New support for a serotonin deficit in depression
Since the 1960s, researchers have postulated that major depression results from disturbances in the serotonin neurotransmitter system, but the evidence for that idea, while abundant, was indirect. In fact, a recent comprehensive review of existing studies concluded that there was no strong evidence to support the “serotonin hypothesis.” In the wake of this, some in the field have called for the hypothesis to be reexamined. Not so fast, says a new study that provides direct evidence for disrupted serotonin release in the brains of people with depression.
The study appears in biological psychiatrypublished by Elsevier.
Depression is one of the most common mental illnesses and causes of disability worldwide. Despite the lack of direct evidence for disruption of serotonin signaling in the depressed brain, medications used to treat depression overwhelmingly target the serotonin signaling system to increase extracellular serotonin, also known as 5-hydroxytryptamine (5-HT). Only about half of patients respond to antidepressants and less than 30% experience complete remission. A better understanding of 5-HT dynamics in depression could help guide more effective therapies.
“Our thinking about the role of serotonin in depression has evolved significantly over the past decade. We once thought that changes in serotonin could explain the entirety of depression. When this simple hypothesis could no longer be supported, some leaned rule out any role for serotonin in depression,” said John Krystal, MD, editor-in-chief of biological psychiatry. “The current study provides important new support for further exploration of the role of serotonin in depression. This is particularly timely as drugs that target serotonin receptors, such as psychedelics, are being explored as potential new treatments for depression.” 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 novel imaging technique to directly observe the magnitude of serotonin. released from neurons in response to a drug challenge. In previous work, these researchers pioneered the use of positron emission tomography (PET) with the radioligand [11C]Cimbi-36 to detect the release of serotonin. In the current study, the researchers applied this methodology to compare serotonin release in 17 depressed patients and 20 healthy individuals.
David Erritzoe, MRCPsych, PhD, lead author of the paper, said: “This study used a new, more direct method of measuring serotonin in the living human brain, and the results suggest reduced serotonin functioning (release) in the depression. This imaging method, in combination with similar methods for other brain systems, has the potential to help us better understand the variable, sometimes limited or even non-existent treatment responses that people with depression have to antidepressant medication.”
Depressed participants and healthy controls underwent a PET scan with [11C]Cimbi-36 to measure the availability of the 5-HT2A receptor in the frontal cortex; the two groups did not differ significantly at baseline. Both groups then received a dose of d-amphetamine, a stimulant drug that works to increase the concentration of 5-HT outside neurons, where it interacts with 5-HT2A receptors and reduces binding of [11C]Cimbi-36. In a second scanning session three hours after drug administration, healthy control participants had significantly reduced 5-HT2A receptor availability, indicating an increase in serotonin levels. Participants with depression, however, did not show a significant decrease in binding potential, suggesting that they had decreased ability to release serotonin in key brain regions.
The study found no relationship between the severity of depression and the extent of deficits in the ability to release serotonin. Notably, all patients were free of antidepressant medication and 11 of the 17 had never received antidepressant treatment, indicating that low serotonin-releasing capacity is a feature of depression rather than the result of antidepressant treatment.
This first direct assessment of serotonin levels in the brains of people with depression is a major step forward in dispelling speculation that serotonergic neurotransmission is involved in the pathology of depression. Depression is a multifaceted disorder that can have multiple causes and different subtypes can involve multiple neurotransmitter systems. It is unlikely that serotonergic dysfunction explains all of the clinical features found in this disorder. However, this study demonstrates that serotonergic deficits are present in non-medicated depressed individuals.
Eugenii Rabiner, MBBCh, FCPsych SA, of Invicro and lead author of the paper, said: “It has taken our field more than 20 years to develop a method that allows the measurement of serotonin release in the living human brain. I am very pleased to that we have managed to develop this method and apply it to clarify this important aspect of the pathophysiology of depression.I hope that we can use this technique in the future to explore the different symptoms of depression, as well as the serotonergic deficits found in other conditions, like Parkinson’s disease.”