Jiyoon Park

A new study by researchers at the Yale School of Medicine found that depression is associated with a lower density of synapses, which allow communication between brain cells.

As the first researchers to measure the synaptic density of the living brain, the team found that individuals with high levels of depression show significantly lower synaptic density compared to non-depressed individuals or individuals with mild depression. The team’s preliminary data also discovered that depression may be associated with a greater decline in synaptic density with aging, but further studies are required to corroborate this finding. Led by Yale psychiatry professor Irina Esterlis, the research was presented on Feb. 15 at a meeting of the American Association for the Advancement of Science.

“Our study is the first of its kind,” said Sophie Holmes, first author of the study and associate research scientist at the School of Medicine. “Synaptic dysfunction has been shown in animal models of depression and in the brains of depressed individuals at autopsy. Direct evidence in living humans has only been made possible recently with the use of a new imaging method which measures synapses in the living brain.”

Esterlis explained that recent technological developments have made it possible to measure certain proteins that represent synaptic density levels in a living human brain — what has previously been only indirectly measured. The study, she said, demonstrates a relationship between depression severity and synaptic density in individuals with major depressive disorder and post-traumatic stress disorder. This relationship adds to the existing literature from preclinical and postmortem studies of synaptogenesis — the formation of synapses between neurons in the nervous system — as a potential treatment for these disorders.

The team also examined the association between depression and aging, using data from individuals aged 20 to 60. The preliminary results showed a clear difference in the synaptic density of healthy individuals, which decreased gradually as a function of increasing age, and of depressed individuals, which declined dramatically and quickly, Esterlis said.

Depressed individuals also performed worse on measures of cognitive functions such as working memory and attention, with lower synaptic density levels linked to greater reductions in performance.

According to Robert Pietrzak, professor of psychiatry and co-author of the study, there was a ten percent greater reduction in synaptic density in depressed individuals than in healthy individuals per age decade. The preliminary findings uncover a possible neurobiological mechanism underlying the relationship between depression and brain aging, and provide insight into a novel treatment target for depression and associated cognitive difficulties.

Esterlis said that she was inspired by previous literature on animal models of depression. Research by Yale psychiatry professor Ronald Duman, for example, showed that a depressed rat has a lower synaptic density than a healthy rat, and the administration of an antidepressant that causes synaptogenesis — like ketamine — can return the depressed rat to a normal state.

All three researchers agreed on the need for further research on antidepressant medication that targets synaptic functions.

According to Esterlis, developing this kind of medication can aid people for whom general medications fail. Serotonin inhibitors, for example, take about six to eight weeks to show effects but are ineffective for about half of individuals with depression. Such an individual could be prescribed a different medication — but it could also turn out to be ineffective and have side effects.

“The process is trial and error, and people who don’t respond to the first line of treatment sometimes give up hope, or decide to go off medication and “just deal” with depression,” Esterlis said. “Depression treatment is varied by individual and we can’t predict what’s going to work for whom. The goal is to figure out what underlies depression, and what symptoms and genetic and cognitive profiles individuals may have, that might be helped by a certain drug.”

Esterlis expressed hope that further research could lead to precision medicine, which provides individualized treatment for depression, but cautioned that this process would take a lot of time and effort.

Pietrzak said that understanding the neurobiological underpinnings of depression can lead to earlier interventions, which can potentially help mitigate reductions in synaptic density, improve depressive symptoms and preserve cognitive functions.

He added that he and Esterlis have designed an accelerated longitudinal study that would allow them to examine the long-term effects of depression on synaptic changes in individuals aged 40 to 70. This study will build on their preliminary results, which demonstrate that depression accelerates normal aging-related changes in synaptic density.

Major depressive disorder affects more than 16.1 million American adults, or about 6.7 percent of the U.S. population age 18 and older in a given year, according to the Anxiety and Depression Association of America.

Eui Young Kim |euiyoung.kim@yale.edu .