More applications for a natural acetylcholinesterase inhibitor …

Benefits for cognition, attention, and verbal episodic memory 

However widespread mental disorders are throughout the population, those that are most severe represent the main burden of mental illness. Fortunately, severity of this sort is concentrated in a much smaller segment, just about 6 percent, or 1 in 17. That’s still a lot of people, in excess of 13 million Americans.How common are mental disorders in the United States? The National Comorbidity Survey estimates that no less than 26.2 percent of Americans over the age of 18 suffer from a diagnosable mental disorder in a given year.1 That’s more than 1 out of 4 Americans, as of 5 years ago when the last survey was taken. Configured to the population of 2004, 57.7 million Americans, suffered from a mental disorder.2 Worse yet, trends indicate that the mental illness in the US may be rising.

Did you know that mental disorders are the primary cause of disability in the U.S. for those between the ages of 15–44?3 Compounding the problems, a great many people suffer from multiple mental disorders at the same time (comorbidity). In fact, almost half (45 percent) of those with any mental disorder meet criteria for 2 or more disorders, with severity strongly related to their comorbidity.

Bipolar Disorder: Mania and Depression

One of the most pervasive of all mental morbidities is bipolar disorder. As of 2004, this affliction affected as many as 5.7 million American adults, about 2.6 percent of the U.S. population over the age of 18 in a given year.1 Bipolar disorder strikes early; the median age of onset for bipolar disorders is 25 years.4 Also known as manic depressive disorder, manic depression, or bipolar affective disorder, bipolar disorder is a psychiatric diagnosis describing what amounts to a category of mood disorders.

If a person has experienced one or more episodes of an abnormal elevated mood—clinically referred to as mania or, of less fervor, hypomania—they may be diagnosed asmanic. People subject to manic incidents also frequently experience depressive symptoms, or mixed episodes featuring both mania and depression together. These concatenations of mood swings are often separated by periods of “normal” moods.

However, in some people, depression and mania may rapidly alternate. This is known as rapid cycling. Extreme manic episodes can lead to psychotic symptoms such as delusions and hallucinations. On overview, bipolar disorder is subdivided into bipolar I, bipolar II, cyclothymia, and other types, determined by the nature and severity of the mood episodes. Together the range is described as the bipolar spectrum.

Bipolar Disorder and Cognitive Dysfunction

Many people who are inflicted with bipolar disorder manifest significant cognitive dysfunction. This is true even for those who are euthymic, i.e., normally non-depressed and reasonably positive in their moods. Yet, to date there have been only a few studies that have examined and assessed biological correlates or treatment strategies for memory and cognitive abnormality.

In a new study—conducted at The Bipolar Clinic and Research Program, Massachusetts General Hospital, Harvard Medical School in Boston, Massachusetts—19 subjects with bipolar disorder in remission, reporting subjective cognitive deficits, were treated with open-label time-release galantamine at doses of 8–24 mg/day for 4 months.5 As controls, 10 healthy volunteers matched for age and gender were used. Both groups were initially assessed with neuropsychological tests, including tests of attention and episodic memory. Using proton magnetic resonance spectroscopy measurements before and after treatment, the researchers focused on the left and right hippocampus to measure hippocampal N-acetyl aspartate (NAA is a gauge for neuronal viability) and choline containing compounds (choline is a marker of lipid metabolism and membrane turn-over). Thereafter, each month, mood and subjective evaluations regarding cognitive functioning were given.

Bipolar subjects had higher baseline subjective cognitive deficits and lower scores on objective tests of attention and verbal episodic memory, compared to healthy volunteers. But after treatment, there was significant improvement. Bipolar subjects reported that they had improved cognitive scores and, objectively, on tests of attention and verbal episodic memory they made important progress.

In the left hippocampus, NAA increased, and choline decreased in bipolar subjects during treatment. At baseline, the bipolar disorder subjects had higher choline levels in both left and right hippocampus, compared to healthy volunteers. This compares with a earlier report showing that, in the right hippocampus, levels of NAA increased, while choline levels increased following the ingestion of galantamine (see “Galantamine Improves Hippocampal Cognition” in the December issue). The meaning of this is unclear.

Treatment with galantamine was associated with improved cognition and neuronal viability enhancement and normalization of lipid membrane metabolism in the left hippocampus. These results cry out for placebo-controlled studies with a greater number of subjects to determine galantamine’s efficacy for improving cognitive dysfunction in bipolar disorder and evaluate these positive effects on overall improvement for bipolar disorder triggered by cognition increases.

Galantamine and Complementary Supplementation for Greater Cognition

In another recent study, the metabolism of rats receiving cognition-enhancement supplementation and their associated cognitive behavioral outcomes was investigated.6Using Male Lister Hooded rats* the researchers administered either galantamine or donepezil (both acetylcholinesterase inhibitors, or AChEIs) or placebo, and subjected the furry subjects to water maze training and novel object recognition tests. Then, behavioral changes induced by the test materials were compared with the metabolic fluctuations of neurologically-related metabolites from multiple neurotransmitter pathways.

* Male Lister Hooded rats are a special breed chosen principally because they are more likely to respond to environmental stimuli and easily trained; they are frequently selected for brain development and neurochemistry studies.

The researchers found significant improvements in cognitive behavior demonstrated in both the water maze and novel object recognition tests, compared to those rats given the vehicle placebo. As hypothesized, these results agreed with the elevation of eight prominent biomarkers—acetylcholine, phenylalanine, tyrosine, GABA, succinic acid, tryptophan, serotonin, and 5-HIAA (the main metabolite of serotonin in vivo)—following the cognitive enhancement therapy.

Accordingly, this study demonstrates the validity of metabolic profiling to determine whether galantamine and donepezil are likely to enhance cognition. Because AChEIs are not always effective, applying this strategy to humans could be used “to screen for fluctuations in neurotransmitter levels when brain receptors are challenged with various agonists and antagonists, contributing to lead discovery and optimization.”

If the tail wags the rat, this could mean that by adjusting these biomarkers through supplementation, it might be possible to customize the use of cognitive supplementation, and produce better results. Think individualized supplementation. The tests used in the study demonstrated that galantamine and donepezil are efficacious cognition enhancers for some rats, but with the use of screening and concomitant complementary supplementation, more rats (and humans!) could be cognitively enhanced.


  1. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of twelve-month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Arch Gen Psychiatr 2005 Jun;62(6):617-27.
  2. U.S. Census Bureau Population Estimates by Demographic Characteristics. Table 2: Annual Estimates of the Population by Selected Age Groups and Sex for the United States: April 1, 2000 to July 1, 2004 (NC-EST2004-02) Source: Population Division, U.S. Census Bureau Release Date: June 9, 2005.
  3. The World Health Organization. The World Health Report 2004: Changing History, Annex Table 3: Burden of disease in DALYs by cause, sex, and mortality stratum in WHO regions, estimates for 2002. Geneva: WHO, 2004.
  4. Kessler RC, Berglund PA, Demler O, Jin R, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Arch Gen Psychiatr 2005 Jun;62(6):593-602.
  5. Iosifescu DV, Moore CM, Deckersbach T, Tilley CA, Ostacher MJ, Sachs GS, Nierenberg AA. Galantamine-ER for cognitive dysfunction in bipolar disorder and correlation with hippocampal neuronal viability: a proof-of-concept study. CNS Neurosci Ther 2009 Winter;15(4):309-19.
  6. Goh DP, Neo AH, Goh CW, Aw CC, New LS, Chen WS, Atcha Z, Browne ER, Chan EC. Metabolic profiling of rat brain and cognitive behavioral tasks: potential complementary strategies in preclinical cognition enhancement research. J Proteome Res 2009 Nov 10. [Epub ahead of print]