Lithium Builds Gray Matter in Bipolar Brains

Lithium has been the mainstay therapy in the management of bipolar disorder for more than 50 years, but until recently, little has been known about the drug’s mechanism of therapeutic action. With the use of a novel imaging technique that enables mapping of the entire surface of the brain, researchers at University of California, Los Angeles, and other institutions have demonstrated that lithium increases the density of gray matter in the brains of patients with bipolar disorder. The findings offer clues to understanding the mechanism of action for lithium’s highly effective therapeutic benefits in bipolar disorder and may have important implications for current clinical practice and future drug discovery.

In the study, the investigators compared brain maps for 28 adults with bipolar disorder—20 of whom were receiving lithium—with the brain maps of 28 controls. The researchers found that compared to the control group, bipolar patients had significantly greater gray matter density in diffused cortical regions. The greatest differences were seen in bilateral cingulate and paralimbic cortices—regions of the brain critical for attentional, motivational, and emotional modulation—which are functions that can be profoundly affected in bipolar illness.

Upon further analysis, however, it became clear that the increase in gray matter density observed in the bipolar group was entirely attributable to the patients who were receiving lithium. Furthermore, in the regions of the brain where differences were found to be significant, the gray matter density in patients treated with lithium were as much as 15% higher—a “striking” increase, according to the investigators.

Such findings were made possible by a novel method of three-dimensional MRI and computational image analysis. This technique allowed the researchers a first-time look at regions of the brain that may be affected by lithium treatment. Previous in vivo neuroimaging studies that involved relatively crude or region-specific volumetric measures have been inconclusive regarding the neuroprotective effects of lithium.

Although this new trial was a naturalistic study and therefore not designed to specifically examine the effects of lithium treatment, the results do raise important questions about duration of therapy and interaction with patient demographic factors. The same research group is currently conducting a controlled longitudinal study that is designed to specifically address the effects of lithium treatment.

As for the present study, which will be published in the July Biological Psychiatry, the findings shed light on neuroanatomical differences between healthy individuals and bipolar patients with and without lithium treatment, said lead author Carrie E. Bearden, PhD, of UCLA.

“The fact that medication and lithium treatment in particular … can increase gray matter volume is a really important finding because it has been shown in animal studies, in rodents, that lithium may have neurotrophic properties,” she said. “In other words, it actually can grow new neurons, which is a really fascinating thing … and [our findings] suggest that what people have found before in rodents may be going on in humans. And this is the first time we’ve been able to visualize exactly which regions of the brain may be affected by this type of medication.”

Dr. Bearden emphasized that she and her colleagues were surprised by the differences in gray matter density detected in certain regions of the brain. “In the anterior cingulate and in paralimbic cortices … we saw increases of 15% in the lithium-treated patients,” she said. “That’s pretty substantial.… We were all really surprised that we saw an increase that was that dramatic.”

Another finding was the emergence of an inverted U-shaped curve depicting the relationship between duration of lithium usage and mean cortical gray matter density. Patients in the middle of the range (about 10 to 100 weeks) had higher gray matter density than those at either end of the range.

Although Dr. Bearden ascribed the slight decrease in gray matter seen with long-term therapy to the advanced age of these patients, she did not rule out other factors. However, she does not view the results as providing any kind of rationale for discontinuation of lithium therapy.

“It’s not really clear how much these findings relate to variability in treatment response,” she said. “Are the people who get better fastest the ones who have the greatest or the most rapid increase in gray matter? And do those people get better cognitively? That’s something I wish I could answer now…. Those are all questions we’re looking at.

“From a clinical perspective, I don’t think any psychiatrist should advise discontinuing medication because of these findings…. When people discontinue their medication, they [often] have a relapse in symptoms. I don’t think these findings argue for doing anything different clinically, but they do provide some clues as to why lithium may be having the therapeutic effects that it does have.”

Dr. Bearden pointed to the coincidence that both lithium and anticonvulsant agents were discovered to be effective in treating bipolar disorder through serendipity. “The fact that all these drugs have been discovered accidentally is kind of unfortunate,” she observed. “It suggests that if we knew more about why these drugs worked, we would be able to develop more effective medications that don’t have the negative side effects.”          

—Fred Balzac

Suggested Reading
Bearden CE, Thompson PM, Dalwani M, et al. Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biol Psychiatry. 2007. Jan 18 [Epub ahead of print].

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