Summary: Recent studies have suggested that there is not enough evidence to support the serotonin hypothesis in depression. However, a new study shows direct evidence of disrupted serotonin release in the brains of people with depression.
Source: Elsevier
Since the 1960s, researchers have postulated that major depression stems from disturbances in the serotonin neurotransmitter system, but evidence for this 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 its wake, some in the field have called for a reexamination of the hypothesis.
Not so fast, according to a new study that provides direct evidence of disrupted serotonin release in the brains of people with depression.
The study appears in Biological psychiatry.
Depression is among the most common causes of mental illness and disability worldwide. Despite the lack of direct evidence for disruption of serotonin signaling 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 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 used to think that changes in serotonin could explain all of depression. When this simple hypothesis could no longer be supported, some were inclined to dismiss 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 targeting serotonin receptors, such as psychedelics, 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, University of Copenhagen and University of ‘Oxford, used a new imaging technique to directly examine the magnitude of serotonin. released from neurons in response to a pharmacological challenge.
In previous work, these researchers pioneered the use of positron emission tomography (PET) with the radioligand [11C]Cimbi-36 detects the release of serotonin. In the current study, researchers applied this methodology to compare serotonin release in 17 patients with depression and 20 healthy people.
David Erritzoe, MRCPsych, Ph.D., 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 suggest a reduction in the functioning of serotonin (release) in 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 missing, therapeutic responses that people with depression have to antidepressants.
Participants with depression and healthy controls underwent PET scans with [11C]Cimbi-36 to measure the availability of 5-HT2A receptors 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 the 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 increased serotonin levels. Participants with depression, however, did not show a significant decrease in binding potential, suggesting they had a blunted serotonin release capacity in key brain regions.
The study found no relationship between the severity of depression and the extent of deficits in serotonin-releasing capacity. Of note, all patients were antidepressant drug free and 11 of the 17 had never received antidepressant medication, indicating that low serotonin release capacity is a hallmark of depression rather than an outcome. antidepressant treatment.
This first direct assessment of serotonin levels in the brains of individuals suffering from depression is a major step forward in putting an end to speculation questioning the involvement of serotonergic neurotransmission in the pathology of depression.
Depression is a multifaceted disorder that can have multiple causes, and different subtypes can involve multiple neurotransmitter systems.
Serotonin dysfunction is unlikely to explain all of the clinical features found in this disorder. Nevertheless, this study demonstrates that serotonergic deficits are present in unmedicated depressed people.
Eugenii Rabiner, MBBCh, FCPsych SA, at Invicro and lead author of the paper, said, “It has taken our field more than 20 years to develop a method to measure serotonin release in the living human brain. I am very happy that we have been able to develop this method and apply it to clarify this important aspect of the pathophysiology of depression.
See also
“I hope 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, such as Parkinson’s disease.”
About this depression and current serotonin research
Author: Press office
Source: Elsevier
Contact: Press office – Elsevier
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“Cerebral serotonin release is reduced in patients with depression: [11c]Study of Cimbi-36 pets with a D-amphetamine challengeby David Erritzoe et al. Biological psychiatry
Abstract
Cerebral serotonin release is reduced in patients with depression: [11c]Study of Cimbi-36 pets with a D-amphetamine challenge
INTRODUCTION
The “serotonin hypothesis” of depression proposes that decreased serotonergic (5-HT) neurotransmission is causative in the pathophysiology of the disorder. Although over 50 years old, there is no firm in vivo evidence of a decrease in 5-HT neurotransmission. We recently demonstrated that 5-HT2a receiver (5-HR2a-R) agonist PET radioligand, [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by acute d-amphetamine challenge. Here we have applied [11C]Cimbi-36 PET to compare cerebral 5-HT releasing capacity (SRC) in patients experiencing a major depressive episode (MDE) with that of healthy non-depressed controls (HC).
METHODS
Seventeen patients without antidepressants with MDE (14m/3f, 44±13 years, HAM-D: 21±4 (16-30)) and 20 HC (17m/3f, 32±9 years), underwent 90 min dynamic [11C]Cimbi-36 PET before (PET-1) and 3 hours after (PET-2) an oral dose of 0.5 mg/kg d-amphetamine. Frontal cortex (primary region of interest) 5-HT2aThe non-displaceable binding -R was calculated from a kinetic analysis using the multilinear analysis-1 (MA1) approach with the cerebellum as the reference region.
RESULTS
Following administration of d-amphetamine, frontal BPn/a was significantly reduced in the HC group (1.04 ± 0.31 vs 0.87 ± 0.24, p < 0.001) but not in the MDE group (0.97 ± 0.25 vs 0.92 ± 0.22 , ns). ∆BPn/a of the MDE group was significantly lower than that of the HC group (HC: 15±14% vs MDE: 6.5±20%, p=0.038).
CONCLUSION
This first direct assessment of 5-HT releasing capacity in people with depression provides clear evidence for dysfunction of serotonergic neurotransmission in depression by demonstrating reduced 5-HT releasing capacity in patients undergoing major depressive episode.
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