Is it time to reevaluate your antidepressant prescription? Current research suggests that a considerable proportion of people, over 27% or more than one in four, might be consuming the wrong antidepressant.

A study conducted by scientists at Stanford Medicine has identified a novel form of depression known as the cognitive biotype. This particular subtype accounts for 27% of individuals with depression and does not respond well to commonly prescribed antidepressant medications.

The study revealed that patients with the cognitive biotype experience difficulties in various cognitive functions such as planning ahead, exercising self-control, maintaining focus despite distractions, and inhibiting inappropriate behavior. Imaging techniques also showed reduced activity in specific brain regions responsible for these tasks.

Traditionally, depression has been classified as a mood disorder, leading doctors to prescribe antidepressants that primarily target serotonin, such as selective serotonin reuptake inhibitors (SSRIs). However, these medications have proven to be less effective in treating patients with cognitive dysfunction. The researchers suggested that alternative antidepressants or other treatments focusing on these cognitive dysfunctions could potentially alleviate symptoms and aid in restoring social and occupational functioning.

The findings of this study, published in JAMA Network Open, contribute to the ongoing efforts of neuroscientists to develop treatments tailored to specific depression biotypes.

Dr. Leanne Williams, the senior author of the study and the Vincent V.C. Woo Professor of Psychiatry and Behavioral Sciences, emphasized “One of the big challenges is to find a new way to address what is currently a trial-and-error process so that more people can get better sooner. Bringing in these objective cognitive measures like imaging will make sure we’re not using the same treatment on every patient.”

New Depression Biotype

In the study, a total of 1,008 adults diagnosed with major depressive disorder, who had not previously received medication, were enrolled. They were randomly assigned one of three commonly prescribed antidepressants: escitalopram (brand name Lexapro) or sertraline (Zoloft), both acting on serotonin, or venlafaxine-XR (Effexor), which affects both serotonin and norepinephrine. Out of the participants, 712 completed the eight-week treatment regimen.

To assess the impact of the antidepressants, the researchers conducted pre- and post-treatment evaluations of the participants’ depressive symptoms using two surveys: one administered by clinicians and the other a self-assessment. These evaluations included questions about changes in sleep patterns, appetite, as well as measurements of social and occupational functioning and quality of life.

Additionally, the participants underwent a series of cognitive tests before and after treatment. These tests evaluated various aspects of cognitive function, such as verbal memory, working memory, decision speed, and sustained attention.

Prior to treatment, functional magnetic resonance imaging (fMRI) scans were conducted on 96 participants while they performed a task called the “GoNoGo.” During this task, participants were required to press a button as quickly as possible when they saw the word “Go” in green, and refrain from pressing when they saw the word “NoGo” in red. The fMRI scans measured changes in blood oxygen levels, which provided insights into neuronal activity and identified specific brain regions associated with Go and NoGo responses. The participants’ fMRI images were then compared to those of individuals without depression.

The results revealed that 27% of the participants displayed more pronounced symptoms of cognitive slowing, insomnia, impaired cognitive function on behavioral tests, and reduced activity in certain frontal brain regions. This distinct profile was termed the cognitive biotype.

The pre-treatment functional magnetic resonance imaging (fMRI) analysis revealed a significant decrease in activity within the dorsolateral prefrontal cortex and dorsal anterior cingulate regions during the GoNoGo task among individuals with the cognitive biotype compared to those without this biotype. These two regions are part of the cognitive control circuit, which plays a crucial role in suppressing unwanted thoughts and responses, enhancing goal-directed behavior, and other cognitive tasks.

Following the treatment, the researchers observed that all three administered antidepressants led to remission rates, indicating the absence of overall depressive symptoms. However, the remission rates differed between participants with the newly identified cognitive biotype and those without it. Overall, the remission rate for participants with the biotype was 38.8%, while it was 47.7% for those without the biotype. Notably, the most noticeable difference in remission rates was observed in the case of sertraline, with rates of 35.9% for individuals with the biotype and 50% for those without it.

“Depression presents in different ways in different people, but finding commonalities -; like similar profiles of brain function,” Williams added, “helps medical professionals effectively treat participants by individualizing care.”

Depression does not adhere to a “one size fits all” approach

Williams and lead author Laura Hack propose that utilizing behavior measurement and imaging techniques can aid in the diagnosis of depression biotypes, ultimately leading to more effective treatment strategies. Patients could complete surveys either on their own computers or in the doctor’s office, and if their responses indicate a specific biotype, they may be referred for imaging to confirm the diagnosis before undergoing treatment.

Researchers at the Stanford Center for Precision Mental Health and Wellness, under the direction of Williams, in collaboration with the Stanford Translational Precision Mental Health Clinic, led by Hack, are investigating the potential of guanfacine, a medication that targets the dorsolateral prefrontal cortex region. They believe that this treatment could offer improved efficacy for patients with the cognitive subtype of depression.

Williams and Hack have plans to conduct studies involving participants with the cognitive biotype. These studies would compare various types of medication with treatments such as transcranial magnetic stimulation (TMS) and cognitive behavioral therapy (CBT). TMS involves stimulating nerve cells using magnetic fields, while CBT focuses on teaching patients problem-solving strategies to counteract negative thoughts contributing to emotional dysregulation and impairments in social and occupational functioning.

“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,” Hack added. “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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