The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter

Surprising information can come to light when you study a chemical substance at atomic level resolution – details that overturn hitherto accepted knowledge and offer unprecedented potential.

This is what the members of a Danish-American research team discovered when they studied the antidepressant vilazodone using cryo-EM, an advanced method of electron microscopy.

This drug has been on the market in the USA since 2011, and in Canada since 2018, and is approved for treating depression.
The research team’s finding was recently published in the high-ranking scientific journal Nature Communications.

Vilazodone is one of the more recent members of the SSRI (selective serotonin reuptake inhibitor) family. It is an antidepressant also known by the somewhat misleading term “happy pill”.

SSRIs regulate the protein that in humans and other mammals transports the serotonin neurotransmitter in the brain. And in many patients in treatment with antidepressants, SSRI regulation of serotonin transport produces good results.

It was previously assumed that all SSRIs have the same basic mechanism of action – they act as a kind of on/off switch.
Professor Claus Juul Løland explains that this was the way it looked when a substance was tested for SSRI characteristics – and thus the potential for developing antidepressants – in the laboratory.

‘But we just had a feeling that, in fact, the way vilazodone binds to the serotonin-transporting protein in the brain is different from that of all other SSRIs. We decided to investigate whether this was the case – and we needed to use cryo-EM to do so. Once the tests were finished and we’d analysed the results with our US colleagues, we could see that our suspicions were right: vilazodone binds in its own unique way.’

Professor Løland headed the project, and as he explains, this knowledge provides exciting potential to develop novel SSRIs.

Fine-tuned antidepressants

The new type of antidepressant now looming on the horizon is an SSRI with a somewhat “customised” effect, says Professor Løland, who is conducting his research with funding from a Lundbeck Foundation Ascending Investigators grant.

‘Thanks to the cryo-EM experiments, we could literally see the vilazodone and serotonin-transporting protein grabbing hold of each other at atomic level. We then performed a wide range of other experiments, which confirmed the cryo-EM result. So, we now know – in detail – where vilazodone binds to the protein. This means we can begin to design other, novel SSRIs to treat depression, and they’ll also need to bind to this specific site.’

The special thing about this binding site on the serotonin-transporting protein is that it is able to accommodate many more functions than the relatively limited on/off mechanism characteristic of all other known SSRIs. 

‘And that’s what makes it realistic to consider developing novel SSRIs with a “customised” effect. We’re not quite sure yet what this will entail. But the bottom line is that we can now aim to design novel drugs in a much more differentiated way than currently possible, making allowance for the many different treatment needs and biological conditions characteristic of depression. Instead of a simple on/off switch, the new binding site may make it possible to turn activity up or down – depending on the amount of serotonin present.’

Hopefully, this means that we will eventually be able to expand our range of antidepressants to enable us to offer a drug that will alleviate the condition of most patients. And, as Professor Løland says:

There’s definitely a need for this. Today, the classic treatments fail to benefit almost a third of patients suffering from severe depression.

Further information

Read the full article in Nature Communications. 

Read the article in Danish published on the website of the Lundbeck Foundation and another article in Danish published by the Danish Broadcasting Media, DR.