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Novel Targets, Novel Meds

© John McManamy

"Basically, the cells can't handle the load."

Husseini Manji MD is the Chief of the Laboratory of Molecular Pathophysiology at the NIMH. In a grand rounds lecture delivered at UCLA Feb 11 this year and webcast the same day, Dr Manji detailed the cutting edge research he and his colleagues are engaged in and what it means for future treatments.

To begin, the brain is a lot more plastic than we once appreciated, which includes structural changes in response to learning, stress, and memory, as well as the neurons making new connections and even regenerating. Unfortunately for many of us, plasticity is synonymous with meltdown, with one classic study by Wayne Drevets MD, Chief of Neuroimaging of Mood and Anxiety Disorders at the NIMH, finding that the subgenual prefrontal cortex of the brain was 38 percent smaller in bipolar patients and 48 percent smaller for those with chronic unipolar depression In experiments by Robert Sapolsky PhD of Stanford, animals subjected to stress resulted in dead or atrophied neurons in the hippocampus, as well as endangered neurons that were more likely to die when subjected to another stressful event.

Stress elevates cortisol, which in turn ups the excitatory neurotransmitter glutamate, which increases calcium influx into the neuron and activates certain calcium-dependent "death" enzymes. Cortisol may also reduce the neuron's capacity to take energy-sustaining glucose into the cell so it doesn't have the strength to deal with a subsequent crisis. Another casualty may be the glia, the "other" brain cell, once thought of as mere mind-glue but now recognized as an active partner of the neuron. One of its functions is thought to be clearing glutamate from the synapse.

Basically, Dr Manji explains, the cells can't handle the load. Their atrophy and death tends to isolate neurons, affecting their ability to connect to and communicate with other neurons. The good news is that some of the meds we are taking may actually prevent and even reverse these processes

With new gene technology, Dr Manji and his colleagues started experimenting with lithium and Depakote on brain cell tissue, and found to their surprise these two completely different medications indirectly affected some of the same cell pathways associated with cell survival and death. One protective protein that utilizes these pathways is Bcl-2, which in one experiment was doubled by lithium and Depakote administration. Subsequent experiments on rats found lithium mitigated the effects of lab-induced stroke and led to the growth of new neurons in the hippocampus. When Dr Manji asked Dr Drevets to revisit his study, it was found that those patients on lithium or Depakote did not show brain atrophy. More recently, a study on human patients with bipolar found lithium increased overall brain grey matter.

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