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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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May 15, 2014

Citalopram for Alzheimer's?

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Posted by Derek

Here's a surprise - the well-known antidepressant citalopram appears to decrease formation of beta-amyloid (press release here). There have been some connections reported between serotonin signaling and amyloid production, but this makes it rather explicit. The paper not only reports rodent data, but shows human levels of beta-amyloid were decreased by nearly 40% in the CSF relative to controls.

This would make a person think that a preventative/early patient trial of the drug to see if it slows the progression of Alzheimer's has to be coming up very shortly. As an approved medication, the barriers are low, and the rewards are high. It could end up being one of the better whacks at the amyloid hypothesis in general. We need all the reads on that one that we can get, so these results good news from a scientific standpoint, no matter what the medical effects.

Comments (21) + TrackBacks (0) | Category: Alzheimer's Disease


COMMENTS

1. MoBio on May 15, 2014 12:44 PM writes...

It will be interesting to see if the work is independently replicated as another group published this a while back:

Prolonged running, not fluoxetine treatment, increases neurogenesis, but does not alter neuropathology, in the 3xTg mouse model of Alzheimer's disease.Marlatt MW, Potter MC, Bayer TA, van Praag H, Lucassen PJ.Curr Top Behav Neurosci. 2013;15:313-40.

Also, as they state in the paper the humans examined were all young healthy folks, not elderly individuals with AD.

Finally, if one peruses the AD literature one will find, perhaps, 100's of reports of various treatments which diminish plaque formation in mice so it appears we can easily cure mouse AD but human AD continues to remain 'insoluble'

Permalink to Comment

2. Luigi on May 15, 2014 1:02 PM writes...

The abstract notes for human that "Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo". For years the amyloid fraternity has argued - using the "amyloid sink" hypothesis - that INCREASING CSF amyloid levels was an indication of a reduction in brain amyloid load. Thus if citalopram DECREASES CSF amyloid then that should reflect an increase in brain amyloid load - quite the opposite of what one would like. As to the mouse data - these have predicted nothing being models of amyloid overproduction not AD.

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3. Anonymous on May 15, 2014 1:07 PM writes...

Peroxynitrite blah blah pap?

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4. Anonymous on May 15, 2014 1:17 PM writes...

Why this is such a big and exiting news and published in Nature ?
Simple Google search can find work from 2011, for example:
https://www.sciencenews.org/article/antidepressants-show-signs-countering-alzheimer%E2%80%99s

and have not been SSRI almost routinely prescribed for Alzheimer patients? Have anybody see any effect on disease progression ?

Permalink to Comment

5. Anonymous on May 15, 2014 1:37 PM writes...

@2. Luigi

You said, "For years the amyloid fraternity has argued - using the "amyloid sink" hypothesis - that INCREASING CSF amyloid levels was an indication of a reduction in brain amyloid load."

Is this really true? Could you please provide some support for this statement. My understanding is that the "amyloid fraternity", as you call it, has argued exactly the opposite of what you claim - that CSF and brain levels are linked, so that if you have an intervention that reduces amyloid beta in the CSF, you reduce it in the brain as well. Or if you reduce amyloid beta in the brain, you observe a reduction in the CSF too.

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6. Anonymous on May 15, 2014 2:26 PM writes...

Actually, Nature 2014 paper looks very like a regurgitation of PNAS 2011 work http://www.pnas.org/content/108/36/14968.short
Main difference is that first and last authors swapped.

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7. notatypwriter on May 15, 2014 2:26 PM writes...

Well... it's exciting and published in STM (Science, not Nature) because it establishes causality in humans (racemic citalopram suppresses Ab in a dose-dependent manner). The 2011 PNAS study (Cirrito et al) established causality in mice, but only associated previous SSRI use with lower plaque formation in humans via retrospective study.

What would be particularly interesting would be to look at Ab suppression by each of (S)- and (R)- citalopram. We know that (R)- is active; however, it does not demonstrate clinical efficacy in depression treatment (hence, escitalopram). What's it doing?

The SSRIs are an odd collection of beasts. fMRI studies seem to indicate that the various molecules act in different ways in different areas of the brain, and also differently in different patients. Maybe an "SSRI" species like (R)-citalopram could provide a neuroprotective reduction in Ab without negative psychotropic effects like agitation in dementia patients.

Permalink to Comment

8. Anonymous on May 15, 2014 2:30 PM writes...

Yes, sorry, read first in Nature News and jumped to the conclusion.

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9. Cantabridgian on May 15, 2014 3:33 PM writes...

Paging Lane Simonian!

Permalink to Comment

10. Cantabridgian on May 15, 2014 3:34 PM writes...

Paging Lane Simonian!

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11. Luigi on May 15, 2014 3:50 PM writes...

@5 Beta Amyloid in Alzheimer's Disease: Increased Deposition in Brain Is Reflected in Reduced Concentration in Cerebrospinal Fluid
Grimmera et al. Biol Psychiatr 2009 65, 927-34

Permalink to Comment

12. Harrison on May 15, 2014 4:05 PM writes...

I have a feeling this will eventually go the way of the statins as a treatment for AD. Large epidemiological studies will suggest a benefit, and then randomized, placebo controlled treatment trials will get nothing. The optimistic view of that is that you need 20 years on the medication to get a benefit. The pessimistic view is that there was never anything there to begin with.

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13. Neil on May 15, 2014 4:32 PM writes...

Retrospective cohort analysis using Danish registry data could help (matches birth/deaths, medical record, hospital admissions)? Compare age matched groups, one receiving citalopram vs 'control.' Adjust for confounding variables and initial diagnosis i,e depression and similar. Compare after 15-years and see rates of AD? Do they differ between groups.

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14. a.nonymaus on May 15, 2014 4:37 PM writes...

It's been on the market for a while now. Can we get some epidemiologists to see whether Alzheimer's incidence is decreased in people who have been taking citalopram since the 90s? Can we get some epidemiologists with blenders to look at brains of cadavers who had been long-term citalopram users?
On the other side, the side effects are not at the level that I'd want in a long-term prophylaxis.

Permalink to Comment

15. SteveM on May 15, 2014 7:35 PM writes...

Looks like it's time for GSK or someone to come up with a patentable Alzheimer's formulation and charge $35,000 a year for a generic drug.

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16. Justin on May 16, 2014 5:21 AM writes...

Along the lines of SteveM's thinking, without pharma backing I don't see how anyone can afford clinical trials, especially one that could last years. And I can't see any pharma getting involved if the prize is just a method of use patent (if it isn't already - First to File don't fail me now), seeing how citalopram is generic.

Or am I just being cynical to think this is a way to boost some sales due to another off-label indication? Probably.

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17. Morten G on May 16, 2014 5:45 AM writes...

Plenty of people with dementia are prescribed antidepressant - pull out the circular saw and slice up some brains!

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18. sgcox on May 16, 2014 9:15 AM writes...

Is it possible to comment in older threads ?
I wanted to comment
http://pipeline.corante.com/archives/2014/04/21/molecular_printing_of_drug_molecules_say_what.php#comments
that the paper has been retracted by the author following the discussion on this blog.

Permalink to Comment

19. Adam Kline on May 16, 2014 10:58 AM writes...

Citalproam would be unlikely to be safe at the dose used in the amyloid-lowering study. QT interval problems are guaranteed at 60mg. Cognitive impairment (as measured by MMSE) is possible:
http://www.alzforum.org/news/research-news/citalopram-calms-agitation-alzheimers-carries-risks

Permalink to Comment

20. NoDrugsNoJobs on May 16, 2014 4:13 PM writes...

There is a significant amount of preclinical data pointing to the common effect of many antidepressants in promoting neurogenesis and neurite outgrowth within the hippocampus of mice.

The opposite pathology is seen in AD brains where hippocampal shrinkage is a known corrollary. Some have speculated that the neuronal growth in the hippocampus is a common mechanism of many antidepressants and explains the time lag from initiation to effects. It is also the basis for some AD hypotheses but I don't think any studies of any note support it. There are so many compounds that do so many good things in mice as Derek alludes to, its hard to get too excited. Though I have always wondered why depressed old folks don't all try antidepressants, at such an age, not much to lose and much to gain. Prozac is a pretty clean drug as far as I can tell!

Permalink to Comment

21. placebo on June 6, 2014 7:08 PM writes...

Anyone able to explain how a placebo could have strong results in a phase 2 Alzheimer trial?

Permalink to Comment

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