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2015

Challenging the Narrative of Chemical

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 Challenging the Narrative of Chemical Imbalance: A Look at the Evidence

Jeffrey R. Lacasse
Florida State University

Jonathan Leo
Lincoln Memorial University – DeBusk College of Osteopathic Medicine

Note:
This is the author’s manuscript as accepted by Springer. The final published version of record is
available at http://www.springer.com/us/book/9783319177731#

Citation:
Lacasse, J.R., & Leo, J. (2015). Challenging the narrative of chemical imbalance: A look at the
evidence (pp. 275-282). In B. Probst (Ed.)., Critical Thinking in Clinical Diagnosis and
Assessment. New York: Springer.
 Challenging the Narrative of Chemical Imbalance: A Look at the Evidence

The idea of a “chemical imbalance” underlying mental disorder is pervasive in our

society. In particular, the idea that clinical depression is caused by an imbalance of the

neurotransmitter serotonin (which can be corrected through use of antidepressant medication)

has been popularized since the introduction of the modern antidepressants in the late 1980s

(Lacasse, 2005). This message has also been disseminated in the media, in direct-to-consumer

advertising, and in educational materials for mental health clients (Lacasse & Leo, 2005; Leo &

Lacasse, 2008; Hess, Gantt, Lacasse, & Vierling-Claasen, 2014). The serotonin theory of

depression has been a crucial piece of the ascendance of biological psychiatry, the viewpoint

which holds that DSM-defined mental disorders are diseases of the brain, no different than

diabetes or cancer (Whitaker, 2010).

Clinical social workers who diagnose will often also play a psychoeducational role,

informing clients about the cause, course and prognosis of their diagnosis. In this situation, the

clinical social worker carries significant power in the clinician-client relationship. The social

worker will be seen as the expert, and the client is likely to believe that what they are told is

scientifically valid information. Thus, telling depressed clients that it is known that they have a

chemical imbalance in their brain- that they have a brain disease- could have major effects

regarding how clients see themselves, their condition, and their treatment needs (Hess et al.,

2014). For instance, Kemp, Lickel & Deacon (2014) found that when participants with a history

of depression who were told they had a serotonin imbalance, this had negative effects. Among

them were a more pessimistic prognosis and the impression that drug treatment was more

effective than psychotherapy (see also Deacon & Baird, 2009).

clients, and that this issue should be carefully considered by practicing social workers. This

raises two crucially important issues. First, do we know that social workers are in fact telling

depressed clients that they suffer from serotonin imbalance? This research question has not

received the extensive attention that it deserves, so far, but there is some evidence that this is

taking place. In a small study, Acker (2013) found that 92% of clinical social workers at least

“sometimes” explain to their clients that depression is caused by a chemical imbalance. Other

research demonstrates that it is common for clients to be informed of this within mental health

treatment more generally (Cohen & Hughes, 2011; Johnston et al., 2007) and there is little

evidence that clinical social workers in general take a contrarian position as compared to

psychiatry or psychology (Gomory, Cohen, Wong, & Lacasse, 2012).

The second and more important question is whether or not the serotonin theory of

depression is true. Social workers have an ethical mandate to “critically examine and keep

current with emerging knowledge relevant to social work” (National Association of Social

Workers, 2008). Therefore, the scientific veracity of the serotonin theory is important. If social

workers are informing clients of well-tested, accurate neuroscience research to help them better

understand their condition, this makes good sense. However, if the serotonin theory has been

scientifically falsified and social workers continue to use this explanation nonetheless, this would

be deeply problematic.

Below, we make the case that the latter case is unfortunately true. The serotonin theory of

depression was falsified many years ago. Its current popularity can be attributed to many

potential factors: Relentless pharmaceutical marketing of antidepressant drugs, the influence of

biological psychiatry on the field of social work, deficits in the education of aspiring mental
health professionals, and the intuitive appeal of reducing complex human behavior to simple

explanations rather than the application of critical thinking (Kirk, Cohen & Gomory, 2013;

Lacasse & Gomory, 2003; Valenstein, 1998). However, what is well established is that the

serotonin theory of depression no longer holds the status of even a viable scientific theory – let

alone information that should be passed on to social work clients. Given how easy it is (see

below) to build the scientific case against the serotonin theory, its continuing popularity and use

in clinical practice could be seen as astonishing.

The Serotonin Theory

In 1965, Joseph Schildkraut put forth the hypothesis that depression was associated with

low levels of norepinephrine (Shildkraut, 1965), and later researchers theorized that serotonin

was the neurotransmitter of interest (Coppen, 1967). In subsequent years, there were numerous

attempts to identify reproducible neurochemical alterations in the nervous systems of patients

diagnosed with depression. For instance, researchers compared levels of serotonin metabolites in

the cerebrospinal fluid of clinically depressed suicidal patients to controls, but the primary

literature is mixed and plagued with methodological difficulties such as very small sample sizes

and uncontrolled confounding variables. In a review of these studies, the chairman of the

German Medical Board and colleagues stated, “Reported associations of subgroups of suicidal

behavior (e.g. violent suicide attempts) with low CSF–5HIAA [serotonin] concentrations are

likely to represent somewhat premature translations of findings from studies that have flaws in

methodology” (Roggenbach et al., 2002). Attempts were also made to induce depression by

depleting serotonin levels, but these experiments reaped no consistent results (Heninger,

Delgado, & Charney, 1996). Likewise, researchers found that huge increases in brain serotonin,

arrived at by administering high-dose L-tryptophan, were ineffective at relieving depression

the serotonin theory of depression was not a viable scientific theory- for instance, in 1990, Astra

pharmaceutical company research scientist John Evenden stated, “The simplistic idea of ‘the 5-

HT [serotonin] neurone does not bear any relationship to reality” (Shorter, 2008).

Contemporary neuroscience research has also failed to confirm any serotonergic lesion in

any mental disorder, and has in fact provided significant counterevidence to the explanation of a

simple neurotransmitter deficiency. Modern neuroscience has instead shown that the brain is

vastly complex and poorly understood (Horgan, 1999). While neuroscience is a rapidly

advancing field, to propose that researchers can objectively identify a “chemical imbalance” at

the molecular level is not compatible with the extant science. In fact, there is no scientifically

established ideal “chemical balance” of serotonin, let alone an identifiable pathological

imbalance. To equate the impressive recent achievements of neuroscience with support for the

serotonin hypothesis is a mistake.

With direct proof of serotonin deficiency in any mental disorder lacking, the claimed

efficacy of SSRIs is often cited as indirect support for the serotonin hypothesis. Yet, this ex

juvantibus line of reasoning (i.e., reasoning “backwards” to make assumptions about

disease causation based on the response of the disease to a treatment) is logically problematic—

the fact that aspirin cures headaches does not prove that headaches are due to low levels of

aspirin in the brain. Serotonin researchers from the US National Institute of Mental Health

Laboratory of Clinical Science clearly state, “[T]he demonstrated efficacy of selective serotonin

reuptake inhibitors…cannot be used as primary evidence for serotonergic dysfunction in the

pathophysiology of these disorders” (Murphy et al., 1998).

highly contested. The validity of this reasoning becomes even more unlikely when one considers

recent studies that call into question the efficacy of the SSRIs.

A series of studies finds only a small, clinically insignificant difference between the

effectiveness of placebo and antidepressants (Kirsch et al, 2008). This modest efficacy and

extremely high rate of placebo response are not seen in the treatment of well-studied imbalances

such as insulin deficiency, and casts doubt on the serotonin hypothesis.

Also problematic for the serotonin hypothesis is the growing body of research comparing

SSRIs to interventions that do not target serotonin specifically. For instance, a Cochrane

systematic review found no major difference in efficacy between SSRIs and tricyclic

antidepressants (Geddes et al., 2005) In addition, in randomized controlled trials, buproprion and

reboxetine are just as effective as the SSRIs in the treatment of depression, yet neither affects

serotonin to any significant degree. The over-the-counter supplement St. John's Wort (Szegedi,

Kohnen, Dienel, & Kesser, 2005) and placebo (Hypericum Depression Trial Study Group, 2002)

have both outperformed SSRIs in randomized controlled trials. Exercise was found to be as

effective as the SSRI sertraline in a randomized controlled trial, and more effective at preventing

relapse (Blumenthal et al., 1999). Perhaps most interestingly, tianeptine, an antidepressant which

lowers serotonin levels of the brain (but which is not available in the United States) has

comparable efficacy to the SSRI drugs (Kasper & Olie, 2002). This alone might be enough for

some to dismiss the serotonin theory – since the theory is that lower serotonin causes depression

and raising serotonin remedies depression.

Although SSRIs are considered “antidepressants,” they are FDA-approved treatments for

many different psychiatric diagnoses, ranging from social anxiety disorder to obsessive-
compulsive disorder to premenstrual dysphoric disorder. Some consumer advertisements (such

as the Zoloft and Paxil Web sites) have in the past promoted the serotonin hypothesis, not just for

depression, but also for some of these other diagnostic categories . Thus, for the serotonin

hypothesis to be correct as presented, serotonin regulation would need to be the cause (and

remedy) of each of these disorders (Healy, 2002). This is improbable, and no one has yet

proposed a cogent theory explaining how a singular putative neurochemical abnormality could

result in so many wildly differing behavioral manifestations.

However, in addition to these critiques, it is also important to look at what is not said in

the scientific literature. To our knowledge, there is not a single peer-reviewed article that can be

accurately cited to directly support claims of serotonin deficiency in any mental disorder, while

there are many articles that present counterevidence. Furthermore, the Diagnostic and Statistical

Manual of Mental Disorders (DSM), which is published by the American Psychiatric

Association and contains the definitions of all psychiatric diagnoses, does not list serotonin as a

cause of any mental disorder. The American Psychiatric Press Textbook of Clinical

Psychiatry addresses serotonin deficiency as an unconfirmed hypothesis, stating, “Additional

experience has not confirmed the monoamine depletion hypothesis” (Dubovsky, Davies, &

Dubvosky, 2003).

In conclusion, there exists no rigorous corroboration of the serotonin theory, and a

significant body of contradictory evidence. Far from being a radical line of thought, doubts about

the serotonin hypothesis are well acknowledged by many researchers, including frank statements

from prominent psychiatrists, some of whom are even enthusiastic proponents of SSRI

medications. For instance, in 2006, Wayne Goodman, chair of the FDA Psychopharmacological

Advisory Committee, admitted that the serotonin theory of depression is but “a useful
metaphor”- and one that he never uses within his own psychiatric practice (Lacasse & Leo,

2006). And in 2011, psychiatrist Ronald Pies, editor of Psychiatric Times, wrote: “In truth, the

“chemical imbalance” notion was always kind of an urban legend – never a theory seriously

propounded by well-informed psychiatrists” (Pies, 2011).

It seems clear, then, that informing clients that their depression is due to a serotonin

imbalance is a serious empirical error. The psychiatric textbooks do not make this claim, and

drug companies no longer run advertisements claiming that serotonin imbalance causes

depression (Lacasse & Leo, 2005). Prominent psychiatrists have in fact abandoned this theory in

response to the data which contradicts it, which is what good science looks like. It has been

decades since huge doubts emerged over the serotonin theory and arguably, psychiatry gave up

on this theory a decade ago. As social workers, we need to respond to empirical evidence and tell

our clients the best-tested information that is out there- and this means jettisoning the chemical

imbalance/serotonin theory.

Other Mental Disorders

We have focused here on the serotonin theory of depression because it is clearly the most

popular bioreductionistic theory of mental disorder. However, a similar case could be made for

claimed chemical imbalances in other mental disorders. Advertisements for psychostimulants

have made claims that Attention-Deficit Hyperactivity-Disorder is due to a chemical imbalance

of dopamine remedied by medication (Leo & Lacasse, 2009). An advertisement for aripirazole

claimed that the drug would adjust the level of neurotransmitters in the patient’s brain like a

thermostat (Lacasse & Leo, 2006). So while we have focused here on depression and serotonin, a

similar case can be made for many other mental disorders and treatments.
 ADHD provides another clear example of the widely held assumption that mental

disorders are due to one or another kind of chemical imbalance. Medications have been given to

children diagnosed with ADHD for more than half a century, beginning with Ritalin, first

licensed by the FDA in 1955 for treating what was known as hyperactivity. At present, 11

percent of American children have been diagnosed with ADHD

(http://www.cdc.gov/ncbddd/adhd/data.html), a 41 percent increase in the past decade, with two-

thirds receiving prescriptions for

psychostimulants (http://www.nytimes.com/2013/04/01/health/more-diagnoses-of-hyperactivity-

causing-concern.html?pagewanted=all ). These stimulants target the neurotransmitters dopamine

and norepinephrine, purportedly to increase focus and self-control by increasing the availability

of these chemical messengers. Many parents have been concerned about the effects of these

powerful drugs on developing brains, fearing that there maybe unforeseen harmful

consequences. On the contrary, some researchers now assert. Not only are these

drugs not neurotoxic, nor simply neurochemically neutral, but they are actually

“neuroprotective.”

In a 2014 interview with Psych Congress Network, Timothy Wilens, professor of

psychiatry at Harvard Medical School, stated that meta-analysis of 30 studies of children who

have taken ADHD medication show that, over the years, the brains of these children turn out to

look more like the brains of non-ADHD youngsters, thus indicating that there is a normalization

in both function and structure of the brain following prolonged use of medication

(http://www.psychcongress.com/video/are-adhd-medications-neurotoxic-or-neuroprotective-

16223). A New York Times report from 2015 (http://well.blogs.nytimes.com/2015/02/02/can-

attention-deficit-drugs-normalize-a-childs-
brain/?hpw&rref=health&action=click&pgtype=Homepage&module=well-

region&region=bottom-well&WT.nav=bottom-well) includes a further argument from

Dr. Wilens that these medications “normalize” children’s brains, rewiring neural connections

over time so the child feels more focused and in control.

It’s not quite so simple, of course. When asked by the interviewer if these changes occur

because the medication is directly altering the brain or because it allows these youngsters to have

more normal interactions with the world, which in turn rewires the brain through the reciprocal

action of neuroplasticity, Wilens admits that we really don’t know. That’s a significant gap in

the causal chain. If it’s experience that leads to changes in the brain, there’s no inherent reason

that pharmaceuticals are the sole or necessary agent for a child to have different experiences.

How about changing the environment? (There’s a novel idea.) Why assume that medication is

the link between experience and brain? Not surprisingly, Wilens and other authors of the 2013

report he cites have received financial support over the years from pharmaceutical firms. In an

email to the Times reporter, Dr. Wilens said he had not received “any personal income” from the

pharmaceutical industry since 2009.

That aside, the ADHD-dopamine link is far from proven. Just because stimulant

medication “works” to make children calmer does not mean that hyperactivity is caused by a

lack of the neurotransmitter that the medication activates - no matter how comforting or

convenient it might be to think so.

Thus, it is critical for social work students, clients and prescribers alike to realize what

psychiatry diagnosis and treatment represents. Currently, by definition, almost every mental

disorder in the DSM-5 is listed there because we do not know the etiology of the mental disorder.

That is, conditions are listed in the DSM because we do not know the pathology of the mental
disorder- and this is true whether it is ADHD, depression, schizophrenia or Generalized Anxiety

Disorder. Medical tests and examinations should be performed to ensure that the client’s mental

distress is not a downstream effect of a known medical disease (e.g., thyroid disease causing

depression). But the reason that clinical assessment and person-in-environment approaches are so

important- the entire reason that social workers and psychiatrists are dealing with mental health

clients rather than neurologists- is that these conditions are somewhat mysterious (Lacasse,

2014)- and that includes the fact that we are ignorant of the pathophysiology.

This uncertainty may be disturbing, but social workers should think twice about solving

this uncertainty by telling clients that they have a chemical imbalance. This is particularly true in

modern age of the World Wide Web, where any client can simply Google “serotonin imbalance”

and find many resources explaining that chemical imbalances are lay myths largely disseminated

by pharmaceutical companies. Telling clients that they have a chemical imbalance when there

isn’t scientific evidence or tests to confirm this is troubling on an ethical level, but given the

wide array of information available to clients, it could also create deep problems in therapeutic

alliance.

Conclusion

The question of what to tell clients in lieu of the outdated chemical imbalance theory is a

good one, if difficult to answer. It is important to point out that while there has been a huge

problem in information dissemination, we have noted accurate portrayals of the chemical

imbalance theory. The following statement, previously published on the website of the Mental

Health Service at McGill University, is perhaps a good place to start:

The term ‘chemical imbalance is thrown around a lot these days. True conditions caused

by chemical imbalances are relatively rare. All thoughts, feelings 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 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.
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