Lamotrigine normalizes NAA in bipolar depression

N-acetylaspartate (NAA) is the second most abundant neurometabolite in the human brain. It is localized primarily in neurons where it may serve as an acetate donor for myelin synthesis, maintain brain fluid balance and regulate glutamate (Glu) metabolism. NAA is readily detected by proton magnetic resonance spectroscopy (MRS) and is increasingly used as a marker for mitochondrial activity and neuronal integrity in many disorders, including Alzheimer's disease.

Paul E. Croarkin, D.O., M.S., and colleagues in the Depression Center at Mayo Clinic's campus in Rochester, Minnesota, hypothesized that patients with bipolar depression have reduced levels of NAA and that therapy with lamotrigine — an anticonvulsant shown to be neuroprotective against Glu excitotoxicity in cellular and animal models — would increase those levels.

To test their theory, the investigators enrolled 15 patients with bipolar depression and nine healthy controls who were similar in age and sex in an exploratory study. All underwent a baseline 2-D MRS scan, and 10 had a second scan after 12 weeks of open-label treatment with lamotrigine. Five patients dropped out of the study before the second scan.

At baseline, patients with bipolar depression had significantly lower levels of NAA (P = 0.02) and total NAA (P = 0.06) than did the healthy controls. But after 12 weeks of lamotrigine treatment, patients with bipolar depression experienced significant increases in NAA (P = 0.01) and total NAA (P = 0.02). Although no differences in Glu or Glu plus glutamine levels were seen in either group at baseline, they were elevated in participants with bipolar disorder post-treatment.

Of the 10 patients with bipolar disorder who completed treatment, five achieved remission with lamotrigine. Dr. Croarkin stresses that no relation was seen between clinical remission and NAA levels, which increased overall.

Nonetheless, this study, which was published in 2015 in Bipolar Disorders, is the first to show that lamotrigine can normalize an NAA deficit in bipolar depression. It also corroborates animal and preclinical models of lamotrigine-associated neuroprotection. Dr. Croarkin says two mechanisms of action may be at work: Increased NAA levels might be mediated through activating aspartate N-acetyltransferase, which promotes NAA synthesis, or they may be associated with a reduction in Glu levels. Other studies have demonstrated increased NAA with lithium therapy and glutamate modulators such as riluzole.

Dr. Croarkin acknowledges that the study's small sample size makes it impossible to determine a relationship between the clinical effects of lamotrigine and changes in NAA.

"For our present results, this was a brain change only and did not correlate with symptom improvement," he says. "We suspect with larger sample sizes a correlation with mood improvement may be evident and so we are pursuing larger studies. MRS measures of NAA are relatively easy to obtain, so perhaps in the future this knowledge could assist clinicians. For example, patients with lower than expected NAA may be better candidates for a drug such as lamotrigine."

For more information

Croarkin PE, et al. N-acetylaspartate normalization in bipolar depression after lamotrigine treatment. Bipolar Disorders. 2015;17:450.