Neuroscientists recently identified molecular mechanisms in the brain that may explain why the active ingredient (fluoxetine) in selective serotonin reuptake inhibitors (SSRIs) sold under brand names like Prozac or Sarafem often takes about two weeks to improve patients' depressive symptoms. These findings (Chottekalapanda et al., 2020) by researchers at Rockefeller University's Laboratory of Molecular and Cellular Neuroscience appear in the July issue of Molecular Psychiatry.
For this study, first author Revathy Chottekalapanda and her team treated a strain of mice that were genetically predisposed to anxiety and depressive-like behavior with fluoxetine for 28 days. During this treatment, they used real-time RNA analysis and behavioral tests to monitor how and when the animals' behavior changed in relation to specific gene expression activity changes.
In general, only about two-thirds of clinically depressed patients respond to fluoxetine-based SSRI antidepressants. The latest fluoxetine research in mice at Rockefeller University traces a complex chain reaction of molecular events that occur like clockwork between 9-14 days of treatment.
On the ninth day of fluoxetine treatment, the researchers observed a significant uptick in mRNA expression of a gene called c-Fos. Notably, by day 14, the mice being treated with fluoxetine began to show fewer depression-like symptoms.
After doing a deeper dive into the domino effect of these molecular mechanisms, Chottekalapanda and colleagues discovered that the upregulation of c-Fos activates the production of activator protein-1 (AP-1). Ultimately, AP-1 influences other players (such as BDNF) that increase neuronal plasticity, which boosts the brain's ability to rewire and remodel itself in ways that reduce depressive symptoms.
Neuroscientists have known for decades that brain-derived neurotrophic factor (BDNF) improves neurogenesis and neuroplasticity. Both aerobic exercise and antidepressants can increase the production of BDNF. As I wrote in The Athlete's Way (2007):
"Contrary to the original idea that antidepressants (especially serotonin reuptake inhibitors) work solely by keeping serotonin in circulation longer, the latest research (Shimizu et al., 2003) shows that the key to their effectiveness may lie in neuroplasticity and neurogenesis. Like exercise, antidepressants work by stimulating cell structures associated with reducing depression to grow and strengthen. Whether neurogenesis and brain plasticity are improved by antidepressants or by exercise (Vaynman et al., 2004), changes in cell growth take time, which helps to explain why it takes two to four weeks for exercise or antidepressants to kick in."
Although the scientific validity of the above passage has held up relatively well over time, based on the most recent findings (2020) from Rockefeller University, AP-1 plays a previously unrecognized role in optimizing neuroplasticity.
Fluoxetine Has Been Around for a Half-Century But Remains Mysterious
SSRIs are the most widely prescribed medication for mood disorders. In the United States, almost 22 million fluoxetine prescriptions were filled in 2017. Although selective serotonin reuptake inhibitors initially elevate extracellular serotonin levels in the brain, whether or not increased serotonin levels drive the long-term therapeutic effects of fluoxetine has been hotly debated for decades. Even though fluoxetine has been widely used since the late 1980s, scientists still don't know precisely how SSRIs work.
The Eli Lilly company discovered fluoxetine in the early 1970s; however, the FDA didn't approve it as a treatment for depression until December 1987. In January 1988, Eli Lilly began marketing and selling Prozac as "happiness in a blister pack."
Unfortunately, not long after, anecdotal reports started to surface that Prozac didn't work for everyone. Additionally, if this SSRI was going to effectively reduce someone's symptoms of clinical depression, fluoxetine seemed to take a couple weeks to kick in.
Understanding all of the molecular players (beyond just serotonin) that make fluoxetine efficacious could, someday, help psychopharmacologists predict who will respond to SSRIs and who won't.
An August 13, 2020 news release from Rockefeller University explains the play-by-play sequence of molecular events that occur in the brain after taking fluoxetine for 28 days:
"First, [fluoxetine] ramps up the amount of serotonin available in the brain; this triggers a molecular chain reaction that ultimately makes brain cells increase their AP-1 production—an effect that only begins to take off on day nine of treatment. AP-1 then switches on several genes that promote neuronal plasticity and remodeling, allowing the brain to reverse the neurological damage associated with depression. After two to three weeks, the regenerative effects of those changes can be seen—and felt."
Interestingly, when a molecular pathway necessary for the production of AP-1 was blocked in these mice, the antidepressant benefits of fluoxetine were "severely blunted." The researchers also found that "blocking the formation of AP-1 partially reversed the activation of some of the genes responsible for the antidepressant response." The researchers speculate that patients who don't respond to SSRIs may not be producing AP-1.
These findings may have some clinical implications. First, targeting AP-1 pathways could be used as a biomarker to predict how a patient will respond to an SSRI. Second, identifying the molecular chain reaction required to activate AP-1 production could lead to interventions that speed up how quickly activator protein-1 begins to affect brain plasticity and remodeling, which could reduce how long it takes for an SSRI to start working.
Chottekalapanda is currently conducting a series of experiments designed to elucidate "precise reasons for the nine-day delay in AP-1 production" and "discover precisely how the genes that AP-1 regulates in response to fluoxetine would promote neuronal plasticity." Solving this part of the puzzle could result in novel treatments that hack into the AP-1 pathway that promotes brain plasticity and might benefit patients with neurological and neurodegenerative conditions like Alzheimer's and Parkinson's disease.
"Future studies to unravel the mechanisms that trigger the activation of these molecules will, therefore, help design novel strategies for treating all neurological disorders that benefit from improving neuroplasticity," the authors conclude.
Revathy U. Chottekalapanda, Salina Kalik, Jodi Gresack, Alyssa Ayala, Melanie Gao, Wei Wang, Sarah Meller, Ammar Aly, Anne Schaefer & Paul Greengard. "AP-1 Controls the p11-dependent Antidepressant Response." Molecular Psychiatry (First published online: May 21, 2020) DOI: 10.1038/s41380-020-0767-8