The Chronicle of Neurology + Psychiatry - Summer 2022

E t h n o r a c i a l b i a s in psychiatric therapy

Fresh approaches needed for Parkinson’s disease research

by John Evans, Senior Editor, The Chronicle

TO ADVANCE RESEARCH into understanding and treating Parkinson’s disease (PD), it may make sense to categorize patients by gene involvement in addition to clinical phenotype or biomarkers, said Dr. Ziv Gan-Or in an interview with THE CHRONICLE OF NEUROLOGY + PSYCHIATRY He also suggested that new models of Parkinson’s are needed to advance therapy development. Dr. Gan-Or is the senior author of a paper published in

Dementia

Neuropharmacology (Jan. 2022; 202:108822) that looked at the existing literature on genetic targets in PD and clinical trials into Parkinson’s treatments to identify potential obstacles to the successful development of new therapies.

“Over the last decades we have been failing again and again in finding treatments for Parkinson’s disease and similar diseases,” said Dr. Gan-Or, who is an assistant professor in the Department of Neurology & Neurosurgery (The Neuro) —please turn to page 5

Examining the early role of

Depression

Cognitive outcomes, antidepressant use in MDD

n

TREATING PATIENTS WITH ACUTE MAJOR DEPRESSIVE DISORDER (MDD) WITH escitalopram followed by aripiprazole does not appear to significantly change their cognitive symptoms, though it is clinically effective at managing mood symptoms.

These findings come from a paper published in CNS Drugs (Mar. 2021; 35(3):291-304).

The study utilized data from the Canadian Biomarker Integration Network in Depression (CAN-BIND-1) please turn to page 10

This issue’s Chronicle Vitae profiles child health and wellness researcher and associate professor at the University of Alberta in Edmonton Dr.

the Calgary Black Achievement Awards See page 14

Morris Scantlebury, the first award winner of

by John Evans Senior Editor, The Chronicle

Cognitive outcomes when using antidepressants in MDD

Parkinson’s disease and new drugs in development

The role of inflammation caused by lifestyle in dementia

n Current framing and research techniques proving ineffective for developing new treatments

Migraine has affected millions of Canadians1*

Migraine is a neurological disease with recurring attacks that causes pain and other disabling symptoms. However, it may be possible to manage migraine.2

AbbVie is committed to helping healthcare providers care for people impacted by migraine.

Empowering people in their pursuit of migraine relief takes all of us.

@abbviecanada

References: 1. Statistics Canada. Table 13-10-046701 Neurological conditions in household population. doi.org/10.25318/1310046701-eng.

2. Worthington I, et al. Canadian Headache Society Acute Migraine Treatment Guideline Development Group. Canadian Headache Society Guideline: acute drug therapy for migraine headache. Can J Neurol Sci 2013 Sep;40(5 Suppl 3):S1-S80.

* Derived from the 2010 and 2011 Canadian Community Health Survey – Annual Component (CCHS); an estimated 8.3% of Canadians (2.7 million) reported being diagnosed with migraine.

“I

which is one of the most demanding vocations in medicine. Where do you stop, after all, with the brain? How does it function? What are its limits?

The work seems unending.”

Sir Roger Gilbert Bannister, English neurologist (1929-2018)

Guest editorial: Parkinson’s disease and novel drugs in development Research

PARKINSON’S DISEASE IS A COMMON neurodegenerative disorder that by current estimates affects more than eight million people worldwide. Parkinson’s disease is more common in the elderly population. Moreover, environmental factors, such as pesticides and air pollution increase the risk of Parkinson’s disease. The prevalence of Parkinson’s disease is increasing at a high speed, like no other neurological disease. For example, in the U.S. projected Parkinson’s disease prevalence will be 1.6 million by 2037, compared to 1.04 million in 2017.1

FAILURE OF ALPHA-SYNUCLEIN TARGETED THERAPY

The hallmark of Parkinson’s disease pathology is an aggregation of alpha-synuclein with the formation of Lewy bodies. Due to the lack of disease-modifying treat ments, there were partic ularly high hopes for the drugs targeting these aggregates. The recent failure of two monoclonal antibodies targeting the break-up of alpha-synuclein aggregates2,3 prompts us to challenge the alpha-synuclein gain-of-function hypothesis. Negative results of two sec ond-phase studies on prasinezumab and cin panemab were published head-to-head in the New England Journal of Medicine. Based on previously reported phase I clinical trials, these antibodies demonstrated brain penetration and dose-dependent reduction of alphasynuclein in peripheral blood.4,5 Nevertheless, in phase II clinical trials, both drugs did not demonstrate any clinical benefits for Parkinson’s disease patients.2,3 These outcomes may be caused by the misclassification of Parkinson’s disease.

POTENTIAL EXPLANATION, THERAPEUTIC ALTERNATIVES

Parkinson’s disease is classified as a singular disease. However, it is more plausible that Parkinson’s disease is an umbrella term for a variety of similar disorders. Several lines of evidence support this hypothesis. First, symptoms of Parkinson’s disease vary drastically from patient to patient. Some patients develop cognitive dysfunction at early stages and have rapid deterioration of motor symptoms. On the other hand, some patients preserve cognition and progress very slowly throughout the years. Second, the pathology of Parkinson’s disease also could

differ between patients. In most patients with Parkinson’s disease, autopsy demonstrated an abundance of hallmark protein alpha-synuclein in aggregated form of Lewy bodies. Nevertheless, some patients have no alpha-synuclein pathology or they might even have aggregation of tau protein, which is more commonly seen in Alzheimer’s disease.

Multiple attempts have been made to classify Parkinson’s disease based on clinical presentation or biomarkers. Stratification based on the molecular subtypes could be more beneficial, as it would allow for the development of diseasespecific drugs. Similar examples already exist in medicine. Molecular classification of breast cancers is widely accepted, and treatment approaches are individually selected based on genotype.6

Likewise in Parkinson’s disease, the diversity of symptoms and pathology among patients could be partially attributed to genetics. About 5 to 10% of all Parkinson’s disease patients bear pathogenic variants in the lysosomal gene GBA. This gene encodes lysosomal enzyme glucocerebrosidase and pathogenic variants lead to diminished activity of this enzyme. Patients with Parkinson's disease, who are carriers of GBA mutations, showed a more frequent development of cognitive impairment and other non-motor symptoms. Also, some studies suggest faster progression of motor symptoms in these patients. Autopsy of patients with GBA-Parkinson’s disease suggests a more prevalent distribution of alpha-synuclein pathology, especially in cortical regions. This could be the reason behind the prevalence of cognitive symptoms. Curiously, more lysosomal genes were linked to the development of Parkinson’s disease, but we know little about their impact on the clinical progression of the disease.

Another example of a distinct phenotype is patients bearing mutations in LRRK2. Carriers of the most common pathogenic LRRK2 variant p.G2019S represent at least 1% of all patients with Parkinson’s disease and 4% if we count only familiar cases of Parkinson’s disease. There are seven more known rare pathogenic variants in this gene. These patients have a relatively benign course of Parkinson’s disease, with slower progression of motor and non-motor symptoms. Based on the current knowledge, alpha-synuclein pathology presented only in 50% of LRRK2 mutation carriers. Curiously, carriers of mutations in both GBA and LRRK2 have a more benign phenotype than carriers of GBA alone.7 This evidence suggests the protective effect of LRRK2 variants on GBAassociated Parkinson’s disease. Another supportive evidence is that the activity of lysosomal enzyme glucocerebrosidase encoded by GBA is higher in carriers of pathogenic LRRK2 variants.8,9

Drugs targeting these two genes are now in development. At least two drugs (ambroxol

416.352.6199. E-mail: health@chronicle.org.

n I n this retrospective cohort study, researchers compared 2,317 ADHD patients three to 18 years of age enrolled in a GP-centred pediatric primary healthcare program to 4,177 control patients who received standard care. The researchers found the patients in the intervention group had a lower risk of mental-disorder-related hospitalization and received fewer prescriptions for stimulants. The findings were published in the European Journal of General Practice (June 2022).

Find more info at https://tinyurl.com/47v2m5mm

n This paper is an overview of evidence for contingency management, offering rewards for achieving recovery goals, for opioid use disorder. The authors discuss common barriers and solutions to implementing contingency management. They provide their views on what will be necessary to implement this type of intervention and improving outcomes for individuals with opioid use disorder. Annals of Medicine (Apr. 26, 2022).

Learn more at https://tinyurl.com/4utrzm88

n In this study 50 pediatric patients in China with refractory, genetically caused epilepsy were treated with adjunctive perampanel therapy. At three, six and nine months after initiation of treatment, the rate of patients achieving a 50% or greater reduction in seizure frequency was 68.0%, 58.0% and 46.0%, respectively. In the paper, published in Epileptic Disorders (Aug. 2022), the authors conclude a low maintenance dose of perampanel may be effective and well-tolerated as adjunctive treatment in these patients.

Learn more at https://tinyurl.com/yck38a9w

Contents

n In adults with migraine and two to four previous preventive treatment failures, the monoclonal antibody eptinezumab provided significant migraine preventive effects compared to placebo, according to findings published in The Lancet Neurology (July 2022). The authors also noted the treatment had acceptable safety and tolerability, and suggest this medication may be an effective treatment option for patients who have failed other options.

Learn more at https://tinyurl.com/8jtxtx2t

The Chronicle of Neurology & Psychiatry is published six times annually by the proprietor, Chronicle Information Resources Ltd., with offices at 555 Burnhamthorpe Rd., Ste. 306, Toronto, Ont. M9C 2Y3 Canada. Telephone: 416.916.2476; Fax.

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Konstantin Senkevich, MD, PhD is a neurologist at The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, and a post-doctoral fellow in the Department of Neurology and Neurosurgery at McGill University.

ABOUT THE AUTHOR

had always wanted to become a neurologist,

D r K o n s t a n t i n S e n k e v i c h please turn to page 12

Founding Editor

Richard Gladstone, MD, FRCPC Psychiatry Editor

s Quick-start guide to The Chronicle, June/July 2022:

Publication Index

n Depression: Escitalopram monotherapy followed by adjunctive aripiprazole does not appear to improve cognitive outcomes in MDD (p. 1)

n Parkinson’s: Current research techniques may be ineffective in advancing new treatments (p. 1) n Editorial: Dr. Konstantin Senkevich outlines potential new therapies for Parkinson’s patients (p. 1) n Dementia: Modifiable lifestyle factors may be the major players in late-life cognitive impairment, new research suggests (p. 12)

n Chronicle Vitae: Dr. Morris Scantlebury, is the first award winner of the Calgary Black Achievement Awards (p. 14)

Dr. Abigail Ortiz, Clinican Scientist at Toronto's Campbell Family Mental Health Research, and Dr. Yuliya Knyahnytska, Clinician Scientist at Temerty Centre for Therapeutic Brain Interventions in Toronto, received the frist-ever womenmind Leadership Fund Award.

The award aims to mitigate inequities for women in the sciences by supporting them in attaining or advancing leadership roles through high-impact leadership training. The womenmind community was launched in March 2020 with the goal of researching and advancing unique gender issues that are underrepresented in mental health.

Images from the world of neurological and psychiatric medicine: We invite you to submit your photographs for THE CHRONICLE OF NEUROLOGY + PSYCHIATRY. Send original high-resolution (2 megapixels and higher) JPGs to: health@chronicle.org.

“

The only normal people

are the ones you don't know very well..”

Alfred Adler,

Evidence suggests that animal models not suitable for research

and Department of Human Genetics at McGill University in Montreal.

PATIENT POPULATION DIVERSE

“There are many potential reasons why we failed,” he said. “It could be the models that we are using to study the drugs, the mouse models, are inaccurate.”

“But one of the things I am focused on is the population itself that we are studying,” Dr. Gan-Or said. “If you go to the clinic and you look at Parkinson's disease patients, they are all different. They have different combinations of symptoms, they have different backgrounds, different environmental factors that they were exposed to, and obviously, they all have also different genetics.”

Dr. Gan-Or’s lab conducts research on how genetics affect disease, disease progression, and treatment to disease, primarily PD but also other neurological disorders, he said. In this review article, he and his team focused on three genes that are relatively common in different types of PD: GBA, LRRK2 and PRKN.

“We wanted to have a review of the current status in the field, what is going on [in PD research], and also the different limitations and caveats that we currently have in terms of how to address these specific subtypes of Parkinson's disease,” Dr. Gan-Or said.

“I am saying subtypes because, for me, Parkinson's disease is not a single disorder. These are multiple disorders that are similar clinically but have different underlying causes. For me, the people who have mutations in the gene GBA, are not the same as people who have mutations in LRRK2, and they are not the same as people who have mutations in PRKN. There is lots of evidence for that. We try to focus on those three genes and explain where we are right now and where we are heading.”

In the article, the authors write that GBA and LRRK2 mutations are the most common genetic causes or risk factors of PD, and PRKN is the most common cause of the autosomal recessive form of PD. They note that patients carrying variants in GBA, LRRK2 or PRKN differ in some of their clinical characteristics, pathology and biochemical parameters, making these three genes important considerations in the development of therapies.

PRESENTATION VARIES BY MUTATION TYPE

“People with GBA mutations, for example, on average they will progress much faster, they will have an earlier age of onset, and they will have more severe disease. They will have many nonmotor symptoms,” said Dr. Gan-Or. Cognitive decline and other symptoms are also part of PD in this population, he said.

“Those with LRRK2, for example, will have milder disease course. Those with PRKN mutations will start much earlier—before the age of 50 and very often before the age of 40 or 30—but their disease will not be very progressive. [Their PD] will remain relatively stable and require low levels of treatment,” he said. The brain pathology in PD patients with PRKN mutations is also different than in other PD patients.

While these differences in presentation associated with mutations in different genes suggest that a precision medicine approach is the way forward, there are several challenges for approaching PD research and treatment development in a precision medicine context, Dr. Gan-Or said.

Precision medicine has been successful in some conditions, said Dr. Gan-Or. Cystic fibrosis, for example, is primarily driven by genetic mutations, and medications have been developed that individually or in combination target cystic fibrosis-related mutations and extend the lives of patients.

However, things are more complicated for PD, he said. “Parkinson's disease is caused by a combination of genes, the environment, many things. Cystic fibrosis is caused by mutations in a single gene.”

“In Parkinson's, in recent years, there have been quite a few preclinical and clinical studies, mainly phase one, targeting mainly GBA and LRRK2,” Dr. Gan-Or said. “In these trials [the investigators] only recruit people carrying mutations in these genes.”

“Maybe that is not precise enough. Maybe as in cystic fibrosis, at least for GBA, we need to examine it not only at the gene level but at the mutation level. Maybe in Parkinson's disease people with GBA mutations will receive different treatments, depending on the type of mutations that they have, not just the fact that they have mutations and mutation in GBA.”

Dr. Gan-Or noted the first phase II clinical trial of a medication targeting mutations in GBA in patients with PD concluded—Sanofi’s candidate drug venglustat. However, that trial was unsuccessful.

“It is difficult to expect that the first precision medicine trial in Parkinson's will succeed. I wish it had, but it did not,” he said. “But it is a really good step forward in the right direction. And there are more trials coming that are similar in the sense of targeting these specific populations.”

Conducting precision medicine research is complicated by the rarity of some Parkinson’s-related mutations, or the time needed to observe results, Dr. Gan-Or noted.

“In LRRK2 the patients progress quite slowly. So in order for researchers to see an effect of a drug, they either need to have a drug with a very strong effect that can be seen even in patients who are progressing very slowly, or they will need to have a huge amount of participants in the trial,” he said. Even with the good drug candidates now being investigated, it will be a long time until their efficacy is known, he said.

Patients with LRRK2 mutations are also quite rare, Dr. Gan-Or said, comprising just 1% to 2% of all Parkinson’s patients in most populations.

“There are subpopulations around the world where you have higher rates [of LRRK2 mutations], such as in Berber Arabs from North Africa and Ashkenazi Jews, but otherwise it is quite rare.”

Another significant challenge Dr. Gan-Or noted is that there is increasing evidence the animal models that have been used for Parkinson’s research are not suitable for the task.

“A lot of the work we were doing [in Parkinson’s research], we were using models that have been failing us over and over again,” said Dr. Gan-Or. He said that it seems that every two weeks an article appears in the literature showing a medication’s efficacy at treating Parkinson’s in a mouse model, and this has been going on for 40 years with little coming of it in terms of human treatment.

“I think another important lesson would be to find better models to study the disease and not relying on these animal models that keep failing us,” said Dr. Gan-Or.

“I would say human-based models, things such as organoids or organs on a chip, which are currently being developed, hopefully, will become better models than the models we currently use for the preclinical development of drugs.”

In the news . . .

n The medication tenecteplase, often used to treat blood clots during heart attacks, is also an effective treatment for acute ischemic stroke, reports CBC News (June 29, 2022). Dr. Bijoy Menon, a University of Calgary professor and a neurologist at Foothills Hospital was the coprincipal investigator of the study that revealed these findings. He told the news outlet that tenecteplase is easier and faster to administer than the medication alteplase, which is commonly used at present.

Read more information at https://tinyurl.com/2rnkawx3

n Poor eyesight may be a modifiable risk factor for dementia, according to research covered in The New York Times on July 3, 2022. The news outlet reports researchers estimated that approximately 62% of current dementia cases were preventable across all risk factors. Treating poor vision could have prevented 1.8% of cases— about 100,000. That may be a small percentage, but could be a comparatively easy fix, said the study’s lead author Dr. Joshua Ehrlich. Dr. Ehrlich is an ophthalmologist and population health researcher at the University of Michigan.

Read this article at https://tinyurl.com/5n93nh5k

n Disruptions in common social contacts due to the Covid-19 pandemic have led to a kind of “social malnutrition” among young people, reports CBC News (June 18, 2022). Dr. Saba Merchant, a pediatrician with a practice in Vaughan, Ont., has used the phrase "social malnutrition" to describe the effect that isolation has had on children and youth during the pandemic, according to the news outlet. She said that she is seeing higher levels of mental health issues in teenagers now compared to any previous time in her 20 years of practice. Teenagers may also be less resilient to these disruptions than younger children, she said.

Read more at https://tinyurl.com/ycyd2p8d

Austrian psychotherapist (1870-1973)

D r. G a n - O r

Bias in coercive refe and intervention in first-episode psycho Black pa refer

by John Evans, Senior Editor, The Chronicle

Persons of Caribbean or African descent with first-episode psychosis (FEP) are significantly more likely to be coercively referred and coercively treated than non-Black individuals with FEP, according to a retrospective sample study.

The project was developed to explore how medical and legal coercion and racial bias may interact in the Canadian mental health system, according to the paper's lead author Sommer Knight, MSc, in an interview with THE CHRONICLE OF NEUROLOGY + PSYCHIATRY

“[Coercion] is, I think, an ethical and clinical issue in psychiatry because it infringes upon patient autonomy, but it is also needed to protect patients with poor knowledge or insight into their illness and who refuse medication,” said Knight. “It is a balance between patient rights and public safety.” At the time of the study Knight was studying in the Division of Social and Transcultural Psychiatry of the Department of Psychiatry, Faculty of Medicine, at McGill University, Montreal.

Knight also noted that racism and racial disparities

“If we look at the 1960s, during the Civil Rights movement, the diagnosis of schizophrenia became weaponized and was used as a form of social control to end civil protests. Many African American men in particular were labelled hostile or paranoid or violent. This led to an over-diagnosis of psychosis compared to white populations, and many [Black men] were held in mental health asylums.”

—Dr. G. Eric Jarvis McGill University

ferral osis

viduals with FEP.

Age and the presence of violent or threatening behaviour were predictors of coercive referral, while ethnoracial status, age, and violent or threatening behaviour predicted coercive intervention.

There is room to improve the accuracy of the method psychiatrists use to evaluate violence or aggression, Dr. Jarvis said. “A checklist reminding clinicians to directly observe the patient and to consult the file, colleagues, and families—to the degree possible—to get more information could make the evaluation less impressionistic.”

LEGAL COERCION EVEN MORE LIKELY

Knight pointed out that findings from the statistical analyses showed that as much as Black patients were more likely to experience coercive referral and coercive intervention, they were even more likely to experience legal coercion with court involvement.

psycho pa refer

involuntarily ferred and treated than other patients

patients

in health access are public health issues. “If medicine is to be used to ensure the well-being of all, irrespective of gender, class, race, or immigration status, that needs to be upheld. However, decades of research have shown that this is not the case. There is differential treatment in psychiatric care among different ethnic or racial groups. Whether this may be due to racial bias or cultural differences or stereotypes, I think it needs to be investigated.”

The study reviewed retrospective data from 208 patients referred to the FEP program at Jewish General Hospital in Montreal between 2008 and 2018. Investigators then used chi-square and logistic regression analyses to explore the relationships among raceethnicity, diagnosis of psychosis, and coercive referral and intervention. As the data was collected from a single centre, it may not reflect the state of the whole Canadian mental health system.

HOW THE NEED FOR COERCION IS ASSESSED

Coercive referral and intervention include placing an individual in a secure medical facility or administering medications without the individual's consent. This often takes place when an individual is deemed to be violent or threatening.

The determination of violence risk is part of the routine clinical assessment made by psychiatrists, said study co-author Dr. G. Eric Jarvis in an email interview. Dr. Jarvis is an associate professor of psychiatry at McGill University and is Director of the Cultural Consultation Service and the First Episode Psychosis

Program at the Jewish General Hospital.

Dr. Jarvis said that the assessment is made through consideration of several factors. One factor is the psychiatrist's direct observation of the patient's behaviour and whether force has been needed to contain aggressive behaviours—such as the application of restraints or the administration of emergency medications to calm the patient.

Next, the patient's medical file is reviewed for reports about the patient's behaviour, including police reports, ambulance reports, nursing reports, and any information from the referring clinician, including physician assessments.

Reports by family members or others who may know the patient or have seen them in their ill state are of great importance, he said.

In cases where few information sources are available, psychiatrists will make their best decision based on the information they have, Dr. Jarvis said.

“To the degree that reports are accurate, the assessment also will be accurate; but the best source of information, and the most convincing, would be aggressive behaviour witnessed by the psychiatrist and by other health care staff near to the time of the report,” he said.

COERCION OF BLACK PATIENTS MORE LIKELY

The results of the study showed that Black persons of Caribbean or African descent with FEP were statistically significantly more likely to be coercively referred and coercively treated than non-Black indi-

“Coercion happens in two sets,” said Knight. “There is the medical coercion which is rendered by medical staff and doctors. . . And then there is the medical-legal coercion side. That is where there is an interaction between psychiatry and the law that happens where mental health legislation is used.” In this study, the authors defined medical-legal coercion as any coercive action ordered by the court of Quebec.

Regarding the medical-legal aspect of coercion, Knight noted that the 'danger' criterion often used in mental health legislation is a potential source of bias in the system that may need to be carefully reviewed by policymakers.

“Especially for black patients who have been racially stereotyped as dangerous or hostile, or violent, and as criminals, this danger criterion might be problematic,” she said. “The question is, does it have the scientific support to be used to justify coercion? Or does it lead to more potential professional, judicial and ethical issues? That was something I wondered: how we assess violent and threatening behaviour in these medical-legal settings and institutional spaces.”

HISTORICAL MISUSE OF HEALTH LEGISLATION

Knight noted how mental health legislation has historically been used against marginalized groups.

“If we look at the 1960s, during the Civil Rights Movement, the diagnosis of schizophrenia became weaponized and was used as a form of social control to end civil protests. Many African American men in particular were labelled hostile or paranoid or violent. This led to an over-diagnosis of psychosis compared to white populations, and many [Black men] were held in mental health asylums.”

Dr. Jarvis noted that public awareness of the reasons for coercive mental health care is important.

“The public should know that psychiatrists evaluate whether or not someone is aggressive or threatening to protect the patient, the family and the society in general,” he said. “The goal is not to punish or detain someone against their will but to protect. In difficult cases, a person may be kept in the hospital against their will so that the treatment team can gather more information.”

are more likely to be

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Severity of MDD was not associated with cognitive changes

Report, a large multi-centre study designed to find biomarkers that might help predict whether someone with depression will respond to antidepressant treatment.

COGNITIVE DATA RECORDED

This data set was chosen because in addition to clinical assessments such as blood tests and neuroimaging, CAN-BIND-1 participants also underwent cognitive assessments, study lead author Dr. Trisha Chakrabarty said in an interview with THE CHRONICLE OF NEUROLOGY + PSYCHIATRY

“The reason we were interested in doing this analysis is that we know that cognitive functioning can be significantly impaired in people who have depression,” said Dr. Chakrabarty. “And not everyone who recovers from the depression, even if their symptoms of depression—such as low mood, decreased ability to enjoy the things that they used to enjoy—get better. Some people with depression will continue to experience cognitive difficulties.”

Dr. Chakrabarty is an assistant professor in the Department of Psychiatry, University of British Columbia, Vancouver.

She noted that adding aripiprazole to an antidepressant is a very commonly used strategy. However, she said that there have not been many studies that have looked at what potential cognitive benefits there may be from this therapeutic approach. There is some evidence from preclinical and animal model studies that adjunctive aripiprazole might have some additional cognitive benefits beyond treating depressive symptoms in patients with MDD, she noted.

“We thought it was a good opportunity since we have the cognitive data [from the CAN-BIND-1 study] to look at that question,” she said.

ESCITALOPRAM NON-RESPONDERS TREATED WITH ARIPIPRAZOLE

This study included 209 acutely depressed participants with MDD. All participants received eight weeks of escitalopram treatment. Patients who did not respond to the escitalopram treatment received an additional eight weeks of adjunctive aripiprazole, while responders continued escitalopram monotherapy. There were 39 patients lost to attrition.

Participants in the two active arms and 112 matched healthy participants completed the Central Nervous System Vital Signs cognitive battery at baseline, as well as at eight and 16 weeks. The investigators also compared cognitive trajectories between participants with MDD and healthy participants.

Overall, participants with MDD displayed poorer baseline global cognition, composite memory and psychomotor speed compared to the healthy participants. However, the research team found no statistically significant changes in the neurocognitive index, reaction time,

complex attention, cognitive flexibility, memory or psychomotor speed from baseline to week eight in the participants with MDD who were receiving escitalopram monotherapy.

MAIN FINDINGS UNSURPRISING

“That accords pretty well with the established research,” said Dr. Chakrabarty. “There have been several studies that have looked at the cognitive effect of standard antidepressants. They have mostly shown equivocal results.”

Changes in the overall severity of MDD symptoms were not found to be associated with cognitive changes. The investigators observed no significant cognitive changes from weeks eight to 16 in the responder group, and in the non-responder group they observed worse reaction times from weeks eight to 16, independent of any changes in MDD symptoms.

“There is a clinical benefit [to the adjunctive treatment] in that adding on aripiprazole resulted in a significant number of participants improving clinically, but in terms of cognitive benefits, there did not seem to be any,” Dr. Chakrabarty said. “If anything, it looked like the addition of aripiprazole may have resulted in some worsening of motor speed.”

COGNITION-FOCUSED RESEARCH NEEDED

Trisha Chakrabarty University of British Columbia

Looking forward, Dr. Chakrabarty said that the paper's findings should remind clinicians that while the common antidepressant treatments are often highly effective for managing mood symptoms, they do not necessarily influence cognitive symptoms.

The findings, she says, highlight “that we do need to think of cognition and cognitiverelated difficulties as their own treatment domain, perhaps requiring different types of treatments than we think of when we think of treating depression in general.”

The CAN-BIND-1 data sets which include neuroimaging data allow for evaluation of structural or functional brain changes which might be seen in individuals who experience a greater degree of cognitive improvement with treatment versus a lesser degree of cognitive improvement, she said.

Dr. Chakrabarty noted that prior research has identified childhood maltreatment as a risk factor of poorer cognitive outcomes in depression. She noted that a data set such as CAN-BIND-1 could help clarify the biological impact of childhood maltreatment and how that impact may relate to cognitive symptoms in adults with depression. That type of biological examination might also identify subgroups that respond differently to treatment, she said.

“It is very possible that if we were to take a more fine-grained view, we would see that there are different kinds of subgroups,” she said.

“There might be a subgroup that experiences a pretty significant degree of cognitive improvement and a subgroup of patients who do not experience or do not show a significant degree of cognitive improvement.”

“There have been several studies that have looked at the cognitive effect of standard antidepressants. They have mostly shown equivocal results.“

—Dr.

Does inflammation driven by lifestyle play a role in dementia?

n Modifiable lifestyle factors may be the major players in late-life cognitive impairment

Continued from page 1

by John Evans Senior Editor, The Chronicle

ALL SOURCES OF LONG-TERM SYSTEMIC INFLAMMATION COULD be early upstream factors in late-life dementia, through the contribution of inflammation to cerebral small vessel disease, according to a new hypothesis.

This hypothesis is raised in a literature review published in Frontiers in Aging Neuroscience (April 29, 2021; 13:679837). The review was inspired in large part by earlier work that revealed many individuals show decreased blood flow to the brain years before they exhibit any measurable signs of dementia, said the review’s author Dr. Antoine Hakim in an interview with THE CHRONICLE OF NEUROLOGY + PSYCHIATRY. In particular, Dr. Hakim referred to research from the Montreal Neurological Institute, which was published in Nature Communications (June 21, 2016; 7:11934).

“So the question for me was ‘What is it that is driving the decline in cerebral blood flow?’” said Dr. Hakim.

Dr. Hakim is the founding director of the Brain and Mind Research Institute and Professor Emeritus at the University of Ottawa and has been the Head of Neurology at the Ottawa Hospital.

He noted that there are a number of lifestyle factors that strongly influence the risk of later cognitive impairment. “It turns out that all of these lifestyle factors that impact cognition negatively are initially associated with the decline in cerebral blood flow.”

After considering the idea of small vessel disease being a contributing factor to dementia, the next logical question is what in the bloodstream is contributing to the vessel damage, Dr. Hakim said. “There is one thing that just kept coming up, and that is inflammation,” he said.

LIFESTYLE-DRIVEN INFLAMMATION

Other papers in the literature have proposed inflammation as the link between lifestyle factors and Alzheimer’s dementia specifically, Dr. Hakim noted in his paper, but the specific mechanism has not been explored.

In this paper, Dr. Hakim reviewed existing literature on three specific lifestyle factors—obesity, sedentary behaviour and insufficient sleep. Each of these is known to negatively impact cognition, he noted. The paper summarizes the research associating each lifestyle factor to subsequent cognitive decline and reviews the potential mechanisms linking each to its eventual impact on perfusion in the brain

“I went through all of the [lifestyle] factors that we now know can increase the likelihood for dementia, and I picked three of them to write about,” said Dr. Hakim, noting that similar connections could be made for the other known lifestyle factors.

He noted that other sources of long-term systemic inflammation, such as rheumatoid arthritis and poor oral hygiene, could also be contributing to cognitive impairment later in life, but have not been studied in detail yet.

There is no question there are many sources of inflammation in the human body that are controllable, Dr. Hakim said. “Inflammation comes in various guises, and it is a very complex system.”

HYPOTHESIS TO BE CONFIRMED

While the three examples examined in this paper are compelling, Dr. Hakim noted that significant research will be needed to confirm

the hypothesis.

“I would like to see blood samples taken from people and stored and analyzed for a wide spectrum of inflammatory components,” he said. “I want to go upstream from small vessel disease and ask: ‘What is it in my blood in terms of the inflammatory components that will lead me to have a decline in cerebral blood flow 20 years from now, and from there lead me to have a decline in cognitive function?’”

ACTION CAN BE TAKEN NOW

The associations identified by other researchers between some modifiable lifestyle factors and cognitive decline are important even if this systemic inflammation hypothesis does not bear out in further studies, Dr. Hakim noted.

“The important thing is that it is never too late,” he said. “You can always improve and delay the onset of cognitive impairment. But there is no question that the literature says the earlier the better, the younger the better. So there is work here for everybody, not just clinicians. Because frankly, by the time the patient comes to a clinician complaining about cognitive impairment, that brain of hers or his has already been suffering for potentially decades.”

Dr. Hakim said he would like to see greater efforts from stakeholders, including government bodies, to encourage good lifestyle habits, particularly among young people.

Editorial: New therapies in development for Parkinson’s

Continued from page 1

and BIA 28–6156/LTI-291) targeting glucocerebrosidase activity are now undergoing the second phase of clinical trials and gene therapy to replace mutated GBA with wild type is now in the 1/2a phase of clinical trials. 10

Furthermore, Phase 3 and Phase 2b are expected to start this year for drugs targeting protein leucine-rich repeat kinase 2, encoded by LRRK2.11

Despite the failure of some drugs targeting Parkinson’s disease as a singular entity, we have new promising studies that target Parkinson’s disease based on causative gene stratification. We still do not know whether this treatment will be clinically beneficent for Parkinson’s disease patients. Nevertheless, we look forward to seeing upcoming results and expect novel approaches targeting singular genes and pathways.

1. Yang W, Hamilton JL, Kopil C, et al: Current and projected future economic burden of Parkinson’s disease in the U.S. npj Parkinson's Disease 2020/07/09 2020; 6(1):15. doi:10.1038/s41531-020-0117-1

2. Pagano G, Taylor KI, Anzures-Cabrera J, et al: Trial of Prasinezumab in Early-Stage Parkinson’s Disease. New England Journal of Medicine 2022; 387(5):421-432.

3. Lang AE, Siderowf AD, Macklin EA, et al: Trial of cinpanemab in early Parkinson’s disease. New England Journal of Medicine 2022; 387(5):408-420.

4. Schenk DB, Koller M, Ness DK, et al: First-in-human assessment of PRX002, an anti–α-synuclein monoclonal antibody, in healthy volunteers. Movement Disorders 2017; 32(2):211-218.

5. Brys M, Fanning L, Hung S, et al: Randomized phase I clinical trial of anti–α-synuclein antibody BIIB054. Movement Disorders 2019; 34(8):1154-1163.

6. Tsang J, Tse GM: Molecular classification of breast cancer. Advances in Anatomic Pathology 2020; 27(1):27-35.

7. Ortega RA, Wang C, Raymond D, et al: Association of dual LRRK2 G2019S and GBA variations with Parkinson Disease progression. JAMA Network Open 2021; 4(4):e215845-e215845. doi:10.1001/jamanetworkopen.2021.5845

8. Sosero YL, Yu E, Krohn L, et al: LRRK2 p. M1646T is associated with glucocerebrosidase activity and with Parkinson's disease. Neurobiology of Aging 2021; 103:142. e1142. e5.

9. Alcalay RN, Levy OA, Waters CH, et al: Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain 2015; 138(9):2648-2658. doi:10.1093/brain/awv179

10. Senkevich K, Rudakou U, Gan-Or Z: New therapeutic approaches to Parkinson's disease targeting GBA, LRRK2 and Parkin. Neuropharmacology 2022; 202:108822.

11. https://www.globenewswire.com/newsrelease/2022/01/10/2363990/0/en/DenaliTherapeutics-Announces-Progression-andExpansion-of-Broad-Therapeutic-Portfoliofor-Neurodegeneration-and-Expected-KeyMilestones-in-2022.html

D r H a k i m

I AM PROOF THAT

STROKE CAN HAPPEN AT ANY AGE

SHANNON RICHARDS THOUGHT SHE WAS TOO YOUNG TO HAVE A STROKE

Pre-interview jitters seemed to be getting the best of Shannon Richards. Hours away from a job interview, the 29-year-old had spent the morning in her bedroom, trying to shake off an upset stomach and throbbing headache.

“I felt really dizzy. It was almost like somebody pushed me,” she recalls.

Unable to keep her balance, Shannon called for her mother, Susan, before crumpling to the floor. Susan came running and found her daughter on the floor, slurring her words. The left side of Shannon’s face was drooping.

“I remember my mom saying, ‘I think you’re having a stroke.’”

Susan called 9-1-1. Within minutes, Shannon was in the back of an ambulance, racing to the nearest hospital in Sault Ste. Marie, Ont. Doctors quickly determined that Shannon was having an ischemic stroke, an interruption in the brain’s blood flow caused by a blood clot.

Because of her mom’s fast response, Shannon got to hospital in time to receive tPA, a clot-busting drug that helps restore blood flow to the brain. Researchers funded by the Heart and Stroke Foundation pioneered the use of tPA for stroke patients. To be effective, it must be given within 4½ hours of the onset of symptoms.

Seven years later, Shannon hopes her story will help others.

“Stroke can happen at any age, but you can always move forward from it. I’m proof of that.”

“Stroke can happen at any age, but you can always move forward from it.”

Dr. Morris Scantlebury

Abook recommendation from a librarian friend was the catalyst that led Dr. Morris Scantlebury—at the time recently graduated from medical school— to pursue neurology as a specialty. An Anatomy of Thought: The Origin and Machinery of the Mind by Ian Glynn introduced Dr. Scantlebury to the advances that were occurring in the neurosciences and captured his attention, he said.

It was working with two mentors, including Lionel Carmant—at the time a pediatric neurologist with an interest in epilepsy and now a Minister for Health and Social Services in Quebec—that guided Dr. Scantlebury to research a greater understanding of seizure in children.

Dr. Scantlebury is a child health and wellness researcher and an associate professor in the Department of Paediatrics at the University of Alberta in Edmonton.

His research developing models of pediatric seizure, and his mentorship to many Black students at the Alberta Children's Health Research Institute—amplifying their research and work—has led to Dr. Scantlebury being honoured as one of the first recipients of the Calgary Black Achievement Awards. These awards are organized by the Calgary Black Chambers and are sponsored by CIBC. They were created to celebrate the achievements of Black Calgarians and their contributions to the community.

T HE C HRONICLE OF N EUROLOGY +

PSYCHIATRY’S senior editor John Evans spoke with Dr. Scantlebury about his career and the award recognition.

What are your thoughts and being one of the first people to be recognized for the Calgary Black Achievement Awards?

I am extremely honoured to be recognized in this way, especially in light of what is happening today. Not in terms of the struggles of Black people for recognition, and inclusion, but I think it is important for Black people to begin to rise and to recognize their Black high achievers and those that have conducted their careers excellently. I am very honoured to be recognized as one of those people and I know it is a responsibility to be carrying this torch.

I think [these awards are] really important and a good thing, and I hope they continue to recognize others in the fields of medicine and science. There are very few Black people in academia, not necessarily in medicine, per se. In academia, there are very few Black people in the scientific fields, in STEM, and so therefore I hope [these awards] encourage young people to go forward and achieve and to consider careers in academia.

That is the 'official statement', but the more Scantlebury statement would be I am happy to achieve it, but I can honestly say there are many more people who were deserving as well.

What have been some of the most rewarding experiences you have had during your research into pediatric neurology, particularly in the areas of seizure?

There were two major experiences in my career. My career involves developing models of pediatric epilepsy. That was a major part of my career at one point. The reason is if you want to understand that condition, you have to have a good model. For a long time, I do not think we had great models of pediatric epilepsy. And I was able to develop two of the seminal models of pediatric epilepsy, one for febrile seizures and another for infantile spasms.

I remember being at the AES [American Epilepsy Society] meeting in New Orleans when the model for febrile seizures was recognized and I was given an award for excellence for best presentation. I thought that was a high in my career at that time. But I think, more important was when I developed the first model of infantile spasms.

Infantile spasm is a terrible, catastrophic epilepsy syndrome that affects babies. And up until 2006, there were no models for that condition, which had been described roughly 175 years ago. At the time we created a model it was thought impossible. But based on some of the work I was doing in febrile seizures, I figured that it might be possible.

Every research career has its claim to fame. So that will be my claim to fame, developing that model of infantile spasms.

Since then we have done more work looking at mechanisms. We are looking at mechanisms of the ketogenic diet, trying to understand it since through understanding the mechanisms we might find cures for certain catastrophic epilepsy syndromes, or we may be able to tweak the ketogenic diet, such that it is more effective.

What would you say are some of the most interesting, outstanding questions in pediatric neurology, with a focus on seizures?

The first one is how do seizures stop. All of our brains have the capacity to control seizures, and we do not understand that very well. If we did, I think that there is a cure there for epilepsy.

The second question I think is important is that the baby brain is resistant to seizure-induced damage as compared to the adult brain. And again, that is not well studied.

I think there are protective treatments that we may discover based on the understanding of how and why baby brains are resistant to seizure damage that we can apply when a patient comes in with a prolonged seizure or multiple seizures which might damage the brain. By gaining an understanding of how the baby brain remains resistant, we may be able to glean some form of strategy to prevent the brain from being damaged.

—Who’s making a difference near you? Tell The Chronicle, so we can tell our readers. Write us at health@chronicle.org

PrBOTOX® (onabotulinumtoxinA for injection) is indicated for the prophylaxis of headaches in adults with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer).

FOR MORE INFORMATION:

Please consult the Product Monograph at: https://pdf.hres.ca/dpd_pm/00060199.PDF for contraindications, warnings, precautions, adverse reactions, interactions, dosing and conditions of clinical use. The Product Monograph is also available by calling: 1-800-668-6424.

All trademarks are the property of their respective owners. BOTOX® and its design are registered trademarks of Allergan Inc., an AbbVie company. © 2022 AbbVie. All rights reserved.

Award winner of the first ever Calgary Black Achievement Awards

Introducing

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The FIRST and ONLY histamine 3 (H3)

antagonist/inverse agonist indicated to treat EDS or cataplexy in patients with narcolepsy1,2*

receptor

• A novel pharmacologic class, a histamine H3 receptor antagonist/inverse agonist. †

• By binding to presynaptic histaminergic H3 autoreceptors, WAKIX® increases the synthesis and release of histamine as well as other neurotransmitters that promote wakefulness (e.g., acetylcholine, dopamine, norepinephrine).†

WAKIX® (pitolisant hydrochloride tablets) is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy.1

Please consult the product monograph at https://www.paladin-labs.com/our_products/Wakix_EN.pdf for important information about:

• Contraindications in patients with hypersensitivity to pitolisant hydrochloride, severe hepatic impairment and in breastfeeding patients.

• Warnings and precautions regarding QTc prolongation, drug abuse, misuse, dependence and rebound effect, driving or operating machinery, increased exposure with moderate hepatic impairment, seizures or worsening of seizures in patients with a history of epilepsy, suicidal ideation in patients with history of psychiatric disorders, renal impairment, end stage renal disease, reduced effectiveness of hormonal contraceptives, use in pregnancy, avoiding pregnancy, fertility, use in pediatrics and use in geriatrics.

• Adverse reactions, drug interactions, dosing, and conditions of clinical use. The product monograph is also available by calling 1-888-867-7426 or by email at medinfo@paladin-labs.com.

* Comparative clinical significance is unknown. † Clinical significance is unknown.

References:

1. WAKIX® Product Monograph. Paladin Labs Inc. August 9, 2021.

2. Data on file. Paladin Labs Inc.

WAKIX® is a registered trademark of Bioprojet Europe Ltd. © 2022 Paladin Labs Inc., St-Laurent, QC 1-888-867-7426. www.paladin-labs.com