MEDICATIONS IN MANAGING DIFFICULT BEHAVIORS A REALITY CHECK reality check Noun informal an occasion on which one is reminded of the state of things in the real world. ROBERT LACOSTE, MD MEDICAL DIRECTOR, BEHAVIORAL CARE SOLUTIONS 1
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LESSON #1 A statistically significant result is not always practically significant. 4
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. 5
THE ACI A 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 ACI However, 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 ACI In 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) 6
THE ACI Lanctot 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 ACI No 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. 7
THE ACI The 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 MEMANTINE Also 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. 8
MEMANTINE Conflicting 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 #3 As 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 9
THE ANTIDEPRESSANTS Studies 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 ANTIDEPRESSANTS Pollock 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. 10
THE ANTIDEPRESSANTS Citalopram 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 #4 The 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. 11
THE MOOD STABILIZERS THE MOOD STABILIZERS Mood 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 12
THE MOOD STABILIZERS In 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 STABILIZERS A 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. 13
THE MOOD STABILIZERS Gabapentin: 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 #5 Among 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 3 rd line agent. 14
THE BENZODIAZEPINES THE BENZODIAZEPINES Billiotti 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. 15
THE BENZODIAZEPINES However, 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 BENZODIAZEPINES 13% 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 BENZODIAZEPINES Some 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. 16
LESSON #6 They 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 17
NUEDEXTA FDA 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%. NUEDEXTA Only 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. 18
NUEDEXTA The 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 19
THE ANTIPSYCHOTICS In 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 20
THE ANTIPSYCHOTICS Subsequent 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 ANTIPSYCHOTICS The 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 ANTIPSYCHOTICS In 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. 21
THE ANTIPSYCHOTICS CMS 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 ANTIPSYCHOTICS 2 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). 22
THE ANTIPSYCHOTICS Maher, 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 ANTIPSYCHOTICS That 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. 23
THE ANTIPSYCHOTICS Overall, 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 ANTIPSYCHOTICS Low 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. 24
LESSON # 8 When 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. 25
LESSON #9 Since 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. 26
RECOMMENDATIONS If 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. 27
RECOMMENDATIONS Antidepressants 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. RECOMMENDATIONS Carbamazepine 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. RECOMMENDATIONS The 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. 28
RECOMMENDATIONS Nuedexta 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. RECOMMENDATIONS Should 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. RECOMMENDATIONS However, 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 29
CONCLUSION 30
CONCLUSIONS Managing 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. 31
CONCLUSIONS Consequently, any improvement, especially if significant, has to be viewed with skepticism and cannot be attributed solely to medication. 32
CONCLUSIONS Thirdly, 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. 33
CONCLUSIONS Finally, 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. 34
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