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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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*p<0.05
*
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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Risperidone for the Treatment of Disruptive Behaviors in Children With Subaverage Intelligence
0.020.06 mg/kg per day
*
*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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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
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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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)
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.
* 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)
*ADHD = 69%
Teacher N= 71 35 36 74
Parent 37 37
Classroom 47 24 23
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 < < < <
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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
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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*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
* *
*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
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
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)
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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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
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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20-mg Study
Time Post First Injection (h)
30 min 1 2
Improvement
-1.0
-1.0
-1.5
-2.0
-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
30
60
90
120
Placebo IM (n=50)
Lorazepam IM 2 mg (n=51)
Olanzapine IM 10 mg (n=98)
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)
+ 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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Dialectical Behavior Therapy Plus Olanzapine for Borderline Personality Disorder (8 Weeks)
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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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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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)
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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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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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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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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A Pooled Analysis Including Three Randomized, Placebocontrolled Double-blind Trials With Risperidone (2)
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
Diagnosis: Alzheimers disease, vascular dementia, or mixed dementia Age: 77.6 9.7 years (range: 54 97)
* 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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Star Trial: PANSS-EC: Mean Change from Baseline Quetiapine in Alzheimers Disease
Improvement
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
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
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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Memantine + Placebo or Donepezil for the Acute Treatment of Behavioral Disturbances in Demented Patients
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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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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.
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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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