AGITATION AND PSYCHOSIS IN DEMENTIA: PRACTICAL MANAGEMENT
Learning Objectives •Describe the clinical presentation of psychosis and agitation in dementia •Employ pharmacological and non-pharmacological treatment strategies to ameliorate psychosis and agitation in patients with dementia
PSYCHOSIS IN DEMENTIA Psychosis is a possible contributor to rejection of care, leading potentially to agitation or aggression
Prevalence of Psychosis in Dementia Stahl SM, Morrissette DM. Stahl’s Illustrated Alzheimer’s Disease and Other Dementias 2019.
Psychotic Symptoms Delusions Hallucinations • Paranoid • Visual -Items are being stolen -Seeing people (large or small) -Caregiver wants to harm person -Seeing insects or animals -Spouse is having an affair • Auditory • Misidentification -Voices -House is not one’s own -Noises -Spouse is someone strange -Music -Someone strange in the mirror • Olfactory and tactile are less common • Somatic and typically have specific medical causes (e.g., seizures, substance -Persistent, unusual symptom withdrawal ) -Parasitic infestation
Neurobiological Basis of Psychosis: 3 Theories Stahl SM, Morrissette DM. Stahl’s Illustrated Alzheimer’s Disease and Other Dementias 2019.
Neurobiological Basis of Psychosis: Dopamine Theory Stahl SM, Morrissette DM. Stahl’s Illustrated Alzheimer’s Disease and Other Dementias 2019.
Neurobiological Basis of Psychosis: Antipsychotic Treatment Stahl SM, Morrissette DM. Stahl’s Illustrated Alzheimer’s Disease and Other Dementias 2019.
Neurobiological Basis of Psychosis: Glutamatergic NMDA Theory Stahl SM, Morrissette DM. Stahl’s Illustrated Alzheimer’s Disease and Other Dementias 2019.
Neurobiological Basis of Psychosis: Serotonin 5HT2A Theory Stahl SM, Morrissette DM. Stahl’s Illustrated Alzheimer’s Disease and Other Dementias 2019.
Treating Psychosis: Antipsychotics FDA Black Box Warning Concerning the Potential Increased Mortality in Elderly Patients With Dementia-Related Psychosis Treated With Antipsychotic Agents-2008 Stahl SM, Morrissette DM. Stahl’s Illustrated Alzheimer’s Disease and Other Dementias 2019.
Treating Psychosis: Pimavanserin • 5HT2A and 5HT2C Antagonist • No dopamine D2 binding affinity • Approved for treatment of psychosis in Parkinson’s Disease • Effective in ↓ visual hallucinations without ↑ motor effects • Side effects may include peripheral edema, confusion, nausea, and potential QTc prolongation Stahl SM, Morrissette DM. Stahl’s Illustrated Alzheimer’s Disease and Other Dementias 2019; Cummings et al. J Prevention of Alzheimer's Disease. 2018;5(4):195-204.
Pimavanserin for Dementia-Related Psychosis (DRP) •On July 20, 2020 the FDA accepted filing for pimavanserin for the treatment of hallucinations and delusions associated with dementia-related psychosis (DRP) •Based on findings from the pivotal phase III HARMONY study •Pimavanserin reduced relapse of psychosis by 2.8 fold compared to placebo (Hazard ratio = 0.353; p=0.0023) Yunusa et al. Froneirs in Pharmacology. 2020;87(11):1-5
AGITATION IN DEMENTIA Caveat: Psychosis is a possible contributor to agitation, but persons with dementia without psychosis can become agitated as well!
What Is Agitation? • Hallmark features: • Motor restlessness • Irritability • Inappropriate or purposeless verbal and/or motor activity • Heightened responsivity to stimuli • Symptoms may include: • Non-aggressive symptoms • Pacing, hand wringing, fist clenching, pressured speech • Aggressive symptoms • Screaming, cursing, breaking objects, threatening others • Agitation does not necessarily entail aggression • However, aggression is often (but not always) preceded by agitation Allen et al. Gen Hosp Psychiatry 2017;47:75-82; Dundar et al. Hum Psychopharmacol 2016;31:268-85; Yu et al. Shanghai Arch Psychiatry 2016;28(5):241-52.
Agitation •Affects at least 50% of patients with AD •First-line treatment is non-pharmacological • Address potential unmet needs such as pain or hunger Porsteinsson and Antonsdottir. Exp Opin Pharmacother 2017;18(6):611-20; Lanctot et al. Alz Dem Transl Res Clin Interv 2017;3:440-9; Farina et al. Geriatr Psychiatry 2017;32:32-49; Garay and Grossberg. Exp Opin Invest Drugs 2017;26(1):121-32; Lochhead et al. Psychiatr Pol 2016;50(2):311-22; Torrisi et al. Geriatr Gerontol Int 2017;17(6):865-74.
A Vulnerable Brain: Neurocircuitry Neurocognitive disorders create a brain more vulnerable to agitation due to structural damage to key neurocircuits or networks and their functions • Affective Regulation: Our ability to perceive and interpret both emotionally- laden events and potential threats can be disrupted, leading to inappropriate and agitated emotional responses • Executive Function: Our ability to understand, organize, prioritize, and respond to challenges and problems can be disrupted, leading to disorganized, exaggerated, and dysfunctional behaviors Porsteinsson AP et al. Expert Opin Pharmacother 2017;18(6):611-20; Algase DL et al. Need-driven dementia- compromised behavior: An alternative view of disruptive behavior. American Journal of Alzheimer’s Disease & Other Dementias 1996;11(6); Hall GR et al. Arch Psychiatr Nurs 1987;1(6):399-406.
Neurobiology of Agitation 5HT • Agitation associated with DA psychosis, mania, and substance use NE =dopamine PFC imbalance • Agitation associated with GABA dementia , A depression, and Glu anxiety =GABA imbalance A: amygdala PFC: prefrontal cortex H: hippocampus S: striatum ACh Hy: hypothalamus T: thalamus NA: nucleus accumbens Stahl's Illustrated Violence. 2014; Amodeo et al. CNS Neurol Disord Drug Targets 2017; 16(8):885-90.
Acetylcholine and Agitation prolonged (supraphysiological) DA release prolonged burst of action potentials ACh neuron = nicotine VTA = Ca++ DA neuron = DA prolonged opening of Stahl's Illustrated Violence. 2014. 4ß2 channel
Assessing Agitation •Patient interview •Interview with family, friends, regular outpatient care providers •Medical history •Psychiatric history •Substance use history •Social and family histories •Mental status examination •Rating scales Garriga et al. World J Biol Psychol 2016;17(2):86-128.
Caveat: Agitation vs. Aggression • Agitation and aggression are two different syndromes—not everyone who is agitated becomes aggressive and not every episode of aggression is immediately preceded by agitation • Agitation is excessive motor or verbal activity without any focus or intent • Aggression is a provoked or unprovoked behavior intended to cause harm • Reactive aggression is often precipitated by rejection of care and may not be associated with agitation •Psychotic patients sometimes resist such care as bathing or medication treatment; this rejection of care is stressful for care providers, and is a common reason for institutionalization Volicer et al. CNS Spectrums 2017;22(5):407-14.
Assessing Agitation: Cohen-Mansfield Agitation Inventory (CMAI) Stahl SM, Morrissette DM. Stahl’s Illustrated Alzheimer’s Disease and Other Dementias 2019.
Principles of De-escalation and Environmental Safety • Respect personal space • Assure patient is physically comfortable • Do not be provocative • Offer food and/or beverages • Establish verbal contact • Offer nicotine replacement • Be concise • Decrease external stimuli • Identify wants and feelings • Minimize waiting time • Listen closely to what the patient is saying • Remove potentially dangerous objects • Agree or agree to disagree • Set clear limits • Offer choices and optimism • Debrief the patient and staff Garriga et al. World J Biol Psychol 2016;17(2):86-128.
Basic Behavioral Approaches • Empathic acknowledgement with active listening • Address unmet needs (e.g., hunger, thirst) and environmental irritants (e.g., excessive noise, heat or cold, disruptive roommates) • Focus on abilities instead of deficits • Engage family and other familial caregivers • Know the person well in terms of interests, preferences, habits • Distract and redirect • It takes a village: Informal and professional caregivers and specialists • Involve in stimulating, pleasant activities • Use individualized behavioral interventions (e.g., ABA Model) • Sensory interventions include music, massage, white noise, sensory stimulation Cohen-Mansfield J et al. J Gerontol A Biol Sci Med Sci 2007;62(8):908-16.
Rx? Pharmacologic Treatment Dilemmas •There is no universally recognized or FDA-designated indication for agitation in dementia •All psychotropic medication use is thus “off label” •Efficacy is limited and variable, with high placebo effects •There are several important potential side effects •Older individuals may be more sensitive to medications •Be aware of comorbid medical conditions •Watch for oversedation, dizziness, and blood pressure changes •Thus, non-pharmacologic approaches recommended as first-line treatment for dementia-related behaviors Kindermann SS et al. Drugs Aging 2002;19(4):257-76; Ballard C et al. Cochrane Database Syst Rev 2006;(1):CD003476.
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