Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive
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Neuropsychopharmacology (2015) 40, 2596–2603 © 2015 American College of Neuropsychopharmacology. All rights reserved 0893-133X/15 www.neuropsychopharmacology.org Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [11C] Harmine Positron Emission Tomography Study 1,2,3,4 1,2 1,2,3 1,2,3 1,2,3,5 Nathan J Kolla , Brittany Matthews , Alan A Wilson , Sylvain Houle , R Michael Bagby , 4,6 3 1,2 *,1,2,3,4 Paul Links , Alexander I Simpson , Amina Hussain and Jeffrey H Meyer 1Centre for Addiction and Mental Health (CAMH) Research Imaging Centre, Toronto, Ontario, Canada; 2Campbell Family Mental Health Research 3 4 Institute, CAMH, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical 5 6 Science, University of Toronto, Toronto, Ontario, Canada; Department of Psychology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Western Ontario, Toronto, Ontario, Canada Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain 11 MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [ C] harmine PET to measure MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A V were lower in ASPD compared with controls (multivariate analysis of variance T (MANOVA): F = 6.8, P = 0.003; OFC and VS MAO-A V each lower by 19%). Similar effects were observed in other brain regions: 2,33 T = = prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F7,28 2.7, P 0.029). In = − − ASPD, VS MAO-A VT was consistently negatively correlated with self-report and behavioral measures of impulsivity (r 0.50 to 0.52, all P-valueso0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity. Neuropsychopharmacology (2015) 40, 2596–2603; doi:10.1038/npp.2015.106; published online 29 July 2015 INTRODUCTION investigations in clinically diagnosed individuals with the condition, although brain phenotypes such as low orbito- The vast majority of violent crime is perpetrated by a small frontal cortex (OFC) 5-HT2A receptor binding in impulsive group of males who exhibit conduct-disordered behavior males with ASPD (Meyer et al, 2008; Rylands et al, 2012) and from childhood onward and fulfill diagnostic criteria for increased amphetamine-induced nucleus accumbens dopa- antisocial personality disorder (ASPD) as adults (Moffitt mine release in humans with high impulsive-antisocial et al, 2002). Pathological impulsivity is a core symptom of psychopathic traits (Buckholtz et al, 2010) have been ASPD (Swann et al, 2009) that relates to the aversive reported. However, low brain monoamine oxidase-A behaviors and comorbidities associated with the disorder, (MAO-A), an enzyme localized to outer mitochondrial including violent offending (Zhou et al, 2014) and alcohol membranes that metabolizes amine neurotransmitters dependence (AD) (Rubio et al, 2008). There are very few implicated in aggressive behavior (Bortolato et al, 2008), molecular imaging studies of ASPD and, to the best of our has emerged as a promising molecular target. knowledge, no abnormalities are identified from postmortem Multiple tiers of evidence from preclinical and clinical studies support a strong relationship between low or absent MAO-A and impulsive aggression. First, males with a rare *Correspondence: Dr JH Meyer, Centre for Addiction and Mental Health Research Imaging Centre, 250 College St, Toronto, Ontario point mutation in the eighth exon of the MAO-A gene M5T 1R8, Canada, Tel: +1 416 535 8501, Fax: +1 416 979 4656, leading to complete and selective deficiency of MAO-A E-mail: [email protected] exhibit severely impulsive and aggressive behavior (Brunner Received 30 October 2014; revised 9 March 2015; accepted 10 March et al, 1993). Second, positron emission tomography (PET) 2015; accepted article preview online 17 June 2015 studies of healthy humans that used MAO-A-selective Lower monoamine oxidase-A in impulsive and violent males NJ Kolla et al 2597 radiotracers found inverse relationships between MAO-A also exclusionary. Sixty-seven percent of the ASPD sample binding in several brain regions and self-reported anger, had no lifetime exposure to psychotropic medication: four aggression, and hostility (Alia-Klein et al, 2008; Soliman subjects had brief exposures to psychostimulants as children et al, 2011). Third, targeted knockout of MAO-A in mouse but had not taken psychotropic medication as adults. One embryonic stem cells produces impulsively aggressive adult subject received intermittent treatment with an atypical mice (Cases et al, 1995; Scott et al, 2008). Fourth, antipsychotic to manage acute aggression while previously pharmacological inhibition of MAO-A during murine incarcerated but had not been treated in over 5 years. embryogenesis increases impulsive aggression on pharma- Another subject was taking clonazepam intermittently until cologic challenge in adult mice (Mejia et al, 2002). Fifth, 2 months prior to study enrollment. Nine subjects addition- MAO-A genetic polymorphisms that are associated with ally met criteria for current AD. lower MAO-A transcription in cell lines have been found to interact with childhood adversity to increase the risk of adult Control Subjects violent convictions (Caspi et al, 2002). However, it has never been empirically determined whether brain MAO-A is lower Control subjects consisted of nine males with AD and nine in violent and clinically impulsive populations. To address subjects without AD. ASPD subjects were matched to this critical issue, the principal aim of the study was to controls based on the presence or absence of AD comorbid- measure MAO-A total distribution volume (MAO-A VT), an ity, given the association of AD with global alterations of index of MAO-A level, in the brains of highly impulsive, brain MAO-A VT (Matthews et al, 2014). Therefore, we violent offenders with ASPD. included controls with AD to optimize matching. Control [11C] Harmine is a PET radiotracer ideally suited to subjects without AD were screened with the SCID I and measure MAO-A level, because it is reversible, selective for SCID II by an experienced rater and verified by review with a the MAO-A isoenzyme, and binds with high affinity to the psychiatrist (JHM). These subjects had no history of substrate cavity in the center of the MAO-A enzyme (Son psychiatric illness and had not endorsed conduct disorder et al, 2008). Lower MAO-A levels are associated with lower symptoms as children or youth. Control subjects with AD MAO-A activity in the brain (Saura et al, 1992). were also screened with the SCID I and SCID II, which was We hypothesized that MAO-A VT would be lower in the verified by a psychiatrist (JHM). This subset of controls had OFC and ventral striatum (VS) of ASPD with impulsive no lifetime history of additional psychiatric illness, including violence and that OFC and VS MAO-A VT would vary ASPD. One AD subject had been treated with diazepam for inversely with measures of impulsivity. The OFC and VS alcohol withdrawal 15 years prior to his involvement in the were chosen as the main regions of interest (ROI), because study. None of the other control participants had any they show consistent functional and/or biological abnorm- previous psychotropic medication exposure. Control subjects alities in ASPD and aggressive behavior (Blair, 2004; were age-matched within 4 years to the ASPD participants. Buckholtz et al, 2010; Glenn and Yang, 2012; Meyer et al, Control subjects formed a subset of participants from 2008; Rylands et al, 2012) and are key structures in the neural previously published studies in our laboratory (Matthews circuitry mediating impulsivity (Dalley et al, 2011). et al, 2014; Soliman et al, 2011). None of the study subjects was a current smoker: 38.9% of the ASPD subjects and 33.3% of the control subjects were past smokers (P = 1.0, two-tailed MATERIALS AND METHODS Fisher’s exact test). Non-smoking status was verified in the Participants ASPD and AD control subjects by self-report and breath- alyzer testing for carbon monoxide (MicroSmokerlyzer; Thirty-six males completed the study protocol: 18 partici- Bedfont Scientific, Kent, United Kingdom) and by self- pants with ASPD and 18 control participants without ASPD. report in the healthy control subjects. All subjects provided Each participant provided written consent following expla- negative urine drug screen tests on assessment and PET nation of study procedures. All study components were scanning days. Study subjects