Optimizing Outcomes for Patients With...

Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Optimizing Outcomes for

Patients With Anxiety

(page 303 in syllabus)

William M. Sauvé, MD

Clinical Director of Military Programs

Poplar Springs Hospital

Sponsored by the Neuroscience Education Institute

Additionally sponsored by the American Society for the Advancement of Pharmacotherapy

This activity is supported solely by the sponsor, Neuroscience Education Institute.


Faculty Editor / Presenter

William M. Sauvé, MD, is the clinical director of military programs at Poplar

Springs Hospital in Petersburg, VA.

Speakers Bureau: Pfizer

Individual Disclosure Statement


Learning Objectives

• Explain the neurobiology of both normal and

pathological stress and anxiety

• Identify the environmental and genetic factors that

can contribute to the development of an anxiety

disorder

• Identify new treatment options in development for

PTSD

• Customize treatment regimens for patients with

PTSD based on symptom profile, comorbidities, and

life situations


Pretest Question 1

38y/o male with PTSD, alcohol dependence, and chronic back

and knee pain presents on these medications: quetiapine

(Seroquel) 50mg qHS, prazosin 3mg qHS, duloxetine (Cymbalta)

90mg daily, gabapentin 300mg TID, clonidine 0.1mg TID,

zolpidem (Ambien) 10mg qHS and clonazepam (Klonopin) 1mg

up to TID as needed. His complaints include ongoing

nightmares, exaggerated startle, depressed mood, difficulty

staying asleep and poor memory. What might you do FIRST to

optimize this patient's medication regimen?

1. Increase quetiapine dose

2. Increase prazosin dose

3. Change the clonazepam to from PRN to BID

4. Discontinue the hypnotics (zolpidem) and the benzodiazepines

(clonazepam)


The Path to PTSD: A Circuit’s Story

Normal Stress in Normal Circuits

normal circuit

at rest

normal circuit

activated normal circuit

at rest

emotional

trauma

emotional

trauma

withdrawn

overactivation normal baseline hypoactivation

Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008.



Stress Sensitization in Normal Circuits

normal circuit

at rest

normal circuit

activated irreversible

stress

sensitization

emotional

trauma

emotional

trauma

withdrawn

normal circuit

continuously

activated

sustained,

repeated

emotional

trauma

overactivation normal baseline hypoactivation




Progression From Stress Sensitization

vulnerable but

presymptomatic

prodromal

symptoms

subsyndromal

symptoms

psychiatric

symptoms

lack of

compensation

emotional

trauma

emotional

trauma

withdrawn

decompensation with

either overactivation

or breakdown

emotional

trauma

continues

irreversible

stress

sensitization

decompensation

is sustained



THE STRESS DIATHESIS

MODEL

Trauma is necessary but not sufficient for the

precipitation of anxiety disorders such as PTSD

Only 5-30% of trauma victims develop PTSD

Mahan, Ressler. TINS 2011;Epub ahead of print.


Stress Diathesis Model:

A Tale of Two Influences, Part 1

normal genes

life events

bad

childhood divorce

virus or

toxin

overactivation

normal

baseline

hypoactivation

normal

circuit

normal

activation

normal phenotype




A Tale of Two Influences, Part 2 risk gene

single life event stressor

divorce

“biased”

circuit

normal phenotype

overactivation

inefficient information

processing

overactivation

normal

baseline

hypoactivation




A Tale of Two Influences, Part 3

risk gene

risk gene

risk gene

risk gene

multiple life events

bad childhood divorce

virus or toxin

psychiatric symptoms

“biased”

circuit

diathesis stress

hypoactivation

with

malfunction

unsuccessful compensation

overactivation

normal

baseline

hypoactivation



Adrenal

Hippocampus

Glucocorticoid

receptor

Cortisol

Corticotropin

releasing

factor (CRF)

Corticotropin

(ACTH)

Pituitary

Hypothalamus

HPA Axis:

A Critical Circuit for Stress Responses

I can’t

believe that

guy shot at

me!


Adrenal

Hippocampus

Glucocorticoid

receptor

Cortisol

Corticotropin

releasing

factor (CRF)

Corticotropin

(ACTH)

Pituitary

Hypothalamus

HPA Axis:

A Critical Circuit for Stress Responses


Adrenal

Hippocampus

Glucocorticoid

receptor

Cortisol

Corticotropin

releasing

factor (CRF)

Corticotropin

(ACTH)

Pituitary

Hypothalamus

HPA Axis:

Chronic Stress

I am so tired from

working 60 hours

per week, taking

care of my small

children and my

elderly parents, and

not being able to

pay the bills.


Reduced Hippocampal Volume and Stress:

Cause or Effect?

coronal plane coronal plane

normal stress/PTSD

Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008;

Woon, Hedges. Hippocampus 2008;18:729-36.


Most Common Mental Illnesses Associated

With Trauma

Depressed mood

Loss of interest/pleasure

Appetite/weight changes

Suicidality

Guilt/worthlessness

Anxiety

Worry

Irritability

Muscle tension

Phobic avoidance

Compulsions

Panic attacks Sleep

Concentration

Fatigue

Psychomotor

MDD


Who Is At Risk?

Trauma type

Small hippocampus

Genetic

polymorphisms

??? MODERATE STRONG

Life stress

Lack of social support

Other previous trauma

Other adverse childhood

experience

Trauma severity

Psychiatric history

Childhood abuse

Family psychiatric

history

Wittchen et al. CNS Spectr 2009;14(Suppl 1):5-12.


Hippocampus

Early Life Stress

early life stress adult trauma

low cortisol

high ACTH

reduced

hippocampal volume

Neigh et al. Trauma Violence Abuse 2009;10:389-410.

stress sensitization

MDD

Anxiety

disorder

Adrenal

Pituitary

Hypothalamus


Early Life Stress: Is It All Bad?

amygdala

multiple

adult life

stressors

mild stress

in infancy

reduced reactivity

to stress

child abuse

stress sensitization

but no symptoms of

anxiety or depression

no stress

in infancy

normal stress

activation

no psychiatric disorder


MDD Anxiety

disorder


Genetic Risk Factors Under Investigation

DA transporter gene

(SLC6A3 9 allele)

An excess of 9 tandem

repeats found in patients

who developed PTSD

5-HT transporter gene

(“s” allele)

Increased risk of PTSD in

high-risk environments

Glucocorticoid receptor

co-chaperone FKBP5 gene

Interaction with childhood abuse

May contribute to increased

sensitivity of the amygdala and

HPA axis

BDNF gene (Val66Met)

Met/Met carriers have

greater recruitment of

amygdala and PFC during

memory formation and

retrieval

Heim, Nemeroff. CNS Spectr 2009;14(Suppl 1):13-24; Mahan, Ressler. TINS 2011;Epub ahead of print;

Binder et al. JAMA 2008;299(11):1291-1305; Shalev et al. Psychoneuroendocrinol 2009;34(3):382-8.


Risks in the Military: More Than Just Combat

Seal et al. Am J Public Health 2009;99:1651-8;

Friedman. Am J Psychiatry 2006;163:586-93;

Stein, McAllister. Am J Psychiatry 2009;166:768-76.

easy weapon access

sepa ration

sepa ration

destruction

readjustment

combat

sepa ration

unpredictable threats

lack of public support

WAR


PTSD and the HPA Axis

Hippocampus

low cortisol

Adrenal

Pituitary

Hypothalamus

downregulated

CRF receptors

increased sensitivity

to negative cortisol

feedback

increased

CRF

reduced

hippocampal volume


Neuroimaging Findings in PTSD

Brain Region Functional Structural Potential Implications

Amygdala ↑ Exaggerated fear

response

Deficits in extinction,

emotion regulation,

attention, contextual

processing

rACC ↓ ↓ volume

dACC ↑ Exaggerated fear

learning

Hippocampus ↑↓ ↓ volume Deficits in contextual

processing

Intrusive memories

Insular cortex ↑↓ ↓ volume Increased anxiety

proneness

Shin, Liberzon. Neuropsychopharmacol 2009;Epub;

Lanius et al. J Psychiatr Res 2006;40:709-29.


Brain Atrophy in PTSD is Ongoing

Cardenas VA et al. Psychiatry Res: Neuroimaging 2011;193:93-100.


PTSD

non-pharmacy

adjunctive

1st-line

2nd-line

PTSD “Non-Pharmacy”

exposure

therapy

cognitive

restructuring

stress

inoculation

acceptance and

commitment

therapy

dialectical

behavior therapy

seeking safety

therapy motivational

interviewing

eye movement

desensitization

and reprocessing

Zayfert C et al. J Trauma Stress 2005;18(6):637-45;

Bisson J, Andrew M. Cochrane Database Syst Rev 2007;(3):CD003388.


Virtual Exposure Therapy

Rizzo et al. Ann NY Acad Sci 2010;1208:114-25.


PTSD

pharmacy

adjunctive

mirtazapine

hypnotic SDA/

DPA beta blocker (preemptive) lamotrigine

topiramate acamprosate

naltrexone

1

antagonist

1st-line

SNRI SSRI

2nd-line

BZ gabapentin/ pregabalin

MAOI TCA

PTSD “Pharmacy”

Only sertraline and paroxetine are FDA-approved to treat PTSD.



5-HT Signaling Increases BDNF Release,

Which Modifies 5-HT Innervation

5-HT

PKA CaMK

CREB

BDNF

synaptogenesis

neuroplasticity

neurogenesis

cell survival



Sertraline

• SSRI

• FDA-approved for the treatment

of PTSD

• Most common side effects are

sexual dysfunction,

gastrointestinal issues, and CNS

problems

• Weight gain and sedation

unusual

• Initial dosing at 25 mg/day

increased to 50 mg/day after

1 week; maximum dose

200 mg/day single dose

• 169 outpatient veterans in randomized, double-blind comparison of sertraline vs placebo

– 12 wks flexible dose (25-200 mg/day)

– Scales: CAPS, Impact of Events, Clinical Global Impressions (CGI-I)

• No significant difference noted between sertraline and placebo

• 37 patients in randomized, double-blind comparison of sertraline vs nefazodone

– 12 wks flexible dose (avg. 153 mg/day sertraline)

– Scales: CAPS, CGI-I

• Both treatment groups showed improvement; no difference between groups in efficacy

Stahl. Prescriber’s Guide 2008; Friedman et al. J Clin Psychiatry 2007;68:711-20;

McRae et al. Depr Anx 2004;19:190-6.

DRI

SRI


Paroxetine for Non-Combat-Related PTSD

• SSRI

• FDA-approved for PTSD treatment

• Aids in treatment of re-experiencing, avoidance, and hyperarousal

• Effective antidepressant and anxiolytic

0

10

20

30

40

0 4 8 12

Weeks of Treatment

David

so

n P

TS

D S

cale

avoidance

hyperarousal

intrusive symptoms

*

*

*

*

* †

†

† † †

† †

n = 10

* Denotes significance between 4-week intervals at p < .05

† Denotes significance between weeks 0 and 8 at p <.001

† † Denotes significance between weeks 4 and 12 at p < .001

Adapted from Marshall et al. J Clin Psychiatry 1998;18(1):10-1.


Other Medications

• Other SSRIs/SNRIs: rationale and some

published data in support of efficacy

• Benzodiazepines: negative studies

• MAOIs: mixed data

• Atypical antipsychotics: mixed data

– Possibly beneficial as adjuncts for psychotic

symptoms, sleep

Ipser, Seedat. Cochrane Database Syst Rev 2006;(1):CD002795.


Pretest Question 2

38y/o male with PTSD, alcohol dependence, and

chronic back and knee pain presents on these

medications: quetiapine 50mg qHS, prazosin 3mg

qHS, duloxetine 90mg daily, gabapentin 300mg TID,

clonidine 0.1mg TID, zolpidem 10mg qHS. He has also

recently started on clonazepam 1mg BID. His

complaints include ongoing nightmares, depressed

mood, difficulty staying asleep and poor memory.

What might you do now to optimize this patient's

medication regimen?

1. Increase quetiapine dose

2. Decrease quetiapine dose


Atypical Antipsychotics for PTSD: Increasing

Serious Side Effects Without Therapeutic Benefits?

• Study investigating risperidone vs placebo in SSRI-

resistant PTSD cases

Krystal et al. JAMA 2011;306(5):493-502.


Noradrenergic Hyperactivity in Anxiety

anxiety / panic attacks

tremor

sweating

tachycardia

hyperarousal

nightmares



Alpha-1 Adrenergic Blockers to Treat Anxiety and Nightmares


tremor

sweating

tachycardia

hyperarousal

nightmares

1 receptor

1 blocker



Pretest Question 3

38y/o male with PTSD, alcohol dependence, and chronic

back and knee pain presents on these medications:

quetiapine 50mg qHS, prazosin 3mg qHS, duloxetine 90mg

daily, gabapentin 300mg TID, clonidine 0.1mg TID,

zolpidem 10mg qHS. He has also recently started on

clonazepam 1mg BID and his quetiapine dose was

increased to 300 mg/day. His is still complaining of ongoing

nightmares, but his depression has improved. He also still

has difficulty staying asleep, chronic knee and back pain,

and poor memory. What might you do now to optimize this

patient's medication regimen?

1. Increase prazosin dose

2. Increase neurontin dose

3. Both of the above


Prazosin (Minipress)

• Alpha-1 adrenergic blocker

• Antihypertensive drug

• Used to prevent nightmares in patients with PTSD; normalizes slow-wave sleep

• Not extensively studied in PTSD

• Dose not established; studied at 1–20 mg/day at bedtime or in divided doses

• Side effects include orthostatic hypotension, insomnia/fatigue, depression, nervousness, dizziness, syncope, headache, gastrointestinal effects

• Side effects generally decrease with time

• Notable interactions: diuretics, other antihypertensive drugs

Raskind et al. J Clin Psychiatry 2002;63(7):565-8.


Prazosin vs. Quetiapine

Byers MG et al. J Clin Psychopharmacol 2010;30:225-9.


Beta Adrenergic Blockers to Treat Anxiety


tremor

sweating

tachycardia

hyperarousal

nightmares

ß1 receptor

beta blocker



Preemptive Treatment: Blocking Fear Conditioning With Beta Blockers

VMPFC

hippocampus

locus coeruleus

fear

conditioning

fear response!!!

Stahl SM. Stahl’s Essential Psychopharmacology. 3rd ed. Cambridge University Press 2008; Orr et al. Biol

Psychiatry 2006;73:262-71; Pitman et al. Biol Psychiatry 2002;51:189-92;

Vaiva et al. Biol Psychiatry 2003;54:947-9.


VMPFC

hippocampus

locus coeruleus

fear

conditioning

ß1 blocker

no fear response


Preemptive Treatment: Blocking Fear Conditioning With Beta Blockers


Propranolol (Inderal)

• Beta blocker and antihypertensive drug

• Might block effects of stress from prior traumatic experiences

• Usual dose range: up to 240 mg/day; effective dose varies greatly

• Side effects include insomnia/fatigue, depression, vivid dreams, gastrointestinal effects

• Notable interactions: most atypical antipsychotics, alcohol, ibuprofen/NSAIDs, SSRIs, duloxetine

• A recent study showed that propanolol was ineffective for reducing PTSD-like onset in a rat model

Cohen H et al. Eur Neuropsychopharmacol 2011;21:230-40.


Pharmacotherapy Following Traumatic Injury

May Prevent Development of PTSD

• 696 injured U.S. military personnel

• Intravenous administration of morphine during

resuscitation and trauma care

Odds Ratio Adjusted for Injury Severity Score (95% CI): 0.48 (0.34–0.68) p<0.001

0

20

40

60

80

100

PTSD No PTSD

Morphine Use

60% 76%

Holbrook TL, Galarneau MR, Dye JL et al. N Engl J Med. 2010;362(2):110-7.


Prophylactic Use of Cortisol

• PTSD may develop as a result of subadequate

cortisol response

• High dose hydrocortisone treatment given in first few

hours immediately following trauma

Zohar et al. Eur Neuropsychopharmacol 2011;Epub ahead of print.


Cortisol Following Stress Increases BDNF in

Hippocampus

Zohar et al. Eur Neuropsychopharmacol 2011;Epub ahead of print.


Fear Conditioning vs Fear Extinction

VMPFC

hippocampus

sensory cortex

thalamus

VMPFC

hippocampus

lateral amygdala

central amygdala

intercalated cell mass

no fear response



Fear Conditioning vs Fear Extinction VMPFC

hippocampus

sensory cortex

thalamus

VMPFC

hippocampus

no fear response

new learning

= glutamate

= GABA

fear response!!!

fear

conditioning

no fear response

fear

extinction



Facilitating Fear Extinction: Enhancing Inhibitory

Learning With the NMDA Agonist D-Cycloserine

D-cycloserine

facilitates

learning

D-cycloserine

no fear response



Adrenal

Hippocampus

Glucocorticoid

receptor

Cortisol

Corticotropin

releasing

factor (CRF)

Corticotropin

(ACTH)

Pituitary

Hypothalamus

vasopressin 1B

antagonist

glucocorticoid

antagonist

Potential Sites of Action

for Novel Treatments for PTSD

CRF-1

antagonist


Common Comorbidities and Complications

Anxiety/Re-experiencing

Worry

Sleep

Irritability

Avoidance/Numbing

Concentration problems

Arousal

Traumatic

brain

injury

Suicidality Alcohol and

drug

dependence

Other

anxiety

disorders

Depression


Suicide Risk Factors

Hopelessness, helplessness

Access to lethal means

Personality traits (impulsive,

aggressive)

Anxiety, panic attacks,

agitation, insomnia*

Current psychiatric illness

(depression, alcohol abuse)

Perceived stress

Unstructured time

Nicotine use

Drinking/drug use

Modifiable

Disciplinary action

Life transitions Cultural/religious belief

about suicide

Physical injury/illness,

chronic physical pain Demographics (male,

unmarried, early 20s)

Relationship difficulties Family history

Financial difficulties

Unemployment (reserves) Patient’s history (experience

of trauma/loss, previous

attempt, psychiatric illness)

Circumstantial Immutable

*Often precede suicide within hours/days/weeks


Are Some Symptoms Precursors to

Suicidality?

• Anxiety

• Agitation

• Panic attacks

• Insomnia

• Irritability

• Hostility

• Aggressiveness

• Impulsivity

• Restlessness

• Hypomania and mania


Suicide Risk Is Highest When:

• The person sees no way out and fears things may get worse

• The predominant emotions are hopelessness and helplessness

• The person is anxious, agitated, and has insomnia

• Thinking is constricted with a tendency to perceive his or her situation as all bad

• Judgment is impaired by use of alcohol or other substances

• There is a lack of future orientation


Suicide Assessment

• Conduct a thorough assessment and reassessment of suicide risk

• Involve patient and family in treatment plan

• Choose appropriate treatment setting and means of monitoring patient based on risk assessment

• Document your thinking about suicide risk and your decision-making based on your assessment

• Remember: 3 out of 4 suicide victims had contact with their primary care provider within 90 days of their suicide


PTSD and Substance Abuse

• Trauma memories may elicit cravings

• Childhood trauma can increase the risk of PTSD in substance abuse patients, especially if multiple traumas have been witnessed as an adult

• Unresolved PTSD can result in a higher risk of substance abuse

• Childhood traumas are a better predictor of adulthood substance abuse cravings than adolescent traumatic events

Schumacher et al. Am J Addict 2006;15:422-5.


Treating Comorbid SUD in Patients With PTSD

acamprosate

varenicline

naltrexone

SUD pharmacy

bupropion

buprenorphine methadone

alcohol

nicotine

opiate

non-

pharmacological

seeking safety

therapy

motivational

interviewing

support

groups


Gabapentin + Naltrexone

Anton RF et al. Am J Psychiatry 2011;168:709-17.

http://ajp.psychiatryonline.org/content/vol168/issue7/images/large/appi.ajp.2011.709b.jpeg

http://ajp.psychiatryonline.org/content/vol168/issue7/images/large/appi.ajp.2011.709e.jpeg


PTSD, Chronic Pain, and Depression

• 80% rate of chronic pain in sample of Vietnam vets with PTSD

• PTSD more influential than depression and other disorders in leading to poor physical health

• Depression found to mediate the relationship between PTSD and pain

• Treatment for PTSD and pain should take potential depressive symptoms into account

Poundja et al. J Traum Stress 2006;19(5):747-51.


Persistent Postconcussive Syndrome (PPCS)

and PTSD: Symptom Overlap

Nightmares

Flashbacks

Guilt

Headaches

Sensitivity to

light/sound

Memory

deficit

Dizziness

Disinhibition

Emotional lability

Depression

Irritability/anger

Concentration/ attention problems

Fatigue

Hyperarousal

Avoidance

Apathy

PTSD PPCS



Brain Regions Vulnerable to TBI:

Overlap With PTSD?

DLPFC

OFC

subcortical

white matter

hippocampus

TBI TBI and PTSD



PTSD

pharmacy

adjunctive

mirtazapine

hypnotic CBT

SDA/

DPA beta blocker (preemptive) lamotrigine

topiramate acamprosate

naltrexone

1

antagonist

1st-line

SNRI SSRI

2nd-line

BZ gabapentin/ pregabalin

MAOI TCA

PTSD and Comorbid TBI “Pharmacy”

Kennedy et al. JRRD 2007;44:895-920.


Summary

• Many factors, both environmental and genetic, may contribute to whether one develops mental illness following trauma

• PTSD is a disorder with significant impact on functioning and quality of life

• Anxiety disorders, including PTSD, should be diagnosed and treated according to the best available evidence

• Maximizing treatment outcomes may require an integrated approach that encompasses both pharmacological and non-pharmacological interventions

Optimizing Outcomes for Patients With...

Documents

Transcript of Optimizing Outcomes for Patients With...