http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/jour
nal.pmed.0020392

Serotonin and Depression: A Disconnect between the
Advertisements and the Scientific Literature

Jeffrey R. Lacasse, Jonathan Leo*

Competing Interests: The authors declare that no
competing interests exist and that they received
no funding for this work.

Citation: Lacasse JR, Leo J (2005) Serotonin and
Depression: A Disconnect between the Advertise-
ments and the Scientific Literature. PLoS Med 2(12):
e392 doi:10.1371/journal.pmed.0020392

Published: November 8, 2005

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 repro-
duction in any medium, provided the original author
and source are credited.

Abbreviations: DTCA, direct-to-consumer advertising;
FDA, Food and Drug Administration; SSRI, selective
serotonin reuptake inhibitor

*To whom correspondence should be addressed.
E-mail: jleo1@tampabay.rr.com

Jeffrey R. Lacasse is at Florida State University
College of Social Work, Tallahassee, Florida, USA.
Jonathan Leo is at Lake Erie College of Osteopathic
Medicine, Bradenton, Florida, USA.

In the United States, selective serotonin reuptake
inhibitor (SSRI) antidepressants are advertised
directly to consumers [1]. These highly successful
direct-to-consumer advertising (DTCA) campaigns
have largely revolved around the claim that SSRIs
correct a chemical imbalance caused by a lack of
serotonin (see Tables 1 and 2). For instance,
sertraline (Zoloft) was the sixth best-selling medi-
cation in the US in 2004, with over $3 billion in sales [2]
likely due, at least in part, to the widely disseminated
advertising campaign starring Zoloft's miserably
depressed ovoid creature. Research has demon-
strated that class-wide SSRI advertising has
expanded the size of the antidepressant market [3],
and SSRIs are now among the best-selling drugs in
medical practice [2].

Given the multifactorial nature of depression and
anxiety, and the ambiguities inherent in psychiatric
diagnosis and treatment, some have questioned
whether the mass provision of SSRIs is the result
of an over-medicalized society. These sentiments
were voiced by Lord Warner, United Kingdom
Health Minister, at a recent hearing: "...I have some
concerns that sometimes we do, as a society, wish
to put labels on things which are just part and parcel
of the human condition"[4]. He went on to say,
"Particularly in the area of depression we did ask
the National Institute for Clinical Excellence [an inde-
pendent health organisation that provides national
guidance on treatment and prevention] to look into
this particular area and their guideline on depression
did advise non-pharmacological treatment for mild
depression" [4]. Sentiments such as Lord Warner's,
about over-medicalization, are exactly what some
pharmaceutical companies have sought to overcome
with their advertising campaigns. For example, Pfizer's
television advertisement for the antidepressant sertra-
line (Zoloft) stated that depression is a serious medical
condition that may be due to a chemical imbalance,
and that "Zoloft works to correct this imbalance" [5].
Other SSRI advertising campaigns have also claimed
that depression is linked with an imbalance of the
neurotransmitter serotonin, and that SSRIs can
correct this imbalance (see Table 2). The pertinent
question is: are the claims made in SSRI advertising
congruent with the scientific evidence?

The Serotonin Hypothesis

In 1965, Joseph Schildkraut put forth the hypothesis
that depression was associated with low levels of
norepinephrine [6], and later researchers theorized
that serotonin was the neurotransmitter of interest [7].
In subsequent years, there were numerous attempts
to identify reproducible neurochemical alterations in
the nervous systems of patients diagnosed with
depression. For instance, researchers compared
levels of serotonin metabolites in the cerebrospinal
fluid of clinically depressed suicidal patients to
controls, but the primary literature is mixed and
plagued with methodological difficulties such as very
small sample sizes and uncontrolled confounding
variables. In a recent review of these studies, the
chairman of the German Medical Board and
colleagues stated, "Reported associations of
subgroups of suicidal behavior (e.g. violent suicide
attempts) with low CSF-5HIAA [serotonin] concen-
trations are likely to represent somewhat premature
translations of findings from studies that have flaws
in methodology" [8]. Attempts were also made to
induce depression by depleting serotonin levels,
but these experiments reaped no consistent results [9].
Likewise, researchers found that huge increases in
brain serotonin, arrived at by administering high-dose
L-tryptophan, were ineffective at relieving depression [10].

Contemporary neuroscience research has failed to
confirm any serotonergic lesion in any mental disorder,
and has in fact provided significant counterevidence to
the explanation of a simple neurotransmitter deficiency.
Modern neuroscience has instead shown that the brain
is vastly complex and poorly understood [11]. While
neuroscience is a rapidly advancing field, to propose
that researchers can objectively identify a "chemical
imbalance" at the molecular level is not compatible with
the extant science. In fact, there is no scientifically
established ideal "chemical balance" of serotonin, let
alone an identifiable pathological imbalance. To
equate the impressive recent achievements of neuro-
science with support for the serotonin hypothesis is a
mistake.

With direct proof of serotonin deficiency in any mental
disorder lacking, the claimed efficacy of SSRIs is often
cited as indirect support for the serotonin hypothesis.
Yet, this ex juvantibus line of reasoning (i.e., reasoning
"backwards" to make assumptions about disease
causation based on the response of the disease to
a treatment) is logically problematic-the fact that
aspirin cures headaches does not prove that head-
aches are due to low levels of aspirin in the brain.
Serotonin researchers from the US National Institute
of Mental Health Laboratory of Clinical Science clearly
state, "[T]he demonstrated efficacy of selective sero-
tonin reuptake inhibitors...cannot be used as primary
evidence for serotonergic dysfunction in the patho-
physiology of these disorders" [12].

Reasoning backwards, from SSRI efficacy to pre-
sumed serotonin deficiency, is thus highly contested.
The validity of this reasoning becomes even more
unlikely when one considers recent studies that even
call into question the very efficacy of the SSRIs. Irving
Kirsch and colleagues, using the Freedom of Informa-
tion Act, gained access to all clinical trials of anti-
depressants submitted to the Food and Drug Admin-
istration (FDA) by the pharmaceutical companies for
medication approval. When the published and unpub-
lished trials were pooled, the placebo duplicated
about 80% of the antidepressant response [13]; 57%
of these pharmaceutical company-funded trials failed
to show a statistically significant difference between
antidepressant and inert placebo [14]. A recent Coch-
rane review suggests that these results are inflated as
compared to trials that use an active placebo [15]. This
modest efficacy and extremely high rate of placebo re-
sponse are not seen in the treatment of well-studied
imbalances such as insulin deficiency, and casts
doubt on the serotonin hypothesis.

Also problematic for the serotonin hypothesis is the
growing body of research comparing SSRIs to inter-
ventions that do not target serotonin specifically. For
instance, a Cochrane systematic review found no
major difference in efficacy between SSRIs and tri-
cyclic antidepressants [16]. In addition, in randomized
controlled trials, buproprion [17] and reboxetine [18]
were just as effective as the SSRIs in the treatment
of depression, yet neither affects serotonin to any
significant degree. St. John's Wort [19] and placebo
[20] have outperformed SSRIs in recent randomized
controlled trials. Exercise was found to be as effective
as the SSRI sertraline in a randomized controlled trial
[21]. The research and development activities of
pharmaceutical companies also illustrate a diminish-
ing role for serotonergic intervention-Eli Lilly, the
company that produced fluoxetine (Prozac), recently
released duloxetine, an antidepressant designed to
impact norepinephrine as well as serotonin. The evi-
dence presented above thus seems incompatible
with a specific serotonergic lesion in depression.

Although SSRIs are considered "antidepressants,"
they are FDA-approved treatments for eight separate
psychiatric diagnoses, ranging from social anxiety
disorder to obsessive-compulsive disorder to pre-
menstrual dysphoric disorder. Some consumer
advertisements (such as the Zoloft and Paxil Web
sites) promote the serotonin hypothesis, not just for
depression, but also for some of these other
diagnostic categories [22,23]. Thus, for the sero-
tonin hypothesis to be correct as currently presented,
serotonin regulation would need to be the cause
(and remedy) of each of these disorders [24]. This is
improbable, and no one has yet proposed a cogent
theory explaining how a singular putative neurochem-
ical abnormality could result in so many wildly
differing behavioral manifestations.

In short, there exists no rigorous corroboration of the
serotonin theory, and a significant body of contradic-
tory evidence. Far from being a radical line of thought,
doubts about the serotonin hypothesis are well
acknowledged by many researchers, including frank
statements from prominent psychiatrists, some of
whom are even enthusiastic proponents of SSRI
medications (see Table 1).

However, in addition to what these authors say about
serotonin, it is also important to look at what is not
said in the scientific literature. To our knowledge,
there is not a single peer-reviewed article that can
be accurately cited to directly support claims of
serotonin deficiency in any mental disorder, while
there are many articles that present counterevi-
dence. Furthermore, the Diagnostic and Statistical
Manual of Mental Disorders (DSM), which is pub-
lished by the American Psychiatric Association
and contains the definitions of all psychiatric
diagnoses, does not list serotonin as a cause of
any mental disorder. The American Psychiatric
Press Textbook of Clinical Psychiatry addresses
serotonin deficiency as an unconfirmed hypothesis,
stating, "Additional experience has not confirmed
the monoamine depletion hypothesis" [25].

Consumer Advertisements of Antidepressants

Contrary to what many people believe, the FDA
does not require preapproval of advertisements.
Instead, the FDA monitors the advertisements once
they are in print or on the air [26]. Misleading content
is frequently found in various DTCA campaigns [27];
hence, it is valuable to compare SSRI advertisements
to the scientific evidence reviewed above. These
SSRI ads are widely promulgated; hundreds of
millions of dollars have been spent disseminating
these advertisements, and one study found that
over 70% of surveyed patients reported exposure
to antidepressant DTCA [28].

The Role of the FDA

In the US, the FDA monitors and regulates DTCA.
The FDA requires that advertisements "cannot be
false or misleading" and "must present information
that is not inconsistent with the product label" [27].
Pharmaceutical companies that disseminate adver-
tising incompatible with these requirements can
receive warning letters and can be sanctioned. The
Irish equivalent of the FDA, the Irish Medical Board,
recently banned GlaxoSmithKline from claiming that
paroxetine corrects a chemical imbalance even in
their patient information leaflets [29]. Should the FDA
take similar action against consumer advertisements
of SSRIs?

As just one example, the prescribing information for
paroxetine, which is typical of the SSRI-class drugs,
states, "The efficacy of paroxetine in the treatment
of major depressive disorder, social anxiety disorder,
obsessive-compulsive disorder (OCD), panic
disorder (PD), generalized anxiety disorder (GAD),
and post-traumatic stress disorder (PTSD) is pre-
sumed to be linked to potentiation of serotonergic
activity in the central nervous system resulting from
inhibition of neuronal reuptake of serotonin. Studies
at clinically relevant doses in humans have demon-
strated that paroxetine blocks the uptake of serotonin
into human platelets" [30].

In other words, the mechanism of action of paroxetine
has not been definitively established, and remains
unconfirmed and presumptive (the prescribing infor-
mation states that the efficacy of the drug "is pre-
sumed to be linked to potentiation of serotonergic
activity" ([30], our italics added). Although there is
evidence that paroxetine inhibits the reuptake of
serotonin, the significance of this phenomenon in
the amelioration of psychiatric symptoms is unknown,
and continually debated [12,31]. Most importantly, the
prescribing information does not mention a serotonin
deficiency in those administered paroxetine, nor does
it claim that paroxetine corrects an imbalance of sero-
tonin. In contrast, the consumer advertisements for
paroxetine present claims that are not found in this
FDA-approved product labeling.

In order to determine whether these advertisements
actually comply with FDA regulations, it is useful to
consult the Code of Federal Regulations under which
DTCA is regulated. The regulations state that an
advertisement may be cited as false or misleading
if it "[c]ontains claims concerning the mechanism or
site of drug action that are not generally regarded
as established by scientific evidence by experts
qualified by scientific training and experience without
disclosing that the claims are not established and
the limitations of the supporting evidence..." ([32],
our emphasis added]).

Stating that depression may be due to a serotonin
deficiency is seemingly allowed, but, as stated in
the regulations, only if the limitations of the support-
ing evidence are provided. In our examination of
SSRI advertisements, we did not locate a single
advertisement that presented any such information.
Instead, the serotonin hypothesis is typically pre-
sented as a collective scientific belief, as in the
Zoloft advertisement, which states that regarding
depression, "Scientists believe that it could be
linked with an imbalance of a chemical in the brain
called serotonin" [33]. Consumers viewing such
advertisements remain uninformed regarding the
limitations of the serotonin hypothesis (reviewed
above).

According to federal regulations, advertisements
are also proscribed from including content that
"contains favorable information or opinions about
a drug previously regarded as valid but which have
been rendered invalid by contrary and more credible
recent information" [32].

This means that a disconnect between the evolving
peer-reviewed literature and advertisements is not
permitted. Regarding SSRIs, there is a growing
body of medical literature casting doubt on the
serotonin hypothesis, and this body is not reflected
in the consumer advertisements. In particular, many
SSRI advertisements continue to claim that the
mechanism of action of SSRIs is that of correcting a
chemical imbalance, such as a paroxetine advertise-
ment, which states, "With continued treatment, Paxil
can help restore the balance of serotonin..." [22].
Yet, as previously mentioned, there is no such thing
as a scientifically established correct "balance" of
serotonin. The take-home message for consumers
viewing SSRI advertisements is probably that SSRIs
work by normalizing neurotransmitters that have gone
awry. This was a hopeful notion 30 years ago, but is
not an accurate reflection of present-day scientific
evidence.

The FDA has sent ten warning letters to antidepress-
ant manufacturers since 1997 [34-43], but has never
cited a pharmaceutical company for the issues
covered here. The reasons for their inaction are
unclear but seem to result from a deliberate decision
at some level of the FDA, rather than an oversight.
Since 2002, the first author (JRL) has repeatedly
contacted the FDA regarding these issues. The only
substantive response was an E-mail received from
a regulatory reviewer at the FDA: "Your concern
regarding direct-to-consumer advertising raises an
interesting issue regarding the validity of reduction-
istic statements. These statements are used in an
attempt to describe the putative mechanisms of
neurotransmitter action(s) to the fraction of the public
that functions at no higher than a 6th grade reading
level" (personal communication, 2002 April 11).

It is curious that these advertisements are rational-
ized as being appropriate for those with poor read-
ing skills. If the issues surrounding antidepressants
are too complex to explain accurately to the general
public, one wonders why it is imperative that DTCA
of antidepressants be permitted at all. However,
contrary to what the FDA seems to be implying,
truth and simplicity are not mutually exclusive.
Consider the medical textbook, Essential Psycho-
pharmacology, which states, "So far, there is no
clear and convincing evidence that monoamine
deficiency accounts for depression; that is, there
is no 'real' monoamine deficit" [44]. Like the
pharmaceutical company advertisements, this
explanation is very easy to understand, yet it
paints a very different picture about the serotonin
hypothesis.

Conclusion

The impact of the widespread promotion of the
serotonin hypothesis should not be underestimated.
Antidepressant advertisements are ubiquitous in
American media, and there is emerging evidence
that these advertisements have the potential to
confound the doctor-patient relationship. A recent
study by Kravitz et al. found that pseudopatients
(actors who were trained to behave as patients)
presenting with symptoms of adjustment disorder
(a condition for which antidepressants are not
usually prescribed) were frequently prescribed
paroxetine (Paxil) by their physicians if they
inquired specifically about Paxil [45]; such
enquiries from actual patients could be prompted
by DTCA [45].

What remains unmeasured, though, is how many
patients seek help from their doctor because anti-
depressant advertisements have convinced them
that they are suffering from a serotonin deficiency.
These advertisements present a seductive concept,
and the fact that patients are now presenting with a
self-described "chemical imbalance" [46] shows
that the DTCA is having its intended effect: the
medical marketplace is being shaped in a way
that is advantageous to the pharmaceutical com-
panies. Recently, it has been alleged that the FDA
is more responsive to the concerns of the pharma-
ceutical industry than to their mission of protecting
US consumers, and that enforcement efforts are
being relaxed [47]. Patients who are convinced
they are suffering from a neurotransmitter defect
are likely to request a prescription for antidepress-
ants, and may be skeptical of physicians who
suggest other interventions, such as cognitive-
behavioral therapy [48], evidence-based or not.
Like other vulnerable populations, anxious and
depressed patients "are probably more suscep-
tible to the controlling influence of advertisements" [49].

In 1998, at the dawn of consumer advertising of
SSRIs, Professor Emeritus of Neuroscience Elliot
Valenstein summarized the scientific data by con-
cluding, "What physicians and the public are read-
ing about mental illness is by no means a neutral
reflection of all the information that is available" [50].
The current state of affairs has only confirmed the
veracity of this conclusion. The incongruence
between the scientific literature and the claims
made in FDA-regulated SSRI advertisements is
remarkable, and possibly unparalleled.
.
.
--

Simple...corporate and political greed. US politicians are some of the
biggest shareholders of drug companies. Further they are allowed to act
on insider-trading information to profit and can not be charged for it.

Lack of knowledge is scary. Knowing the truth is scarier. So we are all
f.cked in the end.

L