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Prazosin: possible treatment for insomnia and/or agitation and aggression
JAB
Posted: Sunday, December 25, 2011 12:12 PM
Joined: 11/30/2011
Posts: 740


About ten months ago, Billstrailrunning reported that he had been searching for a good sleep aid for his wife.  He ran across a prescription med, Prazosin, which has a long history of use as an anti-hypertensive med.  It is inexpensive and has a pretty good safety profile.  He began trying it for his wife, monitoring her sleep pattern with a device called ZEO that enables noninvasive monitoring of sleep stages including dreaming sleep.  He noted that Alzheimer's patients are reported to have little or no REM sleep. One of the benefits of REM sleep is that it helps consolidate daily experiences into long-term memories.  He also noted that the drug has been found to act as a mood stabilizer in ADLOs.  At the time of his first posting, his wife had been titrated up to 2mg at bedtime, and for the past 2 weeks had been sleeping through the night without benefit of other sleep aids, and her mood has shown improvement, as well.

This intrigued me, so I looked for more information.  What I pulled up was so interesting that I started a new thread, in the hopes that more members would see it.  Several members did, and, with the help of their loved ones' doctors (and Bill's reports on his continuing treatment of his wife), began trying it and reporting success, too.

So ... I'm starting a new thread on the new boards, to continue the discussion.  As soon as the archives are available, I'll provide links to the earlier threads on the old boards.

Prazosin is a centrally active antagonist of the α1-adrenoreceptor (α1-AR) in the noradrenergic system. This drug is used for a number of applications, not just hypertension. 

The noradrenergic system plays an important role in learning and memory.  Moderate levels of norepinephrine released under control conditions strengthen prefrontal cortical functions via actions at post-synaptic α-2A adrenoceptors with high affinity for norepinephrine, while high levels of norepinephrine release during stress impair prefrontal cortex (PFC) cortical functions via α1 and possibly β1 receptors with lower affinity for norepinephrine. Thus, levels of norepinephrine determine whether prefrontal cortical or posterior cortical systems control behavior and thought.  The successful use of atypical antipsychotics is thought to be related to their α1- and 5HT2A-blocking properties.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151919/

Aggressive behavior is associated with an increase in the number of α1-adrenoceptors in AD patients.
http://www.ncbi.nlm.nih.gov/pubmed/17463193

I found reports of two successful (albeit tiny) trials on treating agitation and aggression in ADLOs. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842091
http://www.alzheimersanddementia.com/article/PIIS1552526008015136/fulltext

Two larger trials are/were when I researched the topic recruiting.
http://clinicaltrial.gov/ct2/show/NCT01126099
http://clinicaltrial.gov/ct2/show/NCT00161473

Changes in noradrenergic neurons appear to be similar in AD and Lewy body patients.
http://neuro.cjb.net/cgi/content/full/26/2/467
It is therefore conceivable that prazosin might help LBD patients who are sensitive to antipsychotics.


What I found even more interesting is that long-lasting memories of aversive or stressful events have been associated with the noradrenergic system activation.  Traumatic stressors are thought to lead to excessive norepinephrine release and α1-AR engagement.  Animal research suggests that high levels of α1-AR stimulation should weaken PFC inhibitory functions and strengthen amygdala function, the profile observed in posttraumatic stress disorder (PTSD). The high CNS noradrenergic outflow in PTSD is thought to stimulate α1-adrenergic regulation of the prefrontal cerebral cortex, disrupting cognitive processing and increasing fear responses.

Trauma-related nightmares in PTSD rarely respond to pharmacologic treatment. However, low doses of prazosin have been found to substantially reduce nightmares and moderately or markedly reduce overall PTSD severity and function in previously treatment-resistant combat veterans.  Given an hour before bedtime, low doses of prazosin reduce light sleep, normalize REM sleep, and increase total sleep time. An additional daytime dose was found to reduce residual daytime symptoms of civilian trauma victims.
http://www.ncbi.nlm.nih.gov/pubmed/10732660
http://ajp.psychiatryonline.org/cgi/content/full/160/2/371
http://www.ncbi.nlm.nih.gov/pubmed/16460691
http://www.ncbi.nlm.nih.gov/pubmed/11799347
http://www.ncbi.nlm.nih.gov/pubmed/12967060
http://www.theannals.com/cgi/content/full/41/6/1013?ijkey=d792a3ea4dc2c2257480eb0df62ba985fcd77d57

The drug is now commonly used for this application, and there are quite a few clinical trials ongoing, as well.

Some of our members are dealing with ADLOs who suffer from PTSD. And I've gotten the impression that the AD worsens the PTSD symptoms.  So perhaps prazosin may offer them some relief, too.

Fatigue is the most common side effect.

Note, please, that the levels of prazosin that are reported to be effective for treating PTSD are typically lower than those that are used to treat hypertension.


For those who are interested, I found an overview of the way in which various drugs for treating insomnia, parasomnias, and circadian rhythm disorders are thought to work:
http://www.bap.org.uk/pdfs/BAP_Sleep_Guidelines.pdf
Billstrailrunning
Posted: Monday, January 9, 2012 8:00 PM
Joined: 12/15/2011
Posts: 6


Hello fellow AD warriors,

I've been unusually busy on work related activities for the past 2 months, pre-occupied to say the least, and then the Holiday season only drew me farther away from posting on this forum.

I wanted to give you all an update on my girl who is I think, as do her doctors to be holding...that is to say doing phenomenally well. Since starting her estradiol patch (0.05 mg) about 9 months ago she has now been re-evaluated by her AD specialist physician 3x now and is holding steady with small gains noted. Hence we have 3 data points on her status overall since starting estradiol.

She is also on prazosin 5-10 mg daily and mirtazapine, 15 mg hs and 4 mg timed release melatonin hs. The following data starts Sept 9, 2009, the first day with prazosin.

 

REM time 1st 4 months and most recent 4 months to date

date          hrs:min

9/09             0 :03

10/09           0:02

11/09           0:02

12/09           0 :03

 

10/11           0:27 

11/11           0:54

12/11           0:59

 01/12          1:53

 

Awake time after lights out

 

09/09           0:46

10/09           1:12

11/09           1:02

12/09           1:13

 

10/11           0:43

11/11           0:37

12/11           0:36

01/12           0:31

 

Briefly, REM sleep time continues to trend upward while poor sleep indicators trend down.

Most days now she is totally lucid with sundowning kicking in around 5 pm and again around bedtime about 5 of every 10 days. If she gets at least 8 hours of sleep the preceding night or gets a 1-2 hour afternoon nap sundowning is absent. Many people she encounters for the 1st time have no idea she has severe AD...she usually can pass as normal in social situations as she is very well compensated.

I will be happy to respond to your questions.

Bill


Billstrailrunning
Posted: Monday, January 9, 2012 8:59 PM
Joined: 12/15/2011
Posts: 6


I failed to mention that prazosin can stop her sundowning behaviors within 5 minutes of 1-2 mg dosage 100% of the time and if I can get her prazosin in her when she starts to become delusional that is about as far as it goes.  I call this "rescue prazosin dosing".
If I anticipate correctly sundowning I can pre-dose her with 1-2 mg and that will usually eliminate sundowning all together for the next few hours and often altogether
Bill.

Lane Simonian
Posted: Thursday, January 12, 2012 10:55 AM
Joined: 12/12/2011
Posts: 4986


Here is an alternative explanation for why Prazosin may help certain people with Alzheimer's disease.  Prazosin lowers levels of catecholamines such as noradrenaline.http://www.sciencedirect.com/science/article/pii/0006295279903356 It may be a deficiency or inhibition of the enzyme that breaks down catecholamines (catechol-0-methyltrasnferase) that explains the rather large variations in behavior in Alzheimer's patients.  Thus, by helping to deplete some of these catecholamines, Prazosin helps with behavioral issues.

 

Peroxynitrites inhibit Prazosin binding.

http://www.ncbi.nlm.nih.gov/pubmed/11940765 

They inhibit most a-adrenergic receptor activation in general.  Inhibiting a-adrenergic receptors appears to increase behavioral problems (especially in individuals who do not readily break down catecholamines).  See research study two, although it is for epinephrine (adrenaline) and not for noradrenaline.http://www.nature.com/npp/journal/v19/n6/full/1395237a.html 

 

The main positive effect of Prazosin may be by lowering levels of catecholamines rather than by inhibiting certain adrenergic receptors.  Whatever the case, it works.

 

 

 


Lane Simonian
Posted: Thursday, January 12, 2012 5:42 PM
Joined: 12/12/2011
Posts: 4986


Admittedly this subject confuses me.  Some research indicates that beta-adrenergic blockers actually worsen behavior and cognitive function in Alzheimer's disease due to the preexisting impairment of cholinergic and serotonin systems.

http://www.nature.com/?file=/npp/journal/v28/n7/full/1300163a.html 

http://www.nature.com/?file=/npp/journal/v28/n7/full/1300163a.html 

 

At least one alpha adrenergic antagonists (Yohimbine not Prazosin) appears to worsen behavior in Alzheimer's patients.  Is it possible that the many of the medications given to treat behavioral problems in Alzheimer's patients are actually making the situation worse?

 

I suppose this is another example of unintended consequences and how careful observations provided by people like Bill are the best guides.


Lane Simonian
Posted: Thursday, January 12, 2012 5:44 PM
Joined: 12/12/2011
Posts: 4986


I duplicated a study.  Here is the one for serotonin.

http://www.nature.com/npp/journal/v33/n6/full/1301518a.html 


Lane Simonian
Posted: Thursday, January 12, 2012 10:14 PM
Joined: 12/12/2011
Posts: 4986


The beneficial effect of Prazosin for Alzheimer's disease may be due to in part to its inhibition of the alpha1 adrenoreceptor whereas the negative effect of Yohimbine on Alzheimer's patients is due to its inhibition of the alpha2 adrenoreceptor. 

 

The stimulation of beta adrenoreceptors increases neurogenesis in the hippocampus via cyclic AMP.

http://www.mendeley.com/research/epinephrine-prevents-nitric-oxideperoxynitrite-induced-apoptosis-neuronal-cells-through-betaadrenergic-receptor-activation/ 

http://www.jneurosci.org/content/22/9/3673.full 

I suppose the latter point is the one new thing that I can add to this thread.


Billstrailrunning
Posted: Friday, January 13, 2012 11:52 AM
Joined: 12/15/2011
Posts: 6


Keep in mind that prazosin works rapidly...too rapidly to be explained by lowering endogenous catecholamine  levels.  However blocking of catecholamine receptors is relatively rapid and better fits with the observation that prazosin is fast acting and can quell delusions, irritability, aggressiveness, rage, etc. in less than 5 minutes post dosing with 1 or 2 mg.

That said, there is nothing to preclude both explanations from being correct.  I would suspect rapid blocking of NA receptors leading to rapid calming would secondarily lead to a general lowering of available catecholamines throughout the body. Being in a catastrophic rage has to be associated with excess catecholamines circulating throughout the body.  Before I found prazosin my girl would have this sort of rage and eventually she would flip back to normalcy after raging on for an hour or more as the catecholamine levels began to subside and a threshold of sorts would appear to have been crossed and the rage almost appeared to flip off.

 

Bill


Lane Simonian
Posted: Friday, January 13, 2012 2:03 PM
Joined: 12/12/2011
Posts: 4986


Thanks, Bill, for the very good and clear explanation.  It makes a great deal of sense to me now.  I am glad that you have found a number of treatments that work for your loved one and will help others as well.
Rosmarinus
Posted: Friday, October 24, 2014 2:53 PM
Joined: 10/3/2014
Posts: 3


My 90 year old mother has Alzheimer's and has currently started Seroquel for behavioral problems which is kind-of (but not completely) helping. I'm very interested in the studies and discussion on this site about Prazosin as it has a MUCH lower side effect profile and seems like it could possible work as well as or better than the Seroquel. Her primary care physician has not heard of it's use for Alzheimer's behavioral issues (so is reluctant to prescribe) and recently, her new geriatric psychiatrist dismissed it as something he only uses for PTSD. Does anyone know of a doctor in the Grand Rapids Michigan area that has any knowledge or experience prescribing this?
edwardhoward
Posted: Tuesday, June 9, 2015 2:10 AM
Joined: 6/9/2015
Posts: 1