Advances In Understanding Depression Offer Potential New Treatments



Illustrations by Jean Wei

While more than one in ten Americans takes antidepressants, some scientists believe popular depression treatments don’t fully address the root causes of depression.

When drugs like Prozac were first introduced in the late 1980s, the leading theory behind their market success was that depressed people lacked serotonin, a key brain chemical. The idea, dubbed the “chemical imbalance theory,” was that you could give patients an SSRI or a serotonin reuptake inhibitor (like Prozac or Zoloft) and their serotonin would spike and relieve their depression.

The problem is that when researchers started testing this theory, they found that it didn’t hold up. Serotonin is implicated in depression — and for many depressed patients, SSRIs are incredibly helpful — but how the drug works is more complicated than it first seemed. But public understanding of how antidepressants work has not kept pace with science.

In September 2022, Ira spoke to Dr. David Hellerstein, Professor of Clinical Psychiatry at Columbia University, and Dr. David Oslin, Professor of Psychiatry at the University of Pennsylvania Perelman School of Medicine. Hellerstein and Oslin explained what we know and don’t know about how antidepressants affect the brain and the latest pharmaceutical treatments for depression.

“The treatments that we use, to the extent that they are effective, affect … brain health. But it will be a while before that happens,” Hellerstein said.

While SSRIs work for many patients, scientists now know that serotonin deficiency is not the only factor affecting clinical depression. Hellerstein points out that antidepressants increase serotonin levels in the brain very quickly, but it can take up to several weeks for a patient’s mood to improve. If depression is solely caused by a lack of serotonin, why don’t SSRIs heal patients immediately?

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“Something happens in the brain that is a delayed process and is clearly a lot more complicated than just ‘filling the tank’. [with serotonin]’ Hellerstein said. Researchers have moved away from this serotonin deficiency model to explain the causes of depression. A chronic stress model has taken its place as another explanation for the underlying causes of depression.

“Some people are at higher risk for depression, anxiety or PTSD. [because] Chronic stress causes changes in the brain that are very difficult to reverse except with some type of treatment,” Hellerstein said.

Chronic stress and pain are known to decrease healthy brain properties, Hellerstein said. The number of connections between brain cells and even the size of the brain decrease when they are constantly exposed to stress and anxiety.

“The brain is basically injured in a state of depression or anxiety,” he said.

Research suggests that depression is caused by a combination of biological and environmental factors, and drugs that chemically treat depression are not the only evidence-based treatment options available. Other types of therapies, including cognitive behavioral therapy, have also been shown to help patients.

However, finding the right drug for every patient can be difficult. Because each drug has different effects on an individual patient and their unique symptoms, doctors sometimes have to use trial and error when prescribing.

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Recent advances toward more accurate mental health care could open up new avenues to help patients find the right treatment faster.

dr David Oslin, a professor of psychiatry at the University of Pennsylvania, recently conducted a Veterans Administration investigation to see if genetic testing could help doctors choose the right drugs for patients. He and his colleagues specifically looked for genes that influence metabolism.

“If I have a genetic test that suggests a drug is poorly or rapidly metabolized,” Oslin said, “it might actually result in a better outcome for that patient if I swap it out or just take it away.”

He is confident that the field is moving towards personalized mental health care.

“I think a lot of people think of mental health as that black box where you just sit down and lie on the couch and talk things out. But we really have a lot of different evidence-based approaches to treating different diseases,” Oslin said.

In addition to being able to prescribe medication, doctors are increasingly looking for alternative methods of treatment. Psilocybin Mushrooms and ketamine, for example, cause immediate changes in brain activity that show promise for mental health researchers. A significant number of patients with treatment-resistant depression using psilocybin mushrooms in clinical settings experienced improvements in their condition for weeksaccording to dr Hellerstein’s research.

These types of fast-acting treatments, Hellerstein explained, can help reconnect the brain in new ways. “There is evidence that these drugs increase plasticity, or the adult brain’s ability to reconnect and regrow,” he said.

This new treatment option offers an opportunity to get out of stressful mental routines that may be essential for some patients.

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“One of the things that seems to happen to a lot of people with depression is some kind of record breaking [effect]. You get a groove thrown into a record that plays the same few notes over and over again,” Hellerstein said.[Newer compounds like psilocybin] can get people out of these record cycles.”

Hellerstein and Oslin are pleased to have moved beyond the serotonin deficiency model of depression and may be able to offer patients better informed and more effective options. Clearly, serotonin isn’t the end of the story, Hellerstein said.

“We’re looking at a complicated system, but one that could have potential locations to have an effect that could start quickly — and have significant repercussions,” Hellerstein said.


Would you like to hear more? Click here to listen to the full SciFri radio interviews this article is based on with Dr. David Hellerstein and Dr. David Oslin based.


Further reading

The following resources are available if you, or someone close to you, need mental health support:


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Meet the writer

Emma Lee Gometz

About Emma Lee Gometz

Emma Lee Gometz is Science Friday’s Digital Producer of Engagement. she is a writer and illustrator who loves to draw primates and caring about their coping mechanisms like יהוה to the Garden of Eden.





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