I keep looking for it and can never find it. The above picture is my stack of psychopharmacology texts dating back to about 1980 and none of them mentions "chemical imbalance". I could add another foot or two to that stack and there still would be no mention of this theory.
Why
is that important? The main reason is that one of the favorite arguments by
anti-psychiatrists is that real psychiatrists believe that psychiatric disorders
are caused by a “chemical imbalance” in the brain. This criticism showed up on
this blog several years ago in a post that I critiqued that was largely a
screed against psychiatrists. Accusing psychiatrists of promoting a chemical
imbalance theory is an almost perfect rhetorical strategy. It uses what
essentially was a marketing device for antidepressants in the late 1980s to
portray psychiatrists as excessively reductionist at the minimum and at the
worst biologically naïve and dishonest.
My
colleague Ron Pies, MD has written a recent piece on the historical,
philosophical, and rhetorical aspects of this argument. What I hope to
accomplish in this post is taking a look at the science behind why no
psychiatrist would consider the brain to be a substrate run by “chemical
imbalances”. Some might find this argument to be quite boring but I can attest
to the fact that the premises used allowed me to state unequivocally to the
first pharmaceutical rep to use the term that no such state exists in the
brain.
The
main factor has to do with how physicians are trained. There’s still a lot of
confusion about whether a psychiatrist is a physician or not. I can assure
anyone reading this that we all are. That means in order to get into medical
school certain prerequisites at the undergraduate level have to be completed.
That includes a year of general chemistry, a year of organic chemistry, and a
year of general physics. A significant number of psychiatrists that I have
encountered were chemistry majors. That training means that physicians in
general have had exposure to physical science and how chemistry works in
solutions and gases. In these basic two
or three component systems there are limited possibilities in terms of reaction
outcomes. Even electrochemical reactions produce electron flow that decays
predictably over time but that is not able to transmit any nuanced signal. In other words the information content in
these systems is low – too low to run biological organisms.
In
the basic science years of medical school biochemistry, neuroanatomy,
neurophysiology, pharmacology, and all of the associated molecular biology
provided medical framework that all of the physical science can be mapped onto.
The study of enzyme and receptor systems highlight the basic concept that the
chemistry involved can only occur because it is in a specific microenvironment.
That microenvironment includes the protein structure of the enzyme or receptor molecules
as well as associated membrane components and cell signaling components. The
intracellular and extracellular environments are exquisitely controlled as is
the synaptic cleft. Many of the reactions involve additional acid-base and
ionic gradients. The degrees of freedom in these many component and many phase
systems are large. They are so large in fact that I have been unable to find an
estimate of degrees of freedom for neurobiological systems.
A good example of the kind of microenvironments and complex interactions that I am taking about is the GABAA receptor depicted diagrammatically below. The GABAA receptor is a transmembrane cylindrical receptor that is a member of the pentameric ligand-gated ion channel superfamily. The diagram is a top down view of the receptor complex cylinder highlighting that it is composed of 5 glycoprotein subunits. Each subunit is composed of 4 domains with one domain that lines the chloride ion channel through the center of the receptor complex. Binding sites on these protein allow for allosteric modification of the cylindrical receptor to facilitate chloride ion influx and fast inhibition of neuronal signals. Allosteric modulation of enzymes and receptors occurs when a molecule reversibly binds to the protein molecule resulting in inhibition or stimulation of the overall process. For example, benzodiazepines bind to a specific site at the α-γ interface leading to increased affinity for GABA at the receptor sites and increased chloride ion influx. Benzodiazepines are the classic allosteric modulators of the GABAA receptor but there are others. Barbiturates, anesthetic agents, neurosteroids and ethanol are also allosteric modulators at the GABAA receptor. The detailed structure of both the benzodiazepine and flumazenil binding sites on the human synaptic GABAA receptor have only recently been detailed (1).
The above paragraph is a glance into the types of systems that modern psychiatry is focused on. In the case of the GABAA receptor global inhibitory effects can be expected at some point, but there are not the product of chemicals floating about inside the body or brain. They are the effects of complex interactions between proteins, positive and negative modulators, neurotransmitter effects, ion fluxes, and additional signaling. The effects result from where these receptors are located in the brain and central nervous system. The education of physicians assures that this level of complexity in the brain is appreciated as both the basis for normal physiology and also the basis for pharmacology and toxicology. It may be tempting to try to simplify things - but real brain function defies simplification. The basic working of the GABA receptor was discovered when I was in medical school back in the 1980s. The lectures in those days showed a simple structure with an arrow showing increased chloride ion permeability but nowhere near the structure that we currently have.
This is one set of receptors and modulators very simplified. To get more of the story read the 22 pages of reference 1. To understand the brain and modern pharmacology much more needs to be understood. Forgetting about the term "chemical imbalance" is a good first step.
George Dawson, MD, DFAPA
This is one set of receptors and modulators very simplified. To get more of the story read the 22 pages of reference 1. To understand the brain and modern pharmacology much more needs to be understood. Forgetting about the term "chemical imbalance" is a good first step.
George Dawson, MD, DFAPA
References:
2: Human GABA-A receptor alpha1-beta2-gamma2 subtype in complex with GABA and flumazenil, conformation A. Detailed structure from the above paper.
