Apr 11, 2019

Looking at ketamine, the short-term wonder antidepressant

Illustration of bottle of antidepressant drug Ketamine with a sad face turning into a happy face

Illustration: Lazaro Gamio/Axios

A key to preventing depression relapse could be figuring out how to maintain the dendritic spines in the neurons, according to a study published on Thursday in Science that examined an antidepressant that's getting a lot of buzz called ketamine.

Why it matters: Depression affects nearly 20% of Americans — 80% of whom will endure a relapse after remission and 30% of whom will have treatment-resistant depression (TRD). Ketamine has been lauded for alleviating TRD in an amazingly short amount of time — but the side effects are quite serious, no one knows quite how it works, and the positive effect doesn't last long.

Background: Researchers continue to seek the causes of depression, with suspected factors including genetics, stress, environmental or social occurrences, physical illnesses and even possible maternal infections while pregnant.

  • Genes thought to be associated with depression include those that help develop chemical neurotransmitters and those that maintain neurons and synapses.
  • Stress has been found to induce neural plasticity in the brain, affecting the functional connectivity and the synapses, but chronic stress is believed to play a role in the appearance of mental disorders.
  • The FDA last month approved a nasal spray version of ketamine for short usage by people with treatment-resistant depression and given only in certified settings, due to concerns over possible side effects, addiction and a lack of knowledge on how it works.

Driving the news: For this new study, the research team essentially did 2 experiments after the first provided unexpected results, study author Conor Liston tells Axios.

The first experiment compared the timeline of the formation of new spines in the neurons with the effect on behavior after ketamine was given.

  • They found "the formation of synapses are important ... but not in the way we thought," says Liston, associate professor of neuroscience and psychiatry at Cornell University.
  • The ketamine had a positive effect on depression and led to increased neural activity in about 3 hours, but the new synapses did not form in the brain until 12 hours or later, he adds. So, ketamine appeared to do something to improve the symptoms almost immediately that was separate from rebuilding some of the synapses.

"This led to the second set of experiments," Liston says.

  • They joined with the University of Tokyo, which developed a new imaging tool to watch dendritic spines in neurons in mice, which were stressed to produce reactions similar to depression in humans.
  • Stress caused the mice to lose some synapses in their brains, but these were mostly restored after given ketamine, Liston says. The tool then erased the newly formed synapses to see how behavior changed — and the mice reverted to their prior "depressed" behavior.
  • Liston says the findings indicate that ketamine's antidepressant effect could last longer if interventions can be created that enhance and protect the new synapse formation.

What they're saying: Outside experts tell Axios the study has revealed some important processes.

  • David Olson, assistant professor at UC Davis, says the FDA's approval of ketamine for TRD "is an important milestone for the field of neuropsychiatry as ketamine appears to work via a mechanism that is distinct from traditional antidepressants.  Studies like [this one] are absolutely critical for understanding ketamine's novel mechanism of action so that we can develop next-generation versions of ketamine that are even safer and more effective."
  • Ronald Duman, professor of psychiatry and neuroscience at Yale University, says "The results demonstrate a lag-time in the formation of synapse relative to the increase in ensemble activity, as well as antidepressant behavioral responses. These findings suggest that increased ensemble activity contributes to the rapid effects of ketamine, while increased spine formation contributes to the sustained antidepressant actions of ketamine."

Caveat: Liston says the team attempted to replicate human depression in mice using 2 types of stressed animal models, both of which showed similar reactions, but he acknowledges the system isn't perfect.

  • Duman agrees, saying "translating studies in rodents to humans is always difficult and must be taken with caution," but also notes that prior research — including his own — has similarly linked a reduction in synapses with chronic stress through imaging and autopsies.
  • He adds that it will "be important in future studies to measure spine formation in the [medial prefrontal cortex] to determine if the same delayed time course is observed in this region, which is more closely associated with the behavioral effects that are being measured."

The big picture: Anna Beyeler, a neuroscientist at the French health institute INSERM, wrote an accompanying piece in Science saying the findings "are crucial not only for understanding the action of [ketamine] but also for the development of more innovative strategies to treat patients affected by treatment-resistant major depression."

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