DBSA-NOVA      July 19,2007

This is a recap of a free talk entitled "Pathophysiology of Affective Disorders and Potential New Treatments to Treatment Resistant Mood Disorders" by Alan G. Mallinger, MD, at July 19 at George Washington University Hospital.

Dr. Mallinger, the unit chief of the Adult Outpatient Clinic's Mood and Anxiety Disorders Programs at the National Institute of Mental Health and a former professor of psychiatry and psychopharmacology at the University of Pittsburgh School Medicine, presented findings and discussed research into medications that help reverse brain cell atrophy caused by repeated exposure to mania and depression.

Dr. Mallinger discussed how research studies have shown that repeated manic and depressive episodes create atrophy – a partial or complete wasting away body tissue – in a part of the brain that regulates emotions. He said that healthy neurotransmitters in that part of the brain look like spring trees, while the ones undergoing atrophy look like a tree in the winter, withered and barren.

“Images of the brain show that we can see atrophy,” said Dr. Mallinger, who has research includes clinical psychiatric work and psychopharmacology research into mood disorders. This, he said, shows “the loss of tissues and less grey matter in the part of the brain that regulates emotions.”

Dr. Mallinger's areas of basic research interest include laboratory studies on cell membrane phenomena and intracellular signal transduction processes, specifically, as these relate to the biological aspects of bipolar disorder and to the therapeutic mechanisms of mood stabilizing drugs. His special focuses are treatment resistance and symptom recurrence. His clinical research interests also include therapeutic options or treatment-resistant mania, mood stabilizer treatment during pregnancy, and pharmacokinetic studies of MAO inhibitors.

When it comes to mania and depression, he said, “There is something going on deep down there that is bad for the brain.”

The actual damage can be linked to Glucocorticoids, the most well known of which is cortisol hormone, and Glutamate, which in two high of dosages can be nuerotoxic. 

“A lot of the treatments we are working with are in the glutamate neurotransmitters,” he said.

Atrophy, he added, is believed to contribute to reoccurrence of manic and depressive episodes and the degenerative nature of bipolar disorder and depression. The two strategies Dr. Mallinger described to combat atrophy have been structural plasticity and  cellular regeneration.

Structural plasticity is based on the theories about nueroplasticity, which argue that changes occur in the organization of the brain as a result of experience, and that as a consequence, given functions of the brain can more to other locations in the brain due to training or because of brain damage. This challenges the previously common notion that each brain function has a particular location that is hard-wired from birth and that once damage is done it cannot naturally be repaired.

Cellular regeneration has turned out, Dr. Mallinger said, to be a side effect of at least two drugs that are used to treatment bipolar disorder, Lithium and Valproate (Depakote). Lithium and Valproate are believed to work in very different ways it comes to treating mania, but one thing that Dr. Mallinger said that they have in common is that they both result in cellular regeneration through something called BCL2.

“They don't have much in common,” Dr. Mallinger said of the two drugs. “They are different by the same when it comes to BCL2.”

BCL2 is a prototype for a family of genes and the proteins that they produce. BCL2 can protect parts of the brain from damage and regenerate areas that have been harmed.

In other words, the tissues in the brain that are damaged by mania and depression are repaired by Lithium and Valproate.

At this point, however, Dr. Mallinger said, there is no Food and Drug Administration approved medication to treat depression that also causes cellular regeneration. Dr. Mallinger said there is hope that studies at the National Institutes for Mental Health on Pramipexole (Mirapex), a drug used to treat Parkinson's Disease, will be able to treat depression and create cellular regeneration in the targeted part of the brain. 

Pramipexole is believed to stimulate dopamine like Effexor and Wellbutron and help with BCL2 protection and regeneration.

“It could do for depression what Lithium and Valeprote have done in terms of regeneration,” he said.

The NIMH study involves comparing those taking Pramipexole to those taking Lexpro to those who taking both drugs.

Dr. Mallinger also discussed ongoing NIMH clinical trials into the use of ketamine – the veterinary anesthetic that goes by the street drug name Special K – as a way to quickly pull patients out of depression. At this point, there are few drugs that quickly relieve the symptoms of depression and there is an ongoing need for drugs and other means to address patients who have treatment resistant mood disorders.

-- Jayson Blair, DBSA-Northern Virginia