Overview of Geriatric Psychopharmacology

Presented by: Ann M. Hamer, PharmD, BCPPDate: 4/16/2015

Disclosures and Learning Objectives

• Learning Objectives– Be able to discuss pharmacokinetic and

neurochemical changes with aging– Be able to describe the properties of

cholinesterase inhibitors– Be able to describe treatment principles

of depression and anxiety in the elderly

Disclosures: Dr. Ann Hamer has nothing to disclose.

Adverse Drug Events and the Elderly

• 82% of American adults take at least one medication and 29% take five or more.

• 700,000 emergency department visits and 120,000 hospitalizations are due to ADEs annually.

• $3.5 billion is spent on extra medical costs of ADEs annually.

• At least 40% of costs of ambulatory (non-hospital settings) ADEs are estimated to be preventable.

• Taking multiple drugs for multiple health conditions increases the risk of ADEs, especially in older adults. Although polypharmacy can be appropriate in cases of multiple comorbidities, prescribers must consider older adults' physiologic changes in organ function due to aging and disease.

www.cdc.gov

ADRs with Increasing Age

Pharmacokinetic Changes with Aging

System Change PK Impact

GI ↓ Blood flow ↓Rate of absorption

Circulation ↓ Plasma albumin, ↑ α-1 glycoprotein

↑ / ↓ % of free drug in circulation

Kidney ↓ GFR ↓ Renal clearance

Muscle ↓ Lean body mass; ↑ Adipose tissue

Increased Vd, t1/2

Liver ↓ Size, blood flow and enzymatic activity

↓ Hepatic clearance

Absorption

Changes • ↓ swallowing; • ↓ gastric emptying; • ↑ gastric pH; • ↓ intestinal motility; • ↑ transit time; • ↓ absorptive surface; • ↓ mesenteric blood flow

Effects ↓ Rate of absorption*; Bioavailability may be altered*Worsened by anticholinergic drugs, antacids, or co-administration with food

Implications • Onset of actions is delayed• Clinical effect is reduced if absorption is incomplete• Factors that reduce absorption should be minimized

Distribution

Changes • ↓ muscle mass; • ↓ total body water; • ↑ total body fat

Effects ↑ Total body fat leads to increased Vd of most lipophilic drugs, resulting in ↑ t1/2 without change in s.s.

Effect of decreased total body H2O increasing half-life of Li+ is offset by age-associated reduction in renal clearance

Implications • Longer treatment interval is needed to reach s.s.• Single doses of agents have a decreased duration of

action due to redistribution into fat stores.

Protein Binding

Changes • ↓ albumin; • ↑ α-1 glycoprotein

Effects Effects of [free drug] vary on whether drug is protein-bound, binds preferentially to albumin or α-1 glycoprotein, or whether hepatic clearance is restricted to unbound drug or not.

Competition for protein-binding sites by drugs may cause increases in [free drug]plasma

Implications • Potentially more potency/toxicity for neuroleptics• Greater effects may occur in malnourished pts or those

with comorbid medical conditions• Increase surveillance for adverse effects when adding

new medications

Hepatic Metabolism/Clearance

Changes • ↓ Liver volume;• ↓ Hepatic blood flow• ↓ Oxidative metabolism• ↓ N-demethylation

Effects • ↓ metabolism results in ↑peak and s.s. plasma levels• Increased ratio of parent drug to demethylated metabolite(s).• Age has a modest effect on biotransformation by glucuronide,

sulfate or acetyl conjugation.

Implications • Reductions in CYP450 enzymes may result from genetic polymorphisms, age-related diseases, or inhibition from other medications

• Reduced dosages of drugs may be needed (especially upon initiation). Proceed with caution when increasing dose and adding additional medications.

Renal Clearance

Changes • ↓ Decreased renal blood flow;• ↓ Decreased GFR

Effects Decreased renal clearance leads to longer t1/2 and greater steady state plasma levels

Drug interactions from diuretics and NSAIDs may further increase half-life and steady state levels. (e.g. with Li+)

Implications • Evaluate renal function before initiation of drugs dependent upon renal excretion (e.g. Li+)

• Common illnesses may worsen renal Cl• Reduce doses when necessary• Toxicity should be monitored in pts with renal failure

Neurochemical Changes in the Aging Brain

• Reduced reserves predisposes elderly to an imbalance of neurotransmitters

Cortex Hippocampus Caudate Thalamus

ACh ↔ ↔ ↔

CAT ↓ ↓ ↓

5HT ↓ ↔ ↓ ↔

DA ↔ ↓ ↓ ↓

MAO-B ↑ ↑ ↑ ↑

Musc receptors ↓ ↓ ↔ ↑

α-receptors ↔ ↔ ↑ ↑

Zubenko, 2000

Marker Location Findings

Dopamine System

DA neurons Substantia nigra ↓

Tyrosine hydroxylase Basal gangliaCaudate nucleus

↓↔

MAO Cortical, subcortical areas MAO-A:↔; MAO-B:↑

D1 Striatum ↔

D2 Basal ganglia ↓

DA transporter Basal ganglia, striatum ↓

Cholinergic System

Cholinergic neurons Basal forebrain ↓

Choline uptake Brain ↓

Acetylcholinesterase CSF ↓

M1, M2 Cortex, thalamus M1: ↓; M2: ↑

Serotonergic System

5-HT transporter Cortex ↓

Tryptophan hydroxylase Selected brain areas ↓

MAO Cortical, subcortical areas MAO-A:↔; MAO-B:↑

5HT receptors Selected brain areas ↓

Zubenko, 2000

Aging and Pharmacodynamics

CNS Sedation, confusion, disorientation, memory impairment, delirium

CV Hypotension, orthostasis, cardiac conduction abnormalities (arrhythmias, QTc prolongation)

Peripheral anticholinergic effects

Constipation, dry mouth, blurred vision, urinary retention

Motor effects EPS, tremor, impaired gait, increased body sway, falling

Other Agitation, mood and perceptual disturbances, headache, sexual dysfunction, GI (N/V, anorexia, appetite changes, bowel changes), metabolic, endocrine, electrolyte changes

Anticholinergics and the Elderly

Anticholinergic Property

Problem

Dry mouth Reduces the ability to communicate, predisposes to malnutrition, promotes mucosal damage, denture misfit or dental caries, and increases the risk of serious respiratory infection secondary to loss of antimicrobial activity of saliva

Mydriasis Impairs near vision and may precipitate narrow angle glaucoma in predisposed patients; could lead to an increased risk of accidents, including falls

Constipation Fecal impaction

Urinary hesitancy Urinary retention

↑Heart rate May precipitate or worsen angina

Thermoregulatory impairment

May lead to life threatening hyperthermia

Central effects Sedation, and problems ranging from mild confusion to inability to concentrate to delirium

Red as a beet, dry as a bone, blind as a bat, hot as a hare, mad as a hatter

Reduces function

Increases dependency

DECREASES QOL

Common Mental Health Disorders in the Elderly•Dementia

•Depression

•Anxiety

Cholinesterase Inhibitors (CIs)

• Treatment trials are recommended for patients with mild to moderate dementia.

• Choice between available agents can be based on cost, individual patient tolerance—efficacy appears to be similar.

• CIs, on average, produce small improvements in measure of cognition and ADL. Not all patients benefit.

• The cholinergic deficit in AD implies loss of ACh producing (presynaptic) neurons, and to the extent that the disease affects neurons that are cholinergically post synaptic, there can be little expectation of effect. Attempts to augment cholinergic activity may be too far downstream in the pathophysiology.

• In patients with severe dementia, CIs can be tapered off over a 2 to 4 week period, but should be restarted if the patient worsens without the medication.

Cholinesterase Inhibitors—Effectiveness

Dementia Effectiveness

Alzheimer’s Disease Improvement in mild to moderate disease

Vascular Dementia Improvement in cognition, behavior, and ADLs

Dementia with Lewy Bodies

Marked improvements in cognition as well as improvements in behavioral symptoms and hallucinations

Parkinson’s Disease Modest benefits; can alleviate visual hallucinations

Frontotemporal Dementia Data does not support use

Mild Cognitive Impairment Trials do not support use; increased mortality noted with galatamine

Huntington Disease No evidence to support use

Cholinesterase Inhibitors

Drug Dose Utility Adverse Effects

Donepezil 5mg QD for 4 weeks; increase to 10mg QD X3 mos, then may increase to 23mg

• Available in tablet or ODT• Efficacy in mild to moderate

AD• Most data in advanced

disease

Little peripheral anti-ACh activity

Diarrhea, nausea, vomiting (20% of pts)

Others: syncope, rhabdomyolysis, NMS

Rivastigmine 1.5mg BID with titration q2 weeks up to 6mg BID

• Available in tablet and transdermal patch

• Efficacy in mild to moderate AD

• More GI side effects than donepezil

Significant nausea, vomiting, anorexia, and headaches

Give with food to minimize nausea

Galantamine (IR) 4 mg BID, incr. 4 mg bid q4wk to 12 mg bid as tolerated; Max: 24 mg/day

• Available in IR and XR forms• Efficacy in mild to moderate

AD• More GI side effects than

donepezil• Benefits have been

sustained for up to 36 months

GI sx most common: nausea, vomiting, diarrhea, anorexia, weight loss

Neuropsychiatric Symptoms in DementiaGeneral Approach

Agitation and other behavioral abnormalities can arise from a variety of underlying causes in patients with dementia, and identifying the genesis of the abnormal behavior is critical to effective management. In many patients, behavioral changes herald a new infection or medication toxicity. In others, agitation is driven by pain, fear, confusion, or poor sleep. As with physical symptoms such as shortness of breath, no single approach or medication can be expected to treat the symptom of agitation without regard to the underlying cause.

Precipitating Factors

Most behavioral changes have precipitants:Delirium—A concomitant medical illness (particularly urinary tract infection or pneumonia), medication toxicity (particularly anticholinergic side effects of drugs used to treat sleep disturbance, bladder incontinence, or other illnesses), and other causes of delirium must be considered whenever new behavioral disturbances arise, particularly in the setting of an acute worsening in cognitionOthers:Cognitive, language, or memory deficitsDiscomfort or painFrightening, paranoid delusionsDepressionSleep disorders

Drugs to Avoid

Benzodiazepines have limited value in patients with dementia. They are not recommended for the management of neuropsychiatric symptoms of dementia. Benzodiazepine side effects include worsening gait, potential paradoxical agitation, and possible physical dependence. Benzodiazepine use should be limited to brief stressful episodes and those with shorter half-lives are preferred. Antihistamines are widely used for mild sleep disturbances but are discouraged because of high rates of side effects, particularly for drugs with anticholinergic effects, such as diphenhydramine. Anticholinergic drugs should be avoided.

Treatment Approach

Identify precipitating cause Rule out and treat medical causes. Treat pain, sleep disturbance and depression. Environmental, behavioral, and other non-pharmacologic therapies can be effective in this population and, when appropriate, are

preferred over medications Antipsychotic agents have limited efficacy and are associated with increased mortality in patients with dementia. Low doses of

olanzapine or risperidone in patients with severe, disabling symptoms are preferred over other APs after informing families of the mortality risk. Short term use when possible, with regular reassessments of risks and benefits, is advised.

Patients with dementia with Lewy bodies are at especially high risk of severe side effects with neuroleptic medications. A trial of selective serotonin reuptake inhibitors (SSRIs) is suggested for the treatment of depression in Alzheimer disease.

Citalopram is often used because of its possible additional benefits for other neuropsychiatric symptoms; the dose of citalopram should not exceed 20 mg daily in elderly patients. Sertraline is a well-studied alternative to citalopram. TCAs should be avoided because of side effects and drug interactions

Sleep disturbances are common in patients with dementia. Non-pharmacologic strategies, including maintenance of good sleep hygiene, avoidance of daytime naps, and daily exercise, are generally preferred to pharmacotherapy. Small doses of melatonin or trazodone can be considered if insomnia is refractory to non-pharmacologic strategies.

Because of the risk of side effects with long-term use, we suggest reserving benzodiazepines for acute stressful episodes

Common Causes of DeliriumDrugs and Toxins

Prescription Medications: opioids, sedative/hypnotics, antipsychotics, lithium, skeletal muscle relaxants, benzodiazepines, anticholinergics, polypharmacy OTC: antihistamines Drugs of Abuse: ethanol, heroin, hallucinogens Withdrawal: ethanol, benzodiazepines Adverse effects: e.g. hyperammonemia from valproic acid, confusion from quinolones, serotonin syndrome Poisons: atypical alcohols (e.g. ethylene glycol), inhaled toxins, plant-derived (e.g. Salvia) 

Infections Sepsis; systemic infections; fever related delirium 

Metabolic Derangements

Electrolyte disturbance (elevated or depressed); Endocrine disturbance (depressed or increased); Hypercarbia; Hyper- or hypoglycemia; Hyper- or hypoosmolar state; Hypoxemia; Inborn errors of metabolism; Nutritional deficiency 

Brain Disorders CNS Infections: encephalitis, meningitis, brain or epidural abscessEpileptic seizuresHead injuryHypertensive encephalopathyPsychiatric Disorders 

System Organ Failure

Cardiac failure; Hematologic (thrombocytosis, hypereosinophilia, leukemic blast cell crisis, polycythemia); Liver failure; Pulmonary disease; Renal failure 

Physical Disorders

Burns; Electrocution; Hyperthermia; Hypothermia; Trauma 

Depression in the Elderly—Risk Factors

•Changes in physical health•Presence of a new or chronic physical disorder (e.g. diabetes), or development of multiple chronic physical disorders

•Stroke, bypass operation, or hip fracture

•Poor health, physical or functional disability, and sensory impairment

•Severe and chronic pain

•Changes in circumstances/ social support

•Income changes, such as retirement or financial difficulties

•Social changes

•Recent loss of a loved one

•Living alone or social isolation

•Diminished social network

•Changes in mental health•Prior episode of depression

•Family history of major depression

•Cognitive impairment

•At-risk drinking, alcohol abuse, or illicit substance abuse

•Medication misuse or abuse

•Side effects of some medications

•Changes in medications or newly prescribed medications for other disorders

•Changes in circumstances

Depression in the Elderly—Prevalence

• Depression, particularly minor depression, is under-recognized and under-treated in the elderly.

• Prevalence of major depression double over the age of 80 years.

• Tends to be higher in female patients (gender stereotyping?)

• AA and Latino older adults less likely than Caucasians to receive treatment.

https://store.samhsa.gov/shin/content/SMA11-4631CD-DVD/SMA11-4631CD-DVD-KeyIssues.pdf

Depressive symptoms can mimic the symptoms of dementia—its victims withdraw, cannot

concentrate, and appear confused. Some experts estimate that as many as 10% of those diagnosed

with dementia actually suffer from depression that, if treated, is reversible.

Depression in the Elderly—Impact

• Depression in the elderly is associated with decreased levels of functioning, worse health status, and reduced quality of life.

• Older adults with depression are more disabled with respect to self care and daily community living skills, compared to older adults without depression.

• They also tend to recover more slowly from physical disorders, such as stroke or hip fractures.

• Older adults with depression are more likely to die, either because of worsening of physical disorders or by suicide.

https://store.samhsa.gov/shin/content/SMA11-4631CD-DVD/SMA11-4631CD-DVD-KeyIssues.pdf

Depression in the Elderly—Treatment

• Treatment selection based on:• The severity and duration of depression;

• The older adult’s clinical presentation;

• The older adult’s prior history of response to treatments;

• The presence of other health conditions or medications;

• The tolerability of the treatments with respect to side effects or required effort; and

• The older adult’s treatment preferences (including cost).

https://store.samhsa.gov/shin/content/SMA11-4631CD-DVD/SMA11-4631CD-DVD-KeyIssues.pdf

50 – 80% of older adults who receive appropriate treatment achieve a reduction in their symptoms of depression.

Depression in the Elderly—Treatment

• No single drug class or ATD has been shown to be more effective in treating geriatric depression than another.

• Initial doses should be low but “average” adult doses may be required to achieve adequate response.

• SSRIs are generally considered first-line.• Most commonly reported adverse events in the elderly are: insomnia, anxiety,

nausea, diarrhea, sexual dysfunction, and headaches.

• SSRIs may increase the risk of GI bleeding (risk is greatest within the 1st month of treatment and in patients w/ cirrhosis or liver failure)

• SSRIs have been linked to SIADH in elderly (monitor Na+)

Depression in the Elderly—Treatment

• Venlafaxine, duloxetine and mirtazapine—good alternatives.

• Use caution with venlafaxine in renal failure

• Use caution with duloxetine in hepatic failure

• Bupropion is recommended as a second-line agent.

• TCAs, trazodone and nefazodone are generally not recommended.

• Lower anticholinergic effects with secondary amines (e.g. nortriptyline, desipramine) compared to tertiary amines

• Efficacy may be delayed in the elderly. Medication trials generally need to be longer.

• Agents with known drug interactions are less desirable

Depression in the Elderly—Treatment

Drug Average Dose Range in Elderly

SSRIs

Citalopram 10-20mg

Escitalopram 10-20mg

Fluoxetine 10-30mg

Fluvoxamine 50-150mg

Paroxetine 10-30mg

Sertraline 25-100mg

SNRIs

Desvenlafaxine 50mg

Duloxetine 10-30mg

Venlafaxine 37.5-150mg

Others

Bupropion 100-250mg

Mirtazapine 7.5-10mg

Vilazodone 10-20mg

Anxiety in the Elderly

• Risk Factors• Increasing frailty, medical illness, and losses can contribute to feelings of

vulnerability and fear, and can reactivate anxiety disorders.

• A lack of social supports, a recent traumatic event, medical illnesses and medications, poor self-rated health, the presence of another psychiatric illness (particularly another anxiety disorder or depression), an early-onset anxiety disorder, and female gender are all risk factors for late-life anxiety disorders.

• Prevalence• Community prevalence rates vary from 3.5 – 10.2% in the geriatric population,

however only 1.3% are diagnosed with anxiety

• Over 45% of patients in LTC facilities have the diagnosis of depression and anxiety

• GAD is the most common anxiety disorder in the elderly

• Over 90% of individuals with GAD also had at least one other psychiatric disorder during their lifetime

Anxiety in the Elderly

• Clinical Course

• Anxiety and GAD rarely starts in the elderly, rather is a continuation of symptoms

• Anxiety disorders in the elderly are associated with:• Decreased physical activities and functional status

• Poorer self-perceptions of health

• Decreased life satisfaction

• Increased loneliness

• More severe chronic diseases

• Anxiety in elderly men has been associated with an increase in mortality

Anxiety in the Elderly

• Anxiety disorders are linked with increased morbidity and mortality among individuals who have medical illness, and the presence of medical illness increases the risk of anxiety disorders.

• Individuals with dementia who have anxiety often show their emotions indirectly through physical signs (tension, restlessness, fidgeting, agitation, sleep disturbance, wringing hands) and through their countenance (anxious or worried appearance).

Anxiety in the Elderly

System Medical Condition

Cardiovascular Angina, arrhythmia, MI, mitral valve prolapse, stroke

Endocrine Diabetes, hypocalcemia, hyperthyroidism, pheochromocytoma

GI/GU PUD, pancreatic cancer, UTI

Metabolic Anemia, hypoglycemia, hyponatremia, hyperkalemia

Pulmonary COPD, pneumonia, PE, hypoxemia

Neurological Delirium, dementia, hearing or visual impairment, Parkinson’s Disease, seizure disorders, brain cancer, strategic strokes

Drugs Associated with Late Life Anxiety: stimulants, sedative/benzo withdrawal, antidepressants, levodopa, neuroleptics, CCBs, alpha- and beta-blockers, digitalis, estrogen, thyroid medications, bronchodilators, steroids, theophylline, antihistamines, pseudoephedrine, analgesics, muscle relaxants, NSAIDs

Anxiety in the Elderly

• Pharmacologic Treatment

• SSRIs are considered to be the drugs of choice• Drugs with fewer DDIs and favorable PK profiles are preferred (e.g. citalopram,

escitalopram, sertraline)

• May take 4 to 6 weeks before effective

• Efficacy with venlafaxine XR has been shown, however caution should be used when treating patients with renal insufficiency and hypertension

• Duloxetine—not much data

• TCAs—generally avoided

• Buspirone has demonstrated efficacy, multiple daily dosing may make it less desirable in the elderly

Anxiety in the Elderly

• Benzodiazepines• Frequently used (despite significant adverse effects) due to fast onset

• If used, lorazepam and oxazepam are preferred because of short half-lives, no active metabolites, and lack of oxidative metabolism.

• Problems:• Cognitive impairment

• Negative effect on gait

• Rebound agitation

• Elderly patients are more vulnerable to the cognitive and psychomotor effects of benzodiazepines and eliminate long-acting drugs more slowly than younger patients, and are predisposed to an increased risk of falls.

The End!

Next Week:

Addiction