Of the nearly 1 in 5 people in the United States suffering from depression, many aren’t properly diagnosed and end up receiving treatment in a trial-and-error manner, which can be costly, ineffective, frustrating, and, in some cases, damaging. Now, research scientists at Stanford aim to change that by identifying unique biomarkers for each type of depression to match them with targeted treatment.
Their findings, recently published in a Nature Medicine study, show the results of machine learning and brain imaging in hundreds of patients while doing specific tasks and at rest—helping the team identify six distinct subtypes of depression.
“Psychiatry, unlike other medical fields, currently relies on self-reported symptoms and does not use biological tests to diagnose and treat patients,” says Leanne Williams, lead author of the study and a professor of psychiatry and behavioral sciences at Stanford University’s School of Medicine. “Because of this, there is a need for tests that provide precise diagnoses that are based on the biological underpinnings of the symptoms to enable personalized treatments.”
While the Stanford study has limitations and is likely still years away from its findings being able to be applied to directly care for patients in a widespread manner, mental health professionals praise the research for helping psychiatrists and psychologists get closer to being able to use brain scans to identify and treat depression in similar fashion to how cardiologists use chest x-rays to identify and treat heart problems.
“Though these results do not have any current clinical application, they are an important step toward trying to find measurable biological markers that can assist with making an accurate diagnosis and tailoring treatment,” says Robert Bright, a noted psychiatrist and chair for the Mayo Clinic Arizona Department of Psychiatry and Psychology, who was not involved in the research.
The six types of depression
The study addresses a growing concern among mental health professionals regarding the nearly 30 percent of people diagnosed with depression whose symptoms don’t improve even after receiving multiple medical interventions.
“Despite all our advancements in other fields of medicine, we still aren’t very good at matching patients (with depression) to the treatment that will work for them, causing some people to spend years cycling through multiple treatments before finding one that’s effective,” says Srijan Sen, a neuroscientist and director at the Eisenberg Family Depression Center at the University of Michigan.
To help, the Stanford researchers used functional magnetic resonance imaging (fMRI) technology to study the regions of the brain most commonly associated with depression such as the amygdala, hypothalamus, hippocampus, and prefrontal cortex, and, more importantly, the connections—called circuits—between those brain structures.
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Determining a patient’s depression subtype—also known as a biotype—is important, explains Williams, because each one represents a different way a major brain connection can malfunction or become disrupted, leading to the unwanted symptoms and behaviors we associate with depression.
Bright says the broken brain connections examined in the study are known to affect a person’s attention span, working memory, cognitive flexibility, planning, decision-making, rumination, motivation, and hormones associated with positive and negative emotions.
The researchers measured these disrupted functions as they relate to depression by scanning the brains of 801 study participants who had already been diagnosed with depression or anxiety, then studying their brain activity while at rest and while they engaged in different tasks designed to stimulate cognitive function or emotional responses to various situations—dual explorations that haven’t been studied this way before.
“By quantifying brain function at rest and during specific tasks, we have shown that depression consists of six specific patterns of dysfunctions in six major brain circuits,” says Williams.
These six circuits and corresponding disruptors (depression biotypes) are named and defined as follows:
1) The default mode circuit is active when an individual is engaged in internal mental processes such as mind-wandering and introspection. “When this circuit is disrupted, these internal mental processes are also affected,” says Williams.
2) The salience circuit helps us focus on important emotional stimuli both inside and outside ourselves. “When this circuit is disrupted, it can lead to physical symptoms of anxiety and an overwhelming sensory experience,” she explains.
3) The positive affect circuit, also known as the reward circuit, is crucial for experiencing pleasure, rewards, social enjoyment, motivation, and a sense of purpose. “Disruptions in this circuit are associated with emotional numbness and increased effort to experience enjoyment,” says Williams.
4) The negative affect circuit is critical for processing and responding to negative emotional stimuli such as threats and sadness. “When disrupted, reactions to negative emotions can become more intensive and prolonged,” she explains.
5) The attention circuit—also known as the frontoparietal or central executive network—is involved in sustaining attention and concentration. “When disrupted, attentional processes are affected and one’s ability to focus is diminished,” says Williams.
6) The cognitive control circuit underpins executive functions such as working memory and planning, along with controlling thoughts and actions. “When disrupted, it can make decision-making difficult and planning ahead challenging,” she explains.
Why different biotypes need specific treatment
When mental health doctors can correctly identify one of these six depression biotypes responsible for disrupting healthy brain function, they’ll be able to recommend tailored treatment, explains Aron Tendler, a board-certified psychiatrist and chief medical officer of BrainsWay in Burlington, Massachusetts, who wasn’t involved in the study but calls its findings “extremely exciting.”
He also praises the researchers for further measuring how a few of the most common treatments for depression worked—or didn’t work—on each biotype.
They did this by randomly assigning 250 of the study’s participants to receive either psychotherapy or one of three of the most prescribed antidepressants: escitalopram (Lexapro), venlafaxine (Efexor), and sertraline (Zoloft).
Williams says their findings show multiple examples of patients with one biotype responding well to one antidepressant over another as well as patients with a different biotype experiencing improvements through talk therapy where they hadn’t responded as well to medication.
Such findings build on previously published research from the Stanford team that focused on just one biotype related to the cognitive control circuit, in which the researchers were able to use fMRI technology to predict the improved likelihood of remission in depression patients who received targeted treatment over patients whose brains weren’t scanned and instead received only general care.
In both studies and subsequent research, the researchers have demonstrated how worthwhile fMRI technology can be in helping doctors match depression patients with the most effective treatment—reducing or eliminating the trial-and-error mental healthcare that has been the status quo.
The study’s—and industry’s—limitations
While Paul Appelbaum, a psychiatrist and distinguished professor at Columbia University, calls the Nature Medicine study “promising,” he says it needs to be replicated by other researchers and across more diverse populations, as most of that study’s participants were white.
Many other established depression treatments also need to be included in future research because the Stanford team only looked at three antidepressants and a limited number of psychotherapies.
There’s also a potentially significant barrier associated with access to the fMRI equipment needed to identify a patient’s correct biotype in the first place because these machines are only available in a small number of major medical centers—making access both limited and expensive.
Because of this, “medical doctors, including psychiatrists, rarely prescribe fMRI scans for their patients, and insurance companies would be highly unlikely to pay for these expensive brain scans until a great deal more research demonstrates that the scans can reliably predict which treatment an individual diagnosed with depression would most benefit from,” says Judith Beck, a clinical professor of psychology at the University of Pennsylvania and the president of the Beck Institute for Cognitive Behavior Therapy.
But if the study’s findings are consistent across additional research and if it can be shown to insurance companies and drugmakers that specific treatments are indeed effective at repairing each disrupted connection, “we could reach a watershed moment in the field,” says Jonathan Rottenberg, a professor of psychology at Cornell University, who was not involved in the Stanford research. “This work has potential to make treatment for depression more efficient and effective.”
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