Download Why is schizophrenia associated with an increased rate of violence

Essay Title: Why is schizophrenia associated with an increased rate of violence
and aggressive behaviour and what are the methods for reducing this risk?
Name: Rachel Lever
Year of study: MBBS3
Name of Supervisor: Dr. Tim McInerny
Word Count of the Text : 4125
Number of Tables : 0
Number of Figures: 3
Why is schizophrenia associated with an increased rate of violence and aggressive behaviour and
what are the methods for reducing this risk?
Abstract
Good epidemiological evidence exists to support a modest, yet significant, association between
violence and schizophrenia. Although the majority of patients with schizophrenia do not display
violent traits, violent behaviour in the minority of patients poses a therapeutic challenge.
Furthermore, public perception of the danger an individual with schizophrenia poses far outweighs
the actual risk and this has played a key role in fostering stigma. The origins of the relationship
between violence and schizophrenia remain unclear and it is evident that it is a heterogeneous
phenomenon. Factors including impulsivity, substance misuse, comorbid personality disorders,
psychotic symptoms and social factors are all thought to play a crucial role. Evidence has also
suggested that there are at least two developmental trajectories leading to violence in
schizophrenia. The first is associated with antisocial behaviour prior to illness onset, whilst the other
is associated with psychotic symptoms. Clearly, it is important to differentiate between the two in
order to best direct therapeutic strategies. Future research is vital in order to further our
understanding into the diverse aetiology of violence in the context of schizophrenia. In turn, this will
improve patient quality of life and will also reduce crime, with obvious positive implications on
society.
An overview of schizophrenia
Schizophrenia is a relatively common, severe mental illness, with a lifetime prevalence of
approximately 0.7% [1,2]. This serious mental illness results from a complex interaction between
social, genetic, psychological and biological factors and usually becomes apparent in early
adulthood. As well as cognitive impairment, schizophrenia is characterised by both positive
(hallucinations and delusions) and negative (social withdrawal, blunted affect) symptoms. Albeit not
a fundamental component of the disease, individuals with schizophrenia commonly experience
mood disturbances. [3,4]. Although the majority of individuals will respond to antipsychotic
treatment, less than one in five will have a sustained recovery over 2-5 years, and the vast majority
of patients will have at least one relapse [5]. Schizophrenia is amongst one of the most costly
illnesses to treat and the individual suffers a serious impact on their community functioning. The
disease is also associated with a 2-3 fold increased mortality rate than the general population,
attributable to both an increased risk of suicide and a higher rate of natural death [6].
The epidemiology of violence in schizophrenia and it’s impact on society
It is important to highlight that the majority of psychiatric patients are not aggressive, nor violent.
However, one landmark epidemiological study well-established the link between schizophrenia and
an increased risk of violence. The study demonstrated that the one-year prevalence of violence in
schizophrenia was 8.4%, significantly higher than that of the general population without the disorder
at 2.1% [7]. The study also provided pivotal evidence that the risk of violence in patients with
schizophrenia was further increased by comorbid substance misuse disorders [8]. In the context of
an inpatient setting, violence rates are even more common. Further studies have confirmed this, and
it is now the general consensus that individuals with schizophrenia-spectrum disorders are more
likely to commit violent acts, particularly assaults [9,10]. Furthermore, robust evidence now states
that both men and women with schizophrenia are more likely to be convicted of homicide [11].
However, it should be noted that although homicides attract much attention from the media, they
occur far less frequently than assaults and actually are very rare [9].
The implications of violence in schizophrenia
Aggression and violence in the context of schizophrenia is a major societal concern. These
behaviours are associated with harm to others, increased stigmatisation, and admission to mental
health services. As well as instigating admission, violence as an inpatient will lead to obstacles in the
individual’s discharge, leading to a prolonged hospitilisation. In turn, this poses a large financial
burden on health services. It is reported that the general population view individuals with
schizophrenia as being “unpredictable” and “dangerous” [12], with public opinion far outweighing
the actual risk of being harmed by an individual with severe mental illness [13]. Although inaccurate,
the general population’s perception of dangerousness plays a fundamental role in fostering stigma.
Consequently, violence perpetrated by the minority of individual’s with schizophrenia further
advocates stigmatisation. Not only does this lead to rejection of individuals with mental illness, it
also poses barriers to an individual’s recovery and integration into the community, significantly
reducing their quality of life [9]. The public’s perception of dangerousness is pervasive, and is
thought to be partly attributable to the media’s selective coverage of high-profile cases [14].
Why is schizophrenia associated with violence and aggression?
It is not yet firmly established as to why schizophrenia is associated with an increased risk of
violence. However, this essay will focus on the major theories which are proposed to underpin this
association and the methods which can be adopted to reduce this risk. Treatment of violent
individual’s with schizophrenia, leading to a reduction in aggression, would not only lower rates of
criminality, but also improve the individual’s quality of life and have a positive impact on society. As
illustrated in Figure 1, there are several theories that propose to explain the interrelationship
between the increased likelihood of aggression and schizophrenia, and it is evident that aggressive
traits in the illness are multi-determined [15]. Therefore, it is crucial to highlight first and foremost
that attempts to treat this association by a ‘one size fits all approach’ will not succeed. The three
most commonly reported causes of aggression associated with schizophrenia in the literature are
psychotic symptoms, psychopathy and impulsivity. Other essential factors include substance misuse,
neurological abnormalities, and poor compliance with medical treatment.
Figure 1
Figure 1 : Many factors possibly contribute to the increased risk of violence displayed
amongst individuals with schizophrenia. Figure from: [16]
Symptoms of schizophrenia can drive violence
Firstly, the positive symptoms of schizophrenia have been associated with increased rates of
violence and this relationship is most marked during a first-episode of psychosis, as opposed to later
stages of the illness [17]. One meta-analysis concluded that in a variety of mental health disorders,
including schizophrenia, psychotic symptoms were significantly associated with a 49-68% increase in
the odds of violent behaviour. Nonetheless, the effect size was low at 0.24-0.32 [18]. Furthermore,
although there is an interlinkage between schizophrenia, positive symptoms and violence, the
strength of this association still remains contentious. For example, one study found that in the
context of an inpatient setting, only 20% of assaults were attributable to positive psychotic
symptoms, with other psychopathology accounting for the remainder [19]. However, other studies
have established that in cases where psychosis is the driving factor, certain symptoms can
significantly increase the risk of violence. In 1994, Link and Stueve proposed that an association
between psychosis and violence exists because “violence is more likely when psychotic symptoms
cause a person to feel personally threatened or involve the intrusion of thoughts that can override
self-controls [20].” These components of psychosis were termed threat-control override (TCO)
symptoms. In further studies, Link and colleagues reported that TCO symptoms are significantly
associated with violent behaviours, in such a way that when an individual experiences a measure of
TCO symptoms, they are at a substantially increased risk of engaging in violence [21]. Following their
results from further studies, Link and colleagues proposed that this particular constellation of
delusional beliefs, were principal determining factors of an outburst of violence [22, 23]. Other
studies however have not found this theory to be true. It is now thought that TCO symptoms may
drive violence particularly in men, whereas women tend to react to stress in a different way than the
“flight or fight response,” and so TCO symptoms may not be a cause of violence in females [24]. To
note, some studies have found no association between TCO symptoms and an increased rate of
violence. Perhaps one reason for the disparity between studies is that different studies have
classified “violence” in different ways. For example, some studies have deemed an individual as
violent if they are verbally abusive or are threatening towards others whereas other studies have
classified violence as only a physical concept [25]. Therefore, more robust evidence is required to
clarify the discrepancies between the data and a standardised definition of “violence” is required
across studies.
Other positive symptoms commonly implicated in the association between violence and
schizophrenia include command hallucinations, persecutory delusions and hallucinations [26]. It has
been proposed that delusions which generate anger are the most likely to result in aggression, which
suggests that urgency, which will be discussed later, could interact with psychotic symptoms to
engender violent behaviour [27]. Research also strongly suggests that feelings of distress, associated
with such positive symptoms, can further the risk of violence [28, 29].
The long-standing dopamine hypothesis of schizophrenia is well-established and has received
empirical affirmation following the use of anti-psychotic treatment as well as from direct imaging
studies. Although the hypothesis cannot fully explain the complexity of schizophrenia, the theory
underpins how the hallmark symptoms of schizophrenia can be managed with medications. The
hypothesis states that the positive symptoms of schizophrenia are attributable to excess
dopaminergic transmission in the mesolimbic pathway (Figure 2) whereas the negative symptoms of
schizophrenia are associated with reduced dopaminergic signalling in the mesocortical pathway [30].
The dopamine D2 receptor is considered the primary target of antipsychotic drugs (APDs) and all
currently used APDs have nanomolar affinity for this receptor and either partially or fully block the
actions of dopamine to reduce psychotic symptoms. The “typical” antipsychotics have a high affinity
for the D2 receptor and thereby provoke extrapyramidal side-effects. In comparison, the “atypicals”
have a lower affinity for the D2 receptor and also have a higher affinity for the serotonin 5-HT2A
receptors, which have also been implicated in the pathophysiology of schizophrenia [31].
Figure 2
Figure 2: The final common pathway to psychosis in schizophrenia. Multiple factors contribute to
dopamine dysregulation in the striatum. The primary defect is at the level of the dopaminergic D2
receptor. Later on, dysregulation occurs at the presynaptic level. The currently available antipsychotics therefore act downstream of the primary dopaminergic dysregulation. Figure from: [32]
The atypical anti-psychotic drug clozapine is of proven benefit in managing treatment-resistant
schizophrenia and remains the gold-standard for the treatment of patients with schizophrenia
displaying violent behaviours [33]. This anti-aggressive effect has also been reported in the context
of other psychiatric disorders including emotionally unstable personality disorder, autism spectrum
disorder, post-traumatic stress disorder and learning disability. However, the quality of this data is
more circumspect [32]. The clinical utility of clozapine in the forensic psychiatry setting has been
verified by an array of studies. Two retrospective studies conducted in two of the UK’s high-security
hospitals (Ashworth, Rampton) demonstrated that clozapine reduced violent behaviour [34] and also
improved the speed of clinical progress [35]. Moreover, both of these trials reported that the drug
resulted in an improved clinical outcome for individuals with schizophrenia displaying violent
behaviour, and in turn this allowed transfer to lower security hospitals [34] or to institutions with a
larger number of patients [35]. The potential role of clozapine in reducing violence rates was also
eluded to after it was shown that when treated with clozapine, 60% of serious offenders sentenced
to life-imprisonment were offence-free in comparison to 25% of serious offenders who were not
treated with the anti-psychotic [36]. According to another study, amongst outpatients with a history
of violence and schizophrenia, the best predictor of reduced arrest rate was clozapine [37]. Along
with others, these studies have provided empirical evidence that clozapine has the potential to
reduce violence rates and the effect of clozapine is thought to be superior to the other antipsychotic medications. Despite promising results, more robust evidence is required to further verify
clozapine’s anti-aggressive effects. The best way of achieving this is through randomised controlled
studies and perhaps this could be a focus in the forensic psychiatry setting in the near future.
Although the exact mechanism by which clozapine mediates these effects are unknown, the
preponderance of studies have speculated that at least some of these anti-aggressive effects are
specific. In other words, this anti-aggressive effect is independent, to some extent, of clozapine’s
general antipsychotic and sedative effects [32]. To note, some animal studies have reported that
clozapine possibly mediates its effects through it’s complex receptor binding affinities to D2 and D4
receptors and also possibly 5-HT2A receptors [38,39].
Emphasising the importance of anti-psychotics, various different trials have shown that noncompliance with medication is a major risk factor for violence in schizophrenia. In fact, a recent
meta-analysis confirmed that untreated psychosis was a major contributor to both violence and
homicide in schizophrenia. Notably, a 15-fold increase in the rate of homicide was reported when
comparing untreated psychosis with individuals whose symptoms were well-controlled by antipsychotic medications [40]. It has been proposed that improved adherence to medications may be a
plausible boosting mechanism underpinning clozapine’s anti-aggressive effects. This could be
mediated in two ways. Firstly, repeated blood tests required with clozapine treatment may help
improve treatment adherence. Secondly, hostility has been shown to be reduced with clozapine
treatment. In turn, this promotes patient’s willingness to adhere to pharmacological therapy [33].
A striking current finding is that positive psychotic symptoms do not influence the risk of adult
violent offending in schizophrenia in those individuals who had a previous history of childhood antisocial behaviour. Rather, positive psychotic symptoms appear to specifically increase the risk of
violence in those individuals without such a history. This would therefore suggest that violence in
the context of schizophrenia has at least two different developmental pathways. The first is
associated with childhood premorbid antisocial personality disorder whilst the other is affiliated with
positive psychotic symptoms (shown in Figure 3) [17]. Although psychotic symptoms may be
present in the first group, the role of antipsychotic medications may be not be useful amongst
individuals who developed schizophrenia following a childhood history of ASPD. Further trials are
therefore required to ascertain whether this hypothesis is true.
Figure 3 : The two main developmental trajectories which can lead to violence in schizophrenia.
Differentiating between these two pathways can help direct treatment strategies for an individual
with schizophrenia in order to lower their risk of becoming violent. Figure adapted from: [17]
Personality disorders and personality traits
As described in Figure 3, it has been suggested that the connection between violence and
schizophrenia may not be attributable to the mental illness itself, but instead personality disorders
including childhood conduct disorder, antisocial personality disorder and psychopathy, may
outweigh the role of the psychotic illness. Whilst positive symptoms may explain aggression and
violence during acute episodes of the illness, they cannot explain these behavioural traits during
other stages of the illness or prior to disease onset. Conduct disorder (CD) is a known precursor of
schizophrenia in approximately 40% of cases and evidence of CD before the age of 15 is a DSM-IV-TR
diagnostic criterion for antisocial personality disorder (ASPD)[16]. In the forensic psychiatry setting,
it has been demonstrated that patients with schizophrenia more commonly have comorbid CD, and
the prevalence is further elevated amongst those in prison [41]. One study showed that in both men
and women, CD prior to age 15 was associated with a two-fold increase in the number of convictions
for violent crimes. Furthermore, it was demonstrated that each CD symptom increased the risk of
aggression by a factor of 1.2 and this association remained after controlling for confounding factors
such as non-compliance with medical treatment and alcohol and drug use [42].
Furthermore, data gathered from the Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE) project was used to determine the relationship between childhood antisocial behaviour and
violence later on during adulthood. Retrospectively, this data showed that individuals with a history
of childhood conduct problems had a higher incidence rate of violence (28.88%) than those without
(14.44%) and the significant attributable risk of 14.44% highlighted that this was indeed of
importance [43]. Again, this study reported that positive symptoms only increased violence risk
amongst individuals without a history of conduct problems supporting the concept of the two
developmental trajectories of violence in schizophrenia. Interestingly, this theory is concordant with
the concept of “pseudopsychopathic schizophrenia,” a term described over 50 years ago to define
cases initially beginning as a conduct-type behavioural disorder, progressing onto schizophrenia [26].
It is important to highlight that CD and ASPD have not been associated with homicide. Consistently,
studies have found that a significant proportion of homicide offenders with schizophrenia do not
have any background of antisocial behaviour [44].
As well as the direct association between premorbid personality traits and increased violence risk,
ASPD and CD can be indirectly linked with an increased rate of violence. This is because ASPD and CD
are established risk factors in themselves for substance misuse, both in the general population and
in the context of schizophrenia. Moreover, as shown in Figure 1, this indirect linkage can also be
mediated by impulsiveness and non-adherence to medication. Since empirical evidence has
confirmed that CD is a precursor of aggressive behaviour, this developmental trajectory offers
several targets for prevention. Effective interventions aimed at established risk factors such as early
cannabis misuse, physical abuse, and a lack of pro-social and employment skills may help prevent
the progression towards criminal activities. Cognitive behavioural therapy is one plausible method of
targeting these risk factors [45]. It has also been demonstrated that parent-training programmes are
effective in reducing conduct problems in children without mental illness and perhaps the same
approach could be applied to those who are developing severe mental illnesses [46]. If effective, the
prevention of substance misuse, antisocial behaviour and the amelioration of social skills would
certainly help the individual in coping with their mental illness, with obvious positive implications.
Other factors
At a psychological level, impulsivity is a fundamental contributory factor of violence, particularly in
severe mental illness. Impulsivity in patients with schizophrenia appears to be attributable to an
inadequate response inhibition. This concept was verified from behavioural and electrophysiological
data obtained during a Go/NoGo task which showed that individuals with schizophrenia had notable
deficits in inhibition of prepotent responses [47]. Ground-breaking research conducted by Whiteside
and Lynam enhanced the understanding of impulsivity with regards to aggression. In their studies,
many different measures of impulsivity were compared and their factor analysis identified four main
constructs; Urgency, (lack of) Premeditation, (lack of) Perseverance and Sensation seeking
(UPPS)[48]. Next came the USSP-P, which added the fifth construct of positive urgency, which
describes impulsivity in the context of strong positive emotion [49]. Studies have found that in the
context of schizophrenia, positive urgency is a key factor predisposing an individual towards
aggression and violence [50]. In terms of neural circuitry, urgency requires the structural integrity of
ventral prefrontal regions and their functional connections to executive and limbic regions. Studies
have gone on to suggest that dysfunction of this circuitry, which is also involved in emotional
regulation, may influence aggression in schizophrenia [51]. From a clinical perspective, this clearly
has implications for treatment. Firstly, interventions aimed at suppressing negative affect could
reduce levels of distress experienced during periods of strong emotional states, thereby averting
urgency related aggression [52]. Secondly, therapeutic targets aimed at the dysfunctional neural
circuitry could have anti-aggressive effects. Interestingly, patients with schizophrenia treated with
clozapine were found to have lower urgency ratings on the UPPS-P than those treated with other
medications [18]. However, the exact mechanism by which this effect is mediated is unknown. Mood
stabilisers have been proposed to have a beneficial effect also, and this is reflected in their relatively
large use as a conjunctive treatment alongside antipsychotics. Other novel approaches have been
proposed, including real-time functional MRI neurofeedback to modulate the neural circuitry
involved in impulsivity and aggression [53]. It therefore seems hopeful that future research in this
area could better equip physicians with methods to improve aggression in schizophrenia.
It is important to note that some of the risk factors that drive violence in schizophrenia are similar to
those which motivate violence amongst individuals in the general population [54,55]. The classical
violence risk prediction schemes such as the Historical-Clinical-Risk-20 (HCR-20) have taken this into
account and assess risk by equally weighted factors, not specific to schizophrenia or mental illnesses,
but instead are associated with substandard functioning. Factors including homelessness, lack of
social support, relationship instabilities, employment problems, victimisation and a past history of
violence are all risk factors for violence. It is highly likely that these troubles are underpinned by
cognitive decline, a common feature of schizophrenia [56].
Interestingly, one meta-analysis reported a distinct association between victimisation and increased
risk of violence. It is well established that the risk of violent perpetration by an individual with
schizophrenia is far less than their risk of victimisation by others [57]. It has been proposed
therefore, that this may set up a “circle of violence” whereby psychotic individuals place themselves
in dangerous situations, making themselves more vulnerable to victimisation as a consequence of
their own criminal behaviour. In turn, this makes the individual more likely to behave in an
aggressive manner. Thus, methods to break this cycle are highly required.
Genetic susceptibilities
Genetic predispositions may also contribute to violent behaviours in schizophrenia. In particular, the
COMT gene found on chromosome 22, has been associated with a predisposition to violent traits.
The catechol-O-methyltransferase (COMT) enzyme is involved in the metabolism of dopamine.
COMT gene functional polymorphisms (valine [Val] or methionine [Met]) on codon 108 result in
alterations of the COMT enzyme’s activity. It has been shown that the Met allele is less stable, and is
associated with a 3-4 fold reduction in COMT activity in comparison to the Val allele. Consequently,
it has been proposed that individuals with two phenocopies of the Met allele have increased levels
of dopamine in certain brain areas, especially in the prefrontal cortex [58]. Therefore, it has been
proposed that the COMT gene is likely to exert genetic influences on aggressive behaviour. Various
trials have since tried to explore this hypothesis further and conflicting results have been reported.
For example, in a community cohort of schizophrenic patients, it was shown that Met/Met
homozygotes displayed significantly higher aggressive behaviour in comparison to Val/Val
homozygotes [59].
However, other studies have not reported significant results [60]. Despite the inconsistent evidence,
this still remains a highly plausible hypothesis. Principally, this theory can be supported by the
dopamine hypothesis. In addition, this theory is also clinically plausible since there is an evident
increase in aggression and violence amongst schizophrenic patients during psychotic episodes.
Further studies involving homicidal patients or amongst individuals with severe aggression are
required to verify this hypothesis and in order to ensure a more reliable result, measures other than
the Overt Aggression scale should be adopted [58]. If this theory proves to be of some importance,
there is a potential role of COMT inhibitors in the treatment of aggression in schizophrenia. Although
some trials have already started to look at the viability of such treatment [61], there still remains a
long way to go in this field.
Substance misuse and the increased risk of violence
As is the case with the general population, substance misuse is associated with a further increase in
violence amongst individuals with schizophrenia. This is particularly concerning since substance
misuse is very common in this cohort. In 2009, NICE reported a substance misuse prevalence of 4050% amongst individuals with the mental disorder, strikingly high compared to 16% of the general
population [62]. In a study of 4186 patients with schizophrenia, the likelihood of violent offending
was almost 14 times greater with comorbid substance misuse compared to the general population
[63]. Similar findings are commonly reported in the literature. The reasons for this association
remain speculative. Firstly, it is possible that schizophrenia (with a genetic aetiology) can precipitate
substance misuse, subsequently increasing violence risk. It is also plausible that a genetic
susceptibility to substance misuse is in common to that of schizophrenia, and thus both are in turn
associated with increased violence. Another explanation for the association between violence,
substance misuse and schizophrenia is that they all share a common genetic susceptibility.
Supporting this concept, various longitudinal studies have shown that violence and serious
aggression precede the diagnosis of schizophrenia, even after controlling for confounding factors
such as preadolescent psychotic symptoms [64,65]. Another factor to consider is that substance
misuse is often accompanied with non-adherence to medications. In turn, this amalgamation of
problems is associated with an increased rate of violent acts by schizophrenic patients in the
community [66]. Although the increased risk of violent offending in schizophrenia cannot be solely
attributed to comorbid substance misuse, the correlation between the two is striking. This highlights
the fact that in forensic settings, when performing a risk assessment on an individual, their
substance use should be considered. Furthermore, programmes should be put in place to tackle the
high prevalence of substance misuse in the disease, reducing risk factors other than the
characteristic symptomatology of the psychotic illness.
Concluding remarks
It is evident that no single variable is responsible for causing violence in the context of
schizophrenia. Instead, the behaviour is multi-determined. Thus, it is logical to assume that the
inconsistent efficacy of pharmacological treatments in violent schizophrenia is due to the fact that
the behaviour is aetiologically heterogeneous. As has been put forward in this essay, the pathways
leading to violence in schizophrenia are multi-dimensional and just one approach for every
individual will not succeed in reducing risk of violence in schizophrenia. Instead, a variety of different
approaches must be adopted. The fact that violence in schizophrenia can be influenced by social
factors such as vocation, social interactions, leisure activities and household composition means that
a holistic approach should be adopted as well as a medication approach. Future understanding of
neurobiological pathways leading to violence in schizophrenia will also hopefully allow for novel
therapeutic targets aimed at reducing this risk. It is also important to identify conduct disorder in
young individuals so that intense interventions can be put in place with the aim of reducing the
likelihood of future criminal activities. To conclude, a better understanding of the heterogeneous
nature of violence in schizophrenia will better equip physicians to manage aggressive behaviour in
schizophrenia. Not only will this have positive effects on the patient’s outcome, it will lead to
reductions in harm, healthcare costs and stigma.
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