Since the 1960s, researchers have postulated that major depression stems from disruptions in the serotonin neurotransmitter system, but the evidence for that idea, though plentiful, was indirect. A recent review of all the existing research found that the available evidence does not support the so-called serotonin hypothesis.
In the aftermath, some researchers have called for a re-examination of the hypothesis. But a new study claims to show direct evidence of disrupted serotonin release in the brains of people suffering from depression.
Despite the lack of direct evidence for disrupted serotonin signalling in the depressed brain, antidepressant medications overwhelmingly target the serotonin signalling system in order to increase extracellular serotonin, also known as 5-hydroxytryptamine (5-HT).
Serotonin Hypothesis Evolving
Only about half of patients respond to antidepressants, and only about 30% achieve complete remission. A better understanding of serotonin dynamics in depression could aid in developing more effective treatments.
“Our thinking about the role of serotonin in depression has evolved significantly over the past decade. We once thought that serotonin changes could account for the entirety 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.
Novel Imaging Technique
Researchers from Imperial College London, Copenhagen University, King’s College London, and the University of Oxford participated in the study, which was carried out by the international imaging contract research organization Invicro. They used a novel imaging technique to examine the amount of serotonin released from neurons in response to a pharmacological challenge.
These researchers were the first to use positron emission tomography (PET) with the radioligand [11C]Cimbi-36 to detect serotonin release. The current study used this methodology to compare serotonin release in 17 patients with depression and 20 healthy people.
“This study used a new and more direct method to measure serotonin in the living human brain, and the results suggest reduced serotonin (release) functioning in depression. This imaging method, in combination with similar methods for other brain systems, has the potential to help us to better understand the varying, sometimes limited or even lacking, treatment responses that people with depression have to antidepressant medication,”
said lead author David Erritzoe, MRCPsych, Ph.D.
Reduced 5-HT2A Receptor Availability
The availability of 5-HT2A receptors in the frontal cortex was measured using PET scanning with [11C]Cimbi-36 in participants with depression and healthy controls; the two groups did not differ significantly at baseline.
Both groups were then given a dose of d-amphetamine, a stimulant that works to increase 5-HT concentration outside of neurons, where it interacts with 5-HT2A receptors and decreases [11C]Cimbi-36 binding.
Three hours after taking the drug, there was a big drop in the number of 5-HT2A receptors in the healthy control group. This showed that serotonin levels had gone up.
On the other hand, participants with depression did not show a significant decrease in binding potential. This suggests that their ability to release serotonin in key brain regions was decreased.
The study found no relationship between the severity of depression and the extent of serotonin release capacity deficits. It is worth noting that all patients were free of antidepressant medication, and 11 of the 17 had never received antidepressant treatment, implying that low serotonin release capacity is a feature of depression rather than a result of antidepressant therapy.
Measurement Of Brain Serotonin Release
This first direct assessment of serotonin levels in the brains of people suffering from depression is a significant step toward putting to rest speculations about the role of serotonergic neurotransmission in the pathology of depression. But depression is a complex disorder with numerous causes, and different subtypes may involve multiple neurotransmitter systems.
Serotonergic dysfunction is unlikely to account for all of the clinical manifestations of this disorder. Nonetheless, this study shows that serotonergic deficits exist in unmedicated depressed people.
“It has taken our field over 20 years to develop a method that enables the measurement of serotonin release in the living human brain. I am very pleased that we 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 future to explore the different symptoms of depression, as well as serotonergic deficits found in other conditions, such as Parkinson’s disease,”
said Eugenii Rabiner, MBBCh, FCPsych SA, at Invicro and senior author of the paper.
Reference: David Erritzoe et al, Brain Serotonin Release Is Reduced In Patients With Depression: A [11c]Cimbi-36 Pet Study With A D-Amphetamine Challenge. Biological Psychiatry (October 28, 2022)