www.LaRCP.ca18 : La Revue canadienne de psychiatrie, vol 59, no 1, janvier 2014

CanJPsychiatry 2014;59(1):18–25

Key Words: schizophrenia, suicide, homicide, executive functions, amygdala, systematic review

Received March 2013, revised, accepted July 2013.

Systematic Review

Neurocognitive Vulnerability: Suicidal and Homicidal

Behaviours in Patients With Schizophrenia

Stéphane Richard-Devantoy, MD, PhD1; Manuel Orsat, MD2; Alexandre Dumais, MD, PhD3;

Gustavo Turecki, MD, PhD4; Fabrice Jollant, MD, PhD5

1 Psychiatrist, Postdoctoral Fellow in Neuroscience, Department of Psychiatry and Douglas Mental Health University Institute, McGill Group for Suicide Studies, McGill University, Montreal, Quebec; Associate Member, Laboratoire de Psychologie des Pays de la Loire, UPRES EA 4638, Université d’Angers, Angers, France. Correspondence: Douglas Institute, Frank B Common Pavilion, 3rd Floor, 6875 LaSalle Boulevard, Montreal, QC H4H 1R3; richarddevantoy@orange.fr.

2 Psychiatrist, Secteur 16 de Psychiatrie Adultes, Centre Hospitalier Spécialisé de la Sarthe, Allonnes, France.3 Psychiatrist, Assistant Professor, Department of Psychiatry and Research Centre—Pinel Institut, University of Montreal, Montreal, Quebec.4 Professor, Departments of Psychiatry, Human Genetics, and Neurology and Neurosurgery, McGill University, Montreal, Quebec; Vice-Chair, Research and Academic Affairs, Department of Psychiatry, McGill University, Montreal, Quebec; Director, McGill Group for Suicide Studies, Montreal, Quebec; Co-Director, Douglas—Bell Canada Brain Bank (suicide studies), Montreal, Quebec; Head, Depressive Disorders Program, Douglas Institute, Montreal, Quebec; Director, Réseau québécois de recherche sur le suicide, Montreal, Quebec.

5 Assistant Professor, Department of Psychiatry and Douglas Mental Health University Institute, McGill Group for Suicide Studies, McGill University, Montreal, Quebec.

Objective: Schizophrenia is associated with an increase in the risk of both homicide and suicide. The objectives of this study were to systematically review all published articles that H[DPLQHG�WKH�UHODWLRQ�EHWZHHQ�QHXURFRJQLWLYH�GH¿FLWV�DQG�VXLFLGDO�RU�KRPLFLGDO�EHKDYLRXUV�in schizophrenia, and to identify vulnerabilities in suicidal and homicidal behaviour that may share a common pathway in schizophrenia.

Methods: A systematic review of the literature was performed using MEDLINE to include all studies published up to August 31, 2012.

Results: Among the 1760 studies, 7 neuropsychological and 12 brain imaging studies PHW�WKH�VHOHFWLRQ�FULWHULD�DQG�ZHUH�LQFOXGHG�LQ�WKH�¿QDO�DQDO\VLV��7KH�QHXURSV\FKRORJLFDO�and functional neuroimaging studies were inconclusive. The structural imaging studies reported various alterations in patients with schizophrenia and a history of homicidal behaviour, including: reduced inferior frontal and temporal cortices, increased mediodorsal white matter, and increased amygdala volumes. Patients with a history of suicidal acts showed volumetric reductions in left orbitofrontal and superior temporal cortices, while ULJKW�DP\JGDOD�YROXPH�ZDV�LQFUHDVHG��WKRXJK��WKHVH�¿QGLQJV�KDYH�UDUHO\�EHHQ�UHSOLFDWHG��Finally, no study has directly compared neurocognitive markers of suicidal and homicidal risk.

Conclusion: These results suggest that brain alterations, in addition to those associated with schizophrenia, may predispose some patients to a higher risk of homicide or suicide in particular circumstances. Moreover, some of these alterations may be shared between homicidal and suicidal patients. However, owing to several limitations, including the small QXPEHU�RI�DYDLODEOH�VWXGLHV��QR�¿UP�FRQFOXVLRQV�FDQ�EH�GUDZQ�DQG�IXUWKHU�LQYHVWLJDWLRQV�are necessary.

:�:�:Vulnérabilité neurocognitive : comportements suicidaires et

homicides chez les patients souffrant de schizophrénie

Objectif : La schizophrénie est associée à un risque accru d’homicide et de suicide. Cette étude avait pour objectifs de mener une revue systématique de tous les articles publiés TXL�RQW�H[DPLQp�OD�UHODWLRQ�HQWUH�OHV�Gp¿FLHQFHV�QHXURFRJQLWLYHV�HW�OHV�FRPSRUWHPHQWV�VXLFLGDLUHV�RX�KRPLFLGHV�GDQV�OD�VFKL]RSKUpQLH��HW�G¶LGHQWL¿HU�OHV�YXOQpUDELOLWpV�GX�comportement suicidaire et homicide qui peuvent partager une trajectoire commune dans la schizophrénie.

Méthodes : Une recherche systématique de la littérature a été effectuée dans MEDLINE pour inclure toutes les études publiées jusqu’au 31 août 2012.

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Neurocognitive Vulnerability: Suicidal and Homicidal Behaviours in Patients With Schizophrenia

Abbreviations

DSM Diagnostic and Statistical Manual of Mental Disorders

MeSH Medical Subject Heading

MRI magnetic resonance imaging

STROBE STrengthening the Reporting of OBservational studies in Epidemiology

SUD substance use disorder

TIAB Title and Abstract

Clinical Implications

• ,QYHVWLJDWLQJ�QHXURFRJQLWLYH�GH¿FLWV�PD\�EHFRPH�SDUW�of a more comprehensive assessment of suicidal and homicidal risk among patients with schizophrenia.

• 1HXURFRJQLWLYH�GH¿FLWV�PD\�EH�WKH�WDUJHW�RI�IXWXUH�interventions to reduce the suicidal and homicidal risk among patients with schizophrenia.

Limitations

• To date, a limited number of studies have investigated the neurocognitive markers of suicidal and homicidal risk among patients with schizophrenia.

• Similarly, a limited number of cognitive domains have EHHQ�DVVHVVHG�LQ�WKHVH�SDWLHQWV�WR�WKLV�VSHFL¿F�DLP�

• No study has directly compared neurocognitive markers of suicidal and homicidal risk.

Suicide and homicide are major public health concerns. According to the World Health Organization,1 one

million people die by suicide, and 10 to 20 times more people attempt suicide each year around the world. Further, more than half a million people die by homicide each year worldwide.2,3�7KHVH�DFWV�UHSUHVHQW�D�VLJQL¿FDQW�FRVW�WR�WKH�people involved, their families, and society as a whole.4

To date, several risk factors for suicide and homicide have EHHQ�LGHQWL¿HG��WKH�PRVW�VLJQL¿FDQW�RI�ZKLFK�LV�WKH�SUHVHQFH�of psychiatric disorders.5–8 Among these, schizophrenia, one of the most debilitating psychiatric disorders, is associated with increased risks of both death by suicide9 and committing homicide.10 Suicide is one of the main causes of premature death among these people (10% to 15% die by suicide).11� $� UHFHQW� PHWD�DQDO\VLV� DOVR� FRQ¿UPHG�that the risk of homicide is 20-fold among patients with schizophrenia, compared with healthy control subjects.10 In line with this, it has been estimated that 6% of murderers suffer from schizophrenia.5–7 Although schizophrenia increases the risk of both suicide and homicide, only a few patients with schizophrenia will die by suicide or commit KRPLFLGH��7KHUHIRUH��VFKL]RSKUHQLD�DORQH�LV�LQVXI¿FLHQW�WR�explain the full suicidal or homicidal risk.Additional risk factors for suicidal and homicidal behaviours KDYH�EHHQ�LGHQWL¿HG�LQ�SDWLHQWV�ZLWK�VFKL]RSKUHQLD��VHYHUDO�RI�which are identical for both behaviours.6,10,12,13 These factors include being male, younger age,13–18 low educational level, low level or absence of a professional activity,19–25 alcohol

abuse,12,26,27 and a history of childhood physical abuse.13,28,29 Impulsivity has also been shown to be a major risk factor of suicide30 and aggression31 in schizophrenia. Moreover, a history of suicide attempts is the strongest predictive factor of future suicide completion,8,32–34 and a prior history of any violent offence is the strongest predictive factor of future homicide.6,10,12,13

7KHVH� VRFLRGHPRJUDSKLF� DQG� FOLQLFDO� ¿QGLQJV� VXSSRUW� ��hypotheses: both suicidal and homicidal behaviours may KDYH�VSHFL¿F�XQGHUO\LQJ�YXOQHUDELOLWLHV�GLVWLQFW�IURP�WKRVH�of schizophrenia; and some of these vulnerabilities may be shared between both suicidal and homicidal behaviours. However, the large number of clinical risk factors of suicidal and homicidal behaviours and the complexity of their interactions limit our ability to predict these behaviours in people suffering from schizophrenia (that is, schizophrenia, schizoaffective, or schizophreniform disorders diagnosed as per the DSM-IV criteria). To overcome this issue, we need to explore other ways, such as neurocognitive impairment, which may be more sensitive in detecting vulnerabilities to these complex acts, keeping in mind that schizophrenia, per se, is associated with a range of

Résultats : Parmi les 1760 études, 7 études neuropsychologiques et 12 études d’imagerie FpUpEUDOH�VDWLVIDLVDLHQW�DX[�FULWqUHV�GH�VpOHFWLRQ�HW�RQW�pWp�LQFOXVHV�GDQV�O¶DQDO\VH�¿QDOH��/HV�études de neuroimagerie fonctionnelle et neuropsychologiques n’étaient pas concluantes. Les études d’imagerie structurelle rapportaient des altérations variées chez les patients souffrant de schizophrénie et ayant des antécédents de comportement homicide, notamment : des cortex frontal et temporal inférieurs réduits, une matière blanche médiodorsale accrue, et des volumes d’amygdale plus larges. Les patients ayant des antécédents de gestes suicidaires présentaient des réductions volumétriques dans le cortex orbitofrontal gauche et le cortex temporal supérieur, alors que le volume de l’amygdale droite pWDLW�DFFUX��ELHQ�TXH�FHV�UpVXOWDWV�DLHQW�UDUHPHQW�pWp�UHSURGXLWV��(Q¿Q��DXFXQH�pWXGH�Q¶D�comparé directement les marqueurs neurocognitifs du risque de suicide et d’homicide.

Conclusion : Ces résultats suggèrent que les altérations du cerveau, outre celles associées à la schizophrénie, peuvent prédisposer certains patients à un risque plus élevé d’homicide ou de suicide dans des circonstances particulières. De plus, certaines de ces altérations peuvent être partagées entre les patients homicides et suicidaires. Cependant, en raison de plusieurs limitations, dont le nombre réduit d’études disponibles, aucune conclusion déterminante ne peut être tirée et plus de recherche est nécessaire.

www.LaRCP.ca20 : La Revue canadienne de psychiatrie, vol 59, no 1, janvier 2014

Systematic Review

FRJQLWLYH�GH¿FLWV�35 In mood disorders, neuropsychological DQG�QHXURLPDJLQJ�VWXGLHV�KDYH�\LHOGHG�LQWHUHVWLQJ�¿QGLQJV�regarding the neurocognitive basis of the vulnerability to suicidal behaviour.36

2XU� SDSHU� DLPV� WR� LGHQWLI\� WKH� VSHFL¿F� QHXURFRJQLWLYH�factors (from neuropsychological and neuroimaging studies) of suicidal and homicidal behaviours in people with schizophrenia, and to examine possible shared pathways between suicidal and homicidal risk at the neurocognitive level. A systematic literature review was performed to synthesize all published articles assessing the association between neurocognitive markers and suicidal and homicidal behaviours in people suffering from schizophrenia. Both neuroimaging and neuropsychological studies were UHYLHZHG��%DVHG�RQ�SUHYLRXV�¿QGLQJV�LQ�VXLFLGDO�EHKDYLRXU�of mood disorders,36 and on the observation that many risk factors for suicide or homicide are shared across diagnoses,37 we expect patients with schizophrenia and histories of suicidal behaviour or homicide to show impaired decision making and cognitive inhibition in relation to amygdala and orbitofrontal, dorsomedial, and dorsolateral prefrontal cortices impairment.

Methods

Literature SearchWe performed a systematic MEDLINE literature search of all clinical trials, cohort, case–control, and cross-sectional human studies published in English until August 31, 2012. The MeSH terms “schizophrenia” and “psychotic disorders” were combined with the MeSH terms “violence,” “homicide,” and “suicide.” Then, these were combined with the MeSH terms and with the TIAB terms of neurocognitive pathways. To explore the neurocognitive pathways of suicide and homicide, the following MeSH terms were used: “cognition,” “neuropsychology,” “neuropsychological tests,” “executive function,” “decision making,” “problem solving,” “magnetic resonance imaging,” “diffusion magnetic resonance imaging,” “positron-emission tomography,” “prefrontal cortex,” “tomography, emission-computed, single-photon,” and “diffusion tensor imaging.” TIAB terms also included “neuropsychological functions,” “executive functioning,” “executive performance,” and “neuroimaging.” For completeness, the search also included the Embase database (Ovid interface) from January 1, 1996, to August 31, 2012. An iterative process was used to ensure that all relevant articles were obtained. We also performed a manual search of bibliographical references of extracted papers and existing reviews to identify potential studies not captured in the electronic database searches.

Study SelectionAbstract selection was based on the STROBE checklist,38 which describes items that should be included in reports of cohort studies. Our review followed the STROBE statement JXLGHOLQHV��$EVWUDFWV�LGHQWL¿HG�WKURXJK�WKH�OLWHUDWXUH�VHDUFK�were independently evaluated by 2 authors for meeting the inclusion criteria. The quality of each study was assessed independently by 2 authors using the Crombie criteria

adapted by Petticrew and Roberts.39 Disagreements were resolved by a third author.Titles, abstracts, and manuscripts were only included in the analyses if they met all of the following 4 inclusion criteria: published in a peer-reviewed, English-language journal; included people with schizophrenia, schizoaffective, or schizophreniform disorders diagnosed as per the DSM-IV criteria; included at least 1 neuropsychological task or an MRI; compared at least 2 groups of patients, one of which comprised patients with a history of suicide DWWHPSWV� �GH¿QHG� DV� DQ\� DFW� FDUULHG� RXW� ZLWK� D� FHUWDLQ�intent to die and different from self-mutilation37) or with D�KLVWRU\�RI�KRPLFLGH��GH¿QHG�DV�IDWDO�LQMXULHV�LQÀLFWHG�E\�a person with intent to injure or kill another person2). The VWXG\�VHOHFWLRQ�SURFHVV�LV�VKRZQ�RQ�D�FKDUW�ÀRZ�GLDJUDP�LQ�Figure 1.

Results

7KH� V\VWHPDWLF� OLWHUDWXUH� UHYLHZ� LGHQWL¿HG� �� QHXUR�psychological studies (eTable 1) and 12 brain imaging studies (eTable 2).

Neuropsychological StudiesThree studies explored executive functions in relation to homicide in schizophrenia (for a total of 82 patients with a history of homicidal behaviour, 89 patient control subjects, and 61 healthy control subjects) (Table 3). In comparison to patients with schizophrenia without such a history, patients with schizophrenia and a history of homicidal behaviour performed more poorly on several executive functions, including mental shifting, cognitive inhibition, and verbal ÀXHQF\�40�,Q�DGGLWLRQ��H[HFXWLYH�GH¿FLWV�ZHUH�PRUH�FRPPRQ�in people with schizophrenia regardless of their history of violence, compared with patients with antisocial personality disorder only.40 However, 2 other studies reported no such group differences.41,42

In the case of suicidal behaviour, 5 studies were found (including 1 prospective study) that showed contradictory results (328 patients with a history of suicidal behaviour; 453 patient control subjects). In 2 studies, outpatient suicide attempters with schizophrenia tended to outperform nonattempters with schizophrenia in executive functioning, QDPHO\��RQ�PHDVXUHV�RI�DWWHQWLRQ�DQG�YHUEDO�ÀXHQF\�43 and FRJQLWLYH�ÀH[LELOLW\�43,44 However, the 3 other studies did not ¿QG�DQ\�JURXS�GLIIHUHQFH�LQ�H[HFXWLYH�SHUIRUPDQFHV�45–47

Neuroimaging StudiesStructural Neuroimaging Studies

Five studies were found in relation to homicidal risk (130 patients with a history of homicidal behaviour, 114 patient control subjects). Patients with schizophrenia and with a prior homicide history showed various brain structural abnormalities, including reduced whole brain volume,48 cortical thinning,49–51 particularly in the medial inferior frontal cortex,49,51 a decrement of temporal48,51 and hippocampus volumes,52 an increment in the volume of the amygdala and the putamen,48 a reduction in the volume of the sensorimotor areas,49 a reduction in the volume of the grey matter in the cerebellum, angular gyrus, and supramarginal

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Neurocognitive Vulnerability: Suicidal and Homicidal Behaviours in Patients With Schizophrenia

Figure 1 Selection of neuropsychological and neuroimaging studies in patients with

schizophrenia at risk of suicidal or homicidal behaviours

Figure 1 Selection of neuropsychological and neuroimaging studies in patients with schizophrenia at risk

of suicidal (left) or homicidal (right) behaviours

[Layout: Please add a footnote: All terms set in quotations are MeSH terms]

“schizophrenia” or “psychotic disorders” and “suicide”

and

“magnetic resonance imaging”; “diffusion magnetic resonance imaging”; “positron-emission tomography”; “prefrontal cortex”; “tomography, emission-computed, single-photon”; “diffusion tensor imaging”; “cognition”; “neuropsychology”; “neuropsychological tests”; “executive function”; “decision making”; “problem solving”; “neuroimaging”

Relevant abstracts (n = 130)

Full-text articles assessed for eligibility (n = 15)

Studies included (n = 7)

Examined titles and abstracts excluded (n = 115): repetition (n = 7); no subjects diagnosed with a schizophrenia spectrum disorder (n = 38); not published in a peer-reviewed, English-or French-language journal (n = 11); no reported samples of suicidal behaviours (n = 46); no reported samples of neurocognitive issues (n = 13)

Excluded (n = 8): no neurocognitive details or no nonsuicidal comparison group

"schizophrenia" or "psychotic disorders" and "violence" or "homicide"

and

"magnetic resonance imaging"; "diffusion magnetic resonance imaging"; "positron-emission tomography"; "prefrontal cortex"; "tomography, emission-computed, single-photon"; "diffusion tensor imaging"; "cognition"; "neuropsychology"; "neuropsychological tests"; "executive function"; "decision making"; "problem solving"; "neuroimaging"

R l t b t t ( 1668)Relevant abstracts (n = 1668)

Examined titles and abstracts excluded (n = 1628): repetition (n = 8); no subjects diagnosed with a schizophrenia spectrum disorder (n = 1457); not published in a peer-reviewed, English-or French language journal (n = 70); no reported samples of those charged with a homicide or

Full-text articles assessed for eligibility (n = 40)

or French-language journal (n = 70); no reported samples of those charged with a homicide orcriminal offence (n = 46); no reported samples of neurocognitive issues (n = 47)

Excluded (n = 28): no well-done reported samples (n =10); no neurocognitive details (n = 6); any homicidal act registered (n = 11), no nonhomicidal comparison group (n = 1)

Studies included (n = 12)

Risk of homicidal behaviour

Risk of suicidal behaviour

All terms set in quotations are MeSH terms.

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Systematic Review

gyrus,50 a reduction in the grey matter volume in the right parahippocampal gyrus, and a grey matter augmentation in the mediofrontal cortex,52 compared with patients with no history of homicidal behaviours.Regarding suicidal acts, 3 studies were found (37 patients with a history of suicidal behaviour, 105 patient control subjects, and 100 healthy control subjects). In patients with schizophrenia and a history of suicide attempt(s), compared with patients with schizophrenia and no suicidal KLVWRU\��WKHUH�ZDV�D�VLJQL¿FDQW�UHGXFWLRQ�LQ�WKH�JUH\�PDWWHU�volume in the left superior temporal lobe and in the left orbitofrontal cortex.53 In addition, there was evidence of VLJQL¿FDQWO\� ODUJHU� LQIHULRU� IURQWDO� ZKLWH� PDWWHU� YROXPHV�bilaterally.54 There was also a selective increase in volume in the right amygdala of patients with a history of suicidal acts, compared with patients without such history and with healthy control subjects.55

Functional Neuroimaging Studies

We found 4 functional neuroimaging studies pertaining patients with homicidal behaviours. These studies reported reduced activation in the right frontal and inferior parietal areas in a working memory paradigm,56 and greater activation in the left medial frontal–cingulate gyrus and bilaterally in the temporal-occipital regions in an experimental manipulation of anticipatory fear induction,57 in patients with schizophrenia with previous homicidal acts, compared with those without. Violent patients with schizophrenia with both comorbid antisocial personality DQG�68'�IDLOHG�WR�VKRZ�KLJKHU�EORRG�ÀRZ�LQ�WKH�RUELWDO�RU�basal regions during the inhibition part of the go–no-go task, compared with patients with schizophrenia only and with

nonviolent healthy control subjects.58�)XUWKHU��VLJQL¿FDQWO\�higher activation in frontal motor, premotor, and anterior cingulate regions were observed in this particular group, compared with patients with schizophrenia only.No functional neuroimaging studies were found in relation to suicidal acts in patients with schizophrenia.

Discussion

2XU� VWXG\� SURYLGHV� WKH� ¿UVW� V\VWHPDWLF� OLWHUDWXUH� UHYLHZ��UHYHDOLQJ�WKH�IROORZLQJ�¿QGLQJV��1) a paucity of available data regarding the

neurocognitive markers of homicidal and suicidal risk in patients with schizophrenia, which contrasts with the accumulating data in mood disorders36;

2) although the neuropsychological and functional neuroimaging studies were inconclusive, structural neuroimaging studies generally support the existence of alterations in patients with a history of suicidal or homicidal acts, compared with patients with no history; and

3) no study has directly compared suicidal and homicidal patients.

%HIRUH�D�GHWDLOHG�GLVFXVVLRQ�RI�WKHVH�¿QGLQJV��ZH�PXVW�VWDUW�by highlighting several main limitations. First, the number of studies available, to date, is small, particularly the ones LQYHVWLJDWLQJ� VXLFLGDO� DFWV�� WKXV� KLQGHULQJ� DQ\� GH¿QLWLYH�conclusions. We selected only studies that compared at least 2 groups of patients; one comprised of patients with either a history of suicide attempts or a history of homicide. This LV�WKH�EHVW�ZD\�WR�HYDOXDWH�VSHFL¿F�YXOQHUDELOLW\�WR�VXLFLGDO�

Table 3 Neurocognitive performances associated with homicidal and suicidal vulnerability in schizophrenia

Patient with schizophrenia

Cognitive domain TaskHomicidal, compared with nonhomicidal (study)

Suicidal, compared with nonsuicidal (study)

Executive functions EGT Altered (Barkataki et al40) No difference (Barrett et al46; Delaney et al47)

Motor control FTT No difference (Lafayette et al41; Silver et al42) No difference (Potkin et al45)

Cognitive inhibition Stroop No difference (Lafayette et al41) Altered (Barkataki et al40)

Go–no-go No difference (Lafayette et al41)Altered (Joyal et al58)

Negative priming Altered (Enticott et al64)

&RJQLWLYH�ÀH[LELOLW\ WCST No difference (Lafayette et al41)Altered (Barkataki et al40)

Better (Kim et al44)

TMT No difference (Lafayette et al41) Better (Nangle et al43)No difference (Potkin et al45)

9HUEDO�ÀXHQF\ FAS No difference (Lafayette et al41) Better (Nangle et al43; Kim et al44)No difference (Potkin et al45)

Attention CPT No difference (Silver et al42)Altered (Barkataki et al40)

Better (Nangle et al43) No difference (Potkin et al45)

CPT = continuous performance test; EGT = executive golf task; FAS = F, A, S Letter Fluence; FTT = Finger Tapping test; TMT = Trail-Making Task; WCST = Wisconsin Card Sorting Test

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Neurocognitive Vulnerability: Suicidal and Homicidal Behaviours in Patients With Schizophrenia

and homicidal behaviour in schizophrenia. Second, the populations studied were very heterogeneous in terms of sociodemographic and clinical characteristics. For instance, some studies included only male subjects,40,42,48,49,51,53,56–58 whereas others grouped male and female participants together.41,43,44,46,50,54,55,59–64 Additional limitations include the small sample sizes; the lack of information on substance abuse or medication; the variability of the primary diagnosis42,46,61,62; and that comorbid antisocial personality disorder was often not assessed.40,48,49,56,58 Moreover, the severity of the psychopathology of a subject, the recurrence RI�SV\FKRWLF�HSLVRGHV��DV�ZHOO�DV�WKH�DJH�RI�WKH�¿UVW�HSLVRGH�SV\FKRVLV�� DUH� RIWHQ� RPLWWHG� DQG� PD\� DOVR� LQÀXHQFH�the variability of results. Moreover, substance abuse in schizophrenia is associated with an increased risk of violent homicide in longitudinal studies12,65 and with suicidal behaviour.18

7KH�GH¿QLWLRQV�RI�VXLFLGDO�DQG�KRPLFLGDO�EHKDYLRXUV�ZHUH�also heterogeneous. The studies included patients with a history of suicide attempts,43,46,53–55,63 suicide attempters with suicidal ideations,44,62 patients who had committed homicide,58 patients with a history of severe violence, including homicide and attempted homicide.41,42,50,59,64,66 Additionally, some authors differentiated severe from less severe suicidal and homicidal acts.The methodology of the studies reviewed also varied. For instance, the delay between the suicidal or the homicidal act and the neuropsychological assessment varied. The tools used to assess suicidal and homicidal behaviours and neurocognitive markers also differed. For example, homicidal behaviour was evaluated using the Gunn and Robertson scale, with a cut-off score of 440,48,56 or 5.51,57 In addition, while some authors used only a single neuropsychological test to evaluate cognitive processes, others used a larger battery of tests.Despite these limitations, there are several important implications that can be derived from our review. First, more homogeneity in assessment is required if we are to understand the neurocognitive basis of the vulnerability to homicidal and suicidal risks in schizophrenia. Second, many more neuropsychological and neuroimaging studies are needed. Data from mood disorders largely support the concept of vulnerability to suicidal behaviour, including but not limited to impairment in decision making67,68 and cognitive inhibition.69–72 In addition, structural and functional neuroimaging have implicated several brain regions, including the orbifrontal, dorsolateral, and dorsomedial prefrontal cortices.36 These cognitive GH¿FLWV�DQG�EUDLQ�G\VIXQFWLRQV�PD\�EHFRPH�SDUW�RI�IXWXUH�assessments and the target of future interventions to reduce the suicidal or homicidal risks.Among the studies published to date pertaining to patients with schizophrenia and a history of suicidal or homicidal DFWV�� PRVW� ¿QGLQJV� FRPH� IURP� VWUXFWXUDO� QHXURLPDJLQJ��Nine studies investigated the homicidal risk in schizophrenia and reported reduced inferior frontal and temporal volume, and increased amygdala volume.48 These results are consistent with previous studies implicating these regions with psychopathy scores, history of violence, antisocial

personality disorder diagnosis, or impulsiveness.57,58,73,74 A recent meta-analysis suggested that patients with a history of violent behaviour, including homicide, were DVVRFLDWHG� ZLWK� VLJQL¿FDQWO\� UHGXFHG� SUHIURQWDO� VWUXFWXUH�and function (right orbitofrontal cortex, right anterior cingulate cortex, and left dorsolateral prefrontal cortex).75 Moreover, in the review by Naudts and Hodgins,76 male patients with schizophrenia who consistently showed a pattern of aggressive and antisocial behaviour had poorer orbitofrontal functions, an increased size of the putamen, and reduced volumes of the amygdala, the hippocampus, and the orbitofrontal cortex, compared with patients with schizophrenia with no history of violence.Literature also suggests that, among patients with schizophrenia, those who present with conduct problems from childhood onward perform better on tests assessing VSHFL¿F� H[HFXWLYH� IXQFWLRQV��+RZHYHU�� WKH\� DOVR� SHUIRUP�more poorly on assessments of orbitofrontal functions, show fewer neurological soft signs, display larger reductions in the amygdala volume, more structural abnormalities in the orbitofrontal cortex, more abnormalities of white matter in the amygdala–orbitofrontal cortex, and smaller reductions of the hippocampus.76 Only one study58 explored neurocognitive pathways of homicidal behaviour and tried to distinguish subtypes of homicide offenders who differ in comorbidity associated with schizophrenia. Using functional MRI, they showed homicidal people with schizophrenia and comorbid antisocial personality disorder and SUD would present a different pattern of prefrontal functioning than homicidal people with schizophrenia RQO\��)URQWDO�EDVDO�FRUWLFHV�ZHUH�VLJQL¿FDQWO\�OHVV�DFWLYDWHG�in people with schizophrenia and comorbidity during the execution of a go–no-go task than in people with schizophrenia only and nonviolent people without mental LOOQHVV�� ,Q� FRQWUDVW�� VLJQL¿FDQWO\� KLJKHU� DFWLYDWLRQV� LQ�frontal motor, premotor, and anterior cingulate regions were observed in the schizophrenia plus comorbidity group than in the schizophrenia only group.58 More studies are needed to disentangle possible subtypes of homicidal histories and their neural basis.Fewer results were found in patients with histories of suicidal acts. Interestingly, decreased orbitofrontal and temporal cortical volumes, and increased amygdala volume were reported, suggesting partial overlap with vulnerability to homicidal behaviour. Also, decreased orbitofrontal cortex volume and increased amygdala volume,77 and altered orbitofrontal cortex activation78 were found in patients with a mood disorder and a history of suicidal behaviour. Biochemical alterations were also found in the orbitofrontal cortex of depressed suicide completers.79 Taken together, WKHVH� ¿QGLQJV� VXJJHVW� WKDW� VRPH� EUDLQ� DOWHUDWLRQV� RFFXU�across diagnoses.

Conclusion

Schizophrenia is associated with numerous cognitive and brain alterations.80�2XU�VWXG\�VXJJHVWV��ZLWKRXW�FRQ¿UPLQJ��that particular brain alterations may add to other disease-UHODWHG� GH¿FLWV� �IRU� H[DPSOH�� KDOOXFLQDWLRQ� DQG� WHPSRUDO�cortex) to affect a patient’s ability to perceive and respond

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Systematic Review

DGHTXDWHO\� WR� WKHLU� HQYLURQPHQW�� 6SHFL¿F� GH¿FLWV� LQ� WKH�prefrontal–limbic circuitry may predispose some patients with schizophrenia to homicidal behaviour or to suicidal behaviour.More studies are needed and future research should directly compare neurocognitive markers of suicidal and homicidal risk. Cohort studies are also necessary to determine the predictive power of these markers. Finally, targeting these GH¿FLWV�PD\�EH�SDUW�RI� IXWXUH� WKHUDSHXWLF� LQWHUYHQWLRQV� LQ�at-risk patients.

Acknowledgements

1RQH�RI�WKH�DXWKRUV�KDYH�DQ\�FRPSHWLQJ�¿QDQFLDO�LQWHUHVWV�for this manuscript. Dr Richard-Devantoy received a grant from the Canadian Institute for Health Research. Dr Turecki and Dr Jollant received a salary grant from the Fond de Recherche du Québec—Santé (FRQS). Dr Dumais received a fellowship grant from the FRSQ. None of the IXQGLQJ�ERGLHV�LQÀXHQFHG�WKH�SURMHFW��WKH�DQDO\VHV��DQG�WKH�publication of this article.

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