Antidepressants and the Chemical Imbalance Theory of Depression: A Reflection and Update on the Discourse (with Responses from Ronald Pies and Daniel Carlat).

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A DECADE AGO, WE PUBLISHED an article
in PLoS Medicine about the serotonin defi-
ciency theory of depression (Lacasse & Leo,
2005). We transposed the psychiatric liter-
ature on serotonin and depression with
what pharmaceutical companies had been
claiming in their consumer advertisements
for years—that a chemical imbalance (sero-
tonin deficiency) caused depression and
this imbalance was corrected by selective
serotonin reuptake inhibitor (SSRI) drugs.
For instance, advertisements for fluoxetine
(Prozac) had stated:
When you’re clinically depressed, one
thing that can happen is the level of sero-
tonin (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 plea-
sure…to help bring serotonin levels closer
to normal, the medicine doctors now pre-
scribe most often is Prozac® (Eli Lilly,
1998)
We knew that such advertisements did
not accurately reflect the scientific status of
the serotonin theory in the psychiatric
research community (see Table 1; we have
modified the original table to integrate new
material that came to our attention since
2005). Some advertisements were more
tentative or clever in their wording than
others, but it seemed obvious that the drug
companies were at least pushing the
boundaries. We thought several of them
were going over the line, in plain sight of
the Food and Drug Administration (FDA),
which ostensibly regulates direct-to-con-
sumer advertising. Our goal was to illus-
trate the clear disconnect between the
existing psychiatric science and what the
public was being told in these advertise-
ments, and we argued that the FDA should
issue warning letters to pharmaceutical
companies (Lacasse, 2005; Lacasse & Leo,
2005). Of course, there were ramifications
for clinicians—if it was illegal to claim this
in advertisements, wasn’t it also an unac-
ceptable thing to be telling vulnerable
clients?
After the publication of the paper, we
were interviewed by numerous journalists.
Several of them thought our work was
provocative and that we were “attacking” a
well-accepted theory. If it was an attack, it
was an inside job, as our sources included
NIMH-funded scientists, an award-win-
ning biological psychiatrist, and a popular
psychiatric textbook. Anyone familiar with
the history of serotonin research would
find our argument unremarkable (e.g.,
Healy, 1997, 2004; Moncrieff, 2008; Valen-
stein, 1998). In the United Kingdom, psy-
chiatrist David Healy has been making this
point for decades (e.g., Healy, 1987, 1997,
2004, 2012, 2015). But the questions from
journalists reminded us that the enormous
marketing campaigns promoting SSRI
drugs (and surely many of the physicians
prescribing them) had convinced the U.S.
public that the serotonin theory of depres-
sion was firmly grounded in science. This
wasn’t just an issue of misleading advertis-
ing. Instead, the incredulity seemed fueled
by the significant number of mental health
clients who had heard the chemical imbal-
ance explanation from their prescribers.
We urged these reporters to query the
FDA, American Psychiatric Association
(APA), NIMH, and other official organiza-
tions about the science behind the adver-
tisements. New Scientist interviewed
Wayne Goodman, at the time a University
of Florida psychiatrist and Chair of the
FDA Psychopharmacological Committee.
Dr. Goodman called the serotonin theory
“a useful metaphor”—but one he never
used when informing his own patients,
stating, “I can’t get myself to say that”
(Lacasse & Leo, 2006; New Scientist, 2005).
One has to expect that patients whose doc-
tors had said that found this news upset-
ting.
Serotonin imbalance as metaphor is
obviously a deep problem for many of the
patients who have heard their physicians
explain that their depression is caused by a
chemical imbalance. These patients must
have assumed that they were hearing real
science, and not metaphor. Goodman’s
public statement raised the question: How
are patients with both diabetes and depres-
sion who listen to their doctor’s explana-
tion of their two conditions supposed to
know that one explanation is based on sci-
entific measurement, and one is just a
metaphor?
The Problematic Advertisements
Disappear
In the early 2000s, the serotonin
metaphor of depression was widely adver-
tised by the makers of antidepressants,
including advertisements for citalopram,
escitalopram, fluoxetine, paroxetine, and
sertraline (Lacasse & Leo, 2005). In partic-
ular, Zoloft (sertraline) advertisements fea-
turing the miserable ovoid creature were
unavoidable in U.S. television and maga-
zines. An on-line repository of direct-to-
consumer advertisements for psychiatric
drugs lists many from 1997–2007 referring
to a chemical imbalance, across many
drugs and diagnostic categories (Hansen,
2015a, 2015b).
A 2010 study compared on-line drug
advertising of antidepressants regarding
the issue of chemical imbalance in both
2004 and 2009 (Lacasse & Hughes, 2010).
The number of websites making such
claims dropped, with some websites going
dark or minimalist as the drug patents ran
out. Interestingly, some on-patent drug
websites had simply removed the chemical
imbalance claims. Newer medications were
promoted as “adjusting” or “affecting”
neurotransmitter levels, in contrast to “cor-
recting a chemical imbalance.”
From 2014–2015, we collected further
data, finding that the simplistic narrative of
chemical imbalance that was so common
in direct-to-consumer advertising in the
2000s is not widespread any longer. Con-
sumers are no longer informed that antide-
pressants will normalize their neurotrans-
mitter levels. The Abilify thermostat is
gone (Lacasse & Leo, 2006) and drugs are
now advertised as “affecting” neurotrans-
mitters. This is mostly true for other classes
of medications as well, as advertisements
for psychostimulants (Leo & Lacasse, 2009)
have also moderated their language sub-
stantially. While we still see problematic
advertisements, the overall situation has
obviously improved.
There is no public explanation for why
this happened. To our knowledge, FDA has
never sent a warning letter to a pharmaceu-
tical company over claims that antidepres-
Antidepressants and the Chemical Imbalance
Theory of Depression: A Reflection and Update
on the Discourse
Jeffrey R. Lacasse, Florida State University
Jonathan Leo, Lincoln Memorial University
206 the Behavior Therapist
L A C A S S E & L E O

sants correct a chemical imbalance. In our
assessment, the promotion of chemical
imbalance theory in advertisements for
SSRI drugs was wildly successful for the
drug companies and the psychiatric profes-
sion alike. While it’s difficult to imagine
that they pulled them arbitrarily, we don’t
know why they largely disappeared.
By roughly 2007, anyone who Googled
“serotonin and depression” could easily
find articles explaining the mythical nature
of serotonin imbalance, or at least the argu-
ment. We don’t claim that our one little
article was responsible, or even original
(see Breggin, 1998; Glenmullen, 2000;
Healy, 1997, 2004). But given that the
public had accepted the serotonin theory as
fact (Pescosolido et al., 2010), the wide-
spread public criticism of it and emerging
transparency of information on the Inter-
net would obviously create problems, or at
least a dilemma. Below, we highlight a few
examples of the recent discourse on these
issues (see also Levine, 2014; Lynch, 2015;
Whitaker, 2010, 2015; Whitaker & Cos-
grove, 2015).
I Don’t Really Believe It,
but I Say It to Patients Anyway
Psychiatrist Daniel Carlat is a practicing
psychiatrist, a clinical instructor at Tufts
University, and editor of The Carlat Psychi-
atry Report, which we have read for years.
On July 13, 2010, he appeared on National
Public Radio (NPR; Davies, 2010) to pro-
mote his book, Unhinged (2010), in which
he describes psychiatry as a profession in
crisis. Carlat had received some attention
in The New York Times, candidly reporting
his experience pitching venlafaxine
(Effexor) to other doctors as a paid consul-
tant for Wyeth. He found himself “tweak-
ing and pruning the truth to stay positive
about the product” and eventually resigned
(Carlat, 2007). We find that Carlat is
unusually transparent, providing interest-
ing insights into uncomfortable issues.
Carlat was asked what we know about
psychiatric medication. He responded:
What we don’t know, is we don’t know
how the medications actually work in the
brain. . . . I’ll often say something like the
way Zoloft works, is, it increases the level
of serotonin in your brain (or synapses,
neurons), and, presumably, the reason
you’re depressed or anxious is that you
have some sort of a deficiency. And I say
that [chuckles] not because I really believe
it, because I know the evidence really isn’t
there for us to understand the mecha-
nism—I think I say that because patients
want to know something. And they want
to know that we as physicians have some
basic understanding of what we’re doing
when we’re prescribing medications. They
certainly don’t want to know that a psychi-
atrist essentially has no idea how these
medications work. (Davies, 2010)
This is surely a remarkable public
admission. Carlat continues:
We’re in a paradoxical situation, I think,
where we prescribe medications that do
work according to the trials. And yet as
opposed to essentially all other branches of
medicine, we don’t understand the patho-
physiology of what generates mental ill-
ness and we don’t understand exactly how
our medications work. (Davies, 2010)
A practicing psychiatrist could under-
standably report that they see the medica-
tions working in their practice and find
them useful. Invoking the clinical trials is
perhaps a strange direction to go here,
because the consistent lack of difference
between SSRI and placebo in the clinical
trial literature is one of the most com-
pelling arguments against the serotonin
deficiency theory. So Carlat is aware of the
clinical trials, which essentially refute the
serotonin theory, yet still tells patients that
they have a serotonin imbalance. And
while some prescribers of psychiatric med-
ication object to misleading SSRI advertise-
ments (Rickels, 2006), Carlat sees wide-
spread pharmaceutical propaganda as an
opportunity:
One thing that has happened is that
because there’s been such a vacuum in our
knowledge about mechanism, the drug
companies have been happy to sort of fill
that vacuum with their own version of
knowledge, that usually if you see a com-
mercial for Zoloft on TV, you’ll be hearing
the line about serotonin deficiencies and
chemical imbalances, even though we
don’t really have the data to back it up. It
becomes a very useful marketing line for
drug companies, and then it becomes a
reasonable thing for us to say to patients to
give them more confidence in the treat-
ment they’re getting from us—but it may
not be true. (Davies, 2010)
Carlat’s straightforward admissions are
likely to cause reactions, and we think they
mostly speak for themselves. It’s worth
noting that he sometimes frames the sero-
tonin issue as one of scientific uncertainty:
we “essentially” or “exactly” don’t know
how SSRI medications work, and the sero-
tonin theory “may not be true.” Such state-
ments need to be evaluated in light of the
existing literature (see Table 1). In fact, sci-
entists have known for a long time that the
serotonin theory presented by the drug
companies and Carlat is not true (see
Healy, 2004, 2012, 2015; Lynch, 2015).
Claiming scientific uncertainty about the
issue could reflect a lack of familiarity with
the scientific literature, or a need to justify
the use of such statements. In our opinion,
neither option is flattering or desirable in
an era of shared clinical decision-making.
The simple alternative would be to tell
patients the truth—that the pathophysiol-
ogy of depression is unknown and that we
have no idea how SSRIs work.
The Positive Aspects
of Misinformed Thinking
On January 23, 2012, NPR Morning
Edition aired “When it Comes to Depres-
sion, Serotonin Isn’t the Whole Story”
(Spiegel, 2012). While Carlat states that the
serotonin theory “may not be true,” psychi-
atrist Joseph Coyle makes a much clearer
statement: “I don’t think there’s any con-
vincing body of data that anybody has ever
found that depression is associated to a sig-
nificant extent with a loss of serotonin.”
Yet part of the segment focuses on the pos-
itive aspects of telling patients that a sero-
tonin imbalance causes depression (see
Levine, 2014). For instance, Alan Frazer,
Professor of Pharmacology and Psychiatry,
stated that the serotonin theory allowed
patients to:
Feel better about themselves if there was
this biological reason for them being
depressed, some deficiency, and the drug
was correcting it. They had a chemical
imbalance and the drug was correcting
that imbalance . . . yeah it’s like, I have
depression but I have a chemical imbal-
ance, and you have hypothyroidism and
you have a chemical imbalance, and my
chemical imbalance just happens to affect
my brain. (Spiegel, 2012)
Psychiatrist Pedro Delgado added,
“When you feel that you understand it, a lot
of the stress levels dramatically are
reduced. So stress hormones and a lot of
biological factors change.”
Not surprisingly, there were many
angry comments on the NPR website.
Apparently, many psychiatric patients
never realized they were hearing a
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metaphor and not science. They didn’t
know that the chemical imbalance
metaphor was used in an attempt to reduce
stigma, or stress hormones, rather than
being accurate information presented by
their trusted health-care provider. Since
chemical imbalance is often presented as a
rationale for taking SSRIs, some such
patients now understandably feel lied to by
their clinicians. Levine (2014) calls this
“Psychiatry’s Manufacture of Consent.”
The claim that presenting the chemical
imbalance metaphor is in the best interests
of patients needs to be considered in light
of the existing empirical research. This in
fact is not what the literature shows (e.g.,
Deacon & Baird, 2009). For instance, in a
rare controlled experiment on this topic,
one group of depressed students were told
they had a confirmed serotonin imbalance
underlying their depression, while a con-
trol group was not (Kemp, Lickel, &
Deacon, 2014). The group who was told
they had abnormal serotonin levels found
medication more credible than psy-
chotherapy and expected it to be more
effective. They also had more pessimism
about their prognosis and a lower per-
ceived ability to regulate negative mood
states, yet experienced no reduction in self-
blame. These results suggest that the chem-
ical imbalance explanation may indeed be
helpful in persuading patients to take med-
ication but that this is likely accompanied
by undesirable effects. Data such as this
should be a major part of the conversation
regarding informed consent in psychiatry.
The Role of Journalism
Perhaps the most interesting part about
both of these NPR pieces is that neither
reporter questioned the experts about the
ethics of telling a falsehood to patients
because you think it is good for them. In
contrast to how, say, a foreign-policy
expert might be grilled on NPR, the tone
was deferential and accepting. We would
have liked both reporters to have asked the
following questions: (a) Do you believe it is
ethical to present a falsified scientific
theory as a fact to a patient? (b) What are
the possible negative effects of doing so? (c)
Should the information you tell your
patients be consistent with the psychiatric
textbooks on your shelf? (d) How does it
affect the psychiatrist-patient relationship
when your patients look up serotonin
imbalance on the Internet and conclude
that they have been misled?
It Wasn’t Us, It Was
the Drug Companies
Ronald Pies is a psychiatrist at Tufts
University and served as editor of the
prominent trade journal Psychiatric Times
from 2007–2010. From 2011 on, he
authored several pieces on the chemical
imbalance issue, which we recommend
(Pies 2011a, 2011b, 2014). These are avail-
able on the web, cited frequently, and Pies
is the most prominent figure in U.S. psy-
chiatry to take up this issue publicly. Pies
doesn’t believe that the chemical imbalance
metaphor should be attributed to psychia-
try:
. . . opponents of psychiatry . . . menda-
ciously attribute the phrase [“chemical
imbalance”] to psychiatrists themselves . . .
And yes [it has] been vigorously promoted
by some pharmaceutical companies, often
to the detriment of our patient’s under-
standing. . . . In truth, the “chemical imbal-
ance” notion was always a kind of urban
legend—never a theory seriously pro-
pounded by well informed psychiatrists.
(Pies, 2011a)
We suspect that Pies had no idea how
many of his fellow psychiatrists he was
throwing under the metaphorical bus by
making this claim. While we don’t know
exactly how many clinicians have told their
patients they were suffering from a chemi-
cal imbalance over the last 25 years, we
believe that the number is significant and
consequential. Among 237 psychology stu-
dents, Frances, Lysaker, and Robinson
(2007) found that 46% had heard the
chemical imbalance explanation from a
physician. Empirical studies report use of
the chemical imbalance theory by pre-
scribers, including psychiatrists (e.g.,
Cohen & Hughes, 2011; Schreiber & Har-
trick, 2002; see also Acker, 2013). Also,
over the years, we’ve been in touch with
many people who reported hearing “it’s a
chemical imbalance” from psychiatrists:
people in our social circles; “consumers” at
conferences; our students who work in
community mental health settings; subjects
in our research (Lacasse, Lietz, Hayes,
Rider & Hess, in press); and people who
emailed us in response to our work. And,
one of the authors once worked with a tal-
ented psychiatrist and heard this explana-
tion given weekly. If Pies is correct, that’s
an awful lot of uninformed clinicians.
A Bumper-Sticker Slogan
to Educate Patients
In subsequent articles Pies moderates
his tone and concedes that practicing psy-
chiatrists may have used the chemical
imbalance explanation at times (Pies,
2011b). He claims that it is the result of
overbooked clinicians looking for quick
explanations to accompany medication,
perhaps to reduce self-blame on the part of
patients (he acknowledges that this may
backfire). He states:
My impression is that most psychiatrists
who use this expression feel uncomfort-
able and a little embarrassed when they do
so. It’s kind of a bumper-sticker phase that
saves time, and allows the physician to
write out that prescription while feeling
that the patient has been “educated.” (Pies,
2011b)
To us, this sounds similar to what Carlat
was reporting. Pies also notes that acade-
mic psychiatry hasn’t done a great job of
communicating with Primary Care Physi-
cians (PCPs), who write most of the pre-
scriptions for SSRIs. This might be seen as
a question of priorities, because academic
psychiatry in general has done a highly
effective job of convincing PCPs to diag-
nose and treat depression with antidepres-
sants.
Academic Psychiatry as Silent
Partner in the Promotion
of Chemical Imbalance
Pies admits that both he and official
psychiatric associations should have done
more to dispel the chemical imbalance
myth (Pies, 2014). He adds that there “were
sincere attempts to do just that, by several
prominent psychiatrists.” Unfortunately,
he doesn’t provide any recent examples (he
does cite Shildkraudtt & Kety, 1967). It is
easy to imagine that a single prominent
academic psychiatrist, authoring an Op-Ed
in The New York Times, could have set the
record straight on serotonin imbalance
decades ago. Yet, to our knowledge, no one
did so.
We have long been concerned about
how conflicts-of-interest with the pharma-
ceutical industry might shape the behavior
(unconsciously or not) of academic psychi-
atrists, including the promotion of the
chemical imbalance metaphor. In 2009, we
wrote about misleading direct-to-con-
sumer advertising of psychostimulants
such as Adderall, where the claims were at
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least as misleading as SSRI advertisements
(Lacasse & Leo, 2009). Noting the lack of
objections to these advertisements from
within academic psychiatry, we asked, “Is it
possible that the flow of money from the
pharmaceutical companies to influential
academic psychiatrists . . . has brought with
it a certain willingness to remain silent?”
We doubt Ronald Pies would find this irra-
tionally conspiratorial, or a crazy question
to ask—because we published this in Psy-
chiatric Times(Editor: Ronald Pies, M.D.).
Thus, while we don’t know why Ronald
Pies himself didn’t speak out on the chem-
ical imbalance issue decades ago, readers
should be aware of his past financial rela-
tionship with pharmaceutical companies.
He sounds vaguely critical of the drug
industry in his recent articles and never
discloses any history of financial conflicts-
of-interest. However, Pies has received
funding from GlaxoSmithKline, Abbot
Laboratories, and Jannsen Pharmaceuti-
cals—the makers of Paxil, Wellbutrin,
Lamictal, Depakote, and Risperdal (Chau-
dron & Pies, 2003; Pies & Rogers, 2005).
For years, Paxil and Wellbutrin were
advertised as correcting a chemical imbal-
ance in the brain. These three companies
have recently been fined a combined $6.7
billion for illegal marketing of their prod-
ucts.1Pies has also consulted for Apothe-
Com, a "Medical Communications
Agency” that “provides services to support
the commercialization of new prod-
ucts…[including]….publications plan-
ning, [and] promotional communica-
tions…” (Pharma Voice Marketplace,
2015). While useful context, this isn’t
uncommon among academic psychiatrists,
and some would say it was par for the
course in the 2000s. However, in a public
forum, more transparency is preferable.
Pies blames the drug companies for run-
ning misleading advertisements about
chemical imbalance, belatedly admits he
should have said something sooner, but
fails to mention that he was paid to help
them promote their products at the time
the advertisements were running.
It’s important to realize that organized
psychiatry doesn’t always remain silent,
such as when the interests of psychiatric
prescribers and pharmaceutical companies
converge. In the mid-2000s, press releases
endorsed by some of the most prominent
psychiatrists in the United States were
issued objecting to the FDA black box
warning on SSRIs (e.g., American College
of Neuropsychopharmacology, 2006;
Healy, 2012). The APA also issued a press
release defending antidepressants (APA,
2004; Healy, 2006). This was at a time when
the chemical imbalance metaphor was
omnipresent in direct-to-consumer adver-
tising. While that was seen as a pressing
issue to present to the public, misleading
messages on chemical imbalance were not.
But We Never Promoted the Theory
Remaining silent is one thing, promot-
ing chemical imbalance theory is another.
Pies has also stated, “I am not aware of any
concerted effort by academic psychiatrists,
psychiatric textbooks, or official psychi-
atric organizations to promote a simplistic
chemical imbalance hypothesis of mental
illness” (2014). In the age of the Internet, it
didn’t take long for MadinAmerica.com
blogger Philip Hickey (2014) to make him
aware of some. We added to the list by con-
sulting Lynch (2015, Chapter 5) and
searching the Internet. The resulting list
(Table 2) is admittedly incomplete but suf-
ficient to address Pies’ point.
Clearly, mainstream psychiatry (includ-
ing academic psychiatry and professional
organizations) has promoted the chemical
imbalance theory. Comparing Table 1 and
Table 2, it is apparent that there are often
two different conversations occurring
(Whitaker, 2010; Whitaker & Cosgrove,
2015). One is the actual scientific discourse,
as exemplified in the APA’s Textbook of
Psychiatry (Hales, Yudofsky, & Talbott,
1999), which accurately describes the
empirical status of serotonin imbalance
theory 16 years ago. The other conversa-
tion is between influential psychiatrists and
the public, or between psychiatrists and
primary care physicians. In this second
conversation, the drug company advertis-
ing line about SSRIs correcting chemical
imbalances is repeated as fact by psychi-
atric authorities, including the APA.
The Chemical Imbalance Theory
as a Little White Lie
Pies started out enthusiastically cri-
tiquing the chemical imbalance theory. We
obviously believe he tried to rewrite some
history along the way. But, by 2014, Pies
refers to the use of the chemical imbalance
metaphor as “a little white lie”2(Pies, 2014;
see also Hickey, 2014). While previously
psychiatrists who used this language were
not well-trained, or knowledgeable, or
well-informed, now they are just telling
white lies—little ones.
We found this disappointing. When our
physicians are educating us, we prefer they
not tell us any lies, white or otherwise.
Unfortunately, characterizing the chemical
imbalance metaphor as a “little white lie”
communicates a paternalistic, hierarchical
approach that sounds suspiciously like the
days of medicine that we thought we had
left behind. It’s a “little white lie” if you’re a
psychiatrist; if you’re a confused, vulnera-
ble depressed person who agrees to take an
SSRI after hearing it, you might not con-
sider it so little. After all, if your trusted
physician tells you that you have a chemical
imbalance in your brain that can be cor-
rected with medication, not doing so
sounds foolish, if not scary (Lacasse, 2005).
How many patients with reservations
about SSRIs have agreed to take medication
after being told this “little white lie”?
Discussion
In the last decade, widespread claims of
chemical imbalance in depression have
essentially been withdrawn by both the
profession of psychiatry and the pharma-
ceutical industry. We believe the profession
of psychiatry should be strongly critiqued
for withdrawing the serotonin theory belat-
edly, long after the science was in, and for
not speaking up while drug advertisements
1We want to be clear that we are not accusing Ronald Pies of anything. Conflicts-of-interest are
routine in academic psychiatry and many of the major pharmaceutical companies have been
fined in the recent past. We do believe that readers deserve to know of his past financial rela-
tionships with the drug companies that promoted their products as correcting a chemical imbal-
ance. The details of these financial relationships are not publicly available.
2Pies’ (2014) original quote reads as follows: “In the narrative of the antipsychiatry movement, a
monolithic entity called 'Psychiatry' has deliberately misled the public as to the causes of mental
illness, by failing to debunk the chemical imbalance hypothesis. Indeed, this narrative insists that
by promoting this little white lie, psychiatry betrayed the public trust and made it seem as if psy-
chiatrists had magic bullets for psychiatric disorders.” It’s important to realize that “little white
lies” is Pie’s characterization of chemical imbalance, not how it is presented in the critical narra-
tive. Writers like Whitaker (2010) vigorously critique the idea of chemical imbalance exactly
because they do not see it as a “little white lie.”
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“By 1970…[biochemist and Nobel Prize Winner Julius] Axelrod had concluded that, whatever was
wrong in depression, it was not lowered serotonin.”
“I spent the first several years of my career doing full-time research on brain serotonin metabolism,
but I never saw any convincing research that any psychiatric disorder, including depression, results
from a deficiency of brain serotonin” (Psychiatrist David Burns, who conducted award-winning sero-
tonin research in the 1970s).
“Tianeptine is an interesting compound with antidepressant activity thought to be related to increased
rather than decreased 5HT [serotonin] uptake” [meaning, in 1989 it was known to be an antidepres-
sant that depletes, not increases, serotonin].
“The simplistic idea of the ‘5-HT [serotonin]’ neurone does not bear any relation to reality” (John
Evenden, Astra pharmaceutical company research scientist, 1990).
“In the 1990s…No one knew if SSRIs raised or lowered serotonin levels; they still don’t know…There
was no evidence that treatment corrected anything.”
“…Patients have been diagnosed with ‘chemical imbalances’ despite the fact that no test exists to sup-
port such a claim, and there is no real conception of what a correct chemical imbalance would look
like…Yet conclusions such as ‘depression is a biochemical imbalance’ are created out of nothing more
than semantics and the wishful thinking of scientists/psychiatrists and a public that will believe any-
thing now that has the stamp of approval of medical science” (Psychiatrist David Kaiser of
Northwestern University Hospital, 1996).
“Although it is often stated with great confidence that depressed people have a serotonin or norepi-
nephrine deficiency, the evidence actually contradicts these claims” (Neuroscientist Elliot Valenstein).
“The monamine hypothesis…holds that monoamines…such as… [serotonin]…are deficient in
depression and that the action of antidepressants depends on increasing the synaptic availability of
these monoamines….However, inferring neurotransmitter pathophysiology from…[SSRIs]…is simi-
lar to concluding that because aspirin causes gastrointestinal bleeding, headaches are caused by too
much blood…Additional experience has not confirmed the monoamine depletion hypothesis.”
(American Psychiatric Association Textbook of Psychiatry, 1999).
“A serotonin deficiency for depression has not been found” (Psychiatrist Joseph Glenmullen, Clinical
Instructor of Psychiatry at Harvard Medical School).
“…I wrote that Prozac was no more, and perhaps less, effective in treating major depression than
prior medications….I argued that the theories of brain functioning that led to the development of
Prozac must be wrong or incomplete” (Brown University Psychiatrist Peter Kramer, author of
Listening to Prozac).
“[We must] abandon the simplistic hypotheses of there being either an abnormally high or abnormal-
ly low function of a given neurotransmitter” (Avrid Carlson, Nobel Prize winner for his work on the
neurotransmitter dopamine, 2002).
“Indeed, no abnormality of serotonin in depression has ever been demonstrated” (Psychiatrist and
historian David Healy in 2004).
Healy, 2004, p. 12
Lacasse & Gomory, 2003, p. 393
Ives & Heym, 1989, p. 22
Shorter, 2009, p. 204
Healy, 2015
Kaiser, 1996; Lynch, 2015,
pp. 31-32.
Valenstein, 1998, p. 100
Dubvosky & Buzan, 1999,
p. 516
Glenmullen, 2000, p. 197
Kramer, 2002
CINP Meeting with the Nobels
(2003); Shorter, 2009, p. 204
Healy, 2004, p. 12
Table 1. Evidence the Chemical Imbalance Theory of Depression Is Not Valid: Selected Quotations
Quote Citation
210 the Behavior Therapist
L A C A S S E & L E O

Table 2. Promotion of the Chemical Imbalance Theory of Depression as Valid: Selected Quotations
Quote Citation
Source
“Celexa helps to restore the brain’s chemical bal-
ance by increasing the supply of a chemical mes-
senger in the brain called serotonin.”
“Antidepressants may be prescribed to correct
imbalances in the levels of chemicals in the brain.”
“Antidepressants…have no effect on normal
mood. They restore brain chemistry to normal.”
“[antidepressants work] only if there was a chemi-
cal imbalance in the brain that needed fixing”
“While the patient may require a somatic therapy
to correct the underlying chemical imbalance, he
may also need psychotherapy…”
“…some depressed patients who have abnormally
low levels of serotonin respond to SSRIs...”
“There is truly a real deficiency of serotonin in
depressed patients.”
“The physician should stress that depression is a
highly treatable medical illness caused by a chemi-
cal imbalance.”
“Patients with neurotransmitter dysregulation may
have an imbalance of serotonin and norepineph-
rine…duloxetine [Cymbalta] may aid in correct-
ing the imbalance of serotonin and norepineph-
rine neurotransmission in the brain.”
“Restoring serotonin’s imbalances not only helps
brighten mood and restore normal sleeping and
eating patterns, but it also seems to promote a
sense of well-being.”
“We now know that mental illnesses—such as
depression or schizophrenia—are not ‘moral
weaknesses’ or imagined but real diseases caused
by abnormalities of brain structure and imbal-
ances in chemicals of the brain….medications and
other treatments can correct these imbalances.
Talk therapy can directly improve brain function-
ing.”
“At some time in the course of their illness, most
patients and families need some explanation of
what has happened and why. Sometimes the
explanation is as simplistic as ‘a chemical imbal-
ance’….”
Celexa website, 2005
Let’s Talk Facts About Depression, a patient
information leaflet distributed by APA
Nada Stotland, president of the American
Psychiatric Association, 2007-2008
Donald Klein, psychiatrist and psychopharmacol-
ogist
Nancy Andreason, psychiatrist and author of The
Broken Brain
Psychiatrist Richard Friedman in The New York
Times
Psychiatrist Charles Nemeroff
MacArthur Foundation Depression Education
Program for Primary Care Physicians
Madkur Trivedi, psychiatrist at University of
Texas Southwest Medical School, in The Primacy
Care Companion of the Journal of Clinical
Psychiatry
Michael Thase, psychiatrist and psychopharmacol-
ogy researcher at the University of Pennsylvania,
and science writer Susan Lang
Richard Harding, president of the American
Psychiatric Association, 2000-2001
Robert Freedman, psychiatrist at the University of
Colorado
Lacasse & Leo, 2005
American Psychiatric
Association, 2005, p. 2
Stotland, 2001, p. 65
Talan, 1997
Andreason, 1985, p. 258
Friedman, 2007
Nemeroff, 2007
Cole, Raju, Barrett, Gerrity, &
Dietrich, 2000, p. 340
Trivedi, 2004, p. 13
Thase & Lang, 2004, p. 106
Harding, 2001, p. 66
Freedman, 2003, as cited by
Hickey, 2014
October • 2015 211
C H E M I C A L I M B A L A N C E

(and many clinicians) were convincing the
American public that the chemical imbal-
ance theory was legitimate. We previously
argued that the propagation of misleading
advertising “is only possible in the absence
of vigorous government regulation . . . or
outcry from professional associations”
(Lacasse & Leo, 2006). That outcry never
came, and these issues weren’t addressed
publicly until the patents for most block-
buster SSRIs had expired, and Big Pharma
moved onto mood stabilizers and atypical
antipsychotics. While we are hesitant to
overemphasize conflicts-of-interest as an
explanation for what has occurred, we can’t
help but notice that the silence of psychia-
try regarding chemical imbalance only
ended when the profits had been extracted
from the SSRI marketplace.
The new narrative will apparently be
that psychiatrists recently discovered that
the chemical imbalance theory was incor-
rect. Psychiatric researchers are changing
their mind based on data, so the story goes,
and it just took a while to let the public
know. We believe this is empirically incor-
rect (Table 1; see Healy, 2015; Shorter,
2015). The idea that the withdrawal of the
chemical imbalance theory was caused by
recent data should be rejected.
As the theory has been withdrawn and a
dialogue has taken place, many mental
health clients have reacted negatively to the
news that there was never any reason to
believe that depression was caused by a
serotonin imbalance (Healy, 2015). Many
mental health clients find it unacceptable,
and perhaps a violation of ethical informed
consent, for clinicians to give patients
metaphorical explanations for their mental
health problems and promote them as sci-
entific truth. Patients who start an SSRI
because they have been told it will correct
their chemical imbalance, that it is like thy-
roid medication for hypothyroidism, are
likely to eventually conclude that they have
simply not been told the truth. This obvi-
ously creates awkward dynamics in
patient-prescriber relationships and also
represents a potential public relations
problem for the profession of psychiatry.
Previously, we argued that misleading
consumer advertisements for SSRIs should
end (Lacasse & Leo, 2005). A decade later,
the serotonin theory of depression is
acknowledged to be dead, and most SSRI
advertising campaigns are now part of his-
tory. We look forward to a day when telling
depressed patients they have a serotonin
imbalance is as anachronistic as the miser-
able ovoid creature from the Zoloft adver-
tisements of the past, and we believe that
day will come sooner than some might sup-
pose. We encourage our colleagues in orga-
nized psychiatry to work towards this end
by improving medical education and ongo-
ing training, by endorsing shared decision-
making, and by ensuring that informed
consent is based on the scientific literature.
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...
Correspondence to Jeffrey R. Lacasse, Ph.D.
jlacasse@fsu.edu
October • 2015 213
C H E M I C A L I M B A L A N C E

260 the Behavior Therapist
neuroimaging biomarkers to achieve
unprecedented levels of precision in pre-
dicting individual patient outcomes follow-
ing CBT (Doehrmann et al., 2013; Siegle et
al., 2012). These are just afew examples of
an ongoing and iterative process of discov-
ery in which neuroscience and clinical psy-
chological science inform one another and
create avenues for continuing to improve
on the valuable tools psychologists already
have at their disposal.
We enthusiastically welcome any of the
contributors to the special issue, as well as
any readers who find the topic engaging, to
attend our SIG meeting which occurs
annually at the ABCT convention. The
meeting will serve as a useful launching
point for ABCT members from all back-
grounds to learn more about the possibili-
ties our SIG members envision for transla-
tional and neurocognitive research and to
engage in an open dialogue around these
issues. We hope and expect that ABCT will
continue to be a place where individuals
utilizing diverse methodologies can learn
from one another, united in the goal of
relieving the suffering caused by psycho-
logical conditions.
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...
Correspondence to Rebecca B. Price, Ph.D.,
University of Pittsburgh, Department of Psy-
chiatry, 3811 O'Hara St., Pittsburgh, PA
15213; rbp18@pitt.edu
FOR THE PAST 33 YEARS as apsychiatrist,
teacher, and writer, I have advocated a
comprehensive, “biopsychosocial” model
of mental illness and its treatment. Indeed,
my 1994 textbook was titled Clinical
Manual of Psychiatric Diagnosis and Treat-
ment: ABiopsychosocial Approach.There is
overwhelming evidence that biological and
genetic factors contribute to the risk of
developing some psychiatric disorders,
including but not limited to major depres-
sive disorder (MDD) (Gold et al., 2015);
however, psychological, social, and cultural
factors are also involved in the genesis of
many psychiatric disorders, including
MDD (Compton &Shim, 2015). Hence, a
purely “chemical imbalance theory” of
depression or any mental disorder is sim-
plistic, incomplete, and unhelpful when it
implies that psychosocial factors are unim-
portant.
Unfortunately, in recent years, antipsy-
chiatrybloggers have argued that “psychia-
try”—in some broad, institutional sense—
has promoted a “chemical imbalance
theory” of mental illness in general. Ihave
argued that there has been no such general
“theory” propounded by academic psychi-
atrists, psychiatric textbooks, or official
psychiatric organizations, such as the
American Psychiatric Association. Istand
by that claim. On the other hand, most psy-
chiatrists would acknowledge that the bio-
genic amine hypothesis of affective disor-
ders (Schildkraut &Kety, 2015) has indeed
led many physicians to use the unfortunate,
shorthand expression “chemical imbal-
ance” to explain how antidepressants may
work. I have repeatedly pointed out that
this expression, even if intended to reduce
the stigma associated with psychiatric ill-
ness, is still misleading (Pies, 2011; Pies,
2014a). I have also acknowledged that in
the 1990s, there was an overemphasis on
the role of serotonin in the etiology of
depression (Pies, 2015b).
Unfortunately, the article by Drs.
Lacasse and Leo (2015) in the October spe-
cial issue of the Behavior Therapist (Deacon
&McKay, 2015) misrepresents my views in
the matter of the so-called “chemical
imbalance theory” (CIT) and insinuates
that I have acted in bad faith, owing to
alleged “conflicts of interest.” These asper-
sions seem based, in part, on the false claim
that Iconsider use of the chemical imbal-
ance metaphor as merely “a little white lie”;
and on the equally false claim that I was
“paid to help [drug companies] promote
their products.” Specifically:
• Lacasse and Leo (2015) mistakenly
imply that I either originated, or
endorse, the phrase “little white lie” in
reference to the CIT. In truth, I have
never applied that expression to, for
example, a clinician's telling a patient,
“Your emotional problem is due simply
LETTER TO THE EDITOR
Response to Lacasse and Leo (2015)
Ronald W. Pies, SUNY Upstate Medical University
PIES

Winter •2015261
to a chemical imbalance.” I would
regard such a statement as simplistic
and reductionistic, and would never
shrug it off—as Lacasse and Leo
imply—as “a little white lie.” Lacasse
and Leo may have made an innocent
mistake in attributing this expression to
me, owing to two online versions of my
“Nuances” article (2014a, 2014b).
However, had they investigated care-
fully, they would have seen that it was
journalist Robert Whitaker who first
employed the “little white lie” expres-
sion in the context of the CIT (Levine,
2014), and that my subsequent use of
that phrase (Pies, 2014b) was in refer-
ence to Whitaker’s comments in his
interview with Bruce E. Levine. Unfor-
tunately, in the Medscape version of my
“Nuances” paper—which originally
appeared in Psychiatric Times (Pies,
2014a)—I did not put Whitaker’s
phrase in quotes, for which omission I
take responsibility. However, I could
easily have cleared up any confusion on
this point, had Drs. Lacasse and Leo dis-
cussed the matter with me, before writ-
ing their article.
•Citing papers Ico-authored in 2003 and
2005—in which I disclosed having
received occasional speaking honoraria
from three pharmaceutical compa-
nies—as well as my consulting work
with the medical communications com-
pany Apothecom (2001–2006), Lacasse
and Leo assert that “. . . he [Pies] was
paid to help [drug companies] promote
their products at the time [their drug]
advertisements were running” (p. 209).
Lacasse and Leo reach this conclusion
without any direct knowledge of formal
arrangements or agreements Imayhave
negotiated in theyears2003–2005, or at
anyothertime.
Let me be clear: never, in any lecture I
delivered that was underwritten by aphar-
maceutical company, did I ever agree to
“promote” a particular product; nor did I
ever use slides or material provided by such
companies, or have any personal contact
with anyone representing the sponsoring
company. I estimate that, in toto, I deliv-
ered 5to 6lectures, over a30-year period,
that were underwritten to some extent by
pharmaceutical companies—with which I
had no ongoing financial relationships.
As for my part-time consulting role
with Apothecom, all stipends came solely
from Apothecom and were paid to me on
an ad hoc (hourly) basis. At no time did I
agree to “promote” any drug company’s
product, nor was Iinduced or expected to
do so by anyone at Apothecom. Of course,
Iam aware that “conflicts of interest” may
sometimes arise inadvertently, even when
physicians are not conscious of them, and I
have written extensively on this issue (Pies,
2013). Furthermore, by 2007, when I
became Editor-in-Chief of Psychiatric
Times (2007–2010), I no longer accepted
any lecture invitations (e.g., from various
hospitals) that were supported by pharma-
ceutical companies.
As forLacasseandLeo's(2015) allega-
tion that I “. . . didn’t speak out on the
chemical imbalance issue decades ago” (p.
209)—for example, with an op-ed in the
New York Times—there is a straightfor-
ward explanation for this. In my more than
30 years in psychiatry, Inever once heard
any of my colleagues or teachers propound
asimplistic “chemical imbalance theory” of
mental illness—or even of depression. I
began addressing this issue in 2011, as I
became increasingly aware of antipsychia-
try bloggers using the “chemical imbal-
ance” canard as acudgel against psychiatry.
More substantively: Lacasse and Leo’s
(2015) article ignores the critical distinc-
tion between ahypothesis and atheory—the
latter being an integrated constellation of
validated hypotheses (Understanding Sci-
ence, 2015). Specifically, they fail to distin-
guishbetweenthebiogenic aminehypothe-
sis of affective illness (which was indeed
propounded by some psychiatrists, on
good evidence) and ageneral, comprehen-
sive theory that “mental illness is caused by
a chemical imbalance”—which has never
been the position of any professional psy-
chiatric organization,or of most academic
psychiatrists. Lacasse and Leo's confusion
is highlighted in their quite unconvincing
Table 2(p. 211), which cites precisely 9psy-
chiatrists (out of over 36,000 in the U.S.!)
who refer in some fashion to a “chemical
imbalance,” chiefly in the context of depres-
sion;or with respect to an antidepressant’s
putative mechanism of action—not as a
causal theory of “mental illness” in general.
Moreover, Lacasse and Leo’s (2015)
paper obscures the difference between a
putative mechanism of action of adrug (e.g.,
serotonin reuptake inhibition) and acausal
theory of mental illness (the focus of my
writings). To say that a drug “corrects a
chemical imbalance”—as, indeed, some
psychiatrists have stated—is not to claim
that the illness being treated is caused by
that imbalance. Many drugs work via
mechanisms that are helpful for symptoms
of adisease without addressing or revers-
ingthenumerous (and oftenunknown)
“causes” of that disease. For example, beta
blockers are used to treat some cardiac
arrhythmias, but nobody infers from this
that the arrhythmia is caused by a defi-
ciency of beta-receptor blockade. (Nor, for
that matter, do cardiologists routinely
explain to patients the mechanism of
action of the medications they prescribe.)
Of note: the most recent publicly available
information from the American Psychi-
atric Association does not use the expres-
sion “chemical imbalance” in discussing
risk factors for depression or the rationale
for antidepressant treatment (What Is
Depression, 2015).
Finally: If there is anything resembling
an “official” psychiatric position on the
causes of mental disorders, it is the 1978
statement from the American Psychiatric
Association—which, unlike off-hand com-
ments from one or another former APA
president, was approved by the APA Board
of Trustees, and is available online to this
day:
“Psychiatric disorders result from the
complex interaction of physical, psycho-
logical, and social factors and treatment
may be directed toward any or all three of
these areas.”
And this is preciselywhat most of my aca-
demic colleagues and I have been teach-
ing—and telling our patients—for the past
three decades (Pies, 2015a).
References
American Psychiatric Assocation. (1979).
Position statement on activetreatment.
Retrievedfrom http://www.psychiatry.
org/File%20Library/Learn/Archives/Posi
tion-1978-Active-Treatment.pdf
Compton, M. T., &Shim,R. S. (Eds.).
(2015). The socialdeterminants of mental
health.Washington, DC: American Psy-
chiatric Publishing.
Deacon, B., &McKay, D. (Eds.). (2015).
The biomedical modelof psychological
problems [Special issue]. the Behavior
Therapist, 38(7).
Gold,P. W., Machado-Vieira, R., &Pavla-
tou, M. (2015). Clinical and biochemical
manifestations of depression: Relation to
the neurobiology of stress. Neural Plastic-
ity, 2015.doi: 10.1155/2015/581976
Lacasse, J. R., &Leo, J. (2015). Antidepres-
santsand the chemical imbalancetheory
of depression: Areflection and updateon
the discourse. the Behavior Therapist, 38,
206-213.
RESPONSETOTHE SPECIAL ISSUE |BIOMEDICAL MODEL

262 the Behavior Therapist
Levine, B. E. (2014). Psychiatry now
admits it's been wrong in big ways—But
can it change? Retreived from
http://www.truth-out.org/news/item/
22266-psychiatry-now-admits-its-been-
wrong-in-big-ways-but-can-it-change-
a-conversation-with-investigative-
reporter-
Pies, R. (2011). Doctor, is my mood disor-
der due to achemical imbalance? Psych
Central. Retrieved from http://psych-
central.com/blog/archives/2011/08/04/d
octor-is-my-mood-disorder-due-to-a-
chemical-imbalance/
Pies, R. (2013). Conflicts of interest: Con-
cepts, conundrums, and course of action.
Medscape, Nov. 11, 2013. http://www.
medscape.com/viewarticle/813912
Pies, R. (2014a). Nuances, narratives, and
the “chemical imbalance” debate.Psychi-
atric Times. April 11, 2014.
http://www.psychiatrictimes.com/couch
-crisis/nuances-narratives-chemical-
imbalance-debate
Pies, R. (2014b). Nuances, narratives, and
the “chemical imbalance” debate. Med-
scape. April 15, 2014. http://www.med-
scape.com/viewarticle/823368_3
Pies, R. (2015a). Psychiatry’s solid center.
Psychiatric Times, Oct. 7, 2015.
http://www.psychiatrictimes.com/blogs/
psychiatrys-solid-center
Pies, R(2015b). Serotonin: How psychiatry
got over its “high school crush.” Psychi-
atric Times, Sept. 15, 2015.
http://www.psychiatrictimes.com/blogs/
couch-crisis/serotonin-how-psychiatry-
got-over-its-high-school-
crush#sthash.cB5eHgSR.dpuf
Schildkraut, J. J., &Kety, S. S. (1967). Bio-
genic amines and emotion. Science, 156,
21-37.
Understanding Science. (2015). Under-
standing science: How science really
works.[Web page.] Retrieved from
http://undsci.berkeley.edu/article/how-
scienceworks_19
What Is Depression. (2015). What is
depression? [Web page.] Retrieved from
http://www.psychiatry.org/patients-
families/depression/what-is-depression
...
Correspondence to Ronald W. Pies, M.D.,
SUNY Upstate Medical University; Clinical
Professor of Psychiatry,Tufts University
School of Medicine; piesr@upstate.edu
IN THEIR RECENT ARTICLE,Drs. Lacasse
and Leo (2015) continue an important dis-
cussion about the use of overly simplistic
explanations of antidepressant actions.
They argue that drug companies have used
such explanations to market their drugs,
and that psychiatrists have often been com-
plicit—or at least silent—partners in this
promotional technique.
In one section of the article, they accuse
me of making deceptive statements to my
patients about how antidepressants work. I
deny this accusation. In talking to patients
Isimplify neurobiological concepts, using
ashorthand to describe, in asimplistic way,
some common theories of mental illness. I
do this to enhance the placebo effect—
which accounts for asignificant portion of
the overall effectiveness of antidepressants.
Two of the most crucial components of the
placebo effect are fostering positive expec-
tations of success and reinforcing the med-
ical ritual of pill-taking (Kaptchuk et al.,
2010; Leuchter, 2014). In order to augment
my patients’ response to antidepressants, I
will say something like, “This is avery effec-
tive medication, you should take this pill
every morning, and you will begin to feel
better within acouple of weeks.” If apatient
asks me how the medication works, Iwill
respond with, “We’re not completely sure,
but it has something to do with increasing
levels of neurotransmitters like serotonin
or norepinephrine—basically, these pills
rebalance certain chemicals in the brain.”
There is nothing deceptive about such
statements. While we don’t understand
exactly what serotonin’s role is, we have
some educated hypotheses. Arecent
review of serotonin and depression identi-
fies 14 known serotonin receptor subtypes.
When antidepressants bind to these recep-
tors,avarietyof chemical processesunfold,
affecting levels of dopamine, norepineph-
rine, acetylcholine, cortisol—and yes, sero-
tonin. While it isn’t clear exactly how these
chemical cascades alleviate depression or
anxiety, it is clear that effective antidepres-
sants exert their actions via shifts in the
brain’s biochemical milieu—and that sero-
tonin is one of the central players in the
drama (Kohler et al., 2015).
The authors, unfortunately, do not
seem to be interested in scientific evidence.
In their role as the serotonin thought
police, they brook no uncertainty: the sero-
tonin theory is discredited, full stop. To
support this conviction, they refer to atable
entitled, “Evidence the Chemical Imbal-
ance Theory of Depression Is Not Valid:
Selected Quotations” (p. 210). But the table
presents no “evidence” as we normally
think of the term. Instead, it is alist of 12
statements made by various psychiatrists
reflecting their personal opinions about the
chemical imbalance theory. But just
because smart people say something does-
n’t make it true. If it did, then their Table 2,
“Promotion of the Chemical Imbalance
Theory of Depression as Valid: Selected
Quotations” (p. 211) would be an effective
refutation of their entire article.
Lost in their polemic is the fact that as
mental health clinicians, we are fortunate
to be able to offer very effective treat-
ments—both psychotherapeutic and psy-
chopharmacologic—for our patients.
There is much we don’t understand, and
we can do better. But mean-spirited attacks
on colleagues are not going to help further
the field.
References
Kaptchuk, T. J., Friedlander, E., Kelley, J.
M., Sanchez, M. N., Kokkotou, E., Singer,
J. P., ...Lembo, A. J. (2010). Placebos
without deception: Arandomized con-
trolled trial in irritable bowel syndrome.
PLoS One, 5(12), e15591.
Kohler, S., Cierpinsky, K., Kronenberg, G.,
&Adli, S. (2015). The serotonergic
system in the neurobiology of depres-
sion: Relevance for novel antidepres-
sants. Journal of Psychopharmacology.
doi: 10.1177/0269881115609072
Lacasse, J.R., &Leo, J. (2015). Antidepres-
sants and the chemical imbalance theory
of depression: Areflection and update on
the discourse. the Behavior Therapist,
38(7), 206-213.
Leuchter, A. F., Hunter, A. M., Tartter, M.,
&Cook, I. A. (2014). Role of pill-taking,
expectation and therapeutic alliance in
the placebo response in clinical trials for
major depression. British Journal of Psy-
chiatry, 205(6), 443-449.
...
Correspondence to Daniel J. Carlat, M.D.,
Tufts University School of Medicine;
drcarlat@comcast.net
LETTER TO THE EDITOR
Response to Lacasse and Leo (2015)
Daniel J. Carlat, Tufts University School of Medicine
CARLAT

Winter •2015263
Response to Daniel Carlat (2015)
In our recent article (Lacasse & Leo,
2015), we transcribed public statements
made by Dr. Carlat on National Public
Radio (NPR). Dr. Carlat disclosed that he
used content similar to the Zoloft market-
ing campaign (Lacasse, 2005) to explain
antidepressants to patients:
I’ll often say something like the way
Zoloft works, is, it increases the level of
serotonin in your brain (or synapses,
neurons), and, presumably, the reason
you’re depressed or anxious is that you
have some sort of adeficiency. And Isay
that [chuckles] not because I really
believe it . . . I think I say that because
patients want to know something . . . .
They certainly don’t want to know that
a psychiatrist essentially has no idea
how these medications work. (Davies,
2010)
Despite Dr. Carlat’s allegation, we are
not the serotonin thought police, ticketing
offenders that violate our sensibilities. But,
we don’t believe we’re alone in thinking it’s
objectionable to tell patients something
you don’t believe yourself. To say things
like this publicly and not expect criticism
seems naïve. We are not cherry-picking
here, as Dr. Carlat has ahistory of such dis-
closures:
While it is true that most of our drugs
affect neurotransmitters in various
ways, when psychiatrists start using
what I call neurobabble, beware,
because we rarely know what we are
talking about. Ifall into this habit with
patients all the time. When Ifind myself
using phrases like “chemical imbalance”
and “serotonin deficiency,” it is usually
because I’m trying to convince areluc-
tant patient to take a medication . . .
(Carlat, 2010, p. 75; see pp. 74–83 for
published content similar to that
reported in the NPR interview)
We don’t think scientific truth is so
flexible, and disagree with shaping it for
purposes convenient to the prescriber (e.g.,
to get patients to take medication, or to
reassure the patient of the prescriber’s
expert knowledge). Dr. Carlat also writes
that he boosts the placebo effect by telling
patients that SSRIs are “a very effective
medication” (Carlat, 2015; this issue, p.
262). Fournier et al. (2010) demonstrated
a Number-Needed-to-Treat (NNT) of 11
for severely depressed patients. In other
words, when prescribing to 11 severely
depressed patients, a prescriber would
expect 1to have an impressive short-term
response as compared to placebo. Given
the existence of such data, we question the
accuracy of claiming that antidepressants
are “very effective” (see also Weitz et al.,
2015).
Response to Ronald Pies (2015)
On the “Little WhiteLie” of Chemical
Imbalance
In his reply, Dr. Pies (2015; this issue)
states that he does not endorse calling the
chemical imbalance a“little white lie,” and
that he was referencing Mr. Robert
Whitaker when he used this phrase. We
take his word on this, appreciate that he
acknowledges his editorial error, and apol-
ogize for the confusion. We are glad that
we and Dr. Pies have this opportunity to
correct the record.1We note that acorrec-
tion has been made to Dr. Pies’ original
article as of November 4, 2015 (Pies, 2014).
On Promotion of Psychiatric Drugs
Like many, we believe that academic
psychiatrists have been too closely aligned
with the pharmaceutical companies (e.g.,
Healy, 2004). In our article, we hypothe-
sized, as we had before (Lacasse & Leo,
2009), that the flow of money from drug
companies to academic psychiatry might
be partially responsible for the resounding
silence in academia regarding misleading
advertising of psychiatric drugs. Dr. Pies
had himself argued that pharmaceutical
companies were responsible for spreading
the chemical imbalance metaphor. While
we agreed that this was part of the problem
(Lacasse &Leo, 2005), we sawsome irony
in the fact that he had received funding
from GlaxoSmithKline, among the worst
offenders in our opinion when it came to
misleading consumer advertising. We
never accused Dr. Pies of acting in bad
faith, and in fact wrote, “We want to be
clear that we are not accusing Dr. Pies of
anything” and that entanglements with
drug companies aren’t “uncommon
among academic psychiatrists, and some
would say it was par for the course in the
2000s” (Lacasse &Leo, 2015, p. 209). How-
ever, Dr. Pies strongly objects to our asser-
tion that he has been involved in the pro-
motion of psychiatric drugs, and so we will
reluctantly respond.
How Psychiatric DrugsAre Promoted
As background, it is useful to under-
stand the strategies that pharmaceutical
companies use to promote2their products.
They often contract with “medical com-
munications companies,” which specialize
in “publication planning” and employ
medical writers who contribute to (or even
author or co-author) peer-reviewed arti-
cles (Lacasse & Leo, 2010), usually with
academics listed as authors on the byline
LETTER TO THE EDITOR
Response to Daniel Carlat (2015)
and Ronald Pies (2015)
Jeffrey R. Lacasse, Florida State University
Jonathan Leo, Lincoln Memorial University–deBusk College of
Osteopathic Medicine
1In his 2014 article, Dr. Pies begins a paragraph by citing an interview of Mr. Robert Whitaker
(Levine, 2014; Pies, 2014). Dr. Pies then writes about the “antipsychiatry movement.” In these
sentences there are no quotations and no citations; they consist of Dr. Pies’ own interpretations.
He mentions chemical imbalance, writing that “by promoting this little white lie…” Mr.
Whitaker had used quotation marks around the phrase as editorial comment, but Dr. Pies did
not. Without quotation marks or citation, we took this as we did his other writing in this section,
as his opinion (we aren’t the first to do so; see Hickey, 2014). We reproduced the entire quota-
tion from Dr. Pies in a footnote, commenting on this exact issue (Lacasse & Leo, 2015, p. 209). A
correction to the article (Pies, 2014) was made in November of 2015, after our article was pub-
lished. Rather than clarifying where the phrase “little white lie” came from, Dr. Pies removed it
and replaced it with “simplistic formulation.” Interestingly, Mr. Whitaker did not characterize
chemical imbalance as “simplistic” (Levine, 2014).
RESPONSETOTHE SPECIAL ISSUE |BIOMEDICAL MODEL

(Sismondo, 2009; Sismondo & Doucet,
2010). Unrestricted educational grants are
another strategy used by pharmaceutical
companies, as they are “. . . a well-estab-
lished tool that all of the major pharmaceu-
tical manufacturers use to disseminate
information to the medical community. ...
The off-label promotion risk of educational
grants appears to pose the greatest threat to
theFederalhealth care programs andben-
eficiaries,butit is also themost difficultto
demonstrate conclusively”3(U.S. Senate
Committee on Finance, 2007). Nonethe-
less, the legal complaint against Glaxo-
SmithKline for illegal marketing of drugs
like Paxil and Lamictal (which was eventu-
ally settled for 3billion dollars; Department
of Justice, 2012) described the following:
GSK’s [GlaxoSmithKline’s] extremely
aggressive off-label marketing cam-
paigns for Lamictal included spending
large sums of money in the form of
unrestricted grants, membership on
advisory boards and speaker’s fees on
physicians and researchers who served
as “national thought leaders.” (United
States of America v. GlaxoSmithKline,
2012)
Certainly many professors believe they
are being hired to share their expert opin-
ion, but in the eyes of pharmaceutical and
medical communications companies, aca-
demics are clearly being paid because their
opinions are helpful in the promotion of
the drug company’s product.4At the risk of
stating the obvious, from the companies’
point of view, it would make no sense to
pay psychiatrists or medical writers if they
didn’t have positive things to say about the
product. From their point of view, the ideal
academic would be someone who believes
that grants, payments, or the assistance of
medical writers have no effect on their
objectivity. In fact, academics receiving
funding from drug companies or proxies
may be genuinely unaware that they have
been retained because their opinions have
promotional value (e.g., Carlat, 2007). We
do not believe that academics agree to just
say anything the companies want in return
for compensation, and we never asserted
that Dr. Pies was a“hired gun.” We share
theviewsof Dr.DavidHealy(2012),who
argues that pharmaceutical companies seek
out academics who already share their
views.
Our Clarification
First of all, our statements were not
based on any direct or firsthand knowledge
of anyverbal or writtenagreementthat Dr.
Pies had with Apothecom, or any other
corporate entity. We were trying to be
brief, and so we wrote that Dr. Pies “fails to
mention that he was paid to help them
[drug companies] promote their products”
(Lacasse &Leo, 2015, p. 209). In retrospect,
we could have written more clearly and
specifically, and we therefore correct this
section to read as follows:
Dr. Pies blames the drug companies for
running misleading advertisements about
chemical imbalance, belatedly admits he
should have done something sooner, but
fails to mention his involvement with the
pharmaceutical industry. In 2005, he dis-
closed that “he has consulted for an inde-
pendent medical education company that
involves work with pharmaceutical com-
pany clients” (Pies &Rogers, 2005).5As of
2003,Dr.Pies disclosedthat he wasarecip-
ient of “ad hoc stipends from Abbott,
Jannsen, GlaxosmithKline, and other phar-
maceutical or related corporate entities”
(Chaudron & Pies, 2003, p. 1284). In this
same 2003 article, Dr. Pies disclosed that he
was a consultant for Apothecom (Chau-
dron &Pies, 2003), amedical communica-
tions agency listed in the Top-100 agencies
by Medical Marketing and Media (Frank,
2015). The Apothecom website boasts that
they are a“communications powerhouse”
employing “130 scientific storytellers” and
that they do “scientific branding ...publi-
cations planning, delivery and maximizing
. . .” (Apothecom.com, 2015). Dr. Pies
reports working with Apothecom from
2001–2006 (Pies, 2015). As of 2003,
Apothecom listed the pharmaceutical
companies Abbott, Sepracor, and Glaxo-
smithKline among their clients (Lieber-
man, 2003).
From 2002–2006, Dr. Pies was author
or co-author of articles funded through
unrestricted educational grants from Glaxo-
SmithKline (makers of the anticonvulsant
drug Lamictal). These include an article
entitled “The 'Softer' End of the Bipolar
Spectrum” (Pies, 2002a); a2002 article on
combining lithium with anticonvulsants
such as Lamictal in bipolar disorder (Pies,
2002b); a review article on “Matching the
Bipolar Patient and the Mood Stabilizer”
(Gelenberg &Pies, 2003); a2003 article on
postpartum psychosis and bipolar disorder
stating that Lamictal “. . . also not FDA-
approved for treatment of bipolar disorder,
does appear especially useful for bipolar
depression” (Chaudron & Pies, 2003, p.
1289);6a review article focused on treat-
ment of bipolar disorder with co-occurring
substanceuse(Albenese&Pies,2004); and
a2006 articlerecommending Lamictal for
use in maintenance treatment of bipolar
disorder (Marken & Pies, 2006). Another
2006 article funded by GlaxoSmithKline
stated that “lamotrigine [Lamictal] may
also have benefits in borderline personality
disorder” (MacKinnon &Pies, 2006, p. 8),
with the co-authors disclosing that “The
authors of this paper do not have any com-
mercial associations that might pose acon-
flict of interest in connection with this
manuscript” (MacKinnon &Pies, 2006, p.
1). Dr. Pies was also co-author of areview
article on treatments for insomnia which
highlights the potential benefits of Lunesta,
and acknowledges the assistance of Sepra-
cor, Inc. (makers of Lunesta) in the prepa-
ration of the manuscript (Winkelman &
Pies, 2005);7and co-author of a2007 arti-
cle on insomnia in which the authors
acknowledge “that they received compen-
sation fromSepracor for services theypro-
2The Oxford Dictionary defines promote as “...Further the progress of (something, especially a
cause, venture or aim); support or actively encourage... Give publicity to (a product, organization,
or venture) so as to increase sales or public awareness...”. The word “promotion” by itself does
not imply that the information is biased, inaccurate or deceptive, nor is it intrinsically negative.
Products can be honestly and enthusiastically promoted. This point may have been overlooked by
some readers of our original article. Sismondo (2009) describes a balance between marketing and
science among publication planners.
3One reason that it so difficult to demonstrate this conclusively, as the Senate notes, is because in
many cases the money trail is complicated and difficult to sort out from the outside.
4Like our original article and the rest of this response, this paragraph reports our academic opin-
ion on these issues.
5This is seemingly Apothecom, but Dr. Pies did not disclose the name of the company.
6Ghaemi, Shirzadi, and Filkowski (2008) examined GlaxoSmithKline’s unpublished negative stud-
ies and wrote: “[Lamictal] has very limited, if any, efficacy in acute bipolar depression and rapid-
cycling bipolar disorder, areas in which practicing clinicians, as well as some academic leaders,
have supported its use.”
7In an Op-Ed in the New York Times, Dr. Daniel Carlat critiqued an arguably similar article as a
form of pharmaceutical company marketing (Carlat, 2006).
264 the Behavior Therapist
LACASSE &LEO

Winter •2015265
vided in support of the development of this
manuscript” (Roth, Roehers, &Pies, 2007,
p. 77). Several of the above-listed articles
acknowledge editorial assistance and/or
content contribution from medical writers
without listing their company affiliation or
who paid them for their work; the online
resume of one such medical writer lists
Apothecom as her employer at the time.
Dr. Pies wrote that his relationship with
Apothecom took place from 2001–2006
(Pies, 2015). In 7of the 8journal publica-
tions discussed above, Dr. Pies does not
disclose arelationship with Apothecom.
Discussion
While we are pleased to make these
clarifications, we think the primary issue
remains the use of the chemical imbalance
metaphor in clinical interactions with vul-
nerable patients. We find Dr. Pies’ argu-
ments unconvincing, and it is obvious to us
that the chemical imbalance theory was
indeed embraced by the field of psychiatry
(Whitaker, 2015), and that the explanation
is still used by prescribers to this day. We
have wondered what has motivated Dr.
Pies’ shifting positions and arguments on
this topic (Lacasse &Leo, 2015; Whitaker,
2015), and in his reply, we think he gave an
answer. Dr. Pies writes, “I began address-
ing this issue in 2011, as Ibecame increas-
ingly aware of antipsychiatry bloggers
using the 'chemical imbalance' canard as a
cudgel against psychiatry” (Pies, 2015, this
issue, p. 261). We think this is useful con-
text to guide interpretation of his argu-
ments. Dr. Pies is apparently defending his
guild against outside attack (Whitaker,
2015; Whitaker &Cosgrove, 2015). Read as
asustained, political defense of his profes-
sion, we think his writings on chemical
imbalance make perfect sense.
We are not part of this guild, so we have
a different point of view. We think these
issues are deeply important, not because
psychiatry is under attack, but because we
believe many depressed and anxious
patients have been hurt by being told that
they have a chemical imbalance in their
brain that is corrected by psychiatric med-
ication. We think calling this “misleading”
is an understatement—and that learning
now that chemical imbalance is only a
metaphor (Lacasse &Leo, 2006) could well
be traumatic. This is true both for the pre-
scribers who were taught to use this
metaphor, as well as for the patients who
heard it from their physicians and believed
it to be ascientific fact. As anyone who has
dealt with trauma knows, the first step is to
acknowledge what happened. Insisting that
it never occurred, or was less severe than
perceived, or was unsanctioned by author-
ities, will inevitably cause negative reac-
tions—especially so when these claims are
not quite true.
We think it is in the best interests of the
psychiatric profession to look closely at
how the chemical imbalance metaphor has
been used over the last 25 years. This is no
easy task (Tavris & Aronson, 2008). It
requires putting ego aside, listening care-
fully rather then lecturing, and a willing-
ness to be open-minded and nondefensive.
Rather than obfuscating the issue, or
demonizing those delivering the bad news
as “antipsychiatry,” the profession will
eventually need to admit that patients were
misinformed and harm was done. Once
this step is taken, perhaps psychiatry can
recapture the public’s trust and move for-
ward.
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...
Correspondence to Jeffrey R. Lacasse,
Ph.D., Florida State University College of
Social Work; jlacasse@fsu.edu
■CLASSIFIED
FELLOWSHIPS IN ADVANCED
COGNITIVE THERAPY FOR SCHIZ-
OPHRENIA WITH AARON T. BECK.
We offer an exciting opportunity for
postdoctoral applicants in the Aaron T.
Beck Psychopathology Research Center
at the University of Pennsylvania.
Specifically, our mission is to develop
professionals who will become leaders in
the field of psychological approaches
that promote recovery for individuals
with schizophrenia. Under the direction
of Aaron T. Beck, M.D., our program
includes basic research in schizophrenia,
clinical trials of innovative treatments
for the disorder, and dissemination and
implementation of these treatment pro-
tocols into community mental health
centers and psychiatric hospitals. We
have been recognized for our cutting
edge work in this field. For more infor-
mation, see http://aaronbeckcenter.org
Applicants who have earned an M.D.,
Ph.D., Psy.D., or equivalent in psycholo-
gy or other related field and have had
previous training in cognitive therapy,
severe mental illness, or recovery- ori-
ented services are encouraged to apply.
Bilingual candidates are especially
encouraged to apply.
Please send a curriculum vita with a
cover letter and two letters of recom-
mendation via email to Aaron T. Beck,
M.D., at abeck@mail.med.upenn.edu.
The University of Pennsylvania is an
Equal Opportunity/Affirmative Action
Employer. Applications will be accepted
until January 1, 2016.
Anne Marie Albano
P. MichaelApolito
John Grebe
Lisa Hale
B. Linnea Lindholm
Matthew Pearson
TomOlson
David Roll
Eileen Senior
On behalf of ABCT, President Jonathan
S. Abramowitz warmly thanks all who
have generously supported our mission
with a voluntary personal
donation in 2015.
Voluntary Contributors
266 theBehavior Therapist
LACASSE &LEO