Depression is a leading cause of disability in the United States. It affects hundreds of millions of people worldwide, according to the National Institute of Mental Health. Little is understood, however, about the biology behind the disease.
Conor Liston, Feil Family Brain and Mind Research Institute/Psychiatry, Weill Cornell Medicine, works at the interface between neuroscience and psychiatry—a position that allows him to unravel the underlying mechanisms that cause such psychiatric disease states.
“This is an exciting time for neuroscience and translational psychiatry,” says Liston. “The fields are being transformed by the development of new technologies. We have the ability to ask questions that seemed like science fiction not so long ago.”
Liston first became interested in psychiatry while attending the Tri-Institutional MD-PhD program, a partnership of Weill Cornell Medicine, The Rockefeller University, and Memorial Sloan Kettering Cancer Institute. He continues to work as a clinical psychiatrist, alongside running his research lab. He says that both have an impact on the other and that many of the questions he asks in his research have been informed by interactions with his patients.
“The work I do in the lab allows me to interact with patients and communicate in a way that can clearly convey the biological basis for what they're suffering.”
“The work I do in the lab allows me to interact with patients and communicate in a way that can clearly convey the biological basis for what they're suffering,” says Liston, who received his doctorate from Rockefeller in 2007 and his medical degree from Weill Cornell Medicine a year later. “For a lot of people, it's really helpful to hear and understand. Depression is not just a reaction to unpleasant, stressful stimuli. There's something going on in the brain.”
Depression, Getting the Right Diagnosis
Liston’s research is concerned with figuring out what exactly is going on inside the brain during depression. Traditionally, psychiatrists have diagnosed mental disorders in patients by adding up a number of symptoms—based on a version of the Diagnostic and Statistical Manual of Mental Disorders (DSM) first developed in the 1970s. While this diagnostic system has been the foundation to psychiatry for years and has been of great benefit to patients and their doctors, Liston says that it, too, has become a hindrance to scientific progress in the field.
For example, patients with varying symptoms receive the same catchall diagnosis. With depression, many symptoms contain opposites. “It stands to reason that someone who comes to me in my office describing four hours of sleep, anxiety, and weight loss does not have the same biological problem as someone who is describing the opposite symptoms of 20 hours sleep and weight gain,” says Liston. “These two people are opposites in so many ways and yet they get the same diagnostic label and treatments. It's fortuitous and surprising that our existing treatments work as well as they do.”
The Brain’s Hubs
In a recent project published in Nature Medicine, Liston aimed to discover and diagnose subtypes of depression, based not on clinical symptom but on biology. To do this, he and his collaborators collected a large dataset of fMRI brain scans from more than 1,100 people, both with clinical depression and healthy controls.
Liston likens the brain to our country’s airport network system. If one major hub, (JFK or LAX, for example) has delays, it has larger effects throughout the rest of the network. “The brain, we think, is organized in a similar way—into hubs,” says Liston. “There is a lot of evidence that one of the root problems in depression and other psychiatric conditions is caused by dysfunctional connection between hubs, that wiring between brain regions is altered.” Using statistical modeling tools, Liston and his lab measured the activity states of different brain regions and inferred how they were connected.
What the lab found were four distinct subtypes of depression, with distinctly different patterns of altered brain connectivity. Liston then asked if these neurobiological subtypes predict particular combinations of clinical symptoms? The answer was yes. For example, one subtype had elevated anxiety and low levels of anhedonia (the inability to feel pleasure). Another subtype had low levels of anxiety and high levels of anhedonia.
Liston says the most important aspect to the work will be coming up with better treatment approaches. “For the most part we don't have a good means of predicting whether a patient is going to respond until after a month or two of a treatment,” says Liston. “It would be great to have a tool like a brain scan before the person started the treatment, that stated, this medication or this antidepressant is 89 percent likely to work or not work. We would rather know that than waste two months and have to try something different.”
Treating Different Types of Depressions
Already, Liston’s lab has found that of the four subtypes of depression discovered, one is highly responsive to transcranial magnetic stimulation (TMS)—a non-invasive treatment that uses magnetic fields to create electrical impulses in the brain. Two of the subtypes did not respond, and another had intermediate response levels. This type of information could help psychiatrists determine how to proceed in treating different types of depression.
Liston says that these diagnostics are still in the early days of development. The next steps would be to replicate the results and show that brain scans are effective in improving response rates to treatment. Finally, the researchers will need to run clinical trials. “If all goes well we might know in about four to five years whether this is something we can rely on and disseminate to the general public,” he says.
Temporal Aspects of Depression and Drug Strategies
Not only are there different subtypes of depression, but the disease too has a temporal aspect that is not well understood. Some people experience depression for short periods of time, and others can be depressed for years. In a new study published April 11, 2019 in Science, Liston and his lab looked at the neurobiological mechanisms underlying the induction and remission of depressive episodes.
For this project, the researchers relied on mouse models and optogenetic tools. “What we set out to do was follow, track, and quantify the remodeling of synapses in the living brain, using advanced imaging methods in mice,” says Liston. The researchers tracked these synapses in real-time, watching how they were affected by stress and antidepressants.
Going into the study, Liston knew that antidepressants increased synapse connections. The connection between depression and synapse loss and formation, however, was unclear. The question the researchers wanted to answer was this: Are the two causally involved or merely correlated?
Working with Haruo Kasai and Haruhiko Bito—collaborators at the University of Tokyo who developed optogenetic tools for deleting new synapses—Liston’s work was able to show that new synapses are required for sustaining antidepressant behavioral effects and maintaining remission over time. Interestingly, however, the synapses were not necessary to induce behavioral changes initially.
Liston’s team tested the effects of a newly FDA-approved antidepressant drug, ketamine, on mice models. They found that changes in behavior and brain circuit function preceded synapse formation. The researchers also found that, without new synapse connections, the behavioral effects from ketamine could not be maintained.
“It tells us that these new synapses are important but not necessarily in the way we thought they were,” says Liston. “Interventions, either new drugs or medications or brain stimulation like TMS, might be useful for sustaining and augmenting the antidepressant effects of ketamine.”
The findings provide another layer to understanding the complex neurological mechanisms of depression. Working directly with patients, Liston says, “There's a real need that I'm actively reminded of for a greater understanding of the biology and hopefully new and effective treatment approaches.”