Why antidepressants don't work for so many; drugs aim at wrong target

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Public release date: 23-Oct-2009

http://www.eurekalert.org/pub_releases/2009-10/nu-wad102309.php

Contact: Marla

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Northwestern University

Why antidepressants don't work for so many

Northwestern research finds drugs aim at wrong target

CHICAGO --- More than half the people who take antidepressants for

depression never get relief.

Why? Because the cause of depression has been oversimplified and drugs

designed to treat it aim at the wrong target, according to new research

from the Northwestern University Feinberg School of Medicine. The

medications are like arrows shot at the outer rings of a bull's eye

instead of the center.

A study from the laboratory of long-time depression researcher Eva

Redei, presented at the Neuroscience 2009 conference in Chicago this

week, appears to topple two strongly held beliefs about depression. One

is that stressful life events are a major cause of depression. The other

is that an imbalance in neurotransmitters in the brain triggers

depressive symptoms.

Both findings are significant because these beliefs were the basis for

developing drugs currently used to treat depression.

Redei, the Lawrence Stein Professor of Psychiatry at

Northwestern's Feinberg School, found powerful molecular evidence that

quashes the long-held dogma that stress is generally a major cause of

depression. Her new research reveals that there is almost no overlap

between stress-related genes and depression-related genes.

" This is a huge study and statistically powerful, " Redei said. " This

research opens up new routes to develop new antidepressants that may be

more effective. There hasn't been an antidepressant based on a novel

concept in 20 years. "

Her findings are based on extensive studies with a model of severely

depressed rats that mirror many behavioral and physiological

abnormalities found in patients with major depression. The rats, after

decades of development, are believed to be the most depressed in the world.

Little Overlap Between Stress and Depression Genes

Redei used microarray technology to isolate and identify the specific

genes related to depression in these animals. She examined the genes in

the brain regions -- the hippocampus and amygdala -- commonly associated

with depression in rats and humans.

Then she took four genetically different strains of rats and exposed

them to chronic stress for two weeks. Afterwards, she identified the

genes that had consistently increased or decreased in response to the

stress in all four strains in the same brain regions.

Redei now had one set of depression-related genes that came out of an

animal model of depression and one set of stress-related genes that came

our of her chronic stress study.

Next she compared the two sets of genes to see if there were any

similarities. " If the 'stress causes depression theory' was correct,

there should have been a significant overlap between these two sets of

genes, " she said. " There weren't. "

Out of a total of over 30,000 genes on the microarray, she discovered

approximately 254 genes related to stress and 1275 genes related to

depression, with an overlap of only five genes between the two.

" This overlap is insignificant, a very small percentage, " Redei said.

" This finding is clear evidence that at least in an animal model,

chronic stress does not cause the same molecular changes as depression

does. "

Antidepressants Treat Stress Not Depression

Most animal models that are used by scientists to test antidepressants

are based on the hypothesis that stress causes depression. " They stress

the animals and look at their behavior, " she said. " Then they manipulate

the animals' behavior with drugs and say, 'OK, these are going to be

good anti-depressants.' But they are not treating depression; they are

treating stress. "

That is one key reason why current antidepressants aren't doing a great

job, Redei noted. She is now looking at the genes that differ in the

depressed rat to narrow down targets for drug development.

She said another reason current antidepressants are often ineffective is

that they aim to boost neurotransmitters based on the popular molecular

explanation of depression, which is that it's the result of decreased

levels of the neurotransmitters serotonin, norepinephrine and dopamine.

But that's wrong, Redei said.

Drugs Aim at Wrong Molecular Target

In the second part of the study, Redei found strong indications that

depression actually begins further up in the chain of events in the

brain. The biochemical events that ultimately result in depression

actually start in the development and functioning of neurons.

" The medications have been focusing on the effect, not the cause, " she

said. " That's why it takes so long for them to work and why they aren't

effective for so many people. "

Her animal model of depression did not show dramatic differences in the

levels of genes controlling neurotransmitters functions. " If depression

was related to neurotransmitter activity, we would have seen that, " she

said.

Similarities Between Human and Rodent Brains

Her findings in depressed rats, she said, are very likely applicable to

humans.

" The similarities between these regions of the human and rodent brain

are remarkable, " Redei explained. " The hippocampus and amygdala are part

of the so-called ancient lizard brain that controls survival and are the

same in even primitive organisms. "

###

Contributors to the study from Redei's lab include Andrus,

Dennis and Schaffer, research assistants, and Pradeep Shukla, a

postdoctoral fellow. Jelena Radulovic, M.D., Dunbar Scholar and

associate professor in psychiatry and behavioral sciences at the

Feinberg School, also contributed as did Vedell, a postdoctoral

associate in professor Churchill's group at The Lab, Bar

Harbor.

--

ne Holden, MS, RD

" Ask About Nutrition " www.parkinson.org/

" Nutrition Reports " http://health.groups.yahoo.com/group/Nutrition_Reports/

" Parkinson's disease: Guidelines for Medical Nutrition Therapy "

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