The Latest on the Effects of Antidepressants

The Latest on the Effects of Antidepressants

By Jim Windell

             It’s conventional wisdom that typical antidepressants are effective because they boost the levels of serotonin and noradrenalin in synapses. In fact, some antidepressants are referred to as SSRIs – selective serotonin reuptake inhibitors.

            On the other hand, it is thought that a relatively new fast-acting antidepressant – ketamine – works by inhibiting receptors for the neurotransmitter glutamate.

            But, what if this conventional wisdom is wrong?

            A new study published this week in Cell suggests that antidepressants bind directly to a BDNF receptor known as TrkB. This discovery challenges the thinking about the primary role of serotonin or glutamate receptors in the effects of antidepressants.

            It is known that neurotrophic factors regulate the development and plasticity of the nervous system. And that all antidepressants increase the quantity and signaling of the brain-derived neurotrophic factor (BDNF) in the brain. Up to now, it was thought that the drugs act on BDNF indirectly, through serotonin or glutamate receptors.

            This new study, led by the Neuroscience Center and the Department of Physics at the University of Helsinki, set out to investigate the binding of antidepressants from different drug classes to the TrkB receptor. All the antidepressants examined, including fluoxetine (an SSRI), imipramine (a tricyclic antidepressant) and the rapid-acting ketamine, interacted with TrkB.

            The principal investigator of the study, Professor Eero Castrén, commented that "We found that all antidepressants boost BDNF signaling by binding to its TrkB receptor. This signaling is necessary for the cellular and behavioral effects of antidepressants in our experimental models. The effects of antidepressant on plasticity do not therefore require increases in the serotonin levels or the inhibition of glutamate receptors, as previously thought."

            Castrén went on to explain that the drugs do not directly activate TrkB. “Instead, they sensitize the receptor to the effects of BDNF," Castrén says.

           In addition to findings pertaining to the effects of antidepressants, the study produced a substantial amount of new information on the structure and function of the growth factor receptor.

           Ketamine, which has been used as an anesthetic, is becoming increasingly utilized as an antidepressant. The researchers were surprised to find that both slow-acting SSRIs and rapid-acting ketamine act by binding to the same site in TrkB.

           SSRI drugs bind to the serotonin transporter protein much more readily than to TrkB, but the binding of ketamine to the glutamate receptor and TrkB occurs at similar drug concentrations.

           "Previous studies have shown that in SSRI therapy, drugs gradually reach the high brain concentration needed for binding to the TrkB receptor,” Castrén says, “whereas intravenously administered ketamine and esketamine as a nasal spray reach the level needed for binding quickly, in a matter of minutes.”  The difference, he says, in the onset of action for SSRIs and ketamine may be caused by their different capacity to reach the concentration needed for binding with TrkB receptors.

           To read the original journal article, find it with this reference:

Plinio C. Casarotto, Mykhailo Girych, Senem M. Fred, Vera Kovaleva, Rafael Moliner, Giray Enkavi, Caroline Biojone, Cecilia Cannarozzo, Madhusmita Pryiadrashini Sahu, Katja Kaurinkoski, Cecilia A. Brunello, Anna Steinzeig, Frederike Winkel, Sudarshan Patil, Stefan Vestring, Tsvetan Serchov, Cassiano R.A.F. Diniz, Liina Laukkanen, Iseline Cardon, Hanna Antila, Tomasz Rog, Timo Petteri Piepponen, Clive R. Bramham, Claus Normann, Sari E. Lauri, Mart Saarma, Ilpo Vattulainen, & Eero Castrén. Antidepressant drugs act by directly binding to TRKB neurotrophin receptorsCell, 2021; DOI: 10.1016/j.cell.2021.01.034

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