How do you fight depression? Faster. —Harvard Gazette

For millions of people each year, depression is not just an illness but a grueling pattern—anxiety, medication, failure, repetition.

Supported by a large grant, two Harvard scientists want to break this pattern, each in their own way.

David Walt works at a microscopic level, observing cellular abnormalities that can contribute to depression. Diego Pizzagalli takes a more comprehensive approach, using MRIs and other methods to identify potential treatments by tracking activity in key brain regions. Their shared goal, supported by the nonprofit organization Wellcome Leap, is to accelerate the journey from diagnosis to an effective medicine for the individual patient.

“We fear that this trial-and-error approach will make people lose hope,” Pizzagalli said. “We are really interested in evaluating whether we can get to the right treatment more quickly by using neuroscience tools.”

More than 22 million adults in the United States experience at least one major depressive episode each year. The experience is lonely, debilitating and dangerous. When anxiety, insomnia and other symptoms occur, patients lose contact with family and friends, depriving them of one of the greatest sources of happiness and well-being – relationships – and increasing their risk of suicide. The damage also spreads to broader society, including U.S. jobs, resulting in an economic burden of more than $330 billion per year.

Studies show that the success of subsequent treatments varies. Only 40 percent of patients find a medication that works for them on the fourth try.

Talk therapy can help, and new technologies, including neurostimulation, have shown promise. But one of the most common treatments for depression — antidepressants such as selective serotonin reuptake inhibitors, or SSRIs, often prescribed by a primary care doctor — has produced mixed results, due in part to a wildly imprecise matching process.

“There are a lot of people who frankly need a personalized, individualized analysis to find the underlying cause of their disease that can be treated by a particular medication,” Walt said. “Right now it's just kind of a guess and there's no solid scientific basis for what's right for each person. It's like, 'Let's try this drug and see if it works.'”

The goal of both researchers is to help shape a more effective and precise approach. “We wanted to convince ourselves – and hopefully the world – that personalized treatment for depression is possible,” said Pizzagalli. “Persistent symptoms can be very debilitating and failed antidepressant treatments are associated with costs to individuals and society as well as loss of productivity.”

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Written in blood

Walt, professor of pathology and Hansjörg Wyss Professor of Bioinspired Engineering at Harvard Medical School, wants to know whether certain proteins that work in the brain can shed light on how depression occurs and allow scientists to identify possible treatments . He and his team are studying four major cell types, Each performs a different function with unique protein molecules.

“We hypothesize that the proteins we detect and measure from these four different cells will be different in people suffering from major depression than in healthy people,” Walt said.

One target is neurons that transmit messages between brain regions. Changes in neurotransmitters such as serotonin can lead to depression. (SSRIs work by increasing serotonin levels in the brain.) The other areas of focus are oligodendrocytes, microglia, and astrocytes, which influence cellular structure, immune response, and metabolic function, respectively.

Any abnormality in these cells can weaken connections in the brain and make a person more susceptible to mood disorders. Previous research has shown that antidepressants can help our brains repair damaged cells and create new connections between them.

If researchers can determine which cell types are affected in patients with depression, they should ultimately be able to determine the underlying mechanism responsible for these changes, Walt said. If it is a neurotransmission problem, specialists may focus on finding medications, including SSRIs, that best target the growth and regulation of neurons. If the problem is related to immune cells, researchers can try to identify drugs that affect the immune system.

Walt focused on extracellular vesicles – pieces of cells that travel from the brain into our blood.

By comparing blood – which contains less than 1 percent material from the brain – with spinal fluid, he and his team were able to identify specific markers in these different cell types, allowing them to isolate extracellular vesicles in the blood.

The goal he has in mind would be life-changing.

“If you could identify the right markers in the blood, you could give someone a drug and then have them come back the next week, take their blood and measure biomarkers to see if the drug is working,” he said.

“You may say, 'This won't work because your markers are exactly where they were last week before you started taking the drug.' “We need to switch you to a new medication immediately.” Our goal is to avoid patients having to wait six months to see if a medication works. If we can do this, it means we are making progress in helping these patients find the right treatment, shortening the time frame and reducing the risk of suicide.”

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Waiting for a breakthrough

Pizzagalli, a professor of psychiatry at the School of Medicine and director of the Center for Depression, Anxiety and Stress Research at McLean Hospital, has spent his career studying psychological, environmental and neurobiological factors associated with mood disorders, including major depression.

For the Wellcome Leap project, his lab is studying behavior and brain function for markers 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 used neurocognitive testing, EEG and functional MRI to identify biomarkers that could predict a positive response to commonly prescribed medications: the atypical antidepressant bupropion, whose brand name is Wellbutrin, or the SSRI Sertaline, whose brand name is Zoloft. This research led the team to imaging techniques that could reliably predict a positive response in both cases. The working premise now is that an MRI may be able to determine whether an SSRI or another medication is the best treatment option.

“We hope that individuals with bupropion markers do very well when given bupropion, and vice versa for patients with sertraline markers,” said Pizzagalli, whose team will also weigh personal characteristics (age, race, gender, etc.). , personality traits and performance on neuropsychological tests.

Functional MRI is performed on the patient at rest. Researchers track which brain regions are activated.

“Brain regions are activated in everything we do. Thoughts, emotions, motivation and so on,” Pizzagalli said, adding: “It's not the case that each individual brain region is activated in isolation and doesn't communicate with the other brain regions. Information is basically passed from region to region.”

The two regions his team is most interested in are part of the brain's so-called reward system. The nucleus accumbens lies very deep in the brain and is known for its role in pleasure and motivation. The rostral anterior cingulate cortex is located in the frontal lobe and is an important hub for cognition and emotion.

Pizzagalli examines the strength of the connection between the two regions, which could help a prescriber decide between an SSRI and a non-SSRI.

“What we're doing is moving from looking at the level of brain activity in a single region to activity in a network,” he said.

Both Walt and Pizzagalli noted that personalized treatment of depression and other brain disorders is challenging for reasons well beyond the capabilities of a single laboratory. A major obstacle is cost, as well as the deep individual complexity of the disease. But making it clear that such personalized treatment is possible and desirable would be a major game-changer, both for doctors and their patients.

“The task for researchers is simply to show whether these types of approaches can actually dramatically improve response rates,” Pizzagalli said.

The path to an answer is still at a very early stage, as he and Walt quickly realized. Pizzagalli's laboratory expects to complete work on its project in mid-to-late 2025. The first phase of Walt's initiative is scheduled to be completed this month, but the larger plan will span years.

Ultimately, researchers hope to have made great strides in freeing up time for patients and families suffering from the sometimes crushing burden of depression.

“It could be a blood test, it could be a blood test combined with imaging, it could be a blood test combined with imaging combined with certain behavioral characteristics,” Walt said. “It may be that all of these tools or a combination are needed to really do precision diagnostics and 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 can help resources that can help. In a crisis, use this 988 Lifeline for Suicide and Crisis. Help is available on campus Counseling and mental health services. There is also a 24/7 support line: 617-495-2042.