Posts Tagged ‘serotonin’

Dandelions and Orchids

March 11th, 2011

Dandelions are hardy. Give them a crack on a city sidewalk, and they will thrive. The beautiful orchid, by contrast, is much more delicate. To thrive it needs conditions like those in Costa Rica: warm, sunny, and moist.

Increasingly, research on the human genome suggests that important gene-environment interactions may lead to psychiatric syndromes. An example is that two short alleles on the serotonin-transporter (5-HTT) gene may heighten vulnerability to depression under adverse circumstances.

Why would such vulnerability genes survive? Shouldn’t people who inherit them be adversely selected, so their genes would decrease and die out over generations? Or, might such genetic patterns give evolutionary advantage in selected environments—something like sickle-cell trait making people more resistant to malaria?

Emerging evidence, including data from studies by Penn State scientists, suggests that some genetic patterns, such as two short 5-HTT alleles, might confer behavioral advantages in an optimal environment. People with two short alleles who grow up in nurturing, intact families, with educational and economic privilege, may actually show greater resilience and creativity, while others with the same genetic pattern, who come from poverty and dysfunction, may do worse than average. If this theory is correct, the people with two short 5-HTT alleles are “orchids,” doing beautifully in ideal environments, but worse than average in bad environments. The majority of people, who have either a short and a long or two long alleles, are “dandelions,” doing moderately well in a broad range of environments.

As I write periodically in BTP, we stand on the threshold of dramatic and exciting breakthroughs in understanding the brain. In time, these discoveries should help people who suffer from psychiatric syndromes—including autism, ADHD, depression, and PTSD

Alan J. Gelenberg, M.D.
Editor,
Biological Therapies in Psychiatry
Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief,
Journal of Clinical Psychiatry

When mechanism matters

December 13th, 2010

Maprotiline (Ludiomil) is a tetracyclic antidepressant introduced in the early 1980s. It is a norepinephrine reuptake inhibitor, which is believed to be its primary mechanism of antidepressant action. It had a particularly high incidence of seizures, which the manufacturer initially minimized. Today maprotiline is seldom prescribed.

Initial advertising for maprotiline featured the headline, “When Mechanism Matters.” Perhaps the people who wrote the ad copy were banking on the Emperor’s-New-Clothes phenomenon: doctors would be too embarrassed to admit we didn’t know when mechanism mattered in selecting an antidepressant for a depressed patient. We still don’t.

We make assumptions. SSRIs work by enhancing serotonin. SNRIs work via both serotonin and norepinephrine. MAOIs work by inhibiting MAO. Perhaps these theories are valid; perhaps not. In theory, a patient who fails to respond to one SSRI should do better with a drug with a different mechanism of action, rather than a different SSRI. But the data say otherwise.

I am convinced that, ultimately, mechanism matters. And psychiatric patients are different one from the other. Someday we will understand the unique pathophysiology that underlies abnormal thinking, feeling, and behavior. Someday we will elucidate the various etiologies that distort normal brain function in these ways. And when that time comes, we will tailor treatments to the abnormalities: targeted treatments; personalized medicine.

But until that time, let’s not become gullible to those who peddle expensive new products with thinly veiled promises that understanding the receptor or other properties of a compound translates into real-life advantages. And remember that sales people are not only the companies’ marketers and representatives, but also some of our colleagues who write and lecture. A professor of mine admonished his students to be “therapeutic skeptics—but not nihilists.” Amen.

- Alan J. Gelenberg, M.D.
Editor,
Biological Therapies in Psychiatry
Professor and Chair, Psychiatry, Penn State University
Editor-in-Chief,
Journal of Clinical Psychiatry