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.

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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 ...