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People with manic symptoms and bipolar disorder type II are at significant risk of later developing an alcohol abuse or dependence problem, a long-term study conducted in Switzerland confirms. The study was published in the January 2008 issue of the Archives of General Psychiatry.

Extensive research using retrospective reports has demonstrated a clear association between mood disorders and substance abuse. But few prospective long-term studies have been able to show evidence of this.

Kathleen Merikangas, Ph.D., of the NIMH Mood and Anxiety Disorders Program, collaborated with colleagues to follow 591 people (292 men and 299 women) over two decades, beginning in 1978 when the participants were 19 or 20 years old. The participants were interviewed six times between 1979 and 1999.

By 1993, almost 10 percent met criteria for major depression. Although bipolar disorder type I was very rare, 4 percent met criteria for bipolar disorder II—a milder form of the disorder. In addition, 24 percent had symptoms of mania but did not meet specific criteria for bipolar disorder.

By 1999, when participants were about 40 years old, 18 percent met criteria for alcohol abuse or dependence problems, while 8 percent met criteria for cannabis (marijuana) abuse and 3 percent met criteria for benzodiazepine abuse.

Merikangas and colleagues found that people who showed symptoms of mania, but who did not meet criteria for bipolar disorder, were at significantly greater risk for later developing an alcohol abuse or dependence problem. Those with bipolar disorder II were even more at risk of developing an alcohol problem or benzodiazepine abuse problem. Major depression was associated only with developing a benzodiazepine abuse problem among this population.

“The findings confirm the link between mood disorders and substance abuse or dependence problems,” said Dr. Merikangas. “They also suggest that earlier detection of bipolar symptoms could help to prevent consequent substance abuse problems.”

The study was known as the Zurich Cohort Study.

Reference

Merikangas, KR, Herrell R, Swendsen J, Rossler W, Ajdacic-Gross V, Angst J. Specificity of bipolar spectrum conditions in the comorbidity of mood and substance abuse disorders . Archives of General Psychiatry. 2008;65(1): 47-52.

Scientists may be able to develop faster-acting medications for the manic phase of bipolar disorder, new research shows.

Current medications take several days to weeks to work, during which the extreme mood shifts of the disease may cause patients to engage in harmful behaviors, such as risky health behaviors or spending sprees. Bipolar disorder, also called manic-depressive illness, affects about 5.7 million Americans age 18 and older in any given year.

The faster medications would be aimed more directly at a molecular site on brain cells that current medications, such as lithium and valproate, reach through a slower, roundabout route. By targeting the site with a protein fragment they designed, NIMH scientists reduced manic-like behaviors and associated brain changes in rats. Jing Du, Ph.D., Husseini Manji, M.D., and colleagues published their results in the January 2 issue of The Journal of Neuroscience.

With further research, the molecular site could become a target for new medications for humans, or could point the way to other targets for new treatments, the scientists say. The site is an amino acid, serine 845 (S845), in the GluR1 subunit of the AMPA receptor. (See “About the Science.”).

The researchers also pinpointed a region of the brain that appears to be involved in mania: the CA1 region of the hippocampus, which feeds stored memories to the prefrontal cortex, the “active-thinking” part of the brain.

Reference: Du J, Creson TK, Wu L-J, Ren M, Gray NA, Falke C, Wei Y, Wang Y, Blumenthal R, Machado-Vieira R, Yuan P, Chen G, Zhuo M, Manji HK. The Role of Hippocampal GluR1 and GluR2 Receptors in Manic-like Behavior. The Journal of Neuroscience, 2008 28: 68-79; doi:10.1523/JNEUROSCI.3080-07.2008. January 2008.

New research adds to evidence of potentially better molecular targets in the brain to treat depression and other mental disorders, according to NIMH-funded scientists.

The researchers suggest that imbalances in the activity of an enzyme called GSK3ß may be closer to the root cause of mental illnesses than are low serotonin levels. Serotonin, a brain chemical, is the ultimate target of several current medications that work by indirectly increasing it to relieve symptoms. In preliminary findings, the scientists suggest that GSK3ß might be a more fundamental – and thus, perhaps, better and faster – target for new medications.

In the new study, even when serotonin levels stayed low, the scientists were able to correct abnormal, mental-illness-like behaviors in mice by blocking GSK3ß. When activated, GSK3ß plays a crucial role inside brain cells by sending chemical signals that help regulate cell function – but this activity must occur at the right time and in the right amount for the brain to function properly.

To assess the effects of blocking GSK3ß, the scientists measured anxiety- and depression-like behaviors shown earlier to be linked to low serotonin levels in mice. For example, compared to normal mice, those with low serotonin gave up sooner when held back by their tails and were slower to come out of dark hiding places to explore their surroundings.

These abnormal behaviors were reversed when scientists blocked GSK3ß in mice with low levels of serotonin. The scientists blocked the enzyme with either genetic engineering or a chemical compound. Success with both approaches strengthens the case for GSK3ß’s involvement in mental illnesses – and its potential, with further research, as a new target for medications, the researchers say.

Reference

Beaulieu J-M, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, Gainetdinov RR, Caron MG. Role of GSK3ß in behavioral abnormalities induced by serotonin deficiency. Proceedings of the National Academy of Sciences, 105(4):1333-1338. January 29, 2008