Antidepressant Drugs May Act in a Previously Unknown Way

Graphical Abstract: Antidepressant drugs act by directly binding to TrkB neurotrophin receptors.

Source: Casarotto et al., 2021/open-access paper in Cell (CC BY 4.0)

Key Points: A new study challenges previously held notions about how antidepressants work. This research suggests that slow-acting SSRIs and fast-acting ketamine bind directly to a brain-derived neuro­trophic factor (BDNF) receptor and promote depression-alleviating neuronal plasticity without help from serotonin or glutamate.

A new international study (Casarotto et al., 2021) collaboratively led by senior author Eero Castrén of the University of Helsinki's Neuroscience Center along with colleagues in the Department of Physics investigates how three different antidepressant drugs—fluoxetine (an SSRI sold under the brand name Prozac), imipramine (a tricyclic antidepressant), and rapid-acting ketamine (a new "breakthrough therapy" for treatment-resistant depression; available only at a certified doctor's office or clinic)—interact with a BDNF receptor known as TrkB. This open-access paper was published on February 18 in the peer-reviewed journal Cell.

Historically, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants' effects were thought to be rooted in their ability to keep more serotonin and norepinephrine available to the brain by increasing levels of these neurotransmitters in the synaptic gap. Along this same line, the antidepressant effect of ketamine was thought to function primarily by inhibiting glutamate receptors.

Notably, the three antidepressant drugs examined in this study (fluoxetine, imipramine, and ketamine) interacted with TrkB without necessarily increasing or inhibiting other neurotransmitters such as serotonin, norepinephrine, or glutamate.

Although previous research has identified a link between antidepressants increasing neurotrophic factors such as BDNF, which play a role in regulating neuroplasticity, until now, researchers thought that antidepressant drugs acted on BDNF indirectly via glutamate and serotonin receptors. This study is potentially groundbreaking because it shows that antidepressants trigger direct binding to BDNF receptors.

"We found that all antidepressants boost BDNF signaling by binding to its TrkB receptor," Castrén said in a news release. "This signaling is necessary for the cellular and behavioral effects of antidepressants in our experimental models. The effects of antidepressants on [neuronal] plasticity do not, therefore, require increases in the serotonin levels or the inhibition of glutamate receptors, as previously thought."

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

Molecular modeling performed by Ilpo Vattulainen's Department of Physics research group as part of this study identified "the binding site of antidepressants in the transmembrane region of TrkB" and "demonstrated that the structure of TrkB is sensitive to the cholesterol concentration of the cell membrane." Creating mutations of the TrkB antidepressant-binding motif both in vitro and in vivo "impaired cellular, behavioral, and plasticity-promoting responses to antidepressants."

Three bullet-pointed highlights from this study:

• Several antidepressants, including SSRIs and ketamine, directly bind to TrkB.
• Antidepressant binding to TrkB facilitates BDNF action and promotes neuronal plasticity.
• Point mutation in TrkB transmembrane region blocks the effects of antidepressant drugs.

Although antidepressants like fluoxetine (Prozac) and sertraline (Zoloft) were dubbed "selective serotonin reuptake inhibitors" soon after their FDA approval in the late 1980s, early '90s, a growing body of 21st-century evidence suggests that these antidepressant drugs don't work solely by increasing serotonin levels in the brain; it's more complicated than that. Based on accumulating evidence, one could speculate that the SSRI nomenclature falls short of accurately describing how these antidepressants work and may be a misnomer.

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Since the early 2000s, researchers have known that antidepressant drugs and aerobic exercise both promote neuronal plasticity and neurogenesis (birth of new neurons). Just like recent studies (Gökçe et al., 2019) have investigated the correlation between an uptick of exercise-induced BDNF and a lower risk of major depressive disorders, other studies have investigated how antidepressants' efficacy may be tied to BDNF. (See "This Is Why Aerobic Exercise Is Like 'Miracle-Gro' for the Brain.")

Last year, researchers at Rockefeller University's Laboratory of Molecular and Cellular Neuroscience (Chottekalapanda et al., 2020) identified how a molecular pathway involving activator protein-1 (AP-1) facilitates a chain reaction that "switches on several genes that promote neuronal plasticity and remodeling, allowing the brain to reverse the neurological damage associated with depression." According to the authors: "After two to three weeks, the regenerative effects of those changes can be seen—and felt." This antidepressant research helped to explain why SSRIs take about 14 days to kick in.

The latest research by Casarotto et al. (2021) also helps to explain why SSRIs tend to be slow-acting. And why, in contrast, ketamine has a rapid effect and can alleviate depressive symptoms within a matter of minutes. "SSRI drugs bind to the serotonin transporter protein much more avidly than to TrkB, but the binding of ketamine to the glutamate receptor and TrkB occurs at similar drug concentrations," the authors note.

First author Plinio Casarotto, a postdoctoral researcher in UH's Neuroscience Center, and coauthors sum up: "The present findings demonstrate that antidepressants bind to TrkB and allosterically increase BDNF signaling, thereby directly linking the effects of antidepressants to neuronal plasticity."

"Antidepressant-induced plasticity is utilized by network-specific neuronal activity to guide re-wiring of plastic networks, allowing beneficial re-adaptation of networks abnormally wired during development or by stress (Castrén, 2013)," they conclude. "Our data suggest a framework that unites the effects of all antidepressants with therapy-mediated guidance to achieve the clinical antidepressant response."

Graphical abstract (Casarotto et al., 2021) from open-access Cell paper "Antidepressant drugs act by directly binding to TRKB neurotrophin receptors" (CC BY 4.0)