Anxiety Disorders

1
Anxiety Disorders
Sarah Melton, PharmD,BCPP,CGP Director of
Addiction Outreach Associate Professor of
Pharmacy Practice Appalachian College of
Pharmacy Oakwood, VA
2
Objectives

• Given a case example, evaluate whether the
  patient meets DSM-IV-TR criteria for an anxiety
  disorder generalized anxiety disorder (GAD),
  panic disorder, obsessive compulsive disorder
  (OCD), social anxiety disorder (SAD), and
  post-traumatic stress disorder (PTSD).
• Interpret common rating scales in the evaluation
  and management of anxiety disorders.
• Distinguish differences in pharmacology,
  kinetics, efficacy, dosing, adverse effects, and
  drug interactions of benzodiazepines in the
  management of anxiety disorders.
• Compare the efficacy, dosing, and adverse effects
  of the serotonergic antidepressants, and the role
  of antipsychotics in the management of anxiety
  disorders.

3
Objectives

• Evaluate whether patient and professional
  education is optimal to facilitate safe and
  effective drug therapy for anxiety disorders.
  (DII)
• Using practice guidelines, develop a
  pharmacotherapy plan, including dosing and
  duration of therapy, and nonpharmacologic
  treatments, for a patient with anxiety disorders.
• Discuss the role of pharmacotherapy in the
  management of anxiety disorders in special
  populations (e.g., children, elderly patients and
  pregnancy).
• Resolve potential drug-related problems in
  patients with anxiety disorders.

4
Epidemiology of Anxiety Disorders

• As a group - most frequently occurring
  psychiatric disorders
• Over the past decade, prevalence has not
  changed, but rate of treatment has increased.
• Patients are frequent users of emergency medical
  services, at high risk for suicide attempts, and
  substance abuse.
• Costs for anxiety disorders represent one-third
  of total expenditures for mental illness.
• In primary care, often underdiagnosed or
  recognized years after onset.

• Median age of onset
• GAD 31 years
• SAD 13 years
• OCD 19 years
• PTSD 23 years
• PD 24 years
• Lifetime prevalence
• GAD 5.7
• SAD 12.1
• OCD 1.6
• PTSD 6.8
• PD 4.7

WFSBP Guidelines for the Pharmacological
Treatment of Anxiety, Obsessive Compulsive , and
Post-Traumatic Stress Disorders- First Revision
(2008), Data from the National Comorbidity
Survey Replication(2005)
5
Treatment Plan

• Patient preference
• Severity of illness
• Comorbidity
• Concomitant medical illness
• Complications like substance abuse or suicide
  risk
• History of previous treatments
• Cost issues
• Availability of treatments in given area

6
Patient Education

• Mechanisms underlying psychic and somatic anxiety
  should be explained.
• Describe typical features of the disorder,
  treatment options, adverse drug effects.
• Explain advantages and disadvantages of the drug
• Delayed onset of effect
• Activation syndrome or initial jitteriness with
  SSRIs/SNRIs

7
Duration of Drug Treatment

• Anxiety disorders typically have a waxing and
  waning course.
• After treatment response, which often occurs much
  later in PTSD and OCD, treatment should continue
  for at least 12 months to reduce the risk of
  relapse.

8
Dosing

• In RCTs, SSRIs and SNRIs have a flat response
  curve with the exception of OCD
• 75 of patients respond to the initial (low) dose
• In OCD, the dose must usually be pushed to
  maximally tolerated dosages
• In elderly patients, treatment should be started
  with half the recommended dose or less to
  minimize adverse effects
• Patients with panic disorder are very sensitive
  to serotonergic stimulation and often discontinue
  treatment because of initial jitteriness
• Antidepressant doses should be increased to the
  highest recommended level if the initial low or
  medium dose fails

9
Dosing

• Controlled data on maintenance treatment are
  scarce
• Continue the same dose as in the acute phase
• For improved compliance, administer medications
  in a single dose if supported by half-life data
• Benzodiazepine doses should be as low as
  possible, but as high as necessary
• In hepatic impairment, dose should be adjusted

10
Monitoring Treatment Efficacy

• Use of symptom rating scales
• Panic and Agoraphobia Scale (PAS)
• Hamilton Anxiety Scale (HAM-A)
• Liebowitz Social Anxiety Scale (LSAS)
• Yale-Brown Obsessive-Compulsive Scale (Y-BOCS)
• Clinician-Administered PTSD Scale (CAPS)
• Scales are time-consuming and require training
• Clinical Global Impression (CGI) or specific
  self-report measures may suffice in busy settings

11
Treatment Resistance

• Many patients do not fulfill response criteria
  after initial treatment
• Commonly used threshold for response is 50
  improvement in total score of commonly used
  rating scale
• Review diagnosis, assess for adherence, maximally
  tolerated dosages, sufficient trial period,
  assess for comorbidities
• Change the dose or switch to another medication?

• If no response after 4-6 weeks (8-12 weeks in OCD
  or PTSD), then switch medication
• If partial response, reassess in 4-6 weeks
• Issue of switching vs. augmentation is debated by
  experts and not clearly defined in the literature

12
Non-pharmacological Treatment

• Psychoeducation is essential
• Disease state, etiology, and treatment options
• Effect sizes with psychological therapies are as
  high as the effect sizes with medications
• Exposure therapy and response prevention
• Agoraphobia, social anxiety, OCD, PTSD
• Cognitive Behavioral Therapy most evidence to
  support in all disorders
• Response is delayed, usually later than
  medications
• Prolonged courses are needed to maintain
  treatment response
• Some evidence to show that treatment gains are
  maintained over time longer than medications
• Expensive, not readily available in rural or
  remote areas

13
Selective Serotonin Reuptake Inhibitors (SSRIs)

• First-line drugs for all anxiety disorders
• Dose and education at initiation of therapy is
  important
• Restlessness, jitteriness, insomnia, headache in
  the first few days/weeks of treatment may
  jeopardize compliance
• Lower starting doses reduces overstimulation
• Adverse effects include headache, fatigue,
  dizziness, nausea, anorexia
• Weight gain and sexual dysfunction are long-term
  concerns
• Discontinuation syndrome paroxetine
• Anxiolytic effect is delayed 2-4 weeks (6-8 weeks
  in PTSD, OCD)

14
Selective Serotonin Norepinephrine Reuptake
Inhibitors (SNRIs)

• Efficacy of venlafaxine and duloxetine in certain
  anxiety disorders has been shown in controlled
  studies
• Early adverse effects such as nausea,
  restlessness, insomnia and headache may limit
  compliance
• Sexual dysfunction long-term
• Modest, sustained increase in blood pressure may
  be problematic
• Significant discontinuation syndrome with
  venlafaxine occurs, even with a missed dose
• Antianxiety effects have latency of 2-4 weeks

15
Tricyclic Antidepressants (TCAs)

• Efficacy in all anxiety disorders is well-proven,
  except in SAD
• Imipramine, clomipramine have most evidence
• Adverse effects initially increased anxiety,
  anticholinergic, cardiovascular, sedation,
  impaired cognition, decreased seizure threshold,
  elevated LFTs (clomipramine)
• Weight gain, sexual dysfunction are problematic
  long-term
• Discontinuation syndrome
• Avoid in elderly, patients with cardiovascular
  disease, seizure disorders, and suicidal thoughts
• Second-line agents because of adverse
  effects/toxicity
• Dosage should be titrated up slowly onset of
  effect is 2-6 weeks, longer in OCD

16
Monamine Oxidase Inhibitors (MAOIs)

• Efficacy of phenelzine established in panic, SAD
  and PTSD
• Last-line agent for treatment resistance used by
  experienced psychiatrists
• Risk of adverse effects
• Life threatening drug and food interactions
• Patient education on dietary restrictions and
  drug interactions imperative
• Give doses in the morning and mid-day to avoid
  overstimulation and insomnia

17
Benzodiazepines

• Anxiolysis begins in 30-60 minutes after oral or
  parenteral administration
• Safe and effective for short-term use
  maintenance requires evaluation of risks vs.
  benefits
• Avoid in patients with history of substance or
  alcohol abuse
• Most commonly used in combination with SSRI/SNRI
  during first few weeks of therapy
• Guideline recommendations Prescribe on
  scheduled, not prn basis
• Not effective in depression

18
Hydrozyzine

• Commonly used in community setting anxiolytic
  effects that may be beneficial in treating GAD
• There are controlled data supporting efficacy,
  but up to 40 of patients report adverse effects
• This agent was similar to buspirone in anxiolytic
  effects in a short-term trial
• Hydroxyzine is not associated with dependence

19
Other Agents

• PREGABALIN
• Not FDA- approved for anxiety, but used commonly
  in Europe
• Effective in acute/long-term GAD and a few trials
  of SAD
• Typical doses of 300-600 mg/day
• Onset of activity was evident after 1 week
• Adverse effects dizziness, sedation, dry mouth,
  psychomotor impairment
• Pregabalin was not associated with clinically
  significant withdrawal symptoms when tapered over
  1 week

• ANTICONVULSANTS
• Not used in routine treatment of anxiety
  disorders, but may some utility as adjunctive
  agents in some disorders
• Carbamazepine, valproate, lamotrigine, and
  gabapentin have shown efficacy in preliminary
  studies for PTSD

20
Buspirone

• Advantages
• Non-sedating
• No abuse potential
• Disadvantages
• No antidepressant effect for comorbid conditions
• Initial therapeutic effect delayed by 1-2 weeks,
  full effects occurring over several weeks
• Ineffective in patients who previously responded
  to benzodiazepines??

• Beneficial only in GAD
• Adverse Effects
• Nausea, headache, dizziness, jitteriness and
  dysphoria (initial)
• Dosing
• Initial 5 mg tid up to maximum 60 mg/day

21
Other Agents

• ATYPICAL ANTIPSYCOTICS
• Quetiapine was effective as monotherapy for GAD
• Atypical antipsychotics have been used as
  adjunctive agents for non-responsive cases of
  anxiety associate with OCD and PTSD

• BETA-ADRENERGIC BLOCKERS
• ß - blockers reduce autonomic anxiety symptoms
  such as palpitations, tremor, blushing
• However, double-blind studies have not shown
  efficacy in any disorder
• Recommended for use in nongeneralized SAD given
  before a performance situation

22
Differentiating Anxiety Disorders

• Many anxiety disorders present similarly
• Key to differentiation is rationale behind fear
• Panic attacks occur in both social anxiety and
  panic disorder
• Fear of anxiety symptoms is characteristic of
  panic disorder
• Fear of embarrassment is from social interactions
  typifies SAD
• GAD is likely diagnosis if anxiety about social
  situations are part of a pattern of multiple
  worries
• Anxiety may also be induced by medications or
  medical conditions

23
CASE 1

• A 70-year-old man presents to his physician
  complaining of having trouble sleeping, being
  nervous all the time, and feeling like he is
  going to lose control. His wife died 2 years
  ago and the symptoms have been getting worse
  since that time. He is retired as an accountant,
  but lately cannot even concentrate to pay his own
  bills. He has seasonal allergies, COPD, angina,
  and Type II diabetes. Medications include
  albuterol/ipratropium inhaler, theophylline,
  enalapril, aspirin, metformin, and loratatadine
  with pseudoephedrine. He smokes 2 ppd (100 pack
  years). He drinks 8-10 drinks/day that are
  caffeinated and also drinks 2-3 beers nightly to
  help him fall asleep and relieve his stress.
• What factors should be considered in the
  assessment and differential diagnosis of this
  patients anxiety?

24
Substance-Induced Anxiety

• CNS Stimulants
• CNS depressant withdrawal
• Psychotropic medications
• Cardiovascular medications
• Heavy metals and toxins

25
Anxiety Secondary to Medical Conditions

• Endocrine
• Addisons disease
• Cushing disease
• Hyperthyroidism
• Hypoglycemia
• Pheochromocytoma
• Cardiovascular
• Angina, MI
• CHF, MVP
• Respiratory
• Asthma, COPD
• Hyperventilation, PE
• Metabolic
• Porphyria, Vitamin B12 deficiency

• Neurologic
• CNS neoplasms, chronic pain
• Encephalitis, PD, epilepsy
• Gastrointestinal
• Crohns Disease, PUD
• IBS, Ulcerative Colitis
• Inflammatory
• RA, SLE
• Other
• HIV, Malignancy

McClure EB, Pine DS. (2009). Clinical Features of
the Anxiety Disorders. In BJ Sadock, VA Sadock ,
P Ruiz (Eds.). Kaplan and Sadocks Comprehensive
Textbook of Psychiatry (9th ed, pp. 1844-1855).
Philadelphia, PA Lippincott, Williams and
Wilkins.
26
CASE 1 (continued)

• Factors that need further investigation before a
  diagnosis of an anxiety disorder can be made
  include
• Medical illness (COPD, angina)
• Possible depression, adjustment to stressors
• Medications/substances
• Pseudoepehdrine
• Theophylline
• Caffeine
• Nicotine

27
CASE 2

• A 30-year-old woman presents to her PCP c/o of
  daily headaches, muscle tension, diarrhea and
  difficulty sleeping. She states that her husband
  says she is a worry wart and she admits that
  she has difficulty controlling her anxiety over
  her financial situation, job security, and the
  safety of her children. She has become irritable
  because she always feels on the edge. The
  symptoms started 7 months ago, following the
  death of her sister but she recalls her mother
  telling her that she worried too much, just like
  her father during her adolescent years.
• She is employed as an office manager, but has
  missed several days of work in the past month
  because of her anxiety, physical symptoms, and
  inability to concentrate.
• No significant past medical history and only
  medications include a multivitamin.
• PPH Major Depression 2 years ago treated with
  fluoxetine 20 mg for 6 months.
• She is married with 2 children (ages 3 and 6),
  denies tobacco or alcohol use. Drinks 1 cup of
  coffee in the morning and an occasional soda in
  the afternoon.

28
Problem Identification

• What symptoms does the patient exhibit that are
  consistent with Generalized Anxiety Disorder?
• What risk factors are present in her history?
• What are treatment options?

29
Diagnostic Criteria for GAD

• The patient reports having excessive anxiety and
  worry occurring more days than not for at least 6
  months about a number of events of activities
  (such as work or school performance).
• The patient has difficulty in controlling worry.
• The anxiety and worry are associated with 3 or
  more of the following 6 symptoms
• Restlessness or feeling keyed up and on edge
• Easily fatigued
• Difficulty concentrating, or mind going blank
• Irritability
• Sleep disturbance (difficulty falling asleep or
  staying asleep, or restless, unsatisfying sleep)

Diagnostic and Statistical Manual of Mental
Disorders-IV-TR, 2000.
30
CASE 2 (continued)

• Risk Factors for GAD present in case
• Gender (female)
• Genetic factors (father)
• Medication/substance induced (stimulant)
• Stressful event (death of sister)
• Treatment options
• Nonpharmacologic - Psychoeducation, CBT
• Pharmacologic (antidepressants, benzodiazepines,
  buspirone, others)

31
Pharmacological Treatment of GAD

• First-line
• Recommended daily doses
• Escitalopram 10-20mg Venlafaxine 75-225 mg
• Paroxetine 20-50 mg Duloxetine 60-120 mg
• Sertraline 50-150 mg
• Second-line
• Benzodiazepines when patient has no history of
  dependency may combine with antidepressants for
  first 2-4 weeks
• Pregabalin 150-600 mg Imipramine 75-200 mg
• Others
• Hydroxyzine 37.5-75 mg effective in trials for
  acute anxiety, but ADRs limit use
• Buspirone 15- 60 mg indicated for GAD, but
  efficacy results were inconsistent
• Treatment resistance
• Augmentation of SSRI with atypical antipsychotic
  (quetiapine, risperidone or olanzapine)
• Quetiapine effective as monotherapy, but not FDA
  approved for anxiety because of metabolic and
  cardiac risks associated with chronic use

WFSBP Guidelines for the Pharmacological
Treatment of Anxiety, Obsessive Compulsive , and
Post-Traumatic Stress Disorders- First Revision
(2008)
32
CASE 3

• A 24-year old college student presents to the
  student mental health facility for follow-up for
  treatment of panic disorder with agoraphobia. He
  presented 5 months ago complaining of attacks of
  chest pain, SOB, tingling fingers, dizziness,
  nausea. During the attacks, he felt like he was
  outside his body and everything was crashing
  in on him. He began staying in his apartment
  nearly all the time and was on the verge of being
  dismissed from college for not attending classes.
  
• He was started on paroxetine 5 mg daily and
  alprazolam 0.5 mg three times daily. His current
  doses are paroxetine 40 mg po daily and
  alprazolam 1 mg in the morning, 1 mg at lunch,
  and 2 mg at bedtime.
• He was doing so well that he decided to
  discontinue the alprazolam yesterday because his
  mother told him she thought he was hooked on
  it. Today, he feels quite anxious, his heart is
  racing, and his hands are tremulous. He wonders
  if he is getting ready to have a full-blown panic
  attack.
• What do you recommend at this point in his
  therapy?

33
Diagnostic Criteria for Panic Disorder

• Presence of at least 2 unexpected panic attacks
  characterized by at least 4 of the following
  somatic or cognitive symptoms, which develop
  abruptly and peak within 10 minutes
• Cardiac, sweating, shaking, SOB or choking,
  nausea, dizziness, depersonalization, fear of
  loss of control, fear of dying, paresthesias,
  chills or hot flashes
• The attacks are followed by one of the following
  for 1 month
• Persistent concern about having another attack
• Worry about consequences of the attack
• Significant change in behavior because of the
  attack
• May occur with or without agoraphobia

Diagnostic and Statistical Manual of Mental
Disorders-IV-TR, 2000.
34
Panic Attack/Agoraphobia

• Panic Attack
• About 7 of the population will experience at
  least one panic attack
• Types
• Unexpected (uncued)
• Situationally bound (cued)
• Situationally predisposed
• Can occur in the context of another anxiety or
  mental disorder

• Agoraphobia
• Anxiety about being in a situation where escape
  is difficult or help is unavailable in the event
  of a panic attack
• Examples of feared situations open spaces,
  trains, tunnels, bridges, crowded rooms
• Situations are avoided or endured with
  significant anxiety about having a panic attack
  or symptoms
• Can persist even after panic attacks abate

35
Panic Disorder - Treatment

• Non-pharmacologic Treatment
• Avoid trigger substances
• Caffeine, OTC stimulants, nicotine, drugs of
  abuse
• CBT
• Correct avoidance behavior
• Train individual to identify and control signals
  associated with panic attacks
• Efficacy 80-90 short term

36
Pharmacological Treatment of Panic Disorder

• First-line
• Recommended daily doses
• Citalopram 20-60 mg Paroxetine 20-60 mg
• Escitalopram 10-20 mg Sertraline 50-150 mg
• Fluoxetine 20-40 mg Venlafaxine 75-225 mg
• Fluvoxamine 100300 mg
• Second-line
• Imipramine 75-250 mg , clomipramine 75-250 mg
• Benzodiazepines when no history of dependency
  may combine with antidepressants for first 2-4
  weeks for more rapid response and to limit ADRs
• Alprazolam 1.5-8 mg/day Diazepam 5-20 mg/day
• Clonazepam 1-4 mg/day Lorazepam 2-8 mg/day
• Treatment-resistance phenelzine

WFSBP Guidelines for the Pharmacological
Treatment of Anxiety, Obsessive Compulsive , and
Post-Traumatic Stress Disorders- First Revision
(2008)
37
Panic DisorderTherapeutic Use of Benzodiazepines

• Antipanic effect begins within the first week
• Effective in 55-75 of panic disorder patients
• Effective in patients needing rapid relief of
  anticipatory anxiety
• Breakthrough (interdose rebound) anxiety may
  occur 3-5 hours after a dose of shorter acting
  benzodiazepines such as alprazolam
• Dependence/withdrawal are associated with
  long-term use or high dose

38
Benzodiazepines Pharmacokinetics

• Onset of Action
• High lipophilicity fastest absorption faster
  onset but also euporic rush
• Diazepam, clorazepate, alprazolam
• Lower lipophilicity longer onset, less euphoria
• Chlordiazepoxide, clonazepam, oxazepam
• Duration of Action (t1/2)
• Long diazepam, chlordiazepoxide, clonazepam
• Short alprazolam, lorazepam, oxazepam

• Metabolic Pathway
• Hepatic microsomal oxidation (Phase I metabolism)
• Impaired by aging, liver disease, or meds that
  inhibit oxidative process
• Prolonged half-life, accumulation
• Alprazolam, clonazepam, chlordiazepoxide,
  clorazepate, diazepam
• Glucuronide conjugation (Phase II metabolism)
• Lorazepam, oxazepam

39
Benzodiazepines Drug Interactions

• Pharmacodynamic
• CNS depressants alcohol, barbiturates, opiates
• Pharmacokinetic
• Inhibitors cimetidine, nefazodone, fluoxetine,
  fluvoxamine, erythromycin, ketoconazole, oral
  contraceptives, protease inhibitors, grapefruit
  juice, isoniazid
• Inducers phenytoin, carbamazepine,
  phenobarbital, rifampin

40
Benzodiazepines Dependence and Abuse

• Physical dependence
• Within 3-4 months, can lead to down-regulation of
  endogenous GABA production
• Withdrawal symptoms common
• Rebound anxiety, insomnia, jitteriness, muscle
  aches, depression, ataxia, blurred vision
• Do not stop therapy abruptly TAPER
• Abuse
• High risk in patients with substance or alcohol
  abuse history
• Alprazolam, lorazepam, and diazepam

41
Benzodiazepine Withdrawal

• Onset, duration and severity varies according to
  dosage, duration of treatment, and half-life, and
  speed of discontinuation
• Short half-life, withdrawal begins in 1-2 days,
  shorter duration, more intense
• Long half-life, withdrawal begins in 5-10 days,
  lasts a few weeks
• Common symptoms anxiety, insomnia, irritability,
  nausea, diaphoresis, systolic hypertension,
  tachycardia, tremor
• Possible consequences delirium, confusion,
  psychosis, seizures

42
CASE 3 (Continued)

• The patient has had excellent response to
  pharmacotherapy however, he has only been
  treated for 5 months.
• Treatment guidelines recommend therapy for at
  least 1 year after resolutions of symptoms before
  considering discontinuation
• Benzodiazepines are typically used in the first
  2-4 weeks as acute therapy, so it is reasonable
  to consider slowly tapering the alprazolam at
  this point.
• Abrupt discontinuation is not appropriate he now
  has withdrawal symptoms that must be addressed,
  as well as his concern about addiction.

43
Benzodiazepine Discontinuation

• Typical tapering schedule for benzodiazepines
• 25 per week reduction in dosage until 50 of
  dose then reduce by one eighth every 4-7 days
• Therapy gt 8 weeks taper over 2-3 weeks
• Therapy gt 6 months taper over 4-8 weeks
• Therapy gt 1 year taper over 2-4 months
• For patients on high potency benzodiazepines for
  monotherapy of panic disorder, a very gradual
  discontinuation is recommended
• Discontinue benzodiazepines slowly over 3-4
  months to prevent relapse and emergence of
  withdrawal symptoms
• Alprazolam doses gt3 mg/d ? by 0.5 mg every 2
  weeks until 3 mg, then ? by 0.25 mg every 2 weeks
  until 1 mg, then ? by 0.125 mg every 2 weeks
• Clonazepam ? by 0.125 mg every 2 weeks
• Diazepam ? by 2.5 mg every 2 weeks
• Lorazepam ? by 0.5 mg every 2 weeks

44
Diagnostic Criteria for SAD

• A marked and persistent fear of one or more
  social or performance situations involving
  exposure to unfamiliar people or possible
  scrutiny by others. The person fears that he or
  she will act in a way (or show symptoms of
  anxiety) that will be humiliating or embarrassing
• Exposure to the feared social situation provokes
  anxiety or even a panic attack
• The person recognizes that the fear is excessive
  or unreasonable
• Feared social or performance situations are
  avoided or endured with intense anxiety or
  distress
• The condition interferes significantly with the
  person's normal routine, occupational (or
  academic) functioning, or social activities or
  relationships, or there is marked distress about
  having the phobia
• Specify the disorder as generalized if fears
  include most situations

Diagnostic and Statistical Manual of Mental
Disorders-IV-TR, 2000.
45
Social Anxiety DisorderTreatment

• Early detection and treatment is important
• Because of the nature of the illness, patients
  are reluctant to to seek treatment
• Pharmacological and nonpharmacological therapy
  both effective

46
Social Anxiety DisorderNonpharmacologic Treatment

• CBT
• Change negative thoughts patterns
• Repeated exposure to feared situation
• Social skills training
• 12-16 weekly sessions, each 60-90 minutes
• Workbook with homework exercise
• Clinical improvement within 6-12 weeks
• Long term gains

47
Pharmacological Treatment of SAD

• First-line
• Recommended doses
• Escitalopram 10-20 mg Fluoxetine 20-40 mg
• Fluvoxamine 100-300 mg Sertraline 50-150 mg
• Paroxetine 20-50 mg Venlfaxine 75-225 mg
• Second-line
• Imipramine 75-200 mg
• Clonazepam 1.5-8 mg/day, when patient has no
  history of dependency may combine with
  antidepressants for first 2-4 weeks
• Treatment resistance
• Addition of buspirone to an SSRI effective in one
  open study buspirone not effective as
  monotherapy.
• Phenelzine

WFSBP Guidelines for the Pharmacological
Treatment of Anxiety, Obsessive Compulsive , and
Post-Traumatic Stress Disorders- First Revision
(2008)
48
Case 4

• A 28-year old woman presents to the Anxiety
  Disorders Clinic after being referred by her PCP.
  The patient recently gave birth to a son 2
  months ago. Within 2 weeks after delivery, she
  started having intrusive thoughts of harming her
  baby. Over and over again, she imagined herself
  dropping the baby, cutting or burning him. She
  checks the appliances in the house multiple times
  to make sure they are cut off because she fears
  starting a fire that will harm the baby. She
  will not use the kitchen knives or scissors.
• She spends 40 minutes every time she goes
  out checking and re-checking the babys car seat,
  so now she just stays at home. She reports some
  relief during the day when she knocks on hard
  objects in 3 sets of 5 knocks. She is so
  concerned about hurting her baby that she has
  started avoiding holding him except when nursing.
  She says that half of her days are consumed with
  her checking behavior. Past psychiatric history
  is positive for depression when she was in
  college that responded well to sertraline. YBOCS
  score 32

49
Diagnostic Criteria for OCD

• Obsessions
• Recurrent and persistent thoughts, impulses or
  images that are intrusive and cause a great
  amount of anxiety
• These thoughts, impulses, or images are not
  worries about daily life issues
• Patient attempts to ignore or suppress the
  thoughts, impulses, images, or to neutralize them
  by applying special thoughts or actions
• The thoughts, impulses, or images are recognized
  as a product of the patients mind
• Compulsions
• Repetitive behaviors that the person feels
  compelled to perform in response to an
  obsession, or according to rigid self-imposed
  rules
• The behaviors or mental acts are aimed at
  preventing or reducing distress or preventing
  some dreaded event or situation but are not
  connected in a realistic or logical way with what
  they are designed to neutralize or prevent
• The person has recognized that the obsessions or
  compulsions are excessive or unreasonable (this
  does not apply to children).

Diagnostic and Statistical Manual of Mental
Disorders-IV-TR, 2000.
50
OCD Comorbidities

• Depression (75)
• Anxiety disorders
• Tic Disorders (20-30)
• 5-7 have full Tourettes syndrome
• PANDAS (pediatric autoimmune neuropsychiatric
  disorders)
• OCD spectrum disorders
• Somatoform disorders (body dysmorphic disorder)
• Eating disorders (anorexia, bulimia,
  binge-eating)
• Impulse control disorders (trichotillomania,
  compulsive nail biting, kleptomania, compulsive
  buying)

51
OCD Non-Pharmacologic Treatment

• CBT
• Exposure therapy with response prevention
• High rate of discontinuation
• Effective in 66-75 of patients if continued
• Neurosurgery
• Intervention to hyperreactive portions of brain
• Effective in 40-90 of treatment resistant
  patients
• Deep brain stimulation

52
Pharmacotherapy of OCD

• First-line
• Recommended doses/day
• Escitalopram 10-20 mg Fluoxetine 40-60 mg
• Fluvoxamine 100-300 mg Paroxetine 40-60 mg
• Sertraline 50-200 mg
• Second-line- typically reserved until after
  failure with 2 SSRIs
• Clomipramine 75-250 mg equally effective as
  SSRIs but less well-tolerated
• Treatment resistance
• Intravenous clomipramine (not FDA approved) was
  more effective than oral clomipramine
• SSRI antipsychotic (haloperiodol, quetiapine,
  olanzapine, risperidone) more effective than SSRI
  alone

WFSBP Guidelines for the Pharmacological
Treatment of Anxiety, Obsessive Compulsive , and
Post-Traumatic Stress Disorders- First Revision
(2008)
53
CASE 4 (continued)

• What is the most appropriate therapy for this
  patient what do we know?
• YBOCS 32 (extremely severe OCD)
• She is breastfeeding
• Previous response to sertraline for depression
• Treatment algorithm developed by the American
  Psychiatric Association considers CBT or SSRI to
  be first-line treatments

54
Case 4 (continued)

• The patient declines CBT because of cost and time
  commitment.
• She prefers therapy with medication as she had
  positive experience when her depression was
  treated.
• Sertraline 25 mg po every AM is prescribed with
  decision to increase dose to 50 mg by the end of
  the week. She will follow-up for assessment in
  one week.

55
Goals of Therapy in OCD

• Marked clinical improvement, recovery, and full
  remission
• Decrease symptom frequency and severity, improve
  the patients functioning, and help the patient
  improve QOL
• Enhance the patients ability to cooperate with
  care
• Anticipate stressors likely to exacerbate OCD and
  help the patient develop coping strategies
• Minimize any adverse effects
• Educate the patient and family about OCD and its
  treatment.
• Reasonable treatment outcome targets include
• less than 1 hour per day spent obsessing and
  performing compulsive behaviors no more than
  mild OCD-related anxiety an ability to live with
  uncertainty and little or no interference of OCD
  with the tasks of ordinary living

56
Assessment of Response in OCD

• Most patients will not experience substantial
  improvement until 46 weeks after starting
  medication, for some 1012 weeks.
• Higher SSRI doses produce higher response rates
  and greater magnitude of symptom relief
• Doses can be titrated more rapidly in OCD (in
  weekly increments to maximum dosage), rather than
  waiting for treatment response for 1-2 months.
• Example (Case 4), the patient would go from 50 mg
  at the end of week 1 to 100 mg at the end of week
  2, with subsequent increases of 50 mg/day at
  weekly intervals up to 200 mg/day.

57
Assessment of Response in OCD

• The Y-BOCS rating scale is helpful to document
  treatment response over time
• In clinical trials, OCD responders
• Y-BOCS scores decrease by at least 2535 from
  baseline
• Rated much improved or very much improved on the
  Clinical Global ImpressionsImprovement scale
  (CGI-I).

58
OCD Duration of Therapy

• After response, patient should remain on
  pharmacotherapy for at least 1-2 years
• Medication should be tapered over an extended
  period of time
• Decrease dose by 25 every 2 months
• Life-long prophylaxis recommended after 2-4
  severe relapses or 3-4 mild relapses

59
Diagnostic Criteria for PTSD

• Criterion A stressor
• The person has been exposed to a traumatic event
  in which both of the following have been present
• The person has experienced, witnessed, or been
  confronted with an event or events that involve
  actual or threatened death or serious injury, or
  a threat to the physical integrity of oneself or
  others.
• The person's response involved intense fear,
  helplessness, or horror. Note in children, it
  may be expressed instead by disorganized or
  agitated behavior.
• Criterion B intrusive recollection
• Criterion C avoidance/numbing
• Criterion D hyper-arousal
• Criterion E duration
• Duration of the disturbance (symptoms in B, C,
  and D) is more than one month.

Diagnostic and Statistical Manual of Mental
Disorders-IV-TR, 2000.
60
Subtypes of PTSD

• Acute symptom duration of lt 3 months
• Chronic symptom duration of gt 3 months
• Delayed onset symptoms begin gt 6 months after
  the traumatic event

61
Acute Treatment After Traumatic Event

• Symptoms should diminish over the first few weeks
• Social support is critical
• 4-5 sessions of time-limited psychotherapy during
  the first month reduces the rates of PTSD by at
  least 50

62
PTSD TreatmentPsychotherapy

• Education
• Nature of the condition
• Process of recovery
• Understanding that symptoms are a psychobiologic
  response to overwhelming stress
• Goals of Psychotherapy
• Reduce the level of distress associated with
  memories of the event
• Reduce the physiological reaction to memories

63
Types of Psychotherapy

• Cognitive therapy
• Exposure therapy
• Imaginal or in vivo exposure
• Anxiety management
• Relaxation training
• Stress inoculation training
• Breathing retraining
• Assertiveness and positive thinking and
  self-talk
• Interpersonal or group therapy
• Play (children) and drama (adults) therapy

64
Pharmacotherapy of PTSD

• First-line
• Recommended doses/day
• Fluoxetine 20-40 mg Paroxetine 20-40 mg
• Sertraline 50-100 mg Venlafaxine 75-300 mg
• Prazosin may be more effective in combat-related
  PTSD
• Second-line therapies
• TCAs amitriptyline, imipramine 75-200 mg
• Mirtazapine 30-60 mg
• Risperidone 0.5-6 mg
• Lamotrigine (study doses ranged from 50-500
  mg/day)
• Nefazodone (effective in small, controlled trial
  in male combat veterans)
• Treatment resistance
• Venlafaxine, prazosin, quetiapine venlafaxine,
  gabapentin SSRI

WFSBP Guidelines for the Pharmacological
Treatment of Anxiety, Obsessive Compulsive , and
Post-Traumatic Stress Disorders- First Revision
(2008)
65
PTSD Treatment Augmenting Agents
Medications PTSD Symptoms
Antiadrenergics Hyperarousal, flashbacks and impulsivity monitor BP, PR Prazosin nightmares and sleep disruption
Anticonvulsants Startle response, nightmares
Antipsychotics Psychosis or flashbacks with hallucinations, dissociation
Cyproheptadine Nightmares
Lithium Irritability, mood swings
Acute administration of propranolol superior to
placebo in reducing subsequent PTSD symptoms and
physiological hyperactivity, but not the
emergence of PTSD. Benzodiazepines are not
recommended in patients with PTSD early
administration does not prevent emergence of PTSD
and may be associated with a less favorable
outcome.
Foa E. Effective treatments for PTSD, Chapter 6.
2nd edition, 2009. The Guilford Press, New York,
NY.
66
Goals of Pharmacotherapy for PTSD

• Reduce core PTSD symptoms
• Reduce disability
• Improve QOL
• Improve resilience to stress
• Reduce co-morbidity

67
Treatment of Anxiety Disorders Under Special
Conditions

• Pregnancy
• Risks of drug treatment must be weighed against
  risk of withholding treatment
• Majority of studies indicate that use of most
  SSRIs and TCAs imposed no increased risk for
  malformations
• Avoid paroxetine due to risk of cardiac
  malformations
• Benzodiazepines are typically avoided in
  pregnancy because of reports of congenital
  malformations however, there is no consistent
  evidence that benzodiazepines are hazardous
• Literature suggests safety with diazepam and
  chlordiazepoxide alprazolam should be avoided
• Breast feeding paroxetine, sertraline,
  nortriptyline are safer avoid benzodiazepines
  and fluoxetine

68
Treatment of Anxiety Disorders Under Special
Conditions

• Children and Adolescents
• Many experts feel drug therapy should be reserved
  for patients who do not respond to psychological
  therapy
• SSRIs are first-line drug treatment
• Careful monitoring required for activation
  syndrome and increased suicidal thoughts or
  behaviors
• Elderly
• Increased sensitivity for anticholinergic
  properties
• Increased risk of EPS, orthostasis, EKG changes
• Increased risk of paradoxical reactions to
  benzodiazepines
• Few trials evaluate anxiety in the elderly
• Venlafaxine efficacious in elderly with GAD
• Citalopram effective in patients older than 60
  with anxiety disorders

69
Anxiety Disorders

• CONCLUSION