Eric Lenze, M.D. Associate Professor of Psychiatry Washington University School of Medicine

11

Detecting and treating anxiety Detecting and treating anxiety disorders in the elderly: clinical disorders in the elderly: clinical applications of new research applications of new research

findings findings

Eric Lenze, M.D.Eric Lenze, M.D.Associate Professor of PsychiatryAssociate Professor of PsychiatryWashington University School of MedicineWashington University School of Medicine

October 2007October 2007

22

Goals of this lectureGoals of this lecture

Describe research in pharmacologic and Describe research in pharmacologic and psychotherapeutic treatment of late-life psychotherapeutic treatment of late-life anxiety disorders and anxious depression.anxiety disorders and anxious depression.

Describe detection and management Describe detection and management strategies for these disorders.strategies for these disorders.

33

Self-Assessment Question 1Self-Assessment Question 1Which of the following should be considered in the Which of the following should be considered in the

differential diagnosis of anxiety symptoms in elderly differential diagnosis of anxiety symptoms in elderly patients?patients?

A. A. Cardiopulmonary and other medical conditionsCardiopulmonary and other medical conditions

B. B. Medication side effectsMedication side effects

C. C. Sedative hypnotic withdrawalSedative hypnotic withdrawal

D. D. All of the aboveAll of the above

E. E. None of the aboveNone of the above

44

Self-Assessment Question 2Self-Assessment Question 2

What risks are associated with chronic What risks are associated with chronic benzodiazepine use in elderly?benzodiazepine use in elderly?

A. A. DeliriumDelirium

B. B. Cognitive impairmentCognitive impairment

C. C. FallsFalls

D. D. FracturesFractures

E. E. All of the aboveAll of the above

55


Which of the following may contribute to Which of the following may contribute to the low estimate of prevalence of anxiety the low estimate of prevalence of anxiety

disorders in the elderly?disorders in the elderly?

A. A. Age-related brain changesAge-related brain changes

B. B. Selective increase in mortality among anxiety Selective increase in mortality among anxiety disorder patientsdisorder patients

C. C. Epidemiologic studies do not necessarily Epidemiologic studies do not necessarily capture anxiety as it presents in older adultscapture anxiety as it presents in older adults



66

Self-Assessment Question 4Self-Assessment Question 4Which of the following contribute to the importance Which of the following contribute to the importance

of identifying and treating Generalized Anxiety Disorder of identifying and treating Generalized Anxiety Disorder in the elderly? in the elderly?

A. A. Its prevalence may be as high as 7%Its prevalence may be as high as 7%

B. B. It is unlikely to remit without treatmentIt is unlikely to remit without treatment

C. C. Effective pharmacotherapeutic treatment has Effective pharmacotherapeutic treatment has been demonstrated. been demonstrated.

D. D. All of the above All of the above


77

Self-Assessment Question 5Self-Assessment Question 5Which of the following is true of late-life depression with Which of the following is true of late-life depression with

comorbid anxiety as compared to “pure” depression?comorbid anxiety as compared to “pure” depression?

A. A. Severity of the illness is no different.Severity of the illness is no different.

B. B. Antidepressant treatment response is better Antidepressant treatment response is better when comorbid anxiety is present. when comorbid anxiety is present.

C. C. Comorbid anxiety is associated with greater Comorbid anxiety is associated with greater long-term cognitive decline.long-term cognitive decline.

D.D. All of the aboveAll of the above


88

How fear works

AmygdalaArousalAcute anxietyPanic attack

Larson et al, 2006

99

How fear works

Amygdala

Frontal cortex

ArousalArousalAcute anxietyAcute anxietyPanic attackPanic attack

WorryEscape Avoidance

Larson et al, 2006

1010

How fear works

Amygdala

Frontal cortex

ArousalAcute anxietyPanic attack

WorryEscape Avoidance

Larson et al, 2006

Control

1111

Worry

Hoehn-Saric et al, 2004

“What if…?”

1212

Worry

Frontal cortex Worry +/- AvoidanceControl

Hoehn-Saric et al, 2004

1313

Anxiety disorders have distinct Anxiety disorders have distinct clinical featuresclinical features

FearFear AvoidanceAvoidanceAutonomic Autonomic

ArousalArousal

AnticipatoryAnticipatoryworryworry

PanicPanicattacksattacks

Panic Panic disorderdisorder xx xx xx xx xx

Social , Social , specifc specifc phobiaphobia

xx xx xx xx xx

OCDOCD xx +/-+/-

GADGAD +/-+/- xx

PTSDPTSD xx xx xx

1414

Anxiety disorders have distinct Anxiety disorders have distinct clinical featuresclinical features

Fear AvoidanceAutonomic

Arousal

Anticipatoryworry

Panicattacks

Panic disorder

x x x x x

Social , specifc phobia

x x x x x

OCDOCD xx +/-+/-

GADGAD +/-+/- xx

PTSDPTSD xx xx xx

1515

What do psychiatrists ask about What do psychiatrists ask about late-life anxiety?late-life anxiety?

How important is it?How important is it?

Who sees these cases?Who sees these cases?

Is there something unique about treating Is there something unique about treating this?this?

1616

Prevalence of anxiety disorders in Prevalence of anxiety disorders in older adultsolder adults

0%

2%

4%

6%

8%

10%

12%

Any anxiety d/o

Major depression

GAD

Phobia

Panic

OCD

Beekman et al., 1995, 1998

1717

GAD: chronic, difficult-to-control worryGAD: chronic, difficult-to-control worry ““I can’t turn my mind off”I can’t turn my mind off” ““I’m a worrier”I’m a worrier”

Associated symptoms of GADAssociated symptoms of GAD Sleep disturbanceSleep disturbance FatigueFatigue IrritabilityIrritability Keyed up/on edgeKeyed up/on edge Muscle tensionMuscle tension Difficulty concentrating (elderly may describe Difficulty concentrating (elderly may describe

as memory)as memory)

1818

Early vs. late-onset GADEarly vs. late-onset GAD

0%

5%

10%

15%

20%

25%

30%

"All mylife"

Child Teens 20s 30s 40s 50s 60s 70s 80s

Le Roux, Gatz, & Wetherell, 2005

1919

Aging: increased vulnerability to Aging: increased vulnerability to sequelae of anxietysequelae of anxiety

50 60 70 80

age

2020


50 60 70 80

Declining homeostasis/reserve

2121


childhood adulthood late life very-late life

Declining homeostasis/reserveDeclining homeostasis/reserve

1. HPA axis functioning

2222





2. Cognitive reserve, brain volumes

2323






3. Functional ability, physical performance

2424






3. Functional ability, physical performance

4. Systemic functions (cardiac, renal, etc)

2525


50 60 70 80

Declining homeostasis/reserveDeclining homeostasis/reserveAnxiety

2626



50 60 70 80

Anxiety

HPA axis hyperactivity

2727

0

1

2

3

4

5

6

wake wake + 30 noon 4pm 8pm bedtime

Time

Sal

ivar

y C

ortis

ol (n

g/m

l))

Controls (n=41)

GAD (n=68)

Mantella et al, in press

HPA Axis in Late-Life GADHPA Axis in Late-Life GAD

2828



50 60 70 80

AnxietyHPA axis hyperactivity

Neuronal atrophy

2929



50 60 70 80

Anxiety HPA axis hyperactivity

Neuronal atrophy

Sympathetic tone

3030



50 60 70 80

Anxiety HPA axis hyperactivity

Neuronal atrophy

Sympathetic tone

Cerebrovascular changes

3131



50 60 70 80

Anxiety


Neuronal atrophy

Sympathetic tone


?Pro-inflammatory cytokine cascade

3232



50 60 70 80

Anxiety


Neuronal atrophy

Sympathetic tone



?Decreased neurogenesis

3333



50 60 70 80

Anxiety


Neuronal atrophy

Sympathetic tone




Treatment-resistance

Comorbidity

3434



50 60 70 80

Anxiety


Neuronal atrophy

Sympathetic tone





Comorbidity

Cognitive decline

Alzheimers Dz

Depression

3535



50 60 70 80

Anxiety

Depression


Neuronal atrophy

Sympathetic tone





Comorbidity

Cognitive decline

Alzheimers Dz

Disability

3636



50 60 70 80

Anxiety


Neuronal atrophy

Sympathetic tone





Comorbidity

Cognitive decline

Alzheimers Dz

Disability

MortalityDepression

3737

Comorbidity in late-life depression Comorbidity in late-life depression and anxietyand anxiety

Anxietyalone

w/ comorbiddepression

Depressionalone

w/ comorbidanxiety

Beekman et al., 2000 (LASA)

3838

Anxiety comorbidity and acute Anxiety comorbidity and acute treatment response in LLDtreatment response in LLD

% Remitted

Days To Remission

Baseline GAD

No Baseline GAD

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 100 200 300 400 500 600 700 800

Steffens and McQuoid, Am J Geriatr Psychiatry. 2005; 13:40-47.

3939

Chi-square=7.05, df=1, p = 0.00895% CI hazard ratio = 1.22-3.72

Weeks

0 20 40 60 80 100 1200.0

0.2

0.4

0.6

0.8

1.0

Drug + Low BSI (n=35)Drug + High BSI (n=23)Placebo + Low BSI (n=31)Placebo + High BSI (n=20)

Time to Recurrence

(%)

Effect of Baseline AnxietyEffect of Baseline Anxietyon Time to Recurrence in MDDon Time to Recurrence in MDD

Andreescu et al, 2007

4040

MDD with comorbid GAD/panic: MDD with comorbid GAD/panic: memory decline over 4 years f/umemory decline over 4 years f/u

19

20

21

22

23

24

baseline 4 years

Ma

ttis

me

mo

ry s

ub

sc

ale

nonanxious MDD(n=42)

anxious MDD (n=37)

*p=0.05 for group x time comparisonDeLuca et al, 2005

*

4141

Medications efficacious for GADMedications efficacious for GAD

From clinical trials in young adults:From clinical trials in young adults:

FDA-approved: escitalopram, paroxetine, FDA-approved: escitalopram, paroxetine, venlafaxine XR, duloxetine, buspirone.venlafaxine XR, duloxetine, buspirone.

Also efficacious: other SSRIs, Also efficacious: other SSRIs, benzodiazepines, pregabalin, antihistaminesbenzodiazepines, pregabalin, antihistamines

4242

Prospective controlled studies in Prospective controlled studies in late-life GADlate-life GAD

AgentAgent studystudy LengthLength NN AgeAge Efficacy ResultsEfficacy Results

oxazepamoxazepam Koepke Koepke 19821982 4 wk4 wk 220220 60+60+ oxazepam > oxazepam >

placeboplacebo

ketazolamketazolam Bresolin Bresolin 19881988 30 dy30 dy 6363 66+66+ ketazolam > ketazolam >

placeboplacebo

alpidemalpidem Frattola Frattola 19921992 3 wk3 wk 4040 65+65+ alpidem > placeboalpidem > placebo

abecarnilabecarnil Small 1997Small 1997 6 wk6 wk 182182 60+60+ abecarnil > abecarnil > placeboplacebo

Koepke HH, et al. Psychosomatics. 1982;23:641-645.Bresolin N, et al. Clin Ther. 1988;10:536-546.Frattola L, et al. Clin Neuropharmacol. 1992;15:477-487.Small GW, Bystritsky A. J Clin Psychiatry. 1997;58(suppl):24-29.

4343

Problems With Problems With BenzodiazepinesBenzodiazepines

Benzodiazepines Benzodiazepines efficacious BUTefficacious BUT

Already heavily Already heavily prescribed in elderlyprescribed in elderly

4444




Associated with fallsAssociated with falls

PsychotropicPsychotropic

Odds Odds Ratio Ratio of Fallof Fall

BenzodiazepineBenzodiazepine 1.4*1.4*

AntidepressantAntidepressant 0.90.9

AntipsychoticAntipsychotic 1.5*1.5*

Sedative/hypnoticSedative/hypnotic 1.11.1

*P<.05.

Landi F, et al. J Gerontol A Biol Sci Med Sci. 2005;60:622-626.

4545




Associated with fallsAssociated with falls

Associated with Associated with cognitive impairmentcognitive impairment

*P<.05.

Landi F, et al. J Gerontol A Biol Sci Med Sci. 2005;60:622-626.

4646

Venlafaxine ER in older GAD ptsVenlafaxine ER in older GAD pts

-16

-14

-12

-10

-8

-6

-4

-2

0

ch

an

ge

in H

am

-A s

co

re venla (n=136)placebo (n=47)

*p < 0.01 for change compared to placebo Katz et al, 2002

Week 8 LOCF Week 8 observed

*

4747

Citalopram in geriatric anxiety Citalopram in geriatric anxiety disordersdisorders

Lenze et al, Am J Psychiatry, 2005

10

12

14

16

18

20

22

0 2 4 6 8week of treatment

Ha

m-A

sc

ore

cit

pbo

4848

Citalopram for Geriatric Anxiety Citalopram for Geriatric Anxiety DisordersDisorders

30 subjects received citalopram for up to 30 subjects received citalopram for up to 32 weeks32 weeksSignificant decreases in 4 of the 6 most Significant decreases in 4 of the 6 most common individual symptoms:common individual symptoms: Fatigue/astheniaFatigue/asthenia HeadacheHeadache Gastrointestinal distressGastrointestinal distress PalpitationsPalpitations

Blank S, et al. J Clin Psychiatry. 2006;67:468-472.Lenze EJ, et al. Am J Psychiatry. 2005;162:146-150.

4949

Cognitive-Behavioral Therapy Cognitive-Behavioral Therapy (CBT) for anxiety(CBT) for anxiety

Relaxation trainingRelaxation training Slow, deep breathingSlow, deep breathing Progressive muscle relaxationProgressive muscle relaxation ImageryImagery

Changing negative automatic thoughtsChanging negative automatic thoughts Overestimation of riskOverestimation of risk CatastrophizationCatastrophization

Exposure to anxiety-provoking situationsExposure to anxiety-provoking situations e.g., systematic desensitizatione.g., systematic desensitization

5050

Comparison of CBT and attention placebo Comparison of CBT and attention placebo for late-life GADfor late-life GAD

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Post-tx 6 month f/u

An

xie

ty e

ffe

ct

size

CBT

Placebo

WL

Wetherell et al., 2003

5151

Many elderly persons will prefer Many elderly persons will prefer psychotherapy to medicationpsychotherapy to medication CBT most efficacious in those who can be CBT most efficacious in those who can be

adherent to homework adherent to homework Cognitive impairment can interfereCognitive impairment can interfere

Psychotherapy in late-life GADPsychotherapy in late-life GAD

Wetherell, Hopko et al., 2005; Mohlman & Gorman, 2005

5252

Relaxation training appears to be Relaxation training appears to be the most effective ingredientthe most effective ingredient

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

0.1

0.2

0.3

0.4

CBT

Relaxation training

Supportive therapy

Cognitive therapy

Ayers, Sorrell, Thorp, & Wetherell, submitted

Mean effect size in studies comparing active treatments

5353

Comparison of SSRI and CBT for Comparison of SSRI and CBT for late-life GAD and panic disorderlate-life GAD and panic disorder

0

0.2

0.4

0.6

0.8

1

1.2

Eff

ect

size

post-treatment 3month f/u

sertraline

CBT

waitlist

Schuurmans et al, 2006

5454

Limitations of medicationsLimitations of medicationsMany respond, few remitMany respond, few remit Construct of “I’m a worrier” does not seem to Construct of “I’m a worrier” does not seem to

change change Many will not accept medicationMany will not accept medication In our current study, many refuse to start In our current study, many refuse to start

Uncertain long-term benefitsUncertain long-term benefits Not thought to have “durable” benefits (i.e., Not thought to have “durable” benefits (i.e.,

maintenance after med discontinuation)maintenance after med discontinuation)

Phobias unlikely to respond to medicationPhobias unlikely to respond to medication Medication could even impair response to Medication could even impair response to

therapytherapy

5555

Possible Possible Risks of SSRIs in ElderlyRisks of SSRIs in ElderlySuicide?Suicide? FDA meta-analysis = protective in age >65FDA meta-analysis = protective in age >65

FallsFalls Association studies, some experimentalAssociation studies, some experimental

BleedingBleeding Particularly in “old-old”, h/o GI bleedParticularly in “old-old”, h/o GI bleed

HyponatremiaHyponatremia Tends to occur within 2 wk of initiationTends to occur within 2 wk of initiation Risk factors: baseline low NaRisk factors: baseline low Na++, on diuretics, on diuretics

5656

Suicidality and SSRIs: effects of ageSuicidality and SSRIs: effects of age

5757





5858





NEW FOR 2007: BONE LOSS!NEW FOR 2007: BONE LOSS!

5959

Pharm management of late-life Pharm management of late-life anxiety disordersanxiety disorders

SSRI seems to be a good first-line choiceSSRI seems to be a good first-line choice Lexapro, Paroxetine, Effexor XR approved by FDALexapro, Paroxetine, Effexor XR approved by FDA Mgmt more important than specific med usedMgmt more important than specific med used

High risk of “side effects” leading to High risk of “side effects” leading to dropoutdropout Anxiety symptoms misperceived as due to Anxiety symptoms misperceived as due to

medication: increased anxiety, GI symptoms, medication: increased anxiety, GI symptoms, fatigue/sedation, restlessnessfatigue/sedation, restlessness

““Medication phobia”Medication phobia”

Start low, go slow – but not too slowStart low, go slow – but not too slow

6060

Detecting anxiety in elderly Detecting anxiety in elderly personspersons

Elders less up-front about anxiety SxElders less up-front about anxiety Sx Asking about anxiety in several ways may Asking about anxiety in several ways may

help (e.g., “anxious”, “worried”, “concerned”)help (e.g., “anxious”, “worried”, “concerned”)““How do you feel in times of stress?”How do you feel in times of stress?”

““What sorts of things do you worry about?”What sorts of things do you worry about?”

““How often do you feel that way?”How often do you feel that way?”

““When you start worrying, what do you do to try When you start worrying, what do you do to try to stop it?”to stop it?”

6161

Managing anxiety about medicationManaging anxiety about medication

Combination of:Combination of: Anticipatory dreadAnticipatory dread Vigilance to interoceptive stimuliVigilance to interoceptive stimuli CatastrophizationCatastrophization

Frequent visits and support, immediate Frequent visits and support, immediate availabilityavailability

Counsel in advance about side effectsCounsel in advance about side effects Likely to be temporary, unlikely to be toxic or Likely to be temporary, unlikely to be toxic or

incapacitatingincapacitating

6262

When they do get side effects…When they do get side effects…

Stay calmStay calm

Remember the attribution errorRemember the attribution error But: don’t argue about their validityBut: don’t argue about their validity

Manage the catastrophizationManage the catastrophization ““How is it today?” “Is it tolerable right now?” How is it today?” “Is it tolerable right now?”

“Are you mainly worried that it will get worse?”“Are you mainly worried that it will get worse?”

Be persistentBe persistent Hear them out, then: “let’s keep going”Hear them out, then: “let’s keep going”

6363

When to choose psychotherapyWhen to choose psychotherapy

Motivated, cognitively intact patientMotivated, cognitively intact patient

PhobiasPhobias Consider delaying medication until after TxConsider delaying medication until after Tx

Will not accept medicationWill not accept medication

Partial response to medicationPartial response to medication

Availability of high-quality psychotherapyAvailability of high-quality psychotherapy

6464

SummarySummary

Late-life anxiety disorders are important.Late-life anxiety disorders are important. CommonCommon Different risk factorsDifferent risk factors Probably more vulnerable to harmful effectsProbably more vulnerable to harmful effects Anxious depression is a particularly severe, Anxious depression is a particularly severe,

treatment-resistant illness.treatment-resistant illness.

Detection: ask, gently.Detection: ask, gently.

Management: be pleasantly persistent.Management: be pleasantly persistent.

6565

Self-Assessment Question 1Self-Assessment Question 1Which of the following should be considered in the Which of the following should be considered in the

differential diagnosis of anxiety symptoms in elderly differential diagnosis of anxiety symptoms in elderly patients?patients?

A. A. Cardiopulmonary and other medical conditionsCardiopulmonary and other medical conditions

B. B. Medication side effectsMedication side effects

C. C. Sedative hypnotic withdrawalSedative hypnotic withdrawal



6666


What risks are associated with chronic What risks are associated with chronic benzodiazepine use in elderly?benzodiazepine use in elderly?

A. A. DeliriumDelirium

B. B. Cognitive impairmentCognitive impairment

C. C. FallsFalls

D. D. FracturesFractures

E. E. All of the aboveAll of the above

6767


Which of the following may contribute to Which of the following may contribute to the low estimate of prevalence of anxiety the low estimate of prevalence of anxiety

disorders in the elderly?disorders in the elderly?

A. A. Age-related brain changesAge-related brain changes

B. B. Selective increase in mortality among anxiety Selective increase in mortality among anxiety disorder patientsdisorder patients

C. C. Epidemiologic studies do not necessarily Epidemiologic studies do not necessarily capture anxiety as it presents in older adultscapture anxiety as it presents in older adults



6868

Self-Assessment Question 4Self-Assessment Question 4Which of the following contribute to the importance Which of the following contribute to the importance

of identifying and treating Generalized Anxiety Disorder of identifying and treating Generalized Anxiety Disorder in the elderly? in the elderly?

A. A. Its prevalence may be as high as 7%Its prevalence may be as high as 7%

B. B. It is unlikely to remit without treatmentIt is unlikely to remit without treatment

C. C. Effective pharmacotherapeutic treatment has Effective pharmacotherapeutic treatment has been demonstrated. been demonstrated.

D. D. All of the above All of the above


6969

Self-Assessment Question 5Self-Assessment Question 5Which of the following is true of late-life depression with Which of the following is true of late-life depression with

comorbid anxiety as compared to “pure” depression?comorbid anxiety as compared to “pure” depression?

A. A. Severity of the illness is no different.Severity of the illness is no different.

B. B. Antidepressant treatment response is better Antidepressant treatment response is better when comorbid anxiety is present. when comorbid anxiety is present.

C. C. Comorbid anxiety is associated with greater Comorbid anxiety is associated with greater long-term cognitive decline.long-term cognitive decline.

D.D. All of the aboveAll of the above


7070

Self-Assessment Question AnswersSelf-Assessment Question Answers

1. 1. DD

2. 2. EE

3. 3. DD

4. 4. DD

5. 5. CC

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