Groundbreaking study, the first evidence to show that serotonin deficiency is directly linked to depression

The first direct evidence of a reduction in serotonin release was provided, consolidating the "serotonin hypothesis"
.

Since the 60s of the 20th century, researchers have hypothesized that depression stems from a disorder
in the serotonin neurotransmitter system.
However, the evidence to support this view, while strong, is circumstantial
.
In fact, a recent comprehensive analysis of existing studies concluded that there is no strong evidence to support the "serotonin hypothesis.
"
Since then, some in the field have called for a revisit to this assumption
.
Not so soon, a new study says it provides direct evidence
of an interruption in the release of serotonin in the brains of people with depression.

The study was recently published in the journal Biological Psychiatry
.

Depression is one of the most common causes of
mental illness and disability worldwide.
Despite the lack of direct evidence of disruption of serotonin signaling in the depressed brain, drugs used to treat depression primarily target the serotonin signaling system to increase extracellular serotonin, also known as serotonin (5-HT).

Only about half of patients respond to antidepressants, and less than 30 percent respond
completely.
A better understanding of serotonin dynamics in depression can help guide more effective treatment
.

"Our understanding of the role of serotonin in depression has evolved
significantly over the past decade.
We used to think that changes in serotonin could explain the full cause of
depression.
When this simple hypothesis is no longer supported, some people tend to overlook any role of 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 very timely because drugs that target serotonin receptors, such as hallucinogens, are being explored as potential new therapies
for mood disorders.
”

The study, conducted by Invicro, a global imaging contract research organization, in collaboration with researchers at 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 size of
serotonin released by neurons as they respond to pharmacological challenges.
In previous work, the researchers pioneered the use of positron emission tomography (PET) with radioligand [11C]Cimbi-36 to detect the release
of serotonin.
In the current study, the researchers applied this method to compare the release of serotonin in 17 depressed patients and 20 healthy people
.

Lead author Dr David Erritzoe, MRCPsych, said: "This study used a new, more direct method to measure serotonin in living brains and showed that the release function of serotonin in depression is reduced
.
This imaging method, combined with similar approaches to other brain systems, has the potential to help us better understand the different—sometimes limited—or even absent—treatment responses
to antidepressants in people with depression.
”

Depressed patients and healthy controls received [11C]Cimbi-36 PET scans to measure the availability of 5-HT2A receptors in the frontal cortex; There was no significant difference
between the two groups at baseline.
Then both groups received a dose of D-amphetamine, a stimulant that increases the concentration of 5-HT outside neurons, where it interacts with the 5-HT2A receptor, reducing [11C]Cimbi-36 binding
.
On a second scan 3 hours after dosing, 5-HT2A receptor availability was significantly reduced in healthy control participants, indicating an increase
in serotonin levels.
However, participants with depression did not show a significant decrease in binding potential, suggesting an impaired
ability to release serotonin in key areas of their brains.

The study found no relationship
between the severity of depression and the degree of insufficient serotonin release.
Notably, none of the patients were on antidepressants, and 11 out of 17 had never received antidepressants, suggesting that low serotonin release is a feature of depression rather than a consequence of
antidepressant treatment.

This is the first direct assessment of serotonin levels in the brains of depressed patients, and is an important step
forward in dispelling speculation that serotonergic neurotransmission is related to the pathology of depression.
Depression is a multifaceted disorder that can have multiple causes, and different subtypes may involve multiple neurotransmitter systems
.
Serotonergic disorders are unlikely to explain all the clinical features
of this disease.
However, this study shows that serotonergic deficiencies are present in depressed patients
who are not taking medication.

Senior author of the paper, FCPsych SA Eugenii Rabiner of Invicro's MBBCh, said: "It took our field more than 20 years to develop a method that can measure the release
of serotonin in the brain of living people.
I am pleased that we have successfully developed this approach and applied it to elucidate important aspects
of the pathophysiology of depression.
" I hope we can use this technique in the future to explore the different symptoms of depression, as well as serotonergic deficiencies
found in other diseases such as Parkinson's disease.
”

References:

Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Pet Study With a D-Amphetamine Challenge” by David Erritzoe, Beata R.
Godlewska, Gaia Rizzo, Graham E.
Searle, Claudio Agnorelli, Yvonne Lewis, Abhishekh H.
Ashok, Alessandro Colasanti, Iro Boura, Chloe Farrell, Hollie Parfit, Oliver Howes, Jan Passchier, Roger N.
Gunn, David J.
Nutt, Philip J.
Cowen, Gitte Knudsen and Eugenii A.
Rabiner, 28 October 2022, Biological Psychiatry.