Researchers ID Substance That May Ease Side Effects of Tricyclic Antidepressants
Danish researchers have discovered a new substance that may help relieve some of the more severe side effects of tricyclic antidepressants.
Tricyclic antidepressants, such clomipramine (Anafranil) and amoxapine (Ascendin), are older generation-drugs still used to treat some patients with depression, bipolar or chronic pain. For some people, tricyclics are more effective for severe levels of depression than the drugs used for mild and moderate depression.
But unfortunately, tricyclic antidepressants have a downside — significantly more serious side effects. The side effects can be anything from life-threatening heart problems to severely dry mouth, visual disorders, development of mania, weight problems and digestive challenges.
Some of these side effects are so severe that many people stop taking the drug and thus are unable to continue treatment for their depression.
In a new study, researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen, in collaboration with Lundbeck A/S and the National Institutes of Health in Baltimore, have discovered a substance that may solve this problem. Their findings are published in the journal Nature Communications.
“We have discovered a substance, Lu AF60097, that works in a different way from the ones presently in use. If the new substance works, it may help the existing drugs get rid of the serious side effects,” says Claus Juul Løland, professor at the department of neuroscience at the Faculty of Health and Medical Sciences.
In people with severe depression, levels of the neurotransmitter serotonin are often very low. Antidepressant drugs make adjustments to get a higher level of active serotonin.
“The antidepressants we use today work by going in and binding to the same site as serotonin on the serotonin transporter (SERT). The antidepressants block the return transport of serotonin and thereby also the removal of the active serotonin. But such blockage requires a relatively large dose of the antidepressant substance. And with the tricyclic antidepressants, that causes some serious side effects,” says Løland.
The substance discovered by the researchers binds to another site on SERT: the ‘allosteric site’. When a substance binds to the allosteric site rather than the same site as serotonin, it is possible to regulate the function of the serotonin transporter instead of completely blocking it.
“In this case, we have shown that when we bind this substance to the allosteric site while giving the tricyclic antidepressant, we can amplify the binding of the antidepressant substance. Therefore, we can use a much smaller concentration of the antidepressant substance. It might cause fewer side effects, but have the same therapeutic effect,” says Løland.
Over a long period of time and in several rounds, the research team has screened a number of substances from Lundbeck’s drug library to find a substance that had a sufficiently strong link to the allosteric site to make it possible to study the pharmacological effect. With Lu AF60097, they finally succeeded.
But there is still a long way to go before the substance can be used as an actual drug. The researchers have shown that a substance that binds to the allosteric site can have this pronounced, pharmacological effect in cells and in rats. From here, it is up to the pharmaceutical companies to develop substances that may have the same effect in humans.
“We have taken the first step. But perhaps also the biggest. We have shown that the concept works. If it also works in practice, hopefully in the future it can be used to treat people with severe depression.”
Pedersen, T. (2020). Researchers ID Substance That May Ease Side Effects of Tricyclic Antidepressants. Psych Central. Retrieved on August 7, 2020, from https://psychcentral.com/news/2020/03/27/researchers-id-substance-that-may-ease-side-effects-of-tricyclic-antidepressants/155138.html