The Media and the Chemical Imbalance Theory of Depression

Abstract

The cause of mental disorders such as depression remains unknown. However, the idea that neurotransmitter imbalances cause
depression is vigorously promoted by pharmaceutical companies and the psychiatric profession at large. We examine media reports
referring to this chemical imbalance theory and ask reporters for evidence supporting their claims. We then report and critique
the scientific papers and other confirming evidence offered in response to our questions. Responses were received from multiple
sources, including practicing psychiatrists, clients, and a major pharmaceutical company. The evidence offered was not compelling,
and several of the cited sources flatly stated that the proposed theory of serotonin imbalance was known to be incorrect.
The media can play a positive role in mental health reporting by ensuring that the information reported is congruent with
the peer-reviewed scientific literature.

Full text

FEATURE ARTICLE
The Media and the Chemical Imbalance Theory
of Depression
Jonathan Leo &Jeffrey R. Lacasse
#Springer Science + Business Media, LLC 2007
Abstract The cause of mental disorders such as depression
remains unknown. However, the idea that neurotransmitter
imbalances cause depression is vigorously promoted by
pharmaceutical companies and the psychiatric profession at
large. We examine media reports referring to this chemical
imbalance theory and ask reporters for evidence supporting
their claims. We then report and critique the scientific papers
and other confirming evidence offered in response to our
questions. Responses were received from multiple sources,
including practicing psychiatrists, clients, and a major
pharmaceutical company. The evidence offered was not
compelling, and several of the cited sources flatly stated that
the proposed theory of serotonin imbalance was known to be
incorrect. The media can play a positive role in mental health
reporting by ensuring that the information reported is
congruent with the peer-reviewed scientific literature.
Keywords Depression .SSRI .Serotonin
In the world of American popular culture, the current view of
mental illness depicts someone walking down the street, and
everything is fine, life is good. Then all of a sudden, out of the
blue, a chemical imbalance emerges. At the root of every
twisted thought lurks a twisted molecule—so the thinking
goes. A large part of the credit for this belief certainly goes to
the pharmaceutical companies, yet they are not the only
source of information on mental health issues. For many
people, another major source of information is the mainstream
press, which often alludes to the chemical imbalance theory as
if it were a proven scientific fact. In an effort to determine
what evidence the press uses to support their statements about
the chemical imbalance theory of depression, we attempted to
engage the media in a conversation to learn more about what
lies behind statements such as: “Mental illnesses are simply
chemical imbalances.”In support of their statements, several
members of the press did not provide any citations, while
some referred us to interesting articles about serotonin
research, but not a single citation could be considered direct
proof of an underlying chemical imbalance as the cause of
depression. (The term ‘mental illness’is used throughout this
article due to the fact that it often appears in media accounts.
The more technical term, “mental disorder,”is considered the
more correct term within modern psychiatric literature. There
is ongoing debate regarding the definition, utility, and
scientific validity of “mental disorder.”)
The Chemical Imbalance Theory
The idea that depression results from a chemical imbalance in
the brain was first proposed in the late 1950s and early 1960s
by several different scientists. The focus was initially on the
neurotransmitter norepinephrine, but by the mid 1960s the
focus had shifted to serotonin, another transmitter, which
ultimately led to the development of the Selective Serotonin
Reuptake Inhibitors (SSRI) such as Prozac and Paxil. At the
time, there were several lines of convergent evidence but
the strongest evidence came from the observation that the
administration of pharmacological agents acting on the brain’s
monoamine system could either increase or decrease mood
levels. For instance, it had been known for several years that, at
least in some people, the drug reserpine could lead to a
depressed state. Subsequent studies in rabbits showed that
reserpine causes reductions in serotonin. Thus, putting the two
facts together, deductive reasoning suggested that depression
Soc
DOI 10.1007/s12115-007-9047-3
J. Leo (*)
Lincoln Memorial University,
6965 Cumberland Gap Parkway,
Harrogate 37752, USA
e-mail: Jonathan.leo@lmunet.edu
J. R. Lacasse
Florida State University (FSU),
Tallahassee, USA

could be the result of too little serotonin. In essence, as
summarized in a table in one of their early papers, the re-
searchers observed that mood could be artificially manipulated
with drugs—those which raised monoamine levels improved
mood, while those which lowered amine levels led to
depression, but it remained to be seen if naturally occurring
fluctuations in neurotransmitter levels were responsible for, or
caused, the ebb and flow of mood levels. In the words of
Schildkraut, one of the early proponents of the theory: “At
best, drug-induced affective disturbances can only be con-
sidered models of the natural disorders, while it remains to be
demonstrated that the behavioral changes produced by these
drugs have any relation to naturally occurring biochemical
abnormalities which might be associated with the illness”
(1965). Like any good hypothesis, the “chemical imbalance
theory,”as it has come to be called, provided a springboard
for a tremendous amount of research, and subsequently trans-
formed two important sectors of the health care system—the
psychiatry profession and the pharmaceutical companies.
For the psychiatry profession, the theory was a major
driving force behind the rise of biological psychiatrists
within the profession, and moved the profession from one
involved in talking to patients about everyday problems, to
a profession that was treating their patients’organic
diseases—just as the internists were treating diabetics
suffering from insulin shortages, the psychiatrists were
now treating depressed patients suffering from serotonin
shortages. Depression was no longer seen as just a natural
response to stress, there was now an underlying biological
factor which was the cause of the depression.
The theory also transformed the pharmaceutical compa-
nies. For instance, Sertraline (Zoloft) was the sixth best-
selling medication in the US in 2004, with over $3 billion in
sales likely due, at least in part, to the widely disseminated
advertising campaign starring Zoloft’s miserably depressed,
and presumably serotonin deficient, ovoid creature. No matter
how you look at the data, the figures are impressive: In July of
2007, a government study found that antidepressants are the
most prescribed drugs in the US; during the past 6 years
patients spent $123 billion on psychotropic drugs; in 2005,
doctors wrote 31 million prescriptions for antidepressants;
and in 2004, the pharmaceutical companies spent $1.5 billion
promoting antidepressants. Prior to the idea of chemical
imbalances, the pharmaceutical companies had advertised
their wares as tonics which could ease people through the ups
and downs of normal, everyday existence. For instance, in the
1950s Butisol was advertised as “the ‘daytime sedative’for
everyday emotional stress”and in the 1970s Valium was
advertised for the “unremitting buildup of everyday emotional
stress resulting in disabling tension.”
As in many discussions about scientific concepts, there is
often confusion over the terms “causation”and “correlation.”
The difference between the two terms may seem trivial at first
glance, but the definitions have enormous implications for any
discussion about the relationship between psychology and
biology. Evidence of biological changes correlating with
environmental stressors is vastly different from evidence that
mental illnesses are “caused”by biological deficits. For
instance, a correlation between abnormal behavior and altered
brain activity does not necessarily imply that the behavior was
caused by a brain defect. There is a growing body of research
showing that biological changes could be due to environmen-
tal stimuli. Take the hippocampus, a brain structure important
in learning and memory: It has been shown that chronic
psychological stress can reduce the size of the hippocampus,
and that, conversely, 3-D spatial relationship training leads to
enlargement of the hippocampus. As another example, a
recent meta-analysis found that 69% of the female patients
diagnosed as psychotic in over 70 studies had reported either
physical or sexual abuse. It is entirely possible that the women
in the study developed a chemical imbalance, but it would be
difficult to determine if their conditions resulted from genetic
defects or environmental stressors.
In addition to psychological stress, physical stress can lead
to depression. A recent study of ex-NFL players documents a
correlation between numbers of concussions and depression
later in life. As this example makes clear, even if some players
have a genetic predisposition to traumatic brain injury, if you
take away the environmental insult (in this case getting
knocked in the head), there would be no disease. Regardless
of any genetic defect, any subsequent deficits are 100%
preventable by avoiding the football field.
As an example of someone who is well placed to understand
the theory, along with the difference between correlation and
causation, take Nancy Andreasen, a prominent biological
psychiatrist, who sums up biological psychiatry’sviewof
mental illness in her book, The Broken Brain:“these diseases
are caused [italics added] principally by biological factors and
most of these reside in the brain.”Andreasen is referring here
to “causation,”not just “correlations.”In the United States,
the diagnosis of depression doubled between 1991 and 2000,
coinciding with the introduction of the SSRI medications.
These medications were not marketed by explaining the
problematic correlational data; instead, they were sold as
remedying the chemical imbalance that caused depression.
As another example of how subtle nuances in semantics
have important implications for our understanding of mental
illness, take the following statement from Diane Patrick,
married to the governor of Massachusetts, Deval Patrick.
Following treatment for her depression, she gave a press
briefing in 2007 in which she said, “I’ve done a little reading
in the time I’ve had. And what I know is that depression is
really a chemical imbalance, which is triggered by systemic
stress [italics added].”Patrick, whose carefully chosen words
also indicate that she understands the difference between
causation and correlation, has a dramatically different view
Soc

of mental illness compared to Andreasen’sviewthat
biological alterations are the cause of mental illness; for
Patrick, the chemical imbalance is caused by prolonged
stress. And these two different scenarios have vastly different
implications for the use of drugs.
With the advent of the chemical imbalance theory, the
companies were no longer just providing soothing tonics, they
were now providing medications to treat diseases, as exempli-
fied by an early SSRI advertisement stating: “When serotonin
is in short supply, you may suffer from depression.”The
wording here is all-important. The advertisement takes a
correlation between serotonin shortage and psychological
stress—and even this is highly questionable and unverifiable
in any individual case—and makes a leap of faith to the
conclusion that depression is caused by a serotonin imbalance,
not that psychological stress impacts the serotonin system.
And the marketing did not stop with depression; eventually
we were told that whatever our problems might be, whether
anxiety, excessive shyness, depression, or the inability to pay
attention, the underlying cause was a faulty transmitter level
which could be rectified with a pill. A 2005 survey from the
Harvard School of Public Health reported that nearly half of
all Americans will at some point develop a mental illness,
presumably from a chemical imbalance, with 29% developing
an anxiety disorder and 20% a mood disorder.
Substances used to rectify a chemical imbalance can be
called medications and are consumed by patients, while sub-
stances that are used to “take the edge off”are typically
considered street drugs and are consumed by users or addicts.
But is this line between legal and illegal really that straight-
forward? When we assign a mood-altering drug to either one
of these two categories are we basing this on science or a
social agenda? There are a whole host of substances, some of
which are legal—alcohol, valium, etc.—and some of which
are illegal—marijuana, heroin, etc.—that humans have taken
for years to ease anxiety and depression. For an example of
how artificial these categories are, take the case of Ricky
Williams, the star running back for the Miami Dolphins who
has been diagnosed with Social Anxiety Disorder. In 2002,
People magazine, in a statement closely resembling a phar-
maceutical company advertisement, referred to Williams’
disease as a “depression-like chemical imbalance that affects
roughly three million Americans.”For several years, Williams
was paid by Glaxo to promote Paxil, an SSRI. During his
career, Williams was in and out of trouble with the NFL and
tested positive for marijuana on several occasions. While his
marijuana use was frowned upon, his use of Paxil was
considered acceptable. One was a medication supposed to
treat a chemical imbalance, while the other was a drug
signaling a lack of willpower. In 2004, Williams’job with
Glaxo came to a sudden halt when he stated that marijuana
was ten times better than Paxil. Williams did not get into
trouble for saying that another drug was better than the
sponsor’s drug (as, say, a Coke representative would have had
he admitted he really preferred Pepsi). What actually got
Williams into hot water was that he put his sponsor’sdrugin
the same category as an illicit drug. The NFL, the psychiatry
profession, the pharmaceutical companies, and People mag-
azine all operate under an assumption that the line between
legal and illegal is simple and concrete. Williams’acknowl-
edgement that it is complicated and uncertain posed a
dilemma for the pharmaceutical companies, who were footing
his bill, and he was let go.
In addition to the correlation–causation issue another
area of confusion is research into the mechanism of SSRI
action. The thinking goes that, because the SSRIs act on the
serotonin system, their efficacy must be due to an existing
imbalance of serotonin. This line of reasoning is logically
problematic as LSD also acts to increase serotonin levels,
and we do not make similar claims about LSD-induced
hallucinations only occurringinchemicallydeficient
individuals. Or take Glaxo’s new over-the-counter diet
drug, Alli, which helps dieters lose weight—no matter what
the person weighs. Alli’s actions are not limited to
overweight people, but will lead to weight loss even in
thin people, just as the SSRIs have an effect on everybody,
not just those who are depressed.
In a 1989 memorandum, the head of Pfizer’s French
headquarters commented on the wording of the French
packaging label for Sertraline (Zoloft): “But considering the
fact that the monoaminergic hypothesis of depression is not
unique and that some authors have even stated a hyperfunc-
tioning of the monoaminergic pathway, it seems therefore
preferable not to write anything about etiopathogeny of
depression, and to describe only the actions [sic] of
Sertraline.”The importance of this document stems from
the fact that, as early as 1989, even Pfizer acknowledged
that talking about a drug’s action is not the same thing as
talking about the etiology of depression. In other words,
evidence of a drug’s action is not evidence of etiology.
Psilocybin is the active ingredient in mushrooms, an
illegal drug which causes hallucinations. Some have
suggested it was the inspiration for Lewis Carroll’sAlice
in Wonderland. Recently, researchers at Johns Hopkins ran
a controlled clinical trial investigating the antidepressant
effects of psilocybin and, according to their results, 79%
reported moderately or greatly increased levels of life
satisfaction. Presumably, few would argue that psilocybin’s
actions on the brain or that the production of Alice in
Wonderland was the result of a chemical imbalance. As this
example illustrates, one cannot simply assert that the
claimed efficacy of mental health drugs necessarily equates
to a chemical imbalance. If we apply the same type of logic
that we use to support the chemical theory of depression to
our thinking about mushrooms then mushrooms should be
categorized as a medication.
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Some professionals have pointed out that from a practical
point of view, the validity of the theory is not really that
important. After all, as long as the medication works, does it
really matter whether we know what the mechanism is? This
argument would be reasonable if the advertisements were
limited to the medication’s effects, however a major portion of
the pharmaceutical company advertising campaigns has
focused on the mechanism of depression. Take this advertise-
ment for Lexapro: “In people with depression and anxiety,
there is an imbalance of serotonin.”If you took away the
chemical imbalance theory and only advertised the SSRI’s
effects, the marketing departments would be left with little.
Without a chemical imbalance, the SSRIs are just another
group of mood-altering drugs.
In spite of the enormous amount of money and time that
has been spent in the quest to confirm the chemical imbalance
theory, direct proof has never materialized. Moreover, during
the past several decades, a significant amount of evidence has
accumulated which calls the theory’s validity into question.
Perhaps most problematic for the theory, over the past two
decades, multiple studies have shown that the once presumed
efficacy of the SSRIs, the foundation upon which the theory
was built, is not nearly as robust as once thought. In 2002,
Irving Kirsch and colleagues at the University of Connecticut,
using the Freedom of Information Act, gained access to all
clinical trials of antidepressants submitted to the Food and
Drug Administration (FDA) by the pharmaceutical companies
as part of the medication approval process. When the
published and unpublished trials were pooled, the placebo
duplicated about 80% of the antidepressant response—in
Prozac’s case it was 89%. In other words, for every ten people
who take an SSRI, only one or two people are truly receiving a
benefit from the medication—afactacknowledgedevenby
the SSRI proponents. The obvious question is: What about the
eight or nine people getting no benefits from the medication
but now put at risk for the medication’ssideeffects?Given
these and other problems with the chemical imbalance theory,
there are now few researchers willing to step up and mount a
full-scale defense of it.
In an earlier paper we examined the differences in how
the theory is portrayed in the scientific literature versus the
pharmaceutical company advertising, and reported that the
incongruence between the scientific literature and the claims
made in the SSRI advertisements is remarkable, and possibly
unparalleled. Take this comparison as just one example: The
American Psychiatric Press Textbook of Clinical Psychiatry
addresses serotonin deficiency as an unconfirmed hypothe-
sis, stating, “Additional experience has not confirmed the
monoamine depletion hypothesis,”while a recent advertise-
ment for Celexa states: “Celexa helps to restore the brain’s
chemical balance by restoring the supply of a chemical
messenger in the brain called serotonin.”The textbook and
the advertisement have very different positions on the theory.
Although silence from critics is certainly not confirma-
tion of our claims, numerous scientists and psychiatrists
have responded either in interviews, or in published letters-
to-the-editor about our thesis, and not a single one has
disagreed. In one interview about our article, the head of
the FDA Psychopharmacology Advisory Committee stated
that the chemical imbalance theory is a “useful metaphor”
but not one that he uses with his own patients.
There is then a dilemma for the majority of the
population who do not read psychiatry journals and who
are much more likely to learn about scientific concepts
from the mainstream media, either from magazines, such as
Time and Newsweek, or from newspapers, such as the New
York Times or LA Times. To determine the evidence behind
the media’s claims about chemical imbalances, for approx-
imately 1 year we performed weekly Internet searches of
the media for “chemical imbalances”and sent e-mails to the
authors asking them for the evidence they were basing their
statements on.
Evidence-based Reporting?
In an article for the Sacramento Bee (3/9/07), about how to
handle teenagers with depression, the author states: “Act
promptly and accept that they may have a chemical
imbalance [italics added] or need help with coping skills.”
In reply to our questions, the author mentioned that:
psychiatrists would be the best people to talk with about
chemical imbalances; mental illnesses have been linked to
chemical imbalances; psychiatrists are trained to figure this
out through a variety of tests; and that “numerous studies
have been done”and “the research is definitely available.”
We pointed out to her that, if there are “numerous studies”
which are “definitely available,”then it should be relatively
easy to cite at least one article. She did not reply. We also
mailed a copy of our e-mails to an editor at the Sacramento
Bee. On March 29, 2007, another newspaper published a
copy of her article with the comment about chemical
imbalances removed. The edited article appears at: http://
www.contracostatimes.com/teens/ci_5513238.
In ScienceNOW Daily News (10/18/06), an article
discussed new research suggesting that Prozac increases
bone density. In the article, the author stated, “Researchers
believe depression results from too little of the neurotrans-
mitter serotonin bathing certain neurons.”In an e-mail, she
replied that she did not go back to find the original
references and that it would be difficult “to start from
scratch every time I wrote a news article.”She did not
supply any references other than to refer us to the original
research paper on bone density, and told us that we were
free to check their references. The initial research article
also mentions the chemical imbalance theory and cites a
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1991 article by Mann which appeared in a Neuropsycho-
pharmacology journal supplement.
In the New York Times (12/31/06), Michael Kimmelman
wrote about the life and work of Joseph Schildkraut, one of
the founders of the chemical theory of depression. The Times
reporter stated, “A groundbreaking paper that he published
in 1965 suggested that naturally-occurring chemical imbal-
ances in the brain must account for mood swings, which
pharmaceuticals could correct, a hypothesis that proved to be
right [italics added].”E-mails to the author requesting a
citation to support his statement went unanswered.
In another New York Times article (6/19/07), “On the
Horizon, Personalized Depression Drugs,”Richard Friedman,
the chairman of Psychopharmacology at the Weill Cornell
Medical College, stated: “For example, some depressed
patients who have abnormally low levels of serotonin
respond to SSRIs, which relieve depression, in part, by
flooding the brain with serotonin.”For his evidence he
supplied a 2000 paper by Nestler titled, “Neurobiology of
Depression,”which focuses on the hypothalamic pituitary
system but not on serotonin.
In the Georgetown News (3/20/07), the author of
“Depression: The Silent Sickness,”who had been diag-
nosed and treated for depression, stated: “When I was first
diagnosed with depression, or a chemical imbalance…” In
an e-mail, she stated that her source was her primary care
doctor who told her that she made too much adrenaline.
An anonymously-written article in the Economist (3/5/
07), defined serotonin as follows: “This molecule is a
neurotransmitter (a chemical messenger between nerve
cells) and one symptom of depression is low levels of it.”
The Economist article was generated from a press release
announcing the results of a study from the University of
Bristol. The press release stated: “The lack of serotonin in
the brain is thought to cause depression in people.”The
author of the press release has not replied to our inquiries.
In the Kane County Chronicle (4/28/07), an article
appeared about suicide with several quotes from Mari
Wittum of Suicide Prevention Services. According to the
reporter, in a talk about reducing suicide in teenagers,
Wittum discussed the causes of mental illness and said that
the “impetus often could be a chemical imbalance or
hereditary illness.”The author forwarded the request to
Wittum who provided two websites, one from her own
organization and one from National Alliance on Mental
Illness (NAMI). She did not provide any specific citations
but said that chemical imbalances were one reason people
committed suicide. She also said that her interest lies in the
clinical side of things.
In the Vancouver Sun (2/24/07), an article quoted several
psychiatrists on the subject of mental illness, one of whom
makes this statement about the antidepressants: “they seek
to correct chemical imbalances in the brain usually caused
by a genetic predisposition to them.”When asked about the
references, the author referred us to the psychiatrist quoted
in the article, who in turn supplied the following citations.
The first, a 1991 study titled, “Measures of Serotonin
Function Are Reduced in a State Dependent Manner”by
Upadhyaya and colleagues in the Journal of Affective
Disorders (Vol. 21),showed that in depressed patients
there is an alteration of receptor numbers. However, as in
all these types of studies, and as pointed out by all the
researchers, it is not clear whether these changes are signs
of an organic defect causing the depression, or if environ-
mental stressors have caused the changes in the brain. We
are not aware of any replications of this study in the
15 years since it was published. Presumably, if it had been
replicated, the subsequent studies would have been cited.
The second citation was a highly theoretical article,
written in 2006, about serotonergic vulnerability by Jans
and colleagues in Molecular Psychiatry (Vol. 9), in which
the authors state, “By now, however, the model of a deficit
in 5-HTergic neurotransmission being primary in the
causation of depressive disorders, and predictive of thera-
peutic response to drugs enhancing 5-HTergic neurotrans-
mission has become obsolete: not all depressed patients
present with 5-HT abnormalities, not all patients benefit
from drugs enhancing 5-HTergic neurotransmission, and
several drugs that are devoid of major effects on 5-HTergic
neurotransmission are known to be effective antidepres-
sants.”The article does present a hypothesis about chemical
imbalances: Just as you can measure and subsequently plot
a graph of a physical trait, such as height, you can
theoretically do the same with serotonin function. There-
fore, just as with height and weight, there must be some
portion of the population on the left-hand side of the graph.
Rather than attribute this to normal biological variation, the
authors speculate that the subjects on the far side of the
curve have “theoretical serotonergic vulnerability”which
makes them more susceptible to environmental stress.
Interestingly, the authors point out that more women than
men have this defect. The article also ends with the rather
surprising idea that we will eventually be able to identify
these people on the far side of the curve and pre-treat them
for environmental stressors. In short, the article is interest-
ing but provides no confirmatory proof for the chemical
imbalance theory.
The third citation was a 1999 article by Porter in The
Journal of Psychopharmacology (Vol. 146) which is not
about chemical imbalance as a cause of depression, but is
about how the SSRIs act on the serotonin receptor. As
mentioned earlier, few, if any, scientists would disagree
with the fact that the SSRIs act on the serotonin receptor,
but as pointed out by the original proponents of the
serotonin theory, this does not provide evidence that
depression is caused by low serotonin.
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In the Philadelphia Inquirer, Alexis Sohrakoff wrote that
“mental illnesses are simply chemical imbalances.”In an e-
mail, she supplied the following references. The first was a
2000 article by Zubieta and colleagues in the American
Journal of Psychiatry (Vol. 200) about transporter binding in
asymptomatic bipolar I disorder. The article noted a differ-
ence in the number of monoaminergic synaptic terminals
between sixteen patients diagnosed with bipolar compared
with normal controls. The study has not been replicated to
the extent that scientists can say that they have found a
marker for bipolar patients.
Sohrakoff also supplied a statement, made by the
president of the Society of Neuroscience, which was part of
a request made to a congressional panel for more funding:
“mental illnesses were due to a chemical imbalance.”When
the problems with these citations were pointed out to the
author, she replied, “I did not conduct an extensive literature
search, as I assumed that if an individual such as the
president of the Society of Neuroscience, among others,
stated that a mental illness represents a chemical imbalance,
there must be some evidence to that fact.”
In the Helena Independent Record (6/10/07), a reporter
wrote, “Sometimes it’s [depression] the result of a chemical
imbalance, such as serotonin levels. Fix the imbalance, fix the
depression.”As evidence, the author supplied a link to a web
page at the National Institutes of Mental Health (NIMH),
whichinturnsaid,“Researchers believe that both depression
and suicidal behavior can be linked to decreased serotonin in
the brain. Low levels of a serotonin metabolite, 5-HIAA,
have been detected in cerebral spinal fluid in persons who
have attempted suicide, as well as by postmortem studies
examining certain brain regions of suicide victims.”
To dig deeper, we contacted NIMH and asked for their
references. As a citation for their statement, they supplied a
2003 review of the genetics of the serotonergic system in
suicidal behavior by Arango and colleagues in the Journal
of Psychiatric Research (Vol. 37). The review discussed the
research of four genetic polymorphisms involved in the
serotonin pathway: one polymorphism had some prelimi-
nary results suggesting a correlation between it and suicide,
while the other three were not promising. In their
conclusions the authors state: “At present there is no
identified ‘suicide’gene, nor is any one gene likely ever
to be found causal to suicidal behavior.”The authors then
go on to speculate about future possibilities. Besides citing
this one review article, NIMH also suggested doing a Pub
Medsearch.WerepliedtoNIMHthatwewerenot
interested in the thousands of general citations on Pub
Med, but, instead, were interested in the specific evidence
that they, NIMH, were using to support their statements.
We have not heard back from NIMH.
In the Pittsburgh Tribune Review (4/2/07), Noelle
Creamer wrote, “It’s not a personal deficit, but something
that needs to be looked at as a chemical imbalance.”This
quote was attributed to a psychiatric nurse practitioner. The
author did not respond to e-mails, and the nurse’s e-mail
was not available.
The Bradenton Herald (3/24/07), published an article
entitled, “Seniors Sought for Depression Study.”The primary
source for the article was Dr. Andrew Cutler, the director of
the Florida Clinical Research Center, who is extensively
quoted and referred to by the reporter. “True depr ession,”
Cutler says, “has its roots in a chemical imbalance in the
brain.”Neither the reporter nor Dr. Cutler replied to e-mails.
In the Gilroy Dispatch (4/24/07), the author wrote, “A
patient with a chemical imbalance that leads to depression
likely receives entirely different insurance coverage than a
patient with a chemical imbalance that leads to hyperthy-
roidism receives.”The author has not responded.
In The Gazette (4/17/07), an article claimed, “Depression
is a medical illness caused by a chemical imbalance in the
brain.”The author has not replied. We also posted our
inquiry as a comment to the article.
Reporters Covering Mental Illness
Prior to our efforts to solicit evidence from reporters, there
were two well-known cases of nationally-recognized reporters
discussing chemical imbalances. Following Tom Cruise’s
controversial remarks in 2005, CNN medical reporter Sanjay
Gupta attempted to counter Cruise by using brain scans to
demonstrate that chemical imbalances were in fact, real. On the
air, he showed PET scans of depressed individuals, remarking
that: “When you don't have enough neurotransmitters firing,
making the connections, your brain doesn't activate in the
area that it should. And you can see what a normal brain
should look like. That is an objective measure…”
Psychiatric Times, a trade journal, published an article
where Gupta defended his remarks, stating that he was just
trying to demonstrate that there is objective research in
mental health. But his statement and the display of PET
scans probably misled the overwhelming majority of CNN’s
audience who are not familiar with the legitimate use of this
technology by the psychiatry profession. That use is for
research purposes, and not for identifying depressed indi-
viduals. Although a PET scan might someday accurately
show how brains differ in terms of serotonin receptors, it is
an entirely different matter to use a scan to document how
the brain reached that state. An X-ray can accurately identify
a broken bone, but it can’t tell you whether the bone was
broken in a car accident or a football game. The same is true
of a PET scan—it cannot tell you whether its findings are
due to stress, thinking patterns, social isolation, trauma, or
whether they are even clinically significant. A neuroimaging
expert cannot look at a PET scan of an individual and make
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a psychiatric diagnosis. The use of technology to imagine
the brain is impressive and promising, but it does not
provide easy answers to the difficult questions that must be
asked of the chemical imbalance theory.
Another instructive example was the June 27, 2005
Today show interview, where psychiatrists Dr. Joseph
Glenmullen and Dr. Steven Sharfstein squared off on the
issue of chemical imbalances. Glenmullen, a clinical
instructor in psychiatry at Harvard Medical School and a
critic of the theory, stated that the chemical imbalance
theory was fallacious, but explained that he still prescribed
the medications when he felt they would be helpful.
Sharfstein, president of the American Psychiatric Associa-
tion, found this point of view to be “total nonsense,”yet he
also stated that there was a constructive debate going on in
psychiatry about these topics. The idea that there is an
ongoing debate sounds nice, but is it true? The Diagnostic
and Statistical Manual of Mental Disorders, which almost
all psychiatrists use to diagnose and treat their patients,
clearly states that the cause of depression and anxiety is
unknown. In addition, for well-accepted diseases, such
statements are not debated, but settled through scientific
research. For instance, if a critic were to argue that
neurosyphillis was not a disease, an infectious disease
specialist could locate and cite the paper which proves this
incorrect—and the debate would be over. Most interest-
ingly, while Sharfstein maintained the idea that the
chemical imbalance theory was a fact, Tod a y ’sKatie
Couric did not ask him what evidence he was referring to—
obviously we would have asked.
The Pharmaceutical Companies and Chemical
Imbalances
Considering the media’s inability, or unwillingness, to cite
evidence in support of their own statements, can the same
group really be expected to go one step further and actively
investigate these issues? The solution is not simply for the
media to modify, or tone down, their own statements about
the chemical imbalance theory, but is for them to take a
more analytical approach with those who promote the
chemical theory as ineluctable truth. In other words, rather
than us questioning the media, shouldn’t the media be
doing the questioning? It’s almost as if these reporters are
blinded by the term, “peer reviewed,”and operate under the
mistaken assumption that the words are some sort of stamp
declaring that the results are unquestionable and that they
can check their skeptical radars at the door when given a
press-release mentioning a peer-reviewed article.
While the press continues to mention chemical imbal-
ances, as mentioned earlier, academic psychiatrists have not
disagreed with the idea that the SSRI advertisements are an
inaccurate portrayal of the chemical imbalance theory, but
at least one pharmaceutical company has. In response to our
article on the SSRI advertisements, a Pfizer spokesman
mentionedtoareporterthat:“There is considerable
scientific literature supporting the widespread belief among
scientists and physicians that an inadequate level of
serotonin in the neuronal synapses of the brain is at least
one of the causes of depression.”The spokesperson also
provided the reporter with the following citations as
evidence in support of the chemical imbalance theory: two
textbook chapters and a review paper.
Pfizer’s first citation, a chapter from The American
Psychiatric Textbook of Psychopharmacology (1998), was
authored by Gary Tollefson, the head of neuroscience at Eli
Lilly, and Jerold Rosenbaum, a member of the pre-
marketing advisory committee for Prozac. The chapter
provides little in the way of a discussion about the
mechanism of depression, and has little bearing on the
chemical imbalance theory, but the chapter does provide
some insight into the commercial success of the SSRIs. The
chapter is mainly concerned with the clinical use of the
SSRIs. Two major concerns for a clinician are efficacy and
side effects, not just for the SSRIs but for any drug.
Clinicians hearing a pharmaceutical company-sponsored
presentation will likely understand that the drug will be
portrayed in the best light possible, with the side effects
being downplayed and the efficacy exaggerated—this
assumes that clinicians are a somewhat representative
sample of the general population, 93% of whom recently
reported being skeptical of pharmaceutical company claims.
However, what about textbook chapters, which are tradi-
tionally thought of as providing a more realistic presenta-
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tion? Should clinicians maintain that same healthy dose of
skepticism when reading textbook chapters as they do when
hearing a pitch from a salesman?
Regarding efficacy, Tollefson and Rosenbaum state: “A
plethora of placebo-controlled, double blind trials have
established the clear superiority of the SSRI’s over placebo”
(p. 224). However, this statement seems overly enthusiastic
regarding the SSRIs. Even when Eli Lilly first submitted its
request for approval from the FDA for Prozac the evidence
was marginal, at best. For instance, out of eight separate
studies combined to make up three trials submitted to the
FDA, only four of the studies found a statistically
significant advantage of Prozac over placebo. One of the
studies lasted 4 weeks and included 11 people. Several of
the studies were pooled together so that two of the three
trials were significant.
In support of their statement about efficacy, Tollefson
and Rosenbaum cite a 1992 review by Kasper published in
an SSRI manufacturer-sponsored (Fluvoxamine) supple-
ment to the journal, Drugs (Vol. 43). Interestingly, as David
Healy documents in Let Them Eat Prozac, Kasper had
previously allowed pharmaceutical companies to publish
papers written by ghostwriters under his name. In 1999, the
pharmaceutical company, Pierre Fabre, presented a pre-
written scientific paper to Healy, asking if it could designate
him as the author before submitting it to a journal. Because
Healy wanted to make changes to the article that the
company did not agree with, Pierre Fabre moved on.
The article was subsequently published with Kasper as the
author.
Regarding their reporting of side effects, when it comes
to the potential link between the SSRIs and suicide,
Tollefson and Rosenbaum state, “that no evidence indicated
that SSRI’s triggered emergent suicidal ideation above base
rates associated with depression.”Their citation for this was
a 1993 report by the American College of Neuropsycho-
pharmacology. However, in 1987, at an FDA hearing,
Tollefson was questioned about a potential link between the
SSRIs and suicide, and he did not discuss the fact that the
German regulatory body had already raised the issue. In
2003, when asked by the New York Times (August 7) why
he did not mention this point at the hearing, he replied:
“That was not the question that was asked so I did not
answer that question.”Yet, textbook chapters are not
hearings. They are supposed to be vehicles for the exchange
of information among academics; at least that is what many
of their readers believe.
While Tollefson and Rosenbaum did not see a correla-
tion between suicidality and SSRI use, apparently others
were concerned. In an April 7, 2003 article contrasting
statements about concerns with the SSRIs in their internal
company documents to the company’s public statements
exonerating the SSRIs, the New York Times reported:
“Documents brought to light in other cases suggest that
Lilly struggled for years to reconcile suicidal events among
patients taking Prozac in its trials. One memo shows that a
top Lilly executive asked the company’s own researchers to
record suicide attempts as ‘overdose’and thoughts of
suicide as ‘depression.’”
Regardless of Tollefson and Rosenbaum’s presentation
of the suicide issue in 1998, this section of the chapter is
now out-of-date as the FDA recently issued a black box
warning about a link between suicidal thoughts and the
SSRIs. In addition, even Glaxo issued a recent statement
warning doctors that there was a six-fold increase in
suicidal behavior in young adults taking Paxil. Most
importantly, and pertinent to this discussion, as acknowl-
edged by both Glaxo and the FDA, these recent acknowl-
edgments about a link between suicide and the SSRIs were
not based on new evidence suddenly coming to light, but
were based on a reevaluation of existing evidence.
Apparently, in 1998 there were two different versions of
the SSRIs, one being the unpublished version in the
pharmaceutical companies’records, and one being the
version that was presented to clinicians and scientists in an
academic textbook—a textbook published by the American
Psychiatric Association, with the first author being an Eli
Lilly employee, who said that he would only mention certain
data if asked, and the second author being a Lilly consultant.
In addition to the textbook chapter in The American
Psychiatric Textbook of Psychopharmacology, the second
piece of evidence that Pfizer cited was a review paper titled,
The Neurobiology of Depression and Suicide,byStockmeier.
In the first two sentences of the abstract he states:
“Alterations in serotonin neurotransmission have been
implicated in the pathophysiology of major depression and
suicide. However, a picture of serotonergic abnormalities has
not emerged from postmortem studies of depression and
suicide”(p.220). It is unclear to us how this paper can be
used to support Pfizer’s position. The paper does mention a
pilot study that found an increase in serotonin 1A receptors
in the ventrolateral subnucleus of the dorsal raphe nucleus,
but it is questionable whether the enormity of the SSRI
marketing campaigns can be justified by a 1997 pilot study.
The third piece of evidence for Pfizer was the textbook,
Essential Psychopharmacology, by Stahl, containing a very
in-depth discussion about the mechanism of action of the
SSRIs. When it comes to the discussion about the proof of
the chemical imbalance theory, Stahl states: “So far, there is
no clear and convincing evidence that monoamine deficiency
accounts for depression; that there is no ‘real’monoamine
deficit.”Again, we are not sure how this text supports the
chemical imbalance theory, in fact, because this citation
refutes Pfizer’s position it is a bit strange that they cited it.
As of August 2007, Pfizer’s website for Zoloft still
contains an explanation of “How Zoloft works”which
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states, “Zoloft works to correct this imbalance of serotonin
levels in the brain.”An animation on the web page shows
how Zoloft works in the brain to accomplish this.
Media Confusion
Many newspapers and websites continue to mention
“chemical imbalances”as if there is an abundance of
evidence in the scientific literature. Several authors claimed
that there were numerous studies available, yet they did not
provide any specifics. One scenario—and it places these
omissions in the best possible light—is that the authors are
fully aware of the sources of their citations, but simply do
not want to spend the time to reply to our requests. Another
possibility, however, is that the authors are unable to cite
specific citations and their claims are essentially based on
hearsay. Either of these scenarios would seem to be an issue
for the editors involved, who apparently allowed statements
to be made with no supporting evidence. In some cases, we
forwarded our dialogue with the reporters to their respective
editors. To date, not one of the editors has responded.
Several of the responses from reporters also seem to
suggest a fundamental misunderstanding of the chemical
imbalance theory as it was originally proposed. For
instance, several reporters provided citations that document
correlations, but not causation, or they supplied citations
that discuss the cellular mechanisms of serotonin binding,
which as mentioned before do not document chemical
imbalances as a cause for depression.
Yet another possibility is that, for some media outlets,
the evidence is just not that important. This scenario
presumes that there are two distinct classes of news
sources; there are reporters, and there are reporters. In
other words, there are media outlets that essentially publish
press releases that are handed to them—a press release
comes into the office and, with little analysis on the part of
the staff, the news bureau simply adds a reporter’s name to
the byline and republishes the report. These types of media
outlets are focused on getting information out to the public in
a readable format, while getting the story correct is simply
not part of their mission. These sorts of outlets would seem
to be more prevalent in the age of the World Wide Web.
On the other hand, there are media outlets that actually
investigate, write, and report on an independent basis, and
getting the information right is an essential part of their
mission. The New York Times would seem to be an example
of this second category. Yet, our experience with the Times
reporter who discussed the life of Joseph Schildkraut
challenges this supposition. While he presented the theory
in very matter-of-fact terms, simply stating that the theory
had been proved, he has not responded to any of our
questions.
A recent newspaper article raises an interesting question:
How watered down can the chemical theory become before
it is palatable? The market research company, IPSOS,
recently conducted a survey of attitudes about mental health
and sent out a press release declaring: “Depression in North
America: Widespread acknowledgement, understanding.”
To back up its statement, IPSOS points to the following
data: “Virtually all (ninety percent) North Americans
believe that depression can [italics added] be caused by a
chemical imbalance in the brain.”But does the fact that a
large group of people believe that depression could be
caused by a chemical imbalance warrant the leap to a
headline declaring that North Americans understand de-
pression? For a group wishing to promote the theory the
headlines certainly sound good, especially as they imply
that those who do not subscribe to the chemical imbalance
theory must not understand mental illness. Yet, if we look a
little closer at the survey’s wording, we discover a
fundamental flaw. The question IPSOS has asked is
virtually meaningless as the vast majority of people,
including us, would answer, “Yes.”Of course, depression
could be caused by a chemical imbalance, but if IPSOS was
really interested in finding out if the public understood the
chemical imbalance theory then its survey should have
asked: Is the belief that depression is caused by a chemical
imbalance supported by strong evidence.
Let’s look at this wording in another way, removing it
from the question of chemical imbalance. We’ll use an
arbitrary subject—one that has not been proven one way or
another. Take the example of extraterrestrials. It is one thing
to say: “Extraterrestrials might exist somewhere in the solar
system.”It is another thing to say, “There is evidence of
extraterrestrials in the solar system.”
As a side note, it is interesting and possibly not a
surprise to see that none of the reports about this survey
mentioned that IPSOS, a market research company, handles
market development for the pharmaceutical industry.
Our findings also raise an interesting question for the
editors of the respective publications: To what extent should
reporters be expected to supply references to inquisitive
readers requesting more documentation for an article,
whether the topic is politics, sports or science? In the world
of science, the notion that readers are not entitled to know the
evidence in support of an article is unacceptable. Based on
the replies we received to our inquiries, in the world of
newspaper and magazine publishing, it is apparently
considered acceptable to leave readers in the dark.
If the editors in charge of the articles mentioned above had
posed the same questions to their own reporters as we had, it is
hard to imagine that those editors would have considered the
answers acceptable. Whether the answer was: listing a single
primary care doctor as their source; citing papers that have
nothing to do with the theory; citing doctors who in turn
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would not provide evidence; citing journal supplements; or
simply not replying, none of the answers seems adequate.
Moreover, in two cases, the authors said they now realized
that the discussion was more complicated then they thought,
suggesting that a little more editorial oversight would have
revealed the problem prior to publication.
Who is Affected by the Reporting?
An important question surrounding the media’s portrayal of
the chemical imbalance theory is: What segment of society
has this portrayal affected? Certainly, this type of reporting
raises issues for the press. A comparison of the media’s
reporting about mental illness to the biased reporting in the
New York Times about the events leading up to the Iraq War
does not seem far-fetched. In hindsight, as the Times editors
now acknowledge (5/326/04), Judith Miller’s war coverage
was overly one-sided. Her fundamental flaw could be
described as a lack of professional skepticism toward the
Bush administration, as she willingly parroted what those
pushing for war were saying, while giving little credence to
the stance of the other side. Writing in the New York Review
of Books, Michael Massing commented that the Times and
Miller’s reporting were examples of media “submissive-
ness.”This depiction could just as well apply to the media’s
reporting of mental health issues. As just one example, in
some cases, the media still go to the people responsible for
the original problems. For instance, several of the research-
ers involved with the studies of SSRIs in children are still
cited in the press even though the following information
has come out about their published studies: they down-
played the suicide risk; they exaggerated the benefits; and
the papers published under their names were actually
written by ghostwriters paid by the pharmaceutical industry.
The Times editors have acknowledged both the problems
with Miller’s reporting and their own lack of editorial
oversight of her. It remains to be seen if members of the
media will ever look inward and reflect on their role in the
promotion of the chemical imbalance theory. (For those
familiar with the New York Times’coverage of mental
health issues over the past 10 years, it is refreshing that
after a series of health reporters who essentially abdicated
their role as investigative journalists, there is a newer group
of Times reporters with more skeptical inclinations.)
In addition to the press, the other segment of society that
would seem to be adversely affected by this reporting
consists of the individual psychiatrists and their profession-
al organizations, which have made very few efforts to
correct these erroneous claims. Most unfortunately, those
who have attempted to do so have been marginalized. For
instance, the late Loren Mosher, once the chief of the
Center for Studies of Schizophrenia at the National Institute
of Mental Health, after years of frustration, in a now-
famous letter, resigned from the American Psychiatry
Association (APA), saying, “This is not a group for me.
At this point in history, in my view, psychiatry has been
almost completely bought out by the drug companies…No
longer do we seek to understand whole persons in their
social contexts rather we are there to realign our patients’
neurotransmitters.”For Mosher, the letter was a career-
changing event; his straightforward letter endeared him to
many patients but ostracized him from the profession.
Mosher, in contrast to the head of the FDA Psychophar-
macology Committee who referred to the chemical theory
as a “useful metaphor,”called the theory a hoax.
When the SSRIs first came on the market the psychiatry
profession played an active role in the promotion of the
theory, but as evidence has accumulated suggesting that the
theory is false, the psychiatry profession has become
relatively quiet –they will not defend it, but neither will
they take an active role in explaining that it is false. We are
not aware of a single psychiatry journal or a related
professional organization that has come forward and
explained to patients, the media, or professionals about
the problematic nature of the advertisements which state
that chemical imbalances are the cause of depression. The
end result is the party with the most at stake, the patients,
have little access to information that would enable them to
understand the issue and make a balanced choice. Clearly, a
pill makes much more sense if there is really an underlying
chemical imbalance. When doctors talk about high blood
pressure, diabetes, or high cholesterol they are talking about
science. Imagine a patient who has been diagnosed with
both high cholesterol and depression talking to his doctor.
Given the dearth of reliable information on the subject in
the press, the patient can hardly be faulted for not realizing
that the discussion about one of his conditions—the high
cholesterol—is about science, while the discussion about his
other condition—the depression—is about a metaphor.
How does the patient know when the discussion has
shifted from science to metaphor? For those interested in
informed consent this scenario seems problematic.
In closing, it is also important to point out that there are
mainstream organizations that accurately portray the chemical
imbalance theory, such as the Mental Health Service at McGill
University: http://www.mcgill.ca/mentalhealth/medication/
(accessed May 15, 2007): “The term ‘chemical imbalance’
is thrown around a lot these days. True conditions caused by
chemical imbalances are relatively rare. All thoughts, feel-
ings and motions in the brain are mediated by the release of
chemicals in brain pathways. Every person's brain is unique,
leading each of us to have different traits and abilities. Just
because your brain works in a particular way does not mean
that you have a chemical imbalance. A certain amount of
sadness, anxiety or other emotional upset is normal, and
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though we may be able to block these feelings by chemicals,
this would tend to dehumanize us. Even when we use
medication to help an individual with overwhelming
emotions, most of the time this is not to repair a ‘chemical
imbalance’but simply to help contain symptoms.”
The author of this paragraph has provided an accurate
summary of the chemical imbalance theory, although it is at
odds with the vast majority of the statements found in the
media, the pharmaceutical companies, and NIMH’s web
page. If patients who have been prescribed antidepressants
are provided this information up front, along with informa-
tion regarding the limited efficacy and potential adverse
effects of the medications, this would represent good
informed consent. As it is, we are concerned that many
patients in clinical encounters are misinformed.
In an earlier paper, we pointed out that to our knowledge;
there is not a single peer-reviewed article that can accurately
be cited to directly support claims of serotonin deficiency in
any mental disorder. Based on our dialogue with the
mainstream media, there appears to be no reason to alter this
claim. In an effort to continue this conversation, we welcome
any replies to the question: What is the evidence that
depression is caused by a chemical imbalance?
Further Reading
Antonuccio, D. et al. (1999). Raising questions about antidepressants.
Psychotherapy and Psychosomatics, Vol. 68.
Healy, D. (2006). Let them eat Prozac. New York: New York
University Press.
Kirsch, I. et al. (2002). The emperor’s new drugs: An analysis of the
antidepressant medication data submitted to the US FDA..
Prevention and Treatment. Vol. 5.
Lacasse, J., & Gomory, T. (2003). Is graduate social work education
promoting a critical approach to mental health practice? Journal
of Social Work Education,39(3), 383–408.
Lacasse, J.R. and Leo, J. (2005). Serotonin and depression: A
disconnect between the advertisements and the scientific literature.
PLoS Med 2(12): e392. Available at: http://dx.doi.org/10.1371/
journal.pmed.0020392.
Lacasse, J. and Leo, J. (2006). Serotonin and depression: A disconnect
between the advertisements and the scientific literature. PLoS
Medicine. Available at: http://medicine.plosjournals.org/perlserv/
?request=get-document&doi=10.1371/journal.pmed.0020392.
Leo, J. (2006). The SSRI trials in children. Ethical Human Psychiatry
and Psychology,8(1), 29–41.
Jonathan Leo, Ph.D. is an Associate Professor of Neuroanatomy at
Lincoln Memorial University in Harrogate TN. He has published
numerous articles about mental health covering topics such as the
genetic basis of schizophrenia, the serotonin theory of depression, and
the pediatric trials of SSRIs. For further questions he can be reached at
jonathan.leo@lmunet.edu.
Jeffrey R. Lacasse, MSW is a Visiting Lecturer at the Florida State
University (FSU). He has published research on practice with
children, critical thinking in graduate social work education, and
consumer advertising of SSRI antidepressants. He can be reached at
jeffreylacasse@mac.com.
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