Presentation - National Autism Conference

Disclosures
Medication Management
in Autism Spectrum Disorder
• None
Martin J. Lubetsky,
Lubetsky, M.D.
WPIC Western Psychiatric Institute and Clinic
UPMC University of Pittsburgh Medical Center
Center for Autism and Developmental
Disorders
Goals of Presentation
• To describe co-occurring mental
health symptoms and diagnosis with
Autism Spectrum Disorder (ASD)
• To identify current evidence-based
pharmacologic treatments in ASD
• To discuss selected research in
pharmacologic treatments in ASD
Assessment- history
• Family - supports, psychosocial stressors
• School or work - success/ failure
• Medical - pregnancy, developmental,
seizures, syndromes, hearing, vision,
physical exam, medical referrals
• Interventions - educational, behavioral
• Medications/ Bio-Integrative - responses,
side effects, doses, levels
• Review records, reports
Functional Behavior Assessments
• Assessing etiology, function/ reason for
symptoms and behaviors
–Functional Analysis of Behavior
• Direct Observation (A-B-C)
– Antecedent - Behavior - Consequence
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Possible additional assessments
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Speech and language/ Hearing
Occupational/ Physical Therapy
Genetics
Cognitive/ Neuropsychological
Nutrition/ Gastroenterology
Neurology
Psychiatry
Diagnostic Overshadowing
• Mental health symptoms and
disorder can be diagnosed and
treated in individuals with Autism
or Intellectual Disability/ Mental
Retardation
Vulnerabilities for developing
mental health symptoms
Diagnostic Formulation
Reduced capacity to withstand stress
Poor coping skills and problem solving
Communication limitations
Cognitive limitations - concrete thought
Suggestibility
Lack critical judgment and abstractions
Emotional lability
Problems with changes, transitions
• Differential Diagnosis (hearing
deficit, language disorder, mental
retardation, reactive attachment
disorder, social anxiety disorder,
obsessive compulsive disorder,
schizophrenia, etc.)
• Further history, ratings, observation,
testing, data
DSM-IV-TR (APA, 2000)
Diagnostic criteria
• Axis I - Primary Clinical Disorders
(including Autism, PDD, Asperger’s
Disorder)
• Axis II - Intellectual Disability/ Mental
Retardation, or Personality Disorder
• Axis III - Medical Conditions
• Axis IV - Psychosocial Stressors
• Axis V - Global Assessment Score
Treatment Plan
• Multidisciplinary, interagency team
meetings
• Treatment recommendations
• Follow up assessment and monitoring
• Coordination of care - case
management, family supports,
community supports, behavioral crisis
plan
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Selected Interventions
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Educational/ vocational approaches
Communication therapies
Behavioral interventions
Social skills training
Psychotherapies - individual, family, group
Pharmacologic
Bio-Integrative
Autism interventions for older
children, adolescents and adults
Challenges: Struggle to meet the increased
social demands of adolescence/ adulthood
- Social skills deficits (develop competency)
- Emotion dysregulation (develop coping)
- Executive functioning deficits (self monitor)
- Passions preoccupation (develop functional
skills)
Research Continuum
• Case reports
• Retrospective case
group studies
• Prospective open label
group studies
• Prospective single or
double-blind, placebocontrolled group studies
Research Range of Variables
• Expect a positive outcome (parent or
clinician)
• Situations improve over time (child
continues to develop; depressive
symptoms gradually subside)
• Other factors might account for change
(new school, new treatment, less stress)
What Does Evidence-Based Mean?
• Strong Support (>2 randomized trials or
>6 controlled single subject trials;
• Moderate Support (<1 randomized trials
or <6 controlled single subject trials)
• Limited or No Support (no randomized
and only case reports)
• Ineffective Treatment (not recommended
or controlled studies have consistently
shown that the treatment does not work)
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What Does “Off-Label”
Off-Label” Use Mean?
“Off-Label”
Off-Label” Medication Use and ASD
• FDA may approve a medication for a
single disorder (e.g., depression, ADHD)
• FDA may approve a medication for a
certain age group or condition (e.g.,
adults, Alzheimer’s Disorder)
• The use of a medication for another
purpose or group is “off-label”
off-label” (e.g.,
giving an antidepressant approved for
adults to an adolescent)
• It has not always been of interest to
companies to pursue FDA approval of a
medication for a relatively small group of
individuals
• Doctors must often base decisions on other
research findings (that does not lead to
FDA approval)
• Recently, a number of companies have
been looking for FDA approval of
medications for ASD
Selecting a Medication for Treatment
Informed consent for medication
• Select a medication based upon
symptoms of a co-occurring disorder,
such as ADHD, Depression, Anxiety
• Select medication based upon
symptoms of concern, such as
aggression/ agitation, self injury,
ritualistic behavior
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name of medication, dose, schedule
effects/ benefits
side effects, monitoring
pharmacokinetics, duration of action
limitations
alternatives
Medication Classes
ADHD –Attention Deficit
Hyperactivity Disorder
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Stimulants/ non-stimulants
Neuroleptics (Antipsychotics)
Antidepressants
Anxiolytics and Sedatives
Antimanics/ Mood Stabilizers
Anticonvulsants
Other medications
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Inattention
Distractibility
Impulsivity
Hyperactivity
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ADHD
- inattention, distractibility,
impulsivity, hyperactivity
• Most common treatment is stimulant
medication
• Stimulant medications used for over 50 years
• 70% - 80% success rate in typically
developing children
• Short-acting (4-6 hours) vs long-acting (6-12
hours)
• Can often see effects quickly
Do Stimulants Work in ASD?
• Prior to 1995, many thought stimulants
did not work in ASD
• Most studies were not well controlled
• Until 2005, largest controlled study had
only 13 children
• In 2005 double-blind methylphenidate
(Ritalin) study of over 60 children found
around 50% response rate with 18%
having side effects (NIMH-RUPP).
Non-stimulant Medication Option
for ADHD: atomoxetine (Strattera
(Strattera))
ADHD
- Stimulant Options
• Short acting (2 to 3 times/day):
– methylphenidate (Ritalin, Metadate)
– dexmethylphenidate (Focalin)
– dextroamphetamine (Dexedrine)
– mixed amphetamine salts (Adderall)
• Long acting (1 time/day):
– methylphenidate (Concerta, Metadate
CD, Ritalin LA, Daytrana patch)
– dexmethylphenidate (Focalin XR)
– mixed amphetamine salts (Adderall
XR, Vyvanse)
Recommendation
• There is Strong Support for the use of
Ritalin in Autism (at least 2
randomized, controlled trials)
• There are no studies involving other
stimulants, such as Adderall, although
likely have a similar response rate.
• Stimulants are FDA approved for
treatment of ADHD in children and
adults
Does Strattera Work in ASD?
• Arnold et al. 2006: Double-blind, placebo
controlled crossover study in 16 children with ASD
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Non-stimulant medication for ADHD
single dose in am
efficacy equal to stimulants?
side effects: decreased appetite,
dizziness, dyspepsia
• no abuse potential
– 9 responders to drug (decrease hyperactivity)
– 4 responders to placebo
– Adverse events were tolerable
• Jou, Handen & Hardan, 2005: Retrospective study
in 20 children with ASD
– 60% were rated as “much” or “very much improved”
– Conners Hyperactivity rating score decrease
– Side effects: constipation, decreased appetite, mood
swings, sedation
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Other Medication Options for ADHD
• Antihypertensives
-clonidine (Catapres)
-guanfacine (Tenex)
• Antidepressants
-bupropion (Wellbutrin)
-bupropion SR (Wellbutrin SR)
Recommendation
• Use of Strattera, Tenex, and Catapres in
ASD are have moderate to limited
support (<randomized control trial or <6
controlled single subject trials; mostly
case reports) (in fact, neither of the
randomized trials have been published)
• Use of Wellbutrin in ASD has no support
• Strattera is FDA approved for treatment
of ADHD (new study in ASD 2009)
Mad, bad, sad…
“Kids teased me and I reacted by smacking
them…anger ripped through me when Mary called
me a ‘retard’ and without hesitation, I threw my
arm…my history book zoomed through the air like
a guided missile and hit Mary in the eye. She
screamed and I walked away, not even bothering
to pick up my history book.”
-Temple Grandin
Emergence: Labeled Autistic, 1986
Tenex in Autism and Mental
Retardation (Handen, Sahl & Hardan)
• Double-blind, placebo-controlled (N=11)
• Parallel group design, 6-week randomized
• Conditions: placebo and 3 mg Tenex (1 mg
three times a day)
• Of 7 children with PDD, 5 were responders
(50% decrease on behavior rating scales)
• Side effects: drowsiness and irritability
Aggression, impulsive behavior,
agitation, psychosis, mania
• Typical antipsychotics
• Atypical antipsychotics
• Also used to treat aggression and
agitation
• Can work quickly, but also needs time to
titrate to ideal dose
• Short-term and long-term side effects
Typical Antipsychotics
(less often used now)
• haloperidol (Haldol)
• chlorpromazine
(Thorazine)
• thioridazine (Mellaril)
• pimozide (Orap)
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NIMH Multi-Center
Risperidone Study 2002
Atypical Antipsychotics
(more often used)
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risperidone (Risperdal)
olanzapine (Zyprexa)
quetiapine (Seroquel)
ziprasidone (Geodon)
aripiprazole (Abilify)
NIMH Multi-Center
Risperidone Study 2002
• FDA approval for the treatment of irritability,
aggression, deliberate self-injury, temper
tantrums in children ages 5-16 with autism
• Possible side effects of weight gain, sedation,
constipation, salivation, etc.
– Research Units on Pediatric Psychopharmacology
Autism Network: Risperidone in children with autism and
serious behavioral problems. N Engl J Med 2002;
347:314–321
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Double-blind, placebo-controlled study
101 children with ASD
Doses ranged from 0.5 to 3.5 mg/ day
69% improved on Risperdal vs 11% on placebo
57% decrease in symptom severity
Symptoms returned during placebo
discontinuation for 62% of subjects
• FDA approval in select symptoms in ASD
FDA Advisory - Atypical
Antipsychotics
• FDA requested updated labeling to
include additional information on
potential for weight gain, and glucose
abnormalities (hyperglycemia/ diabetes)
with: Risperdal, Zyprexa, Seroquel,
Geodon, Abilify, Clozaril.
• May choose to monitor fasting glucose,
cholesterol, LDL, HDL, lipid panel
Recommendations
Only Risperdal has Strong Support (>2
randomized trials or >6 controlled single
subject trials) for use in children with ASD.
FDA approved for select symptoms in ASD.
• All other atypicals have only open label studies
and case reports (therefore, limited research
support)
• Haloperidol had Strong Support from studies
in the 1970’s (decreasing irritability and social
withdrawal), but problems with side effects.
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Emotion/ affect dysregulation
• Emotions are immature
• Variable affect regulation
• Limited and basic understanding of
emotions
• Limited and basic perception skills
• Treatment usually involves teaching
basic emotion skills
- Mazefsky, C., 2007
Emotion/ affect dysregulation
• Clinical manifestations of emotional
distress and agitation in autism:
– “meltdown” – aggression, increased
repetitive behaviors, verbal
perseveration, self-injury
Emotion/ affect dysregulation
• Emotion/ affect dysregulation in autism
may increase risk of mood disorders and
may be correlated to:
– autism impairments in communication, social
skills, flexibility, sensory inhibition
– environmental/ psychosocial stressors such
as transitions/ change, noise, teasing
- Mazefsky, C., 2007
Birthday parties are not
always fun…
fun…
“Birthday parties were
torture….confusion created by noise
startled me and I invariably reacted
by hitting another child…even today
sudden noises make me jump and a
panicky feeling overwhelms
me….loud, high-pitched sounds are
still painful for me.”
- Ghazziudin, 2005; Lainhart, 1999;
Leyfer et al., 2006
Mood Disorders
• Depression - sadness, unhappy,
-Temple Grandin,
Emergence: Labeled Autistic, 1986
Mood Disorders - Depression
• Video clip
down, blue, withdrawn, isolative,
appetite/ weight change, sleep
change, suicidal thoughts
• Anxiety - anxious, nervous,
worried, agitated
• OCD-Obsessive Compulsive
Disorder
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Bullies
• Children who are bullied more often
depressed and suicidal thoughts
• Children who are bullies more often
depressed and suicidal thoughts
• Pediatrics, 2003: 111:1312-1317
• Carol Gray social stories on bullying
Other Antidepressants
• venlafaxine (Effexor XR)
• nefazodone (Serzone)
• bupropion (Wellbutrin SR)
Depression, sadness, OCD,
anxiety, rituals, compulsions
• Tricyclic Antidepressants (e.g., Anafranil)
• Selective Serotonin Reuptake Inhibitors (SSRIs)
-fluoxetine (Prozac)
-sertraline (Zoloft)
-paroxetine (Paxil)
-fluvoxamine (Luvox)
-citalopram (Celexa)
-escitalopram (Lexapro)
Anxiolytics
• clonazepam (Klonopin) antianxiety/ anticonvulsant
• buspirone (Buspar) antianxiety
Antidepressants
Research in Tricyclic
antidepressant use in ASD
• Require a longer period of time to titrate
to efficacious dose (a number of weeks)
• Also take longer time to “washout” from
body when discontinuing medication
• Side effects can include: increased
irritability, activation, insomnia,
tiredness, weight gain
• Series of controlled studies of
desipramine and clomipramine in autism
(n=50)
• Clomipramine resulted in significant
decreases on ratings of autism
symptoms, anger, repetitive, and
compulsive behavior in comparison to
both placebo and desipramine
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Research in SSRI
antidepressant use in ASD
Recommendations
• Prozac: most studied but all but 1 was
open label. One controlled trial
included children and adults reporting
gains in autism symptoms.
• Luvox: Controlled trial (n=18) children
with ASD improved eye contact and
language
• Other SSRIs: No controlled trials of
other SSRIs (case reports)
• Use of antidepressants in ASD have
moderate to limited support
(<randomized control trial or <6
controlled single subject trials; mostly
case reports)
• Only Prozac is FDA approved for
depression in children
• Prozac, Zoloft, Luvox, and Anafranil
are FDA approved for OCD in children
FDA Advisory -Antidepressants
• FDA asked manufacturers of antidepressant
medications to include in their labeling a warning
statement that recommends close observation of
adult and pediatric patients for worsening
depression, or the emergence of suicidal ideation or
behavior when treated with: Prozac, Zoloft, Paxil,
Luvox, Celexa, Lexapro, Wellbutrin, Effexor,
Serzone, Remeron
Bipolar disorder, mood lability,
lability,
aggression
• Moodiness, Irritability
• Manic/ hypomanic – pressured
speech, talk fast, move fast,
hyperactive, impulsive, grandiose/
bizarre thoughts, hypersexual
• Sleep change
Bipolar disorder, mood lability,
lability,
aggression (mood stabilizers,
anticonvulsants)
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lithium (Eskalith, Lithobid)
carbamazapine (Tegretol)
valproic acid (Depakene/ Depakote)
topiramate (Topamax)
lamotrigine (Lamictal)
oxcarbazepine (Trileptal)
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Research in mood stabilizers,
anticonvulsants in ASD
• Few controlled studies in ASD
• Lamictal (Belsito et al., 2001):
Placebo controlled, parallel group
design, n=28 (3-11 years of age)
• No significant differences between
placebo and Lamictal on autism
symptoms and behavior problems
Recommendations
• Use of mood stabilizers in ASD have limited
support (mostly case reports)
• Many mood stabilizers are FDA approved as
anticonvulsants in children
• Lithium is FDA approved for treatment of mania
in children 12 years and older
– Side effects can include irritability, activation,
tiredness, weight gain, blood abnormalities
– Some require regular blood work monitoring
(difficult in ASD)
Bio-Integrative/
CAT: Complementary &
Alternative Treatments
• Seek to alter physiology or change underlying
processes that lead to symptoms of autism
• Administered orally, via injection, or topically
• Some treatments are based on touch,
movement, or other sensory experiences
• Much of the support for treatments are based
upon subjective data from practitioners
Open Label Studies
• Divalproex sodium: retrospective study
(n=14 children and adults) found 71%
improved on autism symptoms, affective
instability, impulsivity, and aggression.
• Keppra: Open label trial (n=10 children,
ages 4-10 yrs) found gains in hyperactivity,
impulsivity, and mood instability.
• Most other are case studies (1-3 individuals)
Sleep Problems
• Assess history & behavioral/ environmental strategies
• Some medication options:
-trazodone (Desyrel) - sedating antidepressant **
-clonidine (Catapres) –alpha-2 adrenergic agonist
• Melatonin
• New sleeping medications
• Other options:
– diphenhydramine (Benadryl)
– hydroxyzine (Atarax, Vistaril)
Summary of 13 Secretin Studies
(from Aman, 2003)
• Total # individuals: 569
• Mean Duration:
4.85 Weeks
• Results:
-Open Label: no improvement
-Double Blind: Improvement in only 3 of
111 variables measured
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Recommendations: Secretin
• Use of Secretin in
Autism is considered to
be an Ineffective
Treatment (not
recommended or
controlled studies have
consistently shown that
the treatment does not
work)
Recommendations: Cognitive
Enhancers
• Between Moderate
Support (<1
randomized trials or
<6 controlled single
subject trials) and
Limited or No Support
(no randomized and
only case reports)
Recommendations: Gluten Free/
Casein Free Diet
• Treatment may be of value for selected
groups of children and selected symptoms
• Existing literature neither supports or
refutes anecdotal reports of success
• A number of well-controlled studies will be
available in the next couple of years
• Currently considered as Limited or
No Support (one randomized and
only case reports)
Rationale for donepezil HCl
(Aricept) in ASD
• Aricept is a cholinesterase inhibitor which increase
brain levels of acetylcholine, used in Alzheimer’s
• Thought to enhance cognitive functioning,
memory, speech production, attention, &
emotional expression
• Individuals with ASD present with cognitive
dysfunction, attention difference, verbal fluency
difference, and lack of emotion expression
• Chez et al. found increased spontaneous speech,
attention and emotional expression in autism
Theoretical Basis for Gluten
Free/ Casein Free Diet
• Increase in urinary opioid peptides among autistic
children (Reichelt study)
– Source of increased opioid peptides thought to
be from dietary gluten and casein
– Gluten and casein break down into opioid
peptides casomorphine and gluteomorphine
– Absorbed through “leaky gut”
– Create morphine like effect social withdrawal
etc.
Omega 3 Fatty Acids
• Popular supplement for children with
ADHD as well as Autism
• Mechanism of action presumes a
deficiency of fatty acids
• Fatty acids are precursers of second
messengers (e.g., prostaglandins,
prostacyclins, leukotrienes), and
constituents of structural lipids in cellular
membranes
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Recommendations: Omega 3
• Limited or No Support (no randomized
and only case reports)
• Recent pilot study suggests fatty acid metabolism
may be higher in children with autism
• Case study of child with autism and severe
behavior problems who improved when fish oil
was added to pharmacotherapy
• No controlled group studies
Research Support: B6 Magnesium
• Two double-blind studies of a low dose of B6
(Tolbert et al., 1993) and a high dose of B6
(Findling, 1997) failed to show efficacy.
• Possible side effect is peripheral neuropathy
– No difference on behavioral checklists, global
impressions, or on measures of OCD-type
behavior
Melatonin
• A hormone produced by the pineal gland
• Affects diurnal rhythms (which affects sleep and
the immune system)
• Used to treat jet-lag
• Few side effects
• Only a few case studies in autism
• 2006 controlled study of efficacy of melatonin
(5 mg) in ADHD and sleep when combined with
strict sleeping routine program
Vitamin B6 and Magnesium
• Among the most commonly used
supplements in autism
• Thought to enhance neurotransmitter
function
• Possible that some children with restricted
diets may have vitamin deficiencies
• Usually doses are above recommended
daily allowance
Recommendations: B6 &
Magnesium
• Nye & Brice (2002) review concluded
that due to small sample sizes and
methodological problems with the
literature, no recommendation could be
made for this treatment.
• Would consider Limited or No Support
(two small, but negative randomized
trials and only positive case reports)
Recommendation: Melatonin
• 2008 study?
• Limited or No
Support (no
randomized and
only case
reports)
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Summary:
Psychopharmacology
Barriers?
• Remains limited research in autism and
psychopharmacology
• No medication that addresses primary
symptoms of Autism; only secondary
behavioral concerns
• A growing number of large, controlled studies
are now available (e.g., Risperdal, Ritalin)
• Efforts being made to obtain FDA approval for
some medications to treat individuals with
autism (Risperdal is the first)
Systems – team work
• Department of Education – early intervention,
schools, vocational training/ transition
• Office of Behavioral Health/ Mental Health – case
management, outpatient services, community
services (mobile/ wraparound)
– Private insurance
– Department of Public Welfare (Medical
Assistance- Medicaid)
• Office of Developmental Disabilities (Intellectual
Disability/ Mental Retardation) – case coordination
• Office of Vocational Rehabilitation (OVR)
WPIC - Center for Autism and
Developmental Disorders Services
ADULT:
• Outpatient assessment
• Outpatient treatment – groups, individual, family
• Vocational training center and day program (transition
from school and in summer)
• Supported Employment Program (transition from school)
• Group home consultation (selected mobile team)
• Acute inpatient, Emergency room, Mobile crisis
• Mental Health case management
WPIC - Center for Autism and
Developmental Disorders Services
CHILD AND ADOLESCENT:
• Outpatient assessment
• Outpatient treatment – groups, individual, family
• Day Program in special ed school
• Summer Day Program & Camp Inclusion Programs
• In home Family-Based
• In home wraparound Early Behavioral Intervention
• In preschool Early Behavioral Intervention
• School consultation
• Acute inpatient, Emergency room, Mobile crisis
• Mental Health case management
WPIC - Center for Autism and
Developmental Disorders
 Autism Service, Education, Research and Training (ASERT)
Regional Center -Bureau of Autism Services DPW
 Autism Treatment Network (ATN) -Autism Speaks
 Clinical Trials Network (CTN) -Autism Speaks
 Pharmacologic studies
 Autism RUPP (NIMH Research Units in Pediatric
Psychopharmacology) collaborators
 NIH Autism Center for Excellence (ACE) and Center For
Autism Research (CeFAR) – Nancy Minshew, MD
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Networking resources
• ASA (Autism Society of America)
www.autism-society.org
• Autism Speaks
www.autismspeaks.org
• Organization for Autism Research (OAR)
www.researchautism.org
• Interactive Autism Network (IAN)
www.ianproject.org
References
• Attwood, Tony. The Complete Guide to Asperger’s
Syndrome. Jessica Kingsley Publishers, 2007.
• Bellini, Scott. Building Social Relationships.
Autism Asperger Publishing Company, 2008.
• Debbaudt, Dennis. Autism, Advocate, and Law
Enforcement Professionals. Jessica Kingsley
Publishers, 2002.
• Ghaziuddin, Mohammad. Mental Health Aspect of
Autism and Asperger Syndrome. Jessica Kingsley
Publishers, 2005.
References
• Ozonoff, Sally. A Parent’s guide to Asperger
Syndrome & High-Functioning Autism. Guilford
Press, 2002.
• Ozonoff, Sally. Autism Spectrum Disorders, a
research review. American Psychiatric
Publishing, 2003.
• Powers, Michael. Children with Autism, a
parent’s guide. Woodbine House, 2000.
Networking resources
• American Association on Intellectual and
Developmental Disabilities www.aaidd.org
• National Association for the Dually
Diagnosed (NADD) www.thenadd.org
• ARC www.thearc.org
• American Academy of Child and Adolescent
Psychiatry www.aacap.org
• National Alliance on Mental Illness (NAMI)
www.nami.org
References
• Hollander, Eric. Clinical Manual for the Treatment
of Autism. American Psychiatric Publishing, Inc.,
2007.
• Meyer, Roger. Asperger Syndrome Employment
Workbook. Jessica Kingsley Publishers, 2001.
• National Research Council. Educating children with
autism. Washington, DC: National Academies Press,
2001.
• Organization for Autism Research (OAR). Life
Journey through Autism, a parent’s guide to
research. 2003.
References
• Schreibman, Laura. The Science and Fiction of
Autism. Harvard University Press, 2005.
• Sicile-Kira, Chantal. Adolescents on the Autism
Spectrum, a parent’s guide. Penguin Group, 2006.
• Szatmari, Peter. A Mind Apart: Understanding
Children with Autism and Asperger Syndrome. The
Guildford Press, 2004.
• Tsai, Luke. Taking the Mystery Out of Medications
in Autism/Asperger Syndromes. Future Horizons,
2001.
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References
• Volkmar, Fred. Healthcare for Children on the
Autism Spectrum. Woodbine House, 2004.
• Volkmar, et.al. Handbook of Autism and
Pervasive Developmental Disorders. John Wiley
& Sons, Inc., 2005.
• Weber, Jayne Dixon. Children with Fragile X
Syndrome, a parent’s guide. Woodbine House,
2000.
• American Psychiatric Association. Diagnostic
and Statistical Manual of Mental Disorders-IVTR. American Psychiatric Press, 2000.
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