Ketamine: the effect of the drug on depression can last a long time



IIn early March, the FDA approved a nasal spray for ketamine-based depression, a substance previously known only as a rave drug. Despite its reputation, ketamine is such a promising anti-depressant that it will soon be available at accredited clinics across the country. A study published in Science Thursday proposes that the new treatment can be further improved.

Ketamine is an exciting new treatment for depression that differs from drugs like SSRIs in that it quickly relieves symptoms. "

In their This paper, a team of scientists from the Brain and Mind Research Institute of the Feil family of Weill Cornell in Medicine, shows that ketamine can help brain synapse synapses, crucial connections between neurons, which can alleviate depressive symptoms. Ketamine is already known for its quick action in relieving depressive symptoms – in days or hours – said co-author Conor Liston, Ph.D. reversebut maintaining these crucial connections is essential to extend its effects.

"Our study shows that formation of new connections (synapses) between brain cells is necessary to maintain the antidepressant effects of ketamine in the days following treatment," says Liston, professor of neuroscience at Weill Cornell. "Ketamine is an exciting new treatment for depression that differs from drugs like SSRIs in that it quickly relieves symptoms. However, these effects are not always lasting. "

upset, depressed
Ketamine Nasal Spray is a new drug approved by the FDA for treatment-resistant depression.

The dendritic spines

In a mouse model, Liston and his coauthors demonstrated that doses of ketamine allowed the brain of mice to reconstruct dendritic spines, small protuberances on neurons that helped them to pick up signals from other cells that were degrading. crucial way when exposed to chronic stress. These dendritic spines are a key element of synapse formation.

The degradation of these spines is not a perfect analogue of human depression, but humans also have, and Liston points out that some of the most important features of depression in humans are also present in mice suffering from stress chronic.

To create conditions similar to depression, the team degraded dendritic spines in their mice using stress hormones. Then, they administered a group of ketamine to a group, which they thought would have antidepressant effects.

dendritic spine
A dendritic spine helps to form a synapse – a connection to another neuron.

The dose of ketamine not only changed the behavior of the mice – they tried harder to escape their cage – it also helped reform the dendritic spines in their brains. It is interesting to note that ketamine does not form random dendritic spines, but actually seems to replace old spines that have been degraded by constant stress. Of the new spines formed, 47.7% grew less than two microns from the old one.

Why dendritic spines are important

The new dendritic spines have an important function in the mouse brain. Within three hours of treatment, previously damaged prefrontal cortex circuits began to come back online, but this happened before new form of synapses. At the end of the experiment, about 20.4 to 31.0% of the lost synapses were restored after taking ketamine by the mice.

The fact that the circuits were restored before synaptic reform suggests that ketamine triggers a two-step process that fights depression. The first step is the rapid antidepressant effect observed in many studies. The second step – regenerating thorns and restoring synapses – is slower, meaning that scientists should focus on the issue if they want the effects of ketamine on depression to last longer, says Liston.

When Liston used a blue light to artificially eliminate newly developed spines during a subsequent experiment, the mice relapsed into depressive symptoms. He suggested that maintaining these dendritic spines is important for fighting depression.

"Our results suggest that interventions aimed at improving the survival of newly formed connections in prefrontal brain circuits could be useful in increasing the antidepressant effects of ketamine by increasing their durability in the days and weeks after treatment."

The FDA's approval of a ketamine-based drug to treat depression was a revolution in itself, especially since it works differently than other antidepressants. But the fact that it was approved does not mean that there is no way to improve it. Ketamine helps relieve depression, but for now, the disease is constantly threatening people in remission. Preventing the potential for relapse by promising more lasting effects is one way to make this already remarkable drug even more useful.

Structured abstract

INTRODUCTION

Depression is an episodic form of mental illness, but the circuit-level mechanisms that govern the induction, remission, and recurrence of depressive episodes over time are not well understood. Ketamine quickly relieves depressive symptoms, allowing us to study the neurobiological substrata of the transition from depression to remission and to verify if the mechanisms inducing antidepressant effects are distinct from those who maintain them.

REASONING

Contrasting variations in the density of the dendritic spine in prefrontal cortical pyramidal cells have been associated with the emergence of depression-related behaviors in chronic stress models and the antidepressant effects of ketamine. But it is not clear if and how the remodeling of the dendritic column is involved, or if it is simply correlated with these effects. To answer these questions, we used two-photon imaging to study the effect of chronic stress and ketamine on dendritic column remodeling and dynamics of neuronal activity in the living prefrontal cortex (PFC). , as well as an optogenetic tool recently developed to manipulate the survival of new spines after ketamine treatment.

RESULTS

The induction of depression-related behavior in several models of chronic stress was associated with a targeted elimination of postsynaptic dendritic spines, specific to each limb, and a loss of activity from Correlated multicellular set in PFC projection neurons. Antidepressant dose ketamine reversed these effects by selectively rescuing discarded spines and restoring coordinated activity in multicellular sets predictive of motivated leak behavior. Unexpectedly, the effects of ketamine on the behavior and activity of the set preceded its effects on the formation of the spine, indicating that spinal formation is not necessary to induce these conditions. effects in an acute manner. However, individual differences in the recovery of lost spines were correlated with behavior 2-7 days after treatment, suggesting that spinogenesis may be important for long-term maintenance of these effects. To test this, we used a photo-activatable probe to selectively reverse the effects of ketamine on the formation of spines in the PFC and found that newly formed spines play a specific and essential role in the maintenance of the antidepressant effects of ketamine on motivated leak behavior. In contrast, the optical removal of a random subset of spines unrelated to ketamine treatment had no effect on behavior.

CONCLUSION

The formation of prefrontal cortical spines ensures the remission of specific behaviors related to depression after ketamine treatment by restoring lost thorns and saving the coordinated overall activity in PFC microcircuits. Pharmacological and neurostimulatory interventions to improve and preserve the rescue of lost synapses may therefore be useful in promoting sustained remission.


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