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MEDICATIONS IN MANAGING DIFFICULT

BEHAVIORSA REALITY CHECK

reꞏalꞏiꞏty checkNoun informalan occasion on which one is reminded of the state of things in the real world.

ROBERT LACOSTE, MDMEDICAL DIRECTOR,

BEHAVIORAL CARE SOLUTIONS

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LESSON #1

A statistically significant result is not always practically significant.

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THE ACETYLCHOLINESTERASE INHIBITORS

LESSON #2

The average benefit of the ACI is a smal improvement

in cognition, neuropsychiatric symptoms and ADLs.

THE ACI• A 2004 study (Lancet) revealed MMSE scores were 0.8 points

better over the first 2 years (1point better on BADLS), but

found no benefit in regards to behavioral symptoms,

institutionalization or progression of disability.

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THE ACIA Cohcrane review (2006) revealed improvements in cognitive

function on average of 2.7 points (3.8%) on the ADAS-cog scale.

No difference between agents.

Main side effects were nausea, vomiting and diarrhea (29% left

the treatment group vs 18% for the placebo group).

THE ACIHowever, other studies have found otherwise. Wallin AK et al

(Dement Geriatr Cogn Disord, 2007) followed outpatients for 3

years on donepezil, with a mean change in MMSE of 3.8 points,

with 30% (of the 38% left) of them unchanged or improved in

global assessment at the endpoint.

THE ACIIn another study, Alzheimer’s patients treated with rivastigmine

had a reduced risk of initiating therapy with an antipsychotic

drug (9.8%) compared to patients not receiving it (25.6%).

This suggests that treatment with an ACI might delay the

emergence of behavioral symptoms (Suh DC, Drugs Aging, 2004)

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THE ACILanctot et al (CMAJ, 2003) reported in a meta-analysis that the

proportion of responders in excess of the placebo rate was 9%.

In addition, NNT to achieve stabilization or better was 7, and for

minimal improvement or better 12.

THE ACINo clear guidelines as to when/if to withdraw therapy.

Literature supports continuing treatment unless significant side

effects, cost, or faster decline after initiating therapy.

Some studies, although not all, have reported cognitive decline

and behavioral symptoms after discontinuation.

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THE ACIThe mean effect is not clinically significant.

The majority of patients do not benefit practically from the ACI.

A small minority (10-15%) does.

However, it is not possible to identify this subgroup of patients

before nor during therapy.

MEMANTINE

MEMANTINEAlso of small/modest benefit, either by itself or in combination with

an ACI.

A study in the NEJM (2012) reported MMSE scores of 1.2 points

higher and 1.5 points lower on the BADLS. No statistically significant

benefit for neuropsychiatric symptoms as measured using the NPI.

Better tolerated than the ACI, with dizziness as main side effect.

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MEMANTINEConflicting data on benefit for neuropsychiatric symptoms, with

some studies showing benefit and others not.

One study (Vidal JS et al, Neuroepidemiology, 2008) found 39-

50% more prescriptions for psychotropics before initiation with

memantine and stabilization (53%) thereafter.

LESSON #3As with the ACI, mixed results suggesting no practical benefit for

most patients, with or w/o combination therapy.

A few studies point to practical significance, possibly delaying

the emergence of behavioral symptoms for a minority of patients.

THE ANTIDEPRESSANTS

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THE ANTIDEPRESSANTSStudies with SSRIs have produced mixed results.

Usually well tolerated, with drop out rates similar to placebo.

May be useful in the management of agitation and psychosis.

Citalopram and sertraline in particular.

THE ANTIDEPRESSANTSPollock et al (Amer J of Geriatr Psychiatry, 2007) found citalopram

as effective as risperidone for the treatment of psychosis and agitation.

Porsteinsson et al (JAMA, 2014) found that 40% (vs 26% placebo) of treated patients with citalopram were “much or very much improved” using ADCS-CGIC, meaning a difference of 14%.

They used 30 mg however, and the QT interval was affected (18 msec.). Not enough patients were on 20 mg to generalize the findings.

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THE ANTIDEPRESSANTSCitalopram lengthens the QTC in a dose dependent manner, and

dosage is capped at 20 mg for those over 60 or taking a CYP2C19 inhibitor (e.g. omeprazole).

In addition, fluoxetine is a strong CYP2D6 3A4 inhibitor while paroxetine is a potent CYP 2D6 inhibitor. Using these agents could lead to significant drug interactions.

THE ANTIDEPRESSANTS

Trazodone did not differentiate from placebo in 3 studies.

Highly antihistaminic, but no anticholinergic effect.

No serotonergic reuptake inhibition under 300 mg.

LESSON #4The data on citalopram is the best data available.

It shows that 14% of patients treated had a response that can

be attributed to the medication.

This again suggests that a minority of patients will derive

practical significance from the use of antidepressants.

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THE MOOD STABILIZERS

THE MOOD STABILIZERSMood stabilizers do not stabilize moods. They are either

antimanic drugs or antidepressant agents, with lithium and

lamotrigine being the only agents with an FDA indication for

prophylaxis.

THE MOOD STABILIZERS“The updated review corroborates the earlier findings that

valproate preparations are ineffective in treating agitation

among demented patients, and that valproate therapy is

associated with an unacceptable rate of adverse effects.”

Cochrane review 2009

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THE MOOD STABILIZERSIn 2012, Abbott Laboratories was assessed $1.6 billion in civil

and criminal penalties for illegally marketing Depakote in nursing

homes to control agitation and aggression in patients with

dementia.

THE MOOD STABILIZERSA 1998 Am J Psychiatry study found benefit for agitation with

carbamazepine with good tolerability, with reduction in BPRS scores of -7.7 for carbamazepine vs -0.9 for the placebo group.

A 2005 JAMA review cited 2 studies with conflicting results.

3 main concerns with this agent: it affects blood elements, has significant anticholinergic properties, and is a CYP P450 enzyme inducer, thereby increasing clearance of many drugs.

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THE MOOD STABILIZERSGabapentin: mild side effect profile, but unproven efficacy.

Oxcarbazepine: a 2009 (Sommer et al) randomnized, double blind, placebo-controlled study found no benefit.

Lamotrigine: advocated on the basis of case reports, but no RCT published to date.

Lithium: case studies show it to be ineffective. No RCT.

LESSON #5Among mood stabilizers, carbamazepine is the only agent with

evidence of efficacy for neuropsychiatric symptoms.

Because its use is fraught with significant side-effects and drug

interactions, carbamazepine could be a 3rd line agent.

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THE BENZODIAZEPINES

THE BENZODIAZEPINESBilliotti de Gage et al (BMJ, 2014) reported that the use of BZP

was associated with a 43-51% greater risk of being diagnosed

with AD.

This was only for use greater than 3 months, and the association

was stronger with longer duration and longer acting agents.

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THE BENZODIAZEPINESHowever, another study (Gray S et al BMJ, 2016) did not

support a causal association between BZP exposure and

dementia.

Oddly, low use was associated with a slightly higher risk (1.27),

suggesting possibly reverse causation.

THE BENZODIAZEPINES13% of nursing home residents were prescribed a BZD in 2004

(Stevenson et al, Am J Geriatr Psychiatry, 2010).

Some short term double blind studies have shown benefit for

acute agitation.

THE BENZODIAZEPINESSome studies have also shown greater cognitive decline with BZP,

but such findings were confounded by polypharmacy.

BZP have been linked with significant ADR including falls,

delirium, dependency and paradoxical agitation.

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LESSON #6They have a role in the treatment of acute agitation.

They are best used on an as needed basis, or for short periods

on a scheduled basis.

Short acting agents are preferred (alprazolam, lorazepam).

NUEDEXTA

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NUEDEXTAFDA approved in 2011 for pseudobulbar affect (PBA), a

condition which affects less than 1% of the population, usually

stemming from ALS or MS.

Since 2012, the number of capsules dispensed to LTC facilities

has gone up 400%.

NUEDEXTAOnly one RCT study (Cummings et al, JAMA 2015).

Showed reduction in NPI agitation/aggression scale scores of 50.7%

(drug) against 26.4% (placebo), and 45.1% (vs 27.1%) were judged

to have a “moderate or marked improvement” on the ADCS CGIC.

Main side effects were falls (9 vs 4%), diarrhea (6 vs 3%) and UTI (5

vs 4%). Because of quinidine, it can prolong the QTC.

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NUEDEXTAThe authors felt that the findings had clinical significance (18% responded

to the drug).

More studies are needed to see if there is a role for this agent.

Cost is a significant issue.

Quinidine is a CYP2D6 inhibitor, which can affect many other drugs. It is a CYP3A4 substrate and Nuedexta should not be used with 3A4 inhibitors.

LESSON #7

Despite limited evidence and modest benefit, Nuedexta could be

a third line agent, following trial of an ACI and antidepressant,

and before starting an antipsychotic.

THE ANTIPSYCHOTICS

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THE ANTIPSYCHOTICSIn 2005, the FDA issued a black-box warning for second

generation antipsychotics about an increased risk of death in elderly dementia patients. In 2011, it was added to the labels of first-generations agents.

Prevalence of use among NH residents (at least 100 days) was 15.7% in 2017, down from 23.9% in 2011 (CMS data).

THE ANTIPSYCHOTICS

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THE ANTIPSYCHOTICSSubsequent studies have confirmed theses findings (JAMA 2005,

Lancet Neurol 2009), with causes of death being cardiac (25%), CVA (8%), and pulmonary disease (8%).

This greater risk is not unique to the elderly or those with dementia, since younger patients with any diagnosis are 4.1 times more likely to die than age matched controls (Murray-Thomas T et al, Cardiovasc Psychiatry Neurol 2013).

THE ANTIPSYCHOTICSThe magnitude of the absolute mortality risk may be greater

than previously estimated.

Maust DT et al (JAMA Psychiatry 2015) found such to be 3.8 %

for haloperidol, 3.7% for risperidone, 2.5% for olanzapine and

2.0 for quetiapine, with NNH respectively of 26, 27, 40 and 50.

THE ANTIPSYCHOTICSIn addition, the evidence suggests that FGA may have a greater

risk of mortality than SGA (Gill SS et al, Ann Intern Med 2007).

Furthermore, higher doses correlate as well, and the effect has

been noted as long as 180 days after initiation of therapy.

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THE ANTIPSYCHOTICSCMS guidelines are that antipsychotic medications can be

considered for elderly residents with dementia, but only after

medical, physical, functional, psychological, emotional,

psychiatric, social and environmental causes (of behaviors) have

been identified and addressed.

THE ANTIPSYCHOTICS2 meta-analyses on typical antipsychotics found them to have

modest benefit, with an effect size of .18, with no difference

between agents (J Amer Geriatr Soc, 1990).

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THE ANTIPSYCHOTICSMaher, AR et al (JAMA, 2011) reviewed 18 RCTs and found

aripiprazole, olanzapine and risperidone to have modest benefit, but not quetiapine.

The effect size was small (0.12-0.20), meaning that the average person in the treatment group would score better than 58% of those in the control group.

THE ANTIPSYCHOTICSThat same study (JAMA, 2011) reported a 35% improvement in

NPI scores vs baseline.

However, the difference in pooled NPI total scores between the treatment group and the placebo group was only 3.41 points.

No difference between agents, but only risperidone is licensed in the UK (2008) for the short term treatment of persistent aggression in Alzheimer’s dementia.

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THE ANTIPSYCHOTICSOverall, the rates of discontinuation of treatment among the four

study groups ranged from 77 to 85%. Although the differences

among the groups may have been significant in a larger trial, our

findings suggest that there is no large clinical benefit of treatment

with atypical antipsychotic medications as compared with

placebo (Schneider L et al, NEJM, 2006).

THE ANTIPSYCHOTICS

THE ANTIPSYCHOTICSLow potency FGA are sedating and have anticholinergic activity.

High potency FGA have a high incidence of EPS and TD.

SGA have side effects of weight gain, diabetes, dyslipidemia, QT prolongation, orthostatic hypotension, EPS, TD, prolactin elevation, sedation and falls.

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LESSON # 8When nonpharmacologic interventions and safer pharmacologic

approaches fail to manage neuropsychiatric symptoms, and they

result in severe distress or safety issues, treatment with an

antipsychotic may become necessary.

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LESSON #9Since their effect size is small and the risks significant in terms of

mortality and morbidity, their use should be temporary and

subject to frequent reassessment.

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RECOMMENDATIONSIf behaviors permit, the use of ACI and/or memantine is an

appropriate first line treatment for neuropsychiatric symptoms.

If already on an ACI, optimize dose and/or add memantine.

There are the only FDA approved agents for Alzheimer’s

patients.

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RECOMMENDATIONSAntidepressants should be second line agents, unless dealing with

depression/anxiety.

There is some evidence for the use of citalopram and sertraline.

Other agents could be used as well, but avoid fluoxetine,

fluvoxamine, paroxetine, and bupropion because of drug

interactions.

RECOMMENDATIONSCarbamazepine is the only mood stabilizer with some evidence

of efficacy.

However, it has BBW for serious dermatologic reactions as well as aplastic anemia and agranulocytosis.

Its anticholinergic side effects and drug interactions (3A4 inducer) make its use impractical, but it could be used before an antipsychotic.

RECOMMENDATIONSThe benzodiazepines are best used for acute behaviors for a

short period of time or on an as needed basis.

There is no evidence for their chronic use to prevent or manage

difficult behaviors.

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RECOMMENDATIONSNuedexta could be a third or fourth line agent, before using an

antipsychotic, but the risks are significant in terms of QT

prolongation and drug interactions.

RECOMMENDATIONSShould the behaviors be severe and/or distressing enough, and

refractory to other agents, and endanger safety, a trial of an

antipsychotic could be initiated.

SGA are preferred over FGA.

RECOMMENDATIONSHowever, such an agent should be discontinued or changed if no

benefit accrues.

Should the behaviors lessen or abate, a GDR is still indicated in

the near future, because…

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CONCLUSION

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CONCLUSIONSManaging difficult behaviors is a COMPLEX problem.

These drugs were not designed for such use, and none of them came from an understanding of the etiologies for such behaviors.

For most patients, there is no benefit from the expectations they might have from taking a pill, as often they have no awareness or expectations of taking such an agent.

As a result, benefit and effect size are small.

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CONCLUSIONSConsequently, any improvement, especially if significant, has to

be viewed with skepticism and cannot be attributed solely to

medication.

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CONCLUSIONSThirdly, the significant risks associated with most of these agents

urge us to substantiate that any improvement stems (at least in

part) from their use.

That is the rationale behind the GDR of these agents.

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CONCLUSIONSFinally, a resumption of behaviors after a GDR does not

necessarily mean that it failed, especially if it does not occur

shortly thereafter, because you’re now…

SMARTER.

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