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Knowledge is Necessity

Neurology and psychology may be merging, with genetics leading the way.

"Somewhere in our own personal arrangements of those one thousand letters which may very well govern my sanity and yours is a 't' that should have been an 'a.'"

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 Knowing Where To Kick

We've been told that the new generation of antidepressants act by blocking the reuptake of the neurotransmitter serotonin in the brain, but what precisely is that supposed to mean? In a Medscape article, Thomas Kramer MD is candid enough to admit:

"Put simply, we know these drugs work, but we have very little idea how. We make guesses based on the neurochemical effects of these compounds. We have very little proof, and sometimes very little data, about whether the neurochemical effects that we find have anything to do with the therapeutic effect of the medication."

In support of his argument, he cites the antidepressant, tianeptine, available only in Europe, that is a selective serotonin reuptake ENHANCER - ie, it works exactly opposite to SSRIs but with the same therapeutic effect. He speculates both classes of drugs may work because of their action rather than type of action, each succeeding in "jolting" the firing of neurons.

To illustrate the principle, Dr Kramer cites a story dating from the golden age of radio when a malfunction in the main transmitter caused CBS to go off the air. When the company’s own engineers failed to figure out what was wrong, they called in an outside expert. The expert walked up to the transmitter, stared at it, then gave it a sharp kick, which put CBS back in commission. The next day CBS got an itemized bill that read: "One kick, $1. Knowing where to kick, $9999."

Tomorrow's psychiatrist may have to know more than merely where to kick. For now, a rose by any other name may smell just as sweet to Shakespeare, but the odds of getting a psychologist, a psychiatrist, and a neurobiologist to agree on even that are about the same as Stephen Hawking embracing astrology as a science. What a psychologist sees as a behavior problem, a psychiatrist views as an Axis I disorder, which a neurobilogist interprets as something gone haywire in the signal transduction pathways.

The Future of Psychiatry

You want to be intimidated, try on for size the titles of these articles from a recent issue of Neuroscience:

"Differential Expression of KCNQ2 Splice Variants: Implications to M Current Function during Neuronal Development"

"Anandamide Excites Central Terminals of Dorsal Root Ganglion Neurons via Vanilloid Receptor-1 Activation"

I’m not sure about you, but I think I had the flu the day those particular items were brought up when I was in college.

Writing in the Journal of the American Medical Association, W Maxwell Cowan MD of the Howard Hughes Medical Institute and Nobel laureate Eric Kandel MD of Columbia University note that neurobiology is a relatively new animal, with only 600 members in the Society of Neuroscience in 1968. Today, that figure is 25,000. These days, neurologists track down individual neurons and connect the dots to other neurons, and with sophisticated imaging techniques they can view whole regions of the brain in crisis or recovery.

According to the authors, the future is just about now, with molecular genetics and molecular cell biology leading the way. The authors foresee an eventual blending of psychiatry and neurology, but what they leave unsaid is the possibility of a breakdown in the distinctions between various forms of mental illness, and ultimately how we perceive it. Vishwajit Nimgaonkar MD of the University of Pittsburgh and John Kelsoe MD of the University of San Diego at California, for instance, are on the hunt for genes that may figure in both schizophrenia and bipolar disorder.

The Quest for Bipolar Genes

Go to the NIH's National Center for Biotechnology Information website and enter GRK3 into the search field. GRK3 is a protein involved in Dr Kelsoe's research. A lack of dialogue between the gene responsible for GRK3 and GRK3 itself may be one of the triggering mechanisms in a small percentage of people with bipolar disorder. Searching for GRK3 gives you the protein's corresponding gene, ADRBK2, standing for adrenergic, beta, receptor kinase 2, whose position on the human genome is 22q12.1.

The 22 stands for chromosome 22, a stubby little strand of DNA that seems lost in the redwoods of most of the other 23 chromosomes. Go back to the page you started from and click on this little fella and you will be taken to an enlarged diagram that tells you 238 genes are present in the region, 20 which have been accounted for. Seven down from the top, isolated from the other genes, is ADRBK2. Click on AV for Ace View, which gives you detailed and contextual diagrams of the gene, then click Details and DNA, and there you have it, the four-letter alphabet soup that stands for this segment of DNA, starting with gcccccc ... and ending a thousand symbols later in ttccagac.

Somewhere in our own personal arrangements of those one thousand letters which may very well govern my sanity and yours is a "t" that should have been an "a" or a "g" that should have been a "c" or some other minor typographical error that is possibly capable of bringing down our brains with a resounding almighty crash.

The simple solution, once we've pinpointed the culprit genes, seems to be to find a way to flip the letters back to where they're supposed to be, or to replace bad genes with good genes, but it's not as simple as all that, says Gary Stix, an editor at Scientific American. Writing in the LA Times, he reports that, "scientists have encountered great difficulty in delivering genes where they are needed in the body and triggering their activation in cells."

Figuring Out the Proteins

Instead of genes, Stix argues, it's the proteins, stupid, and here life gets a lot more complicated. We may have sequenced the human genome, but no one has come up with a map of amino acids, the building blocks of proteins. We now know there are about 25,000 genes in the human genome, but there may be as many as a million proteins dispersed along 100 billion human cells, and even if we produced a picture of all of them at work, there exists yet another layer of the onion represented by a million constantly changing connections among our brain cells for each of the three billion units of DNA.

Meanwhile, an editorial in the Lancet contends that "only hypertension might succumb to the power of genetic understanding. But even for hypertension there is no simple gene-disease correlate."

But Raymond DePaulo MD, who heads up genetics research at Johns Hopkins, at the 2001 NAMI conference, argued that eventually our knowledge of genes will be used to illuminate the pathology of mental illness and find targets for rational treatment, something equivalent to giving insulin for diabetics - it's not a cure but it's smart.

Redefining Depression and Bipolar Disorder

These days, we define mental illness by a cluster of symptoms. Tomorrow, our treating physicians, armed with definitive readouts of our genetic and molecular markers, may simply tell us we suffer from a few chromosomal anomalies affecting some activity in the brain, and send us on our merry way with the perfect remedy. Since my chromosomal anomalies may look nothing like yours, saying we have the same illness could be as accurate as confusing the flu with a common cold.

Or the opposite could very well occur, that by drilling down deeper we may in fact uncover a common set of genes. A Harvard/McLean Hospital survey of 178 relatives of 64 subjects with major depression and 152 relatives of 58 subjects without major depression found that “affective spectrum disorder” (ASD) clusters in families and that major depression displays a familial affinity with other forms of affective disorders, suggesting that various forms of ASD share the same genetic features.

Forms of ASD include major depression, ADHD, bulimia nervosa, cataplexy, dysthymia, fibromyalgia, generalized anxiety disorder, irritable bowel syndrome, migraine, OCD, panic disorder, PTSD, premenstrual dysphoric disorder, and social phobia.

Of course, as long as we have emotions, we will always need the term depression, even if it no longer clinically defines a particular illness. But the word bipolar can take a long walk off a short pier. The psychiatrists may insist on one last crack at the DSM, but after that, it may be time for the neurologists and geneticists to start picking names, something equivalent to Huntington's disease and Hashimoto's disease, designations that don't invite prejudice and encourage stigma. The harder to spell, the better. Let those who find the culprit genes have naming rights. Dr Nimgaonkar, I'm rooting for you.

For three free online issues of McMan's Depression and Bipolar Weekly, email me and put "Sample" in the heading and your email address in the body.

Updated July 11, 2003

Eric (Sept 20, 2002): This was a great article. Formally merging psychiatry into neurology is indeed the ONLY hope for the severely mentally ill. Psychiatry is too backwards and low tech to ever figure out severe mental illness. If severe mental illness is truly a brain/CNS disease, then the only logical thing to do is to formally give these problems to neurology to fix.

This is exactly what Dr Fuller Torrey is constantly saying, that psychiatry should be formally merged into neurology. Its arguable that only neurology has the academic/high tech capability to conduct real research into severe mental illness. The mentally ill have been waiting decades for psychiatry or psychology to research our diseases sufficiently and it has not materialized...and probably never will as long as the mental health field controls the treatment of mental illness.

Basically, these problems will only be fixed someday if the following occurs:

1) All the severe forms of mental illness (bipolar, schizophrenia and severe depression) are formally removed from being classified as psychiatric illnesses. And are formally RECLASSIFIED as neurological disorders of the brain.

2) Psychiatry is formally merged into neurology and neurologists diagnose and treat severe mental illness in the future. Neurologists should also run mental hospitals...or better yet just merge mental hospitals into the neurology ward sections of major hospitals.

3) Genetic engineering research focuses on brain based diseases just as much as it does on cardiovascular disease, cancer, etc. I'm personally concerned about this, that the genetic research will not be focused enough on brain based illnesses.

4) Psychiatry is kicked to the curb and thought of in the future as an aberration, as a distasteful way to handle serious brain based medical problems. The treatment of the severely mentally ill should have never been handled by psychiatry and should have been the forte of Neurology since day one.

There are a lot of unhappy customers with psychiatry. And the main reason why is psychiatrists are treating physical, brain based illnesses as "psychological" problems. When in fact these problems are just as real or physical as cancer or diabetes. That angers a lot of people and drives a rift between psychiatry and the public.

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Nobel Laureate Eric Kandel: Foresees a blending of psychiatry and neurology.