EDITORIAL

Challenges of the Treatment of Neuropsychiatric Symptoms Associated with Dementia Benoit H. Mulsant, M.D., M.S.

or the past decade, most published studies1,2 but not all of them3 have shown that antipsychotic medications are associated with a significant risk of mortality and morbidity in older patients with dementia. Guidelines and expert opinion now recommend that, when treating neuropsychiatric symptoms associated with dementia, clinicians use first nonpharmacological interventions; when patients do not respond to these nonpharmacological interventions, clinicians should carefully weigh the potential risks and benefits of antipsychotics and alternative pharmacological treatment (e.g., selective serotonin reuptake inhibitors [SSRIs], cognitive enhancers, or anticonvulsants); if they decide to use an antipsychotic, they should obtain consent from the surrogate decision maker after having informed him or her of the potential risks associated with the use of antipsychotics and they should carefully document the discussion; finally, they should discontinue antipsychotics in non-responders and systematically attempt to discontinue antipsychotics after a few months in responders. Four articles in the current issue4e7 illustrate the challenges faced by clinicians when engaging in this process and by the field of geriatric psychiatry in general when trying to collect better evidence on which to base clinical algorithms and guidelines. The article by Langballe et al.4 reports on a longitudinal cohort analysis of 26,940 Norwegian outpatients with dementia who were prescribed cognitive enhancers and either an antipsychotic or other

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psychotropic medications (antidepressants, benzodiazepines, lithium, or anticonvulsants) for up to seven years. Compared with other psychotropic drugs, antipsychotics were associated with about a doubling of the risk of mortality both in the short term (during the first 30 days after initiating treatment) and in the long term (during the 2- to 7-year follow-up period). The analysis adjusted for age, sex, doses, and—as a proxy for comorbid physical conditions—drugs used for the treatment of cancer, diabetes, and cardiovascular, lung, or musculoskeletal diseases. Congruent with several previous analyses,8 haloperidol was associated with a higher mortality risk than risperidone and the risk associated with risperidone was not different from the risk associated with olanzapine or quetiapine. As in previous studies, Langballe et al.4 found a very high relative increase in the risk of mortality associated with antipsychotic use; the corresponding absolute increase, however, was quite low. During the first 30 days of use, the adjusted hazard ratio (HR) for the use of antipsychotics versus other psychotropic drugs was 2.1, corresponding to about a doubling (110% increase) of the risk. The absolute risk of dying, however, was 1.13% (93 deaths among the 8,214 outpatients treated with an antipsychotic) versus 0.42% (79 deaths among the 18,726 outpatients treated with other psychotropic drugs), yielding an (unadjusted) absolute increase of only 0.71% (1.13%e0.42%). Similarly for the 2- to 7-year follow-up period, the adjusted HR was 1.7 (about a 70% increase) but the

Received January 15, 2014; accepted January 17, 2014. From the Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Send correspondence and reprint requests to Benoit H. Mulsant, M.D., M.S., Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, 101 Stokes St. e CAMH, Bell Gateway Building e 6th Floor, Toronto, ON M6J 1H4, Canada. e-mail: [email protected] Ó 2014 American Association for Geriatric Psychiatry http://dx.doi.org/10.1016/j.jagp.2014.01.008

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Editorial absolute risk was 39.6% (479 deaths among 1,209 outpatients treated with an antipsychotic) versus 30.5% (3,484 deaths among 11,424 outpatients treated with other psychotropic medications) for an (unadjusted) absolute increase of 9.1% (39.6%e30.5%) over an average follow-up period of 4.5 years—or about 2% per year. In all likelihood, a surrogate decision maker would make a different decision if she was informed that an antipsychotic increases the chance that her loved one will die during the next 30 days by 110% (relative increase) or by 0.7% (absolute increase). Finally, as in almost all similar studies using a large administrative database, Langballe et al.4 were not able to control for “confounding by indications”, namely, the fact that neuropsychiatric symptoms for which antipsychotics are prescribed to patients with dementia may be responsible for their association with mortality as suggested in two recent studies.9,10 For instance, Lopez et al.9 showed that the use of conventional or atypical antipsychotics was associated with mortality in 947 patients with a diagnosis of probable dementia (241 of whom were treated with antipsychotics) but that this association did not remain significant once the analysis controlled for neuropsychiatric symptoms—including psychosis and agitation. This is another reminder that because one cannot control for all potentially relevant variables, a definite assessment of causality requires a randomized clinical trial (RCT). At the same time, the article by Flint et al.5 in the current issue illustrates some of the challenges when trying to ascertain causality in an RCT. After antipsychotics, the strongest evidence for the pharmacologic treatment of neuropsychiatric symptoms of dementia supports the use of SSRIs, in particular citalopram.11 SSRIs have also been associated with specific adverse effects in older patients, including an increased risk of fall reported in several observational studies. As discussed earlier, such an increased risk may be due to confounding by indications (i.e., falls due to disorders for which the SSRIs are prescribed) or by contraindications (i.e., preferential use of SSRIs in patients at higher risk for falls). Thus, Flint et al. analyzed the rate of falls in the Study of Pharmacotherapy of Psychotic Depression, an RCT that compared the efficacy and tolerability of olanzapine plus placebo versus olanzapine plus sertraline in 107 younger and 142 older nondemented patients with a major depressive disorder with psychotic features. As expected, older patients were

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significantly more likely to fall than younger patients: odds ratio (OR): 2.47; 95% confidence interval (CI): 1.08e5.65. In the older patients, sertraline was also associated with an increased risk of falls (OR: 1.56). The 95% CI was wide (0.63e3.83), however, and the difference was not statistically significant. The authors estimated that 3,361 patients would have been needed to adequately power an analysis that included both age groups or 858 older patients for an analysis limited to older patients. Trials of this size would cost between $15 million and $50 million, making it very unlikely that they will be conducted. While meta-analyses could muster the number of patients of this magnitude, Flint et al.5 note that none of the 10 published trials of SSRI in older patients provided data on the rate of falls. The issue of the low statistical power common in many pharmacological RCTs is even worse in RCTs that assess behavioral interventions for neuropsychiatric symptoms in patients with dementia.12,13 In a brief report in the current issue, Houser et al.6 compared standard activities plus group storytelling twice per week for six weeks versus standard activities in 20 older residents with dementia in a long-term care facility. There were no statistical differences between the two groups in terms of change in mood or behavior scores. The authors comment on the need for larger and longer studies. Finally, Freund-Levi et al.7 present in the current issue the results of an open RCT that compared galantamine and risperidone in the treatment of neuropsychiatric symptoms in 100 patients with mild dementia or mild cognitive impairment. Treatment was initiated on an inpatient unit and patients were followed for 12 weeks. More than 90% of subjects completed the trial and most improved and both galantamine and risperidone were associated with statistically significant and similar improvement in delusions, hallucinations, disinhibition, depression, anxiety, and apathy. Risperidone, however, was associated with statistically larger reductions in the severity of agitation (93% versus 54%) and irritability (78% versus 45%). The absence of a placebo group limits the interpretation of these results. These four studies in the current issue illustrate the limitations and the uncertainty in the available evidence guiding the treatment of neuropsychiatric symptoms associated with dementia. These limitations could be addressed by a series of multicenter RCTs involving several hundreds to thousands of

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Mulsant patients, similar to some of the RCTs for cardiovascular diseases, cancers, or human immunodeficiency virus infection that have been conducted during the past two decades. Given the public health and economic burden due to the neuropsychiatric symptoms of dementia,9 the very large costs of such trials could be justified. For a variety of reasons, however, it is unlikely that either pharmaceutical companies or governmental agencies fund such trials in the near future.14 Even if funding was available, it would take five to ten years to design, implement, complete, and report on these trials. Thus, during at least the next decade, clinicians will need to continue managing neuropsychiatric symptoms of dementia based on the evidence currently available. In the face of uncertainty, clinicians tend to rely on expert opinions and published guidelines, but when the evidence is lacking or ambiguous, guidelines are vague and one wonders what the basis for more definite expert opinion is. In the end, when our patients and their family suffer, we have to accept the uncertainty and make clinical decisions. We can rely on tried and true general principles that should guide judicious prescribing for any condition,15 including considering nonpharmacologic interventions; being skeptical about new medications or fancy but unproven theories;

avoiding unwarranted drug switching, polypharmacy, or restarting medications that have not been beneficial in the past; close monitoring for adverse effects; and discontinuing interventions that are not effective. Still, we have to recognize that although we undoubtedly help many patients with dementia (in large part due to nonspecific factors such as clinical attention), some of our treatments may hurt and even kill other patients.16 Although the level of scrutiny, criticism, and self-doubt may vary, the predicament of geriatric psychiatrists is not different from the predicament of our colleagues in the rest of psychiatry17 or in other medical specialties.18,19 We can only hope that the next generations of geriatric psychiatrists will wonder why we were struggling so much, because their harsh judgments would mean that our field has made some significant progress.20,21 Disclosure: Dr. Mulsant currently receives research support from the Canadian Institutes of Health Research, the U.S. National Institute of Health (NIH), Bristol-Myers Squibb (medications for a NIH-funded clinical trial), and Pfizer (medications for a NIH-funded clinical trial). He directly own stocks of General Electric (less than $5,000). Within the past three years, he has also received some travel support from Roche.

References 1. Hollis J, Grayson D, Forrester L, et al: Antipsychotic medication dispensing and risk of death in veterans and war widows 65 years and older. Am J Geriatr Psychiatry 2007; 15:932e941 2. Simoni-Wastila L, Ryder PT, Qian J, et al: Association of antipsychotic use with hospital events and mortality among Medicare beneficiaries residing in long-term care facilities. Am J Geriatr Psychiatry 2009; 17:417e427 3. Raivio MM, Laurila JV, Strandberg TE, et al: Neither atypical nor conventional antipsychotics increase mortality or hospital admissions among elderly patients with dementia: a twoyear prospective study. Am J Geriatr Psychiatry 2007; 15: 416e424 4. Langballe EM, Engdahl B, Nordeng H, et al: Short- and long-term mortality risk associated with the use of antipsychotics among 26, 940 dementia outpatients: a population-based Study. Am J Geriatr Psychiatry 2014; 22:321e331 5. Flint AJ, Iaboni A, Mulsant BH, et al: Effect of sertraline on risk of falling in older adults with psychotic depression on olanzapine: results of a randomized placebo-controlled trial. Am J Geriatr Psychiatry 2014; 22:332e336 6. Houser WS, George DR, Chinchilli VM: Impact of TimeSlips creative expression program on behavioral symptoms and psychotropic medication use in persons with dementia in long-term care: a cluster-randomized pilot study. Am J Geriatr Psychiatry 2014; 22:337e340

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7. Freund-Levi Y, Jedenius E, Tysen-Bäckström AC, et al: Galantamine versus risperidone treatment of neuropsychiatric symptoms in patients with probable dementia: an open randomized trial. Am J Geriatr Psychiatry 2014; 22:341e348 8. Nasrallah HA, White T, Nasrallah AT: Lower mortality in geriatric patients receiving risperidone and olanzapine versus haloperidol: preliminary analysis of retrospective data. Am J of Geriatr Psychiatry 2004; 12:437e439 9. Lopez OL, Becker JT, Chang YF, et al: The long-term effects of conventional and atypical antipsychotics in patients with probable Alzheimer’s disease. Am J Psychiatry 2013; 170:1051e1058 10. Vilalta-Franch J, Lopez-Pousa S, Calvo-Perxas L, et al: Psychosis of Alzheimer disease: prevalence, incidence, persistence, risk factors, and mortality. Am J Geriatr Psychiatry 2013; 21:1135e1143 11. Pollock BG, Mulsant BH, Rosen J, et al: A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry 2007; 15:942e952 12. Brodaty H, Burns K: Nonpharmacological management of apathy in dementia: a systematic review. Am J Geriatr Psychiatry 2012; 20:549e564 13. Stanley M, Calleo J, Bush A, et al: The peaceful mind program: a pilot test of a cognitive-behavioral therapyebased intervention for anxious patients with dementia. Am J Geriatr Psychiatry 2013; 21:696e708

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Editorial 14. Pollock BG, Mulsant BH: Between Scylla and Charybdis: antipsychotic and other psychotropic medications in older nursing home residents. CMAJ 2011; 183:778e779 15. Schiff GD, Galanter WL, Duhig J, et al: Principles of conservative prescribing. Arch Intern Med 2011; 171:1433e1440 16. Ray WA, Chung CP, Murray KT, et al: Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360:225e235 17. Mulsant BH, Eric EJ: Is there a role for antidepressant and antipsychotic pharmacogenetics in clinical practice in 2014? Can J Psychiatry 2014; 59:59e61

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18. Carney DN: Lung cancer—time to move on from chemotherapy. N Engl J Med 2002; 346:126e128 19. Weeks JC, Catalano PJ, Cronin A, et al: Patients’ expectations about effects of chemotherapy for advanced cancer. N Engl J Med 2012; 367:1616e1625 20. Lerner BH: Last-ditch medical therapy—revisiting lobotomy. N Engl J Med 2005; 353:119e121 21. Malmberg L, Fenton M: Individual psychodynamic psychotherapy and psychoanalysis for schizophrenia and severe mental illness. Cochrane Database Syst Rev 2000; (2): CD001360

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Challenges of the treatment of neuropsychiatric symptoms associated with dementia.

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