Why antidepressants don't work for so many Northwestern research finds drugs aim at wrong target

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 David 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.

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Biocapture Surfaces Produced For Study Of Brain Chemistry

A research team at Penn State has developed a novel method for attaching small molecules, such as neurotransmitters, to surfaces, which then are used to capture large biomolecules. By varying the identity and spacing of the tethered molecules, researchers can make the technique applicable to a wide range of bait molecules including drugs, chemical warfare agents, and environmental pollutants. Ultimately, the researchers also hope to identify synthetic biomolecules that recognize neurotransmitters so that they can fabricate extremely small biosensors to study neurotransmission in the living brain.

In the brain, dozens of different small signaling molecules interact with thousands of large receptive proteins as part of the fundamental communication process between nerve cells. This cacophony of specific interactions is highly dependent on nanoscale molecular structure. One key to advancing our understanding of how the brain works is to identify the nature of the association between neurotransmitters and their binding partners.

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Happy Days: Unraveling the Mystery of How Antidepressants Work

The mechanism behind antidepressant drugs is unveiled, which could lead to better treatments for depression and anxiety disorders.

New research shows how certain antidepressants work, paving the way to new, improved versions of the drugs used to treat depression, anxiety and attention deficit disorder.

Two separate studies—published this week in Science and Nature—provide a window into the way tricyclic antidepressants, such as clomipramine and desipramine, provide therapeutic relief by adhering to proteins on the part of a nerve cell's outer membrane that extends into the brain's synapses (spaces between the cells). These so-called transporter proteins, so-named because they carry molecules inside the nerve cell, gobble up neurotransmitters (chemical messengers such as norepinephrine, serotonin and dopamine) sent by neighboring cells. The drainage of these neurotransmitters from synapses—resulting, ironically, from the reimportation of the chemical just secreted by the sending neuron—has been linked to anxiety disorders; tricyclic antidepressants boost the activity of these neurotransmitters in synapses. But scientists have never been sure how this was accomplished.

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Cheerful news for antidepressant research

Two research groups have independently reported new findings on the mechanism of action of an important class of antidepressant drugs. The work provides key insights into how tricyclic antidepressants interfere with neurophysiology at the molecular scale, and could eventually open the way to the development of more efficient therapies.

Tricyclic antidepressants (TCAs) are molecules that resemble a kite, with a central seven-membered ring trailing a short tail and flanked by two benzene rings. TCAs work by inhibiting neurons from taking up the monoamine neurotransmitters serotonin, norepinephrine and dopamine, which regulate mood. By blocking the re-uptake of these transmitters by their specific transporter proteins, the transmitter molecules remain in circulation for longer, prolonging their action.

However, the precise way in which the drugs work had remained unresolved. Now, Maarten Reith, Da-Neng Wang and colleagues1 at the New York University School of Medicine, US, and a team led by Eric Gouaux2 at the Oregon Health and Science University, US, have independently provided data on how TCA molecules bind to a bacterial analogue of a mammalian neurotransmitter transporter.

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