1. Aggression, Violence and Psychopathology: A Developmental Approach Hans Steiner, MD Professor, Division of Child Psychiatry Stanford University School of Medicine

2. 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

3. Disclaimer All current psychopharmacologic treatments for aggression and its disorders in children and adolescents are off-label.

4. 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

5. The Aggression System Pragmatics: Assertion, Aggression, Violence Striatum Event Primary Appraisal: Perception, Defense Sensorium Secondary Appraisal (EF) Prefrontal Lobes Affective Activation: Anger Limbic System

6. 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

7. 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

8. 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

9. 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

10. 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 Psychopharmacology of Aggression Effects of Stimulants in ADHD

11. The Aggression System: Influences and Limits Environment (e.g., substances, socialization, education) Constitution (e.g., genetics, perinatal injury) Psychiatric Trauma & related pathologies Development and Maturation (e.g., diversification of affect, intentionality, cruelty) Aggression System

12. 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)

13. PTSD in Delinquents: What events do boys and girls report?  2 =43.0 DF= 4, p= 0.001 % of Subjects Types of Trauma PDI-R Results Steiner et al, 1997

14. PTSD in Female Incarcerated Delinquents: 1997 X 2 =10.7 p<0.005 % Cauffman et al, 1998

15. PTSD in California Youth Authority Study REM-71 Factors: Primary Appraisal - Defenses All p’s <0.05 Standard Scores Steiner et al, 1997 Cauffman et al, 1998

16. PTSD in CYA Study WAI Factors: Activation and Secondary Appraisal Standard Scores Steiner et al, 1997 All p’s <0.05 Cauffman et al, 1998

17. Structured Interviews in Incarcerated Youth: Externalizing and Internalizing Disorders Females (n=140) Externalizing Disorders - 96% –Disruptive Disorders94% –Substance Use 85% Internalizing Disorders - 64% –Depression 24% –Anxiety55% Males (n=650) Externalizing Disorders - 97% –Disruptive Disorders95% –Substance Use85% Internalizing Disorders - 29% –Depression 8% –Anxiety26% Steiner et al, 2002 – new data (unpublished)

18. 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)

19. Clinical Subtypes of Aggression: Form and Causal Process Aggression Premed-itated Escalating Explosive Situa-tional OppositionalCovert Reactive, Affective, Defensive Psychopathological Overt Act Process Steiner et al, 2002 – new data (unpublished)

20. 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

21. Divalproex Sodium in CD: Design Weeks 0-701234567 Measures Best est. dx (open)X CGI (O)X WAI (Blind) DSS/RSTXXXXXXXX REM (B) F1/F2X YSR (B) Int/ExtX HD/LDCD (B)X CGI (B)X High dose = 1000 mg/d Low Dose  250 mg/d WOWO SESE THTH XXXX XXXX XXXX XXXX XXXX Steiner, 2002

22. 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

23. 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

24. HDCD and LDCD in Double-Blind, Placebo-Controlled Divalproex Trial 2x2 ANOVA; HD/LDCD effect p=.049 Standard Scores Low Dose High Dose Weekly Slopes of Distress Weekly Slopes of Restraint 2x2 ANOVA; NS Low Dose High Dose 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

25. Predictors of Response to DVPX in CD Week 0Week 8 Distress Factor 2 (Mature) Defenses Restraint Likelihood ratio Chi Square (DF 5)= 20.51, p=0.001 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) Good Response 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

26. 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

27. Divalproex Study in PTSD: Outcome by Blind Global Clinician Ratings (Intent to Treat Analyses) RS 1-5 p= 0.045 0.03.1 0.02 Total N=12 Observer Ratings Silverman M et al, Scientific Proceedings Of The Annual Meeting Of The American Academy Of Child And Adolescent Psychiatry, 17: 115, 2001

28. Divalproex Study in PTSD (Intent to Treat Analyses) p=.2.3.08.5.4 WAI Subscales R/S Total N=12 Weekly Slopes of Distress Weekly Slopes of Restraint p=0.0250.02.3.03.6 Silverman M et al, Scientific Proceedings Of The Annual Meeting Of The American Academy Of Child And Adolescent Psychiatry, 17: 115, 2001

29. 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)

30. The Developmental Model for Disruptive Behavior Disorders Peer Relationship Factors Performance Factors Personality Factors Parenting Factors Constitutional Factors Ecological Factors Time Risk FactorsProtective Factors CD, ODD Health

31. 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

32. 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

33. Early Developmental Manifestations of Reactive/affective/defensive Aggression Parent Child Anxiety, Depression, Parenting Stress, Abuse Potential Negative affective reactivity, poor emotion regulation, aggression 2002

34. 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