Stephen J. Kish

University of Toronto, Toronto, Ontario, Canada

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Publications (265)1714.42 Total impact

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    ABSTRACT: Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [(11) C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [(11) C]-(+)-PHNO binding in D3 -rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [(11) C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [(11) C]-(+)-PHNO binding is associated with D2 receptor levels, [(11) C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved. © 2015 International Parkinson and Movement Disorder Society. © 2015 International Parkinson and Movement Disorder Society.
    Movement Disorders 01/2015; 30(2). DOI:10.1002/mds.26135 · 5.63 Impact Factor
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    ABSTRACT: (11)C-carbonyl-URB694 ((11)C-CURB) is a novel (11)C-labeled suicide irreversible radiotracer for PET developed as a surrogate measure of activity of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase. The aim of the study was to investigate the whole-body biodistribution and estimate the radiation dosimetry from (11)C-CURB scans in humans. Six healthy volunteers (3 men and 3 women) completed a single whole-body scan (∼120 min, 9 time frames) on a PET/CT scanner after administration of (11)C-CURB (∼350 MBq and ∼2 μg). Time-radioactivity curves were extracted in 11 manually delineated organs and corrected for injected activity, specific organ density, and volume to obtain normalized cumulated activities. OLINDA/EXM 1.1 was used to estimate standard internal dose exposure in each organ. The mean effective dose was calculated using the male and female models for the full sample and female-only sample, respectively. (11)C-CURB was well tolerated in all subjects, with no radiotracer-related adverse event reported. The mean effective dose (±SD) was estimated to be 4.6 ± 0.3 μSv/MBq for all subjects and 5.2 ± 0.3 μSv/MBq for the female sample. Organs with the highest normalized cumulated activities (in h) were the liver (0.117), gallbladder wall (0.046), and small intestine (0.033), and organs with the highest dose exposure (in μGy/MBq) were the gallbladder wall (111 ± 60), liver (21 ± 7), kidney (14 ± 3), and small intestine (12 ± 2). Organ radiation exposure for the irreversible fatty acid amide hydrolase enzyme probe (11)C-CURB is within the same range as other radiotracers labeled with (11)C, thus allowing for safe, serial PET scans in the same individuals. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 11/2014; DOI:10.2967/jnumed.114.146464 · 5.56 Impact Factor
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    ABSTRACT: Animal data show that high doses of the stimulant drug methamphetamine can damage brain dopamine neurones; however, it is still uncertain whether methamphetamine, at any dose, is neurotoxic to human brain. Since gliosis is typically associated with brain damage and is observed in animal models of methamphetamine exposure, we measured protein levels (intact protein and fragments, if any) of markers of microgliosis (glucose transporter-5, human leukocyte antigens HLA-DRα [TAL.1B5] and HLA-DR/DQ/DPβ [CR3/43]) and astrogliosis (glial fibrillary acidic protein, vimentin, and heat shock protein-27) in homogenates of autopsied brain of chronic methamphetamine users (n=20) and matched controls (n=23). Intact protein levels of all markers were, as expected, elevated (+ 28%-1270%, P< 0.05) in putamen of patients with the neurodegenerative disorder multiple system atrophy (as a positive control) as were concentrations of fragments of glial fibrillary acidic protein, vimentin and heat shock protein-27 (+ 170%-4700%, P< 0.005). In contrast, intact protein concentrations of the markers were normal in dopamine-rich striatum (caudate, putamen) and in the frontal cortex of the drug users. However, striatal levels of cleaved vimentin and heat shock protein-27 were increased (by 98%-211%, P< 0.05), with positive correlations (r=0.41-0.60) observed between concentrations of truncated heat shock protein-27 and extent of dopamine loss (P= 0.006) and levels of lipid peroxidation products 4-hydroxynonenal (P= 0.046) and malondialdehyde (P= 0.11). Our failure to detect increased intact protein levels of commonly used markers of microgliosis and astrogliosis could be explained by exposure to methamphetamine insufficient to cause a toxic process associated with overt gliosis; however, about half of the subjects had died of drug intoxication suggesting that “high” drug doses might have been used. Alternatively, drug tolerance to toxic effects might have occurred in the subjects, who were all chronic methamphetamine users. Nevertheless, the finding of above-normal levels of striatal vimentin and heat shock protein-27 fragments (which constituted 10-28% of the intact protein), for which changes in the latter correlated with those of several markers possibly suggestive of damage, does suggest that some astrocytic “disturbance” had occurred, which might in principle be related to methamphetamine neurotoxicity or to a neuroplastic remodeling process. Taken together, our neurochemical findings do not provide strong evidence for either marked microgliosis or astrogliosis in at least a subgroup of human recreational methamphetamine users who used the drug chronically and shortly before death. However, a logistically more difficult quantitative histopathological study is needed to confirm whether glial changes occur or do not occur in brain of human methamphetamine (and amphetamine) users.
    Neurobiology of Disease 07/2014; DOI:10.1016/j.nbd.2014.03.015 · 5.20 Impact Factor
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    ABSTRACT: IMPORTANCE Perimenopause is a period of high risk for mood disorders, and it has been proposed that perimenopause is also a window of risk for processes linked to later dementia. However, in human perimenopause, the neurobiological changes implicated in the genesis of mood disorders or dementia have not been identified. Monoamine oxidase A (MAO-A) is an important brain enzyme that creates oxidative stress, influences apoptosis, and metabolizes monoamines. After declines in estrogen level, MAO-A density may be elevated for a month or longer, and repeated declines in estrogen level occur with greater magnitude during perimenopause. OBJECTIVE To investigate whether MAO-A total distribution volume (VT), an index of MAO-A density, is elevated in women of perimenopausal age (41-51 years). DESIGN, SETTING, AND PARTICIPANTS In a cross-sectional study at a tertiary care psychiatric hospital, 58 women underwent carbon 11-labeled harmine positron emission tomography. These included 19 young women of reproductive age (mean [SD], 28.26 [5.05] years), 27 women of perimenopausal age (mean [SD] age, 45.21 [3.41] years; including 14 women with change in menstrual cycle length with a mean [SD] age of 45.50 [4.00] years and 13 women with no change in menstrual cycle length with a mean [SD] age of 44.92 [2.81] years), and 12 women in menopause (mean [SD] age, 56.25 [3.19] years). MAIN OUTCOMES AND MEASURES Values of MAO-A VT in the prefrontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, thalamus, hippocampus, and midbrain. RESULTS On average, MAO-A VT in perimenopausal age was elevated by 34% compared with reproductive age and by 16% compared with menopause (multivariate analysis of variance, group effect, F16,94 = 3.03; P < .001). Within the perimenopausal age group, meeting Stages of Reproductive Aging Workshop criteria for perimenopause, which is mainly based on menstrual cycle length, was not associated with MAO-A VT (F8,18 = 0.548; P = .81) but tendency to cry was positively correlated with MAO-A VT in the prefrontal cortex (r = 0.54; P = .008). CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report of a change in a central biomarker during perimenopausal age that is also present during major depressive episodes and high-risk states for major depressive episodes. The functions of MAO-A influence oxidative stress and apoptosis, 2 processes implicated as excessive in both mood disorders and dementia. Hence, greater MAO-A VT during perimenopause may represent a new target for assessing novel interventions to prevent mood disorders and reduce longer-term risk of neurodegenerative disease.
    JAMA Psychiatry 06/2014; 71(8). DOI:10.1001/jamapsychiatry.2014.250 · 12.01 Impact Factor
  • Journal of clinical psychopharmacology 04/2014; 34(3). DOI:10.1097/JCP.0b013e3182a95a27 · 5.09 Impact Factor
  • JAMA Psychiatry 01/2014; · 12.01 Impact Factor
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    ABSTRACT: Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the D3 receptor-preferring radioligand [(11)C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n=12) and healthy controls (n=11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54-63% greater [(11)C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by D3 receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, and support the hypothesis that dopaminergic sensitization involving D3-related mechanisms might contribute to the pathophysiology of behavioral addictions.Molecular Psychiatry advance online publication, 10 December 2013; doi:10.1038/mp.2013.163.
    Molecular Psychiatry 12/2013; 19(12). DOI:10.1038/mp.2013.163 · 15.15 Impact Factor
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    ABSTRACT: Inadequate treatment response occurs in approximately 40% of major depressive episodes (MDE), and one approach to solve this is careful matching of treatment to the specific pathologies of MDE. One such biological abnormality is elevated monoamine oxidase A (MAO-A) levels, which occurs primarily in the prefrontal and anterior cingulate cortex (PFC and ACC) during MDE however, the subtypes for which this abnormality is most prominent are unknown. We hypothesized that MAO-A levels in the PFC and ACC are most elevated in MDE with greater severity and reversed neurovegetative symptoms (hypersomnia and either hyperphagia or weight gain). MAO-A VT (an index of MAO-A density) was measured using [(11)C]harmine positron emission tomography (PET) in 42 subjects with MDE secondary to major depressive disorder (MDD) and 37 healthy controls. The effect of severity and reversed neurovegetative symptoms on MAO-A VT in the PFC and ACC were analyzed using a multivariate analysis of variance (MANOVA). Greater severity and reversed neurovegetative symptoms were associated with elevated MAO-A VT in the PFC and ACC (MANOVA, severity: F (2,38)=5.44, p=0.008; reversed neurovegetative symptoms: F (2,38) =5.13, p=0.01). Increased MAO-A level, when greater severity and reversed neurovegetative symptoms are present, may explain the association of these clinical features with a preferential response to MAO inhibitors, which is especially well-evidenced for reversed neurovegetative symptoms in MDE. Since MAO-A creates oxidative stress, facilitates apoptosis and metabolizes monoamines, therapeutics opposing these processes are predicted to best treat MDE with greater severity and reversed neurovegetative symptoms.Neuropsychopharmacology accepted article preview online, 24 October 2013; doi:10.1038/npp.2013.297.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2013; DOI:10.1038/npp.2013.297 · 8.68 Impact Factor
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    ABSTRACT: Alcohol dependence (AD) is a multiorgan disease in which excessive oxidative stress and apoptosis are implicated. Monoamine oxidase A (MAO-A) is an important enzyme on the outer mitochondrial membrane that participates in the cellular response to oxidative stress and mitochondrial toxicity. It is unknown whether MAO-A levels are abnormal in AD. We hypothesized that MAO-A VT, an index of MAO-A level, is elevated in the prefrontal cortex (PFC) during AD, because markers of greater oxidative stress and apoptosis are reported in the brain in AD and a microarray analysis reported greater MAO-A messenger RNA in the PFC of rodents exposed to alcohol vapor. Sixteen participants with alcohol dependence and 16 healthy control subjects underwent [(11)C]-harmine positron emission tomography. All were nonsmoking, medication- and drug-free, and had no other past or present psychiatric or medical illnesses. MAO-A VT was significantly greater in the PFC (37%, independent samples t test, t30 = 3.93, p < .001), and all brain regions analyzed (mean 32%, multivariate analysis of variance, F7,24 = 3.67, p = .008). Greater duration of heavy drinking correlated positively with greater MAO-A VT in the PFC (r = .67, p = .005) and all brain regions analyzed (r = .73 to .57, p = .001-.02). This finding represents a new pathological marker present in AD that is therapeutically targetable through direct inhibition or by novel treatments toward oxidative/pro-apoptotic processes implicated by MAO-A overexpression.
    Biological psychiatry 10/2013; DOI:10.1016/j.biopsych.2013.10.010 · 8.93 Impact Factor
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    ABSTRACT: The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioural relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [(11)C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7-240 days on scan day) and 15 matched healthy control (HC) subjects completed two PET scans: One with [(11)C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [(11)C]raclopride to assess D2/3 binding. CD subjects also completed a behavioural battery to characterize the addiction behavioural phenotype. CD subjects showed higher [(11)C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioural impulsiveness and risky decision-making. In contrast, [(11)C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in 2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment.Neuropsychopharmacology accepted article preview online, 7 August 2013. doi:10.1038/npp.2013.192.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2013; DOI:10.1038/npp.2013.192 · 8.68 Impact Factor
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    ABSTRACT: AimsPathological gambling (PG) shares diagnostic features with substance use disorder (SUD), but the neurochemical mechanisms underlying PG are poorly understood. Because dopamine (DA), a neurotransmitter implicated in reward and reinforcement, is probably involved, we used positron emission tomography (PET) to test whether PG is associated with abnormalities in D2 and D3 receptor levels, as observed in SUD. DesignCase–control study comparing PG to healthy control (HC) subjects. SettingAcademic research imaging centre. ParticipantsThirteen non-treatment-seeking males meeting DSM-IV criteria for PG, and 12 matched HC (11 of whom completed PET). MeasurementsTwo PET scans (one with the D3 receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) and the other with [11C]raclopride) to assess D2/3 DA receptor availability, and behavioural measures (self-report questionnaires and slot-machine game) to assess subjective effects and relationships to PET measures. FindingsBinding of both radiotracers did not differ between groups in striatum or substantia nigra (SN) (all P > 0.1). Across PG, [11C]-(+)-PHNO binding in SN, where the signal is attributable primarily to D3 receptors, correlated with gambling severity (r = 0.57, P = 0.04) and impulsiveness (r = 0.65, P = 0.03). In HC, [11C]raclopride binding in dorsal striatum correlated inversely with subjective effects of gambling (r = −0.70, P = 0.03) and impulsiveness (r = −0.70, P = 0.03). Conclusions Unlike with substance use disorder, there appear to be no marked differences in D2/D3 levels between healthy subjects and pathological gamblers, suggesting that low receptor availability may not be a necessary feature of addiction. However, relationships between [11C]-(+)-PHNO binding and gambling severity/impulsiveness suggests involvement of the D3 receptor in impulsive/compulsive behaviours.
    Addiction 05/2013; 108(5). DOI:10.1111/add.12066 · 4.60 Impact Factor
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    ABSTRACT: Positron emission tomography (PET) imaging of monoamine oxidases (MAO-A: [(11)C]harmine, [(11)C]clorgyline, and [(11)C]befloxatone; MAO-B: [(11)C]deprenyl-D2) has been actively pursued given clinical importance of MAOs in human neuropsychiatric disorders. However, it is unknown how well PET outcome measures for the different radiotracers are quantitatively related to actual MAO protein levels. We measured regional distribution (n=38) and developmental/aging changes (21 hours to 99 years) of both MAOs by quantitative immunoblotting in autopsied normal human brain. MAO-A was more abundant than MAO-B in infants, which was reversed as MAO-B levels increased faster before 1 year and, unlike MAO-A, kept increasing steadily to senescence. In adults, regional protein levels of both MAOs were positively and proportionally correlated with literature postmortem data of MAO activities and binding densities. With the exception of [(11)C]befloxatone (binding potential (BP), r=0.61, P=0.15), correlations between regional PET outcome measures of binding in the literature and MAO protein levels were good (P<0.01) for [(11)C]harmine (distribution volume, r=0.86), [(11)C]clorgyline (λk(3), r=0.82), and [(11)C]deprenyl-D2 (λk(3) or modified Patlak slope, r=0.78 to 0.87), supporting validity of the latter imaging measures. However, compared with in vitro data, the latter PET measures underestimated regional contrast by ∼2-fold. Further studies are needed to address cause of the in vivo vs. in vitro nonproportionality.Journal of Cerebral Blood Flow & Metabolism advance online publication, 13 February 2013; doi:10.1038/jcbfm.2013.19.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2013; DOI:10.1038/jcbfm.2013.19 · 5.46 Impact Factor
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    ABSTRACT: Endocannabinoid tone has recently been implicated in a number of prevalent neuropsychiatric conditions. [(11)C]CURB is the first available positron emission tomography (PET) radiotracer for imaging fatty acid amide hydrolase (FAAH), the enzyme which metabolizes the prominent endocannabinoid anandamide. Here, we sought to determine the most suitable kinetic modeling approach for quantifying [(11)C]CURB that binds selectively to FAAH. Six healthy volunteers were scanned with arterial blood sampling for 90 minutes. Kinetic parameters were estimated regionally using a one-tissue compartment model (TCM), a 2-TCM with and without irreversible trapping, and an irreversible 3-TCM. The 2-TCM with irreversible trapping provided the best identifiability of PET outcome measures among the approaches studied (coefficient of variation (COV) of the net influx constant K(i) and the composite parameter λk(3) (λ=K(1)/k(2)) <5%, and COV(k(3))<10%). Reducing scan time to 60 minutes did not compromise the identifiability of rate constants. Arterial spin labeling measures of regional cerebral blood flow were only slightly correlated with K(i), but not with k(3) or λk(3). Our data suggest that λk(3) is sensitive to changes in FAAH activity, therefore, optimal for PET quantification of FAAH activities with [(11)C]CURB. Simulations showed that [(11)C]CURB binding in healthy subjects is far from a flow-limited uptake.Journal of Cerebral Blood Flow & Metabolism advance online publication, 5 December 2012; doi:10.1038/jcbfm.2012.180.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2012; DOI:10.1038/jcbfm.2012.180 · 5.46 Impact Factor
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    ABSTRACT: The thalamus occupies a pivotal position within the corticobasal ganglia-cortical circuits. In Parkinson's disease (PD), the thalamus exhibits pathological neuronal discharge patterns, foremost increased bursting and oscillatory activity, which are thought to perturb the faithful transfer of basal ganglia impulse flow to the cortex. Analogous abnormal thalamic discharge patterns develop in animals with experimentally reduced thalamic noradrenaline; conversely, added to thalamic neuronal preparations, noradrenaline exhibits marked antioscillatory and antibursting activity. Our study is based on this experimentally established link between noradrenaline and the quality of thalamic neuronal discharges. We analyzed 14 thalamic nuclei from all functionally relevant territories of 9 patients with PD and 8 controls, and measured noradrenaline with high-performance liquid chromatography with electrochemical detection. In PD, noradrenaline was profoundly reduced in all nuclei of the motor (pallidonigral and cerebellar) thalamus (ventroanterior: -86%, P = .0011; ventrolateral oral: -87%, P = .0010; ventrolateral caudal: -89%, P = .0014): Also, marked noradrenaline losses, ranging from 68% to 91% of controls, were found in other thalamic territories, including associative, limbic and intralaminar regions; the primary sensory regions were only mildly affected. The marked noradrenergic deafferentiation of the thalamus discloses a strategically located noradrenergic component in the overall pathophysiology of PD, suggesting a role in the complex mechanisms involved with the genesis of the motor and non-motor symptoms. Our study thus significantly contributes to the knowledge of the extrastriatal nondopaminergic mechanisms of PD with direct relevance to treatment of this disorder. © 2012 Movement Disorder Society.
    Movement Disorders 10/2012; 27(13). DOI:10.1002/mds.25109 · 5.63 Impact Factor
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    ABSTRACT: Understanding the mortality rate of methamphetamine users, especially in relation to other drug users, is a core component of any evaluation of methamphetamine-related harms. Although methamphetamine abuse has had a major impact on United States (US) drug policy and substance-abuse treatment utilization, large-scale cohort studies assessing methamphetamine-related mortality are lacking. The current study identified cohorts of individuals hospitalized in California from 1990 to 2005 with ICD-9 diagnoses of methamphetamine- (n=74,139), alcohol- (n=582,771), opioid- (n=67,104), cannabis- (n=46,548), or cocaine-related disorders (n=48,927), and these groups were followed for up to 16 years. Age-, sex-, and race-adjusted standardized mortality rates (SMRs) were generated. The methamphetamine cohort had a higher SMR (4.67, 95% CI 4.53, 4.82) than did users of cocaine (2.96, 95% CI 2.87, 3.05), alcohol (3.83, 95% CI 3.81, 3.85), and cannabis (3.85, 95% CI 3.67, 4.03), but lower than opioid users (5.71, 95% CI 5.60, 5.81). Our study demonstrates that individuals with methamphetamine-use disorders have a higher mortality risk than those with diagnoses related to cannabis, cocaine, or alcohol, but lower mortality risk than persons with opioid-related disorders. Given the lack of long-term cohort studies of mortality risk among individuals with methamphetamine-related disorders, as well as among those with cocaine- or cannabis-related conditions, the current study provides important information for the assessment of the comparative drug-related burden associated with methamphetamine use.
    Drug and alcohol dependence 04/2012; 125(3):290-4. DOI:10.1016/j.drugalcdep.2012.03.004 · 3.60 Impact Factor
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    ABSTRACT: Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior. We tested the hypothesis that D3 receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin ([11C]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [11C]-(+)-PHNO. Compared with control subjects, drug users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN; +46%; p<0.02) and in the globus pallidus (+9%; p=0.06) and ventral pallidum (+11%; p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (approximately -4%, NS; -12% in heavy users, p=0.01) and related to drug-use severity. The [11C]-(+)-PHNO binding ratio in D3-rich SN versus D2-rich dorsal striatum was 55% higher in MA users (p=0.004), with heavy but not moderate users having ratios significantly different from controls. [11C]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users, although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2012; 32(4):1353-9. DOI:10.1523/JNEUROSCI.4371-11.2012 · 6.75 Impact Factor
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    ABSTRACT: Monoamine oxidase A (MAO-A) is an important target in the pathophysiology and therapeutics of major depressive disorder, aggression, and neurodegenerative conditions. We measured the effect of changes in MAO-A substrate on MAO-A binding in regions implicated in affective and neurodegenerative disease with [(11)C]-harmine positron emission tomography in healthy volunteers. Monoamine oxidase A V(T), an index of MAO-A density, was decreased (mean: 14%±9%) following tryptophan depletion in prefrontal cortex (P<0.031), and elevated (mean: 17%±11%) in striatum following carbidopa-levodopa administration (P<0.007). These findings suggest an adaptive role for MAO-A in maintaining monoamine neurotransmitter homeostasis by rapidly compensating fluctuating monoamine levels.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2011; 32(3):443-6. DOI:10.1038/jcbfm.2011.184 · 5.46 Impact Factor
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    ABSTRACT: Clinical investigators in Japan have long suggested that exposure to methamphetamine might cause a persistent schizophrenia-like psychosis. This possibility is discounted in the Western literature. To investigate the relationship between drug use and later schizophrenia, the authors conducted a large-scale cohort study of drug users initially free of persistent psychosis. A population-based cohort study was conducted using data from California inpatient hospital discharge records from 1990 through 2000. Patients with methamphetamine-related conditions (N=42,412) and those with other drug use disorders (cannabis, cocaine, alcohol, and opioids) were propensity score-matched to individuals with primary appendicitis who served as a population proxy comparison group; the methamphetamine cohort was also matched to the other drug cohorts. Cox modeling was used to estimate differences between matched groups in the rates of subsequent admission with schizophrenia diagnoses. The methamphetamine cohort had a significantly higher risk of schizophrenia than the appendicitis group (hazard ratio=9.37) and the cocaine, opioid, and alcohol groups (hazard ratios ranging from 1.46 to 2.81), but not significantly different from that of the cannabis group. The risk of schizophrenia was higher in all drug cohorts than in the appendicitis group. Study limitations include difficulty in confirming schizophrenia diagnoses independent of drug intoxication and the possibility of undetected schizophrenia predating drug exposure. The study's findings suggest that individuals with methamphetamine-related disorders have a higher risk of schizophrenia than those with other drug use disorders, with the exception of cannabis use disorders. The elevated risk in methamphetamine users may be explained by shared etiological mechanisms involved in the development of schizophrenia.
    American Journal of Psychiatry 11/2011; 169(4):389-96. DOI:10.1176/appi.ajp.2011.10070937 · 14.72 Impact Factor
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    ABSTRACT: Cytochrome P450 2D6 (CYP2D6) is a drug-metabolizing enzyme expressed in the brain that also metabolizes endogenous neural compounds (e.g., catecholamines) and inactivates neurotoxins (e.g., 1-methyl-4-thenyl-1,2,3,6-tetrahydropyridine; MPTP). Genetically poor CYP2D6 metabolizers are at higher risk for developing Parkinson's disease (PD), a risk that increases with exposure to pesticides. As age is a risk factor for PD we measured the ontogenic expression of CYP2D6 in human brain, and compared brain CYP2D6 levels in PD cases with age-matched controls. CYP2D6 increased from fetal to 80 years of age (n = 76), exhibiting 3 distinct phases of change. Compared with PD controls, PD cases had approximately 40% lower CYP2D6 levels in the frontal cortex, cerebellum, and the hippocampus, even when controlling for CYP2D6 genotype. In contrast, CYP2D6 levels in cases were similar to controls in PD-affected brain areas, the substantia nigra, and caudate, consistent with higher astrocytic and cellular CYP2D6 staining observed in PD cases. In summary, the lower CYP2D6 levels in PD cases may have reduced their ability to inactivate PD-causing neurotoxins contributing to their disease risk.
    Neurobiology of aging 09/2011; 33(9):2160-71. DOI:10.1016/j.neurobiolaging.2011.08.014 · 5.94 Impact Factor
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    ABSTRACT: Greater prefrontal cortex and anterior cingulate cortex monoamine oxidase A (MAO-A) binding is associated with depressed mood. Substances in cigarette smoke, such as harman, inhibit MAO-A, and cigarette withdrawal is associated with depressed mood. Dysphoria during cigarette withdrawal predicts relapse. It is unknown whether MAO-A binding increases during early cigarette withdrawal. To measure prefrontal and anterior cingulate cortex MAO-A binding during acute cigarette withdrawal and to assess the relationship with smoking severity, plasma levels of harman, and severity of depression. Study via positron emission tomography of healthy control and cigarette-smoking individuals. Twenty-four healthy nonsmoking and 24 otherwise healthy cigarette-smoking individuals underwent positron emission tomography with harmine labeled with carbon 11. Healthy nonsmoking individuals underwent scanning once. Cigarette-smoking individuals underwent scanning after acute withdrawal and after active cigarette smoking. Cigarette smoking was heavy (≥25 cigarettes per day) or moderate (15-24 cigarettes per day). Tertiary care psychiatric hospital. An index of MAO-A density, MAO-A V(T), was measured in the prefrontal and anterior cingulate cortices. In heavy-smoking individuals, prefrontal and anterior cingulate cortex MAO-A V(T) was greater during withdrawal (23.7% and 33.3%, respectively; repeated-measures multivariate analysis of variance, F(1,22) = 25.58, P < .001). During withdrawal from heavy smoking, prefrontal and anterior cingulate cortex MAO-A V(T) was greater than in healthy controls (25.0% and 25.6%, respectively; multivariate analysis of variance, F(2,33) = 6.72, P = .004). The difference in MAO-A V(T) in the prefrontal cortex and anterior cingulate cortex between withdrawal and active, heavy smoking covaried with change in plasma harman levels in the prefrontal cortex and anterior cingulate cortex (multivariate analysis of covariance, F(1,10) = 9.97, P = .01). The change in MAO-A V(T) between withdrawal and active, heavy smoking also covaried with severity of depression (multivariate analysis of covariance, F(1,10) = 11.91, P = .006). The increase in prefrontal and anterior cingulate cortex MAO-A binding and associated reduction in plasma harman level represent a novel, additional explanation for depressed mood during withdrawal from heavy cigarette smoking. This finding resolves a longstanding paradox regarding the association of cigarette smoking with depression and suicide and argues for additional clinical trials on the effects of MAO-A inhibitors on quitting heavy cigarette smoking.
    Archives of general psychiatry 08/2011; 68(8):817-26. DOI:10.1001/archgenpsychiatry.2011.82 · 12.26 Impact Factor

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  • 1985–2015
    • University of Toronto
      • • Department of Psychiatry
      • • Institute of Medical Sciences
      • • Division of Neurology
      • • Department of Pharmacology and Toxicology
      Toronto, Ontario, Canada
    • University of Vienna
      Wien, Vienna, Austria
  • 2014
    • Creatis Medical Imaging Research Center
      Lyons, Rhône-Alpes, France
  • 1998–2014
    • Centre for Addiction and Mental Health
      • • Research Imaging Centre
      • • Addictions Research Group
      Toronto, Ontario, Canada
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
  • 2012
    • University Health Network
      Toronto, Ontario, Canada
  • 2007–2008
    • University of Utah
      • Department of Pharmacology and Toxicology
      Salt Lake City, Utah, United States
  • 2003
    • Arkansas State Crime Laboratory
      Little Rock, Arkansas, United States
  • 2000–2001
    • Armed Forces Institute of Pathology
      Ralalpindi, Punjab, Pakistan
  • 1999
    • University of Maryland, Baltimore
      • Department of Pathology
      Baltimore, Maryland, United States
  • 1996
    • University of Alabama at Birmingham
      • Department of Psychiatry and Behavioral Neurobiology
      Birmingham, AL, United States
  • 1987–1996
    • McGill University
      • Centre for Research in Neuroscience
      Montréal, Quebec, Canada
  • 1993
    • Montreal Heart Institute
      Montréal, Quebec, Canada
  • 1990
    • Toronto Western Hospital
      Toronto, Ontario, Canada
    • UHN: Toronto General Hospital
      Toronto, Ontario, Canada
  • 1979–1985
    • University of British Columbia - Vancouver
      • • Department of Anesthesiology, Pharmacology and Therapeutics
      • • Faculty of Pharmaceutical Sciences
      Vancouver, British Columbia, Canada