Patients with Depression Release Less Brain Serotonin
Post by Elisa Guma
The takeaway
Depressive symptoms have been associated with diminished serotonin neurotransmission in numerous brain areas. By directly measuring in vivo serotonin release capacity in the frontal lobe, this study finds that patients experiencing a major depressive episode have reduced serotonin release capacity in their frontal cortices.
What's the science?
Reduced serotonin neurotransmission is thought to play a causal role in the pathology of depression. While depression is one of the most common mental illnesses worldwide, it is even more prevalent in individuals with Parkinson’s disease who experience a loss of serotonin neurons in the raphe nucleus, which provides more evidence for the “serotonin hypothesis”. However, most studies drawing associations between decreased serotonin and depression are based on indirect measurements of this neurotransmitter. This week in Biological Psychiatry Erritzoe and colleagues leverage a novel positron emission tomography (PET) radioligand – serotonin 2A receptor agonist ([11C]Cimbi-36) – to investigate whether individuals with either depressive disorder or a depressive disorder due to Parkinson’s Disease have altered serotonin releasing capacity in their frontal cortex following a d-amphetamine challenge (a common monoamine and serotonin releasing agent).
How did they do it?
The authors recruited seventeen antidepressant-free patients with major depressive disorder (five of whom had the diagnosis due to an underlying Parkinson’s Disease diagnosis) as well as twenty healthy controls. Depressive symptoms were assessed at baseline using the standard Hamilton Depression Rating Scale. Self-rating of effects due to d-amphetamine was recorded, and blood samples were taken, both immediately before and after the PET scan. PET imaging was focused on the frontal cortex, while the cerebellum was used as a reference region (as is customary in many PET studies). The authors measured serotonin release capacity by comparing the change in binding potential (how much radioligand binds to receptors in the brain) in the frontal cortex (relative to the cerebellum) both at baseline and following the dose of d-amphetamine. Thus, an increase in extracellular serotonin (due to d-amphetamine challenge) should result in a decrease in radioligand binding.
The authors first compared the serotonin release capacity of individuals with depression relative to healthy controls (covarying with age). Additionally, they investigated putative relationships between the severity of depressive symptoms and the effect of baseline binding potential between patients and controls (prior to d-amphetamine challenge).
What did they find?
High (and similar) binding across the frontal cortex for the serotonin 2A radioligand ([11C]Cimbi-36) was observed, confirming the proper function of the radioligand. Age was shown to decrease the binding potential, and thus, accounted for in subsequent analyses. D-amphetamine administration was found to significantly decrease binding potential in healthy individuals, which suggests that they were releasing serotonin extrasynaptically. The effect in patients with depression was less pronounced. This suggests that in response to the d-amphetamine challenge (which elicits serotonin release, among other things), individuals experiencing depression released less serotonin than healthy controls (they had reduced serotonin release capacity). Individuals whose depressive symptoms were a result of Parkinson’s Disease did not appear different from those with major depressive disorder, however, this may be due to a smaller sample size in the Parkinson’s disease group. Finally, there was no relationship between depressive scores and the serotonin release capacity in either of the groups nor was there a correlation between depressive scores and baseline radioligand binding for the individuals with depression.
What's the impact?
This study provides the first direct measure of serotonin release capacity in the frontal cortex of individuals with depressive symptoms. The authors find a decrease in the serotonin release capacity of individuals with depression relative to healthy controls in response to a d-amphetamine challenge. Increased serotonin catabolism or dysfunction of certain reuptake transporters may contribute to these observed decreases. Future research is required to better understand the mechanisms driving this decrease in serotonin release capacity and whether therapies that increase serotonin release capacity might be effective.
