Pharmacotherapy of Dementia Behaviors

Transcription

1 This Clinical Resource gives subscribers additional insight related to the Recommendations published in June 2017 ~ Resource # Pharmacotherapy of Dementia Behaviors (Also see our chart specific to patients with Parkinson s Dementia and Dementia with Lewy Bodies.) Psychological symptoms and inappropriate behaviors such as agitation, wandering, aggression, and psychosis (hallucinations, delusions) are common in patients with dementia. 1 These symptoms may be due to dementia itself, or other causes such as depression, constipation, dehydration, infection, hunger, boredom, or pain (see footnote a). 1,2,23 Vision or hearing loss plus environmental factors may cause problems with perception and coping, resulting in behaviors that may be mistaken for hallucinations or delusions. 2 Also consider medications as a cause of behavioral symptoms. For example, medication-associated akathisia can cause wandering or pacing (symptoms which don t typically respond to pharmacotherapy), and benzodiazepines can cause disinhibition. 2,18 Anticholinergics and drug interactions can worsen cognition or cause delirium. 6 Nonpharmacologic interventions should usually be tried first to manage these behaviors; all pharmacotherapy has limited efficacy, and causes side effects. 25 Provide a safe, calm, and predictable environment. 18 Reduce clutter and noise, improve lighting, set routines, and orient or redirect attention as needed. 1,2 Individualize interventions. For example, some patients may like music, hand massage, or pet therapy; others may find it upsetting. 2 Tips on interventions for caregivers are available at Keep in mind that cognition and symptoms can change over time. 2 If a medication is tried, attempt a taper as the patient s condition permits (e.g., every three to six months) to prevent chronic use of potentially unnecessary medications. 1,13 Consider using the DICE approach to behavioral symptoms: Describe the symptoms, Investigate causes, Create a treatment plan, and Evaluate the interventions. 1 Medication options, target symptoms, and other pertinent information are delineated in the table below. Abbreviations: NMDA = N-methyl-D-aspartate; SSRI = selective serotonin reuptake inhibitor; SNRI = serotonin-norepinephrine reuptake inhibitor Drug or Drug Class Target Symptoms Comments Antidepressants Depression 1 Anxiety (SSRI, SNRI, trazodone) 25 Agitation (citalopram, trazodone) 15,22 Irritability (trazodone) 22,25 Psychosis (citalopram) 16 Depression may affect 25% of Alzheimer s patients. 1 Associated with wandering, agitation, and aggression. 14 Evidence of antidepressant benefit for depression is conflicting in dementia, perhaps due to differences among studies. 1 Antidepressants are relatively well-tolerated compared to antispychotics. 17 Citalopram is effective for agitation and reducing caregiver distress, but can cause QT prolongation and worsen cognition [Evidence level B; lower-quality RCT]. 15 The starting dose in this study was 10 mg/day, increased over three weeks to a target dose of 30 mg/day, which is above the maximum recommended dose of 20 mg for the elderly. 15 Citalopram may also be as effective as risperidone for behavioral and psychotic symptoms. 16 Antidepressants have shown mixed results in studies of depression in Alzheimer s patients. 11,14,26 Continued Diabetic Sertraline has the most data. Experts support trying them for depressed mood in dementia neuropathy patients. 17,26 Sertraline may also improve behavior and functioning, and reduce caregiver stress. 14

2 (Clinical Resource #330601: Page 2 of 6) Drug or Drug Class Target Symptoms Comments Antidepressants, continued (venlafaxine, duloxetine) 4 Consider starting with sertraline 25 mg daily, increasing by 25 mg each week to a max daily dose of 150 mg. 14 Limited evidence suggests trazodone may improve agitation, irritability, and depression. 22 Concern for sedation, falls, hypotension. 25 Antipsychotics, atypical Continued Agitation or psychosis that is severe, significantly distressing to the patient, or causes the patient to act in a way that creates a danger to themselves or others 2 Not to be used as a chemical restraint (e.g., for discipline or staff convenience) 31 Benefits are small, at best. 2 Consider risks: cardiovascular events (e.g., stroke), metabolic effects (weight gain, diabetes, dyslipidemia), pneumonia, pulmonary embolism, movement disorders, anticholinergic effects, orthostatic hypotension, sedation, fatigue, cognitive decline, QT prolongation, and death. 2 There is one more death for every 50 to 100 dementia patients on an atypical antipsychotic over 8 to 12 weeks. 24,25 Our chart, Parkinson s Dementia and Dementia with Lewy Bodies, has information on the use of antipsychotics specific to this population (including Nuplazid [pimavanserin]). Use one-third to one-half the usual starting dose, or the smallest strength available (but consider risk to patient and others if underdosed), and uptitrate to the lowest dose that is effective. 2 Limit to a four-week trial. 2 If there is no clinically significant response, taper by no more than 50% every two weeks and discontinue. 2,29 Also consider tapering and discontinuing in the event of side effects. 2 If response is good, continue use but attempt to taper and discontinue within four months. 2 Monitor for recurrence at least monthly during the taper and for at least four months after discontinuation. 2 Decisions about tapering should be made with input from the patient (if possible), decisionmaker, and others who interact with the patient. Consider preferences, concerns, goals, benefits, side effects, risks of long-term use, and the results of previous tapering attempts (e.g., symptom recurrence). 2 Set expectations; explain that many patients can be tapered successfully. 20 In long-term care facilities in the U.S., unless contraindicated, a taper must be attempted twice in the first year, in two separate quarters, with at least a month between attempts. After the first year, an attempt must be made annually, unless contraindicated. 13 Aripiprazole, risperidone, and olanzapine have the best evidence of efficacy. 1 Risperidone is Health Canada-approved for aggression and psychosis in severe Alzheimer s dementia at a starting oral dose of 0.25 mg twice daily, increased by 0.25 mg/day every two to four days. The optimum dose for most patients is 0.5 mg twice daily (max 1 mg twice daily). 30 Suggested oral olanzapine dose: 2.5 mg at bedtime, initial. Max 10 mg/day, usually divided twice daily. 18 U.S. Centers for Medicare & Medicaid Services has suggested a max of 5 mg/day

3 (Clinical Resource #330601: Page 3 of 6) Drug or Drug Class Target Symptoms Comments Antipsychotics, atypical, continued for dementia behaviors in nursing home residents. 31 Suggested oral aripiprazole dose: 2 mg/day, initial (lowest available tablet strength). Max 10 mg once daily. 31 Reserve haloperidol for emergency situations such as acute delirium. 2 For help getting acute agitation under control quickly, see our chart, Pharmacotherapy of Acute Agitation in Adults. Reserve long-acting injectables for patients with a concomitant chronic psychotic disorder. 1 Benzodiazepines Generally avoid; reserve for acute crisis (agitation, alcohol withdrawal, or severe anxiety) 1,18,19 Paucity of evidence for behavioral and psychologic symptoms of dementia. 1 Benzodiazepines are among the drugs that should generally be avoided in most elderly patients. 6 Benzodiazepines are among the medications that pose the greatest fall risk in the elderly, especially at high doses. 12 Elderly prone to benzodiazepine-associated confusion, cognitive impairment, delirium, paradoxical excitation, and night wandering. 6,12 Associated with increased mortality. 2 In general, start with one-third to one-half the recommended adult dose. 12 See our chart, Benzodiazepine Toolbox, for geriatric dosing, dosing in renal or hepatic impairment, cautions, alternatives, and tapering tips. Buspirone Mild to moderate agitation or irritability 18,25 Anxiety 25 Limited data. 5 mg twice daily, initial. Max 20 mg three times daily. 18 May take two to four weeks for efficacy. 18 Cholinesterase Inhibitors (e.g., donepezil, rivastigmine) and/or memantine Agitation, aggression, irritability 18 Unlikely to have clinically significant effect on behavior. 26 Side effects of cholinesterase inhibitors include nausea, vomiting, diarrhea, bradycardia, and syncope. 1 Memantine may cause constipation, dizziness, headache, and confusion. 1 Consider tapering and discontinuing these drugs in advanced disease. 28

4 (Clinical Resource #330601: Page 4 of 6) Drug or Drug Class Target Symptoms Comments Anticonvulsants (mood stabilizers) Agitation, aggression 8,9,10,25 Low-dose carbamazepine (e.g., 300 to 400 mg/day) seems effective, but evidence limited [Evidence level B; lower quality RCTs]. 8,9 Requires lab monitoring. Many drug interactions due to induction of CYP450 and P-glycoprotein. Open-label data suggests efficacy for lamotrigine. 10 Main side effects are potentially serious rash, dizziness, ataxia, vision disturbance. sedation, nausea/vomiting. 3 Current evidence does not support efficacy of valproate for agitation in patients with dementia [Evidence level A; high-quality meta-analysis and RCT]. 7,32 Cognitive changes, falls, sedation, other serious side effects. 1,7 If tried, experts suggest a low dose (e.g., 125 mg twice daily initial 18 ). Requires lab monitoring. Dextromethorphan 20 mg/ quinidine 10 mg (Nuedexta) Agitation 21 Labeled indication is pseudobulbar affect. 27 Labeled dose is one capsule daily for seven days, increased to one capsule every 12 hours. 27 Dextromethorphan blocks NMDA receptors and quinidine boosts dextromethorphan levels. 27 May modestly improve agitation in one in six Alzheimer s patients over 10 weeks at a dose of 30/10 mg twice daily [Evidence level B; lower-quality RCT]. 21 Costs about $750/month. Many drug interactions due to inhibition of CYP2D6 by quinidine and metabolism of quinidine via CYP3A4, and potential for serotonin syndrome with dextromethorphan (e.g., if used with SSRI or tricyclic). 27 Serious adverse effects include falls and QT prolongation. 21,27 a. Patients with dementia may not be able to tell you they hurt. 4 Consider an empiric analgesic trial in patients with persistent agitation. 33 Look for evidence of pain when patients are moving or walking. 5 Use acetaminophen for musculoskeletal pain. Topicals such as Lidoderm (U.S.), or topical NSAIDs (e.g., Pennsaid) for nonneuropathic pain, are options if pain is localized. Oral NSAIDs are not first-line, and should be used with gastroprotection (e.g., proton pump inhibitor). Consider opioids for moderate to severe pain, especially when pain adversely affects quality of life or function. Oral agents for neuropathic pain include venlafaxine, duloxetine, gabapentin, or pregabalin. 4 Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

5 (Clinical Resource #330601: Page 5 of 6) Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65: Project Leader in preparation of this clinical resource (330601): Melanie Cupp, Pharm.D., BCPS References 1. Kales HC, Gitlin LN, Lyketsos CG. Assessment and management of behavioral and psychological symptoms of dementia. BMJ 2015 Mar 2;350:h369.doi: /bmj.h Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. s (Accessed April 29, 2017). 3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; (Accessed April 30, 2017). 4. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc 2009;57: Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary expert consensus statement on assessment of pain in older persons. Clin J Pain 2007;23:S1 S Clinical Resource, Potentially Harmful Drugs in the Elderly: Beers List. Pharmacist s Letter/Prescriber s Letter. December Lonergan E, Luxenberg J. Valproate preparations for agitation in dementia. Cochrane Database Syst Rev 2009 Jul 8;(3):CD Olin JT, Fox LS, Pawluczyk S, et al. A pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistant outpatients with Alzheimer disease. Am J Geriatr Psychiatry 2001;9: Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998;155: Suzuki H, Gen K. Clinical efficacy of lamotrigine and changes in the dosages of concomitantly used psychotropic drugs in Alzheimer s disease with behavioral and psychological symptoms of dementia: a preliminary open-label trial. Psychogeriatrics 2015;15: Banerjee S, Hellier J, Dewey M, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebocontrolled trial. Lancet 2011;378: Clinical Resource, Benzodiazepine Toolbox. Pharmacist s Letter/Prescriber s Letter. August Centers for Medicare and Medicaid Services (CMS). Letter regarding State Operations Manual (SOM) surveyor guidance revisions related to psychosocial harm in nursing homes. March 25, and- Certification/SurveyCertificationGenInfo/Downloads/ Survey-and-Cert-Letter pdf. (Accessed April 29, 2017). 14. Lyketsos CG, DelCampo L, Steinberg M, et al. Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch Gen Psychiatry 2003;60: Porsteinsson AP, Drye LT, Pollock BG, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized controlled trial. JAMA 2014;311: Pollock BG, Mulsant BH, Rosen J, et al. A doubleblind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry 2007;15: [abstract]. 17. Herrmann N, Lanctot KL, Hogan DB. Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia Alzheimers Res Ther 2013;5(Suppl 1):S Sadowsky CH, Galvin JE. Guidelines for the management of cognitive and behavioral problems in dementia. J Am Board Fam Med 2012;25; American Geriatrics Society. Ten things clinicians and patients should question. Choosing Wisely. Revised April 23, content/uploads/2015/02/ags-choosing-wisely- List.pdf. (Accessed April 29, 2017).

6 (Clinical Resource #330601: Page 6 of 6) 20. Declercq T, Petrovic M, Azermai M, et al. Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database Syst Rev 2013;(3):CD Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA 2015;314: Lebert F, Stekke W, Hasenbroekx C, Pasquier F. Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord 2004;17: Alzheimer Society Canada. Delusions and hallucinations. October 11, (Accessed April 29, 2017). 24. Maust DT, Kim HM, Seyfried LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry 2015;72: American Geriatrics Society. Guide to the management of psychotic disorders and neurospsychiatric symptoms of dementia in older adults. April ines_for_telligen.pdf. (Accessed April 30, 2017). 26. American Psychiatric Association. Guideline watch for the practice guideline for the treatment of patients with Alzheimer s disease and other dementias. ctice_guidelines/guidelines/alzheimerwatch.pdf. (Accessed April 30, 2017). 27. Prescribing information for Nuedexta. Avanir Pharmaceuticals, Inc. Aliso Viejo, CA January Clinical Resource, Chronic Meds in the Elderly: Taking a Less is More Approach. Pharmacist s Letter/Prescriber s Letter. November Clinical Resource, Common Oral Medications That May Need Tapering. Pharmacist s Letter/Prescriber s Letter. March Product monograph for Risperdal. Janssen, Inc. Toronto, ON M3C 1L9. November Centers for Medicare and Medicaid Services (CMS). State Operations Manual (SOM) surveyor guidance revisions related to psychosocial harm in nursing homes. March 25, and- Certification/SurveyCertificationGenInfo/Downloads/ Survey-and-Cert-Letter pdf. (Accessed May 10, 2017). 32. Tariot PN, Schneider LS, Cummings J, et al. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry 2011;68: Husebo BS, Ballard C, Sandvik R, et al. Efficacy of treating pain to reduce behavioural disturbances in residents of nursing homes with dementia: cluster randomised clinical trial. BMJ 2011;343:d4065. doi: /bmj.d4065. Cite this document as follows: Clinical Resource, Pharmacotherapy of Dementia Behaviors. Pharmacist s Letter/Prescriber s Letter. June Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2017 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com

7 This Clinical Resource gives subscribers additional insight related to the Recommendations published in June 2017 ~ Resource # Pharmacotherapy of Dementia Behaviors Algorithm These are examples of a stepwise approach to pharmacotherapeutic interventions for dementia-related neuropsychiatric symptoms. 1,2 Nonpharmacologic management is generally preferred. Pharmacotherapy is of limited efficacy; assess risk/benefit frequently. 1 The flowchart is not inclusive of all therapy options. Options listed may not be appropriate for all patients, for example, patients with Lewy Body or Parkinson s dementia have special considerations. For these patients, see our chart, Parkinson s Dementia and Dementia with Lewy Bodies. Psychosis (delusions, hallucinations, paranoia) causing significant distress or safety issue Aggression or Agitation Anxiety Irritability Depression Atypical Antipsychotic or benzo (acute agitation) a,b Danger To Self/ Others SSRI (citalopram has the most data) b,c Anticonvulsant b SSRI, SNRI, buspirone, trazodone b Benzodiazepine (if severe) b Buspirone, trazodone b Antidepressant efficacy data in dementia conflicting, but can be tried. b a. For help getting acute agitation under control quickly, see our chart, Pharmacotherapy of Acute Agitation in Adults. b. See our chart, Pharmacotherapy of Dementia Behaviors, for details about specific agents. c. Citalopram might also help with psychosis. 3

8 (Clinical Resource #330601: Page 2 of 2) Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Project Leader in preparation of this clinical resource (330601): Melanie Cupp, Pharm.D., BCPS References 1. American Geriatrics Society. Guide to the management of psychotic disorders and neurospsychiatric symptoms of dementia in older adults. April ines_for_telligen.pdf. (Accessed April 30, 2017). 2. Clinical Resource, Pharmacotherapy of Dementia Behaviors. Pharmacist s Letter/Prescriber s Letter. June Pollock BG, Mulsant BH, Rosen J, et al. A doubleblind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Pscychiatry 2007;15: [abstract]. Cite this document as follows: Clinical Resource, Pharmacotherapy of Dementia Behaviors Algorithm. Pharmacist s Letter/Prescriber s Letter. June Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2017 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com