Pharmacologic Considerations in
the Treatment of Anxiety Disorders
Presented by: Ann M. Hamer, PharmD, BCPP
Date: 1/15/2015
Disclosures and Learning Objectives
• Learning Objectives
–
–
–
Be able to discuss first-line treatment
recommendations for common anxiety
disorders
Be able to discuss benefits and risks of
benzodiazepines
Be able to identify differences between
benzodiazepines
Disclosures: Dr. Ann Hamer has nothing to disclose.
Guideline Recommendation Grade
Drug Class
SSRIs
Paroxetine
Sertraline
SNRIs
Venlafaxine
TCAs
Amitriptyline
Clomipramine
MAOIs
Phenelzine
Ca Channel Modulators
Pregabalin
Gabapentin
Panic
GAD
SAD
OCD
PTSD
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3
2
1
3
2
2
5
1
Grade Key:
1=Category A evidence and good risk-benefit ratio
2=Category A evidence and moderate risk-benefit ratio
3=Category B evidence (limited positive evidence)
4=Category C evidence (evidence from uncontrolled studies or case reports
5=Category D evidence (inconsistent results)
3
5
Guideline Recommendation Grade
Drug Class
Benzodiazepines
Alprazolam
Clonazepam
Tricyclic Anxiolytic
Buspirone
Atypical Antipsychotic
Quetiapine
Risperidone
Other
Mirtazapine
Hydroxyzine
Panic
GAD
SAD
2
2
OCD
PTSD
3
5
1
3
3
2
Grade Key:
1=Category A evidence and good risk-benefit ratio
2=Category A evidence and moderate risk-benefit ratio
3=Category B evidence (limited positive evidence)
4=Category C evidence (evidence from uncontrolled studies or case reports
5=Category D evidence (inconsistent results)
3
Dosing Ranges of Grade 1 Agents
Drug Class
Panic
SSRIs
Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
20-60
10-20
20-40
100-300
20-60
50-150
SNRIs
Venlafaxine
Duloxetine
75-225
GAD
SAD
OCD
10-20
10-20
10-20
20-60
100-300
20-60
50-200
20-50
50-150
75-225
60-120
Ca Channel Modulators
Pregabalin
150-600
Atypical Antipsychotics
Quetiapine
50-300
100-300
20-50
50-150
75-225
PTSD
20-40
20-40
50-100
75-225
Buspirone
How does it work?
•
Selective 5HT1A partial agonist, with activity at both presynaptic
and postsynaptic 5-HT1A receptors
•
Interacts with dopamine receptors as an agonist and/or an
antagonist.
•
Appears to block presynaptic dopamine receptors selectively and
produces an increased firing of midbrain dopamine neurons.
•
Thus, buspirone produces anxiolytic effects via postsynaptic
receptor activity, while its activity at autoreceptors initially
suppresses neuronal firing but gradually restores serotonergic
neurotransmission.
Buspirone
Use in GAD:
• Initial dose is 7.5mg BID.
•
•
•
May be increased every 2-3 days in increments of
2.5 mg twice daily to a maximum of 30 mg twice
daily.
There is a significant delay in the onset of clinical
activity, which can vary from 2 weeks to much
longer.
Role: treating GAD in patients who cannot tolerate,
or fail to respond to, an SSRI or SNRI
Benzodiazepines
• Since their introduction into medical practice in
the 1960s, benzodiazepines have become one
of the most widely used groups of medications
• A WHO Task Force from the mid 1990s found
that:
•
•
80% are prescribed by general practitioners
Majority of users are chronic users
https://www.erowid.org/pharms/benzodiazepine/benzodiazepine_info1.pdf
Benzodiazepines
National Ambulatory Medical Center Survey
(NAMCS) found:
• 12.6% of the primary care visits involved
benzodiazepine or opioid prescriptions
•
32.4% of ED visits
• Prescription of benzodiazepines was found to
increase by a rate of 12.5% per year (95%
confidence interval [CI], 9.4% - 15.7%)
http://www.cdc.gov/nchs/ahcd.htm
Benefits of Use
• Reduction of anxiety, induction and
maintenance of sleep, muscle relaxation, and
treatment and prevention of epileptic seizures.
• These properties are shared by most currently
approved benzodiazepines but to varying
degrees, depending on their potency and
pharmacokinetic properties.
Baldwin DS, et al. Benzodiazepines: Risks and Benefits. A Reconsideration. J of
Psychpharm. 2013; 27(11) 967–971.
Agent Comparison
Drug
Onset of
Action
Peak Onset
(hrs)
Half-life (hrs)
Elimination
Dose
Equivalent
Chlordiazepoxide
(Librium)
Int
2-4
5-30 (parent)
3-100 (metab)
Oxidation
10mg
Diazepam (Valium)
Rapid
1
20-50 (parent)
3-100 (metab)
Oxidation
5mg
Flurazepam (Dalmane)
Rapid
0.5-2
47-100 (metab)
Oxidation
30mg
Alprazolam (Xanax)
Int
0.7-1.6
6-20 (parent)
Oxidation
0.5mg
Clonazepam (Klonopin)
Int
1-4
18-39 (parent)
Oxidation
0.25mg
Lorazepam (Ativan)
Int
1-1.5
10-20 (parent)
Conjugation
1mg
Oxazepam (Serax)
Slow
2-3
3-21 (parent)
Conjugation
15mg
Temazepam (Restoril)
Slow
0.75-1.5
10-20 (parent)
Conjugation
30mg
Int
0.75-2
1.6-5.5 (parent)
Oxidation
0.5mg
Long-Acting
Intermediate Acting
Short Acting
Triazolam (Halcion)
Onset of Action: Rapid=within 15 min; Intermediate=15-30min; Slow=30-60min
Risks of use
• Cognitive effects
•
Sedation and drowsiness, mental slowing and
anterograde amnesia
•
Dose dependent; +/- diminish with continued use
• Psychomotor effects
•
•
Impaired driving (potentiated by alcohol)
Risk of falls
•
Psychomotor effects greater in elderly and with longeracting agents
Baldwin DS, et al. Benzodiazepines: Risks and Benefits. A Reconsideration. J of
Psychpharm. 2013; 27(11) 967–971.
Risks of use
• Tolerance
•
•
Greatest with anticonvulsant and sedative effects
Less with anxiolytic and hypnotic effects
• Dependence
•
Physical and psychological withdrawal
• Abuse
•
Greater attention to prescribing practices, particularly
in combination with narcotics
Baldwin DS, et al. Benzodiazepines: Risks and Benefits. A Reconsideration. J of
Psychpharm. 2013; 27(11) 967–971.
Reasons for discontinuation of BZs
•
Tolerance develops so they are no longer effective for the condition
for which they were prescribed.
•
Dependence may develop, so that stopping will result in withdrawal
symptoms, and the end result is long-term continuation in order to
avoid withdrawal syndromes.
•
Prevention of adverse effects such as cognitive and psychomotor
impairment, depression, irritability, loss of concentration and
emotional blunting.
•
Reduce risk of falls in the elderly.
•
Reduce risk of accidents while driving.
•
Avoid potential interaction with other medication and with alcohol.
http://www.patient.co.uk/doctor/benzodiazepine-dependence
Clinical Considerations
•
Use lowest dose for shortest period of time
•
Benefit has been seen with short-term use (2-4 weeks)
•
Consider alternative agents for long-term needs
•
•
Consider both nonpharmacologic and pharmacologic alternatives
Dependence can be a significant issue for patients taking
BZs for >1 month
•
All patients should be made aware of the risks of dependence
with ongoing use
•
Periodic trials of dose reduction and cessation are recommended
•
High potency, short half-life agents more likely to cause
dependence
Benzodiazepine Withdrawal
Dependence
•
•
Associated with use >4 weeks
Prevalence estimate:
• 40% general practice pts; 63% psychiatric pts
Factors associated with long-term use:
•
Psychiatric comorbidity, older age, less educated,
living alone and using more avoidance coping
behavior
Kan CC, et al. Acta Psychiatr Scan 1997;96:85-93
Zandstra
et al.
Fam
Pract 2004;21:266-9
Kan CC, et al. Acta Psychiatr Scan 1997;96:85-93, Zandstra
SM, SM,
et al.
Fam
Pract
2004;21:266-9
Benzodiazepine Withdrawal
Advantages of withdrawal in long-time users
Study reviewed changes in elderly patients’ cognitive
function, quality of life, mood and sleep
Findings:
• 60% of pts had been taking the bz for >10yrs
• 27% of pts had been taking the bz for >20yrs
• Those that tapered off of the bz showed improvement
on several cognitive and psychomotor tasks
• Withdrawers vs. control did not differ in sleep or
benzodiazepine withdrawal symptoms
Curran HV, et al. Psychol Med 2003;33:1223-37
Curran et al. Psychological Medicine, 2003, 33, 1223–1237.
Benzodiazepine Withdrawal
Signs and Symptoms
Tremors
Anxiety
Perceptual disturbances
Dysphoria
Psychosis
Seizures
Abrupt withdrawal can be dangerous
Withdrawal Strategies
Taper schedules
Early stages of withdrawal are easier to tolerate than the later and
last stages.
Even short-term use may require a tapering off regimen (e.g. 2
weeks at lower doses)
Optimal duration is not clear and may vary from patient to patient.
In most patients, a brisk schedule (8-12 weeks) is possible.
Longer-term users may require longer tapers (up to several
months).
4 week taper at 25% per week—51% require slower d/c
Withdrawal Strategies
Taper schedules
In patients who have tried and failed to withdraw previously, a 6-month
schedule may be necessary.
% of baseline dose
Dosage (diazepam equivalents)
1
100.0%
15
2
73.3%
11
4
56.7%
8.5
6
40.0%
6
8
31.7%
4.75
10
23.3%
3.5
12
16.7%
2.5
100.0%
100.0%
% of original dose
Week
73.3%
75.0%
50.0%
40.0%
56.7%
23.3%
25.0%
14
13.3%
2
16
10.0%
1.5
13.3%
31.7%
6.7%
1
20
5.0%
0.75
22
3.3%
0.5
24
1.7%
0.25
26
0.0%
0 (STOP)
3.3%
0.0%
10.0%
0.0%
18
6.7%
16.7%
1.7%
5.0%
1
2
4
6
8
10
12
14
Week Number
16
18
20
22
24
26
Withdrawal Strategies
Other considerations:
Patients with underlying depressive illness
should be treated with an antidepressant
before withdrawal is started (consider an
antidepressant with low withdrawal potential)
Augmentation strategies have limited data
Monitor for recurrence of original disorder
The End!
Next Week:
Looking forward
to a
presentation by
Dr. Betlinski