3. MAJOR ANXIETY DISORDERS PREVALENCE RATES YEARLY 17% YEARLY 17% LIFETIME 25% LIFETIME 25%

4. CHRONICITY Can be Transient: Can be Transient: > Adjustment Disorders > Adjustment Disorders > Acute Stress Disorder > Acute Stress Disorder (20% spontaneous remission (20% spontaneous remission within 30 days) within 30 days)

5. CHRONICITY Low Rates of Spontaneous Remission: Low Rates of Spontaneous Remission: > PTSD (50% remit in 2 years) > PTSD (50% remit in 2 years) > OCD…GAD… > OCD…GAD… Social Anxiety Disorder Social Anxiety Disorder > Panic Disorder (20 yr…25% remission)* > Panic Disorder (20 yr…25% remission)* * Pollack, et al. 2003

6. Meds or Psychotherapy ?

7. Pharmacological strategies based on neurobiology

8. BRAIN STRESS CIRCUITS AND NEUROENDOCRINE PATHWAYS

10. Norepinephrine Cell: Locus Coeruleus

11. CHLORIDE ION CHANNELS: GABA/BENZO RECEPTORS

14. Alpha 2 adrenergic cells

16. Drugs used to treat anxiety disorders

17. Classes of Medications Benzodiazepines (minor tranquilizers) Potent anti-anxiety medications

18. Potential Problems with Benzos Cognitive impairment Sedation Balance and coordination Addiction Dependency Discontinuation withdrawal

19. Benzodiazepine Withdrawal (short acting) Appears 6-12 hours Reaches peak: 2-4 days Subsides: 2-3 weeks Symptoms: anxiety, depression, insomnia, seizures (occasionally)

20. A General precaution when prescribing benzodiazepines don’t use with those with a history of substance abuse

21. Classes of Medications BuSpar (atypical tranquilizer): > not habit forming > decreases worry > onset: 2-4 weeks > ineffective: panic; acute anxiety

22. Classes of Medications Antidepressants: especially: SSRI’s…Cymbalta…Effexor …Remeron not: Wellbutrin

23. Initial Intensification of Anxiety with Antidepressants Activation (vs. switching) Can occur with all antidepressants Strategies (AD and Benzos)

24. Antidepressants: Tx Anxiety Similar dosing as with depression > EXCEPT OCD: often requires high doses Onset of actions: (depends on dosing) > children and teenagers: 1-2 weeks > adults: 2-6 weeks > EXCEPT: OCD: very gradual improvement

25. Anxiety Disorders and Medication Treatment Strategies Adjustment Disorders Specific Phobias cont…

26. GAD Generalized Anxiety Disorder

27. BuSpar Targets worry; NO impact on panic Sx Not habit forming Onset of actions: 2+ weeks Very Mild Side effects: GI Sx, dizziness

28. Antidepressants used to Treat GAD Benzodiazepines

29. Social Anxiety Disorder Fear of negative evaluation

30. Public Speaking Anxiety Beta blockers: Inderal (20 mg) Onset of actions: one hour Not habit-forming For occasional use only Side effects: light headedness

31. Antidepressants and Social Anxiety SSRIs: 50-65%: 50% Sx ↓

32. Panic Disorder Phase One: Panic Attacks Phase Two: Phobias

33. PATTERNS OF PRACTICE: PD PHARMACOLOGY: PHARMACOLOGY: > Antidepressants 34% > Antidepressants 34% > Benzodiazepines 66% > Benzodiazepines 66% PSYCHOTHERAPY: PSYCHOTHERAPY: > Generic Talk Therapy 62% > Generic Talk Therapy 62% > Relaxation Therapy 13% > Relaxation Therapy 13% > Cognitive Therapy 25% > Cognitive Therapy 25%

34. Panic Disorder Medication Treatment Strategies Phase One Phase One > Panic Free: 62% > Marked Reduction: 90+% > Recurrence with discontinuation: 70+% Phase two: phobias Phase two: phobias

35. Panic Disorder SSRIs > advantages > disadvantages: onset; activation Benzodiazepines > 24 hours a day > nocturnal attacks: Ativan, Klonopin extended release Xanax

36. Phase Two: Dealing with Phobias

38. Anxiety Disorders Medication Treatment Strategies Obsessive-Compulsive Disorder Obsessive-Compulsive Disorder : > Reoccurrence with discontinuation: 95% + > SSRIs or Anafranil * Higher doses * Time frames for response

39. OCD Treatments: SSRIs 6-10 weeks: 25-30% reduction in Sx 18-24 weeks: 40-50% reduction in Sx Over one year: > 50%+ Effect Sizes: 0.4-0.5

40. Augmentation with Atypical antipsychotics

41. Acute Stress Disorder and Post-traumatic stress disorder (PTSD)

42. Psychodynamics of Medication Effects Can create a sense of increased Can create a sense of increased locus of control locus of control

43. Solutions that Backfire Chemical assault on Overwhelm and Intrusions

44. The Central Feature of Successful Therapy The Central Feature of Successful Therapy: To facilitate cognitive processing of the traumatic event and construct realistic, organized memories of the events… this must be done without re-traumatizing the client. Research suggests: as memories become more organized, symptoms  Foa and Riggs (1993)

45. An Additional Critical Factor Contributing to the Persistence of PTSD Shut down of Language Processing in the CNS Processing in the CNS

46. Metabolic Changes During Intrusive Experiences

47. Goal: Reducing affective arousal without CNS depression

48. Problems with Benzodiazepines: Early Administration: Early Administration: Worse outcome: 1 and 6 Worse outcome: 1 and 6 month follow-ups month follow-ups Ineffective with : Ineffective with : > Intrusive Symptoms > Intrusive Symptoms > Dissociation > Dissociation (Gelpin, et al., 1996) (Gelpin, et al., 1996)

49. Problems with Benzodiazepines: Dependency Dependency Abuse Abuse General CNS depressants: General CNS depressants: impact on cognition impact on cognition

50. Drugs Reducing Arousal without Cortical depression SSRIs Alpha-2 agonists (clonidine)

51. The LOCUS COERULEUS

52. Norepinephrine Cell: Locus Coeruleus

53. Experimental Treatments

54. Pharmacology: Preventive Strategies Alpha-2 agonists (e.g. clonidine) Alpha-2 agonists (e.g. clonidine) Excessive Adrenergic Activation Excessive Adrenergic Activation Does not shut down cortex Does not shut down cortex AND AND May prevent progressive May prevent progressive neurobiologic impairment neurobiologic impairment

55. DCS: D-cycloserine Used to treat tuberculosis Impact on glutamate receptors Facilitates extinction 50 mg prior to exposure

56. D-cycloserine and CBT (Stefan, 2006) Exposure based treatment: public speaking anxiety (double-blind, placbo controlled) 50 mg one hour prior 5 sessions Measures: pre, post, one month later Significant improvement vs. placebo

57. Nightmares Minipress : antihypertensive (alpha-1 adrenergic antagonist) 8 week study. Ss: 40 veterans Average dose: 13 mg (start at 1 mg) vs. placebo Distressing dreams: 0.94 (effect size) Quality of sleep: 1.0

58. Dissociation and Marked amnesia: Poorer Prognosis

59. Encodes Explicit Memory

60. Problems in the Synapse and Amnesia NCAM: neuronal cell adhesion molecule Synaptic “glue” PSA: solvent Hi cortisol: increased binding PSA to NCAM

61. Pharmacology: Preventive Strategies Inderal: propranolol: Inderal: propranolol: Impact on Memory Impact on Memory and Amnesia  and Amnesia 

62. Maintaining Synaptic Integrity Inderal interferes with PSA binding to NCAM (rapid administration) Also: SSRIs  PSA Helps preserve synapses

63. Targeting Intrusion and Hyperarousal SSRIs Combined treatments: Combined treatments: > SSRI and BuSpar > SSRI and BuSpar > SSRI and Atypical > SSRI and Atypical Antipsychotics Antipsychotics

64. Pharmacologic Strategies Intrusive Symptoms Hyperarousal Dissociation

66. Break Through Symptoms Compliance Substance use / abuse New stressors Sleep disturbance

67. ANXIETY DISORDERS IN CHILDREN

68. Obsessive-Compulsive Disorder Lifetime Prevalence Rate: 3% Lifetime Prevalence Rate: 3% 33-50% have childhood onset 33-50% have childhood onset boys: 7, girls: 11 boys: 7, girls: 11 Very Chronic course Very Chronic course Lowest Placebo Response Rate: 6% Lowest Placebo Response Rate: 6% CBT: 50-65% Sx reduction CBT: 50-65% Sx reduction 25% refuse; 25% drop out 25% refuse; 25% drop out

69. OCD Treatments: SSRIs Prozac and Zoloft 6-10 weeks: 25-30% 6-10 weeks: 25-30% reduction in Sx reduction in Sx 18-24 weeks: 40-50% 18-24 weeks: 40-50% reduction in Sx reduction in Sx Over one year: > 50%+ Over one year: > 50%+ Effect Sizes: 0.4-0.5 Effect Sizes: 0.4-0.5

70. Augmentation

71. OCD: SSRI with BuSpar Augmentation Not supported in group studies Not supported in group studies Works for some kids Works for some kids High doses: 60 mg qd High doses: 60 mg qd

72. OCD: SSRI with Clomipramine Augmentation Best Combo: Luvox and Anafranil Best Combo: Luvox and Anafranil Low Dose Anafranil: 10-50 mg (kinetics) Low Dose Anafranil: 10-50 mg (kinetics) Pharmacy: formulates Pharmacy: formulates Labs: HR, BP, EKG Labs: HR, BP, EKG Monitor Blood Levels Monitor Blood Levels IV dosing for 2-3 weeks IV dosing for 2-3 weeks (highly treatment resistant) (highly treatment resistant)

73. School Avoidance (J. March, 2002) Cognitive Behavioral Therapy 30% Cognitive Behavioral Therapy 30% CBT + SSRI 70% CBT + SSRI 70% Use Benzodiazepine first… Use Benzodiazepine first… get back in the get back in the classroom ASAP classroom ASAP

74. The Role of Anxious Parents in Separation Anxiety

75. Simple/Specific Phobias Dental Dental Exam Exam 70%: there is 70%: there is co-morbidity co-morbidity

76. Pediatric Anxiety Pharmacology Study: N. England J. Med., 2001 Separation, social, and Separation, social, and generalized anxiety disorders generalized anxiety disorders Ages: 6-17 Ages: 6-17 8 week, placebo controlled 8 week, placebo controlled

77. Pediatric Anxiety Pharmacology Study: N. England J. Med., 2001 Luvox (mean dose 169 Luvox (mean dose 169 [up to 300] mg/day) [up to 300] mg/day) Significant response: Significant response: Placebo: 29%, Luvox: 76% Placebo: 29%, Luvox: 76% Effect Size: 1.1 Effect Size: 1.1

78. ADHD

79. History of the Diagnosis Defects in Moral Code (1902) Minimal Brain Dysfunction (1937) Neurologic Etiology: * post-encephalitis * Benzedrine (1930s) * “soft signs” * Intact families

80. Prevalence and Etiology of ADHD PREVALENCE: PREVALENCE: CHILDREN 5-7% CHILDREN 5-7% ADULTS 4% ADULTS 4% ETIOLOGY: ETIOLOGY: GENETIC 80% GENETIC 80% ACQUIRED 20% ACQUIRED 20%

81. Course of the DisorderChildhood………..Adolescence..………Adulthood Full Syndrome… (100) (100) “H” drops out……… “H” drops out……… Remission Remission Rate: 33% Rate: 33% (66) (66)

82. Neurobiology

83. Genetic Risk Factors Twins Male Female Dizygotic 35% 20% Monozygotic 92% 50% Parent ADHD: 35% risk of child ADHD of child ADHD

84. Brain Structure Smaller Right Pre-frontal Cortex Smaller Right Pre-frontal Cortex Smaller cerebellum Smaller cerebellum Decreased volume: basal ganglia Decreased volume: basal ganglia

85. Frontal Lobe Dysfunction Decreased Frontal Blood Flow Decreased Frontal Blood Flow (CBF) (CBF) Hypo-Frontal Glucose Metabolism Hypo-Frontal Glucose Metabolism Decreased Spinal Fluid Dopamine Decreased Spinal Fluid Dopamine Metabolites Metabolites Marked increase in dopamine Marked increase in dopamine reuptake transporters (NARSAD: vol 13, 2002) reuptake transporters (NARSAD: vol 13, 2002)

87. HYPOMETABOLIC STATES FRONTAL LOBES

88. FRONTAL LOBE SYMPTOMS Difficulties Inhibiting Behavior (Impulsivity) Difficulties Inhibiting Behavior (Impulsivity) Impaired “Executive Functions” Impaired “Executive Functions” 1. “Temporal Myopia” 1. “Temporal Myopia” 2. Impaired Self-Monitoring 2. Impaired Self-Monitoring 3. Deficiencies in Intrinsic Motivation !!! 3. Deficiencies in Intrinsic Motivation !!!

89. Maturational Factors in Frontal Lobe Development Vx2

90. DIAGNOSTIC ISSUES SUBTYPES: SUBTYPES: > ADHD > ADHD > ADHD Minus the “H” > ADHD Minus the “H” > Inattentive Subtype > Inattentive Subtype CONTEXT-DEPENDENT SYMPTOMS CONTEXT-DEPENDENT SYMPTOMS ONSET: (first diagnosed) ONSET: (first diagnosed) > ADHD 4 years > ADHD 4 years > Inattentive 9 years > Inattentive 9 years

91. Diagnosis Infancy Infancy > Cries a lot > Cries a lot > Hard to Soothe > Hard to Soothe > Irregular sleep patterns > Irregular sleep patterns > Restless > Restless

92. DIAGNOSIS CHILDHOOD: CHILDHOOD: > Impaired Self-Control > Impaired Self-Control > Hyperactivity > Hyperactivity > Impulsivity > Impulsivity ADOLESCENCE: ADOLESCENCE: > Disorganization > Disorganization > Inflexibility in Problem > Inflexibility in Problem Solving Solving > Procrastination > Procrastination

93. Differential Diagnosis Diffuse Brain Damage (e.g. fetal alcohol) Anxiety Disorder Situational Stress Agitated Depression Bipolar Pre-Psychotic Impaired Affect Regulation: secondary to early abuse/neglect Boredom

94. INATTENTIVE SUBTYPE THIS IS NOT ADHD THIS IS NOT ADHD NO IMPULSIVITY NO IMPULSIVITY HYPO-ACTIVE HYPO-ACTIVE DAYDREAMER…”SPACE CADET” DAYDREAMER…”SPACE CADET” TRUE INFORMATION TRUE INFORMATION PROCESSING DEFICITS PROCESSING DEFICITS MEDICATION RESPONSES MEDICATION RESPONSES

95. TREATMENT IMPLICATIONS PSYCHOSOCIAL & PSYCHOSOCIAL & BEHAVIORAL BEHAVIORAL PHARMACOLOGIC PHARMACOLOGIC

96. MTA Study N= 579 N= 579 80% males, 20% females 80% males, 20% females Mean Age: 8.5 years Mean Age: 8.5 years Co-morbidity not excluded Co-morbidity not excluded Random assignment Random assignment 14 month study 14 month study

97. MTA Study Groups: Groups: > Psychosocial/ Behavioral > Psychosocial/ Behavioral (27 weeks of parent training) (27 weeks of parent training) > Stimulant Medication Treatment > Stimulant Medication Treatment > Combined > Combined > Treatment “as usual” > Treatment “as usual” Outcomes Outcomes

98. Pharmacologic Treatments

100. % of ADHD Children Treated 5%+ experience ADHD 5%+ experience ADHD 13.6% receive treatment 13.6% receive treatment Pliszka, et.al. (2000) Pliszka, et.al. (2000)

101. Some Consequences of Failure To Treat Increased risk of Substance Abuse Increased risk of Substance Abuse Decreased white matter volumes Decreased white matter volumes (Castellanos, et al. 2002) (Castellanos, et al. 2002) Stimulants may act to normalize Stimulants may act to normalize white matter maturation white matter maturation

102. Stimulants 100+ well controlled studies N= 6000+ Safest psychiatric medication Watch for cardiac problems ! Most effective psychiatric medication

103. Stimulants Mechanism of Action: > promotes vesicle release (amphetamine) > inhibits re-uptake of DA 

105. STIMULANTS FAST ACTING FAST ACTINGMethylphenidateDextroamphetamineAmphetamineVyvance(pro-drug)

106. New: Daytrana Methylphenidate Transdermal System Daily Doses: 10-30 mg Requires 3 hour to reach therapeutic blood levels Lasts 9 hours Side effects: insomnia, nausea, poor appetite

107. STIMULANT TREATMENT OUTCOMES Individual Medications, each: 72% Individual Medications, each: 72% Systematic Trials: 92% Systematic Trials: 92% Complete Remission: 50-65% Complete Remission: 50-65% Effect Size: 1.0 Effect Size: 1.0 Age Variables: Age Variables: > Below 3 20% > Below 3 20% > Below 5 50% > Below 5 50% Inattentive Subtype (low doses) 20% Inattentive Subtype (low doses) 20%

108. PRE- and POST TREATMENT SPECT SCANS

109. ADHD Algorithm (Barbara Coffee, Harvard, 2002) Stimulant Trials (x 3) Stimulant Trials (x 3) Antidepressant Antidepressant Alternative Antidepressant Alternative Antidepressant Alpha-2 agonist Alpha-2 agonist Combination of the above Combination of the above

110. New Treatment Guidelines on: co-morbid ADHD and anxiety

111. Some Treatment Specifics Start meds on weekends: so parents won’t only see rebound Start with short acting stimulants The question of tolerance (usually it’s co-morbidity)

112. Stimulant Side Effect Management Insomnia: Insomnia: > Clonidine: Kids: 0.05 mg. > Clonidine: Kids: 0.05 mg. Teens: 0.1 mg. Teens: 0.1 mg. > Trazodone 25-50 mg. > Trazodone 25-50 mg. > Remeron 7.5-15 mg. > Remeron 7.5-15 mg. > Melatonin 1-3 mg. > Melatonin 1-3 mg. Anorexia: Focalin Anorexia: Focalin

113. Stimulant Side Effect Management Dysphoria: switch stimulants Dysphoria: switch stimulants or add Wellbutrin or add Wellbutrin Stomach ache: give with food Stomach ache: give with food Inhibition of Growth Inhibition of Growth Cognitive Impairment  Cognitive Impairment 

114. Impact on Cognitive Functioning

115. Consequences of Mis-Diagnosis and Stimulant Treatment Anxiety:  anxiety Anxiety:  anxiety Pre-schizophrenic: psychosis Pre-schizophrenic: psychosis Bipolar: cycle acceleration Bipolar: cycle acceleration Agitated Depression:  agitation Agitated Depression:  agitation Situational Stress: Situational Stress: neglecting psychological issues neglecting psychological issues

116. ALTERNATIVE TREATMENTS  -2 Agonists (e.g. clonidine) (+/-)  -2 Agonists (e.g. clonidine) (+/-) Tricyclics (e.g. nortriptyline) (+/-) Tricyclics (e.g. nortriptyline) (+/-) SSRIs (e.g. Prozac) (-) SSRIs (e.g. Prozac) (-) Wellbutrin, SR XL (+) Effect: 0.6 Wellbutrin, SR XL (+) Effect: 0.6 (espec. with dysphoria) (espec. with dysphoria) NRIs (+) atomoxetine NRIs (+) atomoxetine

117. Strattera Brand name: Strattera Brand name: Strattera 0.5 mg/kg = Placebo 0.5 mg/kg = Placebo 1.2-1.8 mg/kg: effective 1.2-1.8 mg/kg: effective Effect Size: 0.7-0.8 Effect Size: 0.7-0.8 Monitor liver functioning Monitor liver functioning Suicide warning Suicide warning

118. Impact: NE re-uptake blocking and Enhancement of Dopamine

119. Antidepressants: Onset of Actions 5 days to 6 weeks

120. ADVANTAGES of ANTIDEPRESSANTS ONCE A DAY DOSING ONCE A DAY DOSING NO NEED FOR SCHEDULE II NO NEED FOR SCHEDULE II NO ABUSE/DEPENDENCE POTENTIAL NO ABUSE/DEPENDENCE POTENTIAL COVERAGE FOR EVENING HOURS COVERAGE FOR EVENING HOURS CO-MORBID DEPRESSION CO-MORBID DEPRESSION

121. Co-Morbidity Anxiety Anxiety Depression Depression Tourette’s Disorder Tourette’s Disorder Bipolar Bipolar Conduct Disorder Conduct Disorder Learning Disabilities Learning Disabilities

122. Pounds to Kilograms Conversion Weight in pounds divided by 2.2= kg