The "chemical imbalance" myth

serotonin illustration“A theory that is wrong is considered preferable to admitting our ignorance.” – Elliot Vallenstein, Ph.D.

The idea that depression and other mental health conditions are caused by an imbalance of chemicals in the brain is so deeply ingrained in our psyche that it seems almost sacrilegious to question it.

Direct-to-consumer-advertising (DCTA) campaigns, which have expanded the size of the antidepressant market (Donohue et al., 2004), revolve around the claim that SSRIs (the most popular class of antidepressants) alleviate depression by correcting a deficiency of serotonin in the brain.

For example, Pfizer’s television advertisement for Zoloft states that “depression is a serious medical condition that may be due to a chemical imbalance”, and that “Zoloft works to correct this imbalance.”

Other SSRI advertising campaigns make similar claims. The Effexor website even has a slick video explaining that “research suggests an important link between depression and an imbalance in some of the brain’s chemical messengers. Two neurotransmitters believed to be involved in depression are serotonin and norepinephrine.” The video goes on to explain that Effexor works by increasing serotonin levels in the synapse, which is “believed to relieve symptoms of depression over time.”

These days serotonin is widely promoted as the way to achieve just about every personality trait that is desirable, including self-confidence, creativity, emotional resilience, success, achievement, sociability and high energy. And the converse is also true. Low serotonin levels have been implicated in almost every undesirable mental state and behavioral pattern, such as depression, aggressiveness, suicide, stress, lack of self-confidence, failure, low impulse control, binge eating and other forms of substance abuse.

In fact, the idea that low levels of serotonin cause depression has become so widespread that it’s not uncommon to hear people speak of the need to “boost their serotonin levels” through exercise, herbal supplements or even sexual activity. The “chemical imbalance” theory is so well established that it is now part of the popular lexicon.

It is, after all, a neat theory. It takes a complex and heterogeneous condition (depression) and boils it down to a simple imbalance of two to three neurotransmitters (out of more than 100 that have been identified), which, as it happens, can be “corrected” by long-term drug treatment. This clear and easy-to-follow theory is the driving force behind the $12 billion worth of antidepressant drugs sold each year.

However, there is one (rather large) problem with this theory: there is absolutely no evidence to support it. Recent reviews of the research have demonstrated no link between depression, or any other mental disorder, and an imbalance of chemicals in the brain (Lacasse & Leo, 2005; (Valenstein, 1998).

The ineffectiveness of antidepressant drugs when compared to placebo cast even more doubt on the “chemical imbalance” theory. (See my recent articles Placebos as effective as antidepressants and A closer look at the evidence for more on this.)

Folks, at this point you might want to grab a cup of tea. It’s going to take a while to explain the history of this theory, why it is flawed, and how continues to persist in light of the complete lack of evidence to support it. I will try to be as concise as possible, but there’s a lot of material to cover and a lot of propaganda I need to disabuse you of.

Ready? Let’s start with a bit of history.

The history of the “chemical imbalance” theory

The first antidepressant, iproniazid, was discovered by accident in 1952 after it was observed that some tubercular patients became euphoric when treated with this drug. A bacteriologist named Albert Zeller found that iproniazid was effective in inhibiting the enzyme monoamine oxydase. As its name implies, monoamine oxydase plays an essential role in inactivating monoamines such as epinephrine and norepinephrine. Thus, iproniazid raised levels of epinephrine and norepinephrine which in turn led to stimulation of the sympathetic nervous system – an effect thought to be responsible for the antidepressant action of the drug.

At around the same time, an extract from the plant Rauwolfia serpentina was introduced into western psychiatry. This extract had been used medicinally in India for more than a thousand years and was thought to have a calming effect useful to quite babies, treat insomnia, high blood pressure, insanity and much more. In 1953 chemists at Ciba, a pharmaceutical company, isolated the active compound from this herb and called it reserpine.

In 1955 researchers at the National Institutes of Health reported that reserpine reduces the levels of serotonin in the brains of animals. It was later established that all three of the major biogenic amines in the brain, norepinephrine, serotonin, and dopamine, were all decreased by reserpine (again, in animals).

In animal studies conducted at around the same time, it was found that animals administered reserpine showed a short period of increased excitement and motor activity, followed by a prolonged period of inactivity. The animals often had a hunched posture and an immobility that was thought to resemble catatonia (Valenstein, 1998). Since reserpine lowered levels of serotonin, norepinephrine and dopamine, and caused the effects observed in animals, it was concluded that depression was a result of low levels of biogenic amines. Hence, the “chemical imbalance” theory is born.

However, it was later found that reserpine only rarely produces a true clinical depression. Despite high doses and many months of treatment with reserpine, only 6 percent of the patients developed symptoms even suggestive of depression. In addition, an examination of these 6 percent of patients revealed that all of them had a previous history of depression. (Mendels & Frazer, 1974) There were even reports from a few studies that reserpine could have an antidepressant effect (in spite of reducing levels of serotonin, norepinephrine and dopanmine).

As it turns out, that is only the tip of the iceberg when it comes to revealing the inadequacies of the “chemical imbalance” theory.

The fatal flaws of “chemical imbalance” theory

As Elliot Valenstein Ph.D., Professor Emeritus of psychology and neuroscience at Michigan University, points out in his seminal book Blaming the Brain, “Contrary to what is often claimed, no biochemical, anatomical or functional signs have been found that reliably distinguish the brains of mental patients.” (p. 125)

In his book, Valenstein clearly and systematically dismantles the chemical imbalance theory:

  1. Reducing levels of norepinephrine, serotonin and dopamine does not actually produce depression in humans, even though it appeared to do so in animals.
  2. The theory cannot explain why there are drugs that alleviate depression despite the fact that they have little or no effect on either serotonin or norepinephrine.
  3. Drugs that raise serotonin and norepinephrine levels, such as amphetamine and cocaine, do not alleviate depression.
  4. No one has explained why it takes a relatively long time before antidepressant drugs produce any elevation of mood. Antidepressants produce their maximum elevation of serotonin and norepinephrine in only a day or two, but it often takes several weeks before any improvement in mood occurs.
  5. Although some depressed patients have low levels of serotonin and norepinephrine, the majority do not. Estimates vary, but a reasonable average from several studies indicates that only about 25 percent of depressed patients actually have low levels of these metabolites.
  6. Some depressed patients actually have abnormally high levels of serotonin and norepinephrine, and some patients with no history of depression at all have low levels of these amines.
  7. Although there have been claims that depression may be caused by excessive levels of monoamine oxydase (the enzyme that breaks down serotonin and norepinephrine), this is only true in some depressed patients and not in others.
  8. Antidepressants produce a number of different effects other than increasing norepinephrine and serotonin activity that have not been accounted for when considering their activity on depression.

Another problem is that it is not now possible to measure serotonin and norepinephrine in the brains of patients. Estimates of brain neurotransmitters can only be inferred by measuring the biogenic amine breakdown products (metabolites) in the urine and cerebrospinal fluid. The assumption underlying this measurement is that the level of biogenic amine metabolites in the urine and cerebrospinal fluid reflects the amount of neurotransmitters in the brain. However, less than one-half of the serotonin and norepinephrine metabolites in the urine or cerebrospinal fluid come from the brain. The other half come from various organs in the body. Thus, there are serious problems with what is actually being measured.

Finally, there is not a single peer-reviewed article that can be accurately cited to 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) does not list serotonin as the 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” (Lacasse & Leo, 2005).

When all of this evidence is taken in full, it should be abundantly clear that depression is not caused by a chemical imbalance.

But, as Valenstein shrewdly observes, “there are few rewards waiting for the person who claims that “the emperor is really nude” or who claims that we really do not know what causes depression or why an antidepressant sometimes helps to relieve this condition.”

How have we been fooled?

There are several reasons the idea that mental disorders are caused by a chemical imbalance has become so widespread (and none of them have anything to do with the actual scientific evidence, as we have seen).

It is known that people suffering from mental disorders and especially their families prefer a diagnosis of “physical disease” because it does not convey the stigma and blame commonly associated with “psychological problems”. A “physical disease” may suggest a more optimistic prognosis, and mental patients are often more amenable to drug treatment when they are told they have a physical disease.

Patients are highly susceptible to Direct-to-Consumer-Advertising (DCTA). It has been reported that patients are now presenting to their doctors with a self-described “chemical imbalance” (Kramer, 2002). This is important because studies show that patients who are convinced they are suffering from a neurotransmitter defect are likely to request a prescription for antidepressants, and may be skeptical of physicians who suggest other interventions such as cognitive behavioral therapy (DeRubeis et al., 2005). It has also been shown that anxious and depressed patients “are probably more susceptible to the controlling influence of advertisements (Hollon MF, 2004).

The benefit of the chemical imbalance theory for insurance companies and the pharmaceutical industry is primarily economic. Medical insurers are primarily concerned with cost, and they want to discourage treatments (such as psychotherapy) that may involve many contact hours and considerable expense. Their control over payment schedules enables insurance companies to shift treatment toward drugs and away from psychotherapy.

The motivation of the pharmaceutical companies should be fairly obvious. As mentioned previously, the market for antidepressant drugs is now $12 billion. All publicly traded for-profit companies are required by law to increase the value of their investor’s stock. Perhaps it goes without saying, but it is a simple fact that pharmaceutical companies will do anything they legally (and sometimes illegally) can to maximize revenues.

Studies have shown that the advertisements placed by drug companies in professional journals or distributed directly to physicians are often exaggerated or misleading and do not accurately reflect scientific evidence (Lacasse & Leo, 2005). While physicians deny they are being influenced, it has been shown repeatedly that their prescription preferences are heavily affected by promotional material from drug companies (Moynihan, 2003). Research also suggests that doctors exposed to company reps are more likely to favor drugs over non-drug therapy, and more likely to prescribe expensive medications when equally effective but less costly ones are available (Lexchin, 1989). Some studies have even shown an association between the dose and response: in other words, the more contact between doctors and sales reps the more doctors latch on to the “commercial” messages as opposed to the “scientific” view of a product’s value (Wazana, 2000).

The motivation of psychiatrists to accept the chemical imbalance theory is somewhat more subtle. Starting around 1930, psychiatrists became increasingly aware of growing competition from nonmedical therapists such as psychologists, social workers and counselors. Because of this, psychiatrists have been attracted to physical treatments like drugs and electroshock therapy that differentiate them from nonmedical practitioners. Psychiatry may be the least respected medical specialty (U.S. General Accounting Office report). Many Americans rejected Fruedian talk therapy as quackery, and the whole field of psychiatry lacks the quality of research (randomized, placebo-controlled, double-blind experiments) that serves as the gold-standard in other branches of medicine.

Dr. Colin Ross, a psychiatrist, describes it this way:

“I also saw how badly biological psychiatrists want to be regarded as doctors and accepted by the rest of the medical profession. In their desire to be accepted as real clinical scientists, these psychiatrists were building far too dogmatic an edifice… pushing their certainty far beyond what the data could support.”

Of course there are also many “benefits” to going along with the conventional “chemical imbalance” theory, such as free dinners, symphony tickets, and trips to the Caribbean; consultancy fees, honoraria and stock options from the pharmaceutical companies; and a much larger, growing private practice as the $20 billion spent by drug companies on advertising brings patients to the office. Psychiatrists are just human, like the rest of us, and not many of them can resist all of these benefits.

In sum, the idea that depression is caused by a chemical imbalance is a myth. Pharmaceutical ads for antidepressants assert that depression is a physical diseases because that serves as a natural and easy segue to promoting drug treatment. There may well be biological factors which predispose some individuals toward depression, but predisposition is not a cause. The theory that mental disorders are physical diseases ignores the relevance of psychosocial factors and implies by omission that such factors are of little importance.

Stay tuned for future articles on the psychosocial factors of depression, the loss of sadness as a normal response to life, and the branding of new psychological conditions as a means of increasing drug sales.

Recommended resources

  • Blaming the Brain, by Elliot Valenstein Ph.D.
  • Rethinking Psychiatric Drugs, by Grace Jackson M.D.
  • America Fooled: The truth about antidepressants, antipsychotics and how we’ve been deceived, by Timothy Scott Ph.D.
  • The Loss of Sadness, by Alan Horwitz and Jerome Wakefield
  • The Myth of the Chemical Cure, by Joanna Moncrieff

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  1. Michael Etts, LMSW’s avatar

    Oops, I guess you can’t cut and paste from MS Word…

  2. Charley’s avatar

    This is the theory I was given behind the shrinkage of the hippocampus:

    The hippocampus has the function of routing experience to parts of the brain that  store it as  recallable and verbal memory.  In trauma, the hippocampus route is shut down to keep the memory stored in the amygdala (the fight-flight-freeze) part of the lower brain.  In severe trauma, the memory is stored as a sort of sensory template in the amygdala for future reference (that is, situations similar to the trauma, from a sensory point of view, but not a verbal point of view — memory as sights, sounds, smells, etc.).  These memories are not accessible consciously, and are triggered by similar events, or even sudden sounds.  They can produce nightmares and flashbacks, all without words.

    For people who have severe PTSD, a lot of daily experience is colored by the anxiety and other biological components that are related to this.  As the hippocampus is kept out of the experiential loop, it starts to lose mass.  Over the years this becomes visible and measurable.

    This is based on the work of Bessel van der Kolk. As I’m a bit out of my league at this point I only offer it for comment.

  3. peter’s avatar

    sorry about that!! more n more people are becoming aware of the fact that the fda is putting out pills that are proven to make poeple sicker n perhaps even die from them!! money money money!! n this is just not right!! i know i’m just nother person to put out a comment like this!! but we need to stop this visiouse sycle!! in my opinion i think fda does have the cure to almost if not all desieses but they keep making pills to sell making people think its the only way to deal with that sertain desiese!! if they know or are aware of the herbal substance that affects the sertain desiese dont you think they have the herbal plant to cure the cause? every one wants to be rich or at least have security but some pople are just doing it the wrong way!! my point is this the fda eventualy will lose its power due to evidence of its conflict of interests!! i wish i had a pland or the herbal remedie to give to you if you yourself want to do something to beter your mental health but the truth is that i myself am having trouble getting it!! be safe eat healthy or just drink a crap load of water lol and alot of salads LOL

  4. mark p.s.2’s avatar

    Another reason why the chemical imbalance idea is popular , is that the parents of the chemically-unbalanced-brain patient who perform mixed messages/”Double Bind”
    get to continue perform their insanity on their child.
    “when examining a patient with suspected hysteria, try not to embarrass or threaten the patient.”
    or the patients family in the case of mental illness.

  5. Charley’s avatar

    Have a family ever done a psychological number on a kid or a kid done a psychological number on their family? Of course.

    Have you ever known a real schizophrenic? I mean someone who is brilliant and wonderful in every way, who’s mind descends a dark stairway into a place where voices tell them to do things? Real voices. Not “imagined” voices – not guilt-trips from a religious education, not drug flash backs, not “the little voice talking to me inside”… REAL live voices that won’t stop.

    What about images? Images of shadows approaching from every angle? Sheiks, howls and cries that nobody else can hear? Yet they are so REAL and relentless.

    The only way these experiences have ever been reproduced in a sustained and predictable way is through the use of psychoactive drugs -

    And, regardless of how any of us feel about drug companies, psychiatrists, or psychotropic medications, the anti-psychotic drugs are one of the only ways most of those so seriously afflicted are able to return to anything resembling “normal” society. And, note my use of the word “normal” suggests a WIDE range… Surely if people can’t feed themselves, bathe themselves, maintain shelter, or any of the other things we consider “normal” they need *something*. And without committing them to locked wards for the rest of their lives, what other options are there?

    Most represent only a danger to themselves. However, many represent a danger to others -

    If we all spoke the same language, prayed to the same god, and lived in a circle of grass huts in the land of milk and honey it would certainly be an easier social question to answer. Maybe we could send them out into the woods with scheduled envoys to pay visits with food until they got “better”.

    I don’t have an answer. I have seen with my own eyes where despondent people came onto a psych unit, clearly detached from the same reality the rest of us were sharing (wide ranging though THAT reality was…). Within days on psychotropic meds I was enjoying dinner and conversation with a brilliant human being who days earlier had been a sloberring, shit spreading, ranting and raving lunatic. I’m pretty certain my medicated dinner companion was somewhat closer to the “real” human being than that frightening and very troubled person he was previously.

    We could talk about side effects and I’d agree with you. We could talk about drug companies selling the public a feel good med for every ail. We could talk about a society who wants to solve everything with a pill and I’d probably agree with you.

    But there are certain things I just know… Because I’ve seen them… And lived them… And blaiming schizophernia, and suggesting treatments, based on the psychodynamics of an individual’s environment? I think not.

  6. Charley’s avatar

    Well, on another note. I thought I’d share this… It would sure be nice if our lives could be lived this way…

    <!– @page { margin: 0.79in } P { margin-bottom: 0.08in } –>
    The Song of A Life

    When a woman in a certain African tribe knows she is pregnant, she
    goes out into the wilderness with a few friends and together they pray
    and meditate until they hear the song of the child.

    They recognize that every soul has its own vibration that expresses
    its unique flavor and purpose.

    When the women attune to the song, they sing it out loud. Then they
    return to the tribe and teach it to everyone else.

    When the child is born, the community gathers and sings the child’s
    song to him or her. Later, when the child enters education, the village
    gathers and chants the child’s song.

    When the child passes through the initiation to adulthood, the
    people again come together and sing. At the time of marriage, the person
    hears his or her song.

    Finally, when the soul is about to pass from this world, the family
    and friends gather at the person’s bed, just as they did at their birth,
    and they sing the person to the next life.

    In the African tribe, there is one other occasion upon which the
    villagers sing to the child.

    If at any time during his or her life, the person commits a crime or
    aberrant social act, the individual is called to the center of the
    village and the people in the community form a circle around them.
    Then they sing their song to them.

    The tribe recognizes that the correction for antisocial behavior is not
    punishment; it is love and the remembrance of identity. When you
    recognize your own song, you have no desire or need to do anything that
    would hurt another.

    A friend is someone who knows your song and sings it to you when
    you have forgotten it.

    Those who love you are not fooled by mistakes you have made or
    dark images you hold about yourself.

    They remember your beauty when you feel ugly; your wholeness
    when you are broken; your innocence when you feel guilty; and your
    purpose when you are confused.

    You may not have grown up in an African tribe that sings your song
    to you at crucial life transitions, but life is always reminding you when
    you are in tune with yourself and when you are not.

    When you feel good, what you are doing matches your song, and
    when you feel awful, it doesn’t.

    - Author Unknown

  7. Sandy Naiman’s avatar

    Heartfelt thanks for all your research and meticulous care in explaining so responsibly and thoughtfully, this dangerous  mythology.

    I wish the psychiatric medical establishment would take heed. LISTEN. And return to talking therapies. They work. 
    In 1991, after 16 years on Lithium Carbonate for psychosis with mania, then called Bipolar Disorder (except I never get depressed), I was diagnosed with Acute Iatrogenic Endstage Kidney Failure. I was practically comatose in the Emergency Room of a teaching hospital in Toronto after spending 24 hours in physical restraints in the psychiatric in-patient unit of that hospital.

    My psychiatrist of 16 years was head of psychiatry there at that time. He hadn’t been monitoring my Lithium levels and later, it was discovered that I was born with only one kidney.

    I almost died, but didn’t.

    Instead, I faced 18 months of getting sick enough to go on dialysis. First Hemodialysis. Then, after two bouts of surgery, when both AV fistulas in my arms failed, along with other spots on my anatomy – I have thick blood and thin veins, a bad combination for hemodialysis – I went onto Peritoneal Dialysis. After a two-year complication-filled ordeal, including about 5 surgical procedures, 18 months on an off in hospital and nine blood transfusions, my sister saved my life by donating her kidney.  

    The trend today is to neurosciences in psychiatry. No one seems to want to listen. Big Pharma is so powerful. I hope I live to see the day when all this madness ends. But I don’t know. I take an innocent-for-me anticonvulsant that stopped my twice-yearly psychotic episodes cold. That was more than 20 years ago. As long as I get enough sleep.

    Psychoanalytic psychotherapy since 1991 has helped me to recover.

    Not drugs. There is no insight in a pill bottle. I wrote about you today in my blog, “Coming Out Crazy.” A mention. But I linked to this post. And another.

    Keep up the good work. I’m a new fan.
    Sandy Naiman

  8. Chris’s avatar


    Welcome to the blog and thanks for your feedback and sharing your story. I was moved by your journey. I wish I could say your story was unique. I’ve heard so many similar stories from readers and friends and family members whose lives have been put in serious jeopardy by psychiatric drugs.

    I’m glad to know that you’re writing about this stuff. The more voices we have in this movement, the better our chances of helping people to understand how dangerous these drugs really are.


  9. stephanie’s avatar

    I have been having an argument with my best friend about the chemical imbalance myth. She is a card carrying PETA member/vegetarian who supports the pharmaceutical industry. My guess is she’s not taking into account all of the testing done on tons of animals for decades in the name of these drugs.  But that’s not really my biggest concern. I am very glad to have found this site.  It disgusts me how many people actually think they should take a pill for everything…..and that taking a pill will change your cognition. It’s ridiculous and hilarious at the same time. I signed up for your daily email.

  10. Chris’s avatar

    Hi Stephanie,

    I’m glad you like the blog. Please note that I am taking a break from writing new posts for a while due to other commitments, but am still responding to comments when I can.


  11. Nyghtmaer13’s avatar

    All of this reminds me of this movie “Equilibrium”, where a drug was used to take away emotions because they were considered a sort of disease. Freakin’ movie turned out to be true after all. Scary. I fear the day that all emotions will be regulated with such drugs. That’s why Equlibrium was so frightening…it’s entirely possible.

    If it happens, well…we’re screwed.

    I just hope it doesn’t come to that.

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