Neuropsychiatric symptoms of dementia are common and have an enormous impact on patients, their caregivers, and the health care system. Behavioral or psychologic symptoms (such as depression, apathy, agitation, or psychosis) develop in nearly all patients over the course of their illness.1 These symptoms, especially agitation or psychosis, cause considerable caregiver distress and hasten institutionalization of patients.2,3 Thus, it is no surprise that neuropsychiatric symptoms lead to increased direct costs of care associated with formal long-term care as well as unpaid caregiving.4
Despite the significant burden of these symptoms, there are few evidence-based treatments for providers and their patients to consider. Currently there are no US Food and Drug Administration (FDA)-approved medications for the treatment of neuropsychiatric symptoms in dementia. Regardless, the largest number of prescriptions for atypical antipsychotics in older adults is for behavioral disturbances in people with dementia.5 Antipsychotic medications are often used as off-label treatments for agitation, aggression, or psychosis—even as both the American Geriatric Society and the American Psychiatric Association have recently included such use on their lists of “Things Physicians and Patients Should Question” for the Choosing Wisely campaign.6,7
The appropriate use of these medications in older adults with dementia can be challenging due to several important safety concerns. Pharmacotherapy in older adults in general is different than in younger adults due to age-associated changes in pharmacodynamics and pharmacokinetics, as well as higher rates of medical comorbidities, which increase the risk of polypharmacy and with it drug-drug interactions and adverse drug events.8 Additionally, there are risks attributed to the use of antipsychotics in older adults, and specific risks for patients with dementia. Understanding these risks and the potential benefits from these medications is essential for patients to make informed decisions about treatment choices. An informed-consent discussion provides this information to patients, helps establish a trusting therapeutic relationship, and facilitates shared decision-making and the discussion of care goals.
Informed consent is the process by which a health care provider discloses appropriate information to a competent patient so a voluntary choice to accept or to refuse treatment can be made. It is an interactive process that involves a continuing conversation between the provider and the patient, integrated throughout the course of diagnosis and treatment.9 Thus, it requires an ongoing discussion as new side effects arise or illness progresses, allowing the provider and the patient to re-evaluate the treatment decision throughout the course of an illness. When a patient is deemed legally incompetent, or when he or she is physically or mentally incapable of giving consent, a surrogate decision-maker must be sought. In an older, frail patient who remains competent to make decisions but who relies upon caregivers for daily support, providers should consider asking the patient whether he or she would like to involve caregivers in the informed consent process as well. As this article proceeds, references to discussions between providers and the patient should be assumed to refer, when appropriate, to conversations with surrogate decision-makers or caregivers.
Informed consent for use of antipsychotic medications in the course of treatment for patients with neuropsychiatric symptoms of dementia should include sufficient discussion and documentation of each of the following components: (1) the patient’s diagnosis and prognosis; (2) the recommended treatment; (3) the risks and benefits of the recommended treatment; (4) alternative treatments; (5) the risks and benefits of alternative treatments; and (6) the risks of refusing or foregoing treatment.
Diagnosis, Prognosis, and Recommended Treatment
The patient’s diagnosis and prognosis should be established as the first step of any informed-consent conversation. Providers should discuss the serious clinical consequences for patients with dementia and agitation, noting the increased mortality associated with behavioral disturbance in general and wandering combined with falls in particular.10 Providers should also explain that patients with neuropsychiatric symptoms of dementia have a decreased quality of life, more rapid cognitive decline, and increased mortality rate.11,12
The specific medication being recommended, including the fact that it is being used as an off-label treatment without FDA-approval for use in dementia, should be discussed explicitly with patients. Providing patients with the generic as well as the brand name in written communication ensures that patients remember this information after the encounter.
Risks Associated with Antipsychotics Use in Dementia
Providers should discuss the general risks associated with use of antipsychotic medications in older adults, as well as the specific risks associated with use in patients with dementia (Table 1). Older adults are more susceptible to the sedation, anticholinergic symptoms (eg, constipation, confusion, and urinary retention), orthostatic hypotension, and extrapyramidal symptoms (EPS) associated with use of antipsychotics. Older patients treated with conventional antipsychotics are particularly at risk for increased rates of tardive dyskinesia (TD).13 Risk factors associated with developing TD in this population include advancing age, longer duration of use, cumulative dose, presence of acute EPS, and use of high-potency agents. Older adults, especially those with comorbid cardiac disease, should also be informed of, and carefully monitored for, potential QTc prolongation, particularly with use of agents like thioridazine, quetiapine, and ziprasidone.
Risks Associated with Antipsychotic Use in Older Patients with Dementia
Atypical antipsychotics have largely replaced conventional agents due to their significantly lower risks of motor side effects and somewhat better overall tolerability.14 However, they are not without concern when used in older individuals. Metabolic side effects warrant consideration and appropriate monitoring in all patients starting treatment with atypical antipsychotics. A recent study found that quetiapine, risperidone, or olanzapine carried an almost 2-fold greater risk for hospitalization with acute kidney injury (AKI) within 3 months.15 In addition, patients had an increased risk for acute urinary retention, hypotension, and even death, which are other adverse outcomes associated with AKI.
In addition to the above-noted general risks associated with conventional and atypical antipsychotics, there are specific risks linked to their use in people with dementia. The most concerning of these is the increased risk of cerebrovascular adverse events (CVAEs) such as stroke and death that led to an FDA black-box warning addition for all antipsychotics. It is imperative that providers specifically discuss the FDA black-box warning with patients when prescribing antipsychotic medications for dementia. The provider should also document that the patient is aware of this warning prior to initiating treatment.
A meta-analysis found that pooled rates of CVAEs were 1.9% in patients treated with atypical antipsychotics versus 0.9% in placebo-treated patients, meaning patients taking atypical antipsychotics have twice the risk of having a CVAE.16 Meta-analysis of the same studies found a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in the placebo group.17 Antipsychotic medications are associated with higher rates of mortality than most other medications used for the treatment of neuropsychiatric symptoms.18 Studies have also shown the risk of death in patients taking conventional antipsychotics is comparable to, or worse than, the risk with atypical antipsychotics.19
Analysis of data from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease (CATIE-AD) study (the largest study of atypical antipsychotics for psychosis or agitation/aggression in people with dementia) has identified two additional risks. Twenty percent of outpatients with Alzheimer’s disease (AD) developed significant weight gain that increased with antipsychotic treatment, reiterating the importance of metabolic monitoring.20 Patients treated with olanzapine in particular showed unfavorable changes in high-density lipoprotein cholesterol and abdominal girth. Additionally, patients receiving atypical antipsychotics performed worse than those given placebo on multiple measures of cognition.21
Benefits of Treatment with Antipsychotics in Dementia
Providers should have a frank conversation with patients about the modest overall effectiveness of both typical and atypical antipsychotics in the treatment of neuropsychiatric symptoms of dementia. Atypical antipsychotics appear to have a small but significant impact in reducing agitation and psychosis, with the best evidence base for risperidone.22 Although CATIE-AD found atypical antipsychotics were more effective than placebo, adverse effects limited their overall efficacy.23 Evidence also suggests that haloperidol is useful in the treatment of aggression (but not behaviors such as wandering or verbal agitation), although it is less well tolerated than the atypical agents.24 Antipsychotic medications have also been associated with a small but significant decrease in caregiver burden, especially caregivers of patients with severe agitation, hostility, and psychosis.25
These adverse events limit the application of these medications and suggest that providers restrict use to patients with severe, persistent, or recurrent symptoms that cause marked distress and functional impairment, or to patients who pose a risk to themselves or to others as a result of ongoing symptoms and behaviors. Treatment should be initiated only after treating or eliminating underlying medical or environmental antecedents and should be limited to cases in which nonpharmacologic measures have failed.6,7,26,27 All patients should be carefully monitored for the development of adverse events and side effects during a time-limited treatment course, given that symptoms often resolve regardless of medication use.27 An ongoing assessment of the risks and benefits should continue throughout the course of treatment, with periodic consideration given to withdrawing the medication. Further discussion of clinical management can be reviewed elsewhere.22,27
Alternatives: Risks and Benefits
Several nonpharmacologic as well as pharmacologic alternatives to antipsychotics for neuropsychiatric symptoms in dementia exist. The nonpharmacologic approaches (such as caregiver education and support, training in problem-solving, behavioral management, music therapy, aromatherapy, and communication skills training) are generally considered first-line treatment because there is some evidence to support their benefit (reduced frequency and severity of symptoms, reduced caregivers’ adverse reactions) and there is minimal potential for adverse effects.27,28 In most cases, these methods should have been tested prior to any discussion with a patient about taking antipsychotic medication for symptom control.
Medications for Dementia
Acetylcholinesterase inhibitors (AChEIs) have a limited evidence base to support their use. The behavioral symptoms most likely to improve appear to be apathy, depression, or aberrant motor behavior; AChEIs have not been found effective in the treatment of either agitation or aggression.22 AChEIs are better tolerated than are antipsychotics, and the discussion of their risks should focus on gastrointestinal (GI) intolerance (eg, nausea, vomiting, diarrhea, loss of appetite), as well as insomnia, fatigue, muscle cramps, and dizziness.
Memantine appears to provide modest benefit for the treatment of agitation and aggression in dementia. In pooled, retrospective analyses of data from three placebo-controlled trials in moderate to severe AD, memantine showed a significant reduction in agitation, aggression, or psychosis.29 Memantine is well tolerated and has occasional side effects of dizziness, headache, or somnolence, with less common occurrence of confusion, hallucinations, or agitation.
The data supporting the use of anticonvulsants is strongest for carbamazepine. There is modest but encouraging evidence to support its use targeting agitation and aggression related to AD.30 Patients should be educated about the risk for common side effects (such as dizziness, sedation, ataxia, confusion, headaches, nausea, vomiting, diarrhea, blurred vision), as well as the more rare but significant adverse effects of the syndrome of inappropriate antidiuretic hormone secretion with hyponatremia, cardiac toxicity, and hepatotoxicity, and an increased risk of suicidal ideation and behavior. Patients should also be explicitly informed of the black-box warnings for aplastic anemia and agranulocytosis, as well as rare but sometimes fatal dermatologic adverse reactions.
The evidence for valproate is mixed, with a meta-analysis of pooled results concluding that valproate is ineffective in the treatment of agitation in dementia and is associated with unacceptable rates of adverse events, notably sedation and urinary tract infections.31 Again, appropriate discussion of the risks of side effects (headache, tremor, dizziness, ataxia, nausea, vomiting, diarrhea, constipation, reduced appetite, weight gain), the increased risk of suicidal ideation and behavior, as well as the black-box warnings for rare hepatotoxicity and pancreatitis is warranted.
There is mixed evidence regarding the benefits of antidepressants to target depressive symptoms in those with dementia. Although several small trials have found selective serotonin reuptake inhibitors (SSRIs) to be efficacious in AD patients with depression, the Depression in Alzheimer’s Disease Study–Phase 2 trial (a large, multicenter trial developed by a consensus panel assembled by the National Institute of Mental Health) found no difference between administration of 100 mg of sertraline compared to placebo.32 It did note, however, that the sertraline group experienced more side effects (diarrhea, dizziness, and dry mouth) and serious adverse pulmonary events. In general, the evidence for the use of non-SSRI antidepressants (eg, mirtazapine, venlafaxine, bupropion) for depression treatment in the setting of dementia is lacking. Tricyclic antidepressants have shown similar efficacy to SSRIs, but they are generally avoided due to their intolerable anticholinergic side effects.22
There is growing evidence to support the use of SSRIs (especially citalopram) to target agitation and aggression in dementia. A recent large, randomized-controlled trial found that citalopram significantly reduced agitation as well as caregiver distress when compared to placebo.33 However, the target dose (30 mg) was higher than what is now the FDA-recommended maximum dose in adults over age 60 years (20 mg). Worsening cognition and QT prolongation were significantly higher in the citalopram-treated group. Comparator studies indicate that sertraline and citalopram are probably as effective as haloperidol or risperidone in the treatment of agitation in dementia.
The risk of mortality is lower in those with dementia taking antidepressants than in those taking antipsychotics,18 but antidepressants carry other notable risks in older adults. Prescribing SSRIs in the elderly is associated with an increased risk of bleeding, falls, and hyponatremia.34 Patients taking citalopram should be warned about dose-dependent QTc prolongation, a known side effect for this agent specifically. Patients should also be informed of common side effects of SSRIs in general, including GI distress (nausea, vomiting, constipation, or diarrhea), sexual dysfunction, insomnia, headache, sedation, dry mouth, and tremor.
Studies have shown use of other antidepressants (ie, mirtazapine, trazodone, venlafaxine) by the elderly is associated with an increased risk of all-cause mortality, attempted suicide/self-harm, stroke, fracture, and seizures when compared with other classes of antidepressants and none at all.34 Patients taking trazodone should be informed of side effects similar to SSRIs and the risk of sedation and priapism. Patients taking mirtazapine should be educated about the risk of sedation, increased appetite, and weight gain. Venlafaxine poses risks similar to SSRIs as well as a risk for hypertension. All patients prescribed a serotonergic antidepressant should be made familiar with the signs of serotonin syndrome.
There is also a small but growing literature to support the efficacy of brain stimulation, specifically electroconvulsive therapy (ECT), to treat patients with neuropsychiatric symptoms of dementia.35 Evidence shows that ECT improves symptoms of depression as well as behavioral manifestations, with safety concerns in most studies noting post-ictal confusion and delirium. It is unclear if there is any sustained impact on cognitive function when ECT is used in patients with dementia. Any consideration of ECT should also include a careful discussion of ECT risks, including adverse reactions to anesthesia, alterations in blood pressure, arrhythmias, ischemia, dental and oral trauma, prolonged apnea, aspiration, prolonged seizures, stroke, and (rarely) death.
Risks of Refusing or Foregoing Treatment
In some cases, foregoing specific treatment may be appropriate. Careful discussion with the patient and their caregiver about the level of distress and functional impairment experienced as a result of symptoms is essential. If distress and functional impairment are mild to moderate, and tolerable (by all involved parties), this may be a reasonable path in the short-term, while closely monitoring symptom progression.
However, in most cases with distressing symptoms or functional impairment, foregoing treatment means that a patient will be at increased risk for poor quality of life, more rapid cognitive decline, institutionalization, and death.2,11,12 Additionally, untreated neuropsychiatric symptoms lead to increased caregiver distress and burnout, a point that should be discussed with patient caregivers.3
There are no easy decisions in the management of neuropsychiatric symptoms in dementia. When management of symptoms has progressed to the point of considering antipsychotics, it is vital to confirm that a patient has all the pertinent information available about the risks, benefits, and alternatives. This will ensure that providers and patients collaborate on making decisions that best meet the patient’s needs and goals for ongoing care.
- Lyketsos CG, Carrillo MC, Ryan JM, et al. Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimers Dement. 2011;7(5):532–539. doi:10.1016/j.jalz.2011.05.2410 [CrossRef]
- Yaffe K, Fox P, Newcomer R, et al. Patient and caregiver characteristics and nursing home placement in patients with dementia. JAMA. 2002;287(16):2090–2097. doi:10.1001/jama.287.16.2090 [CrossRef]
- Allegri RF, Sarasola D, Serrano CM, et al. Neuropsychiatric symptoms as a predictor of caregiver burden in Alzheimer’s disease. Neuropsychiatr Dis Treat. 2006;2(1):105–110.
- Murman DL, Colenda CC. The economic impact of neuropsychiatric symptoms in Alzheimer’s disease: can drugs ease the burden?Pharmacoeconomics. 2005;23(3):227–242. doi:10.2165/00019053-200523030-00004 [CrossRef]
- Weiss E, Hummer M, Koller D, Ulmer H, Fleischhacker WW. Off-label use of antipsychotic drugs. J Clin Psychopharmacol. 2000;20(6):695–698. doi:10.1097/00004714-200012000-00018 [CrossRef]
- American Geriatrics Society: Ten things physicians and patients should question. http://www.choosingwisely.org/societies/american-geriatrics-society/. Accessed June 15, 2015.
- American Psychiatric Association: Five things physicians and patients should question. http://www.choosingwisely.org/societies/american-psychiatric-association/. Accessed June 15, 2015.
- Steinman MA, Hanlon JT. Managing medications in clinically complex elders: “There’s got to be a happy medium.”JAMA. 2010;304(14):1592–1601. doi:10.1001/jama.2010.1482 [CrossRef]
- Lidz CW, Appelbaum PS, Meisel A. Two models of implementing informed consent. Arch Intern Med. 1988;148(6):1385–1389. doi:10.1001/archinte.1988.00380060149027 [CrossRef]
- Walsh JS, Welch HG, Larson EB. Survival of outpatients with Alzheimer-type dementia. Ann Intern Med. 1990;113(6):429–434. doi:10.7326/0003-4819-113-6-429 [CrossRef]
- Banerjee S, Smith SC, Lamping DL, et al. Quality of life in dementia: more than just cognition. An analysis of associations with quality of life in dementia. J Neurol Neurosurg Psychiatry. 2006;77(2):146–148. doi:10.1136/jnnp.2005.072983 [CrossRef]
- Rabins PV, Schwartz S, Black BS, et al. Predictors of progression to severe Alzheimer’s disease in an incidence sample. Alzheimers Dement. 2013;9(2):204–207. doi:10.1016/j.jalz.2012.01.003 [CrossRef]
- Caligiuri MR, Jeste DV, Lacro JP. Antipsychotic-induced movement disorders in the elderly: epidemiology and treatment recommendations. Drugs Aging. 2000;17(5):363–384. doi:10.2165/00002512-200017050-00004 [CrossRef]
- Dolder CR, Jeste DV. Incidence of tardive dyskinesia with typical versus atypical antipsychotics in very high risk patients. Biol Psychiatry. 2003;53(12):1142–1145. doi:10.1016/S0006-3223(03)00170-7 [CrossRef]
- Hwang YJ, Dixon SN, Reiss JP, et al. Atypical antipsychotic drugs and the risk for acute kidney injury and other adverse outcomes in older adults: a population-based cohort study. Ann Intern Med. 2014;161(4):242–248. doi:10.7326/M13-2796 [CrossRef]
- Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006;14(3):191–210. doi:10.1097/01.JGP.0000200589.01396.6d [CrossRef]
- Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294(15):1934–1943. doi:10.1001/jama.294.15.1934 [CrossRef]
- Kales HC, Valenstein M, Kim HM, et al. Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am J Psychiatry. 2007;164(10):1568–1576; quiz 1623. doi:10.1176/appi.ajp.2007.06101710 [CrossRef]
- Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ. 2007;176(5):627–632. doi:10.1503/cmaj.061250 [CrossRef]
- Zheng L, Mack WJ, Dagerman KS, et al. Metabolic changes associated with second-generation antipsychotic use in Alzheimer’s disease patients: the CATIE-AD study. Am J Psychiatry. 2009;166(5):583–590. doi:10.1176/appi.ajp.2008.08081218 [CrossRef]
- Vigen CL, Mack WJ, Keefe RS, et al. Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: outcomes from CATIE-AD. Am J Psychiatry. 2011;168(8):831–839. doi:10.1176/appi.ajp.2011.08121844 [CrossRef]
- Gauthier S, Cummings J, Ballard C, et al. Management of behavioral problems in Alzheimer’s disease. Int Psychogeriatrics. 2010;22(3):346–372. doi:10.1017/S1041610209991505 [CrossRef]
- Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525–1538. doi:10.1056/NEJMoa061240 [CrossRef]
- Lonergan E, Luxenberg J, Colford J. Haloperidol for agitation in dementia. Cochrane Database Syst Rev. 2002;(2):CD002852.
- Mohamed S, Rosenheck R, Lyketsos CG, Kaczynski R, Sultzer DL, Schneider LS. Effect of second-generation antipsychotics on caregiver burden in Alzheimer’s disease. J Clin Psychiatry. 2012;73(1):121–128. doi:10.4088/JCP.10m06574 [CrossRef]
- Jeste DV, Blazer D, Casey D, et al. ACNP white paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology. 2008;33(5):957–970. doi:10.1038/sj.npp.1301492 [CrossRef]
- Kales HC, Gitlin LN, Lyketsos CGDetroit Expert Panel on Assessment and Management of Neuropsychiatric Symptoms of Dementia. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014;62(4):762–769. doi:10.1111/jgs.12730 [CrossRef]
- Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia. Am J Psychiatry. 2012;169(9):946–953. doi:10.1176/appi.ajp.2012.11101529 [CrossRef]
- Wilcock GK, Ballard CG, Cooper JA, Loft H. Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer’s disease: a pooled analysis of 3 studies. J Clin Psychiatry. 2008;69(3):341–348. doi:10.4088/JCP.v69n0302 [CrossRef]
- Ballard CG, Gauthier S, Cummings JL, et al. Management of agitation and aggression associated with Alzheimer disease. Nat Rev Neurol. 2009;5(5):245–255. doi:10.1038/nrneurol.2009.39 [CrossRef]
- Lonergan E, Luxenberg J. Valproate preparations for agitation in dementia. Cochrane Database Syst Rev. 2009;(3):CD003945.
- Weintraub D, Rosenberg PB, Drye LT, et al. Sertraline for the treatment of depression in Alzheimer disease: week-24 outcomes. Am J Geriatr Psychiatry. 2010;18(4):332–340. doi:10.1097/JGP.0b013e3181cc0333 [CrossRef]
- Porsteinsson AP, Drye LT, Pollock BG, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311(7):682–691. doi:10.1001/jama.2014.93 [CrossRef]
- Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ. 2011;343:d4551. doi:10.1136/bmj.d4551 [CrossRef]
- Liu AY, Rajji TK, Blumberger DM, Daskalakis ZJ, Mulsant BH. Brain stimulation in the treatment of late-life severe mental illness other than unipolar nonpsychotic depression. Am J Geriatr Psychiatry. 2014;22(3):216–240. doi:10.1016/j.jagp.2013.02.017 [CrossRef]
Risks Associated with Antipsychotic Use in Older Patients with Dementia
Metabolic side effects
Acute kidney injury
Cerebrovascular adverse events