How antidepressants, ketamine and psychedelics can make brains more resilient

How antidepressants, ketamine and psychedelics can make brains more resilient

The first-line drug treatment for major depressive disorder (MDD) is antidepressant medications known as selective serotonin reuptake inhibitors (SSRIs). But a large percentage of people do not respond to these medications.

Because major depression is a growing global mental health problem, it is important to find new drug treatments for those who do not respond to current treatments. But to do that, we have to understand exactly how drugs work, which we don’t currently understand.

MDD is a debilitating and disturbing mental health disorder, trapping sufferers in a rigid and negative state of mind. There is even evidence to suggest that this lack of flexibility is linked to cognitive changes, including negative thoughts and biases, and problems with learning and memory.

In our new study, published in the journal Molecular Psychiatry, we show that an SSRI called escitalopram may make brains more “plastic” — meaning more flexible and adaptive; More able to facilitate communication between neurons (brain cells). Brain plasticity is simply the ability of neural circuits to change through growth and reorganization. Learning involves brain plasticity, including changes in neural circuits, and can help people recover from depression.

One new treatment option for depression, approved by the US Food and Drug Administration, is intranasal esketamine (an anesthetic made from ketamine), although it has not yet been approved for use by the NHS. The psychedelic drugs LSD and psilocybin are also being studied for treatment-resistant depression in research studies, but have not yet been approved by regulatory agencies. When conducting these studies, there is careful monitoring by a medical professional to ensure the safety of the participants.

We know that both SSRIs and narcotics target the same brain receptor (known as 5HT-2A). In contrast, esketamine, which is similar to ketamine, acts on a different receptor (N-methyl-D-aspartate or NMDA) and affects the brain chemical glutamate.

So how do SSRIs and psychedelics work to reduce symptoms of depression? At present, we do not have the full picture. But the 5HT-2A receptor binds to the brain chemical serotonin, increasing its levels in the brain. A recent study has actually shown that serotonin decreases in people with depression.

However, SSRIs also affect the neurotransmitters GABA and glutamate. The latter has been linked to learning, cognition, and memory, suggesting that SSRIs may actually help restore cognitive function. Although the exact mechanisms of the drug are not yet fully understood, its antidepressant effects appear to work in a similar way to SSRIs due to their effects on 5HT-2A receptors. However, there are also other reactions to the drug, such as hallucinations.

Measuring brain plasticity

It has therefore been suggested that all of these drugs affect brain plasticity. However, in humans, levels of brain plasticity can be difficult to estimate. One common method scientists have used is to measure a protein called brain-derived neurotrophic factor (BDNF) in blood samples.

BDNF helps brain plasticity by increasing the number of synapses (sites where neurons can communicate with each other), as well as the branches and growth of developing neurons. Synapses are particularly important in the functioning of the brain because they allow the transmission of chemical and electrical signals from one nerve cell to another. Likewise, synapses also store chemicals in the brain for release.

There have been some studies that have shown that antidepressant medications increase BDNF. However, better techniques are needed to study plasticity in the human brain.

To develop better drugs, one approach is to find antidepressant drugs with a faster mechanism of action. According to the NHS website, SSRIs usually need to be taken for two to four weeks before any benefit is felt.

We suspected that one reason for this late effect may be that brain plasticity must occur with SSRI treatment. Because this process involves rewiring, such as creating synapses and circuits, it is not instantaneous, but is thought to take approximately 14 to 21 days.

In our study, which was a collaboration between the University of Cambridge and the University of Copenhagen, we used a new technique to measure plasticity in the human brain, after SSRI treatment, for the first time.

Thirty-two participants underwent positron emission tomography (PET) scans to detect the amount of a protein called synaptic vesicle glycoprotein 2A, or SV2A, in the brain. We know that SV2A is a marker for the presence of synapses. An increased quantity indicates a greater number of synapses, and thus higher brain plasticity.

Our results showed an increase in this protein as a result of escitalopram (SSRI). We found that in those taking escitalopram, increased SV2A was associated with increased duration of drug administration. Our findings suggest that brain plasticity increases over three to five weeks in healthy humans after daily escitalopram administration.

This is the first real evidence in humans that SSRIs actually promote neuroplasticity – which appears in the brain – and that this is one of the reasons why they can treat depression. Similar evidence from studies on the human brain is still needed for drugs.

It stands to reason that if antidepressant treatment facilitates brain plasticity, this would make it easier for people taking these treatments to learn new things. We know that the ability to adopt new strategies, and change them if they don’t work (supported by what researchers call cognitive flexibility), is key to recovering from depression.Conversation

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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