Pharmacologic Considerations in the Treatment of Anxiety Disorders

Presented by: Ann M. Hamer, PharmD, BCPPDate: 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

Grade Key:1=Category A evidence and good risk-benefit ratio2=Category A evidence and moderate risk-benefit ratio3=Category B evidence (limited positive evidence)4=Category C evidence (evidence from uncontrolled studies or case reports5=Category D evidence (inconsistent results)

Drug Class Panic GAD SAD OCD PTSDSSRIsParoxetine 1 1 1 1 1Sertraline 1 1 1 1 1SNRIsVenlafaxine 1 1 1 1TCAsAmitriptyline 3Clomipramine 2 1 2MAOIsPhenelzine 3 2 5 5Ca Channel ModulatorsPregabalin 1Gabapentin 3

Guideline Recommendation Grade

Grade Key:1=Category A evidence and good risk-benefit ratio2=Category A evidence and moderate risk-benefit ratio3=Category B evidence (limited positive evidence)4=Category C evidence (evidence from uncontrolled studies or case reports5=Category D evidence (inconsistent results)

Drug Class Panic GAD SAD OCD PTSDBenzodiazepinesAlprazolam 2Clonazepam 2 3Tricyclic AnxiolyticBuspirone 5Atypical AntipsychoticQuetiapine 1Risperidone 3Other Mirtazapine 3 3Hydroxyzine 2

Dosing Ranges of Grade 1 Agents

Drug Class Panic GAD SAD OCD PTSD

SSRIsCitalopramEscitalopramFluoxetineFluvoxamineParoxetineSertraline

20-6010-2020-40

100-30020-60

50-150

10-20

20-5050-150

10-20

100-30020-50

50-150

10-2020-60

100-30020-60

50-200

20-40

20-4050-100

SNRIsVenlafaxineDuloxetine

75-225 75-22560-120

75-225 75-225

Ca Channel ModulatorsPregabalin 150-600

Atypical AntipsychoticsQuetiapine 50-300

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.

Drug Onset of Action

Peak Onset (hrs)

Half-life (hrs) Elimination Dose Equivalent

Long-Acting

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

Intermediate Acting

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

Short Acting

Triazolam (Halcion) Int 0.75-2 1.6-5.5 (parent) Oxidation 0.5mg

Onset of Action: Rapid=within 15 min; Intermediate=15-30min; Slow=30-60min

Agent Comparison

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 longer-

acting 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;96:85-93Zandstra SM, et al. Fam Pract 2004;21:266-9Kan CC, et al. Acta Psychiatr Scan 1997;96:85-93, Zandstra SM, et al. Fam

Pract 2004;21:266-9

Benzodiazepine Withdrawal

Advantages of withdrawal in long-time usersStudy 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 SymptomsTremors

Anxiety

Perceptual disturbances

Dysphoria

Psychosis

Seizures

Abrupt withdrawal can be dangerous

Withdrawal Strategies

Taper schedulesEarly 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 schedulesIn patients who have tried and failed to withdraw previously, a 6-month schedule may be necessary.

Week % 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

14 13.3% 2

16 10.0% 1.5

18 6.7% 1

20 5.0% 0.75

22 3.3% 0.5

24 1.7% 0.25

26 0.0% 0 (STOP)

100.0%

73.3%

56.7%40.0%

31.7%

23.3%

16.7%

13.3%

10.0%

6.7%

5.0%

3.3%

1.7%0.0%

0.0%

25.0%

50.0%

75.0%

100.0%

1 2 4 6 8 10 12 14 16 18 20 22 24 26

% o

f o

rig

inal

do

se

Week Number

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