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 Quotation
“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 notThe 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 Antidepressants
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 Medication 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
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