Transcript ANXIETY DISORDERS BIOLOGY- Limbic System

16th Annual ETSU Nurse Practitioner/Physician Assistant Primary Care Conference
March 27, 2011 , Johnson City, TN
Jay M Griffith MD
MHC Asst. Chief, Quillen VAMC
Clinical Associate Professor, ETSU
Dept of Psychiatry and Behavioral Sciences
Diplomate, ABPN Psychiatry and Pain Medicine
AMYGDALA
Drives autonomic
and emotional
responses
HIPPOCAMPUS
Evaluates threat
contexts
PREFRONTAL
CORTEX
Regulates limbic
responses of
amygdala and
hippocampus
PFC
HC
AMYG
Diagram from Bisson 2007 BMJ Content created by Karleyton Evans, MD.
Adapted from Rauch, et al. CNS Spectrums. 1998;3(suppl 2):30-34.
PFC
- DANGER
AMYG
-
HC
- Social Phobia 13.3%
- Post Traumatic Stress Disorder (PTSD) 7.8%
- Generalized Anxiety Disorder (GAD) 5.1%
- Panic Disorder 3.5%
- 25% Lifetime prevalence for all anxiety disorders
- High Comorbidity (depression, other anxiety
disorders, substance use disorders)
- Generally occur in Females > Males
- 1/3 of Americans will experience a panic attack
- Serotonin (SE) is most frequently implicated
- Norepinephrine (NE) and Dopamine (DA) have
roles
- Calcium, glutamate, oxytocin, and other
neurotransmitter/neuropeptide systems are
relevant
(eg. Oxytocin Nasal decreases fear responses of social
phobics to anxiety provoking social stimuli)
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Anxiety, fear, avoidance, or increased arousal
R/O physiological/medication causes
R/O substance induced (caffeine) and obtain UDS
Unexpected Panic Attacks: Panic Disorder
Fear of humiliation: Social Phobia
6 mos of excessive worry and anxiety: GAD
Traumatic event + reexperiencing: PTSD
Which of these anxiety disorders can have
associated panic attacks?
Panic Disorder – basis of the diagnosis
Social Phobia – in public situations
GAD – during peaks of anxiety
PTSD – during heightened arousal
A Panic Attack is a discrete period in which there
is the sudden onset of intense apprehension,
fearfulness, or terror, often associated with
feelings of impending doom. During these
attacks, symptoms such as shortness of breath,
palpitations, chest pain or discomfort, choking
or smothering sensations, and fear of "going
crazy" or losing control are present.
DSMVI-TR
The development of emotional or behavioral symptoms in response to an
identifiable stressor(s) occurring within 3 months of the onset of the
stressor(s).
These symptoms or behaviors are clinically significant as evidenced by either
of the following:
 marked distress that is in excess of what would be expected from
exposure to the stressor
 significant impairment in social or occupational (academic)
functioning
Specify if:
Acute: if the disturbance lasts less than 6 months
Chronic: if the disturbance lasts for 6 months or longer
With Anxiety
With Mixed Anxiety and Depressed Mood
DSIVM-TR
Significant impairment in social or
occupational (academic) functioning
Panic Disorder – SSRI/SNRI – (use BZP early or late);
Cognitive Behavior Therapy (CBT)
Social Phobia – SSRI/SNRI, (BZP), CBT; for
performance anxiety (B-blocker, Toastmasters
International)
GAD – SSRI/SNRI , buspirone, (BZP), pregabalin in
Europe, CBT
PTSD – SSRI/SNRI(SNRIs not for hyperarousal), for
nightmares and possibly hyperarousal consider
prazosin off label, no BZPs, Exposure-Based CBT
It may take 8-12 weeks to see a response
CONSIDER OFF-LABEL MIRTAZAPINE FOR ALL DIAGNOSES
START LOW AND GO SLOW WITH ALL MEDICATIONS
AT ½ THE STANDARD STARTING DOSE FOR SSRIs/SNRIs
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5 HT1A partial agonist
NE metabolite
Begin 7.5mg bid then increase by 5mg q 2-3 days
BID or TID
Faster increases may produce jitteriness
2-3 weeks before onset
A study demonstrated less efficacy for buspirone
in those previously treated with a benzodiazepine
- No adverse cognitive effects
- No physiological dependence
- Not cross-tolerant with alcohol
- Few side-effects (jitteriness, headache)
Middle-aged male with a history of “panic
attacks” 3-4 times a month and two phobias. +
sexual side effects on SSRIs/SNRIs
Consumes 2-3 oz of liquor equivalents nightly
and 3-4 oz on some occasions
Further history demonstrates he experiences GAD
and when panic attacks occur during
elevations of GAD intensity
1 month later 10mg tid of buspirone decreases
anxiety by 70%
3 months later the patient calls to report increases
of all anxiety symptoms
He is missing midday doses of medication
Change to BID and he’s had sustained benefit
- α -1 adrenergic antagonist
- Most lipophilic drug in its class (crosses the
blood brain barrier)
- Previous indications for hypertension (also
used off label for benign prostatic hypertrophy)
(triple play)
- Murray Raskind et al. reported a series of
studies into its impact on the re-experiencing of
PTSD symptoms, particularly nightmares
- Begin at 1mg hs and increase by 1mg/week to
10mg to 12 mg hs in males; 3mg hs in females
- Side Effects: First dose syncope and possible
priapism; lowers LDL
- Efficacious in war-related and civilian PTSD
- May also be uptitrated in the AM at < than the
HS dose
- Addressing hyperarousal/hyperadrenergic c/o
First line PTSD treatment in the 2011 Harvard
Algorithm (psychopharm.mobi)
BENZODIAZEPINES
“I’ve been feeling more stressed because
________ happened last week. Can give
me something for this?”
“I need a nerve pill.”
“Yeah, my anxiety is better on the
medication (citalopram) but I sure wish
you’d give me something for my nerves.”
(Longing for the halcyon days).
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“If you aren’t giving me Valium then I
don’t want any of your other
medications” (walks out of the office)
“I want to make a complaint about one of
your doctors who’s committing
malpractice”
“Cancel my appointment with that
doctor…he’s useless”
Benzodiazepines, Other Anxiolytic
Medications, and Meditations:
Selected Topics in Anxiety Management
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Dispersed across 50 years
Many questions are still unanswered
including:
appropriate indications for and durations
of therapy and short and long-term
adverse effects
There are vast differences of opinion both
within the US and between the US and
other countries regarding these issues
Benzodiazepines, Other Anxiolytic
Medications, and Meditations:
Selected Topics in Anxiety Management
WHAT DO WE KNOW ABOUT
BENZODIAZEPINES?
From 1969 to 1982 diazepam was the most
prescribed medication in America with
2.3 billion tablets sold in 1978
Lader 2011
“In all studies concerning prescription patterns of
benzodiazepines, it is noted that scarce information
is given on diagnosis and/or indications for
benzodiazepine prescriptions on patient charts, in
contrast to prescriptions of various other (nonpsychotropic) drugs (Buchsbaum et al. 1986).”
“… it was found that initial benzodiazepine
prescriptions were given in 35 and 38.5 per cent of
cases respectively for other reasons than the
recognized indications (van der Waals et al., 1993)
(Zisselman et al., 1994).”
Writing controlled substances for non-FDA approved reasons
“One user in four uses the benzodiazepine for a
year or longer.”
Balter 1991
“Rates of use increase with age. Persons older than
65 years account for 27% of all benzodiazepine
prescriptions and 38% of all benzodiazepine
hypnotics.” IMS America 1991
APA Textbook of Psychopharmacology
Benzodiazepine studies were 2 months in duration
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Hypnotic-sedative
Anxiolytic
Muscle relaxant
Anterograde amnesia
Antiseizure
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Enhance GABA effects at the GABA-A
receptor producing increased Cl- flux
and inhibitory neurotransmission
Decrease SE and NE turnover (can
generate depression)
Dependence involves dopaminergic
systems
Endozapines are purported endogenous
benzodiazepines
www.benzo.org. uk Ashton
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METABOEQUIV LISM
DOSE
???????
HALF
LIFE
ONSET
0.5mg
Oxidation
3A4
6-20
Intermediate Negligible (4OH)
chlordiazepoxide 10mg
Oxidation
3A4
30-100
Intermediate Desmethylchlordiazepoxide
clonazepam
0.25mg
Oxidation
3A4
18-40
Intermediate 4 amino
derivative
clorazepate
7.5mg
Oxidation
(unknown)
30-100
Rapid
Desmethyldiazepam (100/200)
diazepam
5mg
Oxidation
2C19; 3A4
30-100
Rapid
(sedation 30
min, peak 1
hour)
Desmethyldiazepam (100/200)
lorazepam
1mg
Glucuronidation
10-20
Intermediate None
DRUG
alprazolam
METABOLITE
Half -life (hours)
Ranked 11th among all prescriptions in the
USA, alprazolam is the #1 psychiatric
drug
With 46.3 million in 2010, aprazolam
prescriptions increased by 3 million/yr
since 2006
IMS Health, National Prescription Audit, Dec 2010
TN Top 10 Most Prescribed Controlled Substances 2010
1 Hydrocodone (Lortab, Vicodin) (TN is #2 in the US)
2 Alprazolam (Xanax) – steady for 3 years
3 Oxycodone (OxyContin, Roxicodone, generic)
4 Codeine
5 Clonazepam (Klonopin) – first year in the top ten
6 Zolpidem (Ambien)
7 Lorazepam (Ativan)
8 Diazepam (Valium)
9 Propoxyphene (Darvon, Darvocet)
10 Pregabalin (Lyrica)
TN Drug Diversion Task Force
1.
Because of its short half-life, alprazolam is
associated with behavioral reinforcement and
interdose anxiety (“clock watching” )
2.
These phenomena produce elevated anxiety
and dose escalations
The Alprazolam to Clonazepam Switch Herman et al. 1987
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ALPRAZOLAM 1MG TID PRN ANXIETY
Develop physiological tolerance while attempting to
get control over anxiety
 Later try taking as a prn
 Withdrawal and anxiety which will be defined as
anxiety or as “panic attacks”
 Conditioned to rely upon Xanax (anecdote: crying
spells with the mention of a minute dose reduction)
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With long term use there is:
Impaired performance on simple repetitive tasks
for up to one year and for several years on tests
of attention
Even after months or years the effects on episodic
memory persist
Verbal memory is particularly affected
May take more than 6 months for the memory
effects to completely resolve after stopping
Accidents
Increased risk of falls in the elderly
Increased risk of MVAs
Behavior problems- may cause paradoxical
excitement in vulnerable groups including:
Borderline personality disorder
Impulse control diosrder
Ongoing alcohol disorders
Sleep apnea: Inhibit respiratory response to CO2
and relax upper airway muscles
Can worsen sleep apnea or convert snoring into
sleep apnea
Many authorities, including the FDA, consider
benzodiazepines contraindicated in sleep
apnea
“The niggling question of possible long
term anatomical and biochemical
changes in the brains of long-term users
needs urgent attention to allay mounting
concerns in view of the continuing
extensive use of BZDs.”
GUIDELINES FOR THE USE OF BENZODIAZEPINES
IN OFFICE PRACTICE IN THE STATE OF MAINE
“There is no evidence supporting the long term
use of BZDs for any mental health indication”
http://www.benzos.une.edu/resources.htm
1,079,683 medications
Benzodiazepines 312,931
Alprazolam 112,552
Clonazepam 57,633
Diazepam 25,150
Lorazepam 36,582
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During 2003--2009, death rates increased for all
substances except cocaine and heroin. The
death rate for prescription drugs increased
84.2%, from 7.3 to 13.4 per 100,000 population.
The greatest increase was observed in the death
rate from oxycodone (264.6%), followed by
alprazolam (233.8%) and methadone (79.2%).
By 2009, the number of deaths involving
prescription drugs was four times the number
involving illicit drugs.
Family and Friends
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Diverted Rx Drugs of Greatest Concern & Sources
“Hydrocodone (Lortab, Lorcet, Vicodin and
generic equivalents), oxycodone (OxyContin,
Roxicodone, and generic equivalents), and
alprazolam (Xanax) are the top three most
prescribed drugs and primarily are among the
most commonly diverted and abused
pharmaceuticals in the State of Tennessee.
These three drugs prescribed and taken
together form what is known to law
enforcement as “the cocktail.”
TN Drug overdose deaths in Tennessee rose from
422 in 2001 to 1,059 in 2010
This bill, if approved, would require all
prescribers and dispensers of schedule II, III, IV
or V controlled substances to register in the
PMP and check the database regularly
All new starts require a database review
Reviews could be conducted by licensed
healthcare personnell and by one non-licensed
person per practice
J. Dreyzehner MD
TN Commissioner of Health
Prescription Substance Abuse
Conference, ETSU, 2012
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Addicted
Use with other illicit drugs to intensify
the intoxicating effects, eg.,
benzodiazepine + methadone
Profit
To manage withdrawal symptoms
associated with addictions to other drug
classes
Diazepam (Valium)
5mg $3.00 - $5.00
10mg $4.00 - $5.00
Alprazolam (Xanax)
1mg $2.00 - $4.00 (#120 1mg= $480.00)
2mg $4.00 - $8.00
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Early refills, lost medications, patient
initiated dose escalations
Increasing anxiety
Other addictions or misuses of
substances, eg., previous alcohol
addiction is a relative contraindication
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Cochrane review recommends 10 week taper
Dennis et al 2006
APA Textbook of Psychopharmacology
Taper clonazepam and alprazolam no faster
than 0.5mg every 2-3 weeks
May go even slower in complicated cases with
a seizure history
Provide clonazepam BID at a TDD at ½ of the of the
alprazolam TDD (or at the same dose)
2.
Inform patients it takes up to 7 days to make the crossover
3.
Throughout the 7 days the patient may take their
previous prescription of alprazolam
4.
Generally, during the 1-3 days they may need to
continue the previous alprazolam prescription
5.
Thereafter, they can take the alprazolam less frequently
or take ½ of a pill
6.
Should be off of the alprazolam at the end of 7 days
Individualize depending upon the patient’s medical status,
compliance history, and the provider’s availability
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Data support short term (up to 4-6
weeks) use for acute anxiety and when
awaiting the onset of a the first-line agent
(SSRI) in the treatment of a primary
anxiety disorder
Select groups may require maintenance.
This requires careful documentation with
a risk-benefit analysis and consent,
particularly in the elderly or medically
infirm
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Urine drug screens and random pill
counts, or the absence of them, should be
accounted for in the chart
Warning signs of diversion or other
forms of misuse require documentation
They are contraindicated in any active
substance use disorder and relatively
contraindicated with any history of
substance use disorders, especially in the
case of alcohol addiction
There is concern that benzodiazepines cause
“difficulty integrating the traumatic experience,
preventing optimal arousal in prolonged
exposure therapy, …”
They may decrease the effectiveness of exposure
therapies in other anxiety disorders.
SSRIs/SNRIs/buspirone/prazosin are not
thought to cause such problems.
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Overwhelming anxiety which blocks adaptation is
pathological
However, optimal anxiety levels promote
adaptation
When we venture into treating anxiety, we must be
certain that our interventions are promoting
adaptation and not hindering it
In this way of thinking, treating chronic anxiety
with benzodiazepines is not unlike using opioids
for chronic pain. Under these circumstances, we
must base interventions on measurable changes in
functioning and not on subjective reports
Significant improvement in social or occupational
(academic) functioning
MEDITATION
AN ADJUNCTIVE AGENT IN THE
MANAGEMENT OF ANXIETY
The act of utilizing attention to guide
changes in brain structure and function
Stress
Blood pressure
Cortisol
Pain
Anxiety
Depression
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Increases attention (the pathway to enhanced
memory and intelligence)
Bolsters self-efficacy
Generates neuroplastic changes in the brain
Gray Matter Increases Associated with Meditation
Adapted from Holzel et al. 2011
Study
Practice
Lazar et al.
2005
Pagnoni and
Cekic
2007
Hölzel et al.
2008
VestergaardPoulsen et al.
2009
gyrus
Luders et al.
2009
Insight
20/15
Zen
13/13
Grant et al.
cortex, 2010
cortex
Holzel et al.
2011
Insight
Meditators/Controls
20/20
Tibetan
10/10
Multiple
22/22
Zen
19/20
Insight
16/17
Brain regions greater in meditators
Right anterior insula and right
middle and superior frontal sulci
Meditators showed no age-related
decline in the left putamen compared
to actives
Left inferior temporal lobe, right
insula, and right hippocampus
Medulla oblongata, left superior and
inferior frontal gyri, anterior lobe
the cerebellum and left fusiform
Right orbito-frontal cortex, right
thalamus, left inferior temporal lobe,
right hippocampus
Right dorsal anterior, cingulate
secondary somatosensory
left hippocampus, posterior cingulate,
cortex, temporo-parietal junction,
cerebellum
AMYGDALA
drives autonomic
and emotional
responses
MEDITATION/MINDFULNESS
HIPPOCAMPUS
evaluates threat
contexts
(safe/unsafe)
PREFRONTAL
CORTEX
Regulates limbic
responses of
amygdala and
hippocampus
CONTEMPLATION
Diagram from Bisson 2007 BMJ Content created by Karleyton Evans, MD.
Adapted from Rauch, et al. CNS Spectrums. 1998;3(suppl 2):30-34.
1.
Sit in a quiet area for 20 minutes or more
2.
Direct your mind to an object of focus such as
your breath, thinking “In” as you breathe in
and “Out” as you breathe out
3.
When your mind drifts away as it inevitably
will, gently direct it back