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David Baxter

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Delving into depression
12/31/2006
by Abram Katz, New Haven Register

Centuries ago, depression was considered an imbalance in the body?s black bile, hence "melancholy."

Later, with psychoanalysis ascendent, depression was seen as the consequence of repression and anger.

Most recently, neurochemistry suggested that the relentless hopelessness of depression was caused by a chemical imbalance in the brain. Patients who complain of chronic low-self esteem, changes in eating and sleeping patterns, poor concentration and burdensome feelings of futility are now often dispensed Zoloft, Prozac or similar drug that is believed to affect levels of serotonin and other neurotransmitters.

However, these modern pharmaceuticals help only about 50 percent of people with major depression. This fact and other recent revelations about the brain?s primary system of exciting and inhibiting neurons has sent Dr. Gerard Sanacora in a different direction.

Sanacora, director of the Yale Depression Research Program, said he aims to redefine the psychopathology of depression and find corresponding novel treatments.

Researchers around the world are following a similar scientific path, he said. Depression?s large variety of symptoms and the partial effectiveness of antidepressants suggests that depression may be dozens of different disorders, he said.

Sanacora and colleagues suspect that irregularities in the largest regulatory systems in the brain, GABA (gamma amino butyric acid) and glutamate, may be responsible for some types of depression.

Current prescription antidepressants work on the monoamine system, which comprises only a few percent of the brain?s neurons. The rest of the brain is equally split between the glutamate and GABA systems.

Glutamate excites neurons and increases activity, while GABA inhibits and calms neurons.

Both GABA and glutamate seem to affect the brain?s "plasticity," or the ability of its neurons to forge new dendritic connections. Each neuron communicates with about 10,000 others through dendrites, so a loss of plasticity in an area of the brain involved in emotions could result in depression.

In fact, rodent experiments and post-mortem examination of human brains suggest depression and loss of plasticity are closely related, Sanacora said.

For example, overstressed rats that show signs suggestive of depression have brains with fewer new neurons and neural connections. These rat brains were similar in some ways to brains of depressed people, he said.

Exercise in rodents increases plasticity by increasing release of growth factors in the brain. So does electro-convulsive therapy, or ECT, the most effective treatment for resistant depression. However, patients who undergo ECT have a high relapse rate.

Sanacora and Lisa Fenton, chief of psychotherapy research in the Depression Research Clinic, hope to find out whether cognitive behavioral therapy following ECT would prolong the effectiveness of the seizure producing procedure. They reason that with more plasticity, the brain might respond better to talk therapy.

Practically, people exposed to stress produce a hormone called cortisol, which readies the body for quick emergency action. It also reduces brain plasticity.

Earlier in human history, cortisol enabled a threatened person to fight or run away. Cortisol levels then rapidly dropped. The answer to modern stress is hardly ever fighting or flight, so cortisol remains elevated in some depressed people.

Measuring cortisol or glutamate metabolism might provide a method to determine which depressed patients will respond to medication, and others who may benefit more from talk therapy.

Sanacora is also engaged in figuring out the connection between glutamate, GABA, plasticity and depression.

Glutamate and GABA are both produced during the metabolism of glucose. This basic connection between the energy cycle and behavior is telling, Sanacora said. Both depend on each other and are vital to well-being.

Depressed people may have higher levels of glutamate because they have fewer glial cells, Sanacora said. Several types of glial cells provide nutrition to neurons, clean up stray molecules, reabsorb neurotransmitters, and provide the myelin that insulates nerves.

Sanacora hypothesizes that depressed people with fewer glial cells cannot reabsorb glutamate pumped into synapses. Glutamate then seeps out beyond synapses, where it inhibits neuronal functions.

At high enough levels, glutamate is actually toxic to neurons. This toxicity may explain the loss of plasticity, and also cause long-term neurodegeneration, Sanacora said.

The brain?s limbic system, which controls emotions, shrinks in severely depressed patients, he said.

Reducing glutamate or speeding its clearance from the synapse, and preventing it from overflowing, might alleviate depression by reducing the neural onslaught.

A drug called riluzole, which is already used to treat Lou Gehrig?s disease, can increase the uptake of glutamate and could possibly normalize its release, Sanacora said. So far, the drug seems to ease depression, but more research must be done.

The efficacy of riluzole on depression suggests that depression may be linked to a greater impairment of the glutamate system, he said.

Ultimately, when a patient is diagnosed with depression, the physician could diagnose the specific type and predict what kind of treatment would be more successful.

The Yale depression clinic is conducting studies on the treatment of hypothesized impairment of plasticity and the accompanying pathophysiology of fewer glial cells and damage caused by glutamate.

This research broadly includes measuring how glucose is made into glutamate in the brain to see if depressed people have characteristic ways that differ from people who are not depressed.

Ongoing studies include:

  • Using riluzole to treat depressed patients who have tried several antidepressants without success.
  • Testing the effectiveness of cognitive behavioral therapy, with and without medication, for people with mild to severe depression. Cognitive therapy essentially concentrates on modifying ingrained and distorted thinking, which is common in depression. For example, a therapist would help a patient train himself not to say "I?m a total failure" in response to a minor mishaps, and not to misinterpret other people?s behaviors toward them.

Those interested in finding out more about the studies, or participating in them, can call the Yale Depression Research Clinic at (203) 764-9131.

Treatments are free and confidential.
 

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