. The goal: pinpoint subtypes of depression, then figure out which treatments have the best chance of success for each particular variant of the disease.

The idea of precision medicine for depression is quickly gaining ground — just last month, Stanford announced it is establishing a Center for Precision Mental Health and Wellness. And depression is one of many diseases targeted by All of Us, the National Institute of Health campaign launched this month to collect DNA and other data from 1 million Americans. Doctors have been treating cancer patients this way for years, but the underlying biology of mental illness is not as well understood.


“There’s not currently a way to match people with treatment,” said Dr. Madhukar Trivedi, a depression researcher at the University of Texas Southwestern Medical Center. “That’s why this is a very exciting field to research.”

A precision approach would be welcome news for many patients with depression. There’s a well-documented cycle of trial and error for these patients, who wait weeks for drugs to kick in, only to find out they don’t work. Then they might have to repeat the process, often more than once.

But it’s not an easy task to break down the many factors that contribute to depression into clean categories with clear treatments. While some in the field are excited about the promise of precision medicine to better tailor treatments for depression, others are worried the idea is being overhyped.


“It remains to be shown that depression coalesces into neat subcategories, as opposed to being a fuzzy set,” said Dr. Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard.

Bringing precision medicine to depression would be difficult for the same reason it would be useful — depression is a heterogeneous disease that varies wildly from one patient to the next.

Take someone with a family history of depression, who first experiences symptoms during adolescence and has several instances of depression over her lifetime, and compare her to a 70-year-old man who is in the early stages of Alzheimer’s disease and is experiencing symptoms of depression for the first time.

“The [Diagnostic and Statistical Manual] would give you the same diagnosis, and clearly there’s reason to think those are very, very different,” said Hyman, a former director of the National Institute of Mental Health.

Leanne Williams, the director of Stanford’s new precision mental health center, acknowledged the task will be tricky, but she believes it’s worth trying to bring more order to depression treatment by making a coordinated push to gather as much data as possible. The center — which will be the focus of a dedicated funding drive — will build on $5 million in grants awarded to the researchers involved. Williams hopes to launch a study to follow patients with depression for years, which would cost much more.

The center’s roughly 35 faculty collaborators — including psychiatrists, engineers, geneticists, and data scientists — are using functional and structural MRI scans to analyze how depression disrupts neural circuits in research subjects’ brains. They’re also sequencing patients’ genomes to find common mutations that might play a role, as well as gathering clinical data on their symptoms.

“We want to use that information [to] guide the treatment by subtype,” she said.

Once researchers define depression subtypes, however, there’s still the question of whether — and how — doctors could use data from genetic studies and brain scans to guide treatment. Williams is planning a pilot project involving roughly 75 patients with depression to answer that question. All of the patients will undergo genetic testing, structural and functional MRIs, diagnostic interviews, and other clinical assessments.

For about half of those patients, the psychiatric team will get that information before coming up with a treatment plan. For the other half, their doctors will get the data after 12 weeks of treatment. Ultimately, Williams wants to find tests that physicians can use to guide their depression treatment decisions. But the onus is on researchers to show whether such tests “can shift the needle enough” to make them worthwhile for doctors to use — and insurers to pay for, she said.

Elsewhere, researchers are on the hunt for genetic mutations and biomarkers in the blood that could be used to diagnose depression — and guide treatment. In his lab at UT Southwestern, Trivedi has his eye on several potential depression biomarkers, including C-reactive protein, which is a marker of inflammation.

In a study published last year, Trivedi and his colleagues randomly assigned 100 patients with depression to receive one of two depression treatments. Patients with lower CRP levels had a higher remission rate on one treatment, while patients with higher CRP levels had a higher remission rate on the other.

But while the finding is intriguing, it’s just a small study. And that, experts say, is part of the problem.

Hyman, for his part, is skeptical — not of the idea of precision medicine for depression, but of the quality of the data.

“My skepticism is not that it’s a bad project, but we better not get ahead of ourselves and overhype,” he said. “I just think people are just a bit ahead of what the data will permit.”

He pointed to several concerns. With fMRI scans, for example, it’s difficult to tease out what might be caused by depression, what might be a cause of depression, what might be due to prior treatment attempts, and what’s just noise. It’s also challenging to collect brain scans from enough patients to have a well-designed study that includes enough patients to make the findings translatable to the general population.

And stratifying patients based on genetic mutations is messy. Depression is highly polygenic, meaning there are likely thousands of genetic variations in different combinations that can contribute to the condition. And depression can’t be explained solely by genetics: Environmental factors, particularly during development, also seem to play a role.

“It’s some grab bag of these thousands of [genetic] variants, plus bad luck as the brain develops, plus lived environments,” Hyman said.

Williams said she hopes to set up a large-scale study to create the kind of data set needed to better understand the factors at play in depression. She sees the Framingham Heart Study — a long-term study that began in 1948 and has followed patients for decades, as a way to identify risk factors for heart disease — as a model for depression research.

“We’ll start with what we can and keep building on it,” she said.

Trivedi, the UT researcher, said he’s well aware that there’s relatively little research on biomarkers that could be used to guide depression treatments — but he and colleagues say each study inches the field toward answers.

“Right now, we are throwing everything at the wall and seeing what sticks,” he said. “Precision medicine is deciding what to throw at the wall so the chances of sticking are better.”

  • Interesting article — I’d like to share that the Veterans Affairs R&D group is on top of the depression and personalized medicine question with several studies, the most forward-thinking one being PRIME run out of the Philadelphia VA group targeting 2000 subjects and assessing patient and physician preferences vs drug effectiveness using pharmacogenomics. I’d just like to suggest that while there are a slew of other well positioned groups to take on challenges like this, we hardly ever hear anything pertaining to the large scale studies out of the VA — it might be useful to take a look at the progress of one of the largest healthcare organizations that the US has, and note them as well. Otherwise, nice article.

  • re: ” Precision medicine…..” article by Megan Thielking.
    ECT (electroconvulsive therapy) is the most effective treatment for severe depression. Read about it in “Shock” by Kitty Dukakis or contact Dr. Stephen Seiner or Charles Welch of the ECT and TMS program at McLean Hospital. ECT has been a life saver for me and for many who attend the monthly Dukakis’s support group for depression and ECT. Also, go to – ECT: A Light in the Darkness for more information.

  • There are fundamentally incorrect assumptions that go with the idea that the organ brain has to be somehow “treated” and “corrected” with medicines when there are mental issues. Numerous studies have repeatedly shown that our brains are constantly changing AS A RESULT OF our mental experiences. For example, psychological stresses (e.g. prolonged worry as a result of losing a job) can bring about structural changes in the brain and these changes are reversible when these stresses are addressed (e.g. getting a job again). Lots of research shows that these changes in the brain happen through neuroplastic and epigenetic mechanisms.

    Regarding this, Dr. Mario Beauregard says that the mind (the psychological world, the first-person perspective) and the brain (which is part of the ‘‘physical’’ world, the third-person perspective) represent two epistemologically and ontologically distinct domains that can interact because they are complementary aspects of the same underlying reality. Metaphorically, he refers to the language of the mind as “mentalese” and the language of the brain as “neuronese”- Here’s the reference to that article:

    Beauregard, M. (2007). Mind does really matter: Evidence from neuroimaging studies of emotional self-regulation, psychotherapy, and placebo effect. Progress in neurobiology, 81(4), 218-236.

    It is also interesting to note how Buddhist philosophical teachings describe the “mind” (consciousness) in terms of constantly changing sense impressions and mental phenomena (this is the full language of “mentalese”). How various factors including past conditioning as well as various attachments we hold influence the moment-by-moment manifestation of mind-stream can also be systematically understood. The following article gives a comprehensive account of all this:

    Karunamuni, N., and Weerasekera, R. (2017). Theoretical Foundations to Guide Mindfulness Meditation: A Path to Wisdom. Current Psychology.

  • I read an article yesterday (can’t remember where) about a test called GeneSight which is actually on the market (and, remarkably, covered by Medicare). It is a DNA test which tries to suggest which available antidepressant drugs are more likely to work for a given patient. In the article some docs felt the test was really helpful, others were less enthused. The company marketing the drug gave a presentation on it at a conference on Monday, and a Google search will turn up a number of articles published on the test over the last couple of days.

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