An Uncertain Future for Antidepressants: New Evidence Challenges Widely Accepted Serotonin Theory for Depression

An Uncertain Future for Antidepressants: New Evidence Challenges Widely Accepted Serotonin Theory for Depression

by Ayanava Ganguly | Edited by Maryam Kamel

Depression has become one of the major public health crises sweeping through the United States. Each year, almost 10% of all adult Americans will suffer from a depressive episode or illness, and the numbers are only continuing to rise. In fact, there has been a 59% increase in the number of depression cases for adolescents since 2007, and the stressors from COVID-19 pandemic have only made it worse.

In light of this, the global market for depression treatment has exploded, topping over $12 billion. From holistic/alternative medicine approaches to professional therapy-oriented solutions, the options for those seeking anti-depression treatment are ever-expanding. Nonetheless, one specific treatment has become particularly widespread: antidepressant medication. Comprising over 63% of the total market, antidepressants are largely categorized into either serotonin and noradrenaline reuptake inhibitors (SNRIs), or selective serotonin reuptake inhibitors (SSRIs). These drugs have become so widespread to the point where the common American could recognize them from their brand names, such as Prozac, Lexapro, and Zoloft. 

Antidepressants typically induce the same mechanism to reconfigure the brain chemistry of those suffering from depression. Though the complete mechanistic pathway of antidepressants has yet to be fully elucidated, it is generally understood that antidepressants target the production of certain neurotransmitters, such as serotonin and noradrenaline, and increase their levels by blocking the receptors that would otherwise inhibit them. Ultimately, increasing the biological levels of such neurotransmitters in the brain improves mood and emotion. In the past few decades, in particular, serotonin has become the vital target molecule for research investigating this explanation for antidepressant drug action. 

From the neurotransmitter-based explanation, it would logically follow that serotonin levels would be able to predict and diagnose depression, thereby enabling earlier intervention to curb the biochemical roots of depression. This concept was initially introduced in the 1960s and continues to serve as a justification for the prescription of antidepressants to this day. However, in a groundbreaking review published this July in the Journal of Molecular Psychiatry, Dr. Joanna Moncrieff and her team have proposed a strong, and potentially damning, challenge to this serotonin theory of depression. 

In their paper titled “The Serotonin Theory of Depression: a Systematic Umbrella Review of the Evidence,” Moncrieff et al. meta-analyzed 17 different reviews that had already been completed on serotonin-depression research. Their analysis revealed that there is no significant evidence that demonstrates a causal relationship between serotonin levels and depression and found that prolonged antidepressant use reduces the overall concentration of serotonin. These findings challenge the heavily purported theory that has thus far informed the course of development of depression treatments, necessitating a reconsideration of our current approach to treat depression. They also are robust enough to sustain any challenge, qualified by their employment of strict filtering criteria in the process of determining data inclusion, which led to the analysis of data from only high-quality reviews. 

So what does this mean for SSRIs and other antidepressant drugs that rely on the serotonin imbalance theory? With their efficacy called into question, these drugs could very possibly begin to witness a decline in prescription rates, particularly if scientists and doctors continue to struggle to validate their efficacy. In fact, in light of this review, researchers have already begun to investigate the potential of other types of solutions, such as the links between exercise and depression. Similar efforts will continue, as it is quite likely that there will be a renewed push towards utilizing forms of therapy or holistic medicine as the primary treatment for depression. The development of non-medication therapies to treat depression may prove more fruitful than the previous methods, which were based on neurotransmitter-based pharmaceutical research that views depression as a mere chemical imbalance—a view that has historically encouraged pessimistic, rigid outlooks on depression and increased the potential for a lifelong drug-dependence

Considering the amount of money invested in SSRIs though, there will certainly be pushback from pharmaceutical companies, who could use their large financial and political lobbying power to fund counter-studies to disprove this review’s results (as they have done historically). This is precisely why it is imperative to conduct unbiased research to produce results with enough weight to help us move forward, even if they oppose our previous judgments and generate controversy. It is these types of work that can better push the boundaries of our understanding of science. Ultimately, these efforts allow us to come a step closer to a world where we are able to provide substantial, effective treatments to those who need it, regardless of their respective illnesses. Hopefully, the Moncrieff et al. paper can act as the springboard for the research necessary to facilitate the development of improved depression treatments. 

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