Understanding the Biology Behind Major Depressive Disorder

Major depressive disorder (MDD) affects about 7% of people in the United States each year. Although researchers and clinicians know that stressful life events can trigger a depressive episode, the biological mechanisms behind it are not well understood. Studies led by Diego A. Pizzagalli, PhD, director of the Center for Depression, Anxiety and Stress Research (CDASR) at McLean Hospital, aim to reveal how depression changes the brain, enabling clinicians to identify people who are prone to the disorder and predict the possibility of recurrent episodes. “If we are able to predict the first onset of depression, we will hopefully one day be able to prevent it,” said Pizzagalli.

MDD is caused by a complex interaction of personality traits, genetic predisposition, and life history, including adverse childhood experiences such as neglect or abuse and stressful events often coupled with feelings of entrapment. “Depression is multifactorial,” said Pizzagalli. “That’s the model that we embrace within the CDASR. We don’t just study biology or psychology. We also study the environment, genetics, the brain, behavior, and stress. We assess all of these variables because we believe they are all important in understanding depression.”

Pizzagalli, who also directs the McLean Imaging Center, uses a variety of imaging techniques to map and describe the brains of people with MDD as well as people who might develop the disorder down the line. To understand why MDD occurs, he believes it is also important to understand why it re-occurs—a distinctive feature of the disorder. When people experience their first major depressive episode, it is usually after a traumatic or stressful life event. But the more relapses a person has, the more likely he or she is to experience an episode without a traditional trigger.

“With every episode, psychologically or biologically, something changes that then leaves people vulnerable to future episodes,” said Pizzagalli. “People become sensitized.” The process, he said, could be described as a scar susceptible to re-injury. “We want to know: can we predict an initial episode? can we predict a relapse? why do later episodes become more uncoupled from stress?”

To answer some of those questions, Pizzagalli teamed up with Roee Admon, PhD, a research fellow at the CDASR.

In one study, Pizzagalli and Admon tested the ways past depression influenced future happiness. They had two groups of people—some who had experienced depression, and some who had not—complete a humor comprehension task, which had been modified to provide an abundant amount of positive feedback. They found that when they were told they had answered the question correctly, people who had been depressed were just as happy as those who never had been. But crucially, the people who had experienced depression stayed happy for a shorter period of time relative to those without a prior history of depression.

While the study was conducted, the participants’ brain activity was monitored using functional magnetic resonance imaging (fMRI). The same subjects who were happy for a shorter time also showed less activation in the nucleus accumbens, a part of the brain associated with the pleasure response, happiness, and motivation. Ultimately, Pizzagalli wants to see if activity in the nucleus accumbens may predict the likelihood of a relapse.

Another part of the brain associated with reward that his lab focuses on is the putamen. In particular, he investigates the putamen’s role in personality traits related to depression such as anhedonia, the loss of interest in previously enjoyable activities. “Some people, for some reason, are more anhedonic than others, meaning they tend to be less responsive to the good things that happen in their lives,” said Pizzagalli. “Research shows that anhedonia can be a precursor to depression and also predict poorer outcomes in treatment.”

Currently, Pizzagalli is working on a long-term study that plans to track 186 adolescents—half with family histories of MDD and half without—over time to see who develops depression, using imaging technology to monitor chemical and biological changes in the brain. In addition to using fMRI, Pizzagalli and his colleagues are using proton magnetic resonance spectroscopy, which allows them to study neurochemicals in the brain. So far, they have found that reduced putamen size predicts anhedonia three months into the future.

None of this is definitive, Pizzagalli noted. There is still a lot of research to be done. He and his colleagues plan to follow the adolescents to identify how stress relates to structural and neurochemical changes in the brain, including disruptions in dopamine signaling, a neurotransmitter involved in reward pathways, and how these changes might predict anhedonic symptoms. In 2016, Pizzagalli received a Method to Extend Research in Time (MERIT) award from the National Institute of Mental Health to continue this long-range research.

“We want to know: can we predict an initial episode? can we predict a relapse? why do later episodes become more uncoupled from stress?”– Diego A. Pizzagalli, PhD

It is Pizzagalli’s hope that his work will not just help predict who might have depression but will also advance development of personalized treatments. It is known that some antidepressants work for certain people, while different ones might work better for others. It is possible that this might result from underlying neurological differences. For example, in some of his past research, Pizzagalli found a relationship between the number of depressive episodes a person had and the volume of the hippocampus and medial prefrontal cortex, both of which are involved in how a person responds to stress. It is unclear if the reduced size causes the depression, or vice-versa, but it is possible that antidepressants, which increase the size of these brain regions, might help. Past research—not conducted by Pizzagalli—has found that successful treatment with antidepressants is associated with an increase in hippocampal volume. Pizzagalli thinks that one day it might be possible to look at the neurological changes underlying a person’s depression and prescribe a personalized treatment.

“Currently, there’s no way to unambiguously predict whether people will respond to treatment,” he said. But with neurological maps of the mechanisms driving depression, like the ones Pizzagalli is developing, that could change.

“In other fields of medicine, such as cancer treatments, you use an array of variables and information to guide treatment selection,” said Pizzagalli. “If we can develop a psychological and biological profile of people with MDD, we could recommend specific treatment regimens for them.”