New Support for A Serotonin Deficit in Depression
Since the 1960s, researchers have theorized that major depression results from disruptions in the serotonin neurotransmitter system. However, evidence for the “serotonin hypothesis” has been largely indirect. A recent comprehensive analysis of existing studies concluded that there was not strong evidence supporting this hypothesis, prompting some to call for a reexamination. Despite this skepticism, a new study has provided direct evidence of disrupted serotonin release in the brains of individuals with depression.
The study, published in Biological Psychiatry by Elsevier, is significant because depression is one of the most common mental illnesses and a leading cause of disability worldwide. Although medications targeting the serotonin signaling system are commonly used to treat depression, only about half of patients respond to these treatments, and fewer than 30% experience total remission. This underscores the need for a better understanding of serotonin (5-hydroxytryptamine, or 5-HT) dynamics in depression to develop more effective therapies.
John Krystal, MD, editor-in-chief of Biological Psychiatry, noted that the understanding of serotonin’s role in depression has evolved significantly. Initially, it was thought that serotonin changes could account for all aspects of depression. When this hypothesis could no longer be supported, some researchers dismissed serotonin’s role entirely. The current study, however, provides new support for further exploration of serotonin’s role in depression, which is particularly timely as drugs targeting serotonin receptors, such as psychedelics, are being explored as potential new treatments for mood disorders.
Conducted by Invicro, a global imaging contract research organization, in collaboration with researchers from Imperial College London, King’s College London, Copenhagen University, and the University of Oxford, the study used a novel imaging technique to measure serotonin release directly. In previous work, these researchers pioneered the use of positron emission tomography (PET) with the radioligand [11C]Cimbi-36 to detect serotonin release. The current study applied this methodology to compare serotonin release in 17 patients with depression and 20 healthy individuals.
Lead author David Erritzoe, MRCPsych, PhD, explained that the study used a new and more direct method to measure serotonin in the living human brain. The results suggest reduced serotonin release functioning in depression. This imaging method, combined with similar methods for other brain systems, has the potential to help understand the varying treatment responses to antidepressant medications.
Participants with depression and healthy controls underwent PET scanning with [11C]Cimbi-36 to measure 5-HT2A receptor availability in the frontal cortex, with no significant differences between the two groups at baseline. Both groups then received a dose of d-amphetamine, a stimulant that increases serotonin concentration outside of neurons. In a second scanning session three hours after drug administration, healthy controls showed significantly reduced 5-HT2A receptor availability, indicating increased serotonin levels. However, participants with depression did not show a significant decrease in binding potential, suggesting a blunted serotonin release capacity in key brain regions.
The study found no relationship between the severity of depression and the extent of serotonin release capacity deficits. Notably, all patients were free of antidepressant medication, and 11 out of the 17 had never received such treatment, indicating that low serotonin release capacity is a feature of depression rather than a result of medication.
This first direct evaluation of serotonin levels in the brains of individuals with depression is a major step forward, challenging speculations about the role of serotonergic neurotransmission in depression. While depression is a complex disorder with multiple causes and subtypes involving various neurotransmitter systems, this research confirms that serotonergic deficits are present in unmedicated depressed individuals.
Eugenii Rabiner, MBBCh, FCPsych SA, at Invicro and senior author of the paper, expressed satisfaction that the field had developed a method to measure serotonin release in the living human brain. This technique could clarify important aspects of depression’s pathophysiology and be used in future research to explore different symptoms of depression and serotonergic deficits in other conditions, such as Parkinson’s disease.
In conclusion, the study provides crucial support for the role of serotonin in depression and opens new avenues for research and therapeutic development. Understanding serotonin’s role could lead to more targeted and effective treatments, addressing the multifaceted nature of depression and improving patient outcomes.
Story Source: Materials provided by Elsevier. [Link] Content may be edited for style and length.