Depression is a common mental condition that affects around 10% of the population. Antidepressant medications are the first-line treatment for moderate to severe major depressive episodes. Pharmaceutical advances have improved the efficacy of the medications over the past three decades. However, despite the improved effectiveness, only 40% of patients respond to the first antidepressant they try.
This reality is challenging as depression is most common in ages 18 to 25 (10.9%) and in individuals belonging to two or more races (10.5%).
In the new study, Canadian researchers investigated a particular protein — GPR56 — that appears to be involved in the biology of depression and the effect of antidepressants. The McGill University led research team believe that this protein could offer a novel target for new antidepressant drugs.
Currently, selective serotonin reuptake inhibitors (SSRIs) are the first line pharmaceutical therapy for depression. This medication class was developed in the mid to late 1980s and this generation of antidepressants is now the most common class used for depression. Examples include citalopram (Celexa), escitalopram (Lexapro), paroxetine (Paxil, Pexeva), fluoxetine (Prozac, Sarafem), and sertraline (Zoloft).
In the study, Professor Gustavo Turecki of McGill University and the Douglas Mental Health University Institute, led an international consortium of researchers and clinicians to investigate changes in the activity of genes in the blood in over 400 patients who were being treated with antidepressants.
The results showed clearly that there were significant changes in the levels of GPR56 in patients who responded favorably to antidepressants, but not in non-responders, or patients receiving placebo. This discovery is particularly interesting, as GPR56 may represent an easy-to-measure biomarker for response to antidepressants.
McGill researchers studied the action of that GPR56 (which can be detected through a simple blood test) by doing experiments with mice, and by studying human brain tissue obtained from the Douglas Bell-Canada Brain Bank. They found the protein was associated with biological changes in the central nervous.
Their findings appear in a recent paper in the journal Nature Communication.
Researchers found that GPR56 was changed in depression, and that it was modified, both in the blood and the brain, when antidepressants were administered. These changes were particularly evident in the prefrontal cortex, an important area of the brain for the regulation of emotions and cognition.
Investigators hope their findings will help solve the mystery of why many patients with depression do not respond to antidepressant treatment.
Researchers studied three groups of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424). They discovered that individuals who benefit from a SSRI display an increase of GPR56 mRNA in the blood. Conversely, individuals who do not respond to SSRIs and continue to have the same level of depression symptoms did not have an increase of the protein in their blood.
Moreover, researchers discovered GPR56 is downregulated in the pre-frontal cortex (a brain region believed to be responsible for depressive-like behaviors and antidepressant response) of individuals with depression that died by suicide.
“Identifying new therapeutic strategies is a major challenge, and GPR56 is an excellent target for the development of new treatments of depression,” said Gustavo Turecki.
“We are hopeful that this will provide an avenue to alleviate the suffering of patients who face this important, and often chronic, mental illness which is also strongly associated with the risk of addiction and an increased risk of suicide.”
Source: McGill University