by Rachel Briggler, PharmD candidate and Lisa Hutchison, PharmD, FCCP, MPH, BCPS, BCGP
University of Arkansas for Medical Sciences (UAMS) College of Pharmacy

 

Drug-induced parkinsonism (DIP) is one of the most common non-vascular neurological disorders in older adults but tends to go undiagnosed due to the similarities with Parkinson’s Disease (PD).^2-3 DIP is an acute movement disorder that is generally characterized by bilateral and symmetric movements with more bradykinesia (slowness of movement) and rigidity than those with PD. However, asymmetric movements are shown to occur in about 30% of cases.^1,4

The presence of other movement disorders such as akathisia (feeling of restlessness and urgent need to move), orofacial dyskinesia (involuntary, repetitive movements of mouth, tongue, and face), or tardive dyskinesia (involuntary, repetitive movements of trunk and limbs) suggest that parkinsonism is more likely to be caused by a medication and not PD.² Since there is significant overlap in their presentation, symptoms alone are not enough to distinguish DIP from PD ³

DIP is caused by the use of drugs or toxins that deplete the dopaminergic system. These drugs are often referred to as dopamine-blocking agents.^4-5 Dopamine-blocking agents that block ³80% of central dopamine receptors will produce parkinsonism symptoms in almost all patients.⁴ The clinical diagnosis of parkinsonism requires that patients meet certain criteria in order to rule out other causes of the movement disorder. The criteria includes the presence of parkinsonism, no history of parkinsonism before use of the offending drug, onset of parkinsonism symptoms during the use of the offending drug, and no significant dopamine transporter (DAT) uptake in the striatum (DAT imaging is used for the differential diagnosis between DIP and PD).¹

As patients age, dopamine cells and dopamine transporters decrease which in turn requires less dopamine receptor blockade to reach the threshold for parkinsonism. ² This puts the patient at a higher risk of developing symptoms. Some other risk factors include female sex, genetic variants, preexisting movement disorders, and cigarette smoking which can increase the likelihood of developing drug-induced parkinsonism when taking certain medications.^1,4-5 DIP usually develops between two weeks and one month following the introduction of a new medication or an increase in the dose^1,3. Knowing some of the medications that have an increased likelihood of causing DIP can potentially decrease the amount of cases seen. Some of the medications known to cause DIP are:

1. Typical Antipsychotics (the most common)
   1. Haloperidol
   2. Prochlorperazine
   3. Thioridazine
   4. Trifluoperazine
2. Atypical Antipsychotics
   1. Aripiprazole
   2. Lurasidone
   3. Olanzapine
   4. Risperidone
   5. Ziprasidone
3. Antiemetics/ Motility Agents
   1. Metoclopramide
   2. Prochlorperazine
4. Antidepressants
   1. Citalopram
   2. Fluoxetine
   3. Fluvoxamine
   4. Paroxetine
   5. Sertraline

Drug-induced parkinsonism can have a major impact on daily living so treatment can be life changing. The best way to treat this condition is to discontinue the use of the offending drug. Most cases have complete resolution of symptoms after the drug is stopped, but there are cases when symptoms may persist for months.⁴ Generally, the symptoms subside within four months but there are instances when it takes longer.⁶ It is important to give an adequate amount of time between the discontinuation of the drug and determining if there is a potential for underlying PD or Lewy body Dementia.^3,6 If symptoms persist for 36 months, then another diagnosis such as tardive dyskinesia or idiopathic PD should be considered.⁴

                Since older adults are at an increased risk of developing DIP, it is important that practitioners and pharmacists take the time to look at a patient’s medications in order to identify potential causative agents. Discontinuation, dose decrease, or a change in medication may be needed to reverse the symptoms.

 

 

References

1. Shin HW, Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012;8(1):15–21. doi:10.3988/jcn.2012.8.1.15
2. Wyant J, Kara and Chou L, Kelvin. Drug-induced parkinsonism. In: Hurtig I, Howard, ed. UpToDate. Waltham, MA: UpToDate; 2019. www.uptodate.com. Accessed June 20, 2019.
3. Pamela J and Stephen J., Williamson. Drug-Induced Parkinsonism In The Elderly. The Lancet. 2019;324:8411. Published 1984 Nov 10. Doi: 10.1016/S0140-6736(84)91516-2
4. Mehta, S., Morgan, J. and Sethi, K. (2015). Drug-induced Movement Disorders. Elsevier, 33(1), pp.153-174. Available at: https://www.sciencedirect.com/science/article/pii/S0733861914000796 .
5. Savica R, Grossardt BR, Bower JH, Ahlskog JE, Mielke MM, Rocca WA. Incidence and time trends of drug-induced parkinsonism: A 30-year population-based study. Mov Disord. 2017;32(2):227–234. doi:10.1002/mds.26839
6. Brandt J., Nicole. Detecting Drug-Induced Parkinsonism. Aging Well. 2010; 3(3): 24. http://www.todaysgeriatricmedicine.com/archive/082510p24.shtml. Accessed June 20, 2019.

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