Alzheimer’s Treatments May Work for Memory Dysfunction in Depression
In a recent BNN article on potential drugs for memory loss, we omitted two conventional classes of drugs used to treat Alzheimer’s Disease—acetylcholine esterase inhibitors (AChE-Is) and the blocker of glutamate NMDA receptors memantine (Namenda). This was intentional, as we hoped to suggest possible approaches prior to the use of these drugs for full-blown dementia. However, we neglected to cite a 1999 study by Fred Jacobsen in the Journal of Clinical Psychiatry that indicated that the AChE-I drug donepezil (Aricept) was effective in improving drug-induced memory dysfunction in patients without dementia. Side effects included insomnia, nausea, vomiting, and diarrhea.
Jacobsen has used AChE-Is to improve memory in over 80 patients with unipolar or bipolar depression, aged 19-85. In a 2016 personal communication to the BNN, he indicated that doses of 5mg/day are typically enough to improve memory. Higher doses of 10mg/day may be more effective, but increase the risk of switching into mania for patients with bipolar depression. Some of Jacobsen’s patients have used AChE-I drugs for 10–15 years without the drugs losing effectiveness. For some patients, Jacobsen has switched from prescribing donezepil to prescribing rivastigmine (Exelon or Exelon patch), which he finds they can more easily tolerate.
We should also remind readers of the BNN of our previous report on memantine (Namenda) for bipolar depressed patients with cognitive impairment. We wrote, “In an abstract presented at the 67th Annual Meeting of the Society of Biological Psychiatry in 2012, Dan V. Iosifescu reported that in a randomized 12-week study in which the anti-Alzheimer’s drug memantine was given to 72 euthymic bipolar subjects experiencing cognitive deficits, the drug was associated with improvement in spatial and working memory, verbal and episodic memory, and other indices that included measurements of attention and language skills. In conjunction with this treatment, a subgroup of subjects had increases in left hippocampal NAA (a measure of neuronal viability) and increases in choline in the right hippocampus. The initial improvements in these neuropsychological test results remained over 12 weeks of open follow-up.”
In an earlier proof-of-concept study published in the journal CNS Neuroscience and Therapeutics in 2009, Iosifescu had also reported that among nineteen subjects with bipolar disorder that was in remission, but who had residual cognitive deficits, open-label treatment with the AChE-I galantamine (extended release) at doses of 8–24 mg/day led to improvement in those cognitive symptoms after 4 months.
Drug Reduces Agitation in Patients with Alzheimer’s
Agitation is common among people with Alzheimer’s dementia. A 2015 phase 2 clinical trial by Jeffrey L. Cummings and colleagues, which was published in the journal JAMA, found that a combination of the drugs dextromethorphan hydrobromide and quinidine sulfate called Nuedexta reduced agitation significantly compared to placebo in patients with probable Alzheimer’s disease over a period of 10 weeks. Dextromethorphan-quinidine was dosed at 20mg/10mg in the morning for one week, then twice daily in weeks 2 and 3, then increased to 30mg/10mg twice daily for weeks 4 and 5. Side effects included falls, diarrhea, and urinary tract infections. Dextromethorphan-quinidine did not cause cognitive impairment, sedation, or irregularities in heart rate.
Changes in Sense of Humor May Be Warning Sign of Dementia
A change in a person’s sense of humor could be an early indicator of dementia, according to a 2015 article by Jason Warren and colleagues in the Journal of Alzheimer’s Disease. The changes can appear as early as 10 years before a diagnosis of dementia. Almost all participants who would go on to be diagnosed with frontotemporal dementia showed an increased preference for slapstick humor over satirical or absurdist compared with those who would not. In contrast, changes in sense of humor appeared in less than half of those who would go on to be diagnosed with Alzheimer’s disease, indicating that changes in sense of humor may allow doctors to distinguish between different types of dementia.
The study has some limitations. It was small (48 patients) and relied on patients’ memory of what kind of humor they enjoyed 15 years earlier. More research is needed to clarify the link between changes in humor preferences and dementia.
Warren suggests that changes in humor appear before other warning signs of dementia, such as memory loss. He called humor a type of “stress test” for the brain, since getting a joke can require a quick shift in perspective.
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.
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.
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
Anti-Alzheimers’s Drug Memantine (Namenda) May Augment the Antidepressant Effects of Lamotrigine
At the 65th Annual Scientific Convention of the Society of Biological Psychiatry in May, Amit Anand reported that the anti-Alzheimer’s drug memantine (20 mg/day) was superior to placebo in augmenting the acute antidepressant effects of lamotrigine. These data are of particular interest since one of the assumed mechanisms of action of lamotrigine is to decrease the release of glutamate.
Memantine is a drug approved for the treatment of Alzheimer’s disease and is a partial antagonist (blocker) of glutamate NMDA receptors. This suggests that the dual actions of inhibiting glutamate’s release pre-synaptically (with lamotrigine) and blocking glutamate receptor activity post-synaptically (with memantine) combine to produce a better effect than that of lamotrigine alone.
Dual Drug Treatment for Alzheimer’s
The two main classes of drugs for the treatment of Alzheimer’s disease currently include cholinesterase inhibitors, which increase brain acetylcholine levels, and memantine (Namenda), which is a partial blocker of glutamate receptors. Treating patients with both types of drugs in combination may help their cognitive functioning.
The brains of patients with Alzheimer’s are deficient in acetylcholine. Acetylcholinesterase breaks down acetylcholine, so the first class of Alzheimer’s drugs inhibits these esterases and makes more acetylcholine available.
Memantine works a different way. Glutamate is the major excitatory neurotransmitter in the brain. Excesses of glutamate may be toxic to cells, so memantine’s ability to partially block glutamate receptors may explain the drug’s effectiveness in Alzheimer’s.
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