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Open access, freely available online
Serotonin and Depression: A Disconnect
between the Advertisements
and the Scientifi c Literature

Jeffrey R. Lacasse, Jonathan Leo*
depressed suicidal patients to controls, Pfi zer’s television advertisement for plagued with methodological diffi culties a chemical imbalance, and that “Zoloft Tables 1 and 2). For instance, sertraline Board and colleagues stated, “Reported behavior (e.g. violent suicide attempts) over $3 billion in sales [2] likely due, at least in part, to the widely disseminated advertising campaign starring Zoloft’s Table 2). The pertinent question is: are fi ndings from studies that have fl aws congruent with the scientifi c evidence? The Serotonin Hypothesis
selling drugs in medical practice [2].
results [9]. Likewise, researchers found tryptophan, were ineffective at relieving Citation: Lacasse JR, Leo J (2005) Serotonin
and depression: A disconnect between the advertisements and the scientifi c literature. PLoS Med Copyright: 2005 Lacasse and Leo. This is an open-
access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source “Particularly in the area of depression Abbreviations: DTCA, direct-to-consumer
advertising; FDA, Food and Drug Administration; SSRI, Jeffrey R. Lacasse is at Florida State University College prevention] to look into this particular of Social Work, Tallahassee, Florida, United States of America. Jonathan Leo is at Lake Erie College of Osteopathic Medicine, Bradenton, Florida, United Competing Interests: The authors declare that no
competing interests exist and that they received no *To whom correspondence should be addressed. The Essay section contains opinion pieces on topics of broad interest to a general medical audience. (Illustration: Margaret Shear, Public Library of Science) DOI: 10.1371/journal.pmed.0020392
December 2005 | Volume 2 | Issue 12 | e392 Table 1. Selected Quotations Regarding Serotonin and Antidepressants
“Although it is often stated with great confi dence that depressed people have a Professor Emeritus of Neuroscience Elliot Valenstein, in Blaming the Brain (1998), which serotonin or norepinephrine defi ciency, the evidence actually contradicts these reviews the evidence for the serotonin hypothesis.
“Given the ubiquity of a neurotransmitter such as serotonin and the multiplicity Science writer John Horgan, in his critical examination of modern neuroscience, The of its functions, it is almost as meaningless to implicate it in depression as it is to “A serotonin defi ciency for depression has not been found” [51].
Psychiatrist Joseph Glenmullen, clinical instructor of psychiatry at Harvard Medical School, in Prozac Backlash (2000).
“So far, there is no clear and convincing evidence that monoamine defi ciency Psychiatrist Stephen M. Stahl, in a textbook used to teach medical students about accounts for depression; that is, there is no “real” monoamine defi cit” [44].
psychiatric medications, Essential Psychopharmacology (2000).
“Some have argued that depression may be due to a defi ciency of NE Psychiatrists Pedro Delgado and Francisco Moreno, in “Role of Norepinephrine in [norepinephrine] or 5-HT [serotonin] because the enhancement of noradrenergic Depression,” published in the Journal of Clinical Psychiatry in 2000. or serotonergic neurotransmission improves the symptoms of depression. However, this is akin to saying that because a rash on one’s arm improves with the use of a steroid cream, the rash must be due to a steroid defi ciency” [52]. “…I wrote that Prozac was no more, and perhaps less, effective in treating major Brown University psychiatrist Peter Kramer, author of Listening to Prozac, which is often depression than prior medications…. I argued that the theories of brain functioning credited with popularizing SSRIs, in a clarifying letter to the New York Times in 2002.
that led to the development of Prozac must be wrong or incomplete” [53].
“I spent the fi rst several years of my career doing full-time research on brain Stanford psychiatrist David Burns, winner of the A.E. Bennett Award given by the serotonin metabolism, but I never saw any convincing evidence that any psychiatric Society for Biological Psychiatry for his research on serotonin metabolism, when asked disorder, including depression, results from a defi ciency of brain serotonin. In fact, about the scientifi c status of the serotonin theory in 2003.
we cannot measure brain serotonin levels in living human beings so there is no way to test this theory. Some neuroscientists would question whether the theory is even viable, since the brain does not function in this way, as a hydraulic system” [54].
“Indeed, no abnormality of serotonin in depression has ever been demonstrated” Psychiatrist David Healy, former secretary of the British Association for Psychopharmacology and historian of the SSRIs, in Let Them Eat Prozac (2004).
“We have hunted for big simple neurochemical explanations for psychiatric Psychiatrist Kenneth Kendler the coeditor-in-chief of Psychological Medicine, in a 2005 disorders and have not found them” [56].
a treatment) is logically problematic—the has failed to confi rm any serotonergic a statistically signifi cant difference infl ated as compared to trials that use state, “[T]he demonstrated effi cacy of selective serotonin reuptake inhibitors… pathophysiology of these disorders” [12].
science. In fact, there is no scientifi cally established ideal “chemical balance” of serotonin, let alone an identifi able serotonin specifi cally. For instance, a into question the very effi cacy of the SSRIs and tricyclic antidepressants [16]. Act, gained access to all clinical trials lacking, the claimed effi cacy of SSRIs signifi cant degree. St. John’s Wort [19] this ex juvantibus line of reasoning (i.e., reasoning “backwards” to make assumptions about disease causation December 2005 | Volume 2 | Issue 12 | e392 also important to look at what is not The Role of the FDA
Statistical Manual of Mental Disorders hypothesis, not just for depression, but disorder. The American Psychiatric Press Textbook of Clinical Psychiatry addresses serotonin defi ciency as an unconfi rmed monoamine depletion hypothesis” [25].
could result in so many wildly differing Consumer Advertisements of
and a signifi cant body of contradictory states, “The effi cacy of paroxetine in Table 2. Selected Consumer Advertisements from SSRIs from Print, Television, and the World Wide Web
Selected Content from Consumer Advertisement
“Celexa helps to restore the brain’s chemical balance by increasing the supply of a chemical messenger in the brain called serotonin. Although the brain chemistry of depression is not fully understood, there does exist a growing body of evidence to support the view that people with depression have an imbalance of the brain’s neurotransmitters” [57].
“LEXAPRO appears to work by increasing the available supply of serotonin. Here’s how: The naturally occurring chemical serotonin is sent from one nerve cell to the next.
The nerve cell picks up the serotonin and sends some of it back to the fi rst nerve cell, similar to a conversation between two people.
In people with depression and anxiety, there is an imbalance of serotonin—too much serotonin is reabsorbed by the fi rst nerve cell, so the next cell does not have enough; as in a conversation, one person might do all the talking and the other person does not get to comment, leading to a communication imbalance.
LEXAPRO blocks the serotonin from going back into the fi rst nerve cell. This increases the amount of serotonin available for the next nerve cell, like a conversation moderator.
The blocking action helps balance the supply of serotonin, and communication returns to normal. In this way, LEXAPRO improves symptoms “When you’re clinically depressed, one thing that can happen is the level of serotonin (a chemical in your body) may drop. So you may have trouble sleeping. Feel unusually sad or irritable. Find it hard to concentrate. Lose your appetite. Lack energy. Or have trouble feeling pleasure…to help bring serotonin levels closer to normal, the medicine doctors now prescribe most often is Prozac®” [59].
“Chronic anxiety can be overwhelming. But it can also be overcome…Paxil, the most prescribed medication of its kind for generalized anxiety, works to correct the chemical imbalance believed to cause the disorder” [60]. “While the cause is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance. You just shouldn’t have to feel this way anymore” [5].
December 2005 | Volume 2 | Issue 12 | e392 interesting issue regarding the validity serotonin. Studies at clinically relevant serotonin into human platelets” [30].
the effi cacy of the drug “is presumed serotonergic activity” ([30], our italics Essential Psychopharmacology, which states, “So far, there is no clear and of serotonin, the signifi cance of this defi ciency accounts for depression; that is, there is no ‘real’ monoamine defi cit” advertisements, this explanation is very easy to understand, yet it paints a very Conclusion
imbalance of serotonin. In contrast, the continued treatment, Paxil can help present claims that are not found in this there is no such thing as a scientifi cally FDA regulations, it is useful to consult experts qualifi ed by scientifi c training and experience without disclosing
that the claims are not established
and the limitations of the supporting
evidence…” ([32], our emphasis
oversight. Since 2002, the fi rst author the regulations, only if the limitations that they are suffering from a serotonin direct-to-consumer advertising raises an December 2005 | Volume 2 | Issue 12 | e392 26. Consumer Reports (2003) Free rein for drug concentration in the cerebrospinal fl uid? ads. Yonkers (New York): Consumer Reports Available: http:⁄⁄ 9. Heninger G, Delgado P, Charney D (1996) The revised monoamine theory of depression: 299631&FOLDER%3C%3Efolder_id=162687. on new fi ndings from monoamine depletion 27. United States General Accounting Offi ce experiments in humans. Pharmacopsychiatry (2002) Prescription drugs: FDA oversight of direct-to-consumer advertising has limitations. 10. Mendels J, Stinnett J, Burns D, Frazer A (1975) Washington (D.C.): United States General Amine precursors and depression. Arch Gen Accounting Offi ce. Available: http:⁄⁄www.gao.
11. Horgan J (1999) The undiscovered mind: How the human brain defi es replication, 28. Mintzes B, Barer ML , Kravitz RL, Basett K, efforts are being relaxed [47]. Patients medication, and explanation. New York: Free Lexchin J, et al. (2003) How does direct- 12. Murphy DL, Andrews AM, Wichems CH, Li Q, Tohda M, et al. (1998) Brain serotonin environments with and without legal DTCA. neurotransmission: An overview and update 29. O’Brien C (2003 October 5) Drug fi rm to drop heterogeneity, multiple receptors, interactions with other neurotransmitter systems, and 30. GlaxoSmithKline (2005) Paxil Prescribing consequent implications for understanding the Information. Research Triangle Park (North actions of serotonergic drugs. J Clin Psychiatry http:⁄⁄
13. Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002) The emperor’s new drugs: An analysis 31. Castren E (2005) Is mood chemistry? Nat Rev of antidepressant medication data submitted to patients “are probably more susceptible the U.S. Food and Drug Administration. Prev 32. Food and Drug Administration (2005) Code Treat 5: article 23. Available: http:⁄⁄journals.
21—Food and drugs. Chapter I—Food and drug administration. Department of Health 14. Kirsch I, Scoboria A, Moore TJ (2002) and Human Services. Part 202—Prescription- advertising of SSRIs, Professor Emeritus drug advertisements. Available: http:⁄⁄www.
revelations, and unanswered questions. Prev Treat 5: article 33. Available: http:⁄⁄journals.
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John’s wort) in major depressive disorder: A randomized controlled trial. JAMA 287: 1807– articleC/0,2777,6599_3665_69890098,00.html. 37. Food and Drug Administration Division 21. Blumenthal J, Babyak M, Moore K, Craighead 3. Donohue J, Berndt E (2004) Effects of direct- W, Herman S, et al. (1999) Effects of exercise letter. Rockville (Maryland): Food and Drug choice: The case of antidepressants. J Pub Pol depression. Arch Intern Med 159: 2349–2356.
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