Violence and Hostility in Schizophrenia: A Danger to Society?

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1 Violence and Hostility in Schizophrenia: A Danger to Society? Image from: danger- background.jpg 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

2 Schizophrenia (SCZ) I. Epidemiology 1,2,3 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 Criteria 4,5 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 Criteria 4,5 Schizophrenia 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 Schizoaffective Disorder 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. Pathophysiology 6 a. Dopamine i. Increase in mesolimbic dopamine activity ii. Decrease in mesocortical dopamine activity iii. Dopamine Pathways 7 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- HT 1A, 5- HT 2A, and D 2 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 Leggette 2

3 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 D 2 5- HT 2A H 1 M 1 Typical Antipsychotics (First Generation) Haloperidol >10,000 Perphenazine >1,000 Atypical Antipsychotics (Second Generation) Clozapine Olanzapine Quetiapine Risperidone >10,000 Ziprasidone Increased Ki indicates reduced affinity *partial agonist Aggressive Behaviors I. Definitions 9 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 armed 11 c. Up to 17% of patients presenting to a university emergency department who were searched were found to be carrying weapons 12 III. Risk Factors 9,13 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) Leggette 3

4 IV. Aggressive Behaviors in SCZ a. Mixed data regarding the risk of violence in SCZ, with some studies suggesting no increased risk 14 and other studies suggesting up to a seven- fold increased risk 15,16 b. Meta- analysis of twenty trials evaluating risk of violent outcomes in SCZ and other psychosis found 13 : 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 Aggression 17 a. Brain regions i. Amygdala: Main aggression center ii. Prefrontal cortex: Regulates amygdala effects on aggression iii. Hypothalamus: Main behavior center Image from: b. Neurotransmitter systems i. Serotonin (specifically 5- HT 2 ): 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 Aggression 18 a. Benzodiazepines (may be administered intramuscularly) b. Antipsychotics (may be administered intramuscularly) Leggette 4

5 VII. Pharmacologic Treatment of Persistent Aggression a. Clozapine: Historical evidence supports anti- aggressive effect i. Decreased number of violent episodes 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 restraint study on 30 patients receiving clozapine in an Ohio state facility 2. Mean time spent in seclusion and restraint decreased from 100 hours (range ) 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 Persistent Violence Antipsychotics, with good evidence (APA) Schizophrenia Guidelines 21 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 Algorithms 22,23 The Schizophrenia Patient Outcomes Research Team (PORT) Treatment Recommendations 24,25 Aggression/ Hostility Persistent Hostility and/or Violence Adjunctive agents: carbamazepine, valproic acid, lithium, oxcarbazepine If no improvement after 1-3 weeks, discontinue mood stabilizer and consider clozapine 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) scale 32 g. Barratt Impulsiveness Scale (BIS) 33 h. Buss- Durkee Hostility Inventory (BDHI) 34 Leggette 5

6 Clinical Trials Atypical Antipsychotic Agents in the Treatment of Violent Patients With Schizophrenia and Schizoaffective Disorder 35 Krakowski MI, Czobor P, Citrome L, et al. Archives of General Psychiatry. 2006;63: 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 Exclusion 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 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 mg, 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 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 Leggette 6

7 Krakowski, et al 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 Olanzapine Haloperidol (n=37) (n=37) (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) Black 20 (54.1) 28 (75.7) 21 (58.3) 0.47 Duration of illness, mean ± SD, years 15.7 ± ± ± Prior psychiatric hospitalizations, mean 12.3 ± ± ± ± SD PANSS, mean ± SD Positive subscale 22.9 ± ± ± Negative subscale 20.3 ± ± ± General subscale 43.2 ± ± ± Total 86.4 ± ± ± 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 Median IQR* Physical aggression Mean Median IQR* Against property Mean Median IQR* Verbal aggression Mean Median IQR* *IQR: interquartile range Leggette 7

8 Krakowski, et al continued Results Clozapine was superior to haloperidol in all measures (P<0.001) continued 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 Author s Conclusion Comments and Conclusions 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 Adverse effects Withdrew consent Other 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. 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 Leggette 8

9 Effects of Clozapine, Olanzapine, Risperidone, and Haloperidol on Hostility Among Patients With Schizophrenia 36 Citrome L, Volavka J, Czobor P, et al. Psychiatric Services. 2001;52(11): Design 14 week, prospective, double- blind trial Objective To compare antiaggressive effects of clozapine with olanzapine, risperidone, and haloperidol Inclusion Criteria Exclusion 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 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 mg, 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 Leggette 9

10 Citrome, et al 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 Primary endpoint Table 9: Hostility Item of PANSS Scores Antipsychotic Baseline 14 weeks Mean SD Mean SD Change Clozapine (n=40) Olanzapine (n=39) Risperidone (n=41) Haloperidol (n=37) 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 Clinical deterioration Discharged Adverse effects No differences in use of medications for side effect management Leggette 10

11 Citrome, et al continued Author s Clozapine has a modest advantage over olanzapine, risperidone, and haloperidol in Conclusion reducing hostility, and this anti- hostility effect appears to be independent of effects on other symptoms of psychosis and sedation Comments and Conclusions 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 Leggette 11

12 Risperidone alone versus risperidone plus valproate in the treatment of patients with schizophrenia and hostility 37 Citrome L, Shope CB, Nolan KA, et al. International Clinical Psychopharmacology. 2007;22: 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) Patients receiving both valproate (at least 1,000mg/day or plasma level of at least 50µg/ml for at least two weeks) and risperidone Exclusion Criteria 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 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) Leggette 12

13 Citrome, et al continued Results Baseline characteristics: n=8 prior to change in inclusion criteria, total n=33 Table 11: Baseline Characteristics Characteristic Risperidone Risperidone and monotherapy (n=16) 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 ± ± 8.3 Number of psychiatric hospitalizations, mean ± SD 14.3 ± ± 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 PANSS Hostility item, mean 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 NOSIE total score, mean ESRS total score, mean 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 Leggette 13

14 Citrome, et al continued Author s Patients receiving combination therapy were more likely to complete the study, but Conclusion there was no advantage for combination therapy in terms of improvement in the endpoint measures. Comments and Conclusions 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) Trial 38,39 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 ( mg), risperidone (1.5-6mg), or perphenazine (8-32mg) b 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 Leggette 14

15 II. European First Episode Schizophrenia Trial (EUFEST) Trial 40,41 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 ( mg/day), olanzapine (5-20mg/day), quetiapine ( mg/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 Leggette 15

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18 Appendices Appendix A Assessment Rating Scales Rating Scale Brief Psychiatric Rating Scale (BPRS) 26 The Modified Overt Aggression Scale (MOAS) 27,28 Positive and Negative Syndrome Scale (PANSS) 29 Extrapyramidal Symptom Rating Scale (ESRS) 30 Nurses Observation Scale for Inpatient Evaluation (NOSIE) 31 Clinical Global Impressions (CGI) scale 32 Barratt Impulsiveness Scale (BIS) 33 Buss- Durkee Hostility Inventory (BDHI) 34 Description Eighteen items on 7- point scale (higher ratings indicate greater severity) to assess a variety of symptoms of psychotic disorders, especially SCZ 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 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 Twelve items Measures extrapyramidal symptoms (pseudoparkinsonism, akathisia, dystonia, dyskinesia) Thirty items on a 4 point scale Nurse evaluation of behavior over the previous three days Three items on a 7- point scale Measures severity, global improvement, and therapeutic response Eleven items on a 4 point scale Most widely cited instrument for assessment of impulsiveness Seventy- five true- false items Measures difference in hostility and guilt Leggette 18

19 Appendix B: Hostility Item of PANSS 29 Leggette 19

20 Appendix C 27,28 Leggette 20