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Hindawi Publishing Corporation Advances in Psychiatry Volume 2014, Article ID 196281, 20 pages http://dx.doi.org/10.1155/2014/196281 Review Article Jan Volavka New York University School of Medicine, P.O. Box 160663, Big Sky, MT 59716, USA Correspondence should be addressed to Jan Volavka; email@example.com Received 25 November 2013; Revised 16 December 2013; Accepted 18 December 2013; Published 12 February 2014 Academic Editor: Jane E. Boydell Copyright © 2014 Jan Volavka. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Most individuals diagnosed with a mental illness are not violent, but some mentally ill patients commit violent acts. PubMed database was searched for articles published between 1980 and November 2013 using the combination of key words “schizophrenia” or “bipolar disorder” with “aggression” or “violence.” In comparison with the general population, there is approximately a twofold increase of risk of violence in schizophrenia without substance abuse comorbidity and ninefold with such comorbidity. eTh risk in bipolar disorder is at least as high as in schizophrenia. Most of the violence in bipolar disorder occurs during the manic phase. Violence among adults with schizophrenia may follow two distinct pathways: one associated with antisocial conduct and another associated with the acute psychopathology, particularly anger and delusions. Clozapine is the most effective treatment of aggressive behavior in schizophrenia. Emerging evidence suggests that olanzapine may be the second most eeff ctive treatment. Treatment nonadherence greatly increases the risk of violent behavior, and poor insight as well as hostility is associated with nonadherence. Nonpharmacological methods of treatment of aggression in schizophrenia and bipolar disorder are increasingly important. Cognitive behavioral approaches appear to be eeff ctive in cases where pharmacotherapy alone is not sufficient. 1. Introduction deal with assaultive patients in the community, and the enor- mous stress imposed on the jails and prisons where many Many people believe that psychiatric patients are dangerous, assaultive psychiatric patients are incarcerated. andfearofviolenceisthe most importantpartofthe stigma This review will examine the epidemiology, underlying of mental illness. This belief persists despite the fact that most mechanisms and pathways to violence, and the management psychiatric patients are in fact not violent and that they are of aggression in schizophrenia and bipolar disorder. much more likely to be victims rather than perpetrators of aggressive behavior. 2. Methods Although the public fear of patients is overblown, there is a general consensus among experts that severe mental illness PubMed database was searched for articles published does increase the risk of violence. Indeed, violent behavior of between 1980 and November 2012. For the general searches the mentally ill presents a multitude of problems. er Th e is the on aggression in psychoses, the combinations of key words risk of injuries or death of victims and perpetrators. Caring “schizophrenia” or “bipolar disorder” with “aggression” or for violent psychiatric patients challenges the clinician. It elic- “violence” were used. For the treatment searches, generic its fear, countertransference problems, and eventual burnout. names of medications were used in combination with key It complicates the efforts of all caregivers. Caring for a violent words “schizophrenia” or “bipolar disorder” and “aggression.” relative is emotionally exhausting; it is obviously very difficult No language constraint was applied. Only articles dealing to live with an assaultive patient. with adults were included. eTh lists of references were Importantly, violence affects the cost of treatment. Today, searched manually to find additional articles. violent behavior is a leading cause of hospitalization, which Additionally, the review draws on the author’s own exp- may be prolonged if that behavior persists. Staff time is costly, erimental and other studies in the area of violence in psy- and violent patients require a lot of it. Finally, there are choses over the past 30 years. Published and unpublished societal costs such as the time spent by the police that have to materials were included. 2 Advances in Psychiatry Change of odds of serious violence as a function of hostility 3. Definitions and Assessment Methods 0.6 Many definitions of aggression have been oer ff ed [ 1]. The most 0.5 useful and parsimonious (albeit imperfect) definition states that aggression is overt action intended to harm. This term may describe animal or human behavior. Human aggression 0.4 can be assessed quantitatively with various rating scales designed for this purpose. The overt aggression scale (OAS) 0.3  and its modification (modified overt aggression scale (MOAS)) [3, 4] have been frequently used to separately assess 0.2 verbal aggression and physical aggression against objects, against self, and against others. Aggression against self is 0.1 outside the scope of this review and it will not be discussed here. eTh term aggression is typically used in biomedical and 0.0 psychological literature. Aggressive behavior has been classified into various sub- 1 23456 7 groups. A useful classification defines two subtypes: impul- PANSS hostility rating sive or premeditated aggression. Impulsive aggression is a Base rate = 1.6% hair-trigger aggressive response to environmental provoca- Base rate = 3.6% tion, characterized by a loss of behavioral control. This is in Base rate = 5.6% contrast with premeditated aggression which is defined as a planned aggressive act that lacks spontaneity and behavioral Figure 1: Change of odds of serious violence as a function of agitation. hostility. The computation and display were provided by Pal Czobor, This discussion leads us back to the definition of aggres- PhD, using the data published by Swanson et al. . sion stated above: “an overt action intended to harm.” Without the intent, the definition would make no sense: any uninten- tional error resulting in an injury to another person would be misclassied fi as aggression. But some cases of impulsive aggression represent a response to provocation that comes or incoherent screams. Agitation may be assessed using the so fast that we mayhavesomedoubtsabout theassailant’s excited component of the positive and negative syndrome ability to fully form an intent in a fraction of a second. Even scale (PANSS) . The excited component consists of five more seriously, that ability may be impaired or lost in cases PANSS items: tension, excitement, hostility, uncooperative- of intoxication. eTh ability to form an intent is in doubt in ness, and poor impulse control; each item is rated from 1 psychotic or demented persons. To make things even more (absent) to 7 (extreme). difficult, we do not fully understand the term “intent.” us, Th Hostility signifies unfriendly attitudes. Manifestations of the den fi ition of aggression offered here is imperfect. But so hostility include overt irritability, anger, resentment, or verbal are all the other definitions that have been published. We aggression. Hostility is assessed and operationally defined have to keep these imperfections in mind when using the by rating scales. eTh most frequently used method to assess definition of aggression. A more extensive discussion of these hostility is the “hostility” item in the PANSS orin issues canbefound elsewhere. the brief psychiatric rating scale (BPRS) . The principal Violence is defined as physical aggression among humans. clinical importance of hostility is in its close association with This term tends to be more commonly used in sociology violence. Hostility item in the PANSS is rated from 1 (absent) and criminology (e.g., violent crime). Some authors use the to 7 (extreme). For each unit increase on this 7-point rating terms violence and aggression interchangeably, depending on of hostility, the odds of serious aggression (assessed with context and style. MacArthur community violence interview) were reported to Violence perpetrated by psychiatric patients in the com- increase by a factor of 1.65 (𝑃<0.001 )(see Figure 1). munity can be assessed (and defined) by the MacArthur The association of hostility rating with overt physical community violence interview that distinguishes two levels aggression has led to its widespread use as a proxy measure of severity: minor violence, corresponding to simple assault of violence. Hostility is also associated with nonadherence to without injury or weapon use, and serious violence, corre- medication  and difficulties in psychological treatments. sponding to any assault using a lethal weapon or resulting in Hostility interferes with therapeutic alliance. injury, any threat with a lethal weapon in hand, or any sexual Psychopathy is currently defined by assessment instru- assault [5–8]. ments developed by Hare and his group. eTh psychopathy The US Bureau of Justice Statistics’s definition of violent checklist-revised (PCL-R) isa20-iteminstrument. Each crime includes murder, rape and sexual assault, robbery, and item is scored on a three-point scale (0 = does not apply, 1 = assault (http://www.bjs.gov/index.cfm?ty=tp&tid=31 access- applies to an extent, and 2 = applies). Items are summed, the ed 11 20 2013). total score range is 0–40. PCL-R can be used as a dimensional Agitation is excessive motor and/or verbal activity. It instrument (employing the total score) or as a categorical may include verbal aggression manifested by threats, abuse, classifier using a cut-off score. eTh recommended cut-off Change of odds of serious violence Advances in Psychiatry 3 score is 30 , but sometimes lower cut-off scores are used diagnosed with schizophrenia and 2.1% in those without . any mental disorder [18, 19]. Males were more violent than females. Comorbid substance abuse substantially increased Psychopathy Checklist. Screening version (PCL : SV) was the prevalence of violent behavior in schizophrenia. developed as a shorter variant of PCL-R, suitable for adminis- A longitudinal study assessed the population rates of vio- tration to individuals with major psychiatric disorders . It lence in schizophrenia linking nationwide Swedish registry has 12 items that are scored in the same way as the PCL-R. The data of hospital admissions for schizophrenia and data on cri- total score range is 0–24. eTh cut-off score for the diagnosis minal convictions between 1973 and 2006 . The study of psychopathy is 18. Analyses of the PCL : SV (and PCL-R) comprised a total of 80,025 individuals, 8,003 of whom were yielded two factors: factor 1 reflects personal and aeff ctive diagnosed with schizophrenia. In this schizophrenia subset, characteristics. Some of these items, such as lack of remorse 13.2% of individuals had a record of at least one violent crim- and empathy, cannot be reliably distinguished from blunted inal oen ff se, compared with 5.3% of individuals in general aeff ct in persons with schizophrenia. Factor 2 comprises population (odds ratio (OR) = 2.0, 95% confidence interval behaviors manifesting continued socially deviant, unstable (CI) = 1.8–2.2). The risk of violence was particularly ele- lifestyle and thus may be indexing the same syndrome as vated in individuals with schizophrenia and comorbid sub- diagnoses of conduct disorder and antisocial personality dis- stance abuse: in individuals without substance abuse, OR = order. Much of the research work on comorbidity of psy- 1.2 (95% CI = 1.1–1.4), whereas with substance abuse OR = 4.4 chopathy with schizophrenia used the PCL : SV. (95% CI = 3.9–5.0) . It should be noted that the antisocial personality disorder To study familial confounding, Fazel et al. also investi- in theDSM-IV-TR andthe DSM-5 is partly defined by gated risk of violence among unaeff cted siblings ( 𝑛=8123 ) acts of violence, but the diagnosis can be given in the absence of patients with schizophrenia. The risk increase among the of aggressive behavior. patients with substance abuse comorbidity was significantly eTh American Psychiatric Association Board of Trustees less pronounced when unaeff cted siblings were used as con- recognized the numerous shortcomings of the current DSM- trols (28.3% of those with schizophrenia had a violent offense 5 system for the classicfi ation of personality disorders. Nev- compared with 17.9% of their unaffected siblings; adjusted OR ertheless, the decision was to preserve the current system to = 1.8; 95% CI = 1.4–2.4;𝑃<.001 for interaction), suggesting maintain continuity with clinical practice. At the same time, significant familial confounding of the association between an alternative DSM-5 model for personality disorders was schizophrenia and violence . eTh se results are further developed and presented [15,page761]. Forthe Antisocial discussed in a subsequent section on genetic influences. Personality Disorder, the alternative system introduces “psy- A meta-analysis of 20 studies comparing risk of violence chopathic features” as a diagnostic specifier, and “psychopa- in schizophrenia and other psychosis with general population thy” is introduced as a “distinct variant.” eTh main new alter- controls  confirmed and expanded the results reviewed native criteria for antisocial personality disorder are some- above . The meta-analysis comprised data from 18,423 what closer to Hare’s concept of psychopathy in that they pay individuals diagnosed with schizophrenia that were com- more attention to personality functioning than the current pared with 1,714,904 individuals in general population. er Th e system. was a modest but statistically significant increase of risk These modifications introduced in the alternative model of violence in schizophrenia (OR = 2.1, 95% CI = 1.7–2.7) represent partial improvements in comparison with the without comorbidity and OR = 8.9 (95% CI = 5.4–14.7) current system. Hopefully, work on these modica fi tions will with substance abuse comorbidity. Risk estimate of violence continue, and DSM-6 will switch from the current model to in individuals with substance abuse (but without psychosis) a new system for the diagnosis of personality disorders. showed an OR of 7.4 (95% CI = 4.3–1) . The national epidemiologic survey on alcohol and related conditions (NESARC) was a two-wave project conducted in 4. Schizophrenia the United States (𝑁 = 34,653: Wave 1: 2001–2003; Wave 2: 4.1.Prevalence of ViolentBehaviorinSchizophrenia. The 2004-2005). Indicators of mental illness in the year prior to National Institute of Mental Health (NIMH) supported the Wave 1 were used to predict violence between Waves 1 and 2. Violence was assessed by self-report in a structured epidemiological catchment area surveys (ECA), an epidemi- ological study that provided prevalence estimates for mental interview. Contrary to prior published evidence, severe men- disorders in the United States [16, 17]. The data were based on tal illness did not independently predict violent behavior. structured diagnostic household interviews conducted at five Comorbid substance use disorder was one of the independent sites in the United States. It should be noted that this classical predictors. study had different sampling and time frames than most other We reanalyzed the same NESARC data using different studies. It included prisoners and it was conducted in the methods . Contrary to the results reported by Elbogen early 1980s before deinstitutionalization was fully completed and Johnson , we found that individuals with severe men- tal illness with or without comorbid substance abuse were and when antipsychotic medications differed from those used today. signicfi antly more likely to be violent than those with no The surveys included questions pertaining to any history mental or substance use disorders. As expected, those with comorbid mental and substance use disorders had the highest of violent behavior. Analyses of these data yielded a one- year prevalence of violent behavior of 8.4% in persons risk of violence. Male gender, history of childhood abuse and 4 Advances in Psychiatry neglect, household antisocial behavior, binge drinking, and (convicted or exculpated) in Austria  detected that 4.3% stressful life events were also associated with violence . male and 13.5% female oeff nders had schizophrenia. Comor- The epidemiological studies reviewed above used samples bid substance abuse/dependence was diagnosed in 46.3% of that aimed to represent populations. Other studies, however, the male (39% alcohol and 24.4% nonalcohol) and 11.8% of used samples that were selected clinically; that is, they the female schizophrenics (5.9% alcohol and 11.8% nonalco- selected individuals who were ascertained to be diagnosed hol). A comparison of risk for schizophrenia or schizophreni- with schizophrenia. form disorder in oender ff s with the general population in The MacArthur violence risk assessment study enrolled Austriashowedage-adjustedORs in men5.85, 95%CI= 1136 patients with mental disorders at three acute inpatient 4.3–8.0; in women OR = 18.4, 95% CI = 11.2–31.6 . For facilities in the United States and followed them up during males and females combined, the proportion of oeff nders their rfi st year aeft r discharge from the hospital to monitor with schizophrenia or schizophreniform disorder (with or their violent behavior . eTh comparison group consisted withoutalcohol useorabuse comorbidity) was5.3%,OR= of 519 people residing in the same neighborhoods. A special 8.8, 95% CI = 6.6–11.5. For those without that comorbidity, assessment tool, the MacArthur community violence inter- the respective numbers were 3.8%, OR = 7.1, 95% CI = 5.1– view,was developedfor this project(seeabove). eTh inter- 9.8. eTh numbers for subjects with alcohol comorbidity were view was conducted with the subjects and collateral infor- substantially higher. mants. The one-year prevalence of violence was 17.9% for Psychiatric diagnoses of 2005 individuals convicted of patients with a major mental disorder and without a sub- homicide or attempted homicide in Sweden were analyzed stance abuse diagnosis and 31.1% for patients with a major . It was found that 8.9% of homicide oender ff s had mental disorder and a substance abuse diagnosis. The results schizophrenia, 2.5% had bipolar disorder, and 6.5% had other showed no significant difference between the prevalence of psychoses. It should be noted that 47.5% of oender ff s with violence by patients without substance abuse and the preva- complete information had a primary or secondary diagnosis lence of violence by comparison group members who were of substance use disorder. A meta-analysis of 10 studies also without substance abuse. Substance abuse raised the rate indicated that the risk of homicide in psychosis is maximal of violence in both groups. eTh methods and interpretation during the rfi st episode before the start of treatment [ 29]. of this influential study raised certain concerns [ 24]. u Th s, schizophrenia may be associated with a somewhat The NIMH supported clinical antipsychotic trials of inter- higher risk for homicide than for less serious violent behavior. vention eeff ctiveness (CATIE) [ 25]enrolledanationalsample However, caution is required when comparing the homicide of 1,445 schizophrenia patients from 57 United States sites. studies with the other studies of violence risk in mental Information on violent behavior during the 6 months prior illness. It should be noted that, except for Schanda et al. , to enrollment was collected using a version of the MacArthur the homicide studies do not present separate estimates of the Community Violence Interview (see above). eTh results risk for homicide in schizophrenia without substance abuse showed that 4% had committed serious acts of violence comorbidity. That comorbidity is high in homicide oender ff s involving weapons or causing injury to another individual, and may be responsible for a substantial proportion of risk and16% hadengaged in less seriousactsthatwould be variance. er Th e may be a gender difference in the risk for described as simple battery, such as slapping, pushing, and homicide in schizophrenia patients, but the evidence is unre- shoving . Minor violence was associated with co-occurring liable (notethe largeCIfor theORinfemales in theSchanda substance abuse. Females were significantly more likely to be et al. study ).Theriskelevation in thefirstepisode of violent than males; this eeff ct appeared to be attributable to a psychosis is well supported and it underscores the need for group of young women with a history of substance abuse and early treatment and monitoring. arrest. When interpreting the prevalence and risk data reviewed Homicide is the violent crime that is almost always above, it is important to remember that they largely apply to reported to the police, and its investigation results more fre- schizophrenia patients dwelling in the community. Except for quently in the identification of the perpetrator in comparison the ECA study [18, 19], hospitalized and incarcerated patients with other crimes. The Finnish police have been able to did not contribute to these estimates. Violent behavior is a fre- solve about 95% of all homicides committed during several quent reason for hospitalization and arrest of schizophrenia decades. eTh prevalence of various mental disorders among patients. us, Th the estimates of prevalence and risk of violent 693 Finnish homicide oender ff s was determined [ 26]. The behavior in the community are lowered by a constant removal prevalence of schizophrenia and schizophreniform psychoses of the most violent schizophrenia patients to hospitals and was 6.4% in male and 6.0% in female oender ff s. Primary or jails. In many cases, violent behavior continues inside these secondary diagnosis of alcoholism was detected in 32.9% of institutions [30, 31]. Furthermore, it is important to point male and 32.1% of female oender ff s. Comparing the preva- out that only some incidents of aggressive behavior lead to lence of schizophrenia and schizophreniform psychoses in prosecution. eTh refore, studies based on self-reports must be oender ff s with the general population, the age-adjusted OR distinguished from those based on convictions. = 9.7, 95% CI = 7.4–12.6 for males and 9.0, 95% CI = 3.6–22.2 In summary, prevalence estimates of violent behavior in for females. patients diagnosed with schizophrenia vary depending on Other data suggested that females diagnosed with schi- the severity of violence. The six-month prevalence of serious zophrenia may be more at risk for committing homicide than violence perpetrated by community-dwelling schizophre- their male counterparts. A study of 1087 homicide oender ff s nia patients in the United States is approximately 4%. Advances in Psychiatry 5 Schizophrenia patients without substance abuse comorbidity A multisite study examined the correlates of antisocial are about twice as likely to perpetrate violent acts as their personality disorder among 232 men with schizophrenic counterparts in the general population and about nine times disorders and comorbid antisocial personality disorder . as likely if that comorbidity is present. us, Th substance abuse Comparisons of the men with and without antisocial person- is a major risk factor for violence in schizophrenia. Future ality disorder revealed no differences in the course or symp- efforts at tertiary prevention and management of schizophre- tomatology of schizophrenia. By contrast, individuals with nia should be targeted at the diagnosis and systematic antisocial comorbidity committed significantly more crimes treatment of comorbid substance use disorder. and signicfi antly more nonviolent crimes than those without that comorbidity. The mean total number of violent crimes 4.2. Comorbidity of Schizophrenia and Psychopathy/Antisocial was5.1(SD=8.6)forpatientswithantisocialcomorbidityand Personality Disorder. Studies in prisoners have established 1.9(SD =3.0)without antisocial comorbidity;𝑡=2.6 ,𝑃= that psychopathy alone (without any comorbidity) is asso- 0.01.This 𝑃 value was uncorrected for multiple comparisons; ciated with violent behavior . A meta-analysis involving the significance was lost aeft r Bonferroni correction [ 40]. 15,826 individuals indicated that the PCL-R had a moderate u Th s, comorbid psychopathy or antisocial personality effect size in predicting interpersonal violence [ 33]. Another disorder in patients with schizophrenia or schizoaeff ctive dis- meta-analysis showed a similar result . order is associated with violent behavior. This risk increase is statistically independent of comorbid substance use disorders The PCL : SV was administered to 26 persistently violent patients and 25 matched nonviolent patients, all diagnosed and the severity of psychotic symptoms that also elevate the with schizophrenia or schizoaffective disorder [ 35]. Mean risk. As stated aboveinthe sectionondenfi itionsand assess- psychopathy scores were higher for violent patients than non- violent patients. Higher psychopathy scores were associated ment methods, Factor 2 of the PCL : SV may be indexing a with earlier age of onset of illness and more arrests for both pattern of aggressive behavior since childhood that is cap- violent and nonviolent oens ff es. tured by a diagnosis of conduct disorder in childhood. Recent The relationship between schizophrenia/psychopathy imaging ndin fi gs suggest that schizophrenia preceded by con- duct disorder represents a distinct subtype of schizophrenia comorbidity and violence was addressed with ratings on the PCL-R that were used to test the hypothesis that psychopathy . predicts violent recidivism in a Swedish forensic cohort of 4.3.RiskFactors andPathwaystoViolence in Schizophrenia. 202 male violent oender ff s with schizophrenia. Psychopathy Risk factors for violence can be classified in several ways. was strongly associated with violent recidivism . One of them is a classification depending on the temporal Interestingly, Finnish homicide oender ff s with schizoph- proximity to a violent event: proximal factors act to some renia (𝑁=72 )had signicfi antly lower mean score on PCL- extent as triggers, whereas the role of distal factors is less R than a comparison sample of homicide oender ff s without schizophrenia . direct. Another classification is based on the factor’s modifi- ability: static factors such as genotype and demographics are The relationship between psychopathy and violence was not modifiable, whereas dynamic factors such as symptoms confirmed in a sample of 94 Australian men diagnosed with are amenable to change. The latter classification is somewhat schizophrenia-spectrum disorders . The predictive valid- more clinically oriented. ity of PCL-R scores remained significant aer ft controlling for substance abuse. Several studies examined relative contributions of psy- 4.3.1. Static Factors. These factors include age, gender, genetic chopathy, psychotic symptoms, and other factors to the influences, childhood maltreatment, development of child- developmentofaggressivebehavior. Oneofthemassessed hood conduct disorder, history of arrest and conviction, and the contributions of psychosis, disordered impulse control, history of adult victimization. and psychopathy to assaults perpetrated by inpatients with There is robust evidence indicating that young age is a schizophrenia or schizoaffective disorder [ 38]. A semistruc- risk factor for violence in general population as well as in turedinterview aimedtoelicitreasons forassaultsfromassai- psychotic patients [1, 42]. As mentioned in the preceding lants and victims. Consensus ratings indicated that approx- section on prevalence, the eeff ct of gender is somewhat imately 20 percent of the assaults were directly related to equivocal. A large recent review reported that male gender positive psychotic symptoms. Factor analysis revealed two was modestly associated with violence in psychotic patients psychosis-related factors, one related to positive psychotic (OR = 1.6, 95% CI = 1.2–2.1) . Thissystematicreviewand symptoms and the other to psychotic confusion and disorga- metaregression analyzed 110 studies involving 45,533 psy- nization, as well as a third factor that differentiated impulsive chotic individuals, 87.8% of whom were diagnosed with from psychopathic assaults . schizophrenia. A total of 8,439 of these individuals (18.5%) In an English study, 33 violent and 49 nonviolent forensic were violent . patients were assessed using neuropsychological tasks and measures of psychotic symptoms and psychopathy (PCL : SV) Genetic Influences. In a nonpatient sample, heritability of . The “violent” group had significantly higher psychopa- assaultiveness was shown to be approximately 50% . A thy scores. Personality factors (factor 1 of PCK : SV) rather large epidemiological project focusing primarily on the risk than symptoms and neuropsychological function predicted of violent crime among schizophrenia patients had a genetic violence . component to study familial confounding . This project 6 Advances in Psychiatry was reviewed in the section on prevalence. The main genetic a Met allele and violence was found such that men’s violence finding was that the variation in violence risk depended on risk increased by approximately 50% for those with at least the degree of relatedness between the patient and the control one Met allele compared with homozygous Val individuals group. Compared with unrelated general population controls, (diagnostic OR = 1.45; 95% CI = 1.05–2.00;𝑧 = 2.37 ,𝑃= theriskofviolent crimeinindividuals with schizophrenia 0.02). No significant association between the presence of a and violent crime was increased approximately 4-fold. How- Met allele and violence was found for women . ever, unaeff cted siblings had higher rates of substance abuse A meta-analysis testing the same association in 14 studies compared with unrelated general population. er Th efore, the was independently conducted by another group . Simi- risk increase for schizophrenia with substance abuse comor- larly, it was found that the Met158 allele of the COMT gene bidity compared with these siblings was substantially reduced confers a significantly increased risk for violent behavior in from4-foldtoapproximately2-fold.Thisreductionsuggested schizophrenia. Taken together, these ndin fi gs have potential familial confounding of this association. It is not clear if this implications for pharmacogenetics of schizophrenia. Future familial confounding occurred through genetic susceptibility research could test the usefulness of this genetic information or early environmental eeff cts [ 20]. for personalized treatment. Efforts to explore a molecular basis of genetic influences Childhood Maltreatment. In a classical cohort study of 908 in this area have focused on neurotransmitters and their child abuse and neglect court cases, Widom established that genes. Enhancement of central dopaminergic or noradren- being maltreated as a child increases risk for delinquency, ergic function facilitates aggressive behavior in most animal adult criminal behavior, and violent criminal behavior . studies . Drugs that increase central dopaminergic trans- However, she observed that the majority of abused and mission, such as amphetamines and cocaine, may elicit psy- neglected do not become delinquent, criminal, or violent. chosis with violentbehavior. Furthermore, drugs that The interaction between childhood maltreatment and MAOA diminish noradrenergic activity (such as propranolol) have polymorphism described above  partially explained the antiaggressive effects in humans [ 46, 47]. u Th s, the prepon- differences in the eeff cts of maltreatment on violent behavior derance of the evidence suggests that catecholamines gen- . More recent reports conrfi m the association between erally enhance violence. childhood maltreatment and adult criminal violence in indi- However, the information on genetic inu fl ences on vio- viduals without schizophrenia [57, 58]. lenceinschizophrenia is limited. Much of themolecular eTh evidence for that association in schizophrenia is more genetic work in schizophrenia and violence has focused on tentative, although individuals with schizophrenia report catechol-O-methyltransferase (COMT), one of the enzymes more childhood adversities than controls . History of involved in the catabolism of catecholamines; amines in the childhood physical abuse was one of the factors associated brain. A functional single nucleotide polymorphism involves with the occurrence of incidents of assaultive behavior among a Val (valine) to Met (methionine) substitution at codon 158 183 male patients of a forensic psychiatric hospital, 106 of of theCOMTgene. eTh Valalleleatthislocus is associated whom were diagnosed with schizophrenia . A group of with high enzymatic activity, whereas the Met allele is 60 male psychotic patients legally detained at a forensic unit associated with low enzymatic activity. Homozygosity for the was assessed for history of violence; the participants were Met allele confers a 3- to 4-fold reduction in COMT activity also asked about any history of childhood abuse, substance relative to Val homozygotes; heterozygotes have intermediate use, medication adherence, and current insight in terms of activity. awareness of mental illness . Multiple regression analysis Male heterozygous COMT knockout mice exhibit indicatedthatthe historyofchildhood abusewas associated increased aggressive behavior . When mouse strains were with the severity of violence independently of substance use, ranked according to their aggressivity, the ranking correlated medication adherence, and insight (beta = 0.18,𝑃 < 0.01 ) with the expression of the COMT gene in the hippocampus: . In a group of 28 schizophrenia patients with a history the lower the level of expression, the more aggressive the of violence, 46% had experienced child abuse and/or neglect strain . u Th s, consistent with the enhancing effects of . Childhood physical (OR = 2.2, 95% CI = 1.5–3.1) or catecholamines on aggression, low expression of the COMT sexual abuse(OR =1.9,95% CI =1.5–2.4)was moderately is associated with increased aggression in animal models. associated with violence . Basedonthe nfi dingsdiscussed above, it wouldseemapp- u Th s, similar to robust evidence in general population ropriate to hypothesize that, in general, the COMT poly- indicating a relationship between childhood maltreatment morphism would exert an eeff ct in humans such that the Met and violent behavior in adulthood, there are data indicating allele would be associated with increased violent behavior. that this relationship also exists in psychotic patients. Inter- COMT had originally been explored as a candidate gene actions between genes and environment that aeff ct risk for for schizophrenia, and the association of COMT polymor- violent behavior have been studied in general population. phism with violence in schizophrenia patients was rfi st tested in this context. Initial association studies yielded encouraging results [50, 51], and numerous attempts at replication fol- Childhood Conduct Problems. Males diagnosed with schizo- lowed. Two meta-analyses of such association studies have phrenia are at increased risk to have exhibited conduct dis- been published to date. One of them included 15 studies order before age 15. A study examined the consequences of comprising 2,370 individuals with schizophrenia . Evi- conduct disorder among 248 adult men with schizophrenia or dence of a significant association between the presence of schizoaffective disorder [ 62]. Participants were assessed at Advances in Psychiatry 7 hospital discharge and repeatedly during the subsequent two A study examined oeff nding among 301 individuals expe- years. In adulthood, the diagnosis and symptoms of conduct riencing their rfi st episode of psychosis [ 66]. The results disorder were associated with increased nonviolent and showed that 33.9% of the men and 10.0% of the women violent criminal oeff nding, aer ft adjusting for diagnoses of had a record of criminal convictions, and 19.9% of the men substance use disorders. During the 2-year follow-up period, and4.6%ofthe womenhad been convictedofatleast one conduct disorder diagnosis and the number of conduct violent crime. This increased their risk for future violent disorder symptoms were associated with aggressive behavior, behavior. eTh se n fi dings have important implications for the controlling for lifetime diagnoses of substance use disor- understanding, prevention, and treatment of violent behavior ders, substancemisusemeasuredobjectively andsubjectively, in psychotic patients. and medication compliance. During the two-year follow- Adult Victimization. Relationships between victimization and up period, neither the diagnosis of conduct disorder nor oendin ff g were addressed by several studies. In individuals the number of conduct disorder symptoms was associated diagnosed with serious mental illness, history of a criminal with levels of positive and negative symptoms, compliance conviction was associated with having been robbed (𝑟=0.09 , with medication, substance use, or readmission. u Th s, it 𝑃<0.05 ), threatened with a weapon (𝑟=0.12 ,𝑃<0.001 ), appears that conduct disorder is a distinct comorbid disorder and beaten (𝑟=0.10 ,𝑃<0.01 ). proceeding alongside the course of schizophrenia and elevat- Relationships between victimization and crime were ing the risk of violent behavior independently of psychotic examined in a sample of 331 involuntarily admitted patients symptoms . with serious mental illness . Being a victim of a crime These results have implications for understanding eti- predicted patients’ violence significantly and independently ology and for treatment. If the relationship between the of age and substance use (OR = 1.76 [95% CI = 1.11–2.79], history of conduct disorder and aggression in schizophrenia 𝑃<0.05 ). is independent of comorbid substance use disorder and of Logistic regression was used to estimate the bivariate medication, then “reduction of substance use disorder would association between being violent towards others and violent reduce violent behavior only among patients with no history victimization. The OR = 7.12 (𝑃 ≤ 0.001) . Patients of aggressive behavior prior to the onset of schizophrenia. with serious mental illness charged with a criminal oeff nse Among adults with schizophrenia and a history of conduct were more likely (OR = 4.80 [95% CI = 3.71–6.20],𝑃≤ disorder, treatments designed to reduce aggressive and anti- 0.001) than patients who were nonoender ff s ( 𝑛 = 2,413) to social behaviors, in addition to treatment of substance use have a record of violent victimization and more likely (OR disorder, may be necessary to reduce violence” . These = 3.07 [95% CI = 2.55–3.69],𝑃 ≤ 0.001 ) to have a record implications for treatment remain to be tested experimen- of nonviolent victimization, controlling for the eeff cts of age, tally. gender, and substance use disorders . u Th s, relationship The findings reported by the Hodgins group are consis- between victimization and violent behavior by patients with tent with evidence suggesting that violence among adults with serious mental illness has been established. schizophrenia may follow at least two distinct pathways: one associated with premorbid conditions, including antisocial conduct, and another associated with the acute psychopathol- 4.3.2. Dynamic Factors. These factors include psychotic ogy of schizophrenia. aTh t evidence came from a reanalysis symptoms, comorbid substance use disorders and psychopa- of data from the CATIE . The prevalence of violence thy, lack of insight, and nonadherence to treatment. Some of was higher among patients with a history of childhood these factors that are in close temporal proximity to a violent conduct problems than among those without this history assault act as triggers. Immediate environmental provocation, (28.2% versus 14.6%;𝑃 < 0.001 ). In the conduct-problems intoxication, and current clinical symptoms play a role. group, violence was associated with current substance use at The environmental provocation can be real. A study using levels below diagnostic criteria. Positive psychotic symptoms video recordings of interactions between psychiatric inpa- were linked to violence only in the group without conduct tients has revealed that threatening and intrusive behaviors problems. Adherence with antipsychotic medications was in assailants and victims preceded 60% of assaults . When associated with significantly reduced violence only in the psychiatric inpatients are asked by staff to do (or to stop group without a history of conduct problems. In the conduct doing) something, they may respond by assaulting the staff problems group, violence remained higher and did not member.Suchsituation wasinfactlistedbystaffmembers as significantly differ between patients who were adherent with the most frequent reason for assaults on a maximum security medications and those who were not . psychiatric unit . However, the assaulters in the same study listed being teased or “bugged” as the most frequent History of Violent and Criminal Behavior. Past violence is one reason. Some of this “bugging” may have been delusional. of the strongest predictors of future violence . Detailed confirmation of this rule has been provided in a recent Intoxication. As discussed repeatedly in previous sections, analysis demonstrating that history of assault, imprisonment, comorbid substance use disorders substantially elevate the arrest, and conviction for any offense were all showing strong risk of violence in individuals diagnosed with schizophrenia. associations with violent behavior, with ORs≥ 4.2 . Acute intoxication is one of the mechanisms for this effect. Most oender ff s diagnosed with schizophrenia get their Binge drinking, the pattern of alcohol consumption that is first conviction before their rfi st psychotic episode [ 65]. most likely to lead to intoxication, was signicfi antly related to 8 Advances in Psychiatry violence in an analysis of the NESARC data mentioned earlier relationships between specific delusions and violence [ 81]. . Recent alcohol misuse was moderately associated with The delusions included being spied upon (OR = 1.62, 95% violence in psychotic patients (OR = 2.2, 95% CI = 1.6–2.9) in CI = 1.06–2.47,𝑃 = 0.027 ), beingfollowed(OR =1.90, 95% a recent meta-analysis of risk factors for violence in psychosis CI = 1.29–2.80,𝑃=0.001 ), being plotted against (OR = 1.70, . 95% CI = 1.14–2.52, 𝑃 = 0.009 ), being under control of Schizophrenic individuals who also abuse drugs may be person/force (OR = 1.92, 95% CI = 1.24–2.97,𝑃 = 0.003 ), particularly likely to become assaultive under the inu fl ence thought insertion (OR = 1.63, 95% CI = 1.00–2.66,𝑃=0.048 ), of alcohol . Furthermore, the lifetime prevalence of and having special gifts/powers (OR = 1.95, 95% CI = 1.31– comorbidity between schizophrenia and any substance use 2.92,𝑃 = 0.001 ). All these delusions were associated with or dependence was estimated at 47.0% (OR = 4.6), and the angry affect ( 𝑃 < 0.05 ). Inclusion of anger in the model analogous numbers for alcohol abuse or dependence were signicfi antly attenuated the main effects (except grandiose 33.7% (OR = 3.3) . These data were determined from delusions), indicating an indirect pathway. us, Th tempo- 20,291 interviews in the ECA study mentioned earlier in the ral proximity is important when investigating relationships section on prevalence. u Th s, schizophrenia patients may be between delusions and violence. Anger due to delusions is the more vulnerable to acute alcohol effects and are more likely key factor in this pathway . eTh importance of temporal to abuse alcohol than members of the general population. proximity for research on causes of violence is now being increasingly accepted . Current Clinical Symptoms. Current clinical psychotic symp- Similar n fi dings were reported by the same group of toms play a role in the development of violent behavior in investigators using data from the East London rfi st episode schizophrenia. As described in the preceding section, approx- psychosis study . The participants were 458 patients with imately 20% of assaults perpetrated by psychotic inpatients rfi st episodepsychosis whowere18to64years of age. Patients are attributable to positive psychotic symptoms . Positive were clinically assessed and interviewed about their overt vio- symptoms of schizophrenia were associated with an increased lent behavior while experiencing psychotic symptoms during risk of violence, whereas negative symptoms showed the the 12-month period prior to interview. The prevalence of opposite relationship . In a large metaregression study, the violence was 38% during the 12-month period, and 12% of the relation between positive symptoms and violence was very sample engaged in serious violence. Anger was the only aeff ct modest (OR = 1.2, 95% CI = 1.0–1.5), whereas negative symp- duetodelusions that waspositivelyassociatedwithviolence. toms had no effect on violence [ 43]. Command hallucinations Three highly prevalent delusions demonstrated pathways to to harm others may increase risk of violence, although the serious violence mediated by anger due to delusional beliefs: level of compliance with such commands varies [75, 76]. persecution, being spied on, and conspiracy. us, Th anger due Mentally ill patients sometimes make threats to kill, to delusions is a key factor that explains the relationship and such threats need to be evaluated by clinicians. An between violence and acute psychosis . Australian study addressed this problem . A total of 613 Patients with first episode of psychosis who had a individuals convicted of threats to kill had their prior contact record of criminal convictions prior to contact with mental with public mental health services established at the time health services showed impaired performance on neuropsy- of this oen ff se. eTh group’s subsequent criminal convictions chological studies in comparison with their nonoeff nding were established 10 years later using the police database. patient counterparts. Offenders had significantly lower IQ Within 10 years, 44% of threateners were convicted of further scores than nonoeff nders, both current and premorbid. The violent oeff nding, including 19 (3%) homicides. os Th e with oender ff s were further distinguished by significantly poorer histories of psychiatric contact (40%) had a higher rate performance on the verbal learning and short-term verbal (58%) of subsequent violence. Homicidal violence was most recall, visual recall memory, a measure of visual-spatial frequent among threateners with a schizophrenic illness. perception and organization, and three subtests of the WAIS, Sixteen threateners (2.6%) killed themselves, and three were digit symbol, which assesses processing speed and vocabulary murdered.Thus,thisstudy revealed high ratesofassault and and comprehension, which index verbal intelligence . even homicide following threats to kill . A group of delusional psychotic symptoms—so-called Lack of Insight. A prospective study of 63 inpatients diagnosed threat/control-override (TCO) symptoms—was reported to with schizophrenia or schizoaeff ctive disorder provided what lead to violence [78, 79]. These symptoms are elicited by was probably the rfi st rigorous demonstration of the relation- questions like “dominated by forces beyond you,” “thoughts ship between insight and violence . Similar observations putintoyourhead,”and “peoplewho wished youharm”. regarding the lack of insight into illness and into legal An analysis of the data from the MacArthur violence risk consequences of their illness were described in a sample assessment study  suggested that although delusions can of 115 violent patients with schizophrenia in a jail or court precipitate violence in individual cases, they do not increase psychiatric clinic . the overall risk of violence. An early analysis suggested that eTh German national crime register was searched for the threat/control-override symptoms were not associated records of criminal oeff nses committed by 1662 patients with with violentbehaviorinthatstudy . schizophrenia treated between 1990 and 1995 at a German However, when the same MacArthur data set was reana- hospital. Analyses were performed to determine predictors lyzed using methods that considered the temporal proximity of later criminal behavior, and psychopathology was assessed. of the symptoms to violent events, the results indicated Sixty-two (3.7%) patients were convicted for physical injury Advances in Psychiatry 9 offenses in the 7–12 years after discharge. Signicfi antly higher poor insight was one of the predictors of poor adherence rates of criminal conviction and recidivism were found for to medication in a sample of 200 patients with first episode patients with lack of insight at discharge. Analyses also psychosis . Furthermore, medication adverse effects such showed a significantly higher risk of nonviolent and violent as parkinsonism, weight gain, and loss of libido may addition- crimes in patients with a hostility syndrome at admission ally reduce the patients’ willingness to take medication . and discharge. er Th e was a significantly lower incidence of While non-adherence to medication certainly elevates the criminal behavior in subjects with a depressive syndrome risk for violence, hostility also appears to contribute to the . development of non-adherence in patients with schizophre- In a study of pretrial detainees that was described in the nia or schizoaffective disorder [ 11]. However, rising hostility segment on childhood maltreatment , impaired insight may be the result of inadequate treatment or inadequate anti- (lack of awareness of having a mental illness) was signifi- psychotic response, leading to patient’s unwillingness to con- cantly related to the severity of reported violence, and that tinue treatment. relationship was statistically independent of the effects of Antisocial personality disorder/psychopathy is perhaps substance use, medication adherence, and childhood abuse. also aeff cting adherence to medication treatment. This is sug- Schizophrenia patients without concomitant substance abuse gested by thefactthathistory of aggressive behavior,arrest, or Axis II disorders (𝑁 = 133 ) were recruited for a Turkish or incarceration was strongly related to non-adherence to study of violence . History of violence, lower self-reflect- treatment in a large prospective naturalistic study of schizo- iveness, worse insight, and delusion severity were significant phrenia patients . predictors of violence in a comparison of 47 violent with 86 In the CATIE study , higher levels of insight at base- nonviolent patients. line were significantly associated with lower levels of schizo- In a study of 168 psychotic patients (86 with schizophrenia phrenia symptoms at followup, and more positive medication and 43 with bipolar disorder) in Spain, it was found that attitudes, which were in turn associated with better adherence patients showing poor insight showed higher hostility and with medication treatment . impaired impulse control; these variables were assessed as Relationships between insight, hostility, and adherence PANSS items . The authors hypothesized that lack of were examinedinapost hocanalysisofthe data obtained insight was the primary problem, leading to increased hos- in the European First Episode Schizophrenia Trial (EUFEST) tility and impairment of impulse control. Lack of insight was . EUFEST was a randomized, one-year open trial compar- moderately associated with violence in a large metaregression ing the eeff ctiveness of haloperidol, amisulpride, olanzapine, analysis (OR = 2.7, 95% CI = 1.4–5.2) . quetiapine, and ziprasidone in rfi st episode schizophrenia, However, a study of 209 schizophrenia patients has shown schizoaeff ctive disorder, or schizophreniform disorder. eTh thatwhileinsightwasassociatedwithaggressioninunivariate primary outcome measure was all-cause treatment discon- analysis, the association was no longer significant aer ft tinuation. Secondary measures included the PANSS and the controlling for psychopathy scores and positive symptoms Hayward scale , a measure of adherence. . eTh reanalysis investigated concurrent and predictive In summary, preponderance of evidence links violence in associations to determine whether medication adherence psychotic individuals to their impaired insight into mental varies as a function of hostility and lack of insight . Pre- illness. This eeff ct may be indirect, mediated through the dictive association of hostility and lack of insight (assessed as reduced adherence to treatment that is associated with poor PANSS items) with non-adherence to medication (Hayward insight. scale) was statistically signicfi ant at one month of treatment (Figure 2). Nonadherence to Treatment. Nonadherence to antipsychotic u Th s, non-adherence to treatment is of central impor- medication treatment is a major problem in treating schizo- tance among pathways to violence in schizophrenia. It phrenia. Less than 50% of schizophrenia patients are adher- is closely related to substance use disorder. Furthermore, ent to their medication [88, 89]. Nonadherence has been impaired insight and probably increased hostility are among associated with symptom worsening, including aggressive the symptoms that are impairing adherence. Also, comorbid behavior . Non-adherence with medication was modestly antisocial features are linked with non-adherence. associated with violence in a large metaregression study (OR=2.0, 95%CI=1.0–3.7). Somewhat surprisingly, 4.4. Treatment of Violent Behavior in Schizophrenia the eeff ct of non-adherence with psychological therapies on violence appeared considerably stronger (OR = 6.7, 95% CI = 4.4.1. Atypical Antipsychotics. Atypical antipsychotics are 2.4–19.2) . It should be noted that only three studies of currently the principal treatment of aggressive behavior in non-adherence to psychological therapies were used for the schizophrenia. computation of the OR, whereas nine studies were used for Aripiprazole was compared with placebo in vfi e random- medication non-adherence. ized, double-blind studies of patients with schizophrenia Comorbidity of alcohol or other drug abuse with poor or schizoaeff ctive disorder, and haloperidol was used as a adherence to medication further elevates the risk of violent comparator in three of these studies. A meta-analysis of behavior among persons with severe mental illness . As thesefive studiesshowedthataripiprazolewas signicfi antly discussed in the preceding section, impaired insight may superior to placebo, but not to haloperidol, in reducing lead to reduced adherence. Canadian researchers noted that hostility . 10 Advances in Psychiatry Lack of adherence aer ft 1 month of treatment incidents was superior to olanzapine, which was in turn predicted by baseline hostility and lack of insight superior to haloperidol. 1.0 Numerous observational studies and uncontrolled trials have indicated superior antiaggressive aeff ctiveness of cloza- 0.9 pine in psychotic patients [103–107]. These studies and similar literature are discussed elsewhere [108, 109]. Although its antiaggressive ecffi acy is rml fi y established 0.8 [110, 111], clozapine is not appropriate or eeff ctive in all patients . Perhapsasmanyas50% of patients fail to 0.7 respondtoclozapine . Patients whose aggressive behav- ior continues despite clozapine treatment are sometimes those with a history of conduct disorder and comorbid 0.6 personality disorder [64, 114]. Furthermore, as mentioned above, clozapine is not fully 0.5 eeff ctive during the dose escalation period [ 101]. The prin- cipal risk of clozapine is agranulocytosis which develops in 0.4 approximately 1% of patients during the rfi st three months of treatment . This requires regular monitoring of white Lack of insight cell counts, which is one of the reasons why patients some- Hostility score 3 times refuse or discontinue clozapine. Finally, some patients 5 cannot receive or continue clozapine treatment for medical contraindications or adverse effects. Figure 2: Lack of adherence after one month of treatment predicted Olanzapine is eeff ctive against hostility [ 99]and overt by baseline hostility and lack of insight. Predictive relationship of physical aggression  in long-term schizophrenia hostility and lack of insight at baseline with medication adherence patients. Olanzapine was less effective against aggression at 1 month of treatment in the study. Logistic regression analysis than clozapine . In the CATIE study , its eeff cts in indicated that both predictor variables reached significance (hostil- reducing violence during the rfi st 6 months of the study were ity𝑃=0.027 ,lackofinsight𝑃<0.0001 ). The figure illustrates the not distinguishable from other atypical antipsychotics . combined effect of the two predictors, that is, the probability of lack of full adherence at 1 month (any score of<7onthe Haywardscale) However, when the treatment effects on PANSS hostility both as a function of lack of insight at baseline (𝑥 -axis) and hostility item scores acquired during the 18-month Phase 1 of the (𝑦 -axis strata depicting additive effects with increasing severity of CATIE study were analyzed, significant differences between hostility). Display and computations were provided by Pal Czobor, treatments were discovered (𝐹 = 7.78,𝑃 < 0.0001 ). 4,1487 PhD, who used data collected in the EUFEST study [95, 97]. Olanzapine was significantly superior to perphenazine and quetiapine at months 1, 3, 6, and 9. It was also significantly superior to ziprasidone at months 1, 3, and 6 and to risperi- done at months 3 and 6 . These results were similar to Clozapine is the most eeff ctive, evidence-based treatment for schizophrenia patients exhibiting violent behavior. eTh those obtained in the EUFEST study , where olanzapine evidence for clozapine superiority in antiaggressive effects is was superior to haloperidol, quetiapine, and amisulpride in its effect against hostility [ 118]. based, in part, on randomized, double-blind, controlled trials. One trial compared clozapine, haloperidol, olanzapine, and Quetiapine reducedhostilityandaggressioninopenstud- risperidone in 157 treatment-resistant patients diagnosed ies [119, 120]. eTh se observations were conrm fi ed by post-hoc with schizophrenia or schizoaffective disorder [ 99]. The analyses of randomized double-blind trials demonstrating scores on hostility item of the PANSS were used as the dep- superior antiaggressive effect of quetiapine in comparison endent variable in analyses that have demonstrated superior with placebo in schizophrenia patients . In CATIE ecffi acy of clozapine in comparison with risperidone and patients, quetiapine’s antiaggressive eeff cts were similar to haloperidol . However, neither risperidone nor olanza- otheratypicalantipsychotics,buttheywereweakerthanthose of perphenazine . pine was superior to haloperidol. Furtheranalysesofthesametrial examined incidents Risperidone showed superiority over placebo in reducing of overt physical aggression . The results demonstrated hostility in a post-hoc analysis of a randomized double-blind study . Reduction of hostility and violent behavior was superiority of clozapine over haloperidol, but this eeff ct only became significant aer ft 24 days of treatment when an eeff c- seen as an effect of risperidone in open studies of schizophre- tive dose of clozapine—around 500 mg/day—was reached. A nia [123, 124]. Other comparisons of risperidone with various principal limitation of this trial  was that the patients were antipsychotics in randomized trials showed mostly no signif- not selected for being violent. icant differences in antiaggressive eeff cts [ 116]. Ziprasidone effects on hostility were studied using data A more recent double-blind randomized controlled trial compared clozapine, olanzapine, and risperidone in 110 from a randomized, open-label study comparing ziprasidone patients diagnosed with schizophrenia or schizoaeff ctive with haloperidol in schizophrenia and schizoaffective disor- der . Post-hoc analyses showed that both drugs reduced disorder who were selected for being violent . Efficacy of clozapinetoreducethe number andseverityofaggressive hostility; ziprasidone was superior to haloperidol only during Probability of lack of adherence Advances in Psychiatry 11 the rfi st week of the study [ 126]. Ziprasidone’s antiaggressive studies show that outpatient civil commitment may reduce eeff ctwasnotsignicfi antlydieff rentfromotherantipsychotics violence in such cases . in CATIE patients . Various cognitive behavioral treatment programs were In summary, clozapine is the most eecti ff ve antipsychotic developed for recidivistically violent and criminal patients. in reducing hostility and aggression in patients diagnosed One such program has been operating at a state hospital with schizophrenia or schizoaeff ctive disorder. However, its providing treatment to the severely mentally ill in New York use in clinical practice is limited by its adverse effects, partic- City. eTh cognitive skills training course is the principal ularly the risk of agranulocytosis. Olanzapine’s effectiveness component of the program. Substance abuse programs are against hostility is inferior to clozapine, but superior to included. eTh program has effects after discharge from the other antipsychotics. Other atypical antipsychotics are also hospital: its graduates exhibit reduced rates of arrest and effective, and there are apparently no major differences rehospitalization, as well as improved adherence to treatment among them in terms of antiaggressive activity. . Reports of similar programs operating elsewhere have been published [138, 139]. Programs of this type have a potential to break the revolving-door cycle of hospitalization- 4.4.2. Other Medications. Adrenergic beta-blockers were dem- discharge-nonadherence to medication and drug abuse- onstrated to possess antiaggressive properties [127–131], but relapse with violent behavior-arrest-jail-hospitalization, and cardiovascular adverse effects such as reduced blood pres- so on. Developing more of these programs in the future could sure and pulse rate occurring at doses required for anti- improve the lives of patients and their families and reduce aggressive effect have limited their clinical use for this indica- thecostofmanagementofthe chronicallyill andviolent tion. Beta-blockers have been supplanted by antipsychotics. individuals. Nevertheless, antipsychotics are not always eeff ctive and have adverse eeff cts of their own. Therefore, efficacy of adjunctive Promising practices for psychosocial treatment of schi- beta-blockers in the treatment of persistently aggressive zophrenia include cognitive adaptive therapy, cognitive schizophrenia patients should be studied further. behavioral therapy for posttraumatic stress disorder, rfi st- Recently published meta-analyses indicating an associ- episode psychosis intervention, healthy lifestyle interven- ation between the polymorphism of the catechol-o-methyl tions, integrated treatment for co-occurring disorders, peer transferase (COMT) gene and violence in schizophrenia [52, support services, physical disease management, prodromal 53]havepointed to aroleofcatecholaminesinthe patho- stage intervention, social cognition training, supported edu- genesis of violence in schizophrenia. es Th e meta-analyses cation, and supported housing . may therefore rekindle future interest in influencing nora- drenergic system as a potential treatment for violent behavior 5. Bipolar Disorder in schizophrenia. Anticonvulsants arewidelyusedfor theadjunctivetrea- 5.1. Prevalence of Violent Behavior in Bipolar Disorder. Clini- tment of aggressive behavior in schizophrenia patients. How- cal observations indicated that the risk of violence is particu- ever, empirical evidence supporting efficacy of this treatment larly high during acute manic episodes during hospitalization is missing. Although it may perhaps be effective in individual andimmediately priortoit[141, 142]. patients, such treatment must be monitored, and it must be Between 1990 and 1992, diagnoses and history of aggres- discontinued if it fails to show benefits or if adverse eeff cts sive behavior during the preceding year were determined by develop . interviews in a representative US sample for the national comorbidity survey . Aggressive behavior or “trouble 4.4.3. Nonpharmacological Treatment. Pharmacological trea- with the police or the law” was endorsed by 12.2% of tmentofaggressivebehaviorinschizophrenia hasvariable individuals with the lifetime diagnosis of bipolar disorder, eecti ff veness. Etiological heterogeneity of this behavior (and 8.2% with alcohol abuse, 10.9% with drug abuse, and 1.9% probably of schizophrenia itself) plays a role in this variability with no disorder. eTh analogous numbers for “last year” of treatment response [133, 134]. As discussed above, history diagnoses were 16.0%, 9.1%, 19.8%, and 2.0% . of conduct disorder and current comorbidity with antisocial The NESARC study (described in the previous segment personality disorder or psychopathy constitute alternative on schizophrenia) determined that the lifetime prevalence pathways to violence in schizophrenia . Aggressive beha- of aggressive behavior aer ft age 15 was 0.66% in persons vior in schizophrenia patients with these problems may not without lifetime psychiatric disorder, but 25.3% and 13.6% be directly caused by psychosis, and therefore it is less likely in bipolar disorders I and II, respectively. eTh odds ratios to respond to antipsychotics. were 3.72 (2.94–4.70) and 1.77 (1.26–2.49). These numbers Non-adherence to treatment constitutes a crucially represent a mixture of bipolar disorders with or without important limit to the eeff ctiveness of pharmacological treat- comorbid diagnoses. The prevalence of aggressive behav- ment. Non-adherence to pharmacological treatment and iorinpurebipolarsIandII(withoutcomorbidity)was, substanceabuse elevatethe risk of relapseand violence in respectively,2.52% and5.12%.Comparableprevalenceof schizophrenia [60, 134, 135]. aggressive behavior for pure alcohol dependence and drug Standard psychiatric treatment programs relying only on dependence was, respectively, 7.22% and 11.32% . High pharmacological approaches have therefore limited success rates of comorbidity of bipolar disorder with alcohol depen- in reducing recidivistic violent and criminal behaviors. Some dence, drug dependence, paranoid personality disorder, and 12 Advances in Psychiatry antisocial personality disorder were reported . These bivariate correlation coefficient between the BGA and the comorbidities substantially increase the risk of violence. total score on the childhood trauma questionnaire was 0.325 A total of 3,743 individuals diagnosed with bipolar disor- (𝑃 = 0.001 ). When specics fi ubtypesofchildhood trauma der were compared with 37,429 general population controls were explored, physical abuse and emotional abuse were in a study using official Swedish records [ 146]. After the diag- foundtobesignicfi antlycorrelatedwithBGA. nosis, 9.5% of individuals with bipolar disorder committed Biological and psychological links between suicide and violent crime compared with 629 general population controls outward aggression have been intensively studied. Patients (1.7%) (adjusted OR = 6.6, 95% CI = 5.8–7.6) . Substance with bipolar disorder who had a history of suicide attempt abuse comorbidity further increased the risk (adjusted OR = scored higher on scales assessing hostility and lifetime history 19.9, 95% CI = 14.7–26.9). In patients without substance of aggression than those without such a history . In a abuse comorbidity, there was still a signicfi ant risk increase similar study of bipolar patients, suicide attempters scored (adjusted OR = 3.1, 95% CI = 2.6–3.8) . significantly higher than nonattempters on a hostility scale Prevalence of criminal justice involvement during , particularly on the subscale measuring overt physical episodes of mania and contribution of manic symptoms to aggression . The attempters also showed higher level such involvement were the subject of additional analyses of of impulsiveness. Furthermore, impulsiveness and hostility NESARC data. Among the 1,044 respondents with bipolar were correlated in the attempter subset. I who experienced a manic episode, 13.0% reported legal involvement (being arrested or jailed) during the most severe 5.2.2. Dynamic Factors. Comorbidities of bipolar disorder manic episode . Legal involvement was associated with with other disorders are frequent, and some of them sub- symptoms of increased self-esteem and libido, high-risk stantially elevate the risk of violence. A study of 983 bipolar pleasurable activities, more manic symptoms, and social and patients showed that the prevalence of comorbidity between occupational impairment . bipolar disorder and alcohol abuse/dependence ranged Prevalence of aggressive behavior was compared in a between 31.9% and 47.3%; drug abuse/dependence abuse sample of 255 individuals with bipolar I and bipolar II range was 15.1%–34.2%, depending on age of onset . disorder, 85 individuals with other psychopathology, and 84 Early onset was associated with higher risk of comorbidity. healthy controls . Lifetime aggression was assessed using Other studies yield a range of 17%–64% for substance abuse a questionnaire that was administered by interviewers in the comorbidity with bipolar disorder . subjects’ homes. Bipolar patients showed significantly higher The impact of alcohol abuse on symptoms was assessed scores on an aggression questionnaire than the other groups. in patients with bipolar mania with and without current Subjects who were currently psychotic showed significantly alcohol abuse . The comorbid group showed higher higher total aggression scores, hostility, and anger than those levels of impulsivity and aggressive behavior. In general, who were not. Patients experiencing a current mood episode the evidence for the role of substance use disorders in the showed significantly higher aggression scores than those not pathophysiology of aggression in the mentally ill is robust [91, in a mood episode. This eeff ct was independent of the severity 147], even though much of the aggression in this population of bipolar disorder and polarity of the episode . is attributable to other factors as well . In summary, the prevalence of violent behavior in bipolar As mentioned in the preceding section on prevalence, disorder is comparable to the prevalence in schizophrenia; comorbidity of bipolar disorder with antisocial personality it may be even higher. The risk is increased during manic disorder was demonstrated in the NESARC sample . It episodes. Similar to schizophrenia, comorbidity of bipolar was also observed in forensic facilities and prisons and disorder with substance use disorders further increases the described in case reports . This comorbidity would be risk. Although the problems caused by violent behavior of expectedtoelevate theriskofaggressionsince thediagnosis bipolar patients are not less important than those caused by of antisocial personality disorder is partly den fi ed by it. similar behavior in schizophrenia, violence in bipolars has Bipolar disorder and borderline personality disorder received considerably less research attention [150–152]. share several clinical features, such as affective lability, impulsiveness, and aggressiveness. These and other shared features have led to discussions debating whether borderline 5.2. Risk Factors for Violence in Bipolar Disorder personality disorder should belong to the bipolar spectrum. 5.2.1. Static Factors. Risk factors for aggression were exam- These disorders co-occur, and there are overlaps as well as ined in a sample of 100 consecutively evaluated patients with important differences in phenomenology and in medication bipolar disorder . The 32-item Brown-Goodwin Aggres- response. A detailed discussion of the relationship between sion scale (BGA)  was used to assess lifetime history these two disorders and its impact on the risk of violence in of aggression. Age was significantly related to BGA scores psychotic patients can be found elsewhere . (𝑟=−0.236 and𝑃=0.020 ), indicating that younger patients Comorbidity with borderline personality disorder ele- were more aggressive. Gender had no significant relation to vates risk of aggression while it is also associated with higher aggression. impulsiveness in patients with bipolar disorder . This is History of childhood trauma was retrieved using the consistent with the fact that impulsive aggression is a core childhood trauma questionnaire which examines 5 types of component of borderline personality disorder . maltreatment (physical abuse, physical neglect, emotional In the study of 100 bipolar patients reviewed above abuse, emotional neglect, and sexual abuse) . The , comorbid substance use disorder, posttraumatic stress Advances in Psychiatry 13 disorder, borderline personality disorder, and antisocial per- Benzodiazepines are frequently administered. eTh y are sonality disorder were all found to be associated with elevated particularly useful in patients who are in withdrawal from BGA scores in bivariate analyses. alcohol or sedatives. Lorazepam is a benzodiazepine that is typically used as injections for nonspecicfi treatment of In a stepwise multiple regression, aer ft iterative entries it agitation since it is reliably absorbed intramuscularly. Its half- was found that the combination of three variables provided life ranges between 10 and 20 hours; usual dose is 0.5–2.0 mg the best-fit model for the data: diagnosis of borderline every 1–6 hours. It has no active metabolites. Respiratory personality disorder, total score on the Hamilton depression depression is a potential adverse effect. Similar to other rating scale , andtotal scoreonthe Youngmania rating benzodiazepines, lorazepam has a potential for developing scale . The model significantly predicted the BGA scores tolerance and dependence. It is therefore not recommended [𝐹(3,91)1/4 21.763,𝑃<0.001 ]. eTh sample multiple correla- for long-term use. tion coefficient (𝑟) was 0.646, indicating that approximately 41.8% of the variance of the aggression score in the sample Antipsychotics. First-generation antipsychotics, mostly halo- could be accounted for by the linear combination of these peridol, have been used to treat agitated behavior in acute three predictors. mania. These agents are associated with extrapyramidal Similar to schizophrenia, bipolar disorder is associated adverse eeff cts, including acute dystonia and akathisia. es Th e with poor insight . eTh predictive eect ff of insight on extrapyramidal symptoms are difficult to tolerate. Akathisia clinical outcomes was investigated in a 2-year prospective can be confused by the staff with underlying agitation; if that study of 65 remitted bipolar I disorder patients who happens, it may be erroneously concluded that the dose of were administered the schedule of assessment of insight haloperidol is too low to be eeff ctive. Raising the dose under toassessbaselineinsight andthenreceivedfollow-up these conditions is a major error; it will make akathisia assessments during subsequent 2 years. Impaired insight into worse. Adverse effects of haloperidol can be mitigated by the treatment significantly increased the risk of adverse clinical administration of promethazine . outcomes with bipolar disorder in the 2-year period. The Short-acting intramuscular formulations of atypical anti- most frequent adverse outcome observed was occurrence psychotics aripiprazole, olanzapine, and ziprasidone are of violent behavior. This observation is consistent with the available to treat acute agitation. eTh effects for the reduction literature on aggression in bipolar disorder. This finding of agitationare similartothatobservedfor haloperidolor is consistent with theliteratureonaggressioninbipolar lorazepam . These atypical antipsychotics have lower disorder . u Th s, impaired insight may be one of the propensity for extrapyramidal adverse effects, which is an mechanisms that raise the risk of violence in bipolar disorder. advantageincomparisonwithhaloperidol.Arecent unpubli- Finally, executive dysfunction predictedaggressivebehav- shed randomized double-blind placebo-controlled trial sug- ior among psychiatric inpatients with various diagnoses, gests that sublingual tablets of another atypical antipsychotic, including bipolar disorder . Stable and euthymic bipolar asenapine, canbeusedfor treatmentofacutely agitated patients performed signicfi antly worse than controls on patients . neuropsychological tests of executive function and showed Loxapine, a typical antipsychotic, has recently become an impairment of inhibition . u Th s, stable and remit- availableinaninhalationform. eTh drug is deliveredusing ted euthymic bipolar patients have distinct impairments of a device that produces an aerosol, resulting in rapid delivery executive function, verbal memory, psychomotor speed, and into the lung and then into the systemic circulation [178, sustained attention . It is possible that some of these 179]. Inhaledloxapinewas demonstratedtobearapid, well- dysfunctions, perhaps present as traits, predispose bipolar tolerated treatment for agitation in patients with bipolar I patients to aggressive behavior. es Th e neuropsychological disorder . impairments, plus the elevated trait hostility and impulsivity mentioned before, may form a diathesis that predisposes 5.3.2. Long-Term Treatment of Violent Behavior in Bipolar some bipolar patients to respond by aggression to the expe- Disorder. Typical symptoms of mania include aggression rience of stress. A manic episode would be a typical stressful and irritability. us, Th the treatment of the underlying manic experience of these patients, but other stresses that may occur episodeshouldreduceoreliminate theconcurrentaggressive during remissions can have a similar effect. behavior. Long-term antiaggressive pharmacological treat- ment of manic patients is therefore implied in the general management of bipolar disorder. Such general information 5.3. Treatment of Violent Behavior in Bipolar Disorder is not in the scope of this review. General guidelines for the 5.3.1. Treatment of Agitation in Acute Manic Episode. Acute pharmacological treatment of bipolar disorder are available agitation is common in manic episodes. Staff training in [181–183]. the management of agitated patients is important, since Nonpharmacological management of bipolar disorder their intervention may prevent an escalation of agitation frequently uses cognitive behavioral therapy (CBT) that can into violence. eTh rfi st interventions include removing the address many aspects of bipolar disorder elevating the risk nonagitated patients from the room, having several staff of aggression, including comorbid personality disorders and members available to assist, and encouraging the patient substance use disorders as well as treatment nonadherence. to talk about his\her needs and concerns. 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