Novel Compounds Show Potential for Treating Anxiety Disorders With Fewer Adverse Effects

Research efforts are continuing to identify pharmacotherapy for the treatment of mental illnesses such as depression and anxiety disorders with a balanced benefit-to-adverse-effect ratio.

Despite the efficacy of some drugs in treating these illnesses, the adverse effects (AEs) associated with treatment can have a detrimental impact on medication adherence and overall health. To address these challenges, investigators from the Medical University of Vienna are exploring new compounds that may be used to treat neuropsychiatric disorders.

They found that lead compounds may lower the risk of abuse and other AEs compared with other drugs currently being evaluated for mental health disorders. Their findings were recently published in Molecular Psychiatry.

Preclinical experiments indicated the potential for certain substances from the family of synthetic cathinone compounds in treating mental illnesses. Cathinones have been shown to release monoamines, such as noradrenaline, dopamine, and serotonin, according to the study, which was led by Harald Sitte of the Institute of Pharmacology at the Medical University of Vienna’s Center for Physiology and Pharmacology.

"These substances first showed serotonin-related effects in our cell models, and then also in our mouse model," Dr Sitte said in a press release.

He added that the messenger substance is considered a vital factor in pharmacotherapy for depression and anxiety disorders, including social phobias or post-traumatic stress disorder. Cathinone compounds utilized in the analysis were targeted because of the preference for releasing serotonin without significantly increasing the dopamine level in the brain's reward center, according to Sitte.

"Consequently, the new drugs we are researching are less likely to be abused and are also associated with fewer adverse effects overall," he said in the release.

Conditions such as depression and anxiety disorders are treated by elevating extracellular serotonin levels in the brain via selective serotonin reuptake inhibitors (SSRIs).

The method of action for SSRIs is based on blocking the reuptake of serotonin from the synaptic cleft. This causes the amount of serotonin in the extracellular space to increase, according to the study authors, who added that traditional antidepressants block the serotonin transporter.

However, recent evidence from preclinical and clinical studies suggests the potential for drugs that cause serotonin release via the serotonin transporter, such as substances that invert the natural transport direction of the transporter, according to the study. The authors noted that the serotonin-releasing agents currently being evaluated in clinical trials, such as MDMA, have a risk for abuse and harmful AEs.

"Our research identified the first representatives of a new serotonin-releasing class of drugs that do not produce various adverse effects," Sitte said in the press release.

Reference

Felix P. Mayer, Marco Niello, Daniela Cintulova, Spyridon Sideromenos, Julian Maier, Yang Li, Simon Bulling, Oliver Kudlacek, Klaus Schicker, Hideki Iwamoto, Fei Deng, Jinxia Wan, Marion Holy, Rania Katamish, Walter Sandtner, Yulong Li, Daniela D. Pollak, Randy D. Blakely, Marko D. Mihovilovic, Michael H. Baumann, Harald H. Sitte. Serotonin-releasing agents with reduced off-target effects. Molecular Psychiatry, 2022; DOI: 10.1038/s41380-022-01843-w. Accessed December 8, 2022.