Publications by authors named "Jeffrey H Meyer"

92 Publications

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging.

Acta Pharm Sin B 2021 Feb 25;11(2):373-393. Epub 2020 Aug 25.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA.

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.
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http://dx.doi.org/10.1016/j.apsb.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893127PMC
February 2021

The Effect of Oral L-cysteine on Breast Milk and Plasma Cysteine Concentrations.

Neuropsychiatr Dis Treat 2020 21;16:3163-3172. Epub 2020 Dec 21.

CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.

Purpose: Greater oxidative signaling is implicated in major depressive disorder; hence, there is considerable interest in developing oral supplements with anti-oxidant properties to prevent or treat mood disorders, such as postpartum depression. L-cysteine is a precursor for glutathione, an important antioxidant in the brain. So, developing L-cysteine as a dietary supplement may be useful, provided oral supplementation substantially raises its concentration in blood plasma yet does not affect its total concentration in breast milk. This study assessed the effect of oral L-cysteine on its concentration in breast milk and blood plasma of breastfeeding mothers.

Participants And Methods: Twenty-four health breastfeeding women were randomly assigned to 0, 1.5, or 3 g of oral L-cysteine. Free and total cysteine in breast milk; and free cysteine in plasma were measured. While breast milk is the gold standard, measurement of infant formulas provides indices of nutritional intake considered safe. Therefore, free cysteine was also measured in six different formulas.

Results: Total cysteine in breast milk was not affected by oral L-cysteine (Repeated Measures of ANOVA (rANOVA), intervention effect: =0.75). Free cysteine levels in breast milk did rise (rANOVA, intervention effect: =0.017), but were within the range of common infant formulas. There was no significant effect of L-cysteine supplementation on free cysteine levels in plasma (rANOVA, intervention effect: =0.25), although a post hoc analysis found a trend towards greater plasma cysteine 30 minutes after oral supplementation ((14)=-1.69, =0.11, 3g versus no-dose).

Conclusion: The negligible effect of oral cysteine administration on its total concentration in breast milk was favorable, but the minimal effect on its blood plasma concentration more strongly argues against further development of oral L-cysteine in postpartum, as well as other conditions.
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http://dx.doi.org/10.2147/NDT.S255205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762443PMC
December 2020

The Effect of Oral L-cysteine on Breast Milk and Plasma Cysteine Concentrations.

Neuropsychiatr Dis Treat 2020 21;16:3163-3172. Epub 2020 Dec 21.

CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.

Purpose: Greater oxidative signaling is implicated in major depressive disorder; hence, there is considerable interest in developing oral supplements with anti-oxidant properties to prevent or treat mood disorders, such as postpartum depression. L-cysteine is a precursor for glutathione, an important antioxidant in the brain. So, developing L-cysteine as a dietary supplement may be useful, provided oral supplementation substantially raises its concentration in blood plasma yet does not affect its total concentration in breast milk. This study assessed the effect of oral L-cysteine on its concentration in breast milk and blood plasma of breastfeeding mothers.

Participants And Methods: Twenty-four health breastfeeding women were randomly assigned to 0, 1.5, or 3 g of oral L-cysteine. Free and total cysteine in breast milk; and free cysteine in plasma were measured. While breast milk is the gold standard, measurement of infant formulas provides indices of nutritional intake considered safe. Therefore, free cysteine was also measured in six different formulas.

Results: Total cysteine in breast milk was not affected by oral L-cysteine (Repeated Measures of ANOVA (rANOVA), intervention effect: =0.75). Free cysteine levels in breast milk did rise (rANOVA, intervention effect: =0.017), but were within the range of common infant formulas. There was no significant effect of L-cysteine supplementation on free cysteine levels in plasma (rANOVA, intervention effect: =0.25), although a post hoc analysis found a trend towards greater plasma cysteine 30 minutes after oral supplementation ((14)=-1.69, =0.11, 3g versus no-dose).

Conclusion: The negligible effect of oral cysteine administration on its total concentration in breast milk was favorable, but the minimal effect on its blood plasma concentration more strongly argues against further development of oral L-cysteine in postpartum, as well as other conditions.
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http://dx.doi.org/10.2147/NDT.S255205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762443PMC
December 2020

Neuroinflammation in psychiatric disorders: PET imaging and promising new targets.

Lancet Psychiatry 2020 12 21;7(12):1064-1074. Epub 2020 Oct 21.

Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA. Electronic address:

Neuroinflammation is a multifaceted physiological and pathophysiological response of the brain to injury and disease. Given imaging findings of 18 kDa translocator protein (TSPO) and the development of radioligands for other inflammatory targets, PET imaging of neuroinflammation is at a particularly promising stage. This Review critically evaluates PET imaging results of inflammation in psychiatric disorders, including major depressive disorder, schizophrenia and psychosis disorders, substance use, and obsessive-compulsive disorder. We also consider promising new targets that can be measured in the brain, such as monoamine oxidase B, cyclooxygenase-1 and cyclooxygenase-2, colony stimulating factor 1 receptor, and the purinergic P2X7 receptor. Thus far, the most compelling TSPO imaging results have arguably been found in major depressive disorder, for which consistent increases have been observed, and in schizophrenia and psychosis, for which patients show reduced TSPO levels. This pattern highlights the importance of validating brain biomarkers of neuroinflammation for each condition separately before moving on to patient stratification and treatment monitoring trials.
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http://dx.doi.org/10.1016/S2215-0366(20)30255-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893630PMC
December 2020

Are There Therapeutic Benefits of Cannabinoid Products in Adult Mental Illness?

Can J Psychiatry 2021 Feb 11;66(2):185-194. Epub 2020 Sep 11.

Department of Psychiatry, University of Calgary, Alberta, Canada.

A position statement developed by the Canadian Psychiatric Association's (CPA) Research Committee and approved by the CPA's Board of Directors on May 13, 2020.
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http://dx.doi.org/10.1177/0706743720945525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918871PMC
February 2021

Excess tau PET ligand retention in elderly patients with major depressive disorder.

Mol Psychiatry 2020 Jul 1. Epub 2020 Jul 1.

Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Depression is one of the common psychiatric disorders in old age. Major depressive disorder (MDD) has been identified as a risk factor or prodrome for neurodegenerative dementias, suggesting neuropathological overlaps and a continuum between MDD and neurodegenerative disorders. In this study, we examined tau and amyloid-β (Aβ) accumulations in the brains of MDD and healthy controls using positron emission tomography (PET) to explore pathological substrates of this illness. Twenty MDD and twenty age-matched, healthy controls were examined by PET with a tau radioligand, [C]PBB3, and an Aβ radioligand, [C]PiB. Radioligand retentions were quantified as a standardized uptake value ratio (SUVR). We also assessed clinical manifestations of the patients using the 17-item Hamilton Depression Scale, the Geriatric Depression Scale, and psychotic symptoms. Mean cortical [C]PBB3 SUVRs in MDD patients were significantly higher than those of healthy controls. These values were higher in MDD patients with psychotic symptoms than in those without any. The present findings indicate that tau depositions may underlie MDD, and especially in patients with psychotic symptoms. PET detection of tau accumulations may provide mechanistic insights into neuronal dysfunctions in these cases and could serve as predictions of their clinical consequences.
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http://dx.doi.org/10.1038/s41380-020-0766-9DOI Listing
July 2020

Serotonin transporter protein in autopsied brain of chronic users of cocaine.

Psychopharmacology (Berl) 2020 Sep 3;237(9):2661-2671. Epub 2020 Jun 3.

Human Brain Laboratory, Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Rationale: The long-held speculation that the brain serotonin system mediates some behavioral effects of the psychostimulant cocaine is supported in part by the high affinity of cocaine for the serotonin transporter (SERT) and by reports that the serotonin transporter (SERT), estimated by SERT binding, is increased in brain of human chronic cocaine users. Excessive SERT activity and consequent synaptic serotonin deficiency might cause a behavioral (e.g., mood) abnormality in chronic users of the drug.

Objective And Methods: Previous studies focused on changes in SERT binding, which might not necessarily reflect changes in SERT protein. Therefore, we compared levels of SERT protein, using a quantitative Western blot procedure, in autopsied brain (striatum, cerebral cortices) of chronic human cocaine users (n = 9), who all tested positive for the drug/metabolite in brain, to those in control subjects (n = 15) and, as a separate drug of abuse group, in chronic heroin users (n = 11).

Results: We found no significant difference in protein levels of SERT or the serotonin synthesizing enzyme tryptophan hydroxylase-2 among the control and drug abuse groups. In the cocaine users, no significant correlations were observed between SERT and brain levels of cocaine plus metabolites, or with levels of serotonin or its metabolite 5-hydroxyindoleacetic acid.

Conclusion: Our postmortem data suggest that a robust increase in striatal/cerebral cortical SERT protein is not a common characteristic of chronic, human cocaine users.
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http://dx.doi.org/10.1007/s00213-020-05562-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502513PMC
September 2020

Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial.

Lancet Psychiatry 2020 06 20;7(6):515-527. Epub 2020 May 20.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Several small studies suggest that the adjunctive use of anti-inflammatory agents might improve depressive symptoms in bipolar disorder. However, there are few well designed, appropriately powered clinical trials assessing the efficacy of these novel treatment strategies. We aimed to assess the efficacy of adjunctive minocycline or celecoxib in this setting.

Methods: This double-blind, 12-week, randomised, placebo-controlled trial was done in four outpatient psychiatric clinics in Pakistan. Eligible participants were adults (aged 18-65 years) with DSM-5 bipolar disorder (type I or II) and a major depressive episode. In a 2 × 2 factorial design, participants were randomly assigned (1:1:1:1) to receive either active minocycline plus active celecoxib, active minocycline plus placebo celecoxib, placebo minocycline plus active celecoxib, or placebo minocycline plus placebo celecoxib. The primary outcome was the mean change from baseline to week 12 in score on the 17-item Hamilton Depression Rating Scale (HAMD-17), assessed in all randomised participants (missing data were imputed and assumed to be missing at random). The trial was registered with ClinicalTrials.gov, NCT02703363.

Findings: 266 (17%) of 1542 patients assessed between May 1, 2016, and March 31, 2019, were randomly assigned to receive minocycline plus celecoxib (n=68), minocycline plus placebo (n=66), celecoxib plus placebo (n=66), or placebo plus placebo (n=66). From baseline to week 12, depressive symptoms as per HAMD-17 reduced in all four groups (from 24·5-25·2 to 11·3-12·8), but these reductions did not differ significantly between the groups. In terms of main effects, reductions in HAMD-17 did not differ for patients treated with minocycline (mean adjusted difference vs non-minocycline 1·48 [95% CI -0·41 to 3·36]; p=0·123) or for celecoxib (mean adjusted difference vs non-celecoxib -0·74 [-2·61 to 1·14]; p=0·443). Rates of serious adverse effects did not differ between groups (31 participants had a manic switch, two self-harmed, and one died in a motor vehicle accident).

Interpretation: We found no evidence that minocycline or celecoxib was superior to placebo for the treatment of bipolar depression. This large trial casts doubt on the potential therapeutic benefits of adjunctive anti-inflammatory drugs for the acute management of bipolar depression.

Funding: Stanley Medical Research Institute.
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http://dx.doi.org/10.1016/S2215-0366(20)30138-3DOI Listing
June 2020

Translocator Protein Distribution Volume Predicts Reduction of Symptoms During Open-Label Trial of Celecoxib in Major Depressive Disorder.

Biol Psychiatry 2020 10 29;88(8):649-656. Epub 2020 Mar 29.

Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Gliosis is common among neuropsychiatric diseases, but the relationship between gliosis and response to therapeutics targeting effects of gliosis is largely unknown. Translocator protein total distribution volume (TSPO V), measured with positron emission tomography, mainly reflects gliosis in neuropsychiatric disease. Here, the primary objective was to determine whether TSPO V in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) predicts reduction of depressive symptoms following open-label celecoxib administration in treatment-resistant major depressive disorder.

Methods: A total of 41 subjects with treatment-resistant major depressive disorder underwent one [F]FEPPA positron emission tomography scan to measure PFC and ACC TSPO V. Open-label oral celecoxib (200 mg, twice daily) was administered for 8 weeks. Change in symptoms was measured with the 17-item Hamilton Depression Rating Scale (HDRS).

Results: Cumulative mean change in HDRS scores between 0 and 8 weeks of treatment was plotted against PFC and ACC TSPO V, showing a significant nonlinear relationship. At low TSPO V values, there was no reduction in HDRS scores, but as TSPO V values increased, there was a reduction in HDRS scores that then plateaued. This was modeled with a 4-parameter sigmoidal model in which PFC and ACC TSPO V accounted for 84% and 92% of the variance, respectively.

Conclusions: Celecoxib administration in the presence of gliosis labeled by TSPO V is associated with greater reduction of symptoms. Given the predictiveness of TSPO V on symptom reduction, this personalized medicine approach of matching a marker of gliosis to medication targeting effects of gliosis should be applied in early development of novel therapeutics, in particular for treatment-resistant major depressive disorder.
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http://dx.doi.org/10.1016/j.biopsych.2020.03.007DOI Listing
October 2020

Minocycline as adjunctive treatment for treatment-resistant depression: study protocol for a double blind, placebo-controlled, randomized trial (MINDEP2).

BMC Psychiatry 2020 04 15;20(1):173. Epub 2020 Apr 15.

Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Background: Available evidence suggests that adjunctive treatment with immunomodulatory medications may be effective in the treatment of major depressive disorder (MDD). A pilot trial of the tetracycline minocycline as adjunctive treatment in treatment-resistant depression (TRD), produced promising results, however, a larger scale trial is needed to confirm the antidepressant actions of this drug.

Methods: This is a 12-week double blind, placebo-controlled, randomized trial of minocycline as an add-on to standard antidepressants for adults (age > 18) with DSM-5 major depressive episode, who have failed to respond to at least two adequate trials of antidepressant treatment. It is a parallel-arm study with 50 participants in each group. The primary outcome measure is change in 17-item Hamilton Depression Rating Scale (HRSD-17) total scores from baseline to week 12. Secondary measures include the Clinical Global Impression (CGI) scale, World Health Organization Quality of Life Short Version (WHOQOL-BREF) and the Generalized Anxiety Disorder scale (GAD-7). Peripheral inflammatory biomarkers will be collected at baseline, week 6 and 12.

Discussion: If minocycline is well tolerated and effective in reducing depressive symptoms in patients with TRD, it would warrant genuine consideration as a treatment option for TRD. Additionally, if results demonstrate that minocycline has antidepressant properties, and that changes in inflammatory status are associated with its antidepressant action, it will inform the development of individualized treatment for a subset of patients with MDD.

Trial Registration: Clinicaltrials.gov identifier: NCT03947827. Registered 13th May, 2019.
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http://dx.doi.org/10.1186/s12888-020-02553-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161279PMC
April 2020

Microglia imaging in methamphetamine use disorder: a positron emission tomography study with the 18 kDa translocator protein radioligand [F-18]FEPPA.

Addict Biol 2021 01 4;26(1):e12876. Epub 2020 Feb 4.

Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Activation of brain microglial cells, microgliosis, has been linked to methamphetamine (MA)-seeking behavior, suggesting that microglia could be a new therapeutic target for MA use disorder. Animal data show marked brain microglial activation following acute high-dose MA, but microglial status in human MA users is uncertain, with one positron emission tomography (PET) investigation reporting massively and globally increased translocator protein 18 kDa (TSPO; [C-11](R)-PK11195) binding, a biomarker for microgliosis, in MA users. Our aim was to measure binding of a second-generation TSPO radioligand, [F-18]FEPPA, in brain of human chronic MA users. Regional total volume of distribution (V ) of [F-18]FEPPA was estimated with a two-tissue compartment model with arterial plasma input function for 10 regions of interest in 11 actively using MA users and 26 controls. A RM-ANOVA corrected for TSPO rs6971 polymorphism was employed to test significance. There was no main effect of group on [F-18]FEPPA V (P = .81). No significant correlations between [F-18]FEPPA V and MA use duration, weekly dosage, blood MA concentrations, regional brain volumes, and self-reported craving were observed. Our preliminary findings, consistent with our earlier postmortem data, do not suggest substantial brain microgliosis in MA use disorder but do not rule out microglia as a therapeutic target in MA addiction. Absence of increased [F-18]FEPPA TSPO binding might be related to insufficient MA dose or blunting of microglial response following repeated MA exposure, as suggested by some animal data.
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http://dx.doi.org/10.1111/adb.12876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398821PMC
January 2021

Replicating predictive serum correlates of greater translocator protein distribution volume in brain.

Neuropsychopharmacology 2020 05 4;45(6):925-931. Epub 2019 Nov 4.

Research Imaging Centre and Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.

Greater activation of glia, a key component of neuroinflammation, is an important process to target in neuropsychiatric illnesses. However, the magnitude of gliosis varies across cases so low-cost predictors are needed to stratify subjects for clinical trials. Here, several such blood serum measures were assessed in relation to TSPO V, an index of translocator protein density, measured with positron emission tomography. Blood serum concentration of several products known to be synthesized by activated microglia (and to some extent astroglia) [prostaglandin E (PGE), prostaglandin F alpha (PGF), and tumor necrosis factor alpha (TNF)], controlled by an index of peripheral inflammation [C-reactive protein (CRP)] and TSPO V were measured in 3 cohorts: prefrontal cortex TSPO V of 20 subjects with major depressive episodes (MDEs) from major depressive disorder (MDD); and 56 subjects with treatment resistant MDEs from MDD; and dorsal caudate TSPO V of 20 subjects with obsessive-compulsive disorder. Ln(PGE/CRP) and ln(TNF/CRP) consistently correlated with TSPO V (R = 0.36 to 0.11, p = 0.0030 to p = 0.0076). Assessment of threshold serum values to predict highly elevated TSPO V, demonstrated that a positive predictive value (PPV) of 80% was possible while retaining 40% of participant samples and that receiver operating curves (ROC) ranged from 75 to 81%. Post-hoc selection of ln(CRP) was more predictive (R = 0.23 to 0.39, p = 0.0058 to p = 0.00013; ROC > 80%). Systematic assessment of selected peripheral inflammatory markers is promising for developing low cost predictors of TSPO V. Marker thresholds with high PPV will improve subject stratification for clinical trials of glial targeting therapeutics.
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http://dx.doi.org/10.1038/s41386-019-0561-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162884PMC
May 2020

Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin.

Lancet Psychiatry 2020 01 24;7(1):93-108. Epub 2019 Oct 24.

Department of Psychiatry and Psychotherapy II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany.

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.
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http://dx.doi.org/10.1016/S2215-0366(19)30290-1DOI Listing
January 2020

In Vivo Imaging of Translocator Protein in Long-term Cannabis Users.

JAMA Psychiatry 2019 12;76(12):1305-1313

Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Importance: Cannabis is the most commonly used illicit drug in the world. Cannabinoids have been shown to modulate immune responses; however, the association of cannabis with neuroimmune function has never been investigated in vivo in the human brain.

Objective: To investigate neuroimmune activation or 18-kDa translocator protein (TSPO) levels in long-term cannabis users, and to evaluate the association of brain TSPO levels with behavioral measures and inflammatory blood biomarkers.

Design, Setting, And Participants: This cross-sectional study based in Toronto, Ontario, recruited individuals from January 1, 2015, to October 30, 2018. Participants included long-term cannabis users (n = 24) and non-cannabis-using controls (n = 27). Cannabis users were included if they had a positive urine drug screen for only cannabis and if they used cannabis at least 4 times per week for the past 12 months and/or met the criteria for cannabis use disorder. All participants underwent a positron emission tomography scan with [18F]FEPPA, or fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide.

Main Outcomes And Measures: Total distribution volume was quantified across regions of interest. Stress and anxiety as well as peripheral measures of inflammatory cytokines and C-reactive protein levels were also measured.

Results: In total, 24 long-term cannabis users (mean [SD] age, 23.1 [3.8] years; 15 men [63%]) and 27 non-cannabis-using controls (mean [SD] age, 23.6 [4.2] years; 18 women [67%]) were included and completed all study procedures. Compared with the controls, cannabis users had higher [18F]FEPPA total distribution volume (main group effect: F1,48 = 6.5 [P = .01]; ROI effect: F1,200 = 28.4 [P < .001]; Cohen d = 0.6; 23.3% higher), with a more prominent implication for the cannabis use disorder subgroup (n = 15; main group effect: F1,39 = 8.5 [P = .006]; ROI effect: F1,164 = 19.3 [P < .001]; Cohen d = 0.8; 31.5% higher). Greater TSPO levels in the brain were associated with stress and anxiety and with higher circulating C-reactive protein levels in cannabis users.

Conclusions And Relevance: The results of this study suggest that TSPO levels in cannabis users, particularly in those with cannabis use disorder, are higher than those in non-cannabis-using controls. The findings emphasize the need for more complementary preclinical systems for a better understanding of the role of cannabinoids and TSPO in neuroimmune signaling.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.2516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751758PMC
December 2019

Concentration, distribution, and influence of aging on the 18 kDa translocator protein in human brain: Implications for brain imaging studies.

J Cereb Blood Flow Metab 2020 05 20;40(5):1061-1076. Epub 2019 Jun 20.

Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Positron emission tomography (PET) imaging of the translocator protein (TSPO) is widely used as a biomarker of microglial activation. However, TSPO protein concentration in human brain has not been optimally quantified nor has its regional distribution been compared to TSPO binding. We determined TSPO protein concentration, change with age, and regional distribution by quantitative immunoblotting in autopsied human brain. Brain TSPO protein concentration (>0.1 ng/µg protein) was higher than those reported by binding assays by at least 2 to 70 fold. TSPO protein distributed widely in both gray and white matter regions, with distribution in major gray matter areas ranked generally similar to that of PET binding in second-generation radiotracer studies. TSPO protein concentration in frontal cortex was high at birth, declined precipitously during the first three months, and increased modestly during adulthood/senescence (10%/decade; vs. 30% for comparison astrocytic marker GFAP). As expected, TSPO protein levels were significantly increased (+114%) in degenerating putamen in multiple system atrophy, providing further circumstantial support for TSPO as a gliosis marker. Overall, findings show some similarities between TSPO protein and PET binding characteristics in the human brain but also suggest that part of the TSPO protein pool might be less available for radioligand binding.
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http://dx.doi.org/10.1177/0271678X19858003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181090PMC
May 2020

Differential levels of prefrontal cortex glutamate+glutamine in adults with antisocial personality disorder and bipolar disorder: A proton magnetic resonance spectroscopy study.

Prog Neuropsychopharmacol Biol Psychiatry 2019 07 5;93:250-255. Epub 2019 Apr 5.

Research Imaging Centre, Campbell Family Mental Health Research Institute, and Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada; Violence Prevention Neurobiological Research Unit, Forensic Psychiatry, CAMH, Toronto, ON, Canada; Faculty of Medicine, Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Faculty of Arts and Science, Department of Criminology and Sociological Studies, University of Toronto, Toronto, ON, Canada; Waypoint Centre for Mental Health Care, Penetanguishene, ON, Canada. Electronic address:

As the main excitatory neurotransmitter in the central nervous system, glutamate, as measured in combination with glutamine (Glx), is implicated in several psychopathologies when levels are aberrant. One illness that shows heightened Glx levels is bipolar disorder (BD), an illness characterized by high impulsivity. In addition, although animal studies have reported elevated levels of Glx in aggressive and impulsive phenotypes, no study, to our knowledge, has reported Glx in the human cortex in relation to aggression. Here, we addressed the question of whether elevated levels of Glx would be present in patients with BD and antisocial personality disorder (ASPD), a condition associated with aggression and, like BD, also presents high impulsivity. We recruited individuals with ASPD (n = 18), individuals with BD (n = 16), and a healthy control group (n = 24). We used proton magnetic resonance spectroscopy to measure relative neurometabolite concentrations in the left dorsolateral prefrontal cortex (dlPFC) and supra-genual anterior cingulate cortex (ACC), two brain regions associated with impulsivity and behavior control. We found significantly elevated levels of Glx in the ASPD group relative to the BD and healthy control groups in the dlPFC (p = .014), and a positive correlation between Glx levels and aggression in the dlPFC in the ASPD group alone (r = .59, p = .026). These findings suggest a link between aggression in ASPD and Glx levels.
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http://dx.doi.org/10.1016/j.pnpbp.2019.04.002DOI Listing
July 2019

Monoamine Oxidase B Total Distribution Volume in the Prefrontal Cortex of Major Depressive Disorder: An [11C]SL25.1188 Positron Emission Tomography Study.

JAMA Psychiatry 2019 06;76(6):634-641

Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Importance: Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala.

Objective: To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder.

Design, Setting, And Participants: This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy.

Main Outcomes And Measures: The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness.

Results: Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus.

Conclusions And Relevance: Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.0044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551845PMC
June 2019

Monoamine Oxidase B Total Distribution Volume in the Prefrontal Cortex of Major Depressive Disorder: An [11C]SL25.1188 Positron Emission Tomography Study.

JAMA Psychiatry 2019 06;76(6):634-641

Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Importance: Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala.

Objective: To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder.

Design, Setting, And Participants: This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy.

Main Outcomes And Measures: The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness.

Results: Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus.

Conclusions And Relevance: Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.0044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551845PMC
June 2019

Depressed mood induction in early cigarette withdrawal is unaffected by acute monoamine precursor supplementation.

Neuropsychiatr Dis Treat 2019 23;15:311-321. Epub 2019 Jan 23.

CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada,

Background: Cigarette smoking is the leading preventable cause of death; however, quitting is difficult and early relapse is common. Dysphoric mood during early cigarette withdrawal is associated with relapse, and with the exception of bupropion and nortriptyline, few interventions have been developed to prevent this. During early cigarette withdrawal there is an elevation in the levels of monoamine oxidase-A (MAO-A), which removes monoamines excessively and induces oxidative stress and is implicated in creating sad mood. Hence, we conducted a randomized, placebo-controlled, double-blind crossover trial of a dietary supplement designed to counter the effects of elevated MAO-A levels on vulnerability to depressed mood.

Methods: Twenty-one otherwise healthy cigarette smokers completed the protocol, receiving either active dietary supplement followed by washout and placebo or the same in reverse order. The dietary supplement was composed of monoamine precursors (2 g tryptophan, 10 g tyrosine) and blueberry antioxidants (blueberry juice with blueberry extract). Vulnerability to depressed mood was measured by the change in scores of depressed mood on the visual analog scale (VAS) following the sad mood induction paradigm (MIP).

Results: There was a significant increase in VAS depressed mood scores after the sad MIP during supplement and placebo, but no difference between active and placebo conditions. There was also a significant increase in urge-to-smoke scores after sad MIP during supplement and placebo but no difference between active and placebo conditions. Reliability of the increase in VAS after MIP was very good.

Conclusion: The dietary supplement had negligible effect on depressed mood, but sad MIP is a very reliable method that can be applied in future studies to assess other interventions for preventing dysphoric mood during early cigarette withdrawal.
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http://dx.doi.org/10.2147/NDT.S172334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352866PMC
January 2019

Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies.

Mol Psychiatry 2019 07 12;24(7):952-964. Epub 2018 Oct 12.

Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.

Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance (H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND (MRS OR "magnetic resonance spectroscopy"). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = -0.38; 95% CI, -0.69 to -0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = -0.50; 95% CI, -0.80 to -0.20), but not in unmedicated patients (SMD = -0.27; 95% CI, -0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.
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http://dx.doi.org/10.1038/s41380-018-0252-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755980PMC
July 2019

Normal glutathione levels in autopsied brain of chronic users of heroin and of cocaine.

Drug Alcohol Depend 2018 09 23;190:20-28. Epub 2018 Jun 23.

Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Background: Animal studies suggest that exposure to either of the two widely used drugs of abuse, heroin or cocaine, causes depletion of the antioxidant, reduced glutathione, a hallmark of oxidative stress, in the brain. However, the relevance of the animal findings to the human is uncertain and clinical trials with the antioxidant GSH precursor n-acetylcysteine have produced mixed results in cocaine dependence.

Methods: Our major objective was to compare glutathione levels, determined by an HPLC-coulometric procedure, in autopsied brain of chronic heroin (n = 11) and cocaine users (n = 9), who were positive for the drugs in the brain, to those of matched controls (n = 16). Six brain regions were examined, including caudate, hippocampus, thalamus and frontal, temporal and insular cortices.

Results: In contrast to experimental animal findings, we found no statistically significant difference between mean levels of reduced or oxidized glutathione in the drug user vs. control groups. Moreover, no correlation was found between levels of drugs in the brain and those of glutathione.

Conclusions: Acknowledging the many generic limitations of an autopsied human brain study and the preliminary nature of the findings, our data nevertheless suggest that any oxidative stress caused by heroin or cocaine in chronic users of the drugs might not be sufficient to cause substantial loss of stores of glutathione in the human brain, at least during early withdrawal. These findings, requiring replication, might also have some relevance to future clinical trials employing glutathione supplement therapy as an anti-oxidative strategy in chronic users of the two abused drugs.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078812PMC
September 2018

Interaction between TSPO-a neuroimmune marker-and redox status in clinical high risk for psychosis: a PET-MRS study.

Neuropsychopharmacology 2018 07 13;43(8):1700-1705. Epub 2018 Apr 13.

Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Altered neuroimmune response and oxidative stress have both been implicated in the pathophysiology of schizophrenia. While preclinical studies have proposed several pathways regarding potential interactions between oxidative stress and neuroimmune imbalance in the development of psychosis, the molecular mechanisms underlying this interaction are not yet understood. To date, no study has investigated this link in vivo in the human brain. We conducted the first in vivo study linking translocator protein 18  kDa (TSPO) expression and glutathione (a major brain antioxidant and a marker for redox status) in the medial prefrontal cortex (mPFC) of a relatively large sample of participants (N = 48) including 27 antipsychotic-naïve individuals at clinical high risk for psychosis and 21 matched healthy volunteers using high-resolution PET with TSPO radioligand, [F]FEPPA, and 3T proton magnetic resonance spectroscopy (H MRS). The omnibus model (including TSPO genotype as covariate) was significant (F = 10.01, p < 0.001), with a significant group interaction (t = -2.10, p = 0.04), suggesting a different relation between [F]FEPPA V and glutathione in each clinical group. In healthy volunteers, but not in individuals at clinical high risk for psychosis, we found a significant negative association between glutathione levels and [F]FEPPA V (r = -0.60, p = 0.006). We observed no significant group differences with respect to [F]FEPPA V or glutathione levels. These findings suggest an abnormal interaction between TSPO expression and redox status in the clinical high risk states for psychosis.
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http://dx.doi.org/10.1038/s41386-018-0061-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006145PMC
July 2018

Corticostriatal Connectivity in Antisocial Personality Disorder by MAO-A Genotype and Its Relationship to Aggressive Behavior.

Int J Neuropsychopharmacol 2018 08;21(8):725-733

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

Background: The influence of genetic variation on resting-state neural networks represents a burgeoning line of inquiry in psychiatric research. Monoamine oxidase A, an X-linked gene, is one example of a molecular target linked to brain activity in psychiatric illness. Monoamine oxidase A genetic variants, including the high and low variable nucleotide tandem repeat polymorphisms, have been shown to differentially affect brain functional connectivity in healthy humans. However, it is currently unknown whether these same polymorphisms influence resting-state brain activity in clinical conditions. Given its high burden on society and strong connection to violent behavior, antisocial personality disorder is a logical condition to study, since in vivo markers of monoamine oxidase A brain enzyme are reduced in key affect-modulating regions, and striatal levels of monoamine oxidase A show a relation with the functional connectivity of this same region.

Methods: We utilized monoamine oxidase A genotyping and seed-to-voxel-based functional connectivity to investigate the relationship between genotype and corticostriatal connectivity in 21 male participants with severe antisocial personality disorder and 19 male healthy controls.

Results: Dorsal striatal connectivity to the frontal pole and anterior cingulate gyrus differentiated antisocial personality disorder subjects and healthy controls by monoamine oxidase A genotype. Furthermore, the linear relationship of proactive aggression to superior ventral striatal-angular gyrus functional connectivity differed by monoamine oxidase A genotype in the antisocial personality disorder groups.

Conclusions: These results suggest that monoamine oxidase A genotype may affect corticostriatal connectivity in antisocial personality disorder and that these functional connections may also underlie use of proactive aggression in a genotype-specific manner.
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http://dx.doi.org/10.1093/ijnp/pyy035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070029PMC
August 2018

Elevated monoamine oxidase A activity and protein levels in rodent brain during acute withdrawal after chronic intermittent ethanol vapor exposure.

Drug Alcohol Depend 2018 04 5;185:398-405. Epub 2018 Feb 5.

University of Toronto, Deparment of Psychiatry, 8th Floor, Toronto, Ontario, M5T 1R8, Canada; University of Toronto, Department of Pharmacology and Toxicology, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, M5S 1A8. Electronic address:

Background: A key component of alcohol dependence (AD), a severe form of alcohol use disorder, is the negative emotional state during withdrawal. Monoamine oxidase A (MAO-A) is an important enzyme that metabolizes monoamines and creates oxidative stress. Elevations in MAO-A level, especially in the prefrontal and anterior cingulate cortex (PFC and ACC), are associated with low mood states, including the dysphoria of early alcohol withdrawal in humans. The aim of the present study was to determine whether chronic alcohol vapor exposure causes an upregulation of MAO-A activity or level in the PFC and ACC of rodents during acute withdrawal.

Methods: Sprague-Dawley rats were exposed to ethanol vapor or control condition for 17 h per day for 8 weeks. MAO-A activity and protein levels were measured immediately after exposure, acute withdrawal (24 h), protracted withdrawal (4 day), and protracted abstinence (3 weeks) (n = 16/group; 8 alcohol exposed, 8 control).

Results: Chronic ethanol vapor exposure significantly elevated MAO-A activity and protein levels in the PFC and ACC at 24-h withdrawal (multivariate analysis of variance (MANOVA), activity: F = 3.82, p = .05, protein: F = 5.13, p = .02). There were no significant changes in MAO-A level or activity at other timepoints.

Conclusions: The results of this study suggest a causal relationship between acute alcohol withdrawal and elevated MAO-A levels and activity, clarifying the observation of greater MAO-A binding in human alcohol withdrawal. This has important implications for developing methods of targeting MAO-A and/or sequelae of its dysregulation in alcohol dependence.
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http://dx.doi.org/10.1016/j.drugalcdep.2017.11.036DOI Listing
April 2018

Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study.

Lancet Psychiatry 2018 04 26;5(4):339-347. Epub 2018 Feb 26.

Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: People with major depressive disorder frequently exhibit increasing persistence of major depressive episodes. However, evidence for neuroprogression (ie, increasing brain pathology with longer duration of illness) is scarce. Microglial activation, which is an important component of neuroinflammation, is implicated in neuroprogression. We examined the relationship of translocator protein (TSPO) total distribution volume (V), a marker of microglial activation, with duration of untreated major depressive disorder, and with total illness duration and antidepressant exposure.

Methods: In this cross-sectional study, we recruited participants aged 18-75 years from the Toronto area and the Centre for Addiction and Mental Health (Toronto, ON, Canada). Participants either had major depressive episodes secondary to major depressive disorder or were healthy, as confirmed with a structured clinical interview and consultation with a study psychiatrist. To be enrolled, participants with major depressive episodes had to score a minimum of 17 on the 17-item Hamilton Depression Rating Scale, and had to be medication free or taking a stable dose of medication for at least 4 weeks before PET scanning. Eligible participants were non-smokers; had no history of or concurrent alcohol or substance dependence, neurological illness, autoimmune disorder, or severe medical problems; and were free from acute medical illnesses for the previous 2 weeks before PET scanning. Participants were excluded if they had used brain stimulation treatments within the 6 months before scanning, had used anti-inflammatory drugs lasting at least 1 week within the past month, were taking hormone replacement therapy, had psychotic symptoms, had bipolar disorder (type I or II) or borderline antisocial personality disorder, or were pregnant or breastfeeding. We scanned three primary grey-matter regions of interest (prefrontal cortex, anterior cingulate cortex, and insula) and 12 additional regions and subregions using F-FEPPA PET to measure TSPO V. We investigated the duration of untreated major depressive disorder, and the combination of total duration of disease and duration of antidepressant treatment, as predictor variables of TSPO V, assessing their significance.

Findings: Between Sept 1, 2009, and July 6, 2017, we screened 134 participants for eligibility, of whom 81 were included in the study (current major depressive episode n=51, healthy n=30). We excluded one participant with a major depressive episode from the analysis because of unreliable information about previous medication use. Duration of untreated major depressive disorder was a strong predictor of TSPO V (p<0·0001), as were total illness duration (p=0·0021) and duration of antidepressant exposure (p=0·037). The combination of these predictors accounted for about 50% of variance in TSPO V in the prefrontal cortex, anterior cingulate cortex, and insula. In participants who had untreated major depressive disorder for 10 years or longer, TSPO V was 29-33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO V was also 31-39% greater in the three primary grey-matter regions of participants with long duration of untreated major depressive disorder compared with healthy participants (p=0·00047).

Interpretation: Microglial activation, as shown by TSPO V, is greater in patients with chronologically advanced major depressive disorder with long periods of no antidepressant treatment than in patients with major depressive disorder with short periods of no antidepressant treatment, which is strongly suggestive of a different illness phase. Consistent with this, the yearly increase in microglial activation is no longer evident when antidepressant treatment is given.

Funding: Canadian Institutes of Health Research and Neuroscience Catalyst Fund.
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http://dx.doi.org/10.1016/S2215-0366(18)30048-8DOI Listing
April 2018

Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders.

Brain 2017 Sep;140(9):2460-2474

Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article. The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson's disease. Inhibitors of MAOB are used clinically in Parkinson's disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson's disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson's disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson's disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is 'substantially' localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson's disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the enzyme in the parkinsonian substantia nigra; instead, increased nigral levels of a MAOA fragment and 'turnover' of the enzyme were observed in the conditions. Our findings provide support that MAOB might serve as a biochemical imaging marker, albeit not entirely specific, for astrocyte activation in human brain. The observation that MAOB protein concentration is generally increased in degenerating brain areas in multiple system atrophy (especially putamen) and in progressive supranuclear palsy, but not in the nigra in Parkinson's disease, also distinguishes astrocyte behaviour in Parkinson's disease from that in the two 'Parkinson-plus' conditions. The question remains whether suppression of either MAOB in astrocytes or MAOA in dopamine neurons might influence progression of the parkinsonian disorders.
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http://dx.doi.org/10.1093/brain/awx172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669411PMC
September 2017

Occupancy of Norepinephrine Transporter by Duloxetine in Human Brains Measured by Positron Emission Tomography with (S,S)-[18F]FMeNER-D2.

Int J Neuropsychopharmacol 2017 12;20(12):957-962

Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan; Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Canada; Department of Psychiatry, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Japan.

Background: The norepinephrine transporter in the brain has been targeted in the treatment of psychiatric disorders. Duloxetine is a serotonin and norepinephrine reuptake inhibitor that has been widely used for the treatment of depression. However, the relationship between dose and plasma concentration of duloxetine and norepinephrine transporter occupancy in the human brain has not been determined. In this study, we examined norepinephrine transporter occupancy by different doses of duloxetine.

Methods: We calculated norepinephrine transporter occupancies from 2 positron emission tomography scans using (S,S)-[18F]FMeNER-D2 before and after a single oral dose of duloxetine (20 mg, n = 3; 40 mg, n = 3; 60 mg, n =2). Positron emission tomography scans were performed from 120 to 180 minutes after an i.v. bolus injection of (S,S)-[18F]FMeNER-D2. Venous blood samples were taken to measure the plasma concentration of duloxetine just before and after the second positron emission tomography scan.

Results: Norepinephrine transporter occupancy by duloxetine was 29.7% at 20 mg, 30.5% at 40 mg, and 40.0% at 60 mg. The estimated dose of duloxetine inducing 50% norepinephrine transporter occupancy was 76.8 mg, and the estimated plasma drug concentration inducing 50% norepinephrine transporter occupancy was 58.0 ng/mL.

Conclusions: Norepinephrine transporter occupancy by clinical doses of duloxetine was approximately 30% to 40% in human brain as estimated using positron emission tomography with (S,S)-[18F]FMeNER-D2.
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http://dx.doi.org/10.1093/ijnp/pyx069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716070PMC
December 2017

Association of monoamine oxidase-A genetic variants and amygdala morphology in violent offenders with antisocial personality disorder and high psychopathic traits.

Sci Rep 2017 08 29;7(1):9607. Epub 2017 Aug 29.

Douglas Mental Health University Institute, Cerebral Imaging Centre, Montreal, H4H 1R3, Canada.

Violent offending is elevated among individuals with antisocial personality disorder (ASPD) and high psychopathic traits (PP). Morphological abnormalities of the amygdala and orbitofrontal cortex (OFC) are present in violent offenders, which may relate to the violence enacted by ASPD + PP. Among healthy males, monoamine oxidase-A (MAO-A) genetic variants linked to low in vitro transcription (MAOA-L) are associated with structural abnormalities of the amygdala and OFC. However, it is currently unknown whether amygdala and OFC morphology in ASPD relate to MAO-A genetic polymorphisms. We studied 18 ASPD males with a history of violent offending and 20 healthy male controls. Genomic DNA was extracted from peripheral leukocytes to determine MAO-A genetic polymorphisms. Subjects underwent a T1-weighted MRI anatomical brain scan that provided vertex-wise measures of amygdala shape and surface area and OFC cortical thickness. We found that ASPD + PP subjects with MAOA-L exhibited decreased surface area in the right basolateral amygdala nucleus and increased surface area in the right anterior cortical amygdaloid nucleus versus healthy MAOA-L carriers. This study is the first to describe genotype-related morphological differences of the amygdala in a population marked by high aggression. Deficits in emotional regulation that contribute to the violence of ASPD + PP may relate to morphological changes of the amygdala under genetic control.
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http://dx.doi.org/10.1038/s41598-017-08351-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575239PMC
August 2017

Neuroprogression and Immune Activation in Major Depressive Disorder.

Authors:
Jeffrey H Meyer

Mod Trends Pharmacopsychiatry 2017 24;31:27-36. Epub 2017 Jul 24.

Department of Psychiatry, University of Toronto, and Research Imaging Centre, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute at CAMH, Toronto, ON, Canada.

Traditionally, the neurobiology of major depressive disorder (MDD) has been largely considered from the perspective of the state of major depressive episodes (MDE) versus being in remission, but the current accumulation of disease markers, largely acquired cross-sectionally, is strongly suggestive of neuroprogressive aspects of MDD. This chapter focuses on the changes in disease markers involved in the reorganization of the nervous system in MDD, including the translocator protein (TSPO; an index of microglial activation), glial fibrillary acidic protein (GFAP; an index of astroglial activation), [11C]harmine (a marker of monoamine oxidase A; MAO-A), and several other indices (metabotropic glutamate receptor 5 [mGluR5], excitatory amino acid transporters, and magnetic resonance imaging spectroscopy measurements) of glutamate dysregulation. These are markers of processes involved in immune activation, oxidative stress, and chronic glucocorticoid exposure. Positron emission tomography studies of the TSPO distribution volume, a marker of microglial activation, provide strong evidence for microglial activation throughout the gray matter of the brain during MDE of MDD. In postmortem studies, GFAP reductions in the orbitofrontal cortex, anterior cingulate cortex, and hippocampus indicate a deficit in reactive astroglia. Elevated MAO-A levels are present throughout the gray matter of the brain, including affect-modulating brain regions, starting in high-risk states for MDE such as the early postpartum period, perimenopause, heavy cigarette smoking, heavy alcohol intake, and prior to MDE recurrence. Evidence is accumulating for glutamate dysregulation, with some findings of reduced glutamate transporter density in the orbitofrontal cortex, and decreased mGluR5 density. Collectively, these changes suggest an imbalance in the immune system with increased microglial activation and decreased astroglial activation, continued elevations of the MAO-A level, and, likely, the development of extracellular glutamate dysregulation. Many of these imbalances involve processes implicated in increased oxidative stress, apoptosis, and neurodegeneration. Future studies are required to assess potential therapeutics targeting these processes to ameliorate progression of MDD.
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http://dx.doi.org/10.1159/000470804DOI Listing
May 2019

Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder.

JAMA Psychiatry 2017 08;74(8):833-840

Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada2Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada3Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

Importance: For a small percentage of obsessive-compulsive disorder (OCD) cases exhibiting additional neuropsychiatric symptoms, it was proposed that neuroinflammation occurs in the basal ganglia as an autoimmune response to infections. However, it is possible that elevated neuroinflammation, inducible by a diverse range of mechanisms, is important throughout the cortico-striato-thalamo-cortical circuit of OCD. Identifying brain inflammation is possible with the recent advance in positron emission tomography (PET) radioligands that bind to the translocator protein (TSPO). Translocator protein density increases when microglia are activated during neuroinflammation and the TSPO distribution volume (VT) is an index of TSPO density.

Objective: To determine whether TSPO VT is elevated in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex in OCD.

Design, Setting, And Participants: This case-control study was conducted at a tertiary care psychiatric hospital from May 1, 2010, to November 30, 2016. Participants with OCD (n = 20) and age-matched healthy control individuals (n = 20) underwent a fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide PET scan. It is a high-quality second-generation TSPO-binding PET radiotracer. All participants were drug and medication free, nonsmoking, and otherwise healthy.

Main Outcomes And Measures: The TSPO VT was measured in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex. Compulsions were assessed with the Yale-Brown Obsessive Compulsive Scale.

Results: In the OCD and healthy groups, the mean (SD) ages were 27.4 (7.1) years and 27.6 (6.6) years, respectively, and 11 (55%) and 8 (40%) were women, respectively. In OCD, TSPO VT was significantly elevated in these brain regions (mean, 32%; range, 31%-36% except anterior cingulate cortex, 24%; analysis of variance, effect of diagnosis: P < .001 to P = .004). Slightly lower elevations in TSPO VT (22%-29%) were present in other gray matter regions. The Yale-Brown Obsessive Compulsive Scale measure of distress associated with preventing compulsive behaviors significantly correlated with TSPO VT in the orbitofrontal cortex (uncorrected Pearson correlation r = 0.62; P = .005).

Conclusions And Relevance: To our knowledge, this is the first study demonstrating inflammation within the neurocircuitry of OCD. The regional distribution of elevated TSPO VT argues that the autoimmune/neuroinflammatory theories of OCD should extend beyond the basal ganglia to include the cortico-striato-thalamo-cortical circuit. Immunomodulatory therapies should be investigated in adult OCD, rather than solely childhood OCD, particularly in cases with prominent distress when preventing compulsions.
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http://dx.doi.org/10.1001/jamapsychiatry.2017.1567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710556PMC
August 2017