A New Subtype of Depression Has Been Identified, And It Could Affect 27% of Patients

Scientists at Stanford University have identified a new subtype of depression that could affect as many as a quarter of all patients with major depressive disorder (MDD). The findings help explain why the most popular drug treatments for depression are not always effective.

The new subtype is unique from other proposed subtypes because it is marked by cognitive deficits in attention, memory, and self-control. These symptoms are often not alleviated by antidepressants that target serotonin, such as Lexapro (escitalopram) or Zoloft (sertraline).

The researchers are referring to the newly identified subtype as the ‘cognitive subtype’. In a randomized clinical trial involving over 700 adults, Stanford researchers – with a colleague from the University of Sydney in Australia – found that 27 per cent of MDD patients performed worse on cognitive tasks. They also had a worse response to standard drug treatments.

If that percentage applies to the US population, then about 5.7 million patients could have this version of depression. Given the size of that potential cohort, behavioural scientist Laura Hack and her colleagues argue that more targeted depression treatments are urgently needed.

“For a substantial minority of depressed patients, it is necessary to improve cognition to improve overall depressed mood and function,” they write.

According to the authors, this is the first “clinically actionable cognitive biotype of depression” that has been found, and their findings suggest a loss in brain power isn’t always a consequence of depression. It could also be a driver of it.

In 2014, a previous study at Stanford involving some of the same researchers found that a quarter of depressed patients showed significant impairments on cognitive tests, even after receiving antidepressant treatment. In 2020, researchers followed up with a brain imaging study that found changes in a patient’s cognitive control circuit can help predict their response to antidepressant treatments.

Now, researchers have attempted to explore this novel subtype even further. Before the trial, participants were surveyed and clinically assessed on their state of depression. They also undertook tests for verbal memory, working memory, decision speed, and sustained attention.

Eight weeks after starting treatment with a selective serotonin reuptake inhibitor (SSRI) – like Lexapro, Zoloft, or Effexor (venlafaxine-XR) – the same surveys and assessments were conducted again.

Of all 712 participants with MDD who completed the clinical trial, only 96 had their brains imaged in further tests. During functional magnetic resonance imaging, these patients undertook a cognitive task designed to measure attention and impulsiveness. The task essentially involves patients quickly hitting a button when they see a green ‘Go’ on a screen and another button when they see a red ‘No Go’ on the screen.

During the task, MDD patients with slower information processing, worse sleep problems, and poorer response inhibition tended to show reduced activation in their prefrontal cortex and cerebral cortex.

This indicates “a distinct neural mechanistic process underlying this biotype,” the authors argue, as these parts of the brain are highly involved in executive functions like planning, meeting goals, and sustained attention.

What’s more, machine learning algorithms found that the extent of a patient’s cognitive impairment was linked to the extent of their depression symptoms and their improvement after treatment.

Following a prescription of an SSRI, patients who fell into this cognitive subtype showed lower rates of remission compared to those with different forms of depression.

Sertraline, which can be sold under the name Zoloft, was the least helpful medication of the lot, with a remission rate of 35.9 per cent in the cognitive biotype compared to 50 per cent for other biotypes.

“This study is crucial because psychiatrists have few measurement tools for depression to help make treatment decisions,” explains Hack.

“It’s mostly making observations and self-report measures. Imaging while performing cognitive tasks is rather novel in depression treatment studies.” But imaging for this type of depression in a clinical setting is only really useful if we know how to treat it.

Today, depression is split into just over a dozen subtypes, and yet researchers keep finding more and more. Nevertheless, treatments remain largely uniform and often ineffective. To date, only one FDA-approved antidepressant, called vortioxetine, has been linked to improved cognition, and no one is really sure how or why it works.

The team notes that although they ruled out certain disorders and factors that could impact cognitive impairment, there may be other behavioural or neurobiological factors that contribute to this cognitive biotype, and we should be cautious about generalizing their findings.

Hack hopes to conduct further research to determine if the approach applies to other antidepressants and treatment methods. “I regularly witness the suffering, the loss of hope and the increase in suicidality that occurs when people are going through our trial-and-error process,” says Hack. “And it’s because we start with medications that have the same mechanism of action for everyone with depression, even though depression is quite heterogeneous. I think this study could help change that.”


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