Introduction
Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by motor and non-motor abnormalities (e.g., cognitive impairments).1, Reference Farah, Haraty, Salame, Fares, Ojcius and Said Sadier2 Although the etiology of PD is not fully known, multiple risk factors have been identified.Reference Payami, Cohen, Murchison, Sampson, Standaert and Wallen3 For example, type 2 diabetes mellitus (T2DM) is identified as a risk factor for PD insofar as approximately 10–30% of persons with PD have T2DM as a comorbid diagnosis.Reference Hu, Jousilahti, Bidel, Antikainen and Tuomilehto4–Reference Miyake, Tanaka and Fukushima7 In addition, some molecular and cellular alterations, although non-specific, do in some cases overlap in PD and T2DM.Reference Bassil, Delamarre and Canron8 For example, incretin deficits are observed in both conditions, and several studies have observed prophylactic effects against PD after the administration of incretin mimetics.Reference Svenningsson, Wirdefeldt and Yin9
The essential pathological features of PD are the loss of spontaneously firing tyrosine-hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of α-synuclein aggregates (a molecular hallmark of PD) into Lewy bodies.Reference Cheong, de Pablo-Fernandez, Foltynie and Noyce10–Reference Elbassuoni and Ahmed15 PD is also associated with microglial activation, which triggers oxidative stress as evidenced by the presence of oxidative markers (e.g., reactive oxygen species).Reference Yun, Kam and Panicker13
Although Food and Drug Administration (FDA)-approved treatments exist for PD, notably dopamine replacement therapies, no intervention is disease-modifying or curative.Reference Ferrazzoli, Carter and Ustun16 In addition, most persons with PD do not achieve optimal acute and long-term efficacy, tolerability, or safety.Reference Tunik, Feldman and Poizner17, Reference Foltynie, Bruno, Fox, Kühn, Lindop and Lees18 The unmet clinical needs in PD provide the impetus for alternative, mechanistically informed therapeutics that are effective, safe, and acceptable.Reference Foltynie, Bruno, Fox, Kühn, Lindop and Lees18
Glucagon-like peptide-1 (GLP-1) receptors are expressed in the central nervous system (CNS) and exhibit neuroprotective and neuroplasticity-enhancing effects.Reference Hölscher19, Reference Gupta, Kaur, Shekhawat, Aggarwal, Nanda and Sahni20 The expression of GLP-1 receptors in the SNpc and striatum suggests that their pharmacologic modulation may affect the functioning and survival of neuronal populations in the SNpc and other dopaminergic target sites within the brain (e.g., prefrontal cortex).Reference Hölscher19–Reference Kopp, Glotfelty, Li and Greig21 GLP-1 receptors are also observed in multiple cell types (e.g., microglia), which supports evidence for the anti-inflammatory properties of GLP-1RAs in PD, increasing cell viability.Reference Reinhardt and Bondy22, Reference Eren-Yazicioglu, Yigit, Dogruoz and Yapici-Eser23 Moreover, preclinical and preliminary clinical data indicate that GLP-1 receptor agonists (GLP-1 RAs) attenuate nigral dopaminergic neuronal loss by inhibiting apoptosis.Reference Kopp, Glotfelty, Li and Greig21
Glucagon-like peptide-1 receptor agonists are incretin mimetics that are FDA-approved for treating T2DM, obesity, and cardiovascular disease.Reference Saini, Badole, Ronald Ross and Dokken24, Reference Collins and Costello25 In addition, GLP-1RAs reduce markers of neuroinflammation and oxidative stress, suggesting that these agents may protect or sustain cellular integrity and survival in brain regions implicated in PD (e.g., SNpc).Reference Yun, Kam and Panicker13, Reference Elbassuoni and Ahmed15, Reference Hölscher19–Reference Eren-Yazicioglu, Yigit, Dogruoz and Yapici-Eser23, Reference Wong, McLean and Baggio26, Reference Kim, Moon and Park27 In keeping with this view, a testable hypothesis is that GLP-1RAs may benefit clinical features and/or prevent the onset and progression of PD by targeting multiple aforementioned effector systems relevant to the viability and function of neurons. Herein, we synthesize the extant preclinical and clinical literature surrounding the conjecture that GLP-1RAs be administered for the prevention and treatment of PD and attenuate the interplay between T2DM and PD.
Methods
Search strategy
A comprehensive search was conducted across online databases, including Embase, PubMed, OVID Medline, and Google Scholar, from inception through July 24, 2024. Subsequent manual searches of the reference lists of the obtained articles were conducted. The following Boolean search string was used: (Parkinson’s disease) AND (GLP-1) OR (glucagon-like peptide-1) OR (exenatide) OR (liraglutide) OR (dulaglutide) OR (lixisenatide) OR (insulin degludec) OR (insulin glargine) OR (semaglutide) OR (tirzepatide). A second search string was also applied to ensure the search was fully comprehensive: (Parkinson’s disease) AND (GLP-1) AND ((treatment) OR (prevention)). Studies were limited to the language of publication (e.g., English).
Two independent reviewers (SL, LY) screened the articles obtained using the Covidence software.28 After removing duplicates, articles were screened by title, abstract, and full text against the eligibility criteria (Table 1). Any discrepancies in screening between reviewers were resolved by discussion.
Eligibility Criteria
Data extraction
Extracted data were established a priori using a piloted data extraction table. Data extraction was conducted by one reviewer (SL). The extracted data included: (1) author(s) and publication year, (2) study design and participants, (3) intervention, (4) duration, (6) intervention outcome(s), and (7) significance of the study outcome(s) (Table 2).
Descriptive Characteristics of Included Preclinical and Clinical Studies
Quality assessment
Study quality was assessed by two independent reviewers (SL, LY). Preclinical studies were evaluated by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) Risk of Bias tool, randomized controlled clinical studies were evaluated using the Cochrane Risk of Bias Tool for Randomized Studies (RoB2), and observational cohort studies were evaluated using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, adapted from the National Institute of Health (NIH) guidelines (Tables 3–5).Reference Hooijmans, Rovers, de Vries, Leenaars, Ritskes-Hoitinga and Langendam37–39
Risk of Bias in the Assessment of Preclinical Studies
Risk of Bias Assessment of Randomized Controlled Clinical Studies
Results
Study results and selection
The initial search generated a total of 203 publications from Embase, PubMed, OVID Medline, and citation searching as seen on PRISMA (Figure 1). After removing duplicates, 164 studies remained for title and abstract screening, of which 28 were deemed eligible for full-text screening. Full-text screening resulted in 12 eligible publications to be included in the systematic review. The majority of articles were excluded due to outcomes not aligned with the eligibility criteria of our analysis.
Risk of Bias Assessment of Observational Cohort Clinical Studies
PRISMA flowchart of literature identification and selection.
Preclinical evidence of GLP-1RAs in PD
A total of nine preclinical studies were retrieved from the search. In all included preclinical studies, rodents were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or α-synuclein to induce sporadic PD models. Liu et al.,Reference Liu, Jalewa, Sharma, Li, Li and Hölscher14 Zhang et al.,Reference Zhang, Chen, Li and Hölscher29 and Zhang et al.Reference Zhang, Zhang, Li and Hölscher12 reported that exendin-4 (Ex-4), liraglutide, lixisenatide, (Val8)GLP-1-glu-PAL, and semaglutide, respectively, exerted neuroprotective effects against MPTP-induced motor impairments such as bradykinesia, abnormal posture, and gait.Reference Zhang, Zhang, Li and Hölscher12, Reference Liu, Jalewa, Sharma, Li, Li and Hölscher14, Reference Zhang, Chen, Li and Hölscher29 Rotarod motor sensory performance, open-field distance, catalepsy, and swimming tests were conducted to evaluate locomotor and exploratory activity in mice.Reference Zhang, Zhang, Li and Hölscher12, Reference Liu, Jalewa, Sharma, Li, Li and Hölscher14, Reference Zhang, Chen, Li and Hölscher29 Liu et al.Reference Liu, Jalewa, Sharma, Li, Li and Hölscher14 reported that liraglutide and lixisenatide reversed some of the identified MPTP-induced motor impairments, while Ex-4 did not.Reference Rodriguez-Oroz, Jahanshahi and Krack11 Additionally, Zhang et al.Reference Zhang, Zhang, Li and Hölscher12 reported that semaglutide was more effective than liraglutide in reversing MPTP-induced motor impairment in mice (p < .001).Reference Zhang, Zhang, Li and Hölscher12, Reference Liu, Jalewa, Sharma, Li, Li and Hölscher14 Moreover, western blot analyses indicated that both (Val8)GLP-1-glu-PAL and semaglutide reversed neurodegeneration by decreasing levels of Bcl-2-associated X protein (BAX), an apoptosis-promoting molecule, and increasing Bcl-2, an anti-apoptotic signaling molecule.Reference Zhang, Zhang, Li and Hölscher12, Reference Zhang, Chen, Li and Hölscher29
Similarly, Cao et al.Reference Cao, Zhang, Chen, Wu, Dong and Wang30 conducted western blot analyses and immunofluorescence of caspase-3, BAX, and Bcl-2 and reported that liraglutide exerted effects on the aforementioned proteins that favored cell viability in murine models.Reference Cao, Zhang, Chen, Wu, Dong and Wang30 In addition, markers of neuroinflammation decreased in the liraglutide group, compared to the control, inhibiting inflammation and protecting dopaminergic neurons through the AMPK/NF-κB signaling pathway.Reference Cao, Zhang, Chen, Wu, Dong and Wang30 Immunofluorescence testing revealed that levels of TH-positive neurons gradually increased with liraglutide concentration at significant values (p = .111 for 25 nmol/kg, p = .011 for 50 nmol/kg, and p = .001 for 100 nmol/kg).Reference Cao, Zhang, Chen, Wu, Dong and Wang30
The foregoing findings are in accordance with Bu et al.Reference Bu, Liu and Shen31 and Liu et al.,Reference Liu, Liu, Yang, Chen, Xue and Chen32 who reported an attenuation of progressive neuronal loss with Ex-4.Reference Bu, Liu and Shen31, Reference Liu, Liu, Yang, Chen, Xue and Chen32 It has been suggested that autophagic pathways such as the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway may be involved in Ex-4-mediated degradation of pathological α-synucleinopathy.Reference Bu, Liu and Shen31 The upregulation of the pathway by PD was reversed by Ex-4, increasing markers that indicate active autophagy and decreasing markers that block autophagy.Reference Bu, Liu and Shen31
Alternatively, it has been proposed that decreased spontaneous dopaminergic neuron firing in PD is associated with the reduced expression of TH and a threat to neuronal survival.Reference Liu, Liu, Yang, Chen, Xue and Chen32 Liu et al.Reference Liu, Liu, Yang, Chen, Xue and Chen32 reported that administering Ex-4 increased the firing rate of 7 out of 14 nigral dopaminergic neurons from 2.20 ± 0.31 to 3.54 ± 0.41 Hz, mediated by ion channels.Reference Liu, Liu, Yang, Chen, Xue and Chen32 The activation of GLP-1 receptor-mediated neuronal firing within the SNpc may be associated with observable functions (e.g., motor activity) that alleviate some clinical features of PD.Reference Liu, Liu, Yang, Chen, Xue and Chen32
A pathophysiologic feature of PD includes microglia activation, which exacerbates dopaminergic neurodegeneration, oxidative stress, and neuroinflammation.Reference Yun, Kam and Panicker13, Reference Elbassuoni and Ahmed15, Reference Eren-Yazicioglu, Yigit, Dogruoz and Yapici-Eser23 Kim et al.Reference Kim, Moon and Park27 and Elbassuoni and AhmedReference Elbassuoni and Ahmed15 assessed matrix metalloproteinase-3 (MMP-3) and malondialdehyde (MDA) levels, respectively, as biomarkers to evaluate microglial activation by neurodegeneration and oxidative stress at the cellular level.Reference Elbassuoni and Ahmed15, Reference Kim, Moon and Park27 Kim et al.Reference Kim, Moon and Park27 reported that Ex-4 prevented MPTP-induced loss of TH-positive SNpc neurons by 83% by attenuating the upregulation of MMP-3.Reference Kim, Moon and Park27 MDA levels evaluated by Elbassuoni and AhmedReference Elbassuoni and Ahmed15 also significantly decreased with exenatide in a dose-dependent manner.Reference Elbassuoni and Ahmed15 In both studies, pro-inflammatory cytokines and striatal inflammatory biomarkers (e.g., TNF-α and IL-1β) were reduced with GLP-1RAs.Reference Elbassuoni and Ahmed15, Reference Kim, Moon and Park27 It has also been reported that microglial-activated conversion of astrocytes into neurotoxic A1 phenotypes caused the loss of TH and Nissl neurons in the SNpc, which the GLP-1RA, NLY01, adequately prevented.Reference Yun, Kam and Panicker13
Clinical evidence of GLP-1RAs in PD
The search generated a total of three clinical studies evaluating the effect of GLP-1 RAs on either the prevention, treatment, or illness progression intervention of PD. A randomized, placebo-controlled study by Athauda et al.Reference Athauda, Maclagan and Skene33 assessed the efficacy of exenatide compared to placebo in persons with PD.Reference Athauda, Maclagan and Skene33 The primary outcome was a change in the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 3 subscale scores.Reference Athauda, Maclagan and Skene33 Participants (n = 62) with moderate PD were randomized to either exenatide (2 mg subcutaneously once weekly) or placebo. At 48 weeks (the post-exposure period), MDS-UPDRS scores in the placebo group deteriorated by 1.7 points, while those in the exenatide group improved by 2.3 points.Reference Athauda, Maclagan and Skene33 At 60 weeks, off-medication scores worsened by 2.1 points in the placebo group and improved by 1.0 points in the exenatide group (p = .0318).Reference Athauda, Maclagan and Skene33 However, no significant differences were reported between the experimental and control groups on the other subsections of the MDS-UPDRS or in qualitative assessments (e.g., quality of life).Reference Athauda, Maclagan and Skene33 No malaise-like symptoms attributable to changes in motor scores were noted.Reference Athauda, Maclagan and Skene33
A separate phase 2, double-blind, randomized, placebo-controlled study compared lixisenatide to placebo as a disease-modifying intervention in PD by comparing MDS-UPDRS part 3 subscale scores in persons with PD.Reference Meissner, Remy and Giordana34 After 12 months, the mean score in the lixisenatide on-medication group exhibited a motor improvement of −0.04 points (a 14.9% improvement), while the placebo exhibited a worsening on the MDS-UPDRS by 3.04 points (an 18.8% worsening) (p = .007).Reference Meissner, Remy and Giordana34 Off-medication scores worsened in both groups, but the placebo group was inferior.Reference Meissner, Remy and Giordana34
A population-based cohort study utilized medical records to assess the incidence of PD among persons with T2DM prescribed GLP-1RAs with an overarching aim to determine whether GLP-1RAs mitigate the incidence of PD.Reference Brauer, Wei and Ma35, Reference Hölscher40 The primary outcome was the first recorded diagnosis of PD, comparing patients who were prescribed metformin, sulfonylureas, or other oral antidiabetic medications.Reference Brauer, Wei and Ma35 The crude relative risks for the incidence of PD were 0.83 (0.64–1.07), 0.54 (0.41–0.73), and 0.40 (0.24–0.66) for users of glitazone (GTZ), dipeptidyl peptidase-4 inhibitors (DPP4), and GLP-1 mimetics, respectively.Reference Brauer, Wei and Ma35 The results indicated that an inverse relationship between the use of DPP4 inhibitors and GLP-1RAs and the onset of PD exists, with an approximate 36–60% relative decrease in the rate of PD onset compared to the use of other oral antidiabetic medications.Reference Brauer, Wei and Ma35 A separate population-based cohort study recorded the crude incidence of PD amongst older persons with T2DM prescribed with GLP-1RAs or DPP4 inhibitors.Reference Tang, Lu and Okun36 These researchers found that the crude incidence rate of PD was lower among GLP-1RA users than DPP4 inhibitor users (2.85 versus 3.92 patients per 1000 person-years).Reference Tang, Lu and Okun36 Moreover, the research demonstrated that GLP-1RAs were associated with a 23% lower risk of PD than DPP4i users (HR, 0.77; 95% CI, 0.63–0.95).Reference Tang, Lu and Okun36
Discussion
Herein, via systematic review, we identified replicated evidence extracted from both preclinical and clinical studies suggesting beneficial effects of select GLP-1RAs on cellular and molecular mechanisms as well as clinical aspects of PD.Reference Zhang, Zhang, Li and Hölscher12–Reference Elbassuoni and Ahmed15, Reference Reinhardt and Bondy22, Reference Kim, Moon and Park27, Reference Zhang, Chen, Li and Hölscher29, Reference Bu, Liu and Shen31–Reference Athauda, Maclagan and Skene33, Reference Tang, Lu and Okun36 It has also been noted that the putative benefit of GLP-1RAs in animal models and persons living with PD extends across both motor and non-motor impairments.Reference Zhang, Zhang, Li and Hölscher12–Reference Elbassuoni and Ahmed15, Reference Reinhardt and Bondy22, Reference Kim, Moon and Park27, Reference Zhang, Chen, Li and Hölscher29, Reference Bu, Liu and Shen31, Reference Athauda, Maclagan and Skene33, Reference Tang, Lu and Okun36 The reported benefits of GLP-1RAs on clinical aspects of PD, as well as the molecular and cellular effects, are aligned with prevailing models of disease pathogenesis in PD.Reference Zhang, Zhang, Li and Hölscher12–Reference Elbassuoni and Ahmed15, Reference Reinhardt and Bondy22, Reference Kim, Moon and Park27, Reference Zhang, Chen, Li and Hölscher29, Reference Bu, Liu and Shen31–Reference Athauda, Maclagan and Skene33, Reference Tang, Lu and Okun36
More specifically, preclinical studies that sought to evaluate the effects of GLP-1RAs in MPTP- or α-synuclein-mediated Parkinsonian models reported meaningful restoration of motor function and protection of dopaminergic neurons.Reference Rodriguez-Oroz, Jahanshahi and Krack11–Reference Elbassuoni and Ahmed15 In addition, biomarkers of neuroinflammation and oxidative stress (e.g., proinflammatory cytokines) were also affected with the administration of GLP-1RAs, along with a suggestion of reduced microglial activation.Reference Yun, Kam and Panicker13, Reference Elbassuoni and Ahmed15, Reference Reinhardt and Bondy22 Although clinical data are preliminary, using change in motor scores as an ancillary measure of disease progression suggests small benefits with some GLP-1RAs in treated PD subjects.Reference Athauda, Maclagan and Skene33, Reference Tang, Lu and Okun36 The potential for GLP-1RAs to affect illness progression in PD has also been investigated in an observational study, wherein a significant decrease in PD incidence was observed in persons with T2DM prescribed GLP-1RAs.Reference Hölscher40
The findings of protective effects of GLP-1RAs on brain regions hypothesized to subserve the phenotypic characteristics of PD are in accordance with other lines of research, also suggesting benefit in other brain-based disorders (e.g., depression and substance use disorder).Reference Badulescu, Badulescu and Badulescu41, Reference Mansur, Lee, Subramaniapillai, Brietzke and McIntyre42 It is noteworthy that GLP-1RAs are not known to be causally related to any adverse CNS effects and/or suicidality, despite reports of suicide in some persons taking these agents.Reference McIntyre, Mansur, Rosenblat and Kwan43–Reference Wang, Volkow, Berger, Davis, Kaelber and Xu45 Moreover, there are separate agents (e.g., antioxidants, kinase inhibitors) that have been promising interventions for PD as demonstrated by several clinical trials.Reference McFarthing, Rafaloff and Baptista46
There are several methodological aspects that affect the interpretation of the studies that we identified as part of this systematic review. For example, there are axiomatic limitations with respect to extrapolating findings from preclinical models of PD to persons living with PD. In addition, although preliminary epidemiologic and controlled trials suggest GLP-1RAs may have protective and treatment effects in persons with PD, there is a need for adequately controlled, extensive replication studies with both acute and long-term outcomes evaluated to determine whether the effects can be replicated with meaningful effect sizes. Whether GLP-1RAs offer additional therapeutic effects as adjunctive agents to dopamine replacement therapy or other FDA-approved interventions is a vista for future research. Also, existing studies have primarily evaluated the effect of GLP-1RAs on motor symptoms in PD, there remains an open question as to the effect of these agents on other aspects of PD that are frequently encountered clinically (e.g., cognitive impairment, depressive symptoms).Reference Cooper, Ramachandra and Ceban47 A final limitation is that we delimited eligibility to those studies evaluating the effect of GLP-1RAs when using the MPTP and a-synuclein model of Parkinson’s disease. We recognize there are other models of Parkinson’s disease (e.g., rotenone, 6-hydroxydopamine); notwithstanding, the great majority of studies evaluating the putative protective effects of GLP-1RAs were confined to MPTP and a-synuclein models; consequently, for consistency reasons, we decided to only focus on these models evaluating GLP-1RA effects.
Conclusion
Some GLP-1RAs are capable of crossing the blood–brain barrier (e.g., liraglutide) and target molecular and cellular processes relevant to the pathophysiology of PD.Reference Rhea, Babin and Thomas48, Reference Mansur, Ahmed and Cha49 These penetrating agents are reported to be most suitable for repurposing as CNS targets.Reference Rhea, Babin and Thomas48, Reference Mansur, Ahmed and Cha49 Although the initial rationale to conduct studies with GLP-1RAs in PD was provided by observations of clinical and pathophysiological overlap with T2DM, the available preclinical and clinical evidence suggests that the putative benefits of these agents in PD are not limited to persons with T2DM and/or metabolic-related disorders. Priority research vistas are to conduct large, adequately powered, controlled studies in persons living with PD, with preferably head-to-head comparison with FDA-approved treatments for PD. In addition to the effects on motor outcomes, there is an equal priority to ascertain if GLP-1RAs may benefit measures of cognitive functions, which has been suggested in other brain-based disorders.Reference Mansur, Ahmed and Cha49 Future research vistas should endeavor to ascertain whether beneficial effects of dual or triple incretin agonists on the clinical features and/or neural biology of PD have relative advantages over one aspect observed heretofore with incretin mono agonists.
Author contribution
Writing - review & editing: R.B.M., J.D.R., B.Y.L., S.F., G.H.L., K.T., H.K.L., N.X., S.W., T.G.R., Y.J.Z.; Conceptualization: S.L., R.S.M.; Data curation: L.Y.
Financial support
This paper was not funded.
Disclosures
Dr. Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences. Dr. S. Roger McIntyre is the CEO of Braxia Scientific Corp.
Kayla Teopiz has received fees from Braxia Scientific Corp.
Dr. Taeho Greg Rhee was supported in part by the National Institute on Aging (#R21AG070666; R21AG078972; R01AG088647), National Institute of Mental Health (#R01MH131528), National Institute on Drug Abuse (#R21DA057540), and Health Resources and Services Administration (#R42MC53154–01-00). Dr. Rhee serves as a review committee member for the National Institutes of Health (NIH), the Patient-Centered Outcomes Research Institute (PCORI), and the Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from NIH, PCORI, and SAMHSA. Dr. Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. Dr. Rhee serves as an advisory committee member for the International Alliance of Mental Health Research Funders (IAMHRF).
Dr. Rodrigo B. Mansur has received research grant support from the Canadian Institutes of Health Research (CIHR), the Physicians’ Services Incorporated (PSI) Foundation, and the Baszucki Brain Research Fund, and support from an Academic Scholars Award from the Department of Psychiatry, University of Toronto.
Dr. Joshua D. Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion, and COMPASS.
Serene Lee, Liyang Yin, Naomi Xiao, Heidi La Ying Lo, Sabrina Wong, Susan Fox, Bess Yin-Hung Lam, Yang Jing Zheng, and Gia Han Le have no conflicts of interest to declare.
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