Rexulti (Brexpiprazole) !!

[mjl1717]

1)It was recently approved for agitation associated with Alzheimer disease dementia, although it came out in 2015.
2)Its the first drug approved for this.
3)*It was surprisingly fast tracked
4)It has the FDA highest box warning.
5)Mortality in the elderly is at least 3 time as high compared to placebo
6)I will not mention side effects!

The age old question:
1) Does the advantage of taking Rexulti out weigh the disadvantages??
2)Any other prudent options for treating agitation related to Alzheimer disease dementia?
3)Would or should this be given to a VIP or anyone??
4))Any thoughts on this?

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[s5260205]

IMO just another antipsychotic where there are already many available for use in those with dementia. The black box warning applies to all antipsychotics with increased mortality when used in those with dementia. Unless agitation is life-threatening to patient or very disruptive to caregivers, then antipsychotics should not be started as first-line therapy. Cause of agitation should first be identified if present (e.g., pain, urinary retention, etc.). Cholinesterase inhibitors should then be considered which can improve many neuropsychiatric symptoms related to Alzheimer's disease (also PDD and DLB). Certain antidepressants that are sedating, such as trazodone or mirtazapine, can also be considered if sundowning. Depakote is another consideration.

 

[neglect]

1)It was recently approved for agitation associated with Alzheimer disease dementia, although it came out in 2015.
2)Its the first drug approved for this.
3)*It was surprisingly fast tracked
4)It has the FDA highest box warning.
5)Mortality in the elderly is at least 3 time as high compared to placebo
6)I will not mention side effects!

The age old question:
1) Does the advantage of taking Rexulti out weigh the disadvantages??
2)Any other prudent options for treating agitation related to Alzheimer disease dementia?
3)Would or should this be given to a VIP or anyone??
4))Any thoughts on this?

1. The company sponsored three clinical trials in AD agitation since it came out, summary is here. These take a lot of time to enroll.
2. Yes! It was actually the first new drug approval in AD since Belsomra for related sleep problems, which resulted in yawns.
3. Agitation is a terrible condition. It results in horrific burden for caregivers. As a result of unmet need, they applied for fast track. Ad Com voted 9-1 for approval. The one vote against was from a "drug safety" advocate.
4. Yes, class effect. Patients and families should be aware that although the drug is generally well tolerated, there is an imbalance in death rates for this class vs. placebo. The mechanism and etiology of these deaths is not clear, and thankfully they are rare, so it is hard to study. No individual deaths in the trials were thought related to the drug.
5. Absolute risk is very low, and benefits are clear.
6. Mention the side effects, same with any drug. This is actually the benefit to the drug. At 2 mg, it is well tolerated. It is also vastly better than alternatives.

Age old answers:
1. Yes. Disadvantages aside from black box are not clear, as the med does not sedate or result in PDism.
2. None are approved! People try anything and everything, even medications that firmly DO NOT WORK like valproic acid, trazodone, AChEis, and ultimately settle on benzos and neuroleptics like seroquel. I should mention that Europe approved risperidol.
3. The notion that one would alter care for a VIP is abhorrent. Never do this. If you cannot, then you MUST refer them elsewhere for their sake and yours. The entire thought process, that some patients are more important than others is highly toxic. It will corrode you from the inside. There are excellent methods to deal with people with connections, money, and fame; really like any other socioeconomic group from homeless to aerospace engineer to never-worked housewife. Probably the first rule is to address the elephant: "you're a prince/doctor/Noble winner/CEO, but here you are my patient and I am your doctor. I will take care of you like anyone else." This also sets good boundaries.
4. Other thoughts: movement disorder docs use anything under the sun to give their patients more on time and treat their non-motor symptoms. ALS docs will infuse a drug for 10 days on and 10 off to gain a month more of function. Stroke docs will move mountains to get a wake up stroke with favorable imaging to the cath lab. You can see the stigma of the disease - and the neglect and dismissal of caregiver burden - by cognitive neurologists and PCPs failing to see the advance as a great win. For the first time we can control a truly horrific neuropsych problem, which I have seen result in many ER visits and admits, and really terrible stuff.

 

[neglect]

IMO just another antipsychotic where there are already many available for use in those with dementia. The black box warning applies to all antipsychotics with increased mortality when used in those with dementia. Unless agitation is life-threatening to patient or very disruptive to caregivers, then antipsychotics should not be started as first-line therapy. Cause of agitation should first be identified if present (e.g., pain, urinary retention, etc.). Cholinesterase inhibitors should then be considered which can improve many neuropsychiatric symptoms related to Alzheimer's disease (also PDD and DLB). Certain antidepressants that are sedating, such as trazodone or mirtazapine, can also be considered if sundowning. Depakote is another consideration.

This is the worst post.

I'll start with brex as "just another antipsychotic." Haldol is an antipsychotic. Is Risperdal "just another antipsychotic"? Is pimvanserin? Is Clozapine? Or do advances in this area permit some actual effort and thought in order to benefit patients.

The black box warning gets stamped on all these meds. So there's danger. But with brexpiprazole, this trial - which sums up the previous two well - showed an absolute risk of 166 as NNH (Seven total deaths across 3 RCTs: 6 (0.9%) brex at all doses and 1 (0.3%) in placebo. And FYI: all deaths "considered unrelated" by the PIs). So we know the NNH 166 for Brex. What is the NNH for depakote in this population? An AD 'mania' trial with VPA was terminated because of dropouts. The conclusion is pick the lowest danger: go with an FDA approved med if you are able. The second conclusion is not to wait until there's homicidal, suicidal, or assaultive behavior.

When we look at the biggest and best trials:
Your claim that ACHE-Is work is false.
Your claim that trazodone works is false.
Your claim that mirtazapine works is false. (And NNH in that trial was 17!)
Your claim that VPA works is false.

Adding this: because there's mixed data on SSRIs, with citalopram showing some efficacy, but not lex (paper pending), it is fair to start an SSRI for mod agitation and other neuropsych problems, then escalate to brex. And if insurance is in the way, then try aripip.

 

[neglect]

On the heels of this, we have another failure in agitation. Pretty big trial with 408 patients over 5 weeks. The drug, which is wellbutrin with DM (wellbutrin makes DM pop like c-dopa does with l-dopa), was previously studied in a withdrawal trial and some other trials that I haven't been following closely. But this is the biggest in terms of n.

The drug is approved in depression, called Auvelity, and it is fast acting (but honestly it is just DM and wellbutrin).

Just shows how hard this stuff is.

FirstWord

firstwordpharma.com

 

[deathmerchant]

1)It was recently approved for agitation associated with Alzheimer disease dementia, although it came out in 2015.
2)Its the first drug approved for this.
3)*It was surprisingly fast tracked
4)It has the FDA highest box warning.
5)Mortality in the elderly is at least 3 time as high compared to placebo
6)I will not mention side effects!

The age old question:
1) Does the advantage of taking Rexulti out weigh the disadvantages??
2)Any other prudent options for treating agitation related to Alzheimer disease dementia?
3)Would or should this be given to a VIP or anyone??
4))Any thoughts on this?

This is a tricky thing and requires some experience and judgement calls, but if you are very specifically asking for agitation, only approved drug is Rexulti (only for 'agitation', not for psychosis or other behavioral issues). And obviously we use/have been using non FDA approved therapies all the time.

Quick summary on how we approach it in practice (for AD only)-

1. Figure out the underlying cause for agitation if you can- is it neuropsychiatric like Grief/Depression, Anxiety, Psychosis (like paranoia, hallucinations, delusions), mood disorder, apathy etc or things like denial, frustration. Or is it social/financial/caregiver related etc.
Also make sure there is no underlying untreated medical issues like mentioned above- pain, urinary issues, sleep or nutrition issues etc

2. Best strategy is to treat it semiologically based on the cause. For eg if it is more from anxiety, place them on anxiolytics like Buspar or even low dose benzos. If it is hallucinations, place them on an antipsychotics so on and so forth you get the idea. If need help consult a Psychiatrist or Cognitive specialist.

3. It is typically also recommended to first or simultaneously try non pharmacological approaches and Cholinesterase inhibitors if not already on them

4. I could give a run down of all medications with their pros and cons, and that would take a while but psychosis is typically the most common underlying cause for agitation and its reasonable to chose amongst Seroquel, Risperidone, Olanzapine, Abilify, Nuplazid and Rexulti depending on individual issues and side effect profile. I typically start with seroquel (more sedating) or risperidone (more extrapyramidal effects). Start slow and slowly go up because the individual differences in positive and negative response can be variable.

5. Rexulti can be tried in specific instances, and its good to have an additional option, esp one that is FDA approved. Obviously its more expensive.

 

[neglect]

This is a tricky thing and requires some experience and judgement calls, but if you are very specifically asking for agitation, only approved drug is Rexulti (only for 'agitation', not for psychosis or other behavioral issues). And obviously we use/have been using non FDA approved therapies all the time.

Quick summary on how we approach it in practice (for AD only)-

1. Figure out the underlying cause for agitation if you can- is it neuropsychiatric like Grief/Depression, Anxiety, Psychosis (like paranoia, hallucinations, delusions), mood disorder, apathy etc or things like denial, frustration. Or is it social/financial/caregiver related etc.
Also make sure there is no underlying untreated medical issues like mentioned above- pain, urinary issues, sleep or nutrition issues etc

2. Best strategy is to treat it semiologically based on the cause. For eg if it is more from anxiety, place them on anxiolytics like Buspar or even low dose benzos. If it is hallucinations, place them on an antipsychotics so on and so forth you get the idea. If need help consult a Psychiatrist or Cognitive specialist.

3. It is typically also recommended to first or simultaneously try non pharmacological approaches and Cholinesterase inhibitors if not already on them

4. I could give a run down of all medications with their pros and cons, and that would take a while but psychosis is typically the most common underlying cause for agitation and its reasonable to chose amongst Seroquel, Risperidone, Olanzapine, Abilify, Nuplazid and Rexulti depending on individual issues and side effect profile. I typically start with seroquel (more sedating) or risperidone (more extrapyramidal effects). Start slow and slowly go up because the individual differences in positive and negative response can be variable.

5. Rexulti can be tried in specific instances, and its good to have an additional option, esp one that is FDA approved. Obviously its more expensive.

When we look at the biggest and best trials:
Your claim that ACHE-Is work is false.
Your claim that quetiapine works is actually mixed, effect - if any - is likely tiny.
Your claim that Nuplazid works in AD, even for psychosis, is false. FDA gave CRL for AD psychosis. They are retrying. Confounding psychosis and agitation is an error.

More importantly for second generation neuroleptics, there are two important papers to consider:
1. The NNH with death is 50 for quetiapine, and 100 for others, including abilify.
2. The CATI-AD trial's endpoint was withdrawal, and shows that these drugs are withdrawn overall at same rates as placebo. Looking at the bottom line, it is impossible to justify using Seroquel.

 

[deathmerchant]

lol not you again. I appreciate the input but you did not understand my point-
These studies have limitations and yes obviously there is no perfect drug for this. I’m talking about how clinical experts approach this suboptimal situation by treating the underlying cause of agitation which is not done in these studies. Find me a cognitive neurologist who does not use seroquel or cholinergics or other drugs I mentioned.

Also, most of what I posted above is written in the new dementia AAN continuum edition I browsed through. I can post excerpts from there disproving all your points- or anyone interested can look it up. Go argue with them.