kleggette pharmacotherapy rounds handout -...

Violence and Hostility in Schizophrenia: A Danger to Society?

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Kasey R. Leggette, PharmD

PGY-‐2 Psychiatric Pharmacy Resident The University of Texas at Austin College of Pharmacy

Austin, Texas

October 18, 2013

Learning Objectives • Review the epidemiology, pathophysiology, and treatment of schizophrenia • Describe the risk factors, incidence, and pathophysiology of violence in patients with

schizophrenia • Evaluate the literature for evidence of effective treatments of violence and hostility • Formulate evidence-‐based conclusions regarding the selection of treatment

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Schizophrenia (SCZ)

I. Epidemiology1,2,3 a. Prevalence: <1% internationally b. Incidence: 15.9 per 100,000 people c. Diagnosed more often in men than women (1.4:1)

i. Men more likely to be diagnosed between the ages of 16 and 25 years ii. Age of onset in women is bimodal, with a peak in the early 20s and in the

30’s – 40’s d. Genetics: 30-‐40% concordance with monozygotic twins

II. Diagnostic and Statistical Manual (DSM) Diagnostic Criteria4,5

a. Schizophrenia: DSM-‐IV-‐TR and DSM-‐5 diagnostic criteria are largely the same, with DSM-‐5 eliminating subtypes and increasing the number of symptoms required

b. Schizoaffective Disorder: DSM-‐IV-‐TR and DSM-‐5 diagnostic criteria are largely the same Table 1: DSM-‐IV-‐TR Diagnostic Criteria4,5 Schizophrenia Schizoaffective Disorder • One or more (two or more in DSM-‐5) of the following,

present for a significant portion of time during a 1-‐month period

o Delusions o Hallucinations o Disorganized speech o Disorganized or catatonic behavior o Negative symptoms: flat affect, alogia, avolition

• Social/occupational dysfunction • Duration of signs/symptoms persist for at least 6 months • Schizoaffective disorder and mood disorder with

psychotic features have been ruled out • Symptoms not attributable to substance use or other

general medical conditions

• A major depressive episode, a manic episode, or a mixed episode concurrent with symptoms of SCZ

• Delusions/hallucinations should also be present for at least 2 weeks in the absence of the mood symptoms

• Symptoms of mood episode are present for a substantial period (in DSM-‐5, “majority”) of the illness

• Symptoms not due to substance use or other general medical conditions

III. Pathophysiology6

a. Dopamine i. Increase in mesolimbic dopamine activity ii. Decrease in mesocortical dopamine activity iii. Dopamine Pathways7

1. Mesolimbic pathway: Positive symptoms 2. Mesocortical pathway: Negative symptoms 3. Nigrostriatal pathway: Extrapyramidal symptoms (EPS) and tardive

dyskinesia (TD) b. Serotonin (5-‐HT)

i. Exerts an inhibitory effect on dopamine (involving 5-‐HT1A, 5-‐HT2A, and D2 receptors)

ii. A reduction of serotonin in SCZ will lead to disinhibition of mesolimbic dopamine neurons and may lead to an increase in positive symptoms

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IV. Treatment: Antipsychotic Therapy a. Typical Antipsychotics: Dopamine antagonists to target positive symptoms b. Atypical Antipsychotics : Multiple receptors to target positive and negative symptoms

Table 2: Antipsychotic Receptor Binding Affinity Expressed as Equilibrium Constant (Ki)8 Antipsychotic D2 5-‐HT2A H1 M1

Typical Antipsychotics (First Generation) Haloperidol 2.6 61 260 >10,000 Perphenazine 1.4 5 8 >1,000 Atypical Antipsychotics (Second Generation) Clozapine 210 2.6 3.1 1.4 Olanzapine 20 1.5 0.1 2.5 Quetiapine 770 31 11 120 Risperidone 3.8 0.15 5.2 >10,000 Ziprasidone 2.6 0.1 4.6 300 Increased Ki indicates reduced affinity *partial agonist

Aggressive Behaviors

I. Definitions9 a. Aggression: A heterogeneous behavior linked to violence, impulsivity, irritability, and

hostility b. Violence: Physical attacks on other people, self, or objects c. Impulsivity: Acting without control or premeditation d. Agitation: Hostile or violent behavior or attitudes; readiness to attack or confront e. Hostility: Unfriendly or threatening behavior or feelings

II. Violence in the Healthcare Setting

a. The healthcare setting represents nearly half of all workplace violence incidents (highest frequency in emergency department)10

b. 4-‐8% of patients presenting to psychiatric emergency departments are armed11 c. Up to 17% of patients presenting to a university emergency department who were

searched were found to be carrying weapons12

III. Risk Factors9,13 a. Psychiatric conditions: SCZ, bipolar disorder, dementia, personality disorders (especially

borderline or antisocial personality disorders), posttraumatic stress disorder, traumatic brain injury, pervasive developmental disorders

b. Comorbid alcohol/substance use disorders c. Positive symptoms of SCZ (bizarre behavior, distressing delusions, command

hallucinations to harm others)

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IV. Aggressive Behaviors in SCZ a. Mixed data regarding the risk of violence in SCZ, with some studies suggesting no

increased risk14 and other studies suggesting up to a seven-‐fold increased risk15,16 b. Meta-‐analysis of twenty trials evaluating risk of violent outcomes in SCZ and other

psychosis found13: i. Increased rate of violence in patients with SCZ or other psychosis (9.9%,

n=18,423) vs. general population comparator (1.6%, n=1,714,904) ii. Four-‐fold increased risk of violence if substance use disorder comorbidity

present, but this was not statistically different than the risk of violence in individuals with substance use disorders without a psychotic disorder

iii. Increased rate of homicide in patients with SCZ or other psychosis (0.3%) or substance use disorder (0.3%) vs. general population (0.02%)

V. Pathophysiology of Aggression17 a. Brain regions

i. Amygdala: Main aggression center ii. Prefrontal cortex: Regulates amygdala effects on aggression iii. Hypothalamus: Main behavior center

Image from: http://its.sdsu.edu/multimedia/mathison/limbic/

b. Neurotransmitter systems i. Serotonin (specifically 5-‐HT2): Facilitates prefrontal cortex modulation and

suppression of aggressive and impulsive behaviors ii. Dopamine: Involved in initiation/action of aggression iii. Acetylcholine and glutamate/ ϒ-‐Aminobutyric Acid (GABA): Imbalances may

lead to hyperactivity in subcortical limbic regions causing irritability

VI. Pharmacologic Treatment of Acute Aggression18 a. Benzodiazepines (may be administered intramuscularly) b. Antipsychotics (may be administered intramuscularly)

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VII. Pharmacologic Treatment of Persistent Aggression a. Clozapine: Historical evidence supports anti-‐aggressive effect

i. Decreased number of violent episodes19 1. 1995 study on first 100 patients receiving clozapine in an Oregon

state hospital 2. Number of violence incidents decreased from >120/month at the time

of clozapine initiation to <30/month six months after initiation ii. Decreased incidence of seclusion and restraint20

1. 1995 study on 30 patients receiving clozapine in an Ohio state facility 2. Mean time spent in seclusion and restraint decreased from 100 hours

(range 14-‐401) in the six months preceding clozapine therapy to 37.9 hours in the first six months of clozapine therapy

3. Improvement in Brief Psychiatric Rating Scale (BPRS) was not statistically significantly different from the patients without aggression

b. Treatment Guideline Recommendations: More emphasis is placed on treatment of acute agitation/violence

Table 3: Summary of Recommendations from Treatment Guidelines Treatment Guideline Psychiatric Feature Recommendations American Psychiatric Association (APA) Schizophrenia Guidelines21

Persistent Violence • Antipsychotics, with good evidence for use of clozapine

• Other agents: mood stabilizers, selective serotonin reuptake inhibitors, benzodiazepines, beta-‐adrenergic blocking agents; but empirical evidence is lacking

Texas Medication Algorithm Project (TMAP) Schizophrenia Treatment Algorithms22,23

Aggression/ Hostility

• Adjunctive agents: carbamazepine, valproic acid, lithium, oxcarbazepine

• If no improvement after 1-‐3 weeks, discontinue mood stabilizer and consider clozapine

The Schizophrenia Patient Outcomes Research Team (PORT) Treatment Recommendations24,25

Persistent Hostility and/or Violence

• Trial with clozapine

VIII. Assessment Rating Scales: see Appendix A

a. Brief Psychiatric Rating Scale (BPRS)26 b. The Modified Overt Aggression Scale (MOAS)27,28 c. Positive and Negative Syndrome Scale (PANSS)29 d. Extrapyramidal Symptom Rating Scale (ESRS)30 e. Nurses Observation Scale for Inpatient Evaluation (NOSIE)31

f. Clinical Global Impressions (CGI) scale32 g. Barratt Impulsiveness Scale (BIS)33 h. Buss-‐Durkee Hostility Inventory (BDHI)34

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Clinical Trials

Atypical Antipsychotic Agents in the Treatment of Violent Patients With Schizophrenia and Schizoaffective Disorder35

Krakowski MI, Czobor P, Citrome L, et al. Archives of General Psychiatry. 2006;63:622-‐629. Design 12 week, randomized, double-‐blind clinical trial Objective To compare the efficacy of clozapine, olanzapine, and haloperidol in the treatment of

aggressive behaviors in physically assaultive patients with SCZ and schizoaffective disorder

Inclusion Criteria

• Age 18 to 60 years • Hospitalized patients diagnosed with SCZ or schizoaffective disorder (using DSM-‐

IV diagnostic criteria) • A confirmed episode of physical assault directed at another person during

hospitalization, identified by research staff monitoring subjects and daily ward documentation, and confirmed by interview with nursing staff

• Evidence of persistence of aggression Exclusion Criteria

• Hospitalized for greater than one year • Administration of a depot antipsychotic injection within 30 days prior to

randomization • History of non-‐response to clozapine, olanzapine, or haloperidol, defined as a lack

of improvement despite adequate trial • History of intolerance to any of the study drugs • Presence of medical conditions that would be adversely affected by any of the

study interventions Intervention • Patients were transferred to the research ward and retrospective information was

collected on any aggressive incidents in the four weeks prior to the qualifying incident

• Baseline screening period (1-‐2 weeks): Pre-‐study antipsychotic dose was adjusted to not exceed 750 mg/day in chlorpromazine equivalents

• Escalation period (6 weeks): Pre-‐study antipsychotic was gradually discontinued; patients were randomly assigned to one of three treatment arms and titrated up to target daily doses (olanzapine 20mg, clozapine 500mg, haloperidol 20mg); mood stabilizers, other than antipsychotics, and antidepressants were continued

• Variable-‐dose period (6 weeks): Blinded psychiatrists could adjust daily doses by choosing different treatment levels (olanzapine 10-‐35mg, clozapine 200-‐800mg, haloperidol 10-‐30mg)

• Side effect/symptom management: Benztropine (all patients in haloperidol group received 4mg daily, other treatment groups received placebo); lorazepam, diphenhydramine, or chloral hydrate were prescribed open-‐label as needed for treatment of restlessness, agitation, and insomnia

• Assessment: Nursing staff monitored for and reported aggression on 30-‐60 minute intervals; raters blinded to treatment group used MOAS to rate incidents; clinical symptoms were assessed by the PANSS at baseline, week 6, and week 12

• Monitoring: At baseline and at regular intervals, all patients received an electrocardiogram (ECG) and physical examination; weekly, white blood cell counts were completed and adverse reactions were assessed using ESRS

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Krakowski, et al. 2006 continued Endpoints • Primary endpoints: MOAS total score and score on physical aggression subscale

• Secondary endpoint: PANSS score Statistical Analysis

• Intent to treat analysis • Generalized linear model analysis

Results Baseline characteristics: n=110 Table 4: Baseline Characteristics

Characteristics Clozapine (n=37)

Olanzapine (n=37)

Haloperidol (n=36) P Value

Male, # (%) 31 (83.8) 29 (78.4) 30 (83.3) 0.8 Race/ethnicity, # (%) White 7 (18.9) 5 (13.5) 7 (19.4) 0.47 Black 20 (54.1) 28 (75.7) 21 (58.3) Duration of illness, mean ± SD, years 15.7 ± 9.5 16.8 ± 11.2 13.9 ± 11.2 0.56

Prior psychiatric hospitalizations, mean ± SD

12.3 ± 9.8 11.4 ± 9.6 8.9 ± 4.7 0.18

PANSS, mean ± SD Positive subscale 22.9 ± 5.4 22.9 ± 5.7 23 ± 6.4 0.99 Negative subscale 20.3 ± 4.5 18.9 ± 3.4 19.8 ± 4.7 0.34 General subscale 43.2 ± 7.2 41.9 ± 7.4 42.6 ± 6.6 0.73 Total 86.4 ± 14.4 83.7 ± 14.1 85.5 ± 13.2 0.7

• No significant difference in length of hospitalization (median of 48 days upon entry in study), proportion of subjects receiving typical or atypical antipsychotics prior to randomization, proportion receiving other psychotropic medications, baseline PANSS scores, or demographic characteristics

• No difference in the total number of aggressive incidents (physical, verbal, or against property) in the four week period preceding the qualifying physical assault

Primary endpoints Table 5: Modified Overt Aggression Scale Scores

MOAS Clozapine Olanzapine Haloperidol Total Score Mean 25.1 32.7 40.9

Median 18 29 25 IQR* 6-‐34 6-‐51 3-‐48

Physical aggression Mean 10.3 14.1 20.7 Median 4 12 6 IQR* 0-‐16 0-‐20 0-‐20

Against property Mean 2.6 2.7 4.7 Median 0 0 0 IQR* 0-‐2 0-‐4 0-‐6

Verbal aggression Mean 12.2 16 15.6 Median 9 22 7.5 IQR* 2-‐15 4-‐23 2-‐25

*IQR: interquartile range

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Krakowski, et al. 2006 continued Results continued

• Clozapine was superior to haloperidol in all measures (P<0.001) • Clozapine was superior to olanzapine in all measures (P<0.001) except aggression

against property (P=0.78) • Olanzapine was superior to haloperidol in all measures (P<0.001) except verbal

aggression (P=0.57) Secondary endpoint • There were no statistically significant differences in change in symptom severity,

as measured by PANSS, from baseline to endpoint • After removal of hostility item from PANSS, results remained the same

Attrition

• No significant difference in median time of survival in study • Mean survival time (weeks): 9.2 for clozapine, 7.8 for olanzapine, 8.3 for

haloperidol Table 6: Reasons for Discontinuation Clozapine Olanzapine Haloperidol Clinical deterioration 2 2 7 Adverse effects 3 1 4 Withdrew consent 6 4 4 Other 2 4 1

Author’s Conclusion

Clozapine shows greater efficacy than olanzapine and olanzapine greater efficacy than haloperidol in reducing aggressive behavior. This antiaggressive affect appears to be separate from the antipsychotic and sedative action of these medications.

Comments and Conclusions

Strengths • Widely used scales and assessments were utilized • Patients were in a uniform environment throughout the trial • Designed to evaluate aggression as an endpoint

Limitations • No comparison between violence in the four weeks prior to randomization with

the measure of violence during the trial • Did not provide detailed information regarding pre-‐study antipsychotic

treatment • Did not report adverse effects (sedation, EPS)

Conclusions • Clozapine does appear to have greater anti-‐aggressive effects than olanzapine,

and olanzapine appears to have greater anti-‐aggressive effects than haloperidol • This anti-‐aggressive affect appears to be separate from improvement in

symptoms because there were no differences in improvement in PANSS between the groups

• It is unclear whether or not sedation played a role because adverse effect data was not presented in this article

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Effects of Clozapine, Olanzapine, Risperidone, and Haloperidol on Hostility Among Patients With Schizophrenia36

Citrome L, Volavka J, Czobor P, et al. Psychiatric Services. 2001;52(11):1510-‐1514. Design 14 week, prospective, double-‐blind trial Objective To compare antiaggressive effects of clozapine with olanzapine, risperidone, and

haloperidol Inclusion Criteria

• Aged 18 to 60 years • Hospitalized at one of four state psychiatric hospitals (two in New York, two in

North Carolina) • Diagnosed with SCZ or schizoaffective disorder (using diagnostic criteria from the

DSM-‐IV) • Minimum score of 60 on the PANSS • History of suboptimal treatment response (must meet both of the following

criteria): Persistent positive symptoms despite an adequate trial, poor level of social functioning over the previous two years

Exclusion Criteria

• History of non-‐response to clozapine, risperidone, or olanzapine despite an adequate trial

• History of intolerance to any of the study drugs • Administration of a depot antipsychotic injection within 30 days prior to

randomization Intervention • Prior to initiation, concomitant psychiatric medications (mood stabilizers,

antidepressants) were gradually discontinued • Period 1 (8 weeks): Pre-‐study antipsychotic was gradually discontinued; patients

were randomized to receive one of four treatment arms and doses were titrated to target doses (olanzapine 20mg, risperidone 8mg, and haloperidol 20mg over one week; clozapine 500mg over 24 days) as tolerated

• Period 2 (6 weeks): Blinded psychiatrists could adjust daily doses based on PANSS scores (clozapine 200-‐800mg, olanzapine 10-‐40mg, risperidone 4-‐16mg, haloperidol 10-‐30mg)

• Side effect/symptom management: Benztropine (all patients in haloperidol group received 2mg twice daily, other treatment groups received placebo); propranolol, lorazepam, diphenhydramine, chloral hydrate

• Assessment: Blinded raters administered PANSS weekly for the first four weeks and then every other week; NOSIE and ESRS rating scales also used

Endpoints • Primary endpoint: Hostility item from the PANSS • Secondary endpoints: Sum of PANSS positive psychotic symptoms (excluding

excitement and hostility) and unusual thought content, and the NOSIE measure of sedation

Statistical Analysis

• Hierarchical linear model analysis • Nonparametric survival analysis with Kaplan-‐Meier estimates was used to detect

difference in time to attrition

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Citrome, et al. 2001 continued Results Baseline characteristics: n=157

• No difference in baseline PANSS hostility item scores or other demographic variables (specific demographics of the treatment groups were not reported)

Table 7: Baseline Characteristics of Patients in Medication Phase Male, # (%) 133 (85) Age, mean ± SD, years 40 ± 9.2 Duration of illness, mean ± SD, years 19.5 ± 8.4 Hospitalizations, # ± SD 10.5 ± 8.3 Race/Ethnicity, # (%) African American 87 (55) White 48 (31) Hispanic 18 (12) Other 4 (3)

Table 8: Daily Dose Ranges Achieved During Periods 1 and 2 (mg/day) Period Clozapine Olanzapine Risperidone Haloperidol

1 241.2 – 562 17.5 – 21.7 5.8 – 10 15.8 – 22 2 386.3 – 666.9 23.8 – 37 8.4 – 14.8 20 – 31.4

Primary endpoint

Table 9: Hostility Item of PANSS Scores

Antipsychotic Baseline 14 weeks

Change Mean SD Mean SD

Clozapine (n=40) 2.68 1.58 2.24 1.34 -‐0.44 Olanzapine (n=39) 2.35 1.47 2.24 1.73 -‐0.11 Risperidone (n=41) 2.40 1.19 2.49 1.61 +0.09 Haloperidol (n=37) 2.42 1.26 2.95 1.51 +0.53 • Reduction in hostility was significant for clozapine only (P=0.019) • Clozapine had a significantly greater effect on reducing aggression than

haloperidol (P=0.021) or risperidone (P=0.012) Secondary endpoint: Results were unchanged after controlling for covariates Attrition • 91 (58%) completed the 14 week study; 133 (85%) completed at least four weeks • Seven patients withdrew secondary to hematological concerns/seizures; 17

withdrew for other reasons (administrative, concurrent medical illnesses, protocol violations)

Table 10: Reasons for Discontinuation Clozapine Olanzapine Risperidone Haloperidol Withdrawal of consent 5 4 8 5 Clinical deterioration 2 4 2 6 Discharged 1 1 3 1

Adverse effects • No differences in use of medications for side effect management

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Citrome, et al. 2001 continued Author’s Conclusion

Clozapine has a modest advantage over olanzapine, risperidone, and haloperidol in reducing hostility, and this anti-‐hostility effect appears to be independent of effects on other symptoms of psychosis and sedation


Strengths • Widely used scale (PANSS) was utilized • Designed to evaluate hostility as an endpoint

Limitations • Baseline PANSS hostility scores were low and patients were not selected based

on history of aggression/hostility • Only one outcome measure was used and did not use a tool specifically designed

to evaluate aggression/hostility • Concomitant psychotropic medications were discontinued, possibly confounding

the results; baseline psychotropic medications were not reported

Conclusions • Because this study recruited patients based on treatment resistance, it appeared

to have been biased towards clozapine • Average baseline PANSS scores for all treatment groups were all below ‘mild’,

leaving minimal room for improvement

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Risperidone alone versus risperidone plus valproate in the treatment of patients with schizophrenia

and hostility37 Citrome L, Shope CB, Nolan KA, et al. International Clinical Psychopharmacology. 2007;22:356-‐362.

Design Eight week, open label, randomized, parallel group, single blind clinical trial Objective To compare the antiaggressive efficacy of risperidone monotherapy with risperidone

plus valproate in patients with SCZ Inclusion Criteria

• Patients with diagnosis of SCZ referred by the treating psychiatrist due to problems with poor impulse control, aggressive behavior, and/or hostility

• Initial 15 months of study: Patients must have had at least two aggressive incidents during the two weeks prior to their transfer to the research unit and then continued to exhibit aggression during the first two weeks after transfer (aggression defined as at least two aggressive incidents or a score of four or more on the PANSS Hostility item or Poor Impulse Control item)

• Inclusion criteria revision: Because only 16 patients entered the protocol and eight were randomized, the inclusion criteria was revised to include patients who scored at least a three on at least one of the PANSS items that comprise the activation factor (Hostility, Impulsivity, Excitement, or Uncooperativeness)

Exclusion Criteria

• Patients receiving both valproate (at least 1,000mg/day or plasma level of at least 50µg/ml for at least two weeks) and risperidone

Intervention • Randomized to either risperidone monotherapy (target daily dose 4-‐6mg/day, titrated over 7-‐14 days based on clinical effect and tolerance) or combination treatment with risperidone and valproate (target steady state plasma valproate level of 50-‐100 µg/ml) for eight weeks

• No other antipsychotics or mood stabilizers were permitted • Side effect/symptom management: Benztropine or lorazepam were prescribed as

needed; in weeks 4-‐8, administration of four or more doses of lorazepam in any one week was considered treatment failure

• Monitoring: Valproate plasma level every two weeks; physical exam and ECG at study entry and endpoint; vital signs weekly; complete blood count, liver function tests, serum prolactin throughout

• Assessment: Study participants and treating psychiatrists/other staff were not blinded, but blinded raters administered the PANSS, CGI, and NOSIE at study entry, randomization, week four, and end-‐point; BIS and BDHI (added when entry criteria was adjusted) were administered weekly; OAS was completed for each incident; ESRS was administered at baseline, week four, and endpoint

Endpoints • PANSS, PANSS Hostility item, NOSIE, BIS, BDHI • Change in severity of aggression as measured by OAS

Statistical Analysis

• Hierarchical linear modeling analyses with repeated measures to test the effect of time and interaction between time and treatments

• Effects: Group (treatment groups) and Pathway (presence or absence of valproate at study entry)

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Citrome, et al. 2007 continued Results Baseline characteristics: n=8 prior to change in inclusion criteria, total n=33

Table 11: Baseline Characteristics

Characteristic Risperidone monotherapy (n=16)

Risperidone and valproate (n=17)

Male, n (%) 15 (93.8) 16 (94.1) Race, n (%) White 0 1 (5.9) Black 13 (81.3) 12 (70.6) Hispanic 3 (18.8) 4 (23.5) Age (years), mean ±SD 41.1 ± 12.3 38.1 ± 8.3 Number of psychiatric hospitalizations, mean ± SD 14.3 ± 7.3 17.8 ± 10.8

Antipsychotic medications immediately prior to study entry (n)

haloperidol (6) olanzapine (7) quetiapine (5) risperidone (2)

chlorpromazine (2) fluphenazine (3)

clozapine (1)

haloperidol (9) olanzapine (7) quetiapine (5) risperidone (1)

chlorpromazine (0) fluphenazine (7)

clozapine (2) PANSS total score, mean 85.9 83.3 PANSS Hostility item, mean 3.13 3.06 BIS total score, mean 73.1 (n=12) 67.3 (n=11) BDHI total score, mean 33.7 (n=11) 33.4 (n=12) CGI total score, mean 5.13 5 NOSIE total score, mean 37.2 35.2 ESRS total score, mean 5.13 6

Endpoints • No significant differences in PANSS, PANSS Hostility item, BDHI, or BIS between

the two groups • No significant differences between completers and noncompleters at baseline,

but completers had significantly lower average OAS total scores Attrition • Significantly fewer patients in the risperidone monotherapy group completed the

study (P=0.003) • More patients withdrew from monotherapy group due to lack of efficacy • Of the patients that were not receiving valproate at baseline that were

randomized to combination therapy, none withdrew due to lack of efficacy • Of the patients that were receiving valproate at baseline, switching to

monotherapy did not cause increased withdrawals due to lack of efficacy

Adverse effects • Number of adverse events reported was greater in the combination treatment

group, specifically increased gastrointestinal related events and weight gain

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Citrome, et al. 2007 continued Author’s Conclusion

Patients receiving combination therapy were more likely to complete the study, but there was no advantage for combination therapy in terms of improvement in the endpoint measures.


Strengths • Reported pre-‐study treatment regimens • Reported adverse effects/tolerance • Incorporated several widely used assessment tools

Limitations • Limited power to detect a difference due to small sample size • Inclusion criteria adjusted during trial • Did not provide raw data, only statistical analyses • Did not compare OAS severity scores between treatment groups, only between

completers vs. noncompleters • Treating psychiatrist/team were not blinded

Conclusions • Despite additional incidences of adverse effects in the combination therapy

treatment group, patients receiving both agents were significantly more likely to complete the study

• Patients that completed the study had significantly lower average OAS scores, but there appeared to be no significant difference in outcomes of the major assessment tools between the two groups

• Overall, there does not appear to be an advantage by adding valproate

Post-‐Hoc Analyses

I. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Trial38,39 a. Original CATIE Trial

i. Prospective, double-‐blind, randomized trial designed to evaluate the effectiveness of antipsychotic medications

ii. Patients were randomized to receive either olanzapine (7.5-‐30mg), quetiapine (200-‐800mg), risperidone (1.5-‐6mg), or perphenazine (8-‐32mg)

b. 1445 patients with baseline violence data available were included in a post-‐hoc analysis of phase 1 (first 6 months) findings, examined rates of violence

c. Results i. Intention to treat sample: Treatment groups did not differ significantly ii. Retained sample: Perphenazine showed a greater reduction in violence risk than

quetiapine (no difference in other treatment groups) d. Conclusion and Comments

i. No advantage for second generation antipsychotics in violence risk reduction ii. Strengths: Large-‐scale randomized pivotal CATIE trial iii. Limitations: Post-‐hoc analysis, only rates of violence were examined as opposed

to measures of severity

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II. European First Episode Schizophrenia Trial (EUFEST) Trial40,41

a. Original EUFEST Trial i. Prospective, open, randomized trial conducted across 14 countries designed to

evaluate effectiveness of antipsychotic medications in first episode SCZ ii. Patients were randomized to receive either haloperidol (1-‐4mg/day),

amisulpride (200-‐800mg/day), olanzapine (5-‐20mg/day), quetiapine (200-‐750mg/day), or ziprasidone (40-‐160mg/day)

b. 302 patients with baseline hostility were included in a post-‐hoc analysis of the change in hostility item of PANSS

c. Results i. Month 1: Olanzapine superior to haloperidol (P=0.0006), quetiapine (P=0.0017),

and amisulpride (P=0.0056) ii. Month 3: Olanzapine superior to haloperidol (P=0.0005), quetiapine (P=0.0009),

and amisulpride (P=0.0011) iii. Month 6: No longer statistically significant difference in improvement;

olanzapine was only nominally superior to other treatment options iv. Months 9, 12: No statistically significant difference v. Overall change: Olanzapine favored over haloperidol and amisulpride; but not

statistically significant after correction for multiple comparisons d. Conclusions and Comments

i. All agents reduced hostility, but olanzapine appeared to have superior effects in the first three months of treatment; in all treatment arms, hostility levels were reduced to ‘minimal’ hostility by month three

ii. Strengths: Large-‐scale randomized pivotal EUFEST trial iii. Limitations: Post-‐hoc analysis, measures of hostility were not available

Conclusions

• Of the antipsychotics, clozapine appears to have the most evidence for treatment of aggression in schizophrenia and schizoaffective disorder

• Because of the extensive monitoring required and potential for severe adverse effects with clozapine, it should not necessarily be recommended as first line treatment in patients with chronic aggression

• Although the data is mixed, there does appear to be evidence supporting the use of olanzapine • Adjunctive valproate use could be considered for chronic aggression in schizophrenia; however,

larger studies are needed to validate efficacy • Given the frequency and social impact of violence in schizophrenia, more prospective trials

designed to evaluate treatment of violence/aggression are necessary

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References

1. McGrath J, Saha S, Chant D, et al. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiologic Reviews. 2008:30:67-‐76.

2. Sham PC, MacLean CF, Kendler KS, et al. A typological model of schizophrenia based on age at onset, sex, and familial morbidity. Acta Psychiatrica Scandinavica. 1994;89:135-‐141.

3. Kringlen E. Twin studies in schizophrenia with special emphasis on concordance figures. American Journal of Medical Genetics. 2000;97(1):4-‐11.

4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC. American Psychiatric Association; 2000.

5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing; 2013.

6. Lyne J, Kelly BD, O’Connor WT. Schizophrenia: a review of neuropharmacology. Irish Journal of Medical Science. 2004;173(3):155-‐159.

7. Chinta SJ, Anderse JK. Dopaminergic neurons. The International Journal of Biochemistry and Cell Biology. 2005;37:942-‐946.

8. Correll C. Switching and Combining Antipsychotics. CNS Spectrums. 2010;15(4) Suppl 6:8-‐11. 9. Comai S, Tau M, Gobbi G. The Psychopharmacology of Aggressive Behavior: A Translational Approach. Part 1:

Neurobiology. Journal of Clinical Psychopharmacology. 2012;32:83-‐94. 10. Kowalenko T, Hauff S, Smith B. Development of a Data Collection Instrument for Violent Patient Encounters against

Healthcare Workers. Western Journal of Emergency Medicine. 2012;13(5):429-‐433. 11. McNiel DE, Binder RL. Patients who bring weapons to the psychiatric emergency room. Journal of Clinical Psychiatry.

1987;48(6):230-‐233. 12. Goetz R, Bloom J, Chenell S, et al. Weapons Possession by Patients in a University Emergency Department. Annals of

Emergency Medicine. 1991;20:8-‐10. 13. Fazel S, Gulati G, Linsell L, et al. Schizophrenia and Violence: Systematic Review and Meta-‐Analysis. Public Library of

Science Medicine. 2009;6(8):e1000120. 14. Steadman H, Mulvey E, Monahan J, et al. Violence by people discharged from acute psychiatric inpatient facilities and

by others in the same neighborhoods. Archives of General Psychiatry. 1998;55:393-‐401. 15. Tiihonen J, Isohanni M, Rasanen P, et al. Specific major mental disorders and criminality: a 26-‐year prospective study

of the 1966 Northern Finland birth cohort. American Journal of Psychiatry. 1997;154:840-‐845. 16. Mullen P, Burgess P, Wallace C, et al. Community care and criminal offending in schizophrenia. Lancet. 2000;355:614-‐

617. 17. Siever L. Neurobiology of Aggression and Violence. American Journal of Psychiatry. 2008;165:429-‐442. 18. Battaglia J. Pharmacologic Management of Acute Agitation. Drugs. 2005;65(9):1207-‐1222. 19. Wilson WH, Claussen AM. 18-‐Month Outcome of Clozapine Treatment for 100 Patients in a State Psychiatric Hospital.

Psychiatric Services. 1995;46(4):386-‐389. 20. Buckley P, Bartell J, Donenwirth K, et al. Violence and Schizophrenia: Clozapine as a Specific Antiaggressive Agent. Bull

American Academy of Psychiatry Law. 1995;23(4):607-‐611. 21. AmericanPsychiatricAssociation.PracticeGuidelinesfortheTreatmentofPatientswithSchizophrenia,

SecondEdition.AmericanJournal ofPsychiatry.2004;(Aprilsuppl):1-‐114. 22. Moore TA, Buchanan RW, Buckley PF, et al. The Texas Medication Algorithm Project Antipsychotic Algorithm for

Schizophrenia: 2006 Update. Journal of Clinical Psychiatry. 2007;68(11):1751-‐1762. 23. Miller AL, Chiles JA, Chiles JK, et al. The Texas Medication Algorithm Project (TMAP) schizophrenia algorithms. Journal

of Clinical Psychiatry. 1999;60(10):649-‐657. 24. Lehman AF, Kreyenbuhl J, Buchanan RW, et al. The Schizophrenia Patient Outcomes Research Team (PORT): Updated

Treatment Recommendations 2003. Schizophrenia Bulletin. 2004; 30: 193-‐217. 25. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 Schizophrenia PORT Psychopharmacological Treatment

Recommendations and Summary Statements. Schizophrenia Bulletin. 2010;36(1):71-‐93. 26. Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychological Reports. 1962;10:799-‐812. 27. Yudofsky SC, Silver JM, Jackson W, et al. Overt Aggression Scale for the Objective Rating of Verbal and Physical

Aggression. American Journal of Psychiatry. 1986;143:35-‐39. 28. Knoedler DW. The Modified Overt Aggression Scale. Am J Psychiatry 1989;/146(8):/1081-‐1082. 29. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia

Bulletin. 1987;13(2):261-‐276. 30. Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophrenia Research.

2005;76(2):247-‐265.

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31. Honigfeld G, Gillis RD, Klett CJ. Nurses’ observation scale for inpatient evaluation: a new scale for measuring improvement in chronic schizophrenia. Journal of Clinical Psychology. 1965;21:65-‐71.

32. Leon AC, Shear MK, Klerman GL, et al. A comparison of symptom determinants of patient and clinician global ratings in patients with panic disorder and depression. Journal of Clinical Psychopharmacology. 1993;13(5):327-‐331.

33. Patton, Stanford, Barratt. Factor structure of the Barratt impulsiveness scale. Journal of Clinical Psychiatry. 1995;51(6):768-‐774.

34. Buss AH, Durkee A. An Inventory for assessing different kinds of hostility. Journal of Consult Psychology. 1957;21:343-‐349.

35. Krakowski MI, Czobor P, Citrome L, et al. Atypical Antipsychotic Agents in the Treatment of Violent Patients with Schizophrenia and Schizoaffective Disorder. Archives of General Psychiatry. 2006;63:622-‐629.

36. Citrome L, Volavka J, Czobor P, et al. Effects of Clozapine, Olanzapine, Risperidone, and Haloperidol on Hostility Among Patients with Schizophrenia. Psychiatric Services. 2001;52(11):1510-‐1514.

37. Citrome L, Shope CB, Nolan KA, et al. Risperidone alone versus risperidone plus valproate in the treatment of patients with schizophrenia and hostility. International Clinical Psychopharmacology. 2007;22:356-‐362.

38. Swanson JW, Swartz MS, Van Dorn RA, et al. Comparison of antipsychotic medication effects on reducing violence in people with schizophrenia. The British Journal of Psychiatry. 2008;193:37-‐43.

39. Lieberman JA, Stroup S, McEvoy JP, et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. The New England Journal of Medicine. 2005;353(12):1209-‐1223.

40. Volavka J, Czobor P, Derks E, et al. Efficacy of Antipsychotics Against Hostility in the European First-‐Episode Schizophrenia Trial (EUFEST). Journal of Clinical Psychiatry. 2011;72(7):955-‐961.

41. Boter H, Peuskens J, Libiger, J, et al. Effectiveness of antipsychotics in first-‐episode schizophrenia and schizophreniform disorder on response and remission: An open randomized clinical trial (EUFEST). Schizophrenia Research. 2009;115:97-‐103.

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Appendices Appendix A Assessment Rating Scales Rating Scale Description Brief Psychiatric Rating Scale (BPRS)26

• Eighteen items on 7-‐point scale (higher ratings indicate greater severity) to assess a variety of symptoms of psychotic disorders, especially SCZ

The Modified Overt Aggression Scale (MOAS)27,28

• Assessment of verbal aggression, aggression against property, towards self, and physical aggression

• Physical aggression score is weighted the most in the total score; verbal aggression score is weighted the least

• Used to track changes in level of aggression over time Positive and Negative Syndrome Scale (PANSS)29

• Thirty items on 7-‐point scale (higher ratings indicate greater severity) that assess positive symptoms, negative symptoms, and general psychopathology of SCZ

• Hostility item: within the positive symptom assessment can be used to measure hostility and aggression, score interpretations below

Extrapyramidal Symptom Rating Scale (ESRS)30

• Twelve items • Measures extrapyramidal symptoms (pseudoparkinsonism, akathisia,

dystonia, dyskinesia) Nurses Observation Scale for Inpatient Evaluation (NOSIE)31

• Thirty items on a 4 point scale • Nurse evaluation of behavior over the previous three days

Clinical Global Impressions (CGI) scale32

• Three items on a 7-‐point scale • Measures severity, global improvement, and therapeutic response

Barratt Impulsiveness Scale (BIS)33

• Eleven items on a 4 point scale • Most widely cited instrument for assessment of impulsiveness

Buss-‐Durkee Hostility Inventory (BDHI)34

• Seventy-‐five true-‐false items • Measures difference in hostility and guilt

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Appendix B: Hostility Item of PANSS29

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Appendix C27,28

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