Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medication for major depressive disorder (MDD), yet scientists still do not understand why the treatment does not work in nearly thirty percent of patients with MDD. Now, Salk Institute researchers have discovered differences in growth patterns of neurons of SSRI-resistant patients. The work, published in Molecular Psychiatry on March 22, 2019, has implications for depression as well as other psychiatric conditions such as bipolar disorder and schizophrenia that likely also involve abnormalities of the serotonin system in the brain.
“With each new study, we move closer to a fuller understanding of the complex neural circuitry underlying neuropsychiatric diseases, including major depression,” says Salk Professor Rusty Gage, the study’s senior author, president of the Institute, and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. “This paper, along with another we recently published, not only provides insights into this common treatment, but also suggests that other drugs, such as serotonergic antagonists, could be additional options for some patients.”
The most commonly prescribed antidepressants, selective serotonin reuptake inhibitors (SSRIs), lift the fog of depression for many people. But for around a third of people with major depressive disorder, SSRIs don’t make much of a difference. Now, researchers from the Salk Institute have pinned down a possible reason why — the neurons in at least some of these patients’ brains may become hyperactive in the presence of the drugs. The study appeared in Molecular Psychiatry on January 30, 2019.
“This is a promising step toward understanding why some patients don’t respond to SSRIs and letting us better personalize treatments for depression,” says Salk Professor Rusty Gage, the study’s senior author, president of the Institute, and the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.
Depression affects 300 million people around the world, and more than 6 percent of the US population experiences an episode of major depressive disorder (MDD) in any given year. MDD has been linked to an imbalance in serotonin signaling, although the exact mechanism is not well understood.
Antidepressants treat symptoms of depression by increasing levels of brain signaling molecules (neurotransmitters) such as serotonin, as with the most widely used type of antidepressant, selective serotonin reuptake inhibitors (SSRIs). However, many of the 350 million people worldwide thought to be affected with depression do not respond to SSRI treatment.
Now, researchers in the Department of Neuroscience and Cell Biology at Osaka University have found that an activator of the serotonin type 3 receptor (5HT3R) produces antidepressant effects in mice and increases nerve cell growth in the part of the brain responsible for memory and spatial navigation (the hippocampus). They also showed that it functions using a different mechanism than the commonly used SSRI fluoxetine, and therefore may be suitable for patients with depression who do not respond favorably to current medication.
Vortioxetine (trade name: Brintellix) has been approved since December 2013 for the treatment of depression in adults, but did not become actually available before May 2015. The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in a dossier assessment whether this drug offers an added benefit over the appropriate comparator therapy. Such an added benefit cannot be derived from the dossier because it contained no data evaluable for the assessment.
SSRI is drug component of comparator therapy
The Federal Joint Committee (G-BA) distinguished between three patient groups depending on the severity of the disease and specified a different appropriate comparator therapy for each of them: no drug treatment for mild episodes of depression, an antidepressant from the group of selective serotonin reuptake inhibitors (SSRIs) for moderate episodes and a combination of an SSRI and an offer of psychotherapy for severe episodes. In addition, differentiation between acute treatment and relapse prevention can be inferred from the Summary of Product Characteristics.