In a recent paper published in the journal Science Translational Medicine, Yvette Sheline and colleagues reported that a typical SSRI-type antidepressant, citalopram, decreases the formation of beta amyloid, a substance that is critically involved in Alzheimer disease. This result has potentially important implications for efforts aimed at preventing the onset of clinical Alzheimer disease.
Let’s start with a brief review: Two substances have been found to accumulate abnormally in the brains of persons with Alzheimer disease. One substance is called beta amyloid, and the other is hyperphosphorylated tau (this means that the tau protein has an excessive amount of phosphate groups attached to it). Recent research has shown that beta amyloid begins to accumulate in human brain about 20 years before ANY clinical symptoms of Alzheimer disease become apparent. Tau starts to accumulate in the brain 5 to 10 years prior to symptoms. Accumulation of both of these substances is bad for the brain; the exact role each plays in symptom development is under active investigation.
Many of the current strategies to prevent or treat Alzheimer disease currently under investigation involve decreasing the accumulation of beta amyloid. For example, several major studies are now examining the effect of an antibody that attacks amyloid and lowers brain amyloid levels.
An important tool in Alzheimer disease research is the ability to generate transgenic mice that exhibit brain changes observed in the human disease. These mice have mutations in genes that are associated with Alzheimer disease in humans, and they demonstrate diminished cognitive abilities as they age. While it remains an open question how well these mouse models mimic the human disorder, the ability to study these models has led to important insights into how amyloid is processed and dysregulated in the brain.
The study by Sheline and colleagues is unique in examining the effects of SSRI antidepressants on beta-amyloid levels in mice and humans. SSRIs, including citalopram, are thought to exert their antidepressant effects by inhibiting the re-uptake of the neurotransmitter serotonin into presynaptic cells, thus increasing the amount of serotonin available to postsynaptic serotonin receptors. Previous research has demonstrated that serotonin signaling may lower beta amyloid levels.
In the current study, Sheline and colleagues showed that citalopram decreased amyloid production by over 75 percent in a mouse model of Alzheimer disease. Interestingly, citalopram did not eliminate amyloid already present in the brain; rather, it strongly decreased the production of new amyloid.
So, does citalopram affect amyloid production in humans? Recently developed techniques allow researchers to measure the brain’s production of amyloid in humans. Sheline’s group used these techniques to determine whether citalopram-altered beta amyloid production in healthy 21- to 50-year old volunteers. The volunteers were given either 60 mg of citalopram (administered orally in two 30 mg doses, two hours apart) or a placebo. The usual daily dose of citalopram in treating depression is 20 to 40 mg per day. The somewhat higher dose in this study was based on information obtained from the mouse studies.
Citalopram led to about a 38 percent drop in the production of beta amyloid in humans when compared to the placebo-treated group. This degree of reduction, if maintained over time, may be clinically relevant. Interestingly, the effects of citalopram on amyloid production occurred within hours of administration in contrast to the antidepressant effects of citalopram that require weeks of treatment.
It isn’t yet known whether decreased production of beta amyloid slows down the development of Alzheimer disease in humans. Ongoing trials using antibodies are designed to examine the effects of decreasing amyloid levels during the 5- to 10-year period prior to the appearance of predicted clinical symptoms.
The results from this paper are important because they suggest that a commonly used medication may decrease beta amyloid levels. Whether this effect of citalopram would be maintained with chronic dosing and, if so, whether this would delay the onset of Alzheimer disease awaits further clinical research. It would be amazing if a common and inexpensive medication used to treat persons with depression and anxiety could also delay the onset of Alzheimer disease.
This column was written by Eugene Rubin MD, PhD and Charles Zorumski MD.