Thursday, October 14, 2010

RIP Chemical Imbalance in the Brain

As to what causes depression, the short answer is we don't know. It is convenient to say that it is a result of a chemical imbalance in the brain, but this is not entirely accurate ...
- Living Well with Depression and Bipolar Disorder, 2006

Let me rephrase that. "Chemical imbalance in the brain" is wholly inaccurate and misleading. My book goes to great lengths to point out that our brains are not chemical soup, but I was willing to concede it was okay to use the term in a pinch. No more.

Last night, I began reading Robert Whitaker's "Anatomy of an Epidemic," published earlier this year. Robert Whitaker (pictured here) is a journalist who got into reporting on mental health quite by accident. His meticulously researched "Madness in America" (2002) challenged the narrative that the introduction of psychiatric meds changed the treatment of mental illness for the better. His current book continues this line of reasoning.

What jumped out and hit me in the face in reading the first 100 pages is that the "chemical imbalance" myth continues to flourish despite overwhelming evidence to the contrary. Here's how it breaks down:

Psychiatric meds were developed serendipitously, with no knowledge of the underlying brain function. This is old news. The first antidepressants, for instance, were originally developed to treat TB. Some of the patients, it was discovered, became lively. In 1958, inproniazid (an MAO-I) hit the market as a psychic "energizer." A year later, imipramine (a tricyclic) came on the scene.

As Whitaker reports: "The New York Times called them antidepressants for the first time."

The first antipsychotics, in the meantime, came out of research for safe anesthetic agents (and before that for malaria). As part of a cocktail, one experimental med induced "artificial hibernation." In France, in 1952, two doctors used a variation of this med to quiet down psychotic patients. Very soon after, Thorazine (chlorpromazine), came on the market as a major tranquilizer or "neuroleptic" (meaning it took hold of the nervous system).

Whitaker notes: "Physicians in the US similarly understood this drug was not fixing any known pathology." Only in 1963, after an NIMH study, did Thorazine and similar compounds become acknowledged as "antipsychotics". Thus the new psychiatric meds were viewed as antidotes for specific disorders, comparable to antibiotics. But to make their case, scientists needed to backfill their claims with a credible theory.

Employing the equivalent of reverse engineering, researchers figured out that antidepressants worked by enhancing serotonin communication between the neurons. Likewise, antipsychotics took effect by blocking dopamine transmission. So far so good. But, could depression be seen as an undersupply of one neurotransmitter and psychosis an oversupply of another? A "chemical imbalance," in other words?

The obvious way to prove that was to analyze the cerebrospinal fluid (CSF) of unmedicated patients. Serotonin that is not recycled in the brain is metabolized as 5-HIAA. Likewise, dopamine is broken down to HVA. The levels of these metabolites in the CSF are acknowledged to relate to the levels of their corresponding neurotransmitters in the brain. Over the course of fifteen years to the mid-seventies, researchers found that the various metabolite levels in patients were no different than those in the general population.

In other words, no chemical imbalance. This is science at its best, disproving its own claims through its own methods, though the theory kept getting revived from time to time, especially with the commercial success of Prozac.

In the meantime, however, researchers began to paint a far more accurate and nuanced picture. With the administration of an SSRI antidepressant, we have learned, the brain attempts to compensate by turning down serotonin release in presynaptic neurons and reducing the density of serotonin receptors in postsynaptic neurons. This is the brain's attempt to maintain homeostatsis (equilibrium), to keep serotonin at levels as they were prior to the introduction of the drug.

Only after two weeks or more does the antidepressant begin to assert itself. The brain's compensating mechanisms break down. Serotonin now floods the synapse and latches onto postsynaptic receptors. Something similar happens with the introduction of an antipsychotic. Presynaptic neurons react by pumping out more dopamine and postsynaptic neurons increase their density. Only later does the blockade begin.

According to Whitaker, "the medicine clearly doesn't fix a chemical imbalance in the brain." Quite the contrary, these meds are causing chemical imbalances, and science is quite okay with that. Exhibit A cited by Whitaker is a 1996 article by former NIMH director Steve Hyman, which notes that the brain on meds is functioning in a manner that is "qualitatively as well as quantitatively different from the normal state."

In his article, Dr Hyman concludes:

Psychiatric research must now extend its efforts beyond the synapse, to an understanding of cellular and molecular neurobiology (in particular, postreceptor signal transduction) as well as to a better understanding of the architecture and function of neural systems.

It's a new world out there. Forget "chemical imbalance."

For an alternative metaphor, check out The Brain is an Ecosystem.


This is the first in a series that intends to use Whitaker's book as a talking point on a vast range of topics. We are not out to prove Whitaker right or wrong. Rather, the purpose is to start a conversation on issues that cry out for our attention. Your comments welcome ...


Willa Goodfellow said...

Yeah. Somewhere I have a reference to a study in which they artificially reduced the serotonin in subjects who were in remission and others who had never been depressed. For the formerly depressed -- relapse. For the never depressed -- no effect.

Prozac Monologues had a chapter explaining the serotonin/chemical imbalance hypothesis. For the last couple years I have been telling myself -- The bad news is that chapter 7 is hopelessly out of date. The good news is that my brain fell apart before I could do the work to get it published. At this point it would embarrass me. The fairy tale is that one day I will be able to rewrite that chapter and clean up the rest. It still is my beloved child, feeling rather abandoned for now.

John McManamy said...

Hey, Willa. Whatever you had wouldn't have been as out of date as the hypothesis. Years ago, I referred to the monoamine hypothesis as making sense in a flat earth sort of way. I think that made it into my book. Bottom line is "chemical imbalance" creates a highly distorted and simplistic view of mental illness and its treatment. We can't expect credible answers if we keep asking ourselves the wrong questions.

Gina Pera said...

You write so clearly about complex things, John. I'm envious!

As for me, though, I'm sticking with "chemical imbalance." Half the country can't even seem to read competently (if the political "discourse" is any guide). I don't think they're at all ready for some high-falutin' explanation. ;-)

Willa, I'm not sure how one could artificially reduce serotonin unless it was through dietary restriction. Doesn't seem a very reliable method.

Perhaps you are thinking of the studies that have pointed to a possible role of amino acids in treating psychiatric?

The most compelling study was done by Pedro Delgado in the early 1990’s. Delgado took a group of patients who had been previously been depressed and administered a diet that was devoid of tryptophan, an essential amino acid for the production of serotonin.

14 out of 21 patients became depressed within hours of receiving this diet. The patient’s depression resolved within hours of reintroducing tryptophan back into the diet. (

John McManamy said...

Hey, Gina. Whitaker describes using the hypertensive agent resperine as agent to deplete serotonin. But these days there is something called "tryptophan depletion" using an amino acid drink. This produces the results Willa is referring to, though I don't think a definitive finding has emerged.

I agree that for the unwashed, "chemical imbalance" will have to go with their tea bags. Sigh ...

herb said...

How’s about we use “bio-neuro-chemical malfunctioning” of the brain.


John McManamy said...

Hey, Herb. You got me thinking. Good old fashioned "nervous breakdown" kinda said it all.

Tony the cretin said...

Yes, let's beat up on the tired old "chemical imbalance" argument. It seems that the pharmaceutical companies are the only ones selling it. The scientific literature is talking about how through interactions with kinases and other proteins that signalling is changed or neurotrophic factors are released. Yes, psychiatrists/neurologists have just scratched the surface as to what is going on with the flawed but effective medications we got. In all fairness, the same can be said for a lot of medicine. Science is just beginning to understand the very complex network of signalling that takes place within cells, not to mention between cells. So much can go wrong and does (i.e. cancer). So we shouldn't be to critical of psych researchers.

As for Whitaker, I get that the central theme of his book "Anatomy of an Epidemic" is that medications are THE main cause of mental illnesses (based on an interview in Salon). He cited a shocking 2007 study that he claims shows that people with schizophrenia were better off off of antipsychotics. He has seriously misread the study. I looked it up. The authors describe how some people with schizophrenia have few psychotic episodes and do not require constant administration of antipsychotics. But they make it clear that some people have a chronic course that requires constant medication. The former are rarely hospitalized whereas the latter are frequently hospitalized because they are more ill. Somehow Whitaker thinks the latter are more ill BECAUSE they take medications whereas the former are better because they don't. That is not what the authors point out. Just makes you wonder about Whitaker's thesis.

John McManamy said...

Hey, Tony. Ironically, researchers at the pharm companies played a lead in discrediting "chemical imbalance." But the marketing departments continue to keep the myth alive.

Re the meds make you sick argument:
My reaction to those studies when I came across them was exactly the same as yours. If your illness is more severe, it stands to reason that you will be on more meds. More meds may be LINKED to greater illness severity, but this is very different than saying more meds CAUSE greater illness severity. I'm on less meds because I am fortunate enough to have that option. Others I know are not.

But it's clear that Whitaker - when he is right and when he is wrong - raises a wealth of invaluable talking points. So in blogs to come, I will be serving them up and will be looking forward to your responses. Stay tuned ...

Moira said...

Robert Whitaker shakes people up. Who cares about brain science and treatment enough to organize for advocacy?

I look forward to all future entries and comments.

Tony said...

Wow 2 Tony's in one comment thread!

Tony the Cretin said...

"Just makes you wonder about Whitaker's thesis."

True enough, and in that particular case I would agree that coming to the conclusion that meds are the cause IS problematic.

Let's face it, some people just don't come back from psychotic episodes.

I have my own feelings about the issue based on my own episodes.

I have experienced a worsening of symptoms on meds, which would lead me to lean towards Roberts assertion, but it just isn't that simple. What resonates with me is that they don't allow us to heal.

For me being on meds is like being in stasis. I'm stuck in neutral. And in a time of crisis, neutral is a good place to be, but I don't want to stay there. I eventually want to put it in drive an go forward.

The overriding theme I got from Roberts book however aren't the scientific methods used. What grabbed me was the amount of "seeming" collusion between pharmaceutical companies, doctors, the insurance industry and the DSM IV. I'm no conspiracy theorist, but I do think all these factors just mixed well together to create it's own ecosystem of illness.

John McManamy said...

Hey, second Tony. Whitaker's book is very interesting in regard to the idea that certain meds (such as antipsychotics) structurally change neurons, which may worsen the illness. I plan to summarize his thesis in a future post, as it's a topic well worth examining. Re your point about being in neutral - a strong yes. Psychiatry clearly doesn't know how to put us in forward. A major problem is their over-reliance on meds. And strong yes to psych-pharma-DSM-etc. We're all in the same camp on this. Not a conspiracy, but an unfortunate convergence that has created a very bad environment for us. Lots and lots to talk about. Let's keep talking.

Kristin said...

Quote from bob Whitaker on from a facebook page where "RIP Chemical Imbalance in the Brain" was linked: "I tried to post my own comment on the blog cited above, but it seems you have to have a google email account to do so. People who say I have misrepresented the Harrow study haven't read it closely, and haven't read what I wrote in Anatomy about the study either. That study needs to be closely dissected, because even if you divide the patients into subgroups (good prognosis, bad prognosis, and other psychotic patients,) you will see--if you read the study closely--that the off-med patients in each group did better over the long term."

Autism Solution Center, Inc. said...

I find it quite interesting also that genetics and metabolics are not considered more here. I am often frustrated as the Founder/CEO of an autism treatment center that sees 5-year-olds coming in on antipsychotics and/or SSRI's, among others, with little to no research done on what the etiology of their supposed "chemical imbalances" could be.

SNP's in the MTHFR gene can wreak havoc with methylation pathways, which in turn, have a significant effect on Seratonin levels. Often putting these children on medications worsens the problem, when sometimes simply giving them the already activated form of B12, called Methyl B12, can remedy the situation. But of course, that isn't in pharma's best financial interest.

There is so much more going on here than meets the naked eye. I hope many more will take the time to do their own homework and understand the need to become their own experts, in order to work along side doctors, who often don't dig deep enough to move beyond simple symptomology, rather than getting to the root of the problem and providing a real, long-term solution.

I am just now beginning to blog on many of these items, in the hopes of educating the public on such issues. You can read more at

Best wishes and thank you for a very insightful article.


Laura Corby, Founder/CEO
Autism Solution Center, Inc.

Anonymous said...

Hey John,

Thanks for the post. I read most of Whitaker's book this summer ("The Anatomy of an Epidemic") and was (somewhat) shocked. I am currently working through my own mental health struggles, and so many people along the way have told me that I should be taking medications. I cannot emphasize how dismissing that feels. Ranging from the general practice doctor I visited over a year ago, who gave me Lexapro like M&M's, to the help I have sought in mentors/spiritual guides, everyone tells me medication is what I need.

Fortunately, I am working with a great therapist now who is not adamant that I take medication. I am currently pursuing graduate studies in religion, psychology, and philosophy. Writing and expressing myself-- is a huge part of my life, both now, and as I look ahead to the future.

I have suffered a lot in my struggles with "depression," "anxiety," "obsessive thoughts," "angst," "despair," "borderline pd"-- all of this stuff and more. But in the end, I prefer to feel, to live life deeply and with intensity, to love deeply, to plunge into the richness of the world. I do not want to be anasthetized to the world around me, a world that especially for those of us who are sensitive, can be a scary, ugly and also, beautiful place. Who is to say that "depression" and "anxiety" are not sometimes appropriate responses?

I must say that I am becoming increasingly exasperated with the current psychatric medicine scene. Mental illness/health have been commodified, and along with this, suffering human beings who just want to be seen and heard. I often think that the increase in medication is yet another product of the modern, capitalist mentality of get-fixed-quick, depersonalized "curing." It is often a matter of "here, take this pill and all will be well." But as Whitaker shows in his book, that is just not the case. I do intend to follow up further on Whitker's research and see what more I can find.

I sometimes wonder that if psychiatric meds had been invented 500 years ago, what kind of art, literature, and poetry would we maybe be missing. The modern person wants a quick fix to everything. Years of psychotherapy are considered too much of an investment. He/she can see no positive value to suffering and pain, no possible growth that can be gained from it. The point has become to live a "normal" life and get from birth to death with as little suffering as possible. Furthermore, I am shocked that the research Whitaker cites (from Harvard, Yale, Johns Hopkins, WHO) has been silenced. At the very least, we need a more responsible and balanced approach to medication. Today's situation is a far cry from that.

As for me, I am fighting my own daily battles, and I continue my fight.