Robin McAtee, Ph.D. is an assistant professor and director of the Arkansas Geriatric Education Collaborative in the UAMS College of Medicine Department of Geriatrics.
Dr. Robin McAtee is the Primary Investigator and Project Director of the UAMS Arkansas Geriatric Education Collaborative, a Geriatric Workforce Enhancement Grant from the Health Resources and Services Administration Health Services.   She has been focused in geriatrics for the past 20 years. She has worked extensively with national foundations and federal agencies to bring in almost $20 M for caregiver and geriatric focused training in Arkansas.

By Priya Priyambada, MD
AGEC Geriatric Fellow
Assistant Professor, College of Medicine Geriatrics
University of Arkansas for Medical Sciences

The elderly population is the fastest growing cohort of people in the United States. The number of Americans 65 and older is approximately 46 million presently but this number is projected to double by 2060, comprising 24% of the U.S. population. As dementia is a disease of elderly people, prevalence of dementia continues to rise with this shift in the population dynamics. According to the Alzheimer’s Association, there were 5.7 million people with dementia in the United States in 2018.

As dementia progresses, in addition to the problems with physical health, behavioral disturbances become more frequent. Studies have shown that up to 80% of the patients with dementia may suffer from behavioral disorders and these continue to worsen with the progression of dementia.

The behavioral disturbances are broadly categorized into mood disorders, psychotic disorders, sleep problems, agitation or aggression and disinhibition. These neuropsychiatric symptoms lead to functional impairment in patients with dementia resulting in premature nursing home placement.

Common mood disorders include anxiety, depression and mania. Depressive symptoms often occur early in dementia when patients still have some insight and are either aware of their decline or have been diagnosed as having dementia. The diagnosis of dementia can be frightening for the patient and symptoms can range from sadness and tearfulness to a total lack of interest in activities and apathy. There may be neglect in self-care activities such as grooming, feeding and reduced socialization. Patients with dementia should be screened for depression and appropriate treatment should be started. Careful attention should be given to the side effects and interactions of anti-depressants with the medications the patient is already taking. Patient can also have irritability and impulsivity leading to agitation and aggressive behavior which can endanger the patients as well as caregivers. In many cases behavioral symptoms can occur concomitantly with evidence of paranoia or delusional thinking or hallucinations which are termed as “psychotic” symptoms. Behavioral symptoms with features of hyperactivity, mood lability, disinhibition and grandiose belief can occur occasionally that resemble manic episodes associated with bipolar affective disorder. When it is unclear if the neuropsychiatric symptoms are related to dementia or when other strategies of non-pharmacological management are needed, a referral to a neuropsychologist is highly recommended. Neuropsychologists can provide counseling for the patient and well as caregivers.

As people age, sleep generally becomes lighter and more fragmented causing frequent arousals and awakenings during the night. Changes in sleep patterns can worsen with dementia leading to insomnia, reversal of sleep awake cycle or hypersomnia. Sleep also becomes more disorganized during acute illness and during hospitalization. Following good sleep hygiene and being physically active during daytime is helpful for a good night’s sleep. Non-sedating medications like melatonin are preferred if pharmacological intervention is required.

Behavioral disturbances can have significant impact on the wellbeing and quality of life of patients and caregivers. The worsening of behavior in individuals with dementia is the leading cause of caregiver stress, repeated hospitalizations, increased utilization of health care facilities, nursing home placements, and ultimately increased economic burden for the family and society. Neuropsychiatric symptoms described above may also be the first indication of dementia even before cognitive decline is recognized.

Although behavioral disturbances can accompany dementia, whenever there is an abrupt change in dementia, it is termed an acute change in mental status or delirium. Delirium can occur in any older adult who is severely ill. However it occurs frequently in patients with dementia even with minor illness and is called delirium superimposed on dementia. Delirium requires rapid clinical evaluation with laboratory tests and often requires hospitalization. A patient with delirium can appear agitated (hyperactive delirium) or quiet and depressed (hypoactive delirium). The common and treatable causes of delirium, both hyperactive or hypoactive, include acute illness like urinary tract infections, respiratory infections, metabolic abnormalities or the side effects of medications. It is important to diagnose delirium and not mistake it for worsening dementia because unlike dementia, delirium is quite reversible with appropriate treatment of the underlying cause.

Some behavioral disturbances are inevitable with worsening of dementia, and measures should be taken to provide education on dementia to family members, close friends, nursing staff, social workers, geriatricians and other healthcare providers and ensure a good support system. As the causes of behavioral disturbances are multifactorial, management should be comprehensive and multidisciplinary. Non-pharmacological interventions should always be used as first-line treatment in the management of behavior symptoms in dementia. The important non-pharmacologic measures are listed below:

1. Evaluation and treatment of underlying medical conditions: reversible and common causes like pneumonia, urinary tract infections, other systemic infections; fever; dehydration; electrolyte disturbances; thyroid disorders; hypo- and hyperglycemia should always be considered in the evaluation of the behavioral disturbances. Prompt treatment of these conditions is rewarding, can avoid hospitalizations or reduce the length of stay and should always be the priority in the care of people with dementia.
2. Review of medications: it is very crucial to review medication history in detail. Use of medications that affect the central nervous system and withdrawal from medications with addictive potential can lead to behavioral disturbances. Avoiding medications like benzodiazepines, antihistamines, anticholinergics (atropine, benztropine, scopolamine) and opioids are the cornerstone for the management of behavioral disturbances. It is important to ask and counsel patients and caregivers about alcohol use and over-the-counter medications for insomnia, allergies or cough that might aggravate behavioral issues.
3. Pain management: pain is an important source of behavioral disturbances in patients with dementia. There should be good balance between adequate pain management and avoiding opioids. Chronic pain should be managed with non-pharmacological measures like physical therapy and with non-opioids like acetaminophen.
4. Miscellaneous: other nonpharmacological interventions like orientation of day and night with blinds up during the day and lights switched off at night time, minimizing noise and disturbances at night-time, ensuring presence of family member(s) at bedtime as much as possible especially at night time, ensuring adequate sleep at night, avoiding arguments with the patients. Restrains are commonly used specially in hospitals and nursing homes when these patients develop agitation or aggression. However, using restraints is not good practice and the agitation gets worse with restraints and these should be avoided.

The non-pharmacologic therapies like aromatherapy, exercise training, music, art, pet therapy and caregiver education have also demonstrated some benefit for the behavior symptoms.

Pharmacologic treatment of behavioral disturbances in dementia is of limited efficacy. It should be used only after environmental and non-pharmacologic interventions have been implemented and tried.

Anti-dementia medications like cholinesterase inhibitors may have additional benefit for cognition and function and hence can be used for patients with neuropsychiatric symptoms and mild to moderate dementia. Patient with behavior disturbances secondary to Lewy body dementia may also receive benefit from acetylcholinesterase inhibitors.

Antidepressants should be considered in patients with dementia who are experiencing mood symptoms like anxiety, depression, resulting in significant distress or functional impairment. Serotonin receptor uptake inhibitors have been a preferred choice for their favorable adverse-event profiles. Studies have demonstrated the efficacy of sertraline and citalopram versus placebo.

If the non-pharmacological measures are unsuccessful for the neuropsychiatric symptoms in dementia, particularly psychosis, and if there is imminent danger to patient or caregiver due to agitation and aggression, antipsychotics might be needed. Both first and second generation antipsychotics have been identified with increased mortality and adverse-events. Evaluation of the cardiac rhythm and electrolytes needs to be performed at the commencement of these medications and at regular intervals thereafter. Therefore these medications should always be used short-term when possible, with regular reassessments of risks and benefits.

In brief, behavioral disturbances in dementia can be quite challenging and the role of education and support cannot be over-emphasized. A multidisplinary approach with geriatric focused healthcare providers, including neuropsychologists, nurse educators, pharmacists and social workers might provide the greatest benefit for the patient and caregiver dyad and improve their quality of life.

References

1. Alzheimer’s Association, 2018
2. Eastwood R., Reisberg B. Mood and behaviors. In: Gauthier S, ed. Clinical Diagnosis and Management of Alzheimer’s Disease. London, UK: Martin Dunitz; 1996;XX:175–190
3. Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer’s disease. Neurology. 1996 Jan; 46(1):130-5.
4. Teri L., Borson S., Kiyak A., et al. Behavioral disturbance, cognitive dysfunction and functional skill: prevalence and relationship in Alzheimer’s disease

5. Geriatrics at your Fingertips, 17th edition, New York, American Geriatric Society 2015

by Sathyanand Kumaran, MFSc, MS, PharmD and Lisa Hutchison, PharmD, FCCP, MPH, BCPS, BCGP
University of Arkansas for Medical Sciences (UAMS) College of Pharmacy

Delirium is a common clinical syndrome characterized by inattention and acute cognitive dysfunction and manifests clinically with a wide range of neuropsychiatric abnormalities. ¹ It can occur at any age, but it occurs more commonly in patients who are elderly and have a previously compromised mental status. One of the common features associated with delirium is disturbances of sleep. ² Disturbances in the sleep-wake cycle observed in delirium include daytime sleepiness, nighttime agitation, and disturbances in sleep continuity. In some cases, complete reversal of the night-day sleep-wake cycle or fragmentation of the circadian sleep-wake pattern can occur. Pharmacological treatment for delirium after non-pharmacologic measures have failed includes antipsychotics such as haloperidol, risperidone, olanzapine and quetiapine. ¹ However, the antipsychotic medications have several side effects including prolonged QT intervals, extrapyramidal symptoms, and increased risk of fatal cardiovascular incidents. ³

The pathophysiology of delirium is still unclear. ⁴ Multiple inflammatory and cholinergic pathways are likely involved and melatonin might play an important role. Melatonin is an important modulator of circadian rhythm, especially sleep-wake cycle. The results from observational studies suggest people with delirium have lower plasma and salivary melatonin than those without delirium. ^5,6  Several studies in older adults provide support for use of melatonin in delirium, particularly as prophylaxis to prevent its occurrence.

In a study assessing the role of perioperative melatonin in the prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly, 300 patients over 65 years of age were randomly distributed to one of the four groups. ⁷ Group 1 was the control and received nothing for sedation. Group 2 received 5 mg melatonin. Group 3 received 7.5 mg midazolam and Group 4 received 100 µg clonidine. These medications were given orally the night before the operation and another dose 90 min before the scheduled time for hip arthroplasty. Patients who developed postoperative delirium received melatonin for three successive days.   The percentage of postoperative delirium in the control group was 32.65% compared to the melatonin group which was 9.43% (p < 0.05). Melatonin was successful in treating 58.06% of patients who demonstrated postoperative delirium (36/62 patients). Overall this study supports melatonin as useful in decreasing postoperative delirium when used preoperatively and in treating postoperative delirium. Some of the weaknesses in this study were exclusion of patients with underlying dementia, severe infections, and acute cardiac events. As a result, the study population is not a true representation of patients who would develop delirium.

Al-Aama et al evaluated low dose melatonin in decreasing delirium. ⁸ A randomized, double-blinded, placebo-controlled study was conducted at an internal medicine service. One hundred and forty patients were randomized to receive either 0.5 mg of melatonin or placebo every night for 14 days or until discharge. The primary outcome was the occurrence of delirium. Melatonin was associated with a lower risk of delirium (12% vs 31%, p = 0.014), with an odds ratio adjusted for dementia and comorbidities of 0.19 (95% CI 0.06 – 0.32).

In a study conducted by de Jonghe et al, 378 patients who were scheduled for acute hip surgery received 3 mg melatonin or placebo for 5 consecutive days. ⁹ The primary outcome was incidence of delirium within 8 days of admission. No effect of melatonin on the incidence of delirium was observed in the study: 55/186 (29.6%) in the melatonin group versus 49/192 (25.5%) in the placebo group. However, the duration of delirium was lower with melatonin compared to placebo.

In another randomized placebo-controlled trial, ramelteon was associated with lower risk of delirium (3% vs 32%; p = 0.03). ¹⁰ Sixty-seven patients were randomly assigned to either ramelteon or placebo every night for 7 days. The primary outcome measure was incidence of delirium.  Although the study showed a lower risk of delirium with ramelteon, the sleep metrics between the two treatments were not different. The investigators mention that melatonin may be preventing delirium by a different pathway other than via sleep. In addition, the study excluded very seriously ill patients and patients with certain types of dementia such as Lewy body dementia.

In a retrospective, observational cohort study evaluating the effectiveness of melatonin for the prevention of intensive care unit delirium, 117 adults who received melatonin for at least 48 hours were compared to a control group of 115 adults. ¹¹ The primary outcome was development of delirium. The development of delirium was significantly lower in the melatonin group: 9 (7.7%) versus 28 (24.3%) patients (p = 0.001).

Although not conclusive, the above studies support use of melatonin prophylaxis in elderly hospitalized patients. However, all the studies had a small population size, the scales for measuring delirium were not uniform, doses of melatonin were different, and exclusion criteria varied from one study to another. It is not clear whether the patients in these randomized controlled studies were treated in the ICU or other units with less aggressive care. Given the fact that the incidence of delirium is as high as 82% in patients in the intensive care, it would be worthwhile to include these patients in the clinical trials. It is not clear whether there is a true benefit with the use of melatonin in all elderly patients admitted to hospitals. Some subgroups of elderly patients might benefit with the use of prophylactic melatonin such as critically ill patients. Interestingly, the studies did not show a difference in sleep parameters between placebo and melatonin which is thought to be the primary effect of melatonin. Larger randomized controlled trials with standard melatonin doses are needed to establish efficacy. However, since the side effects are few and some studies indicate a possible benefit, administering prophylactic melatonin to hospitalized critically ill elderly patients at high risk for development of delirium may be considered.

References

1. Fong TG, Tulebaev SR, Inouye SK. Delirium in elderly adults: diagnosis, prevention and treatment. Nat Rev Neurol. 2009;5(4):210–220. doi:10.1038/nrneurol.2009.24.
2. APA. Diagnostic and Statistical Manual of Mental Disorders. Text Revision (DSM-IV-TR). 4th ed Arlington, VA: American Psychiatric Press; (2000). p. 553–7
3. Blaszczyk AT, Hutchison LC. Central nervous system disorders. In: Hutichison LC, Sleeper RB, EDS. Geriatric Pharmacotherapy 2^nd ed. American Society of Health System Pharmacists, Bethesda, MD.
4. Choy SW, Yeoh AC, Lee ZZ, Srikanth V, Moran C. Melatonin and the Prevention and Management of Delirium: A Scoping Study. Front Med (Lausanne). 2018;4:242. Published 2018 Jan 8. doi:10.3389/fmed.2017.00242
5. Yoshitaka S, Egi M, Morimatsu H, Kanazawa T, Toda Y, Morita K. Perioperative plasma melatonin concentration in postoperative critically ill patients: its association with delirium. J Crit Care. 2013. 28(3):236–42.10.1016/j.jcrc.2012.11.004
6. Angeles-Castellanos M, Ramirez-Gonzalez F, Ubaldo-Reyes L, Rodriguez-Mayoral O, Escobar C. Loss of melatonin daily rhythmicity is associated with delirium development in hospitalized older adults. Sleep Sci. 2016: 9(4):285–8.10.1016/j.slsci.2016.08.001
7. Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth. 2010;4(3):169–173. doi:10.4103/1658-354X.71132
8. Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM,Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011: 26(7):687–694. doi:10.1002/gps.2582
9. De Jonghe A, van Munster BC, Goslings JC, et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. CMAJ. 2014;186(14):E547–E556. doi:10.1503/cmaj.140495
10. Hatta K, Kishi Y, Wada K, et al. Preventive Effects of Ramelteon on Delirium: A Randomized Placebo-Controlled Trial. JAMA Psychiatry. 2014;71(4):397–403. doi:10.1001/jamapsychiatry.2013.3320
11. Baumgartner L, Lam K, Lai J, Barnett M, Thompson A, Gross K, Morris A. Effectiveness of melatonin for the prevention of intensive care unit delirium. Pharmacotherapy. 2019:39(3) 280-287

By Christopher S. Walter, PT, DPT, PhD
AGEC Geriatric Fellow
Assistant Professor
Department of Physical Therapy
University of Arkansas for Medical Sciences – Fayetteville

Have you ever considered that your current treatment of drug therapies is not working for you? If you have, you aren’t alone. In fact, the top-ten highest grossing drugs in the United States only benefit 4-33% of the people who take them¹.  Unfortunately, research suggests that motor rehabilitation therapies are no different².

Rehabilitation is the action of restoring someone to health or normal life through therapy after an injury, illness, or disease process. Generally speaking, we know that rehab works.  For example, an individual who gets therapy following an injury (e.g., fractured hip, stroke, etc.) is more likely to improve faster, and to a greater extent, than someone who does not get therapy.  This is good news for those getting therapy and those in the rehab field.  However, a closer, individualized look at the process shows that it’s not all sunshine and roses. Some individuals have very good results after rehabilitation, while others show little to no improvement².  This problem is made worse by the fact that the rehab clinician (i.e., physical therapist, occupational therapist, and/or other allied healthcare provider) is unable to predict who might or might not respond to therapy.

The problem is clear; the solution is not.  Science has yet to develop a process that predicts who will respond to therapy and who will not respond.  We do know that age is a factor.  The older the patient, the less they respond to the given therapies^3-5.

There is good news, though. Just because an individual does not respond to one intervention does not mean he/she will not respond to all interventions.   To put this into perspective, consider the following example.  If a medication prescribed by your doctor to lower your cholesterol does not have the desired effect, your doctor could 1) prescribe a larger dose of that medication, or 2) choose a different drug all together.  The goal to lower cholesterol is the same only the method has changed.   Rehabilitation is no different.

There are steps that rehab therapists and professionals can take to ensure that therapy is successful for as many people as possible. First, our treatments should only be selected after thoughtful examination of the patient’s individual characteristics. Further, it is important that our interventions are evidence based with documented effectiveness.  This is where we need your help. You can help by signing up to be a participant in rehab research trials.  Reach out to the local university to see if there is an open study for people like yourself.  Additionally, ARresearch.org is a secure website that allows the community a first-hand look at the research being conducted at UAMS.  Volunteers can provide their information if interested in participating in research. The researchers are then able to contact potential volunteers for their studies.

The goal of rehabilitation is to restore health and quality of life following an injury. To meet this goal, rehab professionals must work to identify characteristics that separate those who will respond to therapy from those who will not.  With passionate professionals and an enthusiastic community willing to volunteer, we can close the gap on rehab success.

1. Schork NJ. Personalized medicine: Time for one-person trials. Nature. 2015;520:609-611.
2. Winstein C. Translating the Science into Neurorehabilitation Practice: Challenges and Opportunities (The Kenneth Viste, Jr. MD Lecture). American Society of Neurorehabilitation Annual Meeting. Washington, DC.2013.
3. Dobkin BH, Nadeau SE, Behrman AL, et al. Prediction of responders for outcome measures of locomotor Experience Applied Post Stroke trial. J Rehabil Res Dev. 2014;51:39-50.
4. Rodeghero JR, Cleland JA, Mintken PE, Cook CE. Risk stratification of patients with shoulder pain seen in physical therapy practice. J Eval Clin Pract. 2017;23:257-263.
5. Walter CS, Hengge CR, Lindauer BE, Schaefer SY. Declines in motor transfer following upper extremity task-specific training in older adults. Exp Gerontol. 2018;116:14-19.

By Katie Cummins, PharmD Candidate 2019 and Lisa Hutchison, PharmD, MPH, BCPS, BCGP, FCCP
Donald W. Reynolds Institute on Aging at UAMS

As our patients age, their bodies undergo physiological changes that alter their responses to many drugs. Kidney and liver function decline so that some drugs stay in the body longer or accumulate to dangerous levels. Body composition changes – muscle decreases while the proportion of fat increases – can lead to the need for smaller doses or longer dosing intervals. In addition, older adults are generally more sensitive to many drugs, especially those that affect the central nervous system. Patients are sensitive to both the effects the drugs are designed for as well as their negative side effects.¹

Medications that are “potentially inappropriate” for older adults are detailed in the Beers’ Criteria. The Beers’ list is a tool for providers to help identify medications that could be problematic for older patients. It can also be used as a guide for future drug selection. Some of the concerns outlined in the 2015 Beers’ criteria include adverse events like: dizziness, drowsiness, constipation, confusion, bleeding risk, orthostatic hypotension, and delirium.²

However, these side effects are not limited to prescription drugs; the over-the counter (OTC) section of the pharmacy contains medications that may be inappropriate or even dangerous to older adults. Though they may appear to be safer options since they are widely available, they are not without risk for harm. Some of these potentially inappropriate OTC medications are:

1. Diphenhydramine: also known as Benadryl³
   1. Commonly found in products branded as PM or Nighttime – Tylenol PM, Advil PM, Unisom, ZzzQuil, Delsym Cough+Cold Nighttime, Theraflu Nighttime Severe Cold and Cough
   2. Used as sleep aid or anti-histamine for allergies
   3. Side effects: confusion, drowsiness, dizziness, delirium, dry mouth, constipation
2. Oxybutynin: also known as Oxytrol for Women⁴
   1. Topical patch marketed for overactive bladder
   2. Side effects: drowsiness, delirium, dizziness, dry mouth, constipation
3. Meclizine: also known as Dramamine Less Drowsy, Bonine⁵
   1. Commonly found in products marketed for motion sickness or vertigo
   2. Side effects: dizziness, drowsiness, dry mouth, constipation, can worsen dementia symptoms
4. NSAIDs (non-steroidal anti-inflammatory drugs): ibuprofen, naproxen,
   1. Common brand names: Motrin, Advil, Aleve
   2. May increase risk of GI bleeding, cardiac events²
      1. Take extra caution if taking daily aspirin or prescription blood thinners or anti-platelets like warfarin, clopidogrel (Plavix), prasugrel (Effient), apixaban (Eliquis), dabigatran (Pradaxa)
5. PPIs (proton pump inhibitors): such as omeprazole, lansoprazole
   1. Common brand names: Prilosec, Prevacid
   2. May contribute to bone loss with long-term use which increases fracture risk with a fall
   3. Can increase risk of bacterial C. difficile infections – symptoms include severe diarrhea²

This is not to say that older adults should avoid all OTC products in the community but rather to show that it is important to for providers to ask if they are taking these products. Documenting this information can prevent the need for additional prescriptions to treat side effects that may be caused by an OTC product – halting a prescribing cascade in its tracks.

References

1. Hajjar ER, Gray SL, Slattum Jr PW, Hersh LR, Naples JG, Hanlon JT. Geriatrics. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; http://accesspharmacy.mhmedical.com/content.aspx bookid=1861&sectionid=146077984. Accessed July 26, 2018.
2. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society. 2015;63(11):2227-2246. doi:10.1111/jgs.13702.
3. Diphenhydramine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed July 26, 2018.
4. Oxybutynin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed July 26, 2018.
5. Meclizine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed July 26, 2018.