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New antidepressants would be of interest to most of us. Well, here’s a paper from Denmark that looks at new antidepressants that aren’t even antidepressants. This is fascinating, and I particularly admire the principal investigator here, Lars Kessing, because he’s done this before. He and his team just come up with a question, and then turned to the Danish Medical Registry—the entire country, all the population is there in this medical registry. So, they can ask epidemiologic questions very directly and relatively easily compared to epidemiologic studies in the United States, for example. And here, they’ve done it again. Interestingly, the question was: Are there compounds that people might take that lower the likelihood they will develop major depression? And there were some tantalizing compounds that Kessing and his team had recognized might have this property. They studied this by looking at the National Registry.
Just so you stay with me on this remarkable tour, all of the medications that I’m going to name were associated with a lower risk of getting depression. They are allopurinol, aspirin, angiotensin agents, compounds that affect the mechanism of action of angiotensin, and nonsteroidal anti-inflammatories. All of them were associated with a lower risk of developing depression. Again, we’re looking at this in this decent statistical fashion. But what they found is that, sure enough, people who were taking these medications did not get a new diagnosis of depression as often as those who weren’t taking such medications.
Now, the problem with an approach like this has been called confounding by indication. Maybe people who take medications like low-dose aspirin are just more health conscious, so they’re healthier and less vulnerable to depression. Or maybe, if they’re conscientious about managing their gout proactively (there’s an implication that allopurinol lowers the risk of developing depression), what you’re really looking at is someone who’s conscientious about managing his or her health.
To avoid this risk, Kessing and colleagues gathered data on periods of time when the same people were not taking these medications. The outcome of interest was incident depression, new cases after the study medications—that would be allopurinol, aspirin, nonsteroidals, and angiotensin agents—were instituted. And sure enough, the rate then in that phase for those patients was lower than in the general population. So, the point is, Kessing and colleagues are using an available database to just explore hypotheses. It’s a way to get some insight here without having to mount a randomized trial. It’s pointing our attention toward compounds that had already been examined in case-control work or where there’s some indication that it’s worth looking at.
What we have then, in summary, is striking results that raise interesting questions about a purine pathway in depression, some sort of connection between angiotensin enzyme polymorphisms that had previously been examined, and serotonin and dopamine transmission. Sure enough, that is supported by this study. And there is more support for anti-inflammatories as potentially having antidepressant properties.
Abstract
New Drug Candidates for Depression – A Nationwide Population-Based Study
L.V. Kessing, H. C. Rytgaard, T. A. Gerds, M. Berk, C. T. Ekstrøm, P. K. Andersen
Objective: To investigate whether continued use of non‐aspirin NSAID, low‐dose aspirin, high‐dose aspirin, statins, allopurinol and angiotensin agents decreases the rate of incident depression using Danish nationwide population‐based registers.
Methods: All persons in Denmark who purchased the exposure medications of interest between 1995 and 2015 and a random sample of 30% of the Danish population was included in the study. Two different outcome measures were included, (i) a diagnosis of depressive disorder at a psychiatric hospital as in‐patient or out‐patient and (ii) a combined measure of a diagnosis of depression or use of antidepressants.
Results: A total of 1 576 253 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015. Continued use of low‐dose aspirin, statins, allopurinol and angiotensin agents was associated with a decreased rate of incident depression according to both outcome measures. Continued uses of non‐aspirin NSAIDs as well as high‐dose aspirin were associated with an increased rate of incident depression.
Conclusion: The findings support the potential of agents acting on inflammation and the stress response system in depression as well as the potential of population‐based registers to systematically identify drugs with repurposing potential.
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Reference
Kessing, L., Rytgaard, H. C., Gerds, T. A., Berk, M., Ekstrøm, C. T., & Andersen, P. K. (2018). New drug candidates for depression – a nationwide population-based study. Acta Psychiatrica Scandinavica, 139(1), 68-77.
