by Since the 1960s, researchers have suggested that major depression is caused by disruptions in the serotonin neurotransmitter system, but evidence for this idea was indirect, although plentiful. In fact, a recent comprehensive analysis of available studies concluded that there is no strong evidence to support the “serotonin hypothesis.” After that, some in the field called for a reexamination of the hypothesis. Not so fast, says a new study, which provides direct evidence that the release of serotonin in the brains of individuals with depression is impaired.
work appears Biological PsychiatryPublished by Elsevier.
Depression is among the most common causes of mental illness and disability worldwide. Although there is no direct evidence that serotonin signaling is impaired in the depressed brain, drugs used to treat depression overwhelmingly target the serotonin signaling system to increase extracellular serotonin, also known as 5-hydroxytryptamine (5-HT). Only half of patients respond to antidepressants and less than 30% experience complete remission. A better understanding of 5-HT dynamics in depression may help guide more effective treatments.
“Our thinking about the role of serotonin in depression has improved significantly over the past decade. We once thought that serotonin changes might be responsible for all of depression. As this simple hypothesis could no longer be supported, some tended to dismiss any role for depression in serotonin in depression,” says John Krystal, Editor-in-Chief. Biological Psychiatry. “The current study provides important new support for further investigation of the role of serotonin in depression. This is particularly timely as drugs that target serotonin receptors, such as psychedelic agents, are being explored as potential new treatments for mood disorders.”
The study, conducted by Invicro, a global imaging contract research organization, in collaboration with researchers from Imperial College London, King’s College London, the University of Copenhagen and the University of Oxford, used a new imaging technique to look directly at the magnitude of serotonin. It is released from neurons in response to a pharmacological challenge. In previous work, these researchers pioneered the use of positron emission tomography (PET) with a radioligand. [11C]Cimbi-36 for detecting serotonin release. In the current study, the researchers applied this methodology to compare the release of serotonin in 17 patients with depression and 20 healthy individuals.
David Erritzoe, MRCPsych, PhD, lead author of the paper, said, “This study used a new and more direct method to measure serotonin in the living human brain, and the results show that functioning serotonin (release) is decreased in depression. This imaging method is in combination with similar methods for other brain systems. has the potential to help us better understand the varying—sometimes limited or even incomplete—treatment responses of people with depression to antidepressant medications.”
PET scans were performed on depressed participants and healthy controls. [11C]Cimbi-36, to measure the presence of 5-HT2A receptors in the frontal cortex; the two groups did not differ significantly at baseline. Both groups then took a dose of d-amphetamine, a stimulant drug that tried to increase the concentration of 5-HT outside of neurons, where it interacted with 5-HT2A receptors and reduced the binding of neurons. [11C]Cimbi-36. At a second screening session three hours after drug administration, healthy control participants had significantly reduced 5-HT2A receptor availability, indicating an increase in serotonin levels. However, participants with depression did not show a significant decrease in bonding potential, suggesting that they had a blunted serotonin-releasing capacity in key brain regions.
The study found no association between the severity of depression and the extent of serotonin-releasing capacity deficits. Remarkably, not all patients were on antidepressant medication and 11 out of 17 patients had never received antidepressant therapy, suggesting that low serotonin releasing capacity is a feature of depression rather than a consequence of antidepressant therapy.
This first direct assessment of serotonin levels in the brains of individuals with depression is a major step forward in ending speculations that question the role of serotonergic neurotransmission in the pathology of depression. Depression is a multifaceted disorder with multiple causes, and different subtypes may involve multiple neurotransmitter systems. Serotonergic dysfunction is unlikely to explain all the clinical features encountered in this disorder. However, this study demonstrates that serotonergic deficiencies are present in depressed individuals who are not taking medication.
Eugenii Rabiner, MBBCh, FCPsych SA, at Invicro, and senior author of the paper, said, “It took more than 20 years in our field to develop a method for measuring the release of serotonin in the living human brain. He was able to develop this method and apply it to clarify this important aspect of the pathophysiology of depression. We can use the technique to investigate different symptoms of depression as well as serotonergic deficiencies found in other conditions such as Parkinson’s disease.”
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