Though it is already administered in off-label doses at clinics across the US for its rapid anti-depressant effects and, significantly, was approved in nasal spray form by the FDA last month, there remains a lot to learn about ketamine and its close chemical relatives. A new study has shed more light on how it can stave off depressive symptoms, with experiments on mice revealing how it repairs busted circuits in the brain.

"Ketamine is the first new anti-depressant medication with a novel mechanism of action since the 1980s," says Janine Simmons, chief of the National Institute of Mental Health's Social and Affective Neuroscience Program. "Its ability to rapidly decrease suicidal thoughts is already a fundamental breakthrough. Additional insights into ketamine's longer-term effects on brain circuits could guide future advances in the management of mood disorders."

In pursuit of such insights, an international team of scientists conducted experiments on mice that were exposed to stressors designed to induce depressive-like behaviors. The scientists took high-resolution images before and after these exposures, with the intent of tracking changes in dendritic spines, membrane outcroppings that jut out from neurons and allow for communications with other neurons nearby.

These images revealed that the mice exhibiting depressive symptoms featured compromised dendritic spines in their prefrontal cortex, either through lower formation or increased elimination of these tiny protrusions. This echoed earlier research outlining the relationship between depressed mice and loss of dendritic spines. Furthermore, stress also negatively impacted functional connectivity and the activity of neurons in the same part of the brain.

The scientists then treated the mice with a single dose of ketamine, and found that it rapidly restored functional connectivity and activity of the neurons, and reduced the mice's depressive behaviors. Twenty four hours after the treatment, the mice exhibited an increase in dendritic spine formation, and these spines proved to be the real deal, forging functional connections with neighboring neurons.

An important takeaway here is not necessarily the fresh observations of the fast-acting anti-depressive impact of ketamine, but its lingering effects. Members of the team from the University of Tokyo used technology developed in-house to delete the spines, and watched on as the depressive behaviors resurfaced. The scientists say that the dendritic spines therefore play an important role in sustained relief from depression, a vital piece of the ketamine-treatment puzzle.

"Ketamine is a potentially transformative treatment for depression, but one of the major challenges associated with this drug is sustaining recovery after the initial treatment," says study author Conor Liston from Weill Cornell Medicine.

The research adds to the growing body of evidence demystifying the mechanics of ketamine when working to relieve depressive symptoms. This includes studies on how it blocks important protein receptors in the brain, and how it functions similarly to traditional anti-depressants but a lot more efficiently.

"Our results suggest that interventions aimed at enhancing synapse formation and prolonging their survival could be useful for maintaining the antidepressant effects of ketamine in the days and weeks after treatment," says Liston.

The research was published in the journal Science.

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