Editorial: Parkinson’s disease and new drugs in development

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)

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 treatments, there were particularly 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 second-phase studies on prasinezumab and cinpanemab 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

Dr. Konstantin Senkevich

ABOUT THE AUTHOR 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. —please turn to page 12

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. 416.352.6199. E-mail: health@chronicle.org. Contents © Chronicle Information Resources Ltd., 2021, except where noted. All rights reserved worldwide. The Publisher prohibits reproduction in any form, including print, broadcast, and electronic, without written permissions. Printed in Canada. Mail subscriptions: $72 per year in Canada, $125 per year in all other countries. Single copies: $12 per issue (plus 13% HST) Canada Post Canadian Publications Mail Sales Product Agreement Number 40016917 The Publisher certifies that advertising placed in this publication meets Revenue Canada requirements for tax deductibility.

Volume 25, Number 2 June/July 2022 ISSN 1209-0565

n In 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 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 June/July 2022 ◼ 3

n Depression: Escitalopram monotherapy followed by adjunctive aripiprazole does not appear to improve cognitive outcomes in MDD (p. 1) n 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 n Chronicle Vitae: Dr. Morris Scantlebury, is the first award winner of the Calgary Black

Achievement Awards (p. 14)

Founding Editor Richard Gladstone,

MD, FRCPC Psychiatry Editor J. J. Warsh, MD, FRCPC

Neurology Editor Sarah A. Morrow, MD, FRCPC

Editor, Innovation in the Mind Sciences Roger S. McIntyre, MD, FRCPC

Editorial Director R. Allan Ryan

Senior Editor John Evans

Associate Editors Kylie Rebernik Jeremy Visser

Communications Coordinator Katherine Brenders

Publisher Mitchell Shannon

Operations Manager Cathy Dusome

Sales & Customer Service Cristela Tello Ruiz

Comptroller Rose Arciero 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.

—Continued from page 1 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.”

D Dr. Gan-Or

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

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 psy-

Sommer Knight chiatry 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

Dr. J G. Er arvis ic 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

—Dr. G. Eric Jarvis McGill University

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 individuals 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.

“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.”

—Continued from page 1 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 Dr. Chakrabarty 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 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.”