Definition of Term and Background/Historical Context
Serotonin is a compound that functions in the human body in blood clotting, muscle contraction, and in regulating mood, appetite, sexual desire, sleep, memory, imagination, and learning (Frey 2012). Despite serotonin’s nickname as the “happiness hormone,” roughly 90% of the body’s serotonin is secreted by cells in the lining of the digestive tract and plays no direct role in mood regulation (Frey 2012). Serotonin that is produced in the gut functions in smooth muscle contraction in the respiratory, cardiovascular, and digestive systems or stored in platelets in the bloodstream, where it aids in blood clotting (Frey 2012).
In fact, what is now known to be serotonin was known only as “enteramine,” a smooth muscle contracting substance stored in the enterochromaffin cell system of the gastrointestinal tract from 1937 until 1952 (Whitaker-Azmitia & Mack 1999). The chemical structure of serotonin was identified as and published in 1948 by biochemist Maurice Rapport and named serotonin as a derivation of the Latin word “serum” and Greek word “tonic” (Rapport 1997). Following its discovery, defining serotonin’s role vexed scientists for years (Rapport 1997). Serotonin wasn’t found in the mammal brain until 1953 research conducted by biochemist Betty Twarog, and was not implicated in mental illness until Dilworth Woolley’s 1963 book The Biochemical Bases of Psychoses or the Serotonin Hypothesis about Mental Illness (Whitaker-Azmitia & Mack 1999).
Today, serotonin is known primarily as a monoamine neurotransmitter, or a neurotransmitter that contains a single amino group, with the chemical formula C10H12N2O (Frey 2012). Neurotransmitters are chemicals produced in the body that allow transmission of signals from one nerve cell to another (Frey 2012). Serotonin is found in plants and animals other than humans and is a common active ingredient in the venom of stinging nettle plants and insects (Frey 2012). In the human body, serotonin is synthesized from tryptophan, an amino acid which is found in many foods including bananas, eggs, milk, tofu, poultry, chickpeas, fish, and chocolate (Frey 2012). The 10% of serotonin in the human body not produced in the digestive system is created by the raphe nuclei, a collection of neurons on the brain stem (Frey 2012).
Diagram showing the role of serotonin in neuron (brain cell) communication (Frey 2012).
The first drug to manipulate serotonin to relieve depression was actually discovered by accident (Ramachandraih 2011). In 1952, scientists using the drug iproniazid to treat tuberculosis found that it had “mood elevating” effects. In subsequent studies, patients given iproniazid showed “increased vigor and appetite, weight gain, improved sleep, and sociability,” causing psychiatrist Max Lurie to coin the term “antidepressant” (Ramachandraih 2011). Iproniazid was later found to increase serotonin levels in the brain and in early studies, resulting in significant improvement in mood in 70% of depressed patients (Ramachandraih 2011). Although iproniazid was eventually taken off the market due to harmful side effects, it paved the way to development of the first selective serotonin reuptake inhibitor (SSRI) zimelidine by Dr. Arvid Carlsson in 1982. Zimeldine was taken off the market in 1984 due to serious neurological side effects, but served as a breakthrough in psychiatry as the first SSRI and laid the groundwork for the development for modern day SSRIs (Ramachandraih 2011).
SSRIs work by preventing serotonin from binding to a transporter protein which would remove serotonin from the synapse, effectively allowing serotonin to build up (Ross-Flanigan and Frey 2012). Also known as serotonin boosters, SSRIs are thought to work by “correcting chemical imbalances in the brain” a claim that will be contested in the next section of this entry (Ross-Flanigan and Frey 2015). SSRis are used to treat “serious, continuing depression that interferes with a person’s ability to function [by] helping reduce the extreme sadness, hopelessness, and lack of interest in life that are typical in people with depression” (Ross-Flanigan and Frey 2015). In addition, SSRIs are used to treat panic disorder, obsessive compulsive disorder, and are used “off-label” to treat other conditions such as premenstrual syndrome, eating disorders, obesity, self-mutilation, and migraines (Ross-Flanigan and Frey 2015).
Prozac, a modern SSRI, was approved by the FDA in 1988 and “rapidly revolutionized the treatment of depression, transform[ing] debilitating depression into a manageable disease for many patients” according to Top Drugs: Their History, Pharmacology, and Synthesis, a book authored by Jie Jack Li in 2015. By 2000, Prozac was the most widely-prescribed antidepressant drug in the United States, with a worldwide sales of almost $3 billion (Li 2015). By 2004, Zoloft, another SSRI, was the sixth best-selling medication in the US, with over $3 billion in sales, likely due “at least in part, to the widely disseminated advertising campaign starring Zoloft’s miserably depressed ovoid creature” (Lacasse and Leo 2005). Today, six SSRIs are approved by the Food and Drug Administration to treat depression: Celexa, Lexapro, Prozac, Paxil, Zoloft, and Viibryd, and about one in ten Americans are on an antidepressant (Frey 2012). From 1995 to 2005, there was a 254% increase in the prescription of antidepressants (Moncrieff and Kirsch 2005). The National Institute for Health and Clinical Excellence, a United Kingdom agency which sets national standards for healthcare, recommends that SSRIs should be “the first line of treatment” for moderate or severe depression, a conclusion that has broadly been accepted as valid (Moncrieff and Kirsch 2005).
Pictured: A shot from a Zoloft advertisement. As the advertisement progresses, the creature is shown becoming happy, suggesting the efficacy of Zoloft as an antidepressant (Activeminds.org).
Controversy/Perspectives
In a recent overview of modern drugs, as stated earlier, the SSRI Prozac was hailed as revolutionary, “transform[ing] debilitating depression into a manageable disease” (Li 2015). According to researchers Jonathan Leo and Jeffrey Lacasse, SSRI advertising has bolstered the antidepressant market, contributing to the fact that SSRIs are now among the best-selling drugs in medical practice (Lacasse and Leo 2005). Advertisements include claims regarding depression such as “Scientists believe that [depression] could be linked with an imbalance of a chemical in the brain called serotonin” continuing with “Zoloft works to correct this imbalance” (Lacasse and Leo 2005). Zoloft is not alone in making these claims, as these researchers also quoted a Paxil advertisement as stating “With continued treatment, Paxil can help restore the balance of serotonin” and included in their paper Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature the chart included below, with plentiful examples of SSRI advertisements making claims about the role of serotonin in causing and alleviating depression.
Selected Consumer Advertisements from SSRIs from Print, Television, and the World Wide Web (Lacasse and Leo 2005).
The problem lies in the fact that “in short, there exists no rigorous corroboration of the serotonin theory, [that a deficiency of serotonin causes depression], and a significant body of contradictory evidence” (Lacasse and Leo 2005). This sentiment is echoed by scientists and researchers across the field of psychiatry. In his 2013 book Spontaneous Happiness, Andrew Weil refers to the serotonin hypothesis of depression as “shaky at best” citing that “several studies have established that lowering serotonin levels does not negatively impact mood (Weil 2013). To further his point, Weil brings attention to the pharmaceutical Tianeptine, also known as Coaxil, which works by lowering synaptic serotonin rather than increasing it as SSRIs do, and has shown to be as effective as Prozac (Weil 2013).
Selected Quotations Regarding Serotonin and Antidepressants (Lacasse and Leo 2005).
To be as effective as Prozac, however, may not be the best benchmark for effectiveness, it turns out. The first analysis of antidepressant effectiveness, published in 1998, analysed 38 manufacturer-sponsored studies which included results from over 3,000 depressed patients, and found negligible differences in improvement in depression between those on actual antidepressants and those on dummy pills, with at least 75% of the effectiveness of these antidepressants stemming from a placebo effect (Weil 2013). Other studies found similar responses: in a 2008 analysis published in the journal Evidence-Based Mental Health, researchers conducted a meta-analysis of 47 clinical trials of the six most widely-prescribed antidepressants between 1987 and 1999 (all SSRIs) and found “virtually no difference in the improvement scores for drug and placebo in patients with moderate depression and only a small and clinically insignificant difference among patients with very severe depression” (Mcallister-Williams 2008). The difference in improvement in patients’ Hamilton Depression Rating Scale (HRSD) only became statistically significant in the most severely depressed statements with HRSD scores of more than 28, reflecting a decreased responsiveness to placebo rather than an increased responsiveness to antidepressants (Mcallister-Williams 2008). These findings are summarized in a chart below, which delineate the lack of clinical significance of antidepressants across 35 clinical trials.
“Mean Drug–Placebo Difference Scores as a Function of Initial Severity” The green horizontal line represents the UK’s National Institute for Health and Care Excellence (NICE) clinical significance threshold, and it is shown that many clinical studies for the most common antidepressants do not meet NICE significance levels. The trend can be observed, however, that the included antidepressants were more effective at improving depression in patients which more severe initial depression, as calculated by the Hamilton Depression Rating Scale (HRSD). Plotted values are sized according to sample sizes of the trial. The solid blue regression line represents the trend across all 35 trials; the dashed red line represents the trend excluding the left-most observation.
The same study which produced the graph above found that the placebo effect accounted for 80% of the found effect of SSRI antidepressants, contrasting the value with the placebo effect of pain medication as estimated to account for 50% of its effectiveness (Mcallister-Williams 2008). This study’s researchers conclude that “there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective” (Mcallister-Williams 2008). It is worth noting that only about 13% of people with depression have these “very severe symptoms” to warrant prescription of new-generation antidepressants by that study’s authors (Weil 2013).
A photo of St. John’s Wort in bloom. St. John’s Wort received its name from the fact that it blooms around the time of the feast of St. John the Baptist, as it has been used in traditional European medicine since the existence of the ancient Greeks, primary as a dietary supplement thought to alleviate depressive symptoms (National Center for Complementary and Integrative Health).
In 2002, the Journal of the American Medical Association (JAMA) published results of a study of 340 depressed adults treated with St. John’s wort, a placebo, or Zoloft – the conclusion of the study that “made front page news around the world” was that St. John’s wort worked no better than the placebo at relieving depression, resulting in television news shows featuring reporters “pointing to St. John’s wort products and advising consumers not to waste their money on natural remedies whose supposed benefits were nothing more than old wives tales (Weil 2013). The aspect of the study that wasn’t highly publicized, however, was that Zoloft also worked no better than the placebo (Weil 2013). In his book, Weil quoted one of the authors of the JAMA paper, Vanderbilt psychiatry researcher Steven Hollon, as saying “Most people [with depression] don’t need an active drug. For a lot of folks, you’re going to do just as well on a sugar pill or in conversations with your physicians as you will on medication. It doesn’t matter what you do, it’s just that you’re doing something” (Weil 2013).
“Doing something” as it turns out, could have an even broader meaning than psychotherapy. In recent randomized controlled trials, exercise was found to be as effective as the SSRI Zoloft at alleviating symptoms of depression (Lacasse and Leo 2005). In a 1996 study, researchers attempted to induce depression by depleting serotonin levels in patients by having them abstain from tryptophan-containing foods (as tryptophan is required for the body’s production of serotonin) and consume and amino acid drink, but even clinically depleting individuals’ serotonin levels yielded no consistent results on mood, resulting in the conclusion that monoamines, the class of compounds to which serotonin belongs due to the fact that it has one amine group, “are not necessary to maintain mood in healthy individuals” (Heninger 1996). Alternately, studies which prompted huge increases in brain serotonin by administering high-dose serotonin precursor L-tryptophan were also ineffective at relieving depression (Lacasse and Leo 2005). The US National Institute of Mental Health released a statement denouncing the efficacy of SSRIs as evidence for the serotonin theory, in other words, denying that serotonin deficiency causes depression (Lacasse and Leo 2005).
Illustration depicting a brain full of pills running empty on serotonin, suggesting the correlation between serotonin, happiness, and SSRIs, and also hinting at the medicalization of poor moods (Lacasse 2005).
How, then, did serotonin become known as the happiness hormone? Some researchers point to “publication bias” which has been found to be common especially in antidepressant research (Turner 2012). One form of publication bias is when trials in which drugs are found to not be effective or to contain unwanted side effects remain unpublished, and therefore less accessible (Turner 2012). Publication bias can result in drugs seeming safer or more effective than they really are, which can affect clinical decision-making and patient outcomes (Turner 2012). In a study analyzing selective publishing in antidepressant studies submitted to the Food and Drug Association (FDA) data on 12,564 patients’ in 74 studies, researchers found that 31% of studies were not published (Turner 2008). In the same analysis, researchers found a bias towards the publication of positive results, stating that positive results were more likely to be published, and that non-positive results were more likely to be framed in a way which made them appear positive (Turner 2008).
Effect of FDA Regulatory Decisions on Publication. The figure above shows that almost all of the antidepressant publications approved by the FDA found antidepressants to have a positive effect, and that most antidepressant publications that did not get published did not find a positive effect of antidepressants. (Turner 2008)
A publication in the British Medical Journal found similar results. In an analysis of 42 placebo-controlled studies of the five SSRIs submitted to the Swedish drug regulatory authority compared with the studies actually published between 1983 and 1999, researchers found that selective publication and selective reporting in studies sponsored by pharmaceutical companies resulted in biased public data (Hans 2003). Due to activities such as non-publishing of studies which don’t support antidepressant efficacy, researchers stated that “any attempt to recommend a SSRI from the publicly available data only is likely to be based on biased evidence” (Hans 2003). Despite an abundance of data contradicting claims of serotonin’s relationship with depression by antidepressant manufacturers, advertisements with unsubstantiated claims continue to run all over the US. Although the FDA has sent ten warning letters to antidepressant manufacturers since 1997 regarding the accuracy of the information they are disseminating, the FDA has never cited a pharmaceutical company for inaccurate information relating to depression’s relationship with serotonin, likely in the financial interests of pharmaceutical companies (Lacasse and Leo 2005).
Putting aside the questionable accuracy of serotonin’s relationship with depression, decrease of synaptic serotonin can have tangible harmful effects on the human body. Some reports have found increase in thoughts of suicide in patients taking SSRIs (Ross-Flanigan and Frey 2015). Suicidal thoughts would be counterintuitive to an antidepressant, yet SSRIs are still one of the most widely prescribed drugs in the world. Another possible negative outcome from consumption of SSRIs is serotonin syndrome, a potentially life-threatening condition which occurs when too much serotonin builds up in the body, which can be caused by taking multiple SSRIs (Basile 2012). Symptoms of serotonin syndrome can include high blood pressure, high fever, nausea, vomiting, diarrhea, headache, sweating, increased heart rate, tremor, muscle twitching and rigidity, shock, coma, and death, although with treatment, the prognosis for serotonin syndrome is good (Basile 2012). Despite lack of a solid foundation of research and the documentation of possible negative symptoms as a result, in 2017 more than one in ten Americans have the serotonin content of their brains manipulated by an SSRI, with SSRI prescription still on the rise (Moncrieff and Kirsch 2005). Regardless of mounting data, one thing is clear: the popular culture association of serotonin with happiness is not going away anytime soon.
Relation to Politics of Health
First and foremost, serotonin relates to the politics of health through the skewed methods of scientific knowledge production. Although not discussed in class, the ideas of selective publication and selective reporting create biased results in so-called scientific studies as discussed earlier, with studies that do not find a positive correlation between SSRI use and alleviation of depression often do not get published (Turner 2008). This skewed method of scientific knowledge production, unbeknownst to the public, creates a false idea of truth in public knowledge.
Widespread dissemination of falsehoods regarding serotonin’s relationship with depression such as in ads which make claims such as “Celexa helps to restore the brain’s chemical balance by increasing the supply of a chemical messenger in the brain called serotonin” despite an absolute lack of a proper “balance” or amount of serotonin in the brain for optimal functioning (Lacasse and Leo 2005). Other advertisements make claims such as “Lexapro appears to work by increasing the available supply of serotonin … Lexapro improves symptoms of depression” (Lacasse and Leo 2005) Advertisements which claim SSRI improvement in symptoms of depression are misleading in that they imply significant improvement in depression symptoms above and beyond the effect of placebos, which doesn’t appear to be true for most suffering with depression (Weil 2013).
Public misinformation regarding serotonin, SSRIs, and depression create an American public that largely falls into the definition of ready to consent that Jill Fisher creates in relation to pharmaceutical trials (Fisher 2007). In relation to SSRIs, most of the American public, with little reason to doubt widespread claims of drug companies, are ready to consent to pharmaceutical SSRI trials but more despairingly, are also ready to consent to SSRI prescription, as they are in a compromised situation without full knowledge of the subject, resulting in almost definite consent for the proposed treatment, most starkly evidenced by lack of public availability of SSRI studies which find no positive effect of SSRIs on mood (Turner 2008).
Finally, serotonin’s commonly-believed association with depression has been used as a vehicle for medicalization, defined by Conrad as as a “process by which non-medical problems become defined and treated as medical problems, usually in terms of illnesses and disorders” (Mintzes 2002). Direct to consumer advertising of SSRIs explicitly use the word serotonin to encourage healthy people that they need medical attention, suggesting that SSRIs can cure their negative feelings, often conveniently coded as serotonin deficiencies, whether or not they are actually the result of a mental illness (Mintzes 2002). In actuality, serotonin is not the simple feel-good chemical which it is commonly believed to be; rather it is a highly politicized neurotransmitter which plays a role in medicalization of normal feelings, and deceitful scientific knowledge production which results in an uninformed populus that can be defined as ready to consent to SSRI prescription.
Works Cited
Basile, Maria Eve. “Serotonin Syndrome.” The Gale Encyclopedia of Mental Health, edited by Kristin Key, 3rd ed., vol. 2, Gale, 2012, pp. 1385-1387. Gale Virtual Reference Library, http://link.galegroup.com/apps/doc/CX4013200426/GVRL?u=nash87800&sid=GVRL&xid=d59b092b. Accessed 7 Apr. 2018.
Göthert, M. (2013). Serotonin discovery and stepwise disclosure of 5-HT receptor complexity over four decades. Part I. General background and discovery of serotonin as a basis for 5-HT receptor identification. Pharmacological Reports: PR, 65(4), 771-86.
Heninger, G., et al. “The Revised Monoamine Theory of Depression: A Modulatory Role for Monoamines, Based on New Findings From Monoamine Depletion Experiments in Humans.” Pharmacopsychiatry, vol. 29, no. 01, 1996, pp. 2–11., doi:10.1055/s-2007-979535.
Fisher, Jill A. “Ready-to-Recruit” or “Ready-to-Consent” Populations … Qualitative Inquiry Fisher, Jill. “’Ready-to-Recruit’ or ‘Ready-to-Consent’ Populations? Informed Consent and the Limits of Subject Autonomy.” Qualitative Inquiry, vol. 13, no. 6, 2007, pp. 875–894.
Frey, Rebecca J. “Serotonin.” The Gale Encyclopedia of Mental Health, edited by Kristin Key, 3rd ed., vol. 2, Gale, 2012, pp. 1380-1385. Gale Virtual Reference Library, http://link.galegroup.com/apps/doc/CX4013200425/GVRL?u=nash87800&sid=GVRL&xid=f06d2d29. Accessed 7 Apr. 2018.
Lacasse, Jeffrey R, and Jonathan Leo. “Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature.” PLoS Medicine, vol. 2, no. 12, Aug. 2005, doi:10.1371/journal.pmed.0020392.
Li, Jie Jack. Top Drugs: Their History, Pharmacology, and Syntheses, Oxford University Press, Incorporated, 2015. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/vand/detail.action?docID=2068362.
Lu, Andrew. “The Communications Culture of Antidepressants.” The Communications Culture of Antidepressants – Emerging Scholars, scholars.activeminds.org
Mcallister-Williams, R H. “Do Antidepressants Work? A Commentary on ‘Initial Severity and Antidepressant Benefits: a Meta-Analysis of Data Submitted to the Food and Drug Administration’ by Kirsch Et Al.” Evidence-Based Mental Health, vol. 11, no. 3, Jan. 2008, pp. 66–68., doi:10.1136/ebmh.11.3.66.
Melander Hans, Ahlqvist-Rastad Jane, Meijer Gertie, Beermann Björn. “Evidence B(i)Ased Medicine—Selective Reporting from Studies Sponsored by Pharmaceutical Industry.” BMJ, vol. 102, no. 3, 2003, p. 638., doi:10.1097/00006250-200309000-00040.
Mintzes, Barbara. “Direct to Consumer Advertising Is Medicalising Normal Human Experience.” BMJ: British Medical Journal 324.7342 (2002): 908–911. Print.
Ross-Flanigan, Nancy, and Rebecca J. Frey. “Selective Serotonin Reuptake Inhibitors.” The Gale Encyclopedia of Medicine, edited by Jacqueline L. Longe, 5th ed., vol. 7, Gale, 2015, pp. 4524-4527. Gale Virtual Reference Library, http://link.galegroup.com/apps/doc/CX3623301653/GVRL?u=nash87800&sid=GVRL&xid=6bcffdc2. Accessed 10 Apr. 2018.
Turner, Erick H., et al. “Publication Bias in Antipsychotic Trials: An Analysis of Efficacy Comparing the Published Literature to the US Food and Drug Administration Database.” PLOS Medicine, Public Library of Science, 2012, journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001189.
Turner, Erick H., et al. “Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy | NEJM.” New England Journal of Medicine, 2008, www.nejm.org/doi/full/10.1056/NEJMsa065779.
“St. John’s Wort.” National Center for Complementary and Integrative Health, U.S. Department of Health and Human Services, 1 Dec. 2016, nccih.nih.gov/health/stjohnswort/ataglance.htm.
Weil, Andrew. Spontaneous Happiness: a New Path to Emotional Well-Being. Little Brown, 2013.
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