Depression: Researchers Find 6 ‘Biotypes’

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Researchers have found six subtypes of depression using brain scans. Yuliya Taba/Getty Images
  • Using brain scans, scientists recently revealed six subtypes of depression.
  • They show that each subtype responds differently to treatment.
  • The scientists hope their discovery will help personalize psychiatric treatment.

Researchers say that thanks to new imaging they have discovered six “biotypes” of depression.

The new study was published in Nature Medicine and found that brain imaging could be used to better understand treatment-resistant depression and anxiety.

Using functional magnetic resonance imaging (fMRI) they compared activity and connectivity between different brain regions. Using this data, the researchers identified the six “biotypes” of depression.

According to the researchers, understanding an individual’s biotype may help guide treatment and increase the chances of better outcomes.

Healthline spoke with Mirela Loftus, MD, who was not involved in the study. Loftus is a psychiatrist and medical director of Newport Healthcare in Hartford, CT. She described the results of the study as “revolutionary.”

Globally, depression affects an estimated 322 million people — 4.4% of the entire population. Similarly, anxiety disorders affect around 260 million people, which is 3.6% of people.

Despite their prevalence, mental health conditions and the mechanisms that underpin them are still fairly mysterious.

Currently, treatment consists of medication, talking therapies, or both. For some, these can effectively relieve depression. But for many others, they simply do not work. Experts call this treatment-resistant depression.

Healthline spoke with Manish Jha, MD, an associate professor of psychiatry at UT Southwestern Medical Center in Dallas, TX. We asked how common treatment-resistant depression is.

“A study led by researchers at UT Southwestern suggests that as many as 1 in 3 treatment-seeking outpatients may have treatment-resistant depression,” Jha said.

“Given that 1 in 5 adults in the United States may experience major depressive disorder during their lifetime and the past-year prevalence of major depressive disorder in the US may vary between 5–7%, it is likely that several millions of adults in the US experience treatment-resistant depression,” explained Jha, who was not involved in the study.

The authors of the new study set out to identify subtypes, or biotypes of depression and anxiety. By identifying differences in brain connectivity, they hope to personalize treatment plans, getting better results more quickly.

For the study, the authors recruited 801 participants with depression and anxiety who underwent fMRI. The scientists conducted these scans twice: once while the participants were at rest, and once while carrying out cognitive and emotional functioning tests.

The scientists focused on brain regions and circuits, which experts already know are important in depression. These brain circuits were:

  • The default mode (D): A circuit that is activated when the individual is focusing on nothing in particular.
  • Salience (S): This network helps individuals focus on the most important stimuli in their field of view.
  • Attention (A)
  • Negative mood circuit activated by sad stimuli (NS)
  • Negative mood circuit activated by conscious threat stimuli (NTS)
  • Negative mood circuit activated by nonconscious threat stimuli (NTC)
  • Positive mood circuit (P)
  • Cognitive circuit (C )

Using a machine learning technique, they were able to categorize the participants’ brain activity into six distinct biotypes. In the six subtypes below, the subscript C stands for connectivity within the brain region, whereas the subscript A denotes activity. The plus and minus symbols indicate whether the dysfunction in the circuit caused increased or decreased activity.

So, in type 1, the scientists measured increased connectivity within the default mode circuit, salience, and attention circuits. In type 2, there was reduction in connectivity in the attention circuit.

  1. DC+SC+AC+
  2. AC−
  3. NSA+PA+
  4. CA+
  5. NTCC-CA−

According to the authors, subtype DXSXAXNXPXCX “was not differentiated by a substantial circuit dysfunction relative to other biotypes” or healthy participants, so they used an x rather than a + or −.

Next, the scientists focused on a subset of 250 participants. They randomly assigned them either one of three antidepressants or talking therapy. In this way, they could determine how different biotypes responded to treatment.

As theorized, they found that different biotypes responded differently to treatments. For instance, one biotype characterized by high levels of activity between three brain regions linked to problem-solving and depression responded best to talking therapy.

Conversely, another biotype characterized by overactivity in cognitive regions of the brain responded best to venlafaxine, a common antidepressant.

“To our knowledge, this is the first time we’ve been able to demonstrate that depression can be explained by different disruptions to the functioning of the brain. In essence, it’s a demonstration of a personalized medicine approach for mental health based on objective measures of brain function,” explained Leanne Williams, PhD, the study’s senior author.

Williams is the Vincent V.C. Woo Professor in Psychiatry and Behavioral Sciences​ at Stanford University School of Medicine, as well as founding director of the Center for Precision Mental Health and Wellness.

This research comes hot on the heels of a previous study by Williams and colleagues. In the earlier study, they also identified six subtypes of depression and showed that individuals within each subtype responded differently to treatment.

Antidepressants and talking therapies can take weeks or even months before they start to work — even in people who respond well to them. So, for people who do not respond to the first, second, or third treatment, this process can take years.

Williams lost her partner to depression in 2015, so she understands how urgent this issue is.

“The goal of our work is figuring out how we can get it right the first time. It’s very frustrating to be in the field of depression and not have a better alternative to this one-size-fits-all approach,” says Williams.

Loftus told Healthline how these results may influence diagnosis in practice:

“Until recently, if a patient asked me whether they could take a test or get an imaging study to diagnose a mental disorder, my answer would invariably be: ‘We know certain parts of the brain function differently in certain disorders by comparing the averaged results in patients diagnosed with that disorder with the averaged results in healthy controls. But there is no test that you can take to diagnose you specifically.,’” Loftus said.

“With the results shared in this article,” she continued, “my answer will have to change. The authors are not only identifying different biotypes based on six brain circuits of interest, but they also provide each person with their own individualized results. This is revolutionary.”

While these results are promising, depression and anxiety are incredibly complex, and a wide range of factors play a part in treatment resistance. For instance, Jha told Healthline that levels of inflammation may influence an individual’s response to medication, as can obesity.

Also, individuals who have depression with anxiety symptoms are more likely to have “poorer improvement with commonly used antidepressants.”

“Other comorbidities that can complicate treatment include the presence of post-traumatic stress disorder, and alcohol or other substance use disorder,” he told us.

Overall, Loftus is excited by the possibilities this research may lead to. “I hope this study will open the gates to explore not only other biotypes, but also a wider range of treatments.”

She hopes that extending this work will help “provide an individualized, targeted treatment plan to our patients rather than a one-trial-at-a-time approach, which is currently the standard of practice.”

Scientists have identified six “biotypes” of depression and anxiety. Each biotype appears to respond differently to medication and talking therapies.

If the results are confirmed, this approach could mean that people with depression get started on the most effective treatment for them.



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