MAJOR ANXIETY DISORDERSPREVALENCE RATES

• YEARLY 17%• LIFETIME 25%

CHRONICITY

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

CHRONICITY• Low Rates of Spontaneous

Remission: > PTSD (50% remit in 2 years)

> OCD…GAD… Social Anxiety Disorder > Panic Disorder (20 yr…25% remission)*

* Pollack, et al. 2003

Meds or Psychotherapy

?

Pharmacologicalstrategies basedon neurobiology

BRAIN STRESS CIRCUITS ANDNEUROENDOCRINE PATHWAYS

Norepinephrine Cell: Locus Coeruleus

CHLORIDE ION CHANNELS:GABA/BENZO RECEPTORS

Alpha 2 adrenergic cells

Drugs used to treatanxiety disorders

Classes of Medications

•Benzodiazepines (minor tranquilizers) •Potent anti-anxiety medications

Potential Problems with Benzos

• Cognitive impairment• Sedation• Balance and coordination• Addiction• Dependency• Discontinuation withdrawal

Benzodiazepine Withdrawal(short acting)

• Appears 6-12 hours• Reaches peak: 2-4 days• Subsides: 2-3 weeks• Symptoms: anxiety, depression, insomnia, seizures (occasionally)

A General precaution when prescribingbenzodiazepines

don’t use with thosewith a history ofsubstance abuse

Classes of Medications

•BuSpar (atypical tranquilizer): > not habit forming > decreases worry > onset: 2-4 weeks > ineffective: panic; acute anxiety

Classes of Medications

• Antidepressants: especially: SSRI’s…Cymbalta…Effexor …Remeron not: Wellbutrin

Initial Intensification ofAnxiety with Antidepressants

• Activation (vs. switching)• Can occur with all antidepressants• Strategies (AD and Benzos)

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

Anxiety Disorders and Medication Treatment Strategies

•Adjustment Disorders•Specific Phobias cont…

GADGeneralized Anxiety Disorder

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

Antidepressants used toTreat GAD

Benzodiazepines

Social Anxiety DisorderFear of negative evaluation

Public Speaking Anxiety

• Beta blockers: Inderal (20 mg)

• Onset of actions: one hour• Not habit-forming• For occasional use only• Side effects: light headedness

Antidepressants and Social Anxiety

• SSRIs: 50-65%: 50% Sx ↓

Panic Disorder

Phase One: Panic AttacksPhase Two: Phobias

PATTERNS OF PRACTICE: PD

• PHARMACOLOGY: > Antidepressants 34% > Benzodiazepines 66%• PSYCHOTHERAPY: > Generic Talk Therapy 62% > Relaxation Therapy 13% > Cognitive Therapy 25%

Panic Disorder Medication Treatment Strategies

• Phase One > Panic Free: 62% > Marked Reduction: 90+% > Recurrence with discontinuation: 70+%

• Phase two: phobias

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

Phase Two:Dealing with Phobias

OCD

Anxiety DisordersMedication Treatment Strategies

• Obsessive-Compulsive Disorder: > Reoccurrence with discontinuation: 95% + > SSRIs or Anafranil * Higher doses * Time frames for response

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

Augmentation withAtypical antipsychotics

Acute Stress Disorder and Post-traumatic stress disorder

(PTSD)

Psychodynamics of Medication Effects

• Can create a sense of increased locus of control

Solutions that Backfire

Chemical assault onOverwhelm and Intrusions

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)

An Additional Critical Factor Contributing to thePersistence of PTSD

Shut down of Language Processing in the CNS

Metabolic Changes During Intrusive Experiences

Goal:Reducing affective

arousal withoutCNS depression

Problems with Benzodiazepines:

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

Problems with Benzodiazepines:

• Dependency• Abuse• General CNS depressants: impact on cognition

Drugs Reducing Arousalwithout Cortical depression

SSRIsAlpha-2 agonists (clonidine)

The LOCUS COERULEUS

Norepinephrine Cell: Locus Coeruleus

Experimental Treatments

Pharmacology: Preventive Strategies

Alpha-2 agonists (e.g. clonidine)Excessive Adrenergic ActivationDoes not shut down cortex AND May prevent progressive neurobiologic impairment

DCS: D-cycloserine

• Used to treat tuberculosis• Impact on glutamate receptors• Facilitates extinction• 50 mg prior to exposure

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

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

Dissociation andMarked amnesia:

PoorerPrognosis

Encodes Explicit Memory

Problems in the Synapse and Amnesia

NCAM: neuronal cell adhesion moleculeSynaptic “glue” PSA: solventHi cortisol: increased binding PSA to NCAM

Pharmacology: Preventive Strategies

Inderal: propranolol: Impact on Memory and Amnesia

Maintaining Synaptic Integrity

Inderal interferes with PSA binding to NCAM (rapid administration)Also: SSRIs PSAHelps preserve synapses

Targeting Intrusion and Hyperarousal

• SSRIs • Combined treatments: > SSRI and BuSpar > SSRI and Atypical Antipsychotics

Pharmacologic Strategies

• Intrusive Symptoms• Hyperarousal• Dissociation

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

ANXIETY DISORDERS INCHILDREN

Obsessive-Compulsive Disorder

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

OCD Treatments: SSRIsProzac and Zoloft

• 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

Augmentation

OCD: SSRI withBuSpar Augmentation

• Not supported in group studies• Works for some kids• High doses: 60 mg qd

OCD: SSRI withClomipramine Augmentation

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

School Avoidance(J. March, 2002)

• Cognitive Behavioral Therapy 30%• CBT + SSRI 70%• Use Benzodiazepine first… get back in the classroom ASAP

The Role of Anxious Parents inSeparation Anxiety

Simple/Specific Phobias

• Dental• Exam• 70%: there is co-morbidity

Pediatric Anxiety Pharmacology Study: N. England J. Med., 2001

• Separation, social, and generalized anxiety disorders• Ages: 6-17• 8 week, placebo controlled

Pediatric Anxiety Pharmacology Study: N. England J. Med., 2001

• Luvox (mean dose 169 [up to 300] mg/day)• Significant response: Placebo: 29%, Luvox: 76%• Effect Size: 1.1

ADHD

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

Prevalence and Etiology of ADHD

• PREVALENCE: CHILDREN 5-7% ADULTS 4%• ETIOLOGY: GENETIC 80% ACQUIRED 20%

Course of the Disorder

Childhood………..Adolescence..………AdulthoodFull Syndrome… (100) “H” drops out……… Remission Rate: 33% (66)

Neurobiology

Genetic Risk Factors

Twins Male Female Dizygotic 35% 20%Monozygotic 92% 50%

Parent ADHD: 35% risk of child ADHD

Brain Structure

• Smaller Right Pre-frontal Cortex• Smaller cerebellum• Decreased volume: basal ganglia

Frontal Lobe Dysfunction

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

HYPOMETABOLIC STATESFRONTAL LOBES

FRONTAL LOBE SYMPTOMS

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

Maturational Factorsin Frontal Lobe Development

Vx2

DIAGNOSTIC ISSUES

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

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

DIAGNOSIS

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

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

INATTENTIVE SUBTYPE

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

TREATMENT IMPLICATIONS

• PSYCHOSOCIAL & BEHAVIORAL• PHARMACOLOGIC

MTA Study

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

MTA Study• Groups: > Psychosocial/ Behavioral (27 weeks of parent training)

> Stimulant Medication Treatment > Combined > Treatment “as usual”• Outcomes

PharmacologicTreatments

% of ADHD Children Treated

• 5%+ experience ADHD•13.6% receive treatment

Pliszka, et.al. (2000)

Some Consequences ofFailure To Treat

• Increased risk of Substance Abuse• Decreased white matter volumes (Castellanos, et al. 2002)

• Stimulants may act to normalize white matter maturation

Stimulants

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

Stimulants

• Mechanism of Action: > promotes vesicle release (amphetamine)

> inhibits re-uptake of DA

STIMULANTS

• FAST ACTINGMethylphenidate

DextroamphetamineAmphetamine

Vyvance(pro-drug)

New: Daytrana Methylphenidate Transdermal System

Daily Doses: 10-30 mgRequires 3 hour to reach therapeutic blood levelsLasts 9 hoursSide effects: insomnia, nausea, poor appetite

STIMULANT TREATMENTOUTCOMES

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

PRE- and POST TREATMENT SPECT SCANS

ADHD Algorithm(Barbara Coffee, Harvard, 2002)

• Stimulant Trials (x 3)• Antidepressant• Alternative Antidepressant• Alpha-2 agonist• Combination of the above

New Treatment Guidelines on:

co-morbidADHD and anxiety

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)

Stimulant Side Effect Management

• Insomnia: > Clonidine: Kids: 0.05 mg. Teens: 0.1 mg. > Trazodone 25-50 mg. > Remeron 7.5-15 mg. > Melatonin 1-3 mg.• Anorexia: Focalin

Stimulant Side Effect Management

• Dysphoria: switch stimulants or add Wellbutrin• Stomach ache: give with food• Inhibition of Growth• Cognitive Impairment

Impact on Cognitive Functioning

Consequences of Mis-Diagnosisand Stimulant Treatment

• Anxiety: anxiety• Pre-schizophrenic: psychosis• Bipolar: cycle acceleration• Agitated Depression: agitation• Situational Stress: neglecting psychological issues

ALTERNATIVE TREATMENTS

• -2 Agonists (e.g. clonidine) (+/-)

• Tricyclics (e.g. nortriptyline) (+/-)

• SSRIs (e.g. Prozac) (-)• Wellbutrin, SR XL (+) Effect: 0.6 (espec. with dysphoria)

• NRIs (+) atomoxetine

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

Impact: NE re-uptake blockingand Enhancement of Dopamine

Antidepressants:Onset of Actions

•5 days to 6 weeks

ADVANTAGES of ANTIDEPRESSANTS

• ONCE A DAY DOSING• NO NEED FOR SCHEDULE II• NO ABUSE/DEPENDENCE POTENTIAL• COVERAGE FOR EVENING HOURS• CO-MORBID DEPRESSION

Co-Morbidity

• Anxiety• Depression• Tourette’s Disorder• Bipolar• Conduct Disorder• Learning Disabilities

Pounds to KilogramsConversion

Weight in poundsdivided by 2.2= kg