Tag: antidepressants

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Why Antidepressants Take Weeks to Provide Relief

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A healthy neuron.
A healthy neuron. Credit: NIH

The findings of a study published in Science Translational Medicine paint a new picture of how current antidepressant drugs work and suggest a new drug target in depression. As with most drugs, antidepressants were developed through trial and observation. Some 40% of patients with the disorder don’t respond adequately to the drugs, and when they do work, antidepressants take weeks to provide relief. Why this is has remained largely a mystery.

To figure out why these drugs have a delayed onset, the team examined a mouse model of chronic stress that leads to changes in behaviours controlled by the hippocampus. The hippocampus is vulnerable to stress and atrophies in people with major depression or schizophrenia. Mice exposed to chronic stress show cognitive deficits, a hallmark of impaired hippocampal function.

“Cognitive impairment is a key feature of major depressive disorder, and patients often report that difficulties at school and work are some of the most challenging parts of living with depression. Our ability to model cognitive impairment in lab mice gives us the chance to try and understand how to treat these kinds of symptoms,” said Professor Dane Chetkovich, MD, PhD, who led the study.

The study focussed on an ion transporter channel in nerve cell membranes known as the HCN channel. Previous work has shown HCN channels have a role in depression and separately to have a role in regulation of cognition. According to the authors, this was the first study to explicitly link the two observations.

Examination of postmortem hippocampal samples led the team to establish that HCN channels are more highly expressed in people with depression. HCN channel activity is modulated by a small signaling molecule called cAMP, which is increased by antidepressants. The team used protein receptor engineering to increase cAMP signaling in mice and establish in detail the effects this has on hippocampal HCN channel activity and, through that connection, on cognition.

Turning up cAMP was found to initially increase HCN channel activity, limit the intended effects of antidepressants and negatively impact cognition (as measured in standard lab tests).

However, a total reversal took place over a period of some weeks. Previous work by the researchers had established that an auxiliary subunit of the HCN channel, TRIP8b, is essential for the channel’s role in regulating animal behaviour. The new study shows that, over weeks, a sustained increase in cAMP starts to interfere with TRIP8b’s ability to bind to the HCN channel, thereby quieting the channel and restoring cognitive abilities.

“This leaves us with acute and chronic changes in cAMP, of the sort seen in antidepressant drug therapy, seen here for the first time to be regulating the HCN channel in the hippocampus in two distinct ways, with opposing effects on behaviour,” Prof Chetkovich said. “This appears to carry promising implications for new drug development, and targeting TRIP8b’s role in the hippocampus more directly could help to more quickly address cognitive deficits related to chronic stress and depression.”

Source: Vanderbilt University

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Can Prozac be Used to Treat Macular Degeneration?

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Source: Unsplash

The antidepressant fluoxetine, best known as Prozac, could offer the first treatment for the leading cause of blindness among people over 50, new research from the University of Virginia School of Medicine suggests.

Researchers have found early evidence that the drug fluoxetine may be effective against atrophic (or ‘dry’) age-related macular degeneration, a condition that affects nearly 200 million people worldwide. An analysis based on bench research, mouse models and huge insurance databases concluded that patients taking fluoxetine were less likely to develop atrophic macular degeneration (AMD).

On the strength of their findings, which were published in PNAS, the researchers are urging the investigation of fluoxetine to treat AMD, possibly as an oral pill or slow-release implant in the eye.

“These findings are an exciting example of the promise of drug repurposing, using existing medicines in new and unexpected ways,” said Bradley D. Gelfand, PhD, of UVA’s Center for Advanced Vision Science. “Ultimately, the best way to test whether fluoxetine benefits macular degeneration is to run a prospective clinical trial.”

The researchers believe fluoxetine works by binding with an inflammasome, NLRP3-ASC, which triggers the breakdown of the pigmented layer of the eye’s retina.

After conducting extensive bench research, Dr Gelfand and his team tested fluoxetine and eight other depression drugs in lab mice. Fluoxetine slowed the progression of the disease, but the others did not, the scientists found.

Encouraged by their findings, the researchers looked at fluoxetine use among patients aged over 50 in two enormous insurance databases with over 100 million records. They found that people taking the drug had a “significantly” slower rate of developing dry AMD.

Their approach, which combines bench research with big-data analysis, could lead to faster repurposing of existing drugs.

“Traditional approaches to drug development can be expensive and time-consuming: On average, a new FDA-approved drug takes 10–12 years and costs $2.8 billion (present-day dollars) to develop,” the researchers wrote. “Our identification of the unrecognised therapeutic activity of an existing FDA-approved drug using big data mining, coupled with demonstrating its efficacy in a disease-relevant model, could greatly accelerate and reduce the cost of drug development.”

Dr Gelfand was involved earlier this year in using a similar approach to determine that HIV drugs known as nucleoside reverse transcriptase inhibitors, or NRTIs, may be useful against dry macular degeneration as well.

“While we have had a great deal of success with the approach of using real-world patient data, we may have only begun to scratch the surface of finding new uses for old drugs,” said Dr Gelfand, of UVA’s departments of ophthalmology and biomedical engineering. “It is tempting to think about all the untapped therapeutic potential of medicines sitting on pharmacy shelves.”

Source: University of Virginia