Lithium May Slow or Prevent Dementia
Lithium inhibits the enzyme glycogen synthase kinase 3, which has been implicated in dementia. To study whether lithium may prevent cognitive decline, researchers led by Tobias Gerhard looked at the medication histories of patients with bipolar disorder who were 50 years of age or older. In their article published in the British Journal of Psychiatry, those patients who had taken lithium 301–365 days out of the previous year had substantially lower risk of dementia than those who had not taken lithium during that time. Patients who had 300 or fewer days of lithium use did not have a significant reduction in dementia risk, nor did patients who were prescribed anticonvulsant drugs.
Editor’s Note: These data are consistent with those of Lars Kessing and colleagues, which suggest that patients in Denmark who renewed their lithium prescriptions were less likely to receive a diagnosis of dementia in old age.
In 2011, Orestes V. Forlenza and colleagues also reported in the British Journal of Psychiatry that compared to placebo, a very small dose of lithium, 150 mg/day, slowed the progression of mild cognitive impairment over one year.
Cynicism Linked to Dementia
A decades-long study called Cardiovascular Risk Factors, Aging and Dementia (CAIDE) observed older participants for signs of dementia, and collected data on participants’ levels of cynical distrust, for example, the belief that others will lie or cheat for personal gain and that it’s safer not to trust anyone.
A 2014 study by Elisa Neuvonen et al. in the journal Neurology reported that after adjusting for demographic and other factors, those participants with the highest levels of cynical distrust of others were at higher risk for dementia as they aged. This relationship was not explained by depressive symptoms. The authors suggest that a positive attitude may protect the brain.
The researchers acknowledge that it is possible the distrust may be a result of brain changes leading to dementia, rather than the cause of it.
Those with the highest levels of cynical distrust were also at higher risk for death, but this association disappeared when the researchers controlled for socioeconomic factors and health behaviors such as smoking.
The researchers hope to investigate whether having a cynical attitude early in life is more robustly linked to mortality. It would be exciting to determine whether a shift to a more positive attitude earlier in life could prevent dementia.
Editor’s Note: A high level of chronic anger is associated with shorter telomeres. Telomeres sit at the end of DNA strands and shorten with each cell replication. Shorter telomeres are linked to multiple medical and psychiatric disorders. It may be that cynical distrust shortens telomeres, and is thus associated with dementia.
Citicoline Might Improve Memory
We’ve written before that the dietary supplement citicoline improved depression in both unipolar and bipolar patients with methamphetamine dependence, reduced cocaine use in bipolar depressed patients with cocaine dependence, and improved cognition in healthy middle-aged women. Findings from a 2013 Italian study by Gareri et al. published in Clinical Interventions in Aging suggests that citicoline improves mild vascular cognitive impairment in older adults, though the study was not randomized, so its results may not be reliable. Citicoline is a natural substance found in the brain and the liver that can also be taken as a nutritional supplement.
The study examined 349 patients over age 64 (mean age 79.9) who had memory impairment and evidence of vascular lesions in the brain (but not Alzheimer’s disease). Participants who received citicoline (500mg twice daily for 9 months) scored better on a memory examination at 3 months and at the completion of the study, while participants who did not receive citicoline performed worse on the exam. Those who received citicoline also saw some statistically non-significant improvement in mood.
The researchers believe that citicoline’s effects may also extend to Alzheimer’s dementia because citicoline contributes to the synthesis of acetylcholine. (Most Alzheimer’s drugs inhibit the breakdown of acetylcholine).
Side effects were minimal, and included occasional excitability or restlessness, digestive intolerance, and headaches.
Statin Benefits for Mood, Brain, and Heart Seem to Outweigh Diabetes Risk
Statins are a class of drugs that are the most commonly prescribed treatment for high cholesterol. They can reduce risk of heart attack and stroke in people with a history of cardiovascular disease. New research is beginning to clarify statins’ other effects, which on the negative side can include increased risk of diabetes and liver and muscle inflammation, and on the positive side can include reduced risk of cataracts and prevention of depression and dementia.
In late 2012, the American Heart Association Scientific Sessions included a discussion of five new studies suggesting that the cardiovascular benefit of taking statins is worth the slightly increased risk of diabetes. Researchers at the conference explained that cardiovascular events are much more serious than the small increase in risk of diabetes. While all five studies showed an increase in diabetes risk, the absolute increase was low and depended on the patients’ level of risk prior to treatment and how high their doses of statins were. There are strategies that can reduce diabetes risk in statins users, including using bile-acid sequestrants, reducing niacin, and monitoring glucose. Consensus at the conference was that statins’ cardiovascular benefits are so important that the drugs shouldn’t be avoided because of concerns about diabetes.
In addition, statins’ beneficial effects on mood have been reported for several years. In 2010, an epidemiological study by Pasco et al. in Psychotherapy and Psychosomatics showed that subjects without depression were less likely to develop a new onset of depression if they were treated with statins compared to those who were not. Stafford et al. reported in the Journal of Clinical Psychiatry in 2010 that patients taking statins had a 79% decreased likelihood of depression at 9 months of follow-up. Moreover, a 2012 meta-analysis by O’Neil et al. in BMC Medicine reported that overall, statins had positive effects on mood.
A recent huge Taiwanese study of statins suggests that the drugs can also prevent dementia. At the European Society of Cardiology congress in 2013, Tin-Tse Lin reported that among 58,000 people studied, those taking the highest dosage of statins had a threefold decrease in risk of developing pre-senile and senile dementia. He explained that it was the potency of statins such as atorvastatin and rosuvastatin that provided the cognitive benefit. However it is high doses that lead to less benign side effects such as liver and muscle inflammation.
A separate US study presented at the congress showed that statin use also lowered risk of developing cataracts by 19%.
Higher Levels of Caffeine in Blood May Be Associated With Lower Likelihood of Dementia
Alzheimer’s disease and other kinds of dementia can be devastating. Researchers are looking for treatments and lifestyle choices that may prevent, slow, or lessen the likelihood of serious dementia. Some epidemiological research in humans and other studies of animals has suggested that consumption of coffee or caffeine may help protect against the development of Alzheimer’s disease. A 2012 study by Arendash et al. published in the Journal of Alzheimer’s Disease sought to clarify the connection between coffee and cognitive status. The researchers also collected data on biomarkers in blood.
In patients with mild cognitive impairment, those patients whose blood levels of caffeine were 1200 ng/mL or higher (an amount that would result from drinking 3–5 cups of coffee daily) did not develop dementia during the following two to four years, while half of those whose blood levels of caffeine were below this threshold did. Moreover, those patients who had mild cognitive impairment at the beginning of the study had lower levels of caffeine than those who had normal cognitive functioning at that time.
Patients with mild cognitive impairment who later developed dementia had low levels of three biomarkers in their blood—the neurotrophic factor granulocyte colony-stimulating factor (G-CSF), the anti-inflammatory cytokine IL-10, and the pro-inflammatory cytokine IL-6. This suggests that low levels of these biomarkers may be an indicator of impending Alzheimer’s disease. G-CSF, in particular, has shown beneficial effects on cognition in mice.
Since half of patients with lower levels of caffeine did not develop dementia, it is clear that caffeine is far from being the only factor that could affect cognitive functioning. Arendash suggested that other factors may include levels of cognitive and physical activity, hypertension (high blood pressure), and antioxidant intake, especially from fruits and vegetables.
Editor’s Note: This study of caffeine was not randomized and is subject to other interpretations. For example, people who drink less coffee may have more hypertension, which is associated with dementia risk. However, the study does raise the possibility that caffeine could have positive effects on the brain (especially if it does not make a patient anxious or insomniac).
The caffeine findings are also supported by studies of dementia in mice. Long-term administration of caffeine to these animals resulted in a similar biomarker profile and prevented cognitive impairment.
Other treatments may also be useful in preventing cognitive decline. In BNN Volume 16, Issue 5 from 2012, we wrote about a one-year prospective study published by Forlenza et al. in the British Journal of Psychiatry in 2011 that showed that lithium at the small dose of 150mg per day reduced the rate of cognitive decline in those with mild cognitive impairment compared to placebo.
Immune Therapy Studied in Alzheimer’s Disease Fails
Following some research that inflammatory changes occur in patients with Alzheimer’s disease, immunotherapy with intravenous immunoglobin (IVIG), a treatment typically used to treat autoimmune diseases and neurological problems, was investigated in Alzheimer’s. The treatment consists of a mix of antibodies derived from the blood plasma of thousands of young, healthy blood donors, which are then delivered in a slow intravenous infusion. IVIG not only includes antibodies to particular proteins implicated in Alzheimer’s disease, but it also has general anti-inflammatory effects.
A particular dosage of IVIG (0.4g/kg every two weeks) seemed to completely stop progression of Alzheimer’s in the four patients who received it consistently for three years as part of a small open study. (Twenty other patients received other doses of IVIG or received placebo for part of the time, and the cognitive functioning of these patients deteriorated.) However, a large, double-blind, randomized study of IVIG did not show that the treatment had greater efficacy than placebo.
A Daily Small Dose Of Lithium May Prevent Progression of Mild Cognitive Impairment
A very small dose of lithium, 150 mg/day, has been reported to lessen the progression of mild cognitive impairment over a period of one year compared to placebo. In a 2011 article by Orestes Forlenza and colleagues published in the British Journal of Psychiatry, the researchers reported the findings from their prospective randomized study of lithium versus placebo in 45 patients.
Editor’s Note: While these findings must still be replicated, there are several reasons to suggest that they may be reliable and valid. Read more
Dopamine D2 and D3 Agonist Pramipexole May Enhance Cognitive Function in Bipolar I Disorder
Anil Malhotra from the Zucker Hillside Hospital found that pramipexole (Mirapex), a dopamine D2 and D3 agonist used in the treatment of Parkinson’s disease, improved measures of processing speed and working memory in euthymic bipolar patients (whose average age was 42) when compared with placebo in an adjunctive clinical trial.
Editor’s Note: Bipolar patients in a euthymic phase have consistently been shown to have some degree of cognitive dysfunction that is typically correlated with the number of prior depressive and/or manic episodes they have experienced. This is one of the first studies to directly target this cognitive dysfunction with a pharmacotherapeutic agent.
Pramipexole may be of additional value among depressed patients, because in two small, placebo-controlled studies, one led by Carlos Zarate at the National Institute of Mental Health and one led by Joseph F. Goldberg in New York, pramipexole has been shown to exert acute antidepressant effects in bipolar patients in the depressive phase of the illness. The new data from Malhotra raise the possibility that there could be a two-for-one benefit when pramipexole is used in the depressive phase of bipolar illness—improvement in both depression and cognition.
Other approaches to improving cognition in patients with bipolar disorder
Inflammation and Oxidative Stress in Bipolar Disorder
A number of studies presented at the 4th Biennial Conference of the International Society for Bipolar Disorders conference in Sao Paulo, Brazil in March reported new data relevant to inflammation and oxidative stress. Both inflammation and oxidative stress increase risk of cardiovascular disorders, and patients with inadequately treated mood disorders lose 10 or more years of life expectancy from cardiovascular disorders compared to the general population. Inflammation and oxidative stress may also contribute to the symptoms, evolution, and progression of the mood disorders themselves.
It is possible that these two processes could become new targets for therapeutic intervention in addition to more traditional psychopharmacological drugs that primarily target the neurotransmitters dopamine, norepinephrine, serotonin, and the neurotrophic factor BDNF. Read more
