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For millions of people every year, depression is not just an illness but a grueling pattern: anguish, medications, failure, repeat.
Supported by a major grant from the nonprofit Wellcome Leap, two Harvard Medical School scientists want to break that pattern, each by his own path.
David Walt, the Hansjörg Wyss Professor of Bioinspired Engineering at HMS and professor of pathology at Brigham and Women’s Hospital, is operating at a microscopic level, observing cell abnormalities that may contribute to depression.
Diego Pizzagalli, HMS professor of psychiatry at McLean Hospital, is taking a bigger-picture approach, using MRIs and other methods to identify potential treatments by tracking activity in key brain regions.
Their common aim is to speed the path from diagnosis to an effective medication for the individual patient.
We’ve wanted to convince ourselves — and the field, hopefully — that personalized treatment is possible in depression.
Diego Pizzagalli
Research shows varying success with subsequent treatments, with as few as 40 percent of patients able to find a drug that works for them by the fourth try.
The mixed results arise in part from an inexact matching process.
“You end up with lots of people who, frankly, need a personalized individualized analysis to figure out the underlying basis of their disease that can be addressed by a particular drug,” said Walt, who is also core faculty at the Wyss Institute for Biologically Inspired Engineering at Harvard University. “It’s just sort of guesswork right now and there is no strong scientific basis for what’s right for each person. It’s, ‘Let’s try this drug and see if it works.’”
The goal of both researchers is to help shape an approach that is more effective for being more precise.
“We’ve wanted to convince ourselves — and the field, hopefully — that personalized treatment is possible in depression,” Pizzagalli said. “The task is on researchers just to show whether [new] types of approaches can actually dramatically improve the response rate.”
Seeking answers in the blood
Walt wants to know whether certain proteins at work in the brain can shed light on how depression develops, allowing scientists to identify potential treatments. He and his team are studying four major cell types, each serving a different function with unique protein molecules.
The four cell types are neurons, which transmit messages among brain regions; oligodendrocytes, which influence cell structure; microglia, which impact immune response; and astrocytes, which are involved in metabolic function.
Walt has zeroed in on extracellular vesicles: pieces of cell membrane that travel out of the brain and into the blood, carrying with them the brain cells’ different proteins.
Using these vesicles to identify biomarkers of depression could allow care providers to administer a drug and then run blood tests a week later to see if the biomarker levels have changed and determine whether the drug is working, Walt said.
“Our goal is to avoid having patients wait six months to see if a drug works,” he said. “If we can, it means we’re making progress toward helping these patients find the right treatment, compress the timeframe, and reduce the risk of suicide.”
Looking for biomarkers in brain imaging
Pizzagalli’s lab is probing behavior and brain function for biomarkers that could be used to assess the severity of a patient’s depression and guide treatment choices.
The work builds on a previous study that deployed neurocognitive tests, EEG, and functional MRI to pinpoint biomarkers that could predict a positive response to widely prescribed drugs: the atypical antidepressant bupropion, whose brand name is Wellbutrin, or the SSRI sertraline, whose brand name is Zoloft. That research led the team to imaging methods that reliably predicted a favorable response.
The working premise now is that an MRI might be able to determine whether an SSRI or other medication is a person’s best avenue of treatment.
“Our hope is that individuals with the bupropion markers will do very well when receiving bupropion, and vice versa for the patients with the sertraline markers,” said Pizzagalli.
The team will also weigh personal attributes (such as age, race, and sex), personality traits, and performance in neuropsychological tests.
Pizzagalli is also exploring the strength of the link between two brain regions flagged in functional MRI studies — the anterior cingulate cortex and the nucleus accumbens, both part of the brain’s so-called reward system — which could further help prescribers decide between an SSRI and a non-SSRI.
“We’re moving from looking at the level of brain activity in a single region to activity across a network,” he said.
Vision for the future
The challenges facing personalized treatment of depression and other brain disorders go beyond the capabilities of any one lab, such as cost and the individual complexity of the illnesses. But showing that personalized treatment is possible would be a turning point for clinicians and patients, Walt and Pizzagalli said.
“It might be a blood test, it might be a blood test combined with imaging, it could be a blood test combined with imaging combined with certain behavioral features,” Walt said. “It could be that all of these tools, or a combination, will be necessary to really do precision diagnostics and be able to identify the right drug for the right person at the right time.”
If you or someone you know is struggling with a mental health issue, the National Institute of Mental Health has resources that can help. In a crisis, use the 988 Suicide and Crisis Lifeline. On campus, help is available through Counseling and Mental Health Services. There is also a 24/7 support line: 617-495-2042.
Adapted from an article in the Harvard Gazette.
