New research in Biological Psychiatry offers the first direct evidence of diminished 5-HT release cements “serotonin hypothesis.”

Researchers have postulated since the 1960s that major depression stems from disruptions in the serotonin neurotransmitter system. However, the evidence for that idea, though plentiful, was indirect. In fact, a recent comprehensive analysis of existing studies concluded that there was not 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, says a new study that provides direct evidence of disrupted serotonin release in the brains of individuals with depression.

The study was published recently in the journal Biological Psychiatry.

Depression is among the most common mental illnesses and causes of disability worldwide. Despite the lack of direct evidence for disrupted serotonin signaling in the depressed brain, medications 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 fewer than 30% experience total 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 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. “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