Transcript PTSD, Substance Use Disorders, and Personality Disorders

Aggression, Violence and
Psychopathology:
A Developmental Approach
Hans Steiner, MD
Professor, Division of Child Psychiatry
Stanford University School of Medicine
Disclosure Information
• Consultant for:
Abbott Laboratories, Janssen Pharmaceutica
• Receives research support from:
Abbott Laboratories, Astra Zeneca, Janssen
Pharmaceutica, Pfizer, Inc., Wyeth-Ayerst, Solvay
Pharmaceuticals, GlaxoSmithKline
• Speaker for:
Abbott Laboratories, Janssen Pharmaceutica,
Pfizer, Inc., AstraZeneca
Disclaimer
All current psychopharmacologic treatments
for aggression and its disorders in children
and adolescents are off-label.
The Current Lecture
• The aggression system
• Update on the psychopharmacology of juvenile
aggression
• Meta-analysis of stimulants and aggression
• Relationship of aggression to psychiatric trauma and
psychopathology
• Reactive/Affective/Defensive/ (RAD) Aggression
• Antikindling treatment of aggression based on this model
• Early developmental manifestations of RAD aggression
The Aggression System
Event
Primary
Appraisal:
Perception, Defense
Sensorium
Affective
Activation:
Anger
Limbic System
Pragmatics:
Assertion,
Aggression,
Violence
Striatum
Secondary
Appraisal
(EF)
Prefrontal Lobes
Randomized, Placebo-Controlled Clinical
Trials of Medication for the Treatment of CD
• 13 studies, 559 subjects, 9 (8?) positive for
medications, 4 (5?) equivocal
• Agents studied: Li, DVPX, Risperidone,
Haloperidol, Molindone, Methylphenidate
(MPH), CBZ, Vitamins
• Average Duration: 10 weeks, no long-term follow
up, few comparative studies, small samples
• BUT antipsychotics are most commonly
prescribed (60-80%) for aggression, regardless
of diagnosis
Steiner, January 2002
Psychopharmacology of Aggression
Effects of Stimulants in ADHD:
A Meta-analysis
• 28 studies
– Criteria: ADHD, peer reviewed, placebo-controlled, age
<18,
scaled aggression
• 2 with MR and CD as primary diagnoses each;
rest were ADHD; 75% comorbid with ODD,CD
• Average N=24
– 88% boys  age: 9.7 (7.7-14.4)
– MPH in 75% (dose 24 mg/day); duration = 13 days
Connor et al, 2002
Psychopharmacology of Aggression
Effects of Stimulants in ADHD
• Overt aggression
–
–
–
–
Clinician (d = .77)
Parent (d = .57)
Teacher ratings (d = .93)
All significant
• Presence of MR and CD/ODD reduces
Effect Size
• AMPH and MPH equally effective (.8);
PEM more (1.6)
Connor et al, 2002
Psychopharmacology of Aggression
Effects of Stimulants in ADHD
• Covert aggression
– Clinician (d= .81) significant
– Parent (d=.37)
– Teacher ratings (d=.54) not significant
(but wide range, only seven studies)
• Drug type did not make a difference,
duration and dose weakly contributed
• Overall sample age correlated positively with
effect size; no gender effects
Connor et al, 2002
Psychopharmacology of Aggression
Effects of Stimulants in ADHD
• Conclusion:
Stimulants have significant effects on
aggression (especially overt, especially when
ADHD is primary diagnosis and not comorbid
with CD, MR); and maybe in older subjects
• Limitations
–
–
–
–
Not all double blind
Short duration
No long term follow-up
Other comorbidities? – PTSD, bipolar
Connor et al, 2002
The Aggression System:
Influences and Limits
Environment
(e.g., substances,
socialization, education)
Psychiatric
Trauma & related
pathologies
Aggression System
Constitution
(e.g., genetics,
perinatal injury)
Development and
Maturation
(e.g., diversification
of affect, intentionality, cruelty)
Is there reason to think that trauma plays
a role in disturbances of aggression?
• Developmental epidemiological studies
(Widom, 1989)
• Community violence exposure studies
(Osofsky, 1995; Schwab-Stone, 1999)
• Clinical self report studies
(Burton et al, 1994)
• Structured interview studies
(Steiner et al 1997; Cauffman et al 1998; Steiner et al 2002)
• Transcultural studies
(Aichhorn, 1935; Rushkin et al, 2002)
PTSD in Delinquents:
What events do boys and girls report?
PDI-R Results
60
Girls
Boys
50
40
% of
Subjects 30
20
10
0
Witness
2 =43.0
DF= 4, p= 0.001
Participant
Victim
Other
None
Types of Trauma
Steiner et al, 1997
PTSD in Female Incarcerated
Delinquents: 1997
70
Negative
Partial
Positive
60
50
40
%
30
20
10
0
Boys
X2=10.7
p<0.005
Girls
Cauffman et al, 1998
PTSD in California Youth
Authority Study REM-71 Factors:
Primary Appraisal - Defenses
80
PTSD Negative
PTSD Positive
60
Standard
40
Scores
20
0
Factor 1 (Immature)
All p’s <0.05
Factor 2 (Mature)
Steiner et al, 1997
Cauffman et al, 1998
PTSD in CYA Study WAI Factors:
Activation and Secondary Appraisal
90
PTSD Negative
PTSD Positive
80
70
Standard
Scores
60
50
40
30
20
10
0
Distress
All p’s <0.05
Restraint
Steiner et al, 1997
Cauffman et al, 1998
Structured Interviews in Incarcerated Youth:
Externalizing and Internalizing Disorders
Females (n=140)
• Externalizing
Disorders - 96%
– Disruptive Disorders
– Substance Use
Males (n=650)
• Externalizing
Disorders - 97%
94%
85%
95%
85%
• Internalizing
Disorders - 29%
• Internalizing
Disorders - 64%
– Depression
– Anxiety
– Disruptive Disorders
– Substance Use
24%
55%
– Depression
– Anxiety
8%
26%
Steiner et al, 2002 – new data (unpublished)
Components of the Aggression System
Which Should Be Affected by Trauma
• Primary Appraisal: Defenses – YES – Feldman,
Araujo & Steiner, 1996; Steiner, Garcia and
Matthews, 1997
• Affective Activation: Anxiety and Aggression often
go together – YES- Steiner, Garcia and Matthews,
1997; Cauffman et al, 1998; NEW DATA
• Secondary Appraisal: Restraint, Impulse control is
impaired as a function of trauma– YES
This profile leads to reactive/affective/defensive (RAD) aggression
Steiner et al, 2002 – new data (unpublished)
Clinical Subtypes of Aggression:
Form and Causal Process
Aggression
Act
Process
Oppositional
Overt
Premeditated
Covert
Reactive, Affective, Defensive
Escalating
Situational
Explosive
Psychopathological
Steiner et al, 2002 – new data (unpublished)
How do we get from psychiatric trauma to
reactive/affective/defensive aggression?
• Eysenk’s antisocialization hypothesis: high levels of
anxiety in high criminogenic environments predict
future maladaptive aggression in adolescents
• LeDoux’s anxiety/active coping hypothesis: trauma
induced anxiety can be controlled by active coping
(in this case of criminogenic environments involving
aggression)
• Post’s PTSD kindling hypothesis: Repeated
traumatization leads to increasingly facile affective
activation which becomes a mixture of anxiety,
depression, anger
Divalproex Sodium in CD: Design
Weeks 0-7
0
1
2
3
4
5
6
7
Measures
Best est. dx (open)
CGI (O)
WAI (Blind) DSS/RST
REM (B) F1/F2
YSR (B) Int/Ext
HD/LDCD (B)
CGI (B)
High dose = 1000 mg/d
Low Dose  250 mg/d
X
X
X
X
X
X
X
X
W
O
S
E
T
H
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Steiner, 2002
Divalproex Sodium for the
Treatment of Severe CD in Boys
• Low ( 125 mg) and high dose (1000 mg) 7-week DBPC
clinical trial
• Sample: 70 boys consented, 61 completed 3 month
protocol (7 weeks on medication); 58 had all outcome
measures
• Multi-method, Multi-trait measures
• CGI-I Intent-to-treat: 35% responded
(53% in high dose vs. 8% in low dose condition)
• Significant differences in self rated slopes of weekly
restraint
• No significant side effects (drowsiness, GI upset),
easily tolerated
Steiner, 2002
Different Patterns of Aggression
Respond to Divalproex Sodium
• 61 adolescent males into predominantly High Distress
(HDCD) and Low Distress (LDCD) Conduct Disorders
• Low distress CD show predominantly premeditated
aggression; High Distress CD are predominantly RAD
aggressive.
• In a 7 week RDBPC trial of DVPX we found that the
HDCD had a more robust response to therapeutic
doses of DVPX Sodium
• Responsive targets were: observer rated CGI, weekly
slopes of self reported Distress (decreased) and
Restraint (increased)
New Poster APA, 2002
HDCD and LDCD in Double-Blind,
Placebo-Controlled Divalproex Trial
Weekly Slopes of Distress
Standard Scores
LDCD
0.01
0
-0.01
-0.02
-0.03
-0.04
-0.05
-0.06
-0.07
Weekly Slopes of Restraint
HDCD
0.06
0.05
0.04
0.03
0.02
0.01
0
-0.01
-0.02
Low
Dose
High
Dose
2x2 ANOVA; HD/LDCD effect p=.049
Low
Dose
High
Dose
2x2 ANOVA; NS
Remsing L, Chang K, Saxena K, Silverman M, Steiner H. Divalproex Sodium in Conduct Disorder: Response
Rates and Aggression. , Scientific Proceedings Of The Annual Meeting Of The APA, May 2002
Predictors of Response to DVPX in CD
Likelihood ratio Chi Square (DF 5)= 20.51, p=0.001
Restraint
Factor 2 (Mature) Defenses
Distress
Good
Response
Factor 1 (Immature) Defenses (OR= 3.1, p=0,046), Acting Out!
Divalproex Sodium at 1000-1500 mg q d (OR=16.3, p=0.002)
Week 0
Week 8
Silverman M, Remsing L, Saxena K, Chang K, Steiner H. Trait and State predictors of
Response to Divalproex Sodium in Conduct Disorders. Annual meeting of the
American Academy of Child and Adolescent Psychiatry, San Francisco, October 2002
Divalproex in PTSD: The Sample
• 12 boys
• Ages 14-17, mean 15.9 (SD=0.9)
• Highly comorbid:
– Conduct disorder (12)
– Mood Disorder (8)
– ADHD (6)
• Average number of diagnoses: 4.8
(SD=1.2)
Silverman M, Carrion V, Chang K, Matthews Z, Peterson M, Steiner H : Divalproex Sodium and
PTSD Treatment: A Randomized Controlled Clinical Trial, Scientific Proceedings Of The Annual
Meeting Of The American Academy Of Child And Adolescent Psychiatry, 17: 115, 2001
Divalproex Study in PTSD: Outcome
by Blind Global Clinician Ratings
(Intent to Treat Analyses)
Total N=12
5
RS 1-5
High Dose (1000 mg; N=6)
Low Dose ( 125 mg; N=6)
4.5
4
3.5
3
2.5
2
1.5
1
Intrusion
p= 0.045
Avoidance
Arousal
0.03
.1
Observer Ratings
CGI
0.02
Silverman M et al, Scientific Proceedings Of The Annual Meeting Of The American Academy Of
Child And Adolescent Psychiatry, 17: 115, 2001
Divalproex Study in PTSD
(Intent to Treat Analyses)
Weekly Slopes of Distress
High Dose (1000 mg; N=6)
0.1
Low Dose ( 125 mg; N=6)
Total N=12
0.1
R/S 0.05
0.05
0
DSS
Anx
Dep Lwb Lsest
-0.05
0
RST Sagr Impc Resp Cons
-0.05
-0.1
p=
Weekly Slopes of Restraint
-0.1
.2
.3
.08
.5
.4
p= 0.025
0.02 .3
.03
.6
WAI Subscales
Silverman M et al, Scientific Proceedings Of The Annual Meeting Of The American Academy Of
Child And Adolescent Psychiatry, 17: 115, 2001
Implications of DBPC trials in CD 2002
Emerging Pathways
• Lithium may be most applicable in prepubertal
aggression with a reactive/affective/defensive profile
• Divalproex may be most useful in pubertal CD with a
high affective component either to mood disorder or
trauma – especially chronic trauma
• Antipsychotics (risperidone; haloperidol; may be most
helpful when executive cognitive functions are impaired
(MR, PDD, psychosis)
• Stimulants should be considered when there is a
comorbid attention deficit (caveat – juvenile bipolar)
The Developmental Model for
Disruptive Behavior Disorders
Risk Factors
Time
Protective Factors
Peer Relationship Factors
Performance Factors
Personality Factors
Parenting Factors
Constitutional Factors
Ecological Factors
Health
CD, ODD
Observing Infants’ Aggression at 1 Year:
Teen Mothers’ and Researchers’ Reports
• Sample of 60 teen mothers at high risk ,
predominantly Hispanic, 33 boys and 28 girls
followed from pre-birth, assessment at 13
months
• Variables: maternal psychopathology, CAPI, PSI;
Reported infant aggression, negative emotional
reactivity and emotion regulation; Same infant
variables observed
• Experimental tasks: strange situation,
Bailey testing
Gschwendt, Zelenko & Steiner, 2002
Observing Infants’ Aggression at
1 year: Results
• In infants, negative affective reactivity, emotion
regulation and aggression were significantly
correlated by mother’s and observer’s reports,
separately (Spearman’s 0.47 to - .81, p’s < 0.05)
• Maternal depression, anxiety, CAPI and PSI
correlated with mother’s reports of infant
aggression, negative affective reactivity
(Spearman’s 0.22 to 0.47, p’s <0.05) in infants
• Mother’s reports correlated with observer ratings
only if their own functioning was taken into
account
Gschwendt, Zelenko & Steiner, 2002
Early Developmental Manifestations of
Reactive/affective/defensive Aggression
Anxiety, Depression, Parenting Stress, Abuse Potential
Parent
Child
Negative affective reactivity, poor emotion regulation, aggression
2002
Trauma and Reactive/Affective/Defensive
(RAD) Aggression – Summary APA 2002
• Traumatic Events are extremely common in the lives of maladaptively
aggressive (MAA) youth
• PTSD is extremely common in MAA youth
• PTSD leads to faulty primary appraisal, anxious/angry activation and
loss of self restraint – reactive/affective/defensive aggression –
kindling
• Treatment with DVPX is effective in CD, even more effective in CD and
PTSD
• Antikindling treatment seems to treat reactive/affective/defensive
aggression; good response is predicted by variables related to PTSD
at baseline
• Early antecedents of reactive/affective/defensive aggression involve
negative affect/ poor emotion regulation and aggression in the infant
(by both observer and mothers’ reports and increased attribution of
negative characteristics by the mother as a function of her anxiety
and depression