Major depressive disorder (MDD) is among the most common psychiatric
disorders, affecting approximately 330 people worldwide. This disorder is
characterized by persistent feelings of sadness, hopelessness, low motivation,
a loss of interest in daily activities, and possible disruptions in sleep
and/or appetite changes.
There are now several treatments for depression, ranging from
antidepressant drugs to different types of psychotherapy. The most prescribed
antidepressants are known as selective serotonin reuptake inhibitors (SSRIs).
While these drugs can be highly effective in treating depression, different
compositions do not work for everyone. Therefore, patients diagnosed with MDD
often need to go through a trial-and-error process before they identify an SSRI
medication that effectively treats their symptoms.
Researchers at Circular Genomics Inc., University of New Mexico, Fondation
FondaMental and other institutes recently identified a new biomarker that could
offer insight into how individuals with depression will respond to specific
SSRI medications. This marker, outlined in a paper published in Molecular Psychiatry, is a type of
non-coding RNA, namely the circular RNA (circRNA) CDR1as.
A new marker of SSRI treatment response
As part of their study, the researchers analyzed blood samples collected
from patients diagnosed with MDD before they started taking antidepressants.
They specifically looked at levels of the circRNA CDR1as, which is found both
in people's blood and in their brain tissue.
"CircRNAs are highly stable and brain-enriched non-coding RNAs that
are mainly derived from the backsplicing and covalent joining of exons and
introns of protein-coding genes," wrote Grigorios Papageorgiou and his
colleagues in their paper.
"They are known to be important for brain development and
function, cross the blood-brain-barrier, and be
highly sensitive to changes in both synaptic activity and neuronal receptor
signaling. We present evidence that expression of the brain-enriched circRNA,
CDR1as, is associated with symptomatic response to SSRI treatment, and
regulated by serotonin and Brain-Derived Neurotrophic Factor (BDNF) receptor
activity."
Papageorgiou and his colleagues measured the levels of CDR1as in the blood
of patients diagnosed with MDD using a specialized laboratory technique that
amplifies and detects genetic material in the blood. They then compared the
levels observed in patients who later responded well to treatment with a widely
prescribed SSRI called sertraline to those in the blood of patients whose
symptoms did not improve after taking the drug.
"We present data using circRNA-specific PCR in baseline whole blood
samples from two independent cohorts, drawn from the Establishing moderators
and biosignatures of antidepressant response in clinical care (EMBARC) and the
Biomarkers of ANTidepressant RESponse (ANTARES) clinical studies, showing that
before treatment CDR1as is differentially expressed between future symptomatic
responders and non-responders to treatment with the SSRI sertraline,"
wrote the authors.
"Additional data from naturalistic antidepressant response studies
further highlight the association between CDR1as and antidepressant effects of
SSRIs as a class."
The researchers also looked at whether the levels of CDR1as in the blood of
individuals changed after they were treated with sertraline. In addition, they
examined the brains of animals and human neurons to shed light on the
mechanisms that could underpin the relationship between CDR1as and the efficacy
of SSRI treatments.
"We show that CDR1as levels are altered following sertraline treatment
in responders with the trajectory of change post-treatment associated with
long-term remission," wrote Papageorgiou and his colleagues.
"Furthermore, we report that levels of CDR1as in the blood can
specifically predict remission with SSRI treatment, but not response/remission
with placebo or bupropion treatments. Lastly, we provide evidence in animal
mechanistic and neuronal culture studies, suggesting mouse Cdr1as is strongly
regulated by 5-HT2A and BDNF receptor signaling."
Towards a more personalized treatment of depression
The findings gathered by this research team suggest that CDR1as levels in
the blood can help to predict how people diagnosed with MDD will respond to
treatment with specific SSRI. While their study specifically focused on the
drug sertraline, future works could also explore the link between CDR1as and
other widely prescribed SSRIs, such as fluoxetine, escitalopram, citalopram,
and paroxetine.
"Taken together, our data identify a brain-enriched circRNA associated
with known mechanisms of antidepressant response that can serve as a blood
biomarker for predicting response and remission with SSRI treatment,"
wrote the authors.
In the future, the insight gathered by Papageorgiou and his colleagues could contribute to the introduction of new protocols aimed at predicting how patients will respond to SSRIs and selecting the most suitable treatment for them. These procedures could prevent patients from having to endure long and arduous trial-and-error processes before their symptoms start improving, ultimately speeding up their recovery from MDD.
Source: A blood marker could predict how people respond to antidepressants
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