Practical Update on Management of Anxiety Disorders

1
Practical Update on Management of Anxiety
Disorders

• Jefferson B. Prince, M.D.
• Director, Child Psychiatry
• MassGeneral for Children at
• North Shore Medical Center
• Staff, Pediatric Psychopharmacology Massachusetts
  General Hospital
• Harvard Medical School
• jprince_at_partners.org

2
Disclosure Statement of Potential Conflicts for
Jefferson Prince, M.D.

• In the past 12 months, I have not had a
  significant financial interest or other
  relationship with the manufacturer(s) of the
  product(s) or provider(s) of following service(s)
  that will be discussed in my presentation.
• This presentation will include discussion of
  pharmaceuticals that have not been approved by
  the FDA for treatment of ADHD.

3
Pediatric Anxiety Disorders

• Simple Phobia
• Generalized Anxiety Disorder (GAD)
• Separation Anxiety Disorder (SAD)
• Social Phobia (SP)
• Panic Disorder with/without Agoraphobia (PD)
• Obsessive-Compulsive Disorder (OCD)
• Acute Stress Disorder (ASD)
• Post-Traumatic Stress Disorder (PTSD)
• Selective Mutism

4
Pediatric Anxiety DisordersCommon Clinical
Characteristics

• Anxiety Disorders are frequently accompanied by
  somatic symptoms (e.g., headaches, bellyaches,
  fatigue)
• These somatic complaints often require
  (?unnecessary?) medical examinations and
  laboratory tests
• Anxiety may exacerbate physical illnesses

5
Circuitry Underlying Emotional Regulation
Orbital PFC
Dorsolateral PFC
Ventromedial PFC
Amygdala
Anterior Cingulate Cortex
Davidson et al., Science vol 289 28 July 2000
591-4
6
Amygdala Response to Fearful Faces in Anxious and
Depressed Children
Thomas et al., (2001) Arch Gen Psychiatry 58
1057-1063
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Assessment and Diagnosis of Anxiety and Depression
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Assessment of Anxiety in Children Adolescents

• Is Anxiety/Sadness Excessive for this child?
• Pediatric Symptom Checklist (PSC)
• Screen for Child Anxiety-Related Emotional
  Disorders (SCARED)
• Pediatric Anxiety Rating Scale (PARS)
• Yale Brown Obsessive Compulsive Disorder Scale
  for Children (Y-BOCDS-C)
• List of Available resources available at
• www.schoolpsychiatry.org

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Differential Diagnosis of Pediatric Anxiety

• Developmentally Appropriate Anxiety or Sadness
• Grief
• Trauma, Abuse, Neglect, Attachment Disorders
• Bipolar (especially mixed states)
• ADHD and/or Learning Disorders
• Substance Use Disorders
• Pervasive Developmental Disorders (e.g.,
  Aspergers, NLD)
• Eating Disorders
• Medical/Neurological Disorders (e.g.,
  hyperthyroidism, seizure)
• Medications

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Caffeinated Energy Drinks
Caffeine concentration (mg/oz) Pepsi Cola 3.2
mg/oz Jolt Cola 11.9 mg/oz Fixx 25 mg/oz Ammo 170
mg/oz
Reissig, Drug Alcohol Depend, 2009
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Treatment of Anxiety Disorders in Children and
Adolescents
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AACAP Guidelines Recommendation 7

• SSRIs should be considered for the treatment of
  youths with anxiety disorders
• SSRIs have emerged as the medication of choice in
  the treatment of childhood anxiety disorders
• Moderate to severe anxiety impairment makes
  therapy difficult partial therapy response
• poorer response in
• greater severity of illness at baseline,
• family history of anxiety disorders

Connolly Bernstein, 2007
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FDA Approved Medications for Anxiety Disorders in
Children and Adolescents
Medication for Anxiety Disorders FDA Approved for My Usual Starting Dose Children My Usual Starting Dose Adolescent My Usual Target Dose (titrate in 1-2 week intervals)
Fluoxetine (Prozac) OCD gt 7 5 mg 10 mg 5-40 mg (children) 20-80 mg (adol)
Sertraline (Zoloft) OCD gt 6 12.5 25 25-200 mg
Fluvoxamine (Luvox) OCD gt 8 12.5 25 200 (lt 11 yrs) 300 mg (12-17 yrs)
Clomimpramine (Anafranil) Must monitor baseline and F/u ECG and Levels OCD gt 10 25 25 Initial 3 mg/kg/d or 100 mg Long-term 3 mg/kg/d or 200 mg
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Child/Adolescent AnxietyMultimodal Study (CAMS)

• Randomized, controlled trial of 488 children
  (7-17 yrs)
• SAD, GAD or social phobia
• 14 sessions of CBT
• Sertraline (to 200 mg/day)
• Combined CBT and sertraline
• Placebo for 12 weeks
• Categorical and dimensional ratings of anxiety
  severity and impairment

Walkup et al, NEJM 2008
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Child/Adolescent AnxietyMultimodal Study
CGI-I response

• Sertraline (N133) a
• 4 wk 19 8 wk 47 12 wk 55
• CBT (N139) a
• 4 wk 9 8 wk 30 12 wk 60
• Combination (N140) a, b
• 4 wk 21 8 wk 54 12 wk 81
• Placebo (N76)
• 4 wk 7 8 wk 22 12 wk 24

a Plt0.001 vs. placebo b Plt0.001 vs. sertraline
vs CBT
Walkup et al, NEJM 2008
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Medication Guide for Pediatric Anxiety Disorders I
Medication Indications Side effects Dosing Dosing Dosing
Medication Indications Side effects Initial (mgs) Range (mgs/day) Schedule
SEROTONIN REUPTAKE INHIBITORS (SSRIs) First line treatment Nonaddictive well tolerated. Nausea Diarrhea Insomnia Somnolence denotes available in liquid form Use lowest dose
Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Duloxetine Venlafaxine Headaches, QTc Activation Sexual dysfunction Sweating Tremor Diastolic hypertension 5-20 QD 5-20 QAM 12.5-50 QHS 5-10mg 12.5-25 mg 20 mg 25 mg IR or 37.5 mg XR 10-40 or gt 10-80 50-300 10-60 50-200 20-60 mg 25-300 QD QD QD-BID QD-BID QD-BID QD QD-BID
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Medication Guide for Pediatric Anxiety Disorders
II
Medication Indications Side effects Dosing Dosing Dosing
Medication Indications Side effects Initial (mgs) Range (mgs/day) Schedule
OTHER ANXIOLYTICS Buspirone Second line treatment for generalized anxiety Nonaddictive well tolerated Headache Nausea Dizziness Lightheaded Somnolence 5 BID 5-60 BID-TID
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Medication Guide for Pediatric Anxiety Disorders
III
Medication Indications Side effects Dosing Dosing Dosing
Medication Indications Side effects Initial (mgs) Range mgs/day Schedule
BENZODIAZEPINES Adjunctive Rx only!! Diazepam Clonazepam Lorazepam Second line treatment Addictive potential and cognitive blunting time-limited circum-stances Sedation Cognitive blunting Dizziness Ataxia Memory disturbance Constipation Diplopia Hypotension 1-2 HS 0.125-0.5 0.125-0.5 BID 0.25-4 0.125-3.0 0.125-4.0 HS-BID HS-BID HS-TID
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Medication Guide for Pediatric Anxiety Disorders
IV
Medication Indication Side effects Dosing Dosing Dosing
Medication Indication Side effects Initial (mgs) Range (mg/d) Target (mg/kg/d) Schedule
TRICYCLIC ANTI-DEPRESSANTS (TCAs) Clomipramine Desipramine Imipramine Nortriptyline Amitruptyline Second line treatment non-addictive low tolerance require blood level and ECG monitoring Sedation Headaches Dry Mouth Constipation Nausea Orthostasis Blurred vision Urinary retn Cardiac Conduction delays 12.5-25 HS 10-25 QHS 10-25 QHS 10 QHS 10-25 QHS 25-150, 2-5 10-250, 1-2 10-200, 2-5 10-150, 1-3 10-100 0.5-2 QHS-BID QHS-BID QHS-BID QHS-BID BID-QID
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Medication Guide for Pediatric Anxiety Disorders V
Medication Indication Side effects Dosing Dosing Dosing
Medication Indication Side effects Initial (mgs) Range mgs/day Schedule
OTHER Third line treatment Non addictive Sedation Dry mouth Constipation
Mirtazapine Propranolol Betaxolol Fatigue Drowsiness Orthostatic hypotension Blurred vision 7.5-15 HS 10 QDBID 5 15-45 10-100 5-20 QHS QD-BID QD
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Is Sadness/Moodiness Excessive for this Student?

• Center for Epidemiologic Studies-Depression
  (CES-D)
• Childhood Depression Rating Scale (CDRS)
• Child Depression Inventory (CDI)
• List of Available resources can be found at
• www.schoolpsychiatry.org

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Clinical Presentation of Depressive Disorders

• Irritable mood and dysphoria (vs. sadness in
  adult depression)
• Inability to enjoy favorite activities (bored)
• Social withdrawal
• Blame/worthlessness/ guilt
• Suicidal preoccupation

• Mood reactive similar to atypical adult
  depression
• Abnormal sleep patterns (ie, nightmares)
• Fatigue
• Diminished ability to concentrate

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Course of Depressive Disorders
Remission
Recovery
Well
Symptom
Progression
Relapse
Recurrence
Relapse
Syndrome
Response
Improvement
Maintenance gt 1 yr
Continuation 6-12 months
Acute 6-12 wks
Treatment Phases
Kupfer DJ. J Clin Psychiatry 1991
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Treatment of Depressive Disorders

• For children and adolescents who are not
  responsive to supportive psychotherapy or who
  have more complicated depressions, a trial with
  specific types of psychotherapy and/or
  antidepressants is indicated CG.

Practice Parameter for the Assessment and
Treatment of Children and Adolescents with
Depressive Disorders JAACAP 2007 46 (11)
1503-1526
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FDA Approved Medications to Treat MDD
Name of Medication Pediatric Adults
Fluoxetine (Prozac) ? (7-17 yrs) ?
Sertraline (Zoloft) ? ?
Paroxetine (Paxil) ? ?
Fluvoxamine(Luvox) ? ?
Citalopram (Celexa) ? ?
Escitalopram (Lexapro) ? (12-17 yrs) ?
Venlafaxine (Effexor) ? ?
Duloxetane (Cymbalta) ? ?
Bupropion (Wellbutrin) ? ?
Mirtazapine (Remeron) ? ?
TCAs ? ?
MAOIs ? ?
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FDA Approved Medications for Major Depressive
Disorders in Children and Adolescents
Medication for Major Depressive Disorders FDA Approved for My Usual Starting Dose Children My Usual Starting Dose Adolescent My Usual Target Dose (titrate in 1-2 week intervals)
Fluoxetine (Prozac) MDD gt 7 5 mg 10 mg 5-40 mg (children) 20-80 mg (adol)
Escitalopram (Lexapro) MDD gt 12 2.5 mg 5 mg 25-200 mg
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Other medications that are not FDA approved for
treatment of Pediatric Depressive Disorders but
may be clinically appropriate include
Medication for Major Depressive Disorders My Usual Starting Dose Children My Usual Starting Dose Adolescent My Usual Target Dose (titrate in 1-2 week intervals) Comments
Citalopram (Celexa) 5 mg 10 mg 5-30 mg (children) 10-60 mg (adol)
Bupropion (Wellbutrin) 37.5 mg IR 100 mg SR 37.5 mg BID to 300 mg XL Do not use in pts with Sz or Eating D/o
Sertraline (Zoloft) 12.5 mg 25 mg IR 25-150 mg
A variety of other antidepressant medications
that are not FDA approved but may be clinically
appropriate
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Treatment of Depressive Disorders in Adolescents
and Young Adults

• Start low, go slow
• After initiation of pharmacotherapy make plan for
  regular follow-up emergency access
• Educate patient and usually family about
• Delay in onset of action
• Possible worsening depression/anxiety/sleep
• Negative behavior change
• Discontinuation Syndrome
• Potential for increase in Suicidality
• Symptoms of mania, hypomania mixed episodes
• www.parentsmedguide.org

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Possible Complications of Treatment with an
Antidepressant Medication

• Activation
• Bipolar Switching
• Celebration
• Dimensional Issues/Comorbid Disorders
• Evolving Psychopathology
• Frontal Lobe Symptoms
• Gastrointestinal Side Effects (? Growth)
• Hey! And Hematological
• Suicidality

Walkup Labellarte, J Child Adol
Psychopharmacology 11 1-4, 2001 Updated 2009
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Black Box Warning

• Antidepressants increased the risk of suicidal
  thinking and behavior (suicidality) in short-term
  studies in children and adolescents with Major
  Depressive Disorder (MDD) and other psychiatric
  disorders. Anyone considering the use of Drug
  Name or any other antidepressant in a child or
  adolescent must balance this risk with the
  clinical need. Patients who are started on
  therapy should be observed closely for clinical
  worsening, suicidality, or unusual changes in
  behavior. Families and caregivers should be
  advised of the need for close observation and
  communication with the prescriber. Drug Name is
  not approved for use in pediatric patients.
• The average risk of such events in patients
  receiving antidepressants was 4, twice the
  placebo risk of 2. No suicides occurred in these
  trials.

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Antidepressant Antianxiety Medications Efficacy
Suicidality
32
Suicidal Ideation and Behavior in Subjects Taking
Antidepressants for Psychiatric Reasons
Friedman RA and Leon AC. New Engl J Med.
20073562343-6.
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OCD SSRIs Efficacy Suicide

• 6 trials N705
• Response to medication 52
• (95 CI, 27-37)
• Response to Placebo 32
• (95 CI, 27-37)
• Pooled Absolute Suicidal Ideation/Attempt
• SSRI Treated 1 (95 CI, 0-2)
• Placebo Treated 0.3 (95 CI, -0.3-2 P.57)
• Number Needed to Treat 6 (95 CI, 4 to 8)
• Number Needed to Harm 200

Bridge, J. A. et al. JAMA 20072971683-1696.
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Non-OCD Anxiety Disorders SSRIs Efficacy
Suicide

• 6 trials N1136
• Response to medication 69
• (95 CI, 65-73)
• Response to Placebo 39
• (95 CI, 35-43)
• Pooled Absolute Suicidal Ideation/Attempt
• SSRI Treated 1 (95 CI, 0.2-2)
• Placebo Treated 0.2 (95 CI, -0.2-0.5 P.21)
• Number Needed to Treat 4 (95 CI, 3 to 6)
• Number Needed to Harm 143 (95 CI,)

Bridge, J. A. et al. JAMA 20072971683-1696.
35
Adjusted Odds Ratios for Phases of Antidepressant
Treatment
The dotted line at OR??1.0 indicates the value
of equal risk (equal odds of prior exposure to
antidepressants for indicated group vs referent
group) OR values higher than 1.0 indicate
elevated risk, OR values lower than 1.0 indicate
reduced risk
Valuck RJ et al., J Clin Psychiatry
200970(8)10691077
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Suicide Rates Reduced By

• Educating Health Care Professionals about
  recognizing and treating depression.
• Restricting access to lethal methods.
• Other interventions need more evidence of
  efficacy.
• Ascertaining which components of suicide
  prevention programs are effective in reducing
  rates of suicide and suicide attempts is
  essential in order to optimize use of limited
  resources.

Mann, J. J. et al. JAMA 20052942064-2074
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Example of Adolescent Support Card

• Safety Plan (write together and rehearse)
• Doctors Number
• Therapists Number
• ER/Hospital Numbers
• Identified Support Network (Family, Pets,
  Friends, Church)
• National Adolescent Suicide Hotline[phone]
• www.suicidehotlines.com/national.html

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Complementary Alternative Treatments for
Anxiety Mood Disorders

• Omega-3 Fatty Acids
• Overall, the data support using omega-3 fatty
  acids as adjunctive treatment for depression, but
  appropriate dosage levels and effective omega-3
  components or ratios of components need to be
  established.
• Folate
• Folate monotherapy may benefit certain depressed
  patients, and augmentation with folate may
  enhance antidepressant efficacy from treatment
  initiation or may convert partial and
  nonresponders into responders or even into
  remitters. Ultimately, many patients with
  depression may safely benefit from folate
  supplementation, whether or not they have
  abnormal folate levels, although more information
  is needed about using folate in depression.

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Complementary Alternative Treatments for
Anxiety Mood Disorders

• SAM-e
• Overall, evidence supports the use of
  intravenous, intramuscular, and oral SAM-e in the
  treatment of depression, with adjunctive therapy
  being possibly the most advantageous use.
  However, additional studies are needed to support
  its clinical relevance.
• St. Johns Wort
• Current evidence does not support the efficacy of
  St Johns wort in major depression, and the
  evidence in mild/minor depression is insufficient
  to draw conclusions.

Freeman MP., et al., J Clin Psychiatry. 2010
Jun71(6)669-81Complementary and alternative
medicine in major depressive disorder the
American Psychiatric Association Task Force
report.
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Light Therapy

• Blue Light Spectrum

Check out www.CET.org Terman and Terman CNS
Spectr. 200510(8)647-663
41
Can Exercise Alleviate Symptoms of Depression

• YES! Exercise reduces patient-perceived symptoms
  of depression
• As monotherapy
• Relieves symptoms as effectively as cognitive
  behavioral therapy (CBT) or pharmacologic
  anti-depressant therapy (SOR B, meta-analysis)
  and more effectively than bright light therapy
  (SOR B, meta-analysis).
• Resistance exercise and mixed exercise
  (resistance and aerobic) work better than aerobic
  exercise alone (SOR B, meta-analysis).
  High-frequency exercise is more effective than
  low-frequency exercise (SOR B, small RCT).
• "Mindful" exercise, which has a meditative focus,
  such as tai chi and yoga, also reduces symptoms
  of depression (SOR B, systematic review of RCTs).

Gill A., et al., J Fam Pract. 2010
Sep59(9)530-1.
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Vitamin D and Depression

• Mixed Results
• Zhao G., e al., British Journal of Nutrition
  (2010) results did not show signi?cant
  associations between serum concentrations of
  25(OH)D and PTH and the presence of
  moderate-to-severe depression, major depression
  or minor depression among US adults.
• Hoogendijk, W. J. G. et al. Arch Gen Psychiatry
  200865508-512

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Treatment of Pediatric Anxiety and Depressive
Disorders Psychotherapy

• Supportive
• Cognitive Behavioral Therapy (CBT)
• Psychodynamic
• Dialectical Behavioral Therapy (DBT)
• Interpersonal
• Family
• Group (vs. Individual or Family)
• Caregivers as co-therapists
• Self Help Resources http//depressionbookstore.com
  /depression_people/teens

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Every moment we experience the world in one of
six ways

• Seeing
• Hearing
• Tasting
• Touching
• Smelling
• Mind door the sixth sense (imagery, thinking,
  emotion)
• ? Mindsight as the seventh sense

45
Working with Anxiety Depression
Thoughts
Emotions
Body Sensations
46
ABCs of CBT
Behaviors
Affects
Cognitions
47
Cognitive Behavioral Therapy (CBT)

• Somatic Management Skills Training
• Target autonomic arousal and related physiologic
  responses
• Cognitive Restructuring Skills
• Identify maladaptive thoughts and teaching
  realistic coping-focused thinking
• Exposure Methods
• Graduated, Systematic and controlled exposure to
  feared stimuli
• Relapse Preventions Plans
• Consolidating and Generalizing Treatment Gains

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3 Core Communication Styles

• Following
• Directing
• Guiding

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3 Core Communication Skills

• Asking
• Listening
• Informing

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What level are you connecting with patient on?

• Transactional fixing the broken part
• Informing _at_ connection between behavior and
  symptoms how broken part related to behavior
  do more for yourself
• Reflecting, investigating, seeking to understand
  how this pattern is working (and not) for this
  particular patient in these circumstances Deep
  Listening.
• Transformational mutual vulnerability, openness
  and emergence. Co-creating.

Adapted from Senge P et al., Presence Human
Purpose and the Field of the Future.
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Shifting the Burden
Aspirin (Symptomatic Solution)
Health Problem (Side Effect)
Headache (Problem Solution)
Reduce Over commitment (Fundamental Solution)
Adapted from Senge P et al., Presence Human
Purpose and the Field of the Future. P205
52
The key lies in transforming both our capacity
to see and our capacity to create.
Fragmented Science Technology
Desire for Efficacy
Side Effects
Integrated human wisdom and development
Adapted from Senge P et al., Presence Human
Purpose and the Field of the Future. P207
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A New Mnemonic for E.M.P.A.T.H.Y.

• E Eye Contact
• M Muscles of Facial Expression
• P Posture/Position
• A Affect
• T Tone of Voice
• H Healing State
• Y Your Response

Articulated by Helen Riess, M.D.
54
Less Feeling More Thinking Mental Tennis

• 1 A
• 2 B
• 3 C
• ..
• 24 X
• 25 Y
• 26 Z

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The Relaxation Response by Herbert Benson, M.D.

1. Pick a focus word, phrase, image, or prayer or
   focus on breathing.
2. Sit quietly in comfortable position.
3. Close eyes relax muscles
4. Breathe slowly naturally as you do, repeat
   focus word or phase as you exhale.
5. When other thoughts come to mind, just go back to
   repetition of word or breathing.
6. Start by practicing 5-10 minutes once or twice
   daily

• Use practice to change physiology
• Inborn set of physiological changes that offset
  flight or fight response
• The physiological responses are reductions in HR,
  BP, RR, muscle tension
• Used to counteract harmful effects of stress.
• Practice slow, deep breathing

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STOP The Almost Moment

• S Stop the same old reaction, pause, being
  aware something is difficult
• T Take a breath exhale (extending the exhale
  relative to the inhale can engage parasympathetic
  Nervous system and be calming), then inhale
  (extending the in-breath relative to the
  out-breath can engage Sympathetic Nervous system
  and be energizing) take these breaths for as
  long as you need to.
• O Observe, what do you notice in your body,
  emotions, thoughts?
• P Proceed in a direction that is in line with
  what is important to you (the adolescent patient)

57
Whenoveractive feelings thenname it to tame
it

• Often suffer form emotional dysregualtion and
  chaotic outbursts.
• Overwhelmed by fragmented autobiographical
  images, filled with bodily sensations, awash in
  emotions that overwhelm and confuse.
• Excess of right mode flow without enough linkage
  to the left.
• Balance entails gaining some mental distance in
  the sanctuary of the left mode.
• Using the left language areas to calm the
  excessively firing right emotional areas.
• Key is to balance via linking the left and right

Lieberman, MD et al., (2008) Psychological
Science 18 (5) 421-428
58
AACAP Guidelines Recommendation 7

• Long-term medication treatment has not been
  studied
• Consider taper/dc medication for children who
  have a significant reduction in anxiety and
  maintain stability in these symptoms for 1 year
• Discontinue medication during a low stress period
• Reinitiate if relapse

Connolly Bernstein, 2007
59

• Where should we go?

60
Change in Social Withdrawal Over 8 Weeks in 10
Subjects With Autistic Disorder Receiving Placebo
Followed by Three Escalating Doses of
D-Cycloserine

• N12 children with autism
• 1 dropped due to worsening sterotypic behavior
• D-cycloserine, a partial agonist at the
  N-methyl-D-aspartate (NMDA) glutamate receptor
  subtype, has been shown to reduce negative
  symptoms in adults with schizophrenia

Posey et al., (2004) Am J Psychiatry
161(11)2115-2117
61
Putting It All Together
Anxious Patient
Sleep Subs Diet Exercise Laugh Stress Reduction
SSRIs ? SNRIs Others
RR Parent Mgt CBT
Clarify LD 504 IEP Advocate
Educational
Psychological
Self
Medical
62
Childhood Anxiety Disorders Take-home Points

• Anxiety disorders frequently onset early, and may
  predispose children to develop later disorders
• Children presenting with other disorders are very
  likely to have comorbid anxiety disorders which
  need to be addressed
• Exposure-based CBT, SSRIs, and their combination
  offer promising treatment approaches, but more
  research is needed

63
Northshore
UMass Memorial
Baystate
MGH
Tufts
McLean
64
Supports for Clinicians Families of Children
with with Anxiety Mood Disorders

• American Academy of Child and Adolescent
  Psychiatry www.aacap.org
• American Academy of Pediatrics www.aap.org
• www.parentsmedguide.org
• Anxiety Disorder Association of America
• www.adaa.org/living-with-anxiety/children
• School Psychiatry
• www.schoolpsychiatry.org
• MCPAP Massachusetts Child Psychiatry Access
  Project
• www.mcpap.org