Pharmacology of Anxiolytic SedativeHypnotics

1
Pharmacology of Anxiolytic/ Sedative-Hypnotics

• Philip G. Janicak, MD
• Professor of Psychiatry and Pharmacology
• University of Illinois at Chicago

2
Abstract
pharmacology of anxiolytic/sedative-hypnotics

• Recent anxiolytic and sedative-hypnotic agents
  offer comparable efficacy, fewer serious adverse
  effects, and less risk of a fatal consequence due
  to accidental or intentional overdose in
  comparison to alcohol, barbiturates and other
  non-barbiturate agents (e.g., meprobamate).
  Unfortunately, they have not entirely eliminated
  the hazards of tolerance, dependency, and
  withdrawal syndromes, although they have a lower
  abuse potential than their predecessors.
• For these reasons, it is important to become
  knowledgeable about the basic pharmacology of
  these drugs, in addition to their appropriate
  clinical indications, dosages, and duration of
  usage. Most importantly, their limitations must
  receive as much attention as their assets.

3
Objectives
pharmacology of anxiolytic/sedative-hypnotics

• Review diagnostic indications for anxiolytic/
  sedative-hypnotics
• Review different classes of antianxiety and
  sedative-hypnotic agents in terms of their
  pharmacodynamics pharmacokinetics adverse
  effects and potential for drug interactions.
• Review treatment strategies for anxiety and sleep
  disorders.

4
Anxiety
pharmacology of anxiolytic/sedative-hypnotics

• Natural human experience
• Subjective qualities of fear or related emotions
• Ensures survival and adaptation
• In excess, can cripple and destroy

5
Anxiety Symptoms
pharmacology of anxiolytic/sedative-hypnotics

• Anxiety symptoms are associated with numerous
  medical conditions
• Cardiovascular disease
• Endocrine disease
• Gastrointestinal disease
• Neurologic disease
• Drug-induced

6
Indications for Antianxiety/Sedative-Hypnotics
pharmacology of anxiolytic/sedative-hypnotics

• Generalized anxiety disorder (GAD)
• Phobic disorders
• Psychological factors affecting medical condition
• Panic disorder
• Obsessive-compulsive disorder
• Posttraumatic stress disorder
• Sleep disorders (dyssomnias parasomnias)

7
GAD
pharmacology of anxiolytic/sedative-hypnotics

• Represents up to 50 of anxious patients seen by
  physicians
• Increased annual medical expenses
• Often unnecessary medical consultations
• 55 million prescriptions for BZDs in 1989
• Anxiolytic agents fourth most prescribed class of
  medication

8
Phobic Disorders
pharmacology of anxiolytic/sedative-hypnotics

• Disabling anxiety (at times associated with panic
  attacks) and avoidance
• Agoraphobia
• Social phobia (Social Anxiety Disorder)
• Specific phobia

9
Psychological FactorsAffecting Medical Condition
pharmacology of anxiolytic/sedative-hypnotics

• Psychologically meaningful environmental stimuli
• Temporally related to the initiation or
  exacerbation of a physical condition
• Demonstrable organic pathology (e.g., rheumatoid
  arthritis)
• Known physiological process (e.g., migraine)

10
Panic Disorder
pharmacology of anxiolytic/sedative-hypnotics

• Sudden, spontaneous, unexpected feelings of
  terror and anxiety
• The autonomic equivalence of anxiety
• The desire to flee the situation and return to a
  safe place
• A phobic avoidance of the places where such
  attacks occur

11
Symptomatology of Panic Attacks
pharmacology of anxiolytic/sedative-hypnotics

• Shortness of breath /smothering sensations
• Dizziness, unsteady feelings, or faintness
• Palpitations/tachycardia
• Trembling/shaking
• Sweating
• Choking

• Nausea/abdominal distress
• Depresonalization/ derealization
• Paresthesias
• Flushes/chills
• Chest pain or discomfort
• Fear of dying
• Fear of going crazy or doing something
  uncontrolled

12
Course of Illness
pharmacology of anxiolytic/sedative-hypnotics
anxiety level
time
13
Obsessive-Compulsive Disorder (OCD)
pharmacology of anxiolytic/sedative-hypnotics

• Recurrent obsessions and/or compulsions
• Cause marked distress, are time-consuming, or
  interfere with functioning
• Are recognized as excessive or unreasonable
• Are not due to the effect of a substance or
  general medical condition

14
Obsessions in OCD
pharmacology of anxiolytic/sedative-hypnotics

• Contamination
• Pathological doubt
• Aggressive impulses
• Somatic concerns
• Need for symmetry
• Sexual impulses

15
Compulsive Behaviors in OCD
pharmacology of anxiolytic/sedative-hypnotics

• Cleaning
• Washing
• Checking
• Excessive ordering/arranging
• Counting
• Repeating
• Collecting

16
Posttraumatic Stress Disorder (PTSD)
pharmacology of anxiolytic/sedative-hypnotics

• Due to an unusual experience that would be very
  stressful for almost anyone (e.g., combat, rape,
  sudden unexpected death of a loved one)
• Symptoms include
• Intrusive recollections frightening dreams
  sense of event recurring
• Intensive physiological stress hyperarousal
• Emotional numbing
• Persistent avoidance of stimuli associated with
  the trauma
• High comorbidity with other psychiatric disorders
• Increase suicide attempt risk
• Female-to-male lifetime prevalence ratio of 21

17
Sleep Disorders
pharmacology of anxiolytic/sedative-hypnotics

• Dyssomnias (difficulty initiating or maintaining
  sleep or not feeling rested)
• Primary Insomnia
• Primary Hypersomnia
• Circadian Rhythm Disorder
• Parasomnias (abnormal event)
• Nightmare Disorder
• Sleep Terror Disorder
• Sleepwalking Disorder

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Pharmacodynamics
pharmacology of anxiolytic/sedative-hypnotics

• Benzodiazepines
• Specific binding site associated with GABAA
  receptor-chloride ion channel
• Potentiate GABA
• Serotonergic effects (e.g., clonazepam)
• Azapirone (e.g., buspirone)
• 5-HT1A agonist acutely, ? firing, in dorsal
  raphe nuclei chronically, receptor
  desensitization ? ? activity
• Beta-blockers
• ? receptors central and peripheral, post synaptic
• Clonidine
• Agonist at ?2 receptors, central, pre-synaptic
• Antidepressants

19
GABA Function and Distribution
pharmacology of anxiolytic/sedative-hypnotics

• Inhibitory neurotransmitter
• Widely distributed throughout CNS
• Local inhibitory action, therefore rapidly alters
  neuronal output
• Desensitization to inhibitory effects with
  chronic stimulation of GABA

20
GABAA-BZD Supramolecular Complex
21
GABAA Receptor Structure
S.M. Paul, 1995
22
pharmacology of anxiolytic/sedative-hypnotics
23
BZD Receptors
pharmacology of anxiolytic/sedative-hypnotics

• Type I
• Predominates in cerebellum
• Anxiolytic properties
• Less sedative properties
• Type II
• Located in cortex, hippocampus, spinal cord
• No anxiolytic properties
• Sedative properties
• Type III
• Located in peripheral tissue
• No anxiolytic properties
• ? other properties

24
BZD Receptor Activity
pharmacology of anxiolytic/sedative-hypnotics
25
Non-Benzodiazepine Agents
pharmacology of anxiolytic/sedative-hypnotics

• Imidazopyridines (e.g., zolpidem, alpidem)
• Pyrazolopyrimidine (e.g., zaleplon)
• Cyclopyrralone (e.g., zopiclone)
• Sedating antidepressants (e.g., trazodone)

26
Non-Benzodiazepine Agents (cont)
pharmacology of anxiolytic/sedative-hypnotics

• Antihistamines (e.g., diphenhydramine)
• Natural Remedies (e.g., melatonin, valerian)
• B-carbolines (e.g., abecarnil)
• BZD structural derivatives (e.g., biretazanil)

27
Serotonin Model
pharmacology of anxiolytic/sedative-hypnotics

• Majority of 5-HT pathways originate in the dorsal
  raphe (DR)
• DR innervates cortex, hypothalamus, thalamus, and
  limbic system
• 5-HT mediates behavioral effects in animal models
  and humans

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Serotonin Receptors
pharmacology of anxiolytic/sedative-hypnotics

• 5-HT1A -Anxiety, alcoholism, sexual function
• 5-HT1C -Anxiety, migraine pain
• 5-HT1D -Migraine pain
• 5-HT2 -Anxiety, depression, schizophrenia
  negative symptoms, sexual function
• 5-HT3 -Migraine pain, emesis, schizophrenia
  (e.g., ondansetron)
• 5-HT4 -Anxiety, schizophrenia?

29
Serotonin Agents Indications forAnxiety-Related
Disorders
pharmacology of anxiolytic/sedative-hypnotics

• SSRI
• Sertraline - OCD PD PTSD
• Paroxetine - OCD PD SAD GAD
• Fluoxetine - OCD BN PMDD
• Fluvoxamine - OCD
• Venlafaxine - GAD
• Buspirone - GAD

30
Noradrenergic Model
pharmacology of anxiolytic/sedative-hypnotics

• Hypersensitivity to autonomic nervous system
• Locus coeruleus (LC)
• Stimuli norepinephrine release stimulation of
  the sympathetic nervous system

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Norepinephrine Receptors
pharmacology of anxiolytic/sedative-hypnotics

• Locus coeruleus
• Alpha -2 adrenergic receptors
• somatodendritic autoreceptors
• terminal autoreceptors
• negative feedback system
• antagonists are anxiogenic
• agonists may be anxiolytic and decrease
  withdrawal symptoms (e.g., clonidine)
• Beta adrenergic receptors
• Beta-blockers (e.g., propranolol)
• Social phobia
• Performance anxiety

32
Pharmacokinetics Benzodiazepines
pharmacology of anxiolytic/sedative-hypnotics

• Absorption rapid absorption, except clorazepate
• Onset of action increase lipid solubility ?
  faster onset
• Duration of action single dose with increased
  lipid solubility ? faster redistribution to fat
  tissues? shorter duration of action. Chronic
  use in equilibrium with fat tissues
• Half life In part, determines duration of
  action
• Metabolism lorazepam, oxazepam, temazepam not
  metabolized by liver

33
Drug Interactions Benzodiazepines
pharmacology of anxiolytic/sedative-hypnotics

• Additive pharmacodynamic effects (e.g., alcohol)
• BZD withdrawal when other drugs that increase
  seizure risk are also taken
• Inhibit BZD metabolism (e.g., nefazodone via P450
  3A 3/4 inhibits metabolism of triazolam)
• Diazepam may increase levels of digoxin and
  phenytoin

34
Adverse Effects Benzodiazepines
pharmacology of anxiolytic/sedative-hypnotics

• Sedation and impairment of performance
• Psychomotor skills driving engaging in
  dangerous physical activities using hazardous
  machinery, especially during initial phase of
  treatment
• Memory impairment
• Anterograde amnesia (desired before surgery,
  other procedures).
• Dose-related, and tolerance may not develop.
• Most likely with triazolam
• Disinhibition
• Possible risk factors history of aggression,
  impulsivity, borderline or antisocial personality

35
Abuse, Dependence, Withdrawal, and Rebound
Anxiety Benzodiazepines
pharmacology of anxiolytic/sedative-hypnotics

• Abuse potential decreased when properly
  prescribed and supervised.
• Dependence may occur at usual doses taken beyond
  several weeks.
• Withdrawal may occur even when discontinuation is
  not abrupt (e.g., by 10 every 3 days). Symptoms
  include tachycardia, increased blood pressure,
  muscle cramps, anxiety, insomnia, panic attacks,
  impairment of memory and concentration,
  perceptual disturbances, derealization,
  hallucinations, hyperpyrexia, seizures. May
  continue for months.
• Rebound anxiety return of target symptoms, with
  increase intensity.

36
Pharmacokinetics/Pharmacodynamics Buspirone
pharmacology of anxiolytic/sedative-hypnotics

• Onset of action (i.e., weeks versus days)
• No sedation or impairment of performance
• No cross-tolerance with BZDs
• No tolerance or withdrawal
• No abuse potential

37
Adverse Effects Buspirone
pharmacology of anxiolytic/sedative-hypnotics

• Nausea
• Headache
• Insomnia, nervousness
• Restlessness
• Dizziness, lightheadedness

38
Treatment Strategy for GAD
CLINICAL PRESENTATION TREATMENT STRATEGY

• Acute anxiety (mild)

PSYCHOTHERAPY Supportive, Cognitive-Behavioral
or Insight-Oriented
(may start)
(insufficient response)
(may add)
Acute anxiety (more severe)
(start)
Benzodiazepine (BZD) plus Psychotherapy
(insufficient response)
(may try)
39
Treatment Strategy for GAD
CLINICAL PRESENTATION TREATMENT STRATEGY

• Chronic anxiety
• (no prior BZD therapy)

Buspirone (up to 90 mg/day for up to 6 weeks)
plus CBT
(may start)
(insufficient response)
Venlafaxine
(insufficient response)
40
Treatment Strategy for GAD
CLINICAL PRESENTATION TREATMENT STRATEGY
Buspirone or Venlafaxine plus BZD initially, then
taper BZD plus CBT

• Chronic anxiety,
• prior BZD therapy

(may start)
(insufficient response)
Buspirone or Venlafaxine plus BZD for longer
period plus CBT
(insufficient response)
Chronic anxiety with panic or depressive symptoms
(may start)
Other Antidepressants (TCA, SSRI, MAOI) w/wo a
BZD or Buspirone
41
Treatment Strategyfor PHOBIC Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY

• Social Phobia, Generalized (Social Anxiety
  Disorder)

Cognitive Behavioral Therapy
(may start)
(or)
(insufficient response)
Selective Serotonin Reuptake Inhibitor (e.g.,
Paroxetine)
(insufficient response)
42
Treatment Strategyfor PHOBIC Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY
BEHAVIORAL THERAPY PLUS SSRI
(insufficient response)
MAOI (must wait at least 2 weeks after
discontinuation of SSRI longer for fluoxetine
before starting MAOI)
or Alprazolam or Clonidine
43
Treatment Strategyfor PHOBIC Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY

• Cognitive Behavioral Therapy
• Systematic desensitization

• Specific Phobia

(start)
(insufficient response)
B-blocker (e.g., performance anxiety)
(insufficient response)
MAOI (e.g., phenelzine)
44
Treatment Strategy for PANIC Disorder with or
without Agoraphobia
CLINICAL PRESENTATION TREATMENT STRATEGY

• Panic attacks (mild) w/wo agoraphobia

• Behavioral Therapy only
• (may require several months)
• Cognitive
• In-vivo exposure
• Relaxation
• Systematic desensitization

(start)
(insufficient response)
(may add)
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
45
Treatment Strategy for PANIC Disorder with or
without Agoraphobia
CLINICAL PRESENTATION TREATMENT STRATEGY

• Panic attacks (moderate) w/wo agoraphobia

SSRI plus Behavioral Therapy
(may start)
(or)
(insufficient response)
Other Antidepressant (e.g., Venlafaxine, TCA)
plus Behavioral Therapy
(insufficient response)
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
46
Treatment Strategy for PANIC Disorder with or
without Agoraphobia
CLINICAL PRESENTATION TREATMENT STRATEGY
ALPRAZOLAM/CLONAZEPAM plus Behavioral Therapy
(insufficient response)
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
47
Treatment Strategy for PANIC Disorder with or
without Agoraphobia
CLINICAL PRESENTATION TREATMENT STRATEGY
TCA/SSRI and Behavioral Therapy

• Panic attacks (severe) w/wo agoraphobia

(start)
(plus)

• Alprazolam/Clonazepam
• for first month

(insufficient response)
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
48
Treatment Strategy for PANIC Disorder with or
without Agoraphobia
CLINICAL PRESENTATION TREATMENT STRATEGY
TCA/SSRI and Behavioral Therapy
(plus)

• Alprazolam/Clonazepam
• indefinitely

(insufficient response)
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
49
Treatment Strategy for PANIC Disorder with or
without Agoraphobia
CLINICAL PRESENTATION TREATMENT STRATEGY

• MONOAMINE OXIDASE INHIBITOR (N.B. SSRI) must be
  stopped prior to beginning MAOI
• Fluoxetine, at least 5 weeks
• Other SSRIs, at least 2 weeks

(insufficient response)
(may try)
Valproate w/wo BZD
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
50
Treatment Strategy for OBSESSIVE-COMPULSIVE and
Related Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY
(may start)

• Mild symptoms

Behavioral Therapy (e.g., exposure and response
prevention)
(insufficient response)
(may add)
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
51
Treatment Strategy for OBSESSIVE-COMPULSIVE and
Related Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY

• Moderate to severe symptoms

• SSRI
• Fluvoxamine
• Sertraline
• Paroxetine
• Citalopram
• Fluoxetine

(start)
(or)
Clomipramine
(plus)
Behavioral Therapy
(insufficient response)
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
52
Treatment Strategy for OBSESSIVE-COMPULSIVE and
Related Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY
Alternate SRI
(insufficient response)
Clonazepam/Buspirone plus SRI
(insufficient response)
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
53
Treatment Strategy for OBSESSIVE-COMPULSIVE and
Related Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY
Pimozide/Haloperidol/Risperidone or Lithium w/wo
SRI

• Trichotillomania
• Tics (e.g., Tourettes)
• Delusional symptoms

(may start)
(insufficient response)
MAOI (SRI must be completely cleared first)
(insufficient response)
(may consider)
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
54
Treatment Strategy for OBSESSIVE-COMPULSIVE and
Related Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY

• Severe, unremitting course (e.g., 5 years failed
  trials with SSRI, CMI, MAOI severe dysfunction)

• Somatic Therapy
• ECT
• Neurosurgery
• TMS (?)

(consider)
From Janicak PG, Davis JM, Preskorn SH, Ayd FJ
Jr. Principles and Practice of Psychopharmacothera
py. 3rd ed. Philadelphia, PA Lippincott Williams
Wilkins 2001.
55
Treatment Strategy for SLEEP Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY
(first)

• Transient or short-term insomnia

• Clarify diagnosis
• treat any medical or psychiatric disorder
• check for non-prescribed drugs

(insufficient response or no other disorder
discovered)
Adapted from Janicak PG, Davis JM, Preskorn SH,
Ayd FJ Jr. Principles and Practice of
Psychopharmacotherapy. 3rd ed. Philadelphia, PA
Lippincott Williams Wilkins 2001.
56
Treatment Strategy for SLEEP Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY

• Nonpharmacological therapies
• Stimulus control
• Sleep restriction
• Relaxation techniques
• Paradoxical intention
• Sleep hygiene techniques

(insufficient response)
Adapted from Janicak PG, Davis JM, Preskorn SH,
Ayd FJ Jr. Principles and Practice of
Psychopharmacotherapy. 3rd ed. Philadelphia, PA
Lippincott Williams Wilkins 2001.
57
Treatment Strategy for SLEEP Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY
Short- to intermediate-acting BZD
Sedative-Hypnotic (e.g., estazolam 0.5-1 mg QHS)
(or)
Zolpidem or Zaleplon (5-20 mg QHS)
(insufficient response)
Adapted from Janicak PG, Davis JM, Preskorn SH,
Ayd FJ Jr. Principles and Practice of
Psychopharmacotherapy. 3rd ed. Philadelphia, PA
Lippincott Williams Wilkins 2001.
58
Treatment Strategy for SLEEP Disorders
CLINICAL PRESENTATION TREATMENT STRATEGY
Non-pharmacological therapies w/wo sedating
antidepressant

• Chronic insomnia (³7-12 weeks)

(start)

• e.g., trazodone (25-50 mg QHS)

(insufficient response)
COMBINED TREATMENT non-pharmacological and
intermittent, sedative-hypnotic when necessary
Adapted from Janicak PG, Davis JM, Preskorn SH,
Ayd FJ Jr. Principles and Practice of
Psychopharmacotherapy. 3rd ed. Philadelphia, PA
Lippincott Williams Wilkins 2001.
59
ANTIANXIETY AGENTS
Generic Names Trade Names Daily Dosage (mg/day)
BENZODIAZEPINES Chlordiazepoxide Librium,
others 10-100 Diazepam Valium,
others 2-40 Oxazepam Serax, others 30-120 Chlora
zepate Tranxene, others 15-60 Lorazepam Ativan 1
-10 Prazepam Centrax 20-60 Halazepam Paxipam 60-
160 Alprazolam Xanax 0.75-4 AZAPIRONES Buspiron
e Buspar 15-60 ANTIDEPRESSANTS SSRI Sertraline,
others 25-250 Venlafaxine Effexor 75-375
60
SEDATIVE-HYPNOTICS
Generic Names Trade Names Daily Dosage (mg
/day) BENZODIAZEPINES Long-acting Flurazepam
Dalmane 15-45 Quaz
epam Doral 7.5-15 Intermediate-acting Estazol
am Prosom 0.5-2 Temazepam Restoril 15-45 Shor
t-acting Triazolam Halcion 0.125-0.25 NONBE
NZODIAZEPINE Zolpidem Ambien 5-20 Zaleplon
Sonata 5-20 SEDATING ANTIDEPRESSANTS Trazodo
ne Dyserel 25-100 BARBITURATE-LIKE Chloral
Hydrate Notec 500-1500 OTHER Melatonin 0.
3-2
61
References
pharmacology of anxiolytic/sedative-hypnotics

• Ayd FJ Jr, Janicak PG, Davis JM, Preskorn SH.
  Advances in the pharmacotherapy of
  anxiety-related disorders. In Janicak PG, ed.
  Principles and Practice of Psychopharmacotherapy
  Update. Baltimore, MD Williams Wilkins 1996.
  Vol 1.
• Janicak PG, Ayd FJ Jr. Sedatives and hypnotics in
  the elderly patient. In Nelson JC, ed. Geriatric
  Psychopharmacology. New York, NY Marcel-Dekker
  1998347-366.
• Janicak PG, Davis JM, Preskorn SH, Ayd FJ Jr.
  Principles and Practice of Psychopharmacotherapy.
  3rd Ed. Philadelphia, PA Lippincott Williams
  Wilkins 2001463-558.
• Israni TH, Janicak PG, Davis JM. Obsessive
  compulsive disorder. In Flaherty JA, Davis JM,
  Janicak PG, eds. Psychiatry diagnosis and
  therapy. 2nd ed. Norwalk, CN Appleton Lange
  1993145-155.