The pieces of the puzzle are coming together—some of them
anyway—toward a true neurobiological understanding of mental disorders,
said Thomas Insel, M.D., director of the National Institute of Mental Health
In an address to psychiatrists at APA's 2005 annual meeting, Insel cited
recent ground-breaking research from which has emerged the beginnings of a
molecular pathophysiology for depression—from genes to cells to systems
He described an often-cited study by Caspi and colleagues in the July 2003
Science showing that a functional polymorphism in the promoter region
of the serotonin transporter (5-HTT) gene was found to moderate the influence
of stressful life events on depression. Individuals with one or two copies of
the short allele of the 5-HTT promoter polymorphism exhibited more depression
and suicidality in response to stressful life events than individuals with the
"This is a gene-environment interaction, and it suggests one way in
which these genetic variations may play out," Insel said.
A new report by psychiatrist Daniel Weinberger, M.D., and colleagues at the
NIMH builds on the finding to extend it to structural changes in a specific
area of the brain.
In a paper published online in May in Nature, Weinberger and
colleagues used neuroimaging to show reduced gray matter volume among
individuals with the short form of the 5-HTT gene in limbic regions of the
brain critical for the processing of negative emotion, especially the
perigenual cingulate and amygdala—areas that had previously been
associated with decreased volume and changes in metabolism among individuals
The researchers then performed functional MRI analysis of those regions as
subjects were being shown images of a threatening face. In individuals with
the long form of the 5-HTT gene, there was increased activity in the
perigenual cingulate and amygdala, but in those with the short form there was
significantly decreased activity directly related to the variation in
temperamental anxiety experienced by subjects.
"The concept is that having this variation along the course of
development leads to changes in cells—in this case, cells that express
the serotonin transporter," Insel explained. "That could lead to a
different pattern in the way connectivity happens in the brain. At the systems
level it would give you a very different way of processing negative stimuli
and make you vulnerable for a complex disorder such as depression.
"This begins to provide a molecular pathophysiology [for depression]
from genes to cells to systems to behavior," Insel said.