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Human Aggression Definition & Prevalence

A multidetermined act that often results in physical (or verbal) injury to others or self (or objects). It appears in several forms and may be defensive, premeditated (e.g., predatory), or impulsive (e.g., non-premeditated). Lifetime prevalence of recurrent, problematic, aggressive behavior may be 1% or higher in the general community. But, nearly 13% of psychiatric outpatients meet criteria for aggressive behavior at any point in their lives
Coccaro EF & Siever LJ. Neuropsychopharmacology: The Fifth Generation of Progress. Ed. Davis KL et al. ACNP 2002
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PSYCHOPHARMACOLOGY OF AGGRESSION AND AGITATION


Jorge M Tamayo, MD, BMSS

Most Common Psychiatric Causes of Aggression


Schizophrenia Substance abuse, intoxication, and withdrawal Medical and neurological conditions (brain injuries, brain tumors, or metabolic disturbances) Dementia/Alzheimer disease Personality disorders (cluster B: antisocial, borderline) Mood disorders (dysthymia, mania, mixed) Posttraumatic stress disorder Pervasive Disorders, ADHD, Autism, Mental Retardation

TREATMENT OF AGGRESSION IN CHILDHOOD ADOLESCENCE DISORDERS

Citrome LL. Medscape. Aug 2007


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Pharmacotherapy for the Treatment of Aggressive Behavior: Mental Retardation (MR)


Risperidone (1-3 mg/day): effective in 4/4 controlled MR studies1-4 and in one 1-year follow-up study5 Lithium: effective in 1 controlled trial6 Typical antipsychotics: effective only in open trials

Risperidone for Conduct Problems in Children With Sub-average Intelligence

*p<0.05

0.02 to 0.06 mg/kg per day

*
1. Buitelaar JK, et al. J Clin Psychiatry 2001;62:239248; 2. Van Bellinghen M & De Troch C. J Child Adolesc Psychopharmacol 2001;11:513; 3. Snyder R, et al. J Am Acad Child Adolesc Psychiatry 2002;41:10261036; 4. Aman MG, et al. Am J Psychiatry 2002;159:13371346; 5. Turgay A et al. Pediatrics 2002;110(3); 6. Craft M et al. Br J Psychiatry 1987;150:685-689
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AEs: somnolence, headache, appetite increase, and dyspepsia


Snyder R et al. J Am Acad Child Adolesc Psychiatry 2002;41:1026-1036
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Risperidone for the Treatment of Disruptive Behaviors in Children With Subaverage Intelligence
0.020.06 mg/kg per day

Pharmacotherapy in Aggressive Behavior: Autism & Pervasive Developmental Disorders


Risperidone (1 - 3 mg/day): effective in 3 controlled trials; 2 in children and 1 in adults1,2,3 Haloperidol (0.25-6.75 mg/day): effective in four crossover studies4 Olanzapine (7.5 12.5 mg/day): partial effective DB trial5 Clonidine (0.005 mg/kg/day): effective in 2 crossovers studies4 Methylphenidate (0.3-0.6 mg/kg BID): effective in 2 crossovers studies4 Naltrexone (0.5-1.2 mg/kg/day): positive in 2 crossover and 1 parallel studies4 SSRIs: effective in 1 crossover with fluoxetine (Prozac), and in 1 parallel with fluvoxamine4,6 Clomipramine (4.3 mg/kg/day): superior to Desipramine and placebo in a small DB crossover study7
1. McCracken JT, et al. N Engl J Med 2002;347:314321; 2. Shea S, et al. Pediatrics 2004; 114:e634e641; 3. McDougle CJ et al. Arch Gen Psychiatry 1998; 55:633-641; 4. Malone et al. CNS Drugs 2005;19:923-934; 5. Hollander E, et al. J Child Adolesc Psychopharmacol 2006;16:541548; 6. McDougle CJ et al. Arch Gen Psychiatry 1996;53:1001-1008; 7. Gordon CT et al. Arch Gen Psychiatry 1993; 50:441-447
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*
*p<0.05

The most common adverse effects reported during risperidone treatment were headache and somnolence. Mean weight increases: 2.2 kg vs. 0.9 kg (risperidone and placebo groups, respectively)

Mean Change in Score on the Conduct Problem Subscale of the Nisonger Child Behavior Rating
Aman MG, et al. Am J Psychiatry 2002;159:13371346
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Risperidone in Aggressive Behavior in Children With Autism

Risperidone in Aggressive Behavior in Children With Autism (2)

Mean Scores for Irritability (Irritability subscale of the Aberrant Behavior Checklist). Data are for all 101 children (49 assigned to the risperidone group [1.80.7 mg] and 52 assigned to the placebo group). P<0.001 Risperidone therapy was associated with an average weight gain of 2.7+/2.9 kg, as compared with 0.8+/-2.2 kg with placebo (P<0.001). Other AEs: Increased appetite, fatigue, drowsiness, dizziness, and drooling

Irritability subscale of ABC (n=79). *P<0.05 from baseline; P<0.01 from baseline; P<0.001 from baseline Risperidone-treated subjects experienced statistically significantly greater increases in weight (2.7 vs 1.0 kg), somnolence, pulse rate, and systolic blood pressure

McCracken JT, et al. N Engl J Med 2002;347:314321


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Shea S, et al. Pediatrics 2004; 114:e634e641


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Pharmacotherapy for the Treatment of Aggressive Behavior/Conduct Disorder: ADHD


Methylphenidate (30-40 mg/day): effective in 3 controlled trials (1 with long-acting formulation)1-3 Methylphenidate plus clonidine: effective in 1 controlled trial after 5 weeks4 Stimulant plus risperidone: modestly effective in 1 controlled study5 Lithium: effective in 2/3 controlled trials6 -blockers: pindolol effective in 1 controlled study, but severe AEs (paraesthesias, nightmares, and hallucinations)7

Methylphenidate OROS for the Treatment of Aggressive Behavior/Conduct Disorder: ADHD

MPH (verum-group): on the basis of Cohens criteria, high effects were found for aggressive symptoms in school (d 1.0), but not in the afternoon (d 0.4). AEs were not reported
Sinzig J et al. J Chils Adolesc Psychopharmacol 2007;17:421432

1. Klein RG et al. Arch Gen Psychiatry 1997;54:1073-1080; 2. Connor DF et al. Clin Pediatr (Phila) 2000;39;15-25; 3. Sinzig J et al. J Chils Adolesc Psychopharmacol 2007;17:421432; 4. Hazell PL et al. J Am Acad Child Adolesc Psychiatry 2003;42:886894; 5. Armenteros JL et al. J Am Acad Child Adolesc Psychiatry 2007;46:558-565; 6. McDougle CJ et al. Arch Gen Psychiatry 1998;55:633-641; 7. Buitelaar JK et al. J Child Psychol Psychiatry 1996;37:587-595
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Pharmacotherapy for the Treatment of Aggressive Behavior: Conduct Disorder


Risperidone(~1-2 mg/day): effective in 5/5 controlled trials1-5 and 1 DB relapse prevention6 Lithium (300-1200 mg/day): effective in 2/4 controlled trials7,8 Molindone vs. thioridazine: both effective in 1 controlled trial9 Paroxetine: effective in 1 small 21-days adult controlled trial10 Methylphenidate (41 60 mg/day): effective in 1 controlled trial [CD + ADHD (69%)]11 Carbamazepine (5-9 g/ml): not effective in 1 controlled trial12 Divalproex sodium (500-1500 mg/day): effective in 1 controlled trial13
1. Snyder R et al. J Am Acad Child Adolesc Psychiatry 2002;41:1026-1036; 2. Aman et al. Am J Psychiatry 2002;159:1337-1346; 3. Findling RL, et al. J Am Acad Child Adolesc Psychiatry 2000;39:509516; 4. Van Bellinghen & Troch. J Chil Adol Psychopharmacol 2001;11:5-13; Buitelaar et al. J Clin Psychiatry 2001;62:239-248; 6. Reyes M et al. Am J Psychiatry 2006;163:402-410; 7. Malone RP et al. Arch Gen Psychiatry 2000;57:649-654; 8. Campbell M et al. J Am Acad Child Adoles Psychiatry 1995;34:445-453; 9. Greenhill LL et al. J Clin Psychiatry 1985;46:20-25; 10. Cherek DR et al. Psychopharmacology (Berl) 2002;159:266-274 11. Klein RG et al. Arch Gen Psychiatry 1997;54:1073-1080; 12. Cueva JE et al. J Am Acad Child Adolesc Psychiatry 1996;35:480-90; 13. Steiner H et al. J Clin Psychiatry 2003;64:1183-1191
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Risperidone +/- Stimulant for the Treatment of Aggressive Behavior in Conduct Disorder + ADHD
N-CBRF=Nisonger Child Behavior Rating ABC= Abnormal behavior Checklist

Placebo (n=77)
Stimulant (n=39) No Stimulant (n=38)

Risperidone (n=78)
Stimulant (n=43) No Stimulant (n=35)

Mean Change From Baseline to Endpoint in Psychometric Score

N-CBRF (Conduct Problem) ABC (Irritability)


*p0.001; **p=0.004 vs placebo

N-CBRF (Hyperactive) ABC (hyperactive)

AEs risperidone alone = somnolence, headache, dyspepsia, vomiting, weight gain


Aman MG et al. J Child Adolesc Psychopharmacol 2004;14:243-254
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Risperidone Maintenance Treatment of Aggressive Behavior in Conduct Disorder

Lithium for the Treatment of Aggressive Behavior in Conduct Disorder


Baseline Week 1 Week 2 Week 3 Week 4

Acute phase was 6 weeks of openlabel risperidone treatment. The continuation phase was 6 weeks of single-blind treatment for those responding to acute phase treatment. Time to symptom recurrence was significantly longer in patients who continued risperidone treatment than in those switched to placebo (119 vs. 37 days)
b From the Nisonger Child Behavior Rating FormParent Version.

Mean Change From Baseline Score in OAS*

Placebo (n=20) Baseline = 5.84

Lithium (n=20) Baseline = 4.69

* OAS = Overt Aggression Scale. The difference in the mean decrease from baseline between groups was statistically significant as indicated by the significant interaction between treatment group and time (F1, 119 = 4.14; p = 0.04)

AEs = nausea, vomiting, urinary frequency


Reyes M. Am J Psychiatry 2006; 163:402410
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Malone RP et al. Arch Gen Psychiatry 2000;57:649-654


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Methylphenidate for the Treatment of Aggressive Behavior in Conduct Disorder*


P < 0.001 Baseline P < 0.003 Aggression (IOWA Scale) P < 0.03 Placebo MPH

TREATMENT OF AGGRESSION IN ACUTE PSYCHOTIC EXACERBATIONS

*ADHD = 69%

Teacher N= 71 35 36 74

Parent 37 37

Classroom 47 24 23

IOWA Scale (aggression) - Sum of five items: 0-15


Klein RG et al. Arch Gen Psychiatry 1997;54:1073-1080
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Old Interventions in Agitated Aggression


Haloperidol (5-10 mg IM): effective in 20 controlled trials1,2 Haloperidol (5-10 mg IM) + promethazine (25-50 mg): effective in 2 controlled trials3,4 Droperidol (2.5-5mg IV): effective in 4 controlled trials1 Lorazepam (2-4 mg IM): effective in 5 controlled trials5-8 Midazolam (7.5-15 mg IM): vs droperidol in 1 DB trial (3 patients in midazolam required active airway management)9
1. Currier GW, Allen MH Psychiatr Serv 2000;51:717-719; 2. Yildiz A et al. Emerg Med J 2003;20;339-346; 3. TREC Collaborative Group BMJ 2003;327:708-713; 4. Alexander J et al. Br J Psychiatry 2004;185:63-69; 5. Salzman C et al. J Clin Psychaity 1991;52:177-180; 6. Battaglia J et al. Am J Emerg Med 1997;15:335-340; 7. Foster S et al. Int Clin Psychopharmacol 1997;12:175-179; 8. Richards JR et al. J Emerg Med 1998;16:567-573; 9. Knott JC et al. Ann Emerg Med 2006;47:61-57
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Mean Modified Brief Psychiatric Rating Scale (MBPRS) Scores


Prospective, Double-Blind (N=98)
60 LOR HAL H+L

Mean Standard Error

50 40 30 20 10 0 0 2 4 6 Hour 8 10
* **

*p=.015, H+L<LZP and HAL; **p=.041, H+L<LZP; and p<.016, H+L<HAL < < < <

12

Battaglia J, et al. Am J Emerg Med. 1997;15(4):335-340


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Tiempo Acumulado de Somnolencia en Pacientes Tratados con Haloperidol IM + Lorazepam IM


60 50 LOR HAL L+H

IM Ziprasidone: Improvement In Mean Behavioural Activity Rating Scale (BARS) Scores After First Injection
Violent 7 Extremely Active 6 Overactive 5 Quiet and Awake 4 * ** Drowsy 3 Asleep 2 Difficult to Rouse 1 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Cambio promedio SE

IM ziprasidone 2 mg (n=54) IM ziprasidone 10 mg (n=63) IM ziprasidone 2 mg (n=38) IM ziprasidone 20 mg (n=41)

40 30 20
* * * * *p<.05, LZP y L*H vs HAL; **p<.05, L+H vs HAL < < * * * ** * **

**

10 0 0 2

No dystonia, akinesia, dyskinesia, tremor, twitching, or hypokinesia were reported in the 20 mg group

10

12

Time since First Injection (Hours) *p<.05 vs IM ziprasidone 2 mg; **p<.01 vs IM ziprasidone 2 mg; p<.001 vs IM ziprasidone 2 mg
Daniel DG, et al. Psychopharmacology (Berl) 2001;155:128-134

Horas LZP: depresin respiratoria, hostilidad paradjica; HAL: acatisia, distona, umbral convulsivo
Battaglia J, et al. Am J Emerg Med. 1997;15(4):335-340.
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Aripiprazole IM: Mean PANSS-EC Scores After First Injection

Olanzapine IM: Control Of Agitation In Schizophrenia After First IM Injection


Time (mins)
0 0 15 30 45 60 75 90 105 120

Mean Change PANSS-EC

-1 -2 -3 -4 -5 -6 -7 -8 -9 IM Olz IM Hal Placebo

*p.05 vs placebo; p.001 vs placebo; p=.051 vs. placebo PEC = Positive and Negative Syndrome Scale-Excited Component AEs ARI = headache, dizziness, somnolence, nausea. AEs HAL = somnolence, akathisia, dystonia, dizziness
Tran-Johnson TK, et al. J Clin Psychiatry 2007;68:111-119
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*
AEs OLZ (10 mg) = somnolence

* *

AEs HAL (7.5 mg) = somnolence, dystonia, EPS

*p < 0.05 Olz vs. Hal; p < 0.001 Olz vs. Pla for each evaluation
Wright P, et al. Am J Psychiatry. 2001;158(7):1149-1151.
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Olanzapine IM: Control Of Agitation In Schizophrenia After First IM Injection (Fixed Doses)
Time (mins)
0 30 60 90 120

Effectiveness of Rapid Initial Dose Escalation of up to Forty Milligrams per Day of Oral Olanzapine in Acute Agitation
0 0 -1 Predicted Mean Change in -2 -3 PANSS-EC -4 -5 -6 -7 -8 -9 -10 1 2 Days of Treatment 3

0 -1 -2 -3 -4 -5 -6 -7 -8 -9 -10
IM Olz 2.5 IM Olz 5.0 IM Olz 7.5 IM Olz 10 IM Hal 7.5 Placebo

Overall therapy effect: p-value=.019

Mean Change

OLZ 10 mg + LZP PRN (max. 4 mg) OLZ 20 mg + OLZ PRN (max. 40 mg)
* p-value=.041 at 24 hours

* * *

* **

** p-value=.002 at 3 days

*p < 0.05 all Olz doses and Hal vs. Placebo except Olz 2.5 at 30 minutes
Jones B, et al. J Clin Psychiatry 2001;62 (suppl 2):224
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No treatment-emergent AEs significantly differed between treatment groups: somnolence, headache, dizziness
Baker RW et al. J Clin Psychopharmacol 2003;23:342-348
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Effects of Clozapine, Olanzapine, Risperidone, and Haloperidol on Hostility Among Patients With Schizophrenia
Scores at baseline and at 14 weeks on the hostility item of the Positive and Negative Syndrome Scale among 157 inpatients

LONG-TERM TREATMENT OF LONGAGGRESSION IN PSYCHOTIC DISORDERS

The effect sizes were .25 for clozapine, .06 for olanzapine, .05 (indicating deterioration) for risperidone, and .30 (also indicating deterioration) for haloperidol. Significant improvement at 14 weeks was observed for clozapine compared with baseline (p=.019) and significant superiority in improvement compared with haloperidol (p=.021) and risperidone (p=.012)

Citrome L et al. Psychiatric Services 2001;52:15101514


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Overt Aggression and Psychotic Symptoms in Patients With Schizophrenia Treated With Clozapine, Olanzapine, Risperidone, or Haloperidol
14-week, double-blind trial in 157 treatment-resistant inpatients with at least 1 incident of overt aggression Atypical antipsychotics = superiority over haloperidol on Total Aggression Severity score (TAS): clozapine: p < 0.007 olanzapine: p < 0.036 risperidone: p < 0.046 Onset of action and a greater effect in delaying the occurrence of overt aggression vs. haloperidol: olanzapine (P < 0.012) risperidone (P < 0.016) clozapine (P < 0.065)
Volavka J et al. J Clin Psychopharmacol 2004;24:225 228
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Antipsychotic Agents in the Treatment of Violent Patients With Schizophrenia

MOAS: Modified Overt Aggression Scale. The odds ratio represents the odds of a lower MOAS score (one point) during the study period for the first as compared with the second medication in the pair for each type of aggressive behavior. Results remain significant after correcting for multiple testing (Bonferroni correction).
Krakowski MI et al. Arch Gen Psychiatry. 2006;63:622-629
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Adjunctive Divalproex and Hostility Among Patients With Schizophrenia Receiving Olanzapine or Risperidone

TREATMENT OF AGGRESSION IN MOOD DISORDERS

Effect sizes for improvement were calculated by dividing the treatment difference for mean change from baseline by the pooled standard deviation and were: Day 3 = .10 and .42 for monotherapy and combination treatment, respectively Day 7 = .29 and .56, for monotherapy and combination treatment, respectively
Citrome L et al. Psychiatric Services 2004;55:290294
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Emergency Treatment Of Manic Agitation in Patients Treated With Lithium

Ziprasidone IM Mean BARS Scores After First Injection in Acute Mania


10-mg Study
Time Post First Injection (h)
0 0 15 min 1 2 0 IM 2-mg control (n=11) -0.5 -0.5 IM 20-mg (n=15) 0

20-mg Study
Time Post First Injection (h)
30 min 1 2

BARS LS Mean Change

Improvement

-1.0

-1.0

-1.5

-1.5 * p=0.005 p<0.001 p=0.002

-2.0

IM 2-mg control (n=15) IM 10-mg (n=20)

-2.0

* *

-2.5

-2.5

Time to response: Haloperidol 5 mg = 5.0 +/- .82 days; Lorazepam 0.5-2 mg = 6.5 +/- .93 days
Lenox RH et al. J Clin Psychiatry 1992;53:47-52
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-3.0

-3.0

Behavioral Activity Rating Scale (BARS)


Daniel DG, et al. Presented at the APA Meeting May 2004; NYC
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Aripiprazole IM Mean PANSS-EC Scores After First Injection in Acute Mania


0 Mean Change in PEC Score
Mean Change in PANSS-EC (OC)

Olanzapine IM in the Control of Agitation in Bipolar Mania After First Injection


Time (min) 0 0 -2 Improvement -4 -6 -8 * -10 -12
*p<.01 vs lorazepam IM and placebo IM
Meehan KM, et al. J Clin Psychopharmacol. 2001;21(4):389-397.
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-2 -4 -6 -8 -10 0 15 30 45 60 75 90 105 120


* * * *

30

60

90

120

Placebo 10 mg ARI 15 mg ARI 2 mg LOR

Placebo IM (n=50)

Lorazepam IM 2 mg (n=51)

Olanzapine IM 10 mg (n=98)

Time After First Dose (min)


*p0.05 vs. placebo for all active groups (45,60,90,120 min.)
Zimbroff DL et al. J Clin Psychopharmacol 2007;27:171-176

PANSS-EC is Positive and Negative Syndrome Scale. PANSS-EC is designed to assess agitation. OC is Observed Case.

Treatment Of Agitation And Aggression In Bipolar Mania: Efficacy Of Oral Quetiapine (4 DB Studies)

Quetiapine versus Divalproex for the Treatment of Impulsivity and Reactive Aggression in Adolescents with Co-Occurring Bipolar Disorder and Disruptive Behavior Disorder(s)
DIV (n = 16) QUE (n = 17) Age (mean SD) 15.4 1.1 15.1 1.8 CD 6 (38) ODD 11 (69) ADHD 5 (31)

7 (41) 13 (77) 6 (35)

+ Li/DVP + Li/DVP

p<0.0001 vs baseline Both groups; p=0.28 DIV vs. QUE Sedation (or fatigue) was experienced by 6 subjects in the divalproex group and 14 subjects in the quetiapine group (p = 0.013).

Combined data from 4 double-blind, randomized, controlled trials. PANSS Supplemental Aggression Risk subscale scores among patients receiving quetiapine or placebo for 12 weeks (left figure) or quetiapine or placebo plus Li/DVP (right figure)
Buckley PF et al. J Affect Disord 2007;100:S33S43
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Barzman DH et al. J Child Adolesc Psychopharmacol 2006;16:665670


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Pharmacotherapy for the Treatment of Aggressive Behavior: Personality Disorders


Fluoxetine (40-60 mg/day): effective in 1/2 controlled trials1,2 Olanzapine and OFC: superior to fluoxetine on Modified Overt Aggression Scale in 1 controlled trial2 OLZ > PLA in other 2 CTs3,4 Phenelzine: effective in 1 trial5 Aripiprazole: effective in 1 controlled trial6 Carbamazepine: effective in 2 small controlled trials7,8 Divalproex sodium: effective in 2 controlled trial9,10 Omega-3 fatty acids: violent offences in antisocials as supplement and aggression in borderline as monotherapy (1 g of E-EPA) in controlled trials11,12
1. Binks CA et al. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005653; 2. Zanarini MC et al. J Clin Psychiatry 2004;65:903-907; 3. Zanarini MC & Frankenburg FR. J Clin Psychiatry 2001;62:849-854; 4. Soler J et al. Am J Psychiatry 2005;162:1221-1224; 5. Soloff PH et al. Arch Gen Psychiatry 1993;50:377-385; 6. Nickel MK et al. Am J Psychiatry 2006; 163:833838; 7. Cowdry RW & Gardner DL. Arch Gen Psychiatry 1988;45:111-119; 8. Gardner DL & Cowdry RW. Am J Psychiatry 1986;143:519-522; 9. Frankenburg FR & Zanarini MC. J Clin Psychiatry 2002;63:442-446; 10. Hollander E et al. Neuropsychopharmacology (2003) 28, 11861197; 11.Gesch CB, et al. Br. J. Psychiatry 2002;181:2228; 12. Zanarini MC & Frankenburg FR. Am J Psychiatry 2003; 160:167169
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TREATMENT OF AGGRESSION IN PERSONALITY DISORDERS

Pharmacotherapy Against Core Traits Of Borderline Personality Disorder: Meta-analysis

Dialectical Behavior Therapy Plus Olanzapine for Borderline Personality Disorder (8 Weeks)

impulsivity and aggression

affective instability and anger

The dialectical behavior therapy format was adapted from the standard version; two of the four types of intervention were applied: skills training and phone calls. Mean olanzapine dose: 8.83 mg/day Olanzapine-treated patients experienced a significant weight gain, but there was no dosedependent relation. Increased levels of cholesterol were above normal reference intervals in three patients
Soler J et al. Am J Psychiatry 2005; 162:12211224
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affective instability and anger

Nose M et al. Int Clin Psychopharmacol 2006;21:345353

Aripiprazole in the Treatment of Patients With Borderline Personality Disorder

Divalproex in the Treatment of Impulsive Aggression in Cluster B Personality Disorders

Median change from baseline OAS-M Aggression

Median change from baseline OAS-M Irritability

The most common side effects of aripiprazole were headache, insomnia, nausea, numbness, constipation, and anxiety
Nickel MK et al. Am J Psychiatry 2006; 163:833838
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17% patients in the divalproex group prematurely discontinued because of an adverse event, as compared to 3% patients in the placebo group (p0.001): nausea, asthenia, increased appetite, depression, SGPT & SGOT increased, tremor, nervousness
Hollander E et al. Neuropsychopharmacology (2003) 28, 11861197
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Divalproex in the Treatment of Impulsive Aggression in Borderline Personality Disorder


Barratt Impulsiveness Scale
80 60 40 20 0 -20 -40 -60 0 1 2 3 4 5 6 7 8 9 10 11 12 Baseline impulsivity score 73 Placebo (n=32) Divalproex (n=18) Baseline impulsivity score >73 Placebo Divalproex 80 60 40 20 0 -20 -40 -60 0 1 2 3 4 5 6 7 8 9 10 11 12

Overt Aggression Scale (outpatients)


Baseline aggression score 34.7 Placebo Divalproex Baseline aggression score >34.7 Placebo Divalproex

TREATMENT OF AGGRESSION IN INTERMITTENT EXPLOSIVE DISORDER

Time (weeks)

Time (weeks)

When response was analyzed with baseline aggression score (34.7 versus >34.7) as a covariate, the drug-bysubgroup interaction approached the level of statistical significance (p<0.06)

AEs were not reported


Hollander E et al. Am J Psychiatry 2005; 162:621624
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Pharmacotherapy for the Treatment of Intermittent Explosive Disorder


There is a lack of controlled trials of agents for the treatment of patients with IED, but there is evidence that mood stabilisers, antipsychotics, -blockers, 2agonists, phenytoin and antidepressants may be useful1 Phenytoin: effective in 2 CTs (impulsive and premeditated aggression)2,3

TREATMENT OF AGGRESSION IN TRAUMATIC BRAIN INJURY

1. Olvera RL. CNS Drugs. 2002;16(8):517-26; 2. Barratt ES, et al. J Clin Psychopharmacol 1997;17:341349; 3. Stanford MS, et al. Psychiatry Res 2001;103:193203
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Pharmacotherapy for the Treatment of Aggressive Behavior: Traumatic Brain Injury


Propranolol (60-800 mg/day): somewhat effective in 2/2 controlled trials1 Pindolol: somewhat effective in 1 controlled trial1 Sertraline: not effective in 1 controlled trial2 Methylphenidate: effective in 1/2 controlled trials2,3

TREATMENT OF AGITATION & AGGRESSION IN DEMENTIA

1. Fleminger S, et al. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003299; 2. Mooney GF & Haas LJ. Arch Phys Med Rehabil 1993;74:153-160; 3. Lee H et al. Hum Psychopharmacol 2005;20:97-104
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Treatment Of Aggressive Behavior In Dementia


Risperidone: effective in 6 controlled trials1-6 Olanzapine: effective in 4 controlled trials (1 IM)6-9 Quetiapine & Aripiprazole: somewhat effective in 1 CT each one10,11 Typical antipsychotics: meta-analysis suggests very small effect size12 Citalopram (20 mg/day): effective in 3 controlled trials13-15 Carbamazepine: somewhat effective in 2 controlled trials16,17 Benzodiazepines: modest improvements; high risk of fractures18 Cholinergic agents: very modest improvements19

Risperidone in Aggressive Behavior: Change in BEHAVE-AD Total Score Over Time

1. DeDeyn PP et al. Neurology 1999;53:946-955; 2. Katz IR et al. J Clin Psychiatry 1999;60:107-115; 3. Brodaty H et al. J Clin Psychiatry 2003;64:134-143; 4. Chan WC, et al. Int J Geriatr Psychiatry 2001;16:11561162; 5. Suh GH, et al. Am J Geriatr Psychiatry 2004;12:509516; 6. Fontaine CS, et al. J Clin Psychiatry 2003;64:726730; 7. Street JS et al. Arch Gen Psychiatry 2000;57:968-976; 8. Meehan KM et al. Neuropsychopharmacology 2002;26:494-504; 9. De Deyn et al. Int J Geriatr Psychiatry 2004;19:115-126; 10. Zhong KX et al. Curr Alzheimer Res 2007;4:81-93; 11. Mintzer JE et al. Am J Geriatr Psychiatry 2007; 15:918-931; 12. Schneider LS et al. J Am Geriatr Soc 1990;38:553563; 13. Nythe Al, Gottfries CG. Br J Psychiatry 1990;157:894-901; 14. Pollock BG et al. Am J Psychiatry 2002;159:460-465; 15. Pollock BG et al. Am J Geriatr Psychiatry 2007; 15:942-952; 16. Olin JT, et al. Am J Geriatr Psychiatry 2001;9:400405; 17. Tariot PN, et al. Am J Psychiatry 1998;155:5461; 18. Herings RM et al. Arch Intern Med 1995; 155:1801-1807; 19. Rainer AV et al. Am Fam Physician 2006;73:647-52
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*p < 0.01 vs. placebo. BEHAVE-AD = Behavioral Pathology of Alzheimers Disease.


Brodaty et al. J Clin Psychiatry 2003;64:134143
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Risperidone in Aggressive Behavior: Change in BEHAVE-AD Total Score At 12 Weeks

A Pooled Analysis Including Three Randomized, Placebocontrolled Double-blind Trials With Risperidone (1)

*p=0.005; **p < 0.01 vs. placebo. BEHAVE-AD = Behavioral Pathology of Alzheimers Disease.
Katz IR, et al. J Clin Psychiatry 1999;60:107-115
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*p < 0.001 vs. placebo. Cohen-Mansfield Agitation Inventory


De Deyn et al. Clin Neurol Neurosurgery 2005;107:497508
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A Pooled Analysis Including Three Randomized, Placebocontrolled Double-blind Trials With Risperidone (2)

IM Olanzapine in Agitated Patients With Dementia - PANSS Excited Component Score


0 30 60 90
IM Olanzapine 2.5 (N=71) IM Olanzapine 5.0 (N=66) IM Lorazepam 1.0 (N=68) IM Placebo (N=36)

More patients discontinued due to AEs in the risperidonetreated group (17.2%) than in the placebo group (11.2%). AEs were more commonly observed risperidone EPS ( 2mg/day), mild somnolence and cerebrovascular adverse events (CAE)

0 -1 -2 -3 -4 -5 -6 -7 -8 -9 -10

120 Time (mins)

Diagnosis: Alzheimers disease, vascular dementia, or mixed dementia Age: 77.6 9.7 years (range: 54 97)

*p < 0.001 vs. placebo. BEHAVE-AD = Behavioral Pathology of Alzheimers Disease.


De Deyn et al. Clin Neurol Neurosurgery 2005;107:497508
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* p .05 for IM Olz 5.0 vs. placebo; p < 0.05 for IM Olz 2.5 vs. placebo; p < .05 for IM Lzp vs. placebo
Meehan KM et al. Neuropsychopharmacology 2002;26:494-504
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IM Olanzapine in Alzheimers Dementia. NPI/NH Agitation/Aggression Item Score


n: Baseline: 0 47 7.4 56 8.4 50 8.4 53 7.9

Star Trial: PANSS-EC: Mean Change from Baseline Quetiapine in Alzheimers Disease

Mean Change from Baseline (LOCF)

-1 -2 -3 -4 -5 Placebo Olz 5 mg Olz 10 mg Olz 15 mg

Improvement

*p<.05 vs. placebo

NPI/NH = Neuropsychiatric Inventory . Nursing Home (12-Items)


AEs were more commonly observed with olanzapine 5 & 10 mg/day: somnolence (25% & 35.8%) and gait disturbance (19.6% & 17.0%)
Street JS et al. Arch Gen Psychiatry 2000; 57:968-976
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ITT-LOCF; *p<0.05; **p<0.01 vs. placebo


Zhong KX et al. Curr Alzheimer Res 2007;4:81-93
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Aripiprazole for the Treatment of Institutionalized Patients With Alzheimer Dementia. Mean Change in CMAI
Weeks
Aripiprazole 10 mg/d (n=118), baseline = 54.2 Aripiprazole 5 mg/d (n=115), baseline = 58.7 Aripiprazole 2 mg/d (n=114), baseline = 57.4 Placebo (n=115), baseline = 55.6

Risk of Death With Atypical Antipsychotic Drug Treatment for Dementia

*p < 0.05 vs. placebo. CMAI = Cohen-Mansfield Agitation Inventory


Cerebrovascular adverse events were reported: aripiprazole 2 mg/day, N = 1; 5 mg/day, N = 2; 10 mg/day, N = 4; placebo, N = 0. Deaths: aripiprazole 2 mg/day, 3%; 5 mg/day, 2%; 10 mg/day, 7%; placebo, 3%
Mintzer JE et al. Am J Geriatr Psychiatry 2007; 15:918-931
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Exposure time to treatment for 4 risperidone and 3 olanzapine trials was obtained from data presented by the US Food and Drug Administration. Exposure time for 1 risperidone trial, 2 olanzapine trials, and 1 quetiapine trial was estimated from sample sizes, trial lengths, and dropout rates. Exposure time for aripiprazole was calculated from sample sizes and incidence and for 2 quetiapine trials.
Schneider et al. JAMA 2005;294:1934-1943
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Risk Of Death Associated With The Use Of Conventional Versus Atypical Antipsychotic Drugs Among Elderly Patients

2-Year Mortality Associated With The Use Of Antipsychotic Drugs Vs. No Treatment with APDs
60 50 40 32,1 30 20 10 0
Conclusion: Among these frail and very old patients with dementia (mean age: 86 years), neither the use of atypical antipsychotics nor the use of conventional neuroleptics increased mortality or hospital admissions. The use of restraints, however, doubled the risk of mortality

49,6 45,3

Atypical AP (n=28) Conventional AP (n=95) Non Users (n=128)

Wang PS et al. N Engl J Med 2005;353:2335-41


PFOL2007

Raivio MM, et al. Am J Geriatr Psychiatry 2007 In press


PFOL2007

Antipsychotic Medication Use for Alzheimer Disease: Benefit-Risk Balance


Psychosis and aggression in people with dementia is a serious problem and is difficult to treat. Antipsychotics are modestly effective when used judiciously and there are no demonstrated, effective pharmacologic alternatives1,2 For patients with severe BPSD such as psychosis, agitation, or aggression, for whom there are few options, atypical antipsychotics, particularly risperidone and olanzapine, should be considered3 conventional antipsychotic medications are at least as likely as atypical agents to increase the risk of death among elderly persons and that conventional drugs should not be used to replace atypical agents discontinued in response to the FDA warning4

Comparison of Citalopram, Perphenazine, and Placebo for the Acute Treatment of Behavioral Disturbances in Hospitalized, Demented Patients

a Significant difference within group between baseline and termination scores (Wilcoxon signed-rank test, p<0.05). b Significant difference between the citalopram and placebo groups (Kruskal-Wallis test, p<0.05). AEs were not reported

1. Schneider LS et al. Am J Geriatr Psychiatry 2006;14:191-210; 2. Schneider LS et al. N Engl J Med 2006; 355:1525-1538; 3. Aupperle P. Am J Alzheimers Dis Other Demen 2006; 21; 101; 4. Wang PS et al. N Engl J Med 2005;353:2335-41
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Pollock BG et al. Am J Psychiatry 2002; 159:460465


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Memantine + Placebo or Donepezil for the Acute Treatment of Behavioral Disturbances in Demented Patients

TREATMENT OF SUICIDAL BEHAVIOR

Cummings, J. L. et al. Neurology 2006;67:57-63


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Pearson Correlations Of Suicide Rates With Antidepressant Prescriptions In Canada (19812003)1

Treating Suicidality in Depressive Illness


Most studies of antidepressant efficacy in suicide prevention are retrospective and not designed with suicidality as the outcome of interest. A few prospective RCTs show a positive effect on suicidal ideation in major depression (Category A evidence, also in youths), but in cluster B and other disorders (obsessivecompulsive disorder [OCD], obesity, and bulimia) the results are inconsistent. The overall conclusion is that antidepressants may prevent suicide through their beneficial effect on depressive illness, but specific antisuicidality has yet to be demonstrated in prospective trials in adults. Lithium has been proposed as an independent antisuicidal drug on account of presynaptic serotonin-agonist and antiaggressivity effects that it can exert (Category C evidence). A new metaanalysis reports that lithium has antisuicidal efficacy in recurrent MDD similar to that in bipolar disorder (Category A).

NS = not significant Suicide rates are from data supplied by Statistics Canada. Antidepressant data are from information supplied by IMS Health Canada. Cohort study with a mean follow-up of 3.4 years with 15,390 people (49% male; mean age 39 years) hospitalised for suicide attempt:2 venlafaxine RR: 1.61 (1.01 - 2.57); fluoxetine RR: 0.52 (0.30 - 0.93) Among subjects who had ever used any antidepressant: increased risk of attempted suicide (39%, P<.001), but decreased risk of completed suicide (-32%, P=.002) and mortality (-49%, P<.001)
1. Sakinofsky I. Can J Psychiatry 2007;52[6 Suppl 1]:71S84S; 2. Tiihonen J et al. Arch Gen Psychiatry 2006;63:1358-1367
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Sakinofsky I. Can J Psychiatry 2007;52[6 Suppl 1]:85S102S; Steele MM & Doey T. Can J Psychiatry 2007:52[6 Suppl 1]:35S45S
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Odds Ratios by Age Group for Suicidal Behavior and Ideation (Psychiatric Indications). The FDA Data

Child And Adolescent MDD RCTs: Definitive Suicidal Behavior Or Ideation in FDA Meta Analysis. ACNP Task Force Report
Systematic questionnaire data do not identify a risk for more suicidal ideation on SSRIs, raising concerns over ascertainment artifacts in the AE report method. Epidemiology, autopsy studies, and recent cohort surveys do not support the hypothesis that SSRIs induce suicidal acts, instead indicating a possible beneficial effect.

FDA used fixed-effects models assuming that there is a common effect across all studies

Hammad TA et al. Arch Gen Psychiatry 2006;63:332-339; Levenson M & Holland C. FDA Division of Biometrics. Nov. 17, 2006
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Mann JJ et al. Neuropsychopharmacology 2006;31:473492


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Clinical Response and Risk for Reported Suicidal Behavior in Pediatric Antidepressant Treatment. A Meta-analysis of Randomized Controlled Trials
Twenty-seven trials of pediatric MDD (n=15), OCD (n=6), and non-OCD anxiety disorders (n=6). Pooled risk differences in rates of primary responder status and NNT: - MDD: 11.0% [7.1% - 14.9%] NNT: 10 (7 15) - OCD: 19.8% [13.0% - 26.6%] NNT: 6 (4 8) - non-OCD: 37.1% [22.5% - 51.7%] NNT: 3 (2 5) Risk difference of suicidal behavior across all indications: 0.7% (0.1% - 1.3%) NNH: 143 (77 - 1000). There were no completed suicides. Risk differences within each indication: MDD: 0.9% (0.1% - 1.9%); OCD: 0.5% (1.2% - 2.2%); non-OCD: 0.7% (0.4% - 1.8%) In summary, a favorable overall risk-to-benefit profile for antidepressants in the treatment of pediatric MDD, OCD, and non-OCD anxiety disorders was demonstrated.

Rates of Suicide Attempts Before and After Antidepressant Treatment


TCAs & trazodone

Bridge JA et al. JAMA. 2007;297:1683-1696


PFOL2007

Simon GE et al. Am J Psychiatry 2006;163:41-47


PFOL2007

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Effect of Regulatory Warnings on Antidepressant Prescribing for Children and Adolescents

Psychopharmacologic Management of Suicidality in Personality Disorders


Suicidal ideation is common in people with PDs, and among people who commit suicide, PDs are common. There is some evidence that SSRI antidepressants can be helpful in lessening symptoms of affective instability, anger, and impulsivity, although studies are inconsistent (Category B). There is evidence that combining pharmacotherapy with psychotherapy is more effective than pharmacotherapy alone in patients with MDD and comorbid PD (Category A). There is evidence from one RCT that trifluoperazine or carbamazepine or tranylcypromine may lower suicidality in patients with PDs (Category A). Olanzapine has been shown to be helpful in lowering anger or hostility and impulsive aggression, thought to be precursor correlates of suicidality in BPD (Category A). Topiramate, divalproex, and lamotrigine (Category A) may be helpful for symptoms considered to be correlates of impulsive suicidality in BPD, but direct suicidal behaviour has not been used as an outcome variable.

Kurian BT et al. Arch Pediatr Adolesc Med. 2007;161(7):690-696


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Cardish RJ. Can J Psychiatry 2007;52[6 Suppl 1]:115S127S


PFOL2007

Managing Suicidality in Schizophrenia1


The literature on the effects of first-generation antipsychotic drugs on suicidal behaviour has been inconsistent in determining whether these neuroleptics have had any impact on suicidality in schizophrenia. The advent of FGA medications has done little to decrease the suicide rate in schizophrenia (in the United States) from pre-neuroleptic times. Overall risk of suicidal behaviors with clozapine vs. other treatments RR: 3.3 (1.76.3). For completed suicides RR: 2.9 (1.55.7).2 The InterSePT study is the only prospective, randomized, large-scale study that sought to explore the effect of antipsychotic drugs on suicidal behaviour. Compared with olanzapine, treatment with clozapine reduced serious suicide attempts and hospitalizations to prevent suicide by 25%.

Managing Suicidality in Bipolar Disorder


Data from a retrospective chart review of 405 veterans with bipolar disorder followed for a mean of 3 years. Non-lethal suicide event rates were 9.4 times greater (p<.0001) during antipsychotic monotherapy (FGA & SGA) and 3.5 times greater during mood stabilizer+antipsychotic (p=0.0001) than during mood stabilizer monotherapy.1 Suicidal behavior event rates (per 100 patient years) were greatest during treatment with antidepressant monotherapy (25.92), intermediate during MS + AD combination treatment (9.75), and least during MS monotherapy (3.48). These differences were statistically significant.2 31 studies suitable for meta-analysis (n= 85,229 person-years of riskexposure). Lithium-treated subjects vs. those not treated with lithium RR = 4.91 (3.82-6.31). The incidence-ratio of attempts-to-suicides increased 2.5 times with lithium-treatment, indicating reduced lethality of suicidal acts.3
1. Yerevanian BI et al. J Affect Disord 2007;103:23-28; 2. Yerevanian BI et al. J Affect Disord 2007;103:13-21; 3. Baldessarini RJ et al. Bipolar Disord 2006;8:625-639
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1. Mamo DC. Can J Psychiatry 2007;52[6 Suppl 1]:59S70S; 2. Hennen J & Baldessarini RJ. Schizophr Res 2005;73:139-145

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