CABF: Speaking of lithium, your research has uncovered some of its intriguing beneficial properties. Can you highlight the most important ones?
MANJI: Many of the genes that are considered neuroprotective [keep brain cells from dying when stressed] are being remarkably turned on by lithium. Is lithium actually neuroprotective? We hadn't thought this way before. A number of studies have taken animal cells and tried to kill them by causing stroke, etc. These studies have consistently shown that lithium, if administered before you try to do the bad things (such as induce a stroke), protects the animal's neurons. In lithium-treated brains, the size of the resulting stroke is smaller, the number of neurons that die is lower, etc. That was amazing. Since these studies were done in rats, you need to be careful about jumping to conclusions that lithium is neuroprotective in people.
Wayne Drevets' group published a finding in Nature about five years ago that in a part of the pre-frontal cortex of bipolar patients or patients with familial recurring unipolar depression, there was almost a 40% reduction in the amount of gray matter. That was a remarkable finding that you have such a reduction in a discrete part of brain. We spoke to him about our lithium findings and asked him to reanalyze the data. He had a small group of patients who had been treated with lithium for a long time and they did not show the brain atrophy compared with the bipolar patients. Interestingly all of the patients with unipolar depression, whether or not they had been treated with antidepressants, still showed the atrophy. That was a suggestion that bipolar treatments might have a protective effect.
We did some studies taking bipolar patients off their meds -- they were referred to us because their treatments weren't working. In every case, they either hadn't been on lithium or had been on lithium sparingly -- had started on it, had side effects, switched, and the new med was not working. These are bipolar depressed patients. We did MRI scans and MRS spectroscopy and then put them on lithium in a blinded fashion for 4-6 weeks. Then we did the scans again. We found that almost every single person taking lithium had an increase in N-acetylaspartic acid (NAA) [an amino acid that is viewed as a marker of neuronal health]. And the actual amount of gray matter was going up when they were treated chronically with lithium. This study was done together with Dr. Greg Moore¹. This was happening in areas of the patients' brains that had been atrophied. The increase was not due to swelling from water retention. The increase was seen only in areas where the brain matter had previously atrophied.
Our working hypothesis, and I think it is reasonable, is that lithium is turning on some of these growth signaling pathways and reversing the damage. It seems that the cells are shrunken, not dead, and are capable of going back to their normal sizes and sending normal projections. What lithium seems to be doing is turning on the signaling pathways that produce growth factors in the brain, such as brain-derived neurotrophic factor (BDNF), and where you have atrophy, turning on this pathway seems to be capable of reversing it. And that is a remarkable finding.
A couple of other studies since then have compared lithium-treated patients with untreated patients. They showed that the lithium-treated patients have the increase in gray matter, suggesting that lithium is causing the increase. If that is the case, lithium has a neurotrophic [nourishing to neurons] effect. Would lithium, then, be beneficial in any bipolar patient, even if he or she can't tolerate it or if his or her symptoms respond better to another mood stabilizer? One question is tolerability. We've done a number of animal studies with low-dose lithium. We found that in animals, with a dose of lithium that is one-half or one-third of a usual dose, you still get a large increase in bcl-2, a neuroprotective protein. This suggests that it is quite possible that even low-dose lithium will exert these effects. Many studies are being planned using low-dose lithium as an additional agent in patients being treated with something else. We will add low-dose lithium and follow them for 2-3 years with repeated MRIs and neuropsych testing to see if the addition would be enough to provide neuroprotective effects that would help them long-term with the illness, even if something else is their appropriate treatment for symptoms. That is extremely important. It is a devastating long-term illness, and brain atrophy may be responsible for that. If we can intervene early on and prevent that, there is reason to believe you will have a big impact on the overall course of the illness.