In response, University of Colorado Anschutz Medical Campus researchers came up with a new framework for understanding how those medications work in treating MDD.
The researcher’s article, published recently in Molecular Psychiatry, pointed out that the nature of the dysfunction at the root of MDD has been under investigation for decades. Because classic antidepressants, such as SSRIs, create an elevation in the levels of the brain chemical messenger, serotonin, the idea took root that antidepressants work because they restore a chemical imbalance, such as a lack of serotonin. Subsequent research showed no significant decrease in serotonin in people with depression, however. That led to a shift in public opinion on the effectiveness of these medications.
“The serotonin deficit hypothesis explanation for major depressive disorder (MDD) has persisted among clinicians and the general public alike despite insufficient supporting evidence,” the study team explained, adding, “To combat rising mental health crises and eroding public trust in science and medicine, researchers and clinicians must be able to communicate to patients and the public an updated framework of MDD: one that is (1) accessible to a general audience, (2) accurately integrates current evidence about the efficacy of conventional serotonergic antidepressants with broader and deeper understandings of pathophysiology and treatment, and (3) capable of accommodating new evidence. In this article, we summarize a framework for the pathophysiology and treatment of MDD that is informed by clinical and preclinical research in psychiatry and neuroscience.”
The authors suggested a discussion about how MDD can be understood as inflexibility in cognitive and emotional brain circuits that involves a persistent negativity bias. Then, patients should be informed that treatments for MDD enhance mechanisms of neuroplasticity—including via serotonergic interventions—to restore synaptic network and behavioral function in ways that facilitate adaptive cognitive and emotional processing.
In addition to SSRIs, treatment might include typical monoaminergic antidepressants, novel antidepressants (e.g., ketamine and psychedelics), and psychotherapy and neuromodulation techniques.
“The best evidence of changes in the brain in people suffering from MDD is that some brain regions are not communicating with each other normally,” noted senior author Scott Thompson, PhD, professor in the Department of Psychiatry at the University of Colorado School of Medicine. “When the parts of the brain responsible for reward, happiness, mood, self-esteem, even problem solving in some cases, are not communicating with each other properly, then they can’t do their jobs properly.
“There is good evidence that antidepressants that increase serotonin, like SSRIs, all work by restoring the strength of the connections between these regions of the brain. So do novel therapeutics such as esketamine and psychedelics. This form of neuroplasticity helps release brain circuits from being ‘stuck’ in a pathological state, ultimately leading to a restoration of healthy brain function.”
The authors said their theory can be described as a car running off the road and getting stuck in a ditch, requiring the help of a tow truck to pull the car out of its stuck state, allowing it to move freely down the road again.
In this metaphor, the driver and the vehicle can be thought of as predisposing factors, such as genetics and a stressful upbringing, that influence the risk of getting stuck in the ditch that is MDD.
The article explained, “Some drivers have a new four-wheel drive car capable of navigating rugged terrain or slick roads, akin to people having a supportive upbringing or genes associated with resilience. Other drivers have an old clunker with threadbare tires that represent vulnerability genes or high exposure to adverse childhood experiences (ACEs). The road is the current experiences of life, such as stress exposure. On a rainy or snowy day, when visibility is poor and the pavement is slick, a car is more likely to run off the road, especially if its tires are worn out. Once stuck in the ditch of MDD, spinning the wheels can get the car even more stuck, like the dysfunctional cognitive and emotional circuits that reinforce MDD. In this sense, the dysfunctional cognitive and emotional circuits that characterize MDD are the ruts on the side of the road…Treatments are the tow trucks that pull the car out of the ditch and the mechanics that get it back on the road.”
In the second metaphor, MDD and its treatments are compared with physical rehabilitation after an injury. As with a broken leg that lacks the full range of motion, the brain with MDD lacks flexibility and the capacity for the full range of emotion. “For the injured leg, regaining function and mobility requires physical therapy, just as the brain in MDD benefits from psychotherapy,” the authors wrote. “In some cases, exercise must be combined with medication to manage pain and inflammation, so that the individual is able to initiate and benefit from the prescribed physical therapy. In the same way, psychotherapy for MDD can be enhanced by pharmacological treatments like typical antidepressants or esketamine. The result is recovery of the brain’s capacity to perceive and interact with the environment in a flexible way that was possible prior to the injury of MDD, ideally combined with the development of new coping strategies, similar to rehabilitated muscles that are even stronger and more flexible than they were before.
The researchers say their goal is that the explanations can increase uptake of and adherence to the drugs.
“We are hoping this framework provides clinicians new ways to communicate the way these treatments work in combating MDD,” added coauthor C. Neill Epperson, MD, Robert Freedman endowed professor and chair of the Department of Psychiatry in the University of Colorado School of Medicine. “Much of the public conversation around the effectiveness of antidepressants, and the role serotonin plays in diagnosis and treatment, has been negative and largely dangerous. While MDD is a heterogenous disorder with no one fits all solution, it is important to emphasize that if a treatment or medication is working for you, then they are lifesaving. Understanding how these medications promote neuroplasticity can help strengthen that message.”
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