New Strategy Makes Ketamine's Effect on Depression Last Up to Two Months

Researchers have found a way to prolong the antidepressant effects of ketamine, which typically last only a few days. By combining ketamine with a substance that keeps a molecule called ERK active in the brain, the beneficial effects lasted up to two months in mice. This could lead to longer-lasting treatments for depression, with fewer repeat doses and fewer side effects.

Depression is a common and debilitating psychiatric condition that affects millions of people worldwide. Although effective treatments such as conventional antidepressants and psychotherapy are available, many people do not respond well or take weeks to feel better.

Ketamine, originally developed as an anesthetic, has gained attention in recent years for its very rapid antidepressant effects, sometimes within hours of a single intravenous dose. However, these effects are temporary, usually lasting only a few days, requiring repeated doses to maintain the benefits.

The problem is that repeated use of ketamine can bring unwanted side effects, such as cognitive disorders, dependence and effects on the urinary system.

With this in mind, scientists at Vanderbilt University, USA, wanted to answer an important question: is it possible to make the positive effects of a single dose of ketamine last much longer, without the need for frequent re-applications?

To do this, they investigated how ketamine acts on the brain and what could be done to prolong its antidepressant effects without increasing the dose. We know that ketamine increases synaptic plasticity, that is, it improves the ability of neurons to communicate with each other, in a specific region of the brain called the hippocampus, more precisely between the areas called CA3 and CA1.

This region is involved in memory, emotions and mood regulation. When this connection between neurons is strengthened, symptoms of depression appear to decrease. However, this strengthening only lasts a short time after ketamine is administered.

In the experiment, scientists used laboratory mice to test whether it would be possible to make this effect last longer. They focused on an enzyme called ERK (extracellular signal-regulated kinase), which is involved in learning, memory, and cellular response to stimuli.

When ERK is active, it helps maintain the ability of neurons to communicate with each other. However, there is another protein called DUSP6, which “turns off” ERK and reduces its activity.

The researchers’ idea was simple: if we inhibit DUSP6, ERK remains active for longer, and this can maintain the brain changes caused by ketamine. To test this hypothesis, they administered ketamine to the animals and then gave them a drug that inhibits DUSP6.

The result was surprising: the antidepressant effects, which would normally last a few days, were maintained for up to 2 months in mice. In other words, a single dose had a prolonged effect thanks to the manipulation of this intracellular pathway.

To confirm that this effect really depended on this pathway, the scientists performed another experiment: they blocked a molecule called TrkB (a type of receptor important for the functioning of neurons) only in excitatory neurons, those most involved in the active transmission of signals.

Without TrkB, the prolonged effects of DUSP6 inhibition disappeared, confirming that this signaling pathway is essential for sustaining the effects of ketamine.

This study therefore shows that it is possible, by modulating an internal neuron pathway, to prolong the antidepressant effect of ketamine with a single application, avoiding the risks associated with repeated use.

Although human studies are still needed to confirm these results, the discovery represents an important advance in the treatment of resistant depression and may pave the way for new, safer and more lasting therapeutic approaches.

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Enhanced ERK activity extends ketamine’s antidepressant effects by augmenting synaptic plasticity

Z. ZACK MA, NATALIE J. GUZIKOWSKI, JI-WOON KIM, EGE T. KAVALALI, AND LISA M. MONTEGGIA 

Science. Vol 388, Issue 6747 pp. 646-655

DOI: 10.1126/science.abb6748

Abstract:

Repeated ketamine treatment to maintain a rapid antidepressant effect can lead to side effects over time, highlighting an unmet clinical need for sustaining this drug’s antidepressant action from a single administration. Ketamine-induced synaptic potentiation at CA3-CA1 synapses has been proposed to be a key synaptic substrate for antidepressant action. Here, we found that ketamine-induced CA3-CA1 synaptic potentiation could be augmented by transiently increasing extracellular signal–regulated kinase (ERK) activity through pharmacological inhibition of dual-specificity phosphatases 6 (DUSP6). The antidepressant-like behavioral effects of acute ketamine treatment were extended by DUSP6 inhibition for up to 2 months. The selective deletion of tropomyosin receptor kinase B (TrkB) in excitatory neurons abolished these DUSP6 inhibition–mediated synaptic and behavioral effects. These data suggest that ketamine’s rapid antidepressant effects can be sustained by selectively targeting downstream intracellular signaling.