As ketamine makes waves in the field of mental health, there’s a mystery around the drug that continues to elude scientists: how, exactly, it works in the brains of people with depression.

Now, scientists have uncovered a process that might contribute to ketamine’s antidepressant effect. In new research in mice published Thursday in Science, researchers report that ketamine appears to spark the growth of neural connections that had been diminished by chronic stress. They also discovered that the survival of those new connections — known as synapses — seems to be critical to maintaining some of ketamine’s effects.

“To the extent that what we’re modeling in the brains of mice captures something that’s happening in the brains of depressed people, this could be a promising future avenue for research,” said Dr. Conor Liston, neuroscientist and psychiatrist in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine and an author of the new study.

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But experts caution that there are still significant unknowns about how ketamine works in the brain — and at this point, it’s not possible to confirm whether the new observations in mice are also happening in humans.

“It’s interesting, it’s fascinating, but it cannot explain the whole story. It’s one additional piece of a very complex puzzle,” said Dr. Cristina Cusin, who leads a ketamine treatment program at Massachusetts General Hospital and who wasn’t involved in the research.

Ketamine — a longtime anesthetic — is known to work on certain receptors in the brain known as NMDA receptors, which are involved in learning and memory. Research over the last two decades has suggested it can ease symptoms of depression, but scientists don’t understand the biology behind that effect, why the response to ketamine varies so much from one patient to the next, or why the drug’s effects wear off over time. With esketamine, a ketamine-derived nasal spray approved by the FDA last month for treatment-resistant depression, patients have to take eight doses over their first month of treatment before being moved to a maintenance dose.

In the new research, neuroscientists at Weill Cornell looked specifically at circuitry in the medial prefrontal cortex, an area of the brain thought to be involved in depression. Research has suggested that chronic stress can affect the number of synapses, or the connection between two neurons in the brain. Liston and his colleagues wanted to see if ketamine might have reversed those effects. So they looked at what are known as dendritic spines, tiny projections that shoot off branches of neurons known as dendrites. Most dendritic spines contain functional synapses, so scientists consider them a sign of a connection between two neurons.

Ketamine - new synapses graphic
New research in mice suggests that ketamine can promote the growth of new synapses in a particular part of the brain, often in places where synapses have been depleted after chronic stress. Nirja Desai/Science

As mice experienced chronic stress, which is commonly used as a stand-in for depression in humans, the researchers saw an uptick in the number of dendritic spines that died off and a decrease in the number of new dendritic spines being formed.

Then, they gave the mice an antidepressant dose of ketamine — and kept watching.

“The effects on behavior were rapid — detectable just three hours after treatment,” Liston said. The mice were more likely to try to escape an unpleasant situation, prefer sugary water over plain water, and explore a maze. All three are considered markers of the chronic stress response: the lack of struggle to escape is interpreted as a lack of motivation, the disinterest in sugar water is seen as a sign that a mouse doesn’t take pleasure in a happy activity, and the tendency to stay in the closed areas of a maze suggests anxiety and a desire to stay in a safe area.

But the effects on synapse formation were slower. They didn’t start seeing new synapses form until about 12 hours after a dose of ketamine. That suggests that ketamine can have a rapid effect even when new synapses haven’t formed.

“What that told us was that the formation of new synapses … couldn’t be required for inducing ketamine’s initial antidepressant effects,” Liston said.

When they did start to form, many appeared near the spots where previous synapses had disappeared, suggesting the ketamine was restoring some lost connections.

To tease out whether the new synapses were the key to sustaining ketamine’s effect on the brain, Liston and his colleagues teamed up with researchers at the University of Tokyo and deleted them, using a tool that causes newly formed synapses to collapse. Two days after they had deleted the new synapses, some of the behaviors that improved after a dose of ketamine reverted back to the behaviors seen during chronic stress.

That suggests that the new synapses — and their survival — are critical to maintaining at least part of ketamine’s effect on behavior.

“We think that’s important and might be useful down the road clinically,” Liston said. But getting rid of the new connections didn’t change the mice’s preference for sugary water, which the ketamine had promoted. That reinforces the idea that there are other factors at play in maintaining the drug’s effects on behavior.

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Experts said it will be all but impossible — at least with the technology currently available — to confirm the finding in humans. There’s no comparable tool to capture the nitty-gritty details of dendritic spine growth and synapse formation in human brains.

The study comes with other significant caveats. Mouse models of chronic stress don’t come anywhere near capturing the full experience of depression in humans — nor can they account for other possible factors that can contribute to depression, including genetics, environmental factors, or life events. The research was also done in relatively small groups of mice and still needs to be independently replicated.

“I don’t think we can say this is the mechanism of action. It’s one part of it. The drug is impacting the entire brain,” said Anna Beyeler, a neuroscientist at the University of Bordeaux in France who wrote a perspective paper on the new study, also published in Science.

Still, experts said the research raises questions about whether it might be possible to pair ketamine with other treatments such as therapy that can activate the circuits in the brain — and in turn, help the newly formed spines to survive. If scientists can figure out how to promote the growth and survival of new synapses, experts said, they might be able to develop ways to make the drug more effective over a longer period of time.

“Getting a better handle [on] the mechanisms that might maintain ketamine’s effects could be really useful for new strategies for augmenting it,” Liston said. That’s what he and his colleagues are planning to study next. They want to see whether other interventions — whether that’s transcranial magnetic stimulation, talk therapy, or exercise — might help enhance the survival of synapses.

Cusin said there is a laundry list of questions to answer about ketamine, from what types of patients should be treated with the drug to the long-term effects of chronic ketamine or the constant remodeling of synapses.

“There is so much more work to do to understand how ketamine works,” she said.

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  • This comment relates to my earlier comment here.

    Several animal (and human) studies have demonstrated that when animals are subjected to various psychological stresses, this results in dendritic atrophy in the brain. But, if these psychological stresses are removed, then the structural changes in the brain naturally RETURN TO NORMAL. This happens due to ‘neuroplasticity.’ See for example the following articles:

    Radley, J.J., et al. (2005). Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress. Experimental Neurology, 196, 199–203.

    Sandi, C., et al. (2003). Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training. Eur. J. Neurosci. 17, 2447–2456.

    Soares, J. M., et al. (2012). Stress-induced changes in human decision-making are reversible. Translational psychiatry, 2(7), e131.

    Davidson, R.J. & B.S. McEwen. (2012). Social influences on neuroplasticity: stress and interventions to promote well-being. Nat Neurosci. 15: 689 – 695.

    Popoli, M., et al. (2012). The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13,
    22–37.

    Now, I had another look at this published ketamine study. According to it, it looks like the artificially induced psychological stressors were removed before the ketamine drug was introduced – so, it is VERY PROBABLE that in this experiment, the structural changes observed would have been due to the mice being longer psychologically stressed, and NOT because the drug worked.

    It is very sad that journals like ‘Science’ would publish these types of poorly conducted studies. I won’t pursue this matter further, but I think someone should look into this more carefully.

    In humans, this ketamine drug probably ‘works’ only due to expectations (placebo effect) – otherwise the drug would have worked equally for everyone. Placebo effects can be very powerful – check out the article titled “The Placebo Effect, Digested – 10 Amazing Findings” by C. Jarrett (published in the BPS Research Digest).

  • Ketamine interacts with a large group of neurohormones, opioid neurotransmitters, and others. Regarding its antidepressant function, one of the main reasons is that it deactivates the function of Norepinephrine, a stress hormone and a neurotransmitter in the sympathetic nervous system.

  • Have fought losing battles for 45 years now, finding no relief in 130 meds if add those taken individually and in combination. Even went to Charleston for TMS which resulted in me worsening after 30 treatments

  • These mice were artificially stressed through repeated restraint stress. I would like to know whether the mice were still retrained when they were treated with the drug. I hope one of the authors of this article would answer this question. I ask this question because studies have demonstrated that the neurons come back to normal if stressed (restrained) animals are simply released (the animals are no longer restrained).

    I also find it scary that natural systems are interfered with, by introducing various compounds that result in changing neurons in various ways. Psychological therapies are known to bring about positive long-term changes in treatment resistance depression and I would think they would be so much safer long-term than drugs that are introduced using a hit or miss manner.

  • My Major Depressive Disorder was diagnosed in 12/2005, 4 months after Hurricane Katrina sent a 35 ft storm surge over my small town and house in August 2005. In December, my husband was diagnosed with terminal, aggressive prostate cancer. By June 2006, we added PTSD, OA CP to my conditions and in those 6 months I lost 2 good friends, a brother and my dad. Husband beat the cancer. I am whining not for sympathy but to portray the stress effect on MDD. At the outset, I was very motivated to beat the MDD. I sought a counselor and psychiatrist that were also committed. twice per weekly talk sessions, visualization, deep breathing, progressive relaxation, white noise machines and my desire to be MOM/WIFE/FRIEND came to naught. Then more meds, wait 6 weeks, go back, raise dose, wait anothe 6 weeks, add med…..well everyone here knows the routine. I would admit myself (after the first 3 years) for a rapid med change. Prozac, Lexapro, Paxil, Welbutrin, Effexor, yad yad. Then 18 ECTs with a single day of refreshing mania, then plunging into the shadows again. I went TRD by 2012.

    By then, all the extra MH counselors from the storm had gone home. We had 2 shrinks for 200,000 residents-the only Medicare/Caid MH providers.

    So when I heard of Ketamine IV TX 3 years ago, I was thrilled. Followed clinical trials of all the possible drugs. Even was recruited for Rapastinel trials but could not deal with the 8 hr round trip ansd hotel $$. It failed badly anyway.

    I cheered when FDA approved Spravato. Then we hear that it would be dispensed in a clinical setting, meaning office staff, nursing, and doctors. Cost: aopprox. $7000/month. I live on the Gulf Coast. It will be a year or two, if ever, before a Spravato clinic is as reality. It is a pipe dream for most of us. At 66, I now musty accept that my last decade will, not only be perfused with the shadowy world of TRD, but made worse by the closing of my PM clinic (been a client for almost 12 years, no problems) and the loss of all pain meds since May, 2018.

    US may be #1 in medical and pharmaceutical innovation, but also #1 in pricing life-saving medicines out of most patients budgets. Why even bother reading or getting excited about rich people having access to it all? Why bother writing and hyping patients up for a treatment a handful might see.

    I started replying that this was a big step towards more effective treatments. Now I realize what a fool I am for even writing this.

    • Meg, your feedback is very important. Many people take the cost issue of medication seriously, including scientists and politicians, as far as I know. The situation will be improved for sure because this is the United States of America.

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