The Chronicle of Neurology & Psychiatry June 2016; 19(3) by The Chronicle of Neurology & Psychiatry

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Canada’s National Newspaper of the CNS Sciences n June 2016 n The Chronicle is committed to maintaining leadership in environmentally sustainable policies, and to encouraging the adoption of “greenaware” practices in healthcare. We invite your comments via e-mail, at: health@chronicle.org

Editorial: ACP guidelines provokes thought ..........................3 Motivational deficits in MDD linked to functional impairments ......6 Modifiable factors to help reduce smoking during pregnancy ......11

Perinatal stroke hemiparesis: exploring rTMS, constraint Stroke

n Adding rTMS, CIMT to therapy improved outcomes

Adults with

by Emily Innes-Leroux,

Associate Editor, The Chronicle

MDD

Non-pharmacologic

transcranial magnetic stimulation (rtMS), or constraint-induced movement therapy (CiMt), or both, to intensive therapy for children with stroke-induced hemiparetic cerebral palsy has been found to increase the chances of clinically significant improvement compared to children who received only intensive therapy. in a factorial-design, blinded, randomized controlled trial, published online ahead of print in the journal DDiNg rePetitive

pharmacologic

therapy?

Neurology (Mar. 30, 2016), lead author Dr. Adam Kirton and colleagues assessed rtMS and CiMt effects in hemiparetic children aged six to 19 years with Mri-confirmed perinatal stroke. All participants (45) completed a two-week, goal-directed, peer-supported motor learning camp and were randomized to receive daily rtMS, CiMt, both, or neither. the primary outcomes were the Assisting Hand Assessment and the Canadian Occupational Performance Measure at baseline, one week,

—please turn to page 8

Light therapy as non-seasonal MDD treatment Depression

please turn to page 12

Schizophrenia associated with CVD

Light therapy, both as monotherapy and in combination with fluoxetine, appears to be efficacious and well tolerated for the treatment of adults with non-seasonal major depressive disorder (MDD), according to a study published in JAMA Psychiatry (Jan. 2016; 73(1):56–63). —See page 7

Schizophrenia

n Consensus guidelines needed for early detection of CVD by Lynn Bradshaw, Senior Editor, The Chronicle

(CvD) among people with schizophrenia needs more serious attention from clinicians and researchers, according to the authors of a literature review published in the Asian Journal of Psychiatry (feb. 2016; 19:28–36). “it has been observed that mortality risk in people with schizophrenia is quite higher than the general population,” said the corresponding author of the report, Dr. tanvir turin Chowdhury. —please turn to page 14 He COMOrbiDity Of CArDiOvASCuLAr DiSeASe

This issue’s Chronicle Vitae profiles Dr. James Rutka, a neurosurgeon who was recently appointed as an officer of the Order of Canada for his contributions to advancing treatment for pediatric brain tumours. See page 18

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REGISTRATION NOW OPEN! L’INSCRIPTION EST OUVERTE!

HIGHLIGHTS / FAITS SAILLANTS Wednesday, 21 September / Le mercredi 21 septembre Pre-Conference Courses / Cours pré-congrès PC01 - Better Health, Better Care, Better Value: Improving the Quality of Mental Health Services Nick Kates*, MD, FRCPC PC02 - The Evidence-Based Psychotherapist: Improving Outcomes With an Understanding of Attachment, Mentalizing, and Trauma Jonathan Hunter*, MD, FRCPC; Molyn Leszcz, MD, FRCPC; Clare Pain, MD, FRCPC PC03 - Towards an Emerging Clinical Science of Mindfulness Evan Collins*, MD, FRCPC; Susan Abbey, MD, FRCPC; Zindel Segal, PhD; Norman Farb, PhD; Steven Selchen, MD, FRCPC; Patricia Rockman, MD, CCFP, FCFP PC04 - Transcranial Magnetic Stimulation: Science, Therapeutics, and Innovation Amer Burhan*, MBChB, MSc, FRCPC; Jeff Daskalakis, MD, PhD, FRCPC; Daniel Blumberger, MD, FRCPC; Jonathan Downar, MD, PhD, FRCPC; Tarek Rajji, MD, FRCPC; Lena Palaniyappan, BA, MBBS, PhD

Thursday, 22 September / Le jeudi 22 septembre All-Delegate Keynote Plenary / Plénières de conférenciers pour tous les délégués Writing About Patients, Their Families, and Their Psychiatrists: Improving Understanding and Fighting Stigma David Goldbloom, OC, MD, FRCPC; Pier Bryden, MD, FRCPC; Kirsten Halpin (patient); Sylvia Orzech (family member) Expert Psychiatry Series with CAPM / Conférences des experts en psychiatrie avec l’ACMP Psychiatric Complications of Critical Illness: Delirium and Beyond Nancy Brager*, MD, FRCPC; Wesley Ely, MD, MPH; Margaret Herridge, MSc, MPH, MD, FRCPC

Friday, 23 September / Le vendredi 23 septembre All-Delegate Keynote Plenary / Plénières de conférenciers pour tous les délégués Pan-Canadian Panel: Bringing Mental Health Into Canada's Quality Health Care Agenda Joshua Tepper, BA, MD, CFPC, MPH. EMBA; Verna Yiu, MD, FRCPC; Linda Courey, PhD CPA-at-the-Movies / L’APC au cinéma Autism in Love Harry Karlinsky, MD, MSc, FRCPC; Vikram Dua, MD, FRCPC All-Delegate Keynote Plenary / Plénières de conférenciers pour tous les délégués Open Heart, Open Mind Clara Hughes, OC, OM, MSC CPA-Meet-the-Author / L’APC Rencontre avec un auteur Authors and Therapists: The Role of Imaginative Empathy Guy Gavriel Kay, BA, LLB, CM All-Delegate Keynote Plenary: Distinguished Member Lecture Plénières de conférenciers pour tous les délégués : Conférence d’un membre distingué Bright Lights Extinguished: Suicides in our Medical Community Mamta Gautam, MD, MBA, FRCPC, CPDC, CCPE

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“If you think of the brain as an orchestra, the thalamus is the

conductor. The players are in the cortex. When the conductor makes a move, the players follow. The conductor then hears their sounds and makes new moves, resulting in a continuous dialogue.” —Dr. Rodolfo Llinás, Colombian-American neurologist

Guest editorial: ACP guidelines provoke thought

in the development of practice guidelines over the last several decades. Although guidelines have existed for the care of patients for centuries it is only in the last several decades that evidence-based guidelines have been developed.1 in Qaseem, et al, reasonable practice guidelines and recommendations specifically related to the comparative effectiveness of treatment for second-generation antidepressants (SgA) versus non-pharmacological treatments for major depressive disorder (MDD) in adults have been developed based on systematic review of published, english lanDr. Rosenbluth guage, randomized, controlled trials from 1990 through to Sept. 2015. in an interesting conclusion, the American College of Physicians (ACP) recommends that clinicians select between either cognitive behaviour therapy (Cbt) or SgAs to treat patients with MDD after discussing treatment effects, adverse effect profiles, cost, accessibility, and preferences with the patient. they refer to this as based on moderate quality evidence indicating that there was no significant difference in response when comparing SgAs (fluoxetine, fluvoxamine, paroxetine, and sertraline) with Cbt in patients with MDD after eight to 52 weeks of treatment. they also make other recommendations vis-a-vis different kinds of therapies, as well as complementary and alternative medicines. the remaining recommendations are based on what they term low quality evidence as they note Here HAS beeN A rAPiD iNCreASe

ABOUT THE AUTHOR Dr. Michael Rosenbluth is the chief, Department of Psychiatry, Toronto East General Hospital and psychotherapy supervisor at Sunnybrook Health Science Centre’s Department of Psychiatry. He is an associate professor in the Department of Psychiatry, University of Toronto. He is the Section Head of the 2012 Canadian CANMAT Task Force Recommendations on the Management of Comorbid Mood and Personality Disorders (published 2012) and a contributor to the 2016 CANMAT Guidelines for the Treatment of Affective Disorders (in press).

for most comparison studies, low quality evidence showed no difference in effectiveness of adverse effects between first line intervention using pharmacological (SgAs) or nonpharmacological (CAM, or exercise monotherapies, or accommodation therapies) in patients with MDD. Perhaps for many clinicians a particularly interesting finding in what they refer to as low quality evidence shows no difference when comparing monotherapy using SgAs with combination therapy using SgAs plus Cbt. this is a clinically important observation—does combining Cbt with pharmacotherapy work better than monotherapy with SgAs, or not? these guidelines are interesting and especially thought-provoking when they differ from other conclusions such as the CANMAt guidelines. (full disclosure, i am a contributor to the CANMAt guidelines). the CANMAt guidelines indicated most SgAs were first-line treatments for patients with MDD of moderate or greater severity. this was in the 2009 guidelines; and this recommendation remains unchanged in the 2016 guidelines to be released this year. Psychoeducation, self-management, and psychological treatment approaches are suggested as first-line treatments for individuals with mild severity. the CANMAt guidelines conclude pragmatically that although there is data indicating that the severity of depression does not differentially predict outcomes of treatment with antidepressants and Cbt, the time course of improvement is typically faster with pharmacological treatment; and thus, pharmacotherapy may still be preferred as the initial treatment in severe and high risk cases. CANMAt emphasizes that in moderately severe and low risk cases, the choice of initial treatment between psychological treatment and antidepressants may be determined by a balance of patient preferences and the availability of each treatment modality. they note that several meta-analyses have indicated that Cbt is as effective as antidepressants and the combination of Cbt and an antidepressant is more effective than either alone. As noted, this contrasts with the current ACP guidelines, which indicates no difference when comparing monotherapy using SgAs with combination therapy using SgAs plus Cbt.2,3 As is not unusual in modern psychiatry, there is not —Continued on 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., 2016, 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 19, Number 3, published June 2016 ISSN 1209-0565

Research

n Most (81.9%) of pediatric concus-

sion cases at the Children’s Hospital of Philadelphia had their first concussion-related health care visit through primary care, not the emergency department, suggesting estimates of pediatric concussion based primarily on emergency department visits underestimate concussion incidence in this population, according to findings published online ahead of print in JAMA Pediatrics (May 31, 2016). —Find more info at http://ow.ly/zbK93016cNJ

n Children with attention deficit hyper-

activity disorder adjust their behaviour less to changing reinforcement than typically developing children do when reinforcement is intermittent and the link between action and consequences is less certain, according to a paper published online ahead of print in the Journal of Child Psychology and Psychiatry (April 15, 2016). This may explain why these children have difficulty adapting their behaviour to new situations. —Read more at http://ow.ly/GStQ300Yy7G

n Alexithymia—an impairment in one’s

ability to identify one’s own emotions—is more associated with atypical interoception—the perception of the internal state of one’s body—than autism spectrum disorder is, researchers report in Cortex (Aug. 2016; 81:215-220). These findings suggest that interoceptive impairments should not be considered a feature of ASD, the authors concluded. —More information at http://ow.ly/bB3Y300YDIf

n Atrophy of subcortical grey matter

(thalamus, caudate, and putamen) volumes at early stages of multiple sclerosis has been found to be associated with subsequent changes in disability measures, according to a study published in the Journal of Neurological Sciences (July 15, 2016; 366:229233). —Discover more info at http://ow.ly/Pigm301dyd2 June 2016 n 3

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s Atelier:

Creative expression utilizes brain functions associated with focus, imagination, and memory. While much emphasis has been placed on the importance of strengthening and/or preserving cognitive abilities as people age, very little has been mentioned about the value of imagination. Imagination requires the ability to combine memories of past experiences or ideas with thoughts of the future. It facilitates creativity, and fosters active participation in life. Elderly people, even those with significant cognitive deficits, can substantially benefit from being creative, as is illustrated by the images above. The images were created by nursing home residents who exhibit varying levels of cognitive impairment. The simple directive ‘draw a face’, inspired them to draw friends or relatives from their past. The artwork facilitated continuity of thought; it served as a concrete visual record for them to refer to. —Andrea Charendoff, professional art therapist, Toronto —More information at www.speakingthroughart.com Founding Editor

Richard Gladstone, MD, FRCPC

Psychiatry Editor

MD, FRCPC

Guest Neurology Editor University of Toronto

Esther Bui, MD

Editor, Innovation in the Mind Sciences

Roger S. McIntyre,

MD, FRCPC

Editorial Director

R. Allan Ryan Senior Editor

Lynn Bradshaw

Associate Editors

John Evans Emily Innes-Leroux Publisher

Mitchell Shannon

Production and Circulation

Cathy Dusome

Sales & Marketing

Sandi Leckie, RN Comptroller

Rose Arciero 4 n June 2016

DR. ESTHER BUI is a staff neurologist and clinician teacher at the University Health Network in Toronto. She is a lecturer in the Divisions of Neurology and Dr. Bui Obstetrical Medicine at the University of Toronto and an active member of the Epilepsy Program at the Krembil Neuroscience Centre. Dr. Bui is a member of the Royal College of Physicians and Surgeons of Canada, is a certified member of the Canadian Society of Clinical Neurophysiology (CSCN), and serves on the executive board of the CSCN. Her clinical and research interest lies in advancing the care of epilepsy, particularly in young adults and women of childbearing age. She has a special interest in the management of women with epilepsy and epilepsy in pregnancy.

Publication Index

n Depression: Light therapy effective for non-seasonal MDD tx (p. 7) n Stroke: Post-stroke mortality elevated by high and low blood platelet counts (p. 9) n Adult MDD: ACP guidelines compare pharmacological versus nonpharmacological treatment options for adults with MDD (p. 12) n Neurology: Women with migraine at greater risk of CvD (p. 13) n Schizophrenia: increased awareness needed about the associated comorbidity of CvD in schizophrenia (p. 1, 14) n CV: Dr. James rutka, appointed officer of the Order of Canada, discusses his international leadership in neurosurgery (p. 18)

Children with cerebral palsy found to be at higher risk for obstructive sleep apnea

RESEARCHERS HAVE FOUND that children who have cerebral palsy (CP)—especially when the condition is severe or combined with epilepsy—are more likely to have from obstructive sleep apnea. The study, published online ahead of print in the journal of Developmental Medicine and Child Neurology (Mar. 2016), also found that children with CP are more likely to be accurately diagnosed with a sleep disorder if routinely screened with a questionnaire. In this study, Dr. John Garcia, a sleep medicine specialist at Gillette Children’s Specialty Healthcare in St. Paul, Minn., and a team of experts at Gillette implemented a questionnaire for patients. Researchers found that if more than one-third of the 20 questions on the questionnaire were answered positively, there was an increased risk of obstructive sleep apnea. The use of this simple, rap-

idly administered and publicly available questionnaire significantly helped researchers identify the risk of sleep disorders. Dr. Garcia and his colleagues propose that sleep disorder screening be used among all CP patients. “Anyone who has CP should be screened for a sleep disorder—it should be standard practice,” said Dr. Garcia. “We can improve quality of life for our patients.” —Read more information at http://ow.ly/J4aS3018vF3

Courtesy of Gillette Children’s Specialty Healthcare

J. J. Warsh,

ABOUT THE GUEST NEUROLOGY EDITOR

s Quick-start guide to The Chronicle, June 2016:

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“It is only when we no longer compulsively need

someone that we can have a real relationship with them.” —Dr. Anthony Storr, English psychiatrist (1920-2001)

Virtual reality might be a potential Replacing disease immune system halts tool to treat patients with paranoia that completely wipes out the immune system and then regenerates a new one using blood stem cells has been found in a clinical trial to eliminate all signs of damaging brain inflammation in patients with early, aggressive multiple sclerosis (MS), and facilitate lasting recovery. the study, published in the Lancet (June 9, 2016), included 24 participants who were followed for up to 13 years. “Our trial is the first to show the complete, long-term suppression of all inflammatory activity in people with MS,” said Dr. Harold Atkins, study colead author and a scientist at the Ottawa Hospital. “this is very exciting. However, it is important to note that this therapy can have serious side effects and risks, and would only be appropriate for a small proportion of people with very active MS.” the procedure, immunoablation and autologous hematopoietic stem cell transplantation, begins by giving a person medication to coax their hematopoietic stem cells to migrate from their bone marrow into their blood. these stem cells are then collected from the blood, purified and frozen. then, high doses of chemotherapy drugs are used to eliminate the person’s diseased immune system. the stem cells are then transplanted back into the same person, so that they can give rise to a new immune system that has no “memory” of the previous pattern of attacking the central nervous system. AFTER THE TREATMENT: • Not a single participant experienced a clinical relapse (before: participants experienced an average of 1.2 relapses per year). • Not a single new active inflammatory lesion could be detected in the brains of any of the participants (before: participants had 188 lesions on 48 scans). • Zero participants required MS-specific drugs to control their disease. • 70% of participants experienced a complete stop in disease progression. —Read more information at http://ow.ly/AqpX3018OOL N iNteNSive PrOCeDure

n Having a stroke more than dou-

n A technique to learn that different environments can be safe

help treat severe paranoia by allowing people to face situations that they fear, according to a study published in The British Journal of Psychiatry (May 2016). researchers from Oxford university in england used virtual reality simulations to allow patients from the Oxford Health NHS foundation trust to learn that the situations (such as a crowded elevator) they feared were actually safe. it combines evidence-based psychological treatment techniques with stateof-the-art virtual reality social situations to reduce paranoid fear. the research team, led by Professor Daniel freeman from Oxford university’s Department of Psychiatry, wanted to test whether patients could ‘relearn’ that a situation was safe, by experiencing situations they feared without using their defence behaviours. irtuAL

reALity

CAN

RECREATE SITUATIONS PATIENTS FOUND FEARFUL but being in a situation they fear is very difficult for many patients, since it causes intolerable anxiety. to overcome this challenge the team used virtual reality to recreate social situations that patients found fearful. All the patients (30) went into virtual reality simulations with increasing numbers of computer characters (‘avatars’)— seeing many people at the same time would normally make these patients quite anxious. but participants were told that by staying in the situations, they would relearn that they were safe. A train ride and an elevator scene were used. the patients were randomly given

Courtesy of Oxford University

MS progression

In the news . . .

different instructions on how to deal with these situations in virtual reality. One group were encouraged to use their normal defence behaviours. the other patients were encouraged to drop their defences and try to fully learn that they were safe by approaching the computer characters and looking at them. the patients who fully tested out their fears in virtual reality by lowering their defences showed substantial reductions in their paranoid delusions. Over 50% of these patients no longer had severe paranoia at the end of the testing day. there were even benefits for those who confronted situations they feared in virtual reality while still using their defences: around 20% of this group no longer having severe paranoia at the end of the testing day. Professor freeman said, “paranoia all too often leads to isolation, unhappiness, and profound distress. but the exceptionally positive immediate results for the patients in this study show a new route forward in treatment. in just a 30 minute session, those who used the right psychological techniques showed major reductions in paranoia.” Dr. Kathryn Adcock, head of neurosciences and mental health at the Medical research Council, which funded the study, said, “virtual reality is proving extremely effective in the assessment and treatment of mental health problems. this study shows the potential of its application to a major psychiatric problem. there is a lot of work to do be done in testing the approach in treating delusions, but this study shows a new way forward.” —Find more information at http://ow.ly/mXvw3016m2o

bles someone’s risk of developing dementia, according to a new report by the Canadian Heart and Stroke Foundation. The report indicates a need to prevent both strokes and dementia at the same time, reports The Toronto Star (June 9, 2016). —Read this article at http://ow.ly/lSO93018owC

n An experimental new drug, TEV-

48125, appears to being working to treat migraines within three to seven days after the first injection, according to a trial published in the journal Neurology. The drug works by blocking calcitonin gene-related peptide, reports CTV News (June 9, 2016). —Read this article at http://ow.ly/B76j3018pm5

n In New York City, St. Joseph’s

Regional Medical Center’s, emergency department has started using opioids only as a last resort. For patients with common types of acute pain, doctors are first trying alternative regimens that include nonnarcotic infusions and injections, ultrasound guided nerve blocks, laughing gas, even “energy healing”, and a wandering harpist, reported The New York Times (June 10, 2016). —Read this article at http://ow.ly/10rPZq

n A London, Ont., researcher has

shown that though patients with schizophrenia experience a loss in brain volume—especially in parts that deal with higher cognitive powers—they have more matter than healthy patients in the parts of the brain that perceive sight and sound. The findings suggest that with proper therapy the brains of patients with schizophrenia may have the capacity to fight back against the illness, reports The London Free Press (May 31, 2016). —Read this article at http://ow.ly/12Gv3018W0f June 2016 n 5

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Motivational deficits in MDD linked to functional impairments

n Deficits are quite prevalent and have an intimate relationship with objective, subjective outcomes by John Evans,

Associate Editor, The Chronicle

in patients with major depressive disorder (MDD) and are strongly and persistently linked to functional impairments in a way similar to what has been observed in patients with schizophrenia. that is according to a paper published in Comprehensive Psychiatry (Apr. 2016; 66:31–38). the study was inspired by previous research on prevalence of motivational deficits in major depressive disorder, as well as by previous work from the research centre on schizophrenia, said senior author Dr. gary remington. that research has led the team to see the day-today function of patients with schizophrenia curtailed by domains other than just hallucinations and delusions, which have traditionally been considered the factors that limit patients returning to their previous level of Dr. functioning, he said. Remington Dr. remington is the lead for the subspecialty clinics in the Schizophrenia Program at the Centre for Addiction and Mental Health (CAMH) in toronto, and also professor of psychiatry with the faculty of Medicine at the university of toronto. With the earlier data showing how prevalent motivational deficits are in MDD, and the link between the motivational symptom group and functional impairments first observed among schizophrenia patients, it made sense to investigate whether those deficits would have similar impacts on patient function in cases of MDD, said the study’s lead author gagan fervaha, a PhD student working in the Schizophrenia Division and Campbell family Mental Health research institute at CAMH. Data from the Sequenced treatment Alternatives to relieve Depression (StArFervaha D) study database was used. files on 1,563 individuals with major depression were examined, with motivational deficits evaluated using a derived measure from the Hamilton Depression rating Scale. Patient functioning was assessed with the Work and Social Adjustment Scale (WSAS), which evaluates functioning in the domains of work, home management, social leisure activities, private leisure activities, and close relationships. Participants were asked to determine how much their illness impairs their ability to function in each domain. Subjective outcomes were determined using the Quality of Life enjoyment and Satisfaction Questionnaire (Q-LeSQ), a 14-item self-report instrument for evaluating patient satisfaction and enjoyment in domains including work, household duties, schoolwork or housework, leisure activities, social relations and general activities. OtivAtiONAL DefiCitS Are COMMON

MOTIVATIONAL DEFICITS FREQUENT, RARELY ALLEVIATED BY ANTIDEPRESSANTS “the findings we had in major depressive disorder have been really congruent with what we were finding in schizophrenia,” said fervaha. Participants in the StAr-D study were treated

6 n June 2016

with citalopram. Of those included in this paper, more than 70% continued to experience motivational deficits post-treatment, and those deficits were significantly associated with greater functional impairment. this included both overall function and each of the sub-domains of function that were evaluated. further, the deficits were also linked to worse overall life satisfaction, worse quality of life, and other subjective outcomes. “these deficits are quite prevalent and have a very intimate relationship with some important outcomes—both objective and subjective,” said fervaha.

MOTIVATIONAL SYMPTOM CLUSTERS OVERLAP DISORDERS fervaha said that the study findings support the idea that these motivational deficits do not necessarily reside within specific disorders. “We do not only see motivational deficits in schizophrenia or major depressive disorder, but we are seeing them across disorders. And the relationships they have with outcomes are similar,” he said. this recategorization is in keeping with some recent efforts to begin looking at symptoms and symptom clusters across disorders, he said, citing initiatives such as the u.S. National institutes of Health’s research Domain Criteria (rDoC). finding this cross-disorder association between motivation and outcomes suggests that it could make sense to target motivational deficits and similar symptom clusters as entities separate from the particular disorder a patient may have, fervaha said. Another example of a symptom cluster seen spanning multiple disorders is apathy, said Dr. remington. “you can see apathy in schizophrenia, Parkinson’s disease, certain head injuries, and in other conditions,” he said. “in theory, the same factors might mediate that syndrome across the different diagnostic categories.” in the patients with MDD, fervaha said that the team did find evidence “that changes in the specific symptoms [including] changes in motivational deficits, and improvements in motivational deficits, were linked to improvements in patients’ functioning and their overall well-being in major depressive disorder.” “targeting these symptoms across diagnoses regardless of the symptoms someone presents with seems to be a way forward in improving outcomes,” fervaha said. However, “what we do not know is, at a more mechanistic level, are the same neurobiological or psychological components or abnormalities contributing to these deficits? We do not know if the same neurobiological symptoms are contributing to motivational deficits in schizophrenia, or in depression, or in individual patients for that matter.” SYMPTOM CLUSTERS, CROSS-SPECIALTY COLLABORATION this sort of categorical shift in looking at symptom clusters as entities in themselves, separate from specific disorders, has not yet been widely embraced, said Dr. remington. from a research standpoint, looking at symptom domains across specialties “seems straightforward, but historically we have opted for the opportunity to look within diagnostic categories.” “Historically we have [isolated] ourselves around specific diagnoses. So even within psychiatry it is a bit of a quantum leap to begin to talk to the people in other areas than our own sub-specialty, and yet another leap again to begin to talk to the other specialists like the neurologists.”

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Light therapy effective for non-seasonal major depressive disorder treatment

n First trial to compare light therapy to antidepressants for the Tx of MDD not associated with seasonal affective disorder

by Lynn Bradshaw,

Senior Editor, The Chronicle

igHt tHerAPy, bOtH AS MONOtHerAPy

and in combination with fluoxetine, appears to be efficacious and well tolerated for the treatment of adults with non-seasonal major depressive disorder (MDD), according to a study published in JAMA Psychiatry (Jan. 2016; 73(1):56–63). this research is the first placebo-controlled trial to compare light therapy to antidepressants for the treatment of individuals with MDD that had not been brought on by seasonal affective disorder (SAD), said Dr. raymond Lam, a professor at the university of british Columbia in vancouver. “there have been good studies looking at the combination of light and antidepressant versus antideDr. Lam pressant alone that demonstrated good effects of the combination treatment, but those studies did not answer whether light therapy by itself would be just as effective as the combination treatment,” said Dr. Lam, a psychiatrist at

the Djavad Mowafaghian Centre for brain Health in vancouver. During the randomized, double-blind, placebocontrolled eight week trial, Dr. Lam and his colleagues followed 122 adults (aged 19 to 60 years) with MDD of at least moderate severity. Data were collected from Oct. 7, 2009, to Mar. 11, 2014 from outpatient psychiatry clinics in academic medical centers consisting of one clinic in vancouver and two clinics in toronto. the trial participants were randomly assigned to the following groups: 1) Light monotherapy consisting of active 10,000-lux fluorescent white light box for 30 minutes per day in the early morning plus oral placebo (n=32); 2) Antidepressant monotherapy consisting of inactive negative ion generator for 30 minutes per day plus fluoxetine hydrochloride, 20 mg per day (n=31); 3) Combination of bright light therapy and antidepressant (n=29); or 4) Placebo consisting of an inactive negative ion generator plus oral placebo (n=30). Over the course of the investigation the researchers used the Montgomery-Åsberg Depression

rating Scale (MADrS) from baseline to the eight-week end point to evaluate the patients. Additionally, the secondary measurement outcome included response (≥50% reduction in MADrS score) and remission (MADrS score ≤10 at end point).

LIGHT MONOTHERAPY, COMBINATION TREATMENT WERE EFFECTIVE the findings revealed that the mean (SD) changes in MADrS score for the light, fluoxetine, combination, and placebo groups were 13.4 (7.5), 8.8 (9.9), 16.9 (9.2), and 6.5 (9.6), respectively. the combination (effect size [d]=1.11; 95% Ci, 0.54 to 1.64) and light monotherapy (d=0.80; 95% Ci, 0.28 to 1.31) were significantly superior to placebo in the MADrS change score, but fluoxetine monotherapy (d=0.24; 95% Ci, -0.27 to 0.74) was not superior to placebo, the authors wrote. Data also showed that for the respective placebo, fluoxetine, light, and combination groups at the end point, response was achieved by 10 (33.3%), nine (29.0%), 16 (50.0%), and 22 (75.9%) and remission was achieved by nine (30.0%), six (19.4%), 14 (43.8%), and 17 (58.6%). —please turn to page 17 Additional findings

Researchers find the habenula functions abnormally in patients with depression

increased habenula activation in healthy volunteers, but decreased activation in depressed people. There were no differences in average habenula size between people with depression and healthy volunteers. However, people with smaller habenulae, in both groups, were found to have more symptoms of anhedonia. “The habenula’s role in depression is clearly much more comThe human habenula (in red, 3 mm diameter) where activation tracked the degree to which electric shocks were plex than previously anticipated. thought,” explains lead author Dr. Rebecca Dr. Lawson. “Animal experiments have shown that stimulatLawson, with the UCL Wellcome Trust Centre for ing the habenula leads to avoidance, and it is possible that Neuroimaging, Institute of Neurology. “From this experi- this occurs for mental as well as physical negative events. So mental fMRI study we can draw conclusions about the one possible explanation is that the habenula may help us to effects of anticipated shocks on habenula activation in avoid dwelling on unpleasant thoughts or memories, and depressed individuals compared with healthy volunteers.” when this is disrupted you get the excessive negative focus “We can only speculate as to how this deactivation is that is common in depression.” linked to symptoms, but it could be that this ancient part of the —Read more information at brain actually plays a protective role against depression,” said http://ow.ly/Pufx3018XIg

Courtesy of Drs. Rebecca Lawson and Jonathan Roiser

A REGION OF THE BRAIN THAT RESPONDS to bad experiences has the opposite reaction to expectations of aversive events in people with depression compared to healthy adults, finds new research conducted at University College London (UCL). The study, published in Molecular Psychiatry (May 31, 2016), found that the habenula functions abnormally in depression. The same team previously showed that the habenula was activated in healthy volunteers when they expected to receive an electric shock. “A prominent theory has suggested that a hyperactive habenula drives symptoms in people with depression: we set out to test that hypothesis,” says senior author Professor Jonathan Roiser, with the UCL Institute of Cognitive Neuroscience. “Surprisingly, we saw the exact opposite of what we predicted. In people with depression, habenula activity actually decreased when they thought they would get a shock. This shows that in depressed people the habenula reacts in a fundamentally different way. Although we still do not know how or why this happens, it is clear that the theory needs a rethink.” The researchers scanned the brains of 25 people with depression and 25 never-depressed individuals using high-resolution functional magnetic resonance imaging (fMRI). The participants were shown a sequence of abstract pictures while they lay inside the scanner. Over time they learned that different pictures were associated with a chance of different outcomes—either good or bad. Images predicting electric shocks were found to cause

June 2016 n 7

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rTMS improves outcomes for stroke-induced hemiparetic CP

two months, and six months post-intervention. the Assisting Hand Assessment gains at six months were additive and largest with rtMS and CiMt (β coefficient=5.54 [2.57– 8.51], p=0.0004), reported the investigators. the authors stated that the intensive therapy camp alone produced large improvements in the Canadian Occupational Performance Measure scores regardless of treatment groups. “We started [the research] about five years ago, at the time there was emerging evidence for brain stimulation helping motor recovery for adults with stroke and some evidence for constraint for kids with hemiparetic cerebral palsy and we have a research program focused here on that specific problem,” said Dr. Kirton, director of the Calgary Pediatric Stroke Program at Albert Children’s Hospital and associate professor of pediatrics and clinical neurosciences at the university of Calgary. “We have been using brain stimulation to map kids’ brains to understand how they develop after an early injury like a stroke, and so the next step was to translate that into trying to modulate their brains to learn better. that is where the idea came from to [conduct] a clinical trial to combine the two [therapies] to [determine] whether one or both of those [treatments] could help with their motor function,” he told tHe CHrONiCLe. Dr. Kirton noted that rtMS, while novel in this pediatric population, has been shown to be safe and effective in a “large volume” of adult stroke patients. “it was certainly experimental, but that is the way to move forward,” he said.

THREE MILLION BRAIN STIMULATIONS “there were no serious adverse events and the procedures were well tolerated,” said Dr. Kirton. “Our lab has now done almost three million different stimulations in about 260 kids with a variety of different conditions and we . . . still have not had any serious adverse events.” One side effect, noted Dr. Kirton, was a mild headache, which resolved or that children quickly adapted to. He said he and his colleagues used a tolerability scale to help rate the safety of the rtMS. Most children rated it similar to watching tv or going for a car ride. “it was not as good as going to a birthday party, but it was better than going to the dentist.” the investigators also used specific safety tests including monitoring the function of both hands of the patient to ensure the function was not shifting in the wrong direction, which Dr. Kirton noted was not found to be an adverse event. While the rtMS sessions were only 20 minutes long, they were completed daily just before the child would receive oneon-one occupational therapy (Ot). the therapy sessions lasted about two hours and were conducted by an occupational ther-

8 n June 2016

Courtesy of Dr. Adam Kirton

—Continued from page 1

apist who designed individualized treatments for children to try to achieve their preset goals.

rTMS IS COMBINED WITH OCCUPATIONAL THERAPY the rtMS may “prime the brain to get it ready to learn so that when the kid goes to do their therapy and practices something the effect is longer or maybe it sticks better,” said Dr. Kirton. “that is the general idea of brain stimulation. We think it is enhancing the natural learning process. So it will not do anything if you are not inducing the natural learning process in the first place. that is why you have to combine it with therapy.” During the rest of the time at the camp the children’s hands and arms were stimulated by playing video games, virtual reality, sports, and arts and crafts. the goals the children wanted to achieve included trying to do up a zipper, catch a football, being able to put their hair up in a ponytail, and others. “the kids who just did the therapy, with no constraint or rtMS, on average gained some function,” said Dr. Kirton. “but if we looked at the kids that got those extras [rtMS or CiMt], their . . . odds of achieving the bar of significant clinical improvement were approximately doubled. it does not mean that every kid who received rtMS reached that bar and there were kids who did not receive rtMS who did reach that bar. it [was] not a black or white story. but their chances of having a bigger improvement were better if they had the extra type of treatment.” Dr. Kirton said that while it is encouraging that this study might lead to more individualized approaches to rehabilitation in the future, he cautioned that rtMS is still in the early stage of research. He noted that rtMS is not an approved therapy and that it is only currently available for research in select locations. “it is not a cure [and] it probably does not work for everybody, but it may help some kids,” he added. “One message is that activity, active lifestyle, practice, and perhaps therapy [are] still the only thing[s] we know can help [these patients] function better.”

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Post-stroke mortality elevated by high and low blood platelet counts

n Higher risk in spite of no difference in initial impairment, length of hospital stay, or disability at release in patients with abnormal counts by John Evans,

Associate Editor, The Chronicle

counts at initial admission for acute ischemic stroke (AiS) appear to be associated with higher mortality after discharge, even though the abnormal counts do not appear to be associated with the degree of initial impairment, disability at discharge, or length of stay in an acute care hospital after AiS. these findings come from a paper published in the Journal of the Neurological Sciences (Mar. 15, 2016; 362:198–203). “given that stroke is a major cause of severe disability and mortality worldwide, this study was elaborated to examine the potential association of abnormal blood platelet count (bPC) (thrombocytopenia and thrombocytosis) at the day of an acute ischemic stroke with disease severity and clinical outcomes after stroke,” said the study’s Dr. Furlan lead author Dr. Julio furlan, a neurologist and principal investigator at the Lyndhurst Centre, university Health Network, toronto, in an email interview with tHe CHrONiCLe. Dr. furlan and his colleagues conducted a retrospective cohort study using data from the Ontario Stroke registry on consecutive patients with AiS admitted between July 2003 and Mar. 2008, dividing the patients into three groups based on bPC. this produced a cohort of 9,230 patients. bNOrMAL bLOOD PLAteLet

individuals with bPC less than 150,000/mm3 were considered low bPC. Normal bPC was considered anything between 150,000 and 450,000/mm3, and high bPC was anything more than 450,000/mm3. Outcome measures included frequency of moderate or severe strokes on admission—less than eight on the Canadian Neurologic Scale, degree of disability at discharge—a modified rankin score of three to six, and 30-day and 90-day mortality. the study population excluded patients with cancer, liver disease, or chronic renal disease; patients taking antiepileptic drugs or chemotherapy; and pregnant patients, and all data analyses were adjusted for age, sex, ethnicity, smoking status, alcohol consumption, thrombolytic treatment with tissue plasminogen activator (tPA), use of antiplatelet therapy, stroke unit admission, timing from stroke onset to the emergency department arrival, and history of prior pre-existing medical comorbidities, including angina or coronary disease, atrial fibrillation or flutter, congestive heart failure, and hyperlipidemia.

HIGHER MORTALITY RISK ONE AND THREE MONTHS POST STROKE the authors found that both low and high bPC were associated with higher mortality at 30 days (p<= 0.0335) and at 90 days (p<=0.048) after AiS. However, abnormal bPC was not associated with initial stroke severity (p=>0.225), degree of disability (p=>0.3761), or length of stay in an acute stroke care centre (p=>0.7818) after major potential confounders were accounted for. “this understanding could ultimately provide insights of novel therapeutic approaches since the cur-

rent guidelines for management of patients with acute stroke remain equivocal with regard to the optimal blood platelet count for prevention and treatment of acute cerebrovascular event,” said Dr. furlan. it is not surprising that patients with abnormally high or low platelet counts have higher morbitity post stroke, said Dr. Philip A. barber, associate professor of neurology in the Department of Clinical Neurosciences at the university of Calgary However, he said “the higher mortality could be attributed to other factors independent of stroke. these patients were sicker—they had a higher incidence of congestive heart failure, atrial fibrillation, and ischemic heart disease. the cause of their platelet disorder was also not described.” Overall, the study design was reasonable, said Dr. barber, but the retrospective cohort did represent a limitation. As well, he said he would like to have seen additional data collected, particularly the causes of patient morbidity and mortality. the Ontario Stroke registry did not collect more detailed information on cause of death, said Dr. furlan, which is what necessitated estimating mortality rates as all-cause of death. the key takeaway from the study findings are that thrombocytopenia and thrombocytosis on the initial admission are associated with higher 30-day and 90-day mortality after acute ischemic stroke, said Dr. furlan. “further investigations are needed to determine whether treatment of thrombocytopenia and thrombocytosis can improve survival of patients with acute ischemic stroke.”

Women more likely to be hospitalized than men for acute ischemic stroke

A LONGITUDINAL STUDY WITH 1.1 million patients with atrial fibrillation has found that women are 23% more likely to be hospitalized for acute ischemic stroke (AIS) than men, according to research presented at the CARDIOSTIM-EHRA EUROPACE 2016 in June. Presenter Dr. Ghanshyam Shantha, a cardiovascular disease fellow at the University of Iowa Hospitals and Clinics, Iowa City, Iowa, said, “there is evidence from around the world that women with atrial fibrillation receive less anticoagulation for stroke prevention than they need . . . We also know that women do not get state-of-the-art ablation and other highly advanced treatments for atrial fibrillation at the same level as men. What is not known is whether these deficiencies in access to care translate into poorer outcomes.” The current study investigated whether gender had an impact on the rate of hospitalization for ischemic stroke in patients with atrial fibrillation. The study used information from the National Inpatient Sample, a nationally representative hospitalization database in the U.S. It holds data on eight million patients admitted to around 1,000 randomly selected hospitals in 46 states during 1998 to 2012.

The study included the 1.1 million patients in the database who had been admitted to hospital with a diagnosis of atrial fibrillation. The investigators examined whether there was any gender difference in the rate of hospitalization for acute ischemic stroke. Across the 15 year period, the rate of stroke hospitalization in patients with atrial fibrillation was 2.64% in women and 2.15% in men. After adjusting for stroke risk factors including age, diabetes, hypertension, previous stroke and heart failure, the researchers found that women had a 23% higher risk of being hospitalized for stroke than men.

WOMEN DO POORER THAN MEN IN TERMS OF ADMISSION FOR AIS The researchers assessed whether the gender differences persisted in different subcategories such as age, ethnicity, socioeconomic status, and region. Women had a higher risk of stroke compared to men regardless of whether they were less or more than 65 years of age, Caucasian or non-Caucasian, low or high socioeconomic status, and lived in one region or another. Dr. Shantha said, “however you slice, dice, and divide

the data, women do poorer than men in terms of admissions for acute ischemic stroke. This was true overall, across different time periods, and in all subcategories. There is no particular region where women with atrial fibrillation get worse care.” “There is a debate about whether it’s the biology and something naturally in women that predisposes them to stroke or whether health care providers are failing to give adequate care,” continued Dr. Shantha. “Our findings corroborate the previous evidence that women receive less treatment and support the conclusion that the gender discrepancy is due to inadequate stroke prevention care in women and not biology.” Professor Michael Giudici, senior author and director of Arrhythmia Services at University of Iowa Hospitals and Clinics, said, “women have a tendency to put everyone else first and say ‘don’t worry about me’. They need to ‘worry about me’ a little more. Women may have more subtle symptoms so they need to pay more attention to their blood sugar and blood pressure and not delay seeking treatment.” —Read more information at http://ow.ly/AihA30186DU June 2016 n 9

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Walking impairment in multiple sclerosis

I can hold it for 1 minute. I need 1.2 minutes to get there. If only I could walk faster.

A significantly greater proportion of patients taking FAMPYRA 10 mg twice daily were responders, compared to patients taking placebo (34.8% vs. 8.3% in MS-F203 and 42.9% vs. 9.3% in MS-F204, respectively), as measured by the Timed 25-foot Walk Test (primary endpoint).*† Pr

FAMPYRA™ (fampridine) sustained release tablets are indicated for the symptomatic improvement of walking in adult patients with multiple sclerosis (MS) with walking disability (EDSS 3.5–7). Refer to the page in the bottom-right icon for additional safety information and for a web link to the product monograph discussing: •

Contraindications in patients with known hypersensitivity to the drug fampridine or to any ingredient in the formulation or component of the container, concurrently taking compounded 4-aminopyridine or other forms of fampridine, with mild, moderate or severe renal impairment, with prior history or current presentation of seizure, taking medicinal products that are inhibitors of the renal Organic Cation Transporter 2 (OCT2), such as cimetidine and quinidine

•

Relevant warnings and precautions regarding timing of doses, determination and monitoring of renal function, seizure risk, carcinogenesis and mutagenesis, caution in cardiovascular symptoms and disorders, low white blood cell counts and infections, neurological, dizziness and balance disorders, dizziness and fatigue, exacerbation of trigeminal neuralgia, occupational hazards, urinary tract infections, use during pregnancy and not recommended during breastfeeding

•

Conditions of clinical use, adverse events, drug interactions, missed dose, and dosing instructions

In addition, the page contains the reference list and study parameters relating to this advertisement. * A responder was defined as a patient whose walking speed on at least 3 of the 4 treatment visits was faster than the fastest speed during any of the 5 ‘no treatment’ visits.

fampridine Sustained release tablets

FAMPYRA™ is manufactured under license from Alkermes Pharma Ireland Ltd, (APIL), utilizing APIL’s MatriX Drug Absorption System (MXDASTM) technology. FAMPYRA™ is a trademark of Acorda Therapeutics, Inc.

See additional safety information on xxx

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Alcohol use a modifiable factor to help reduce smoking during pregnancy

n Depression was not found to be a factor that could be modified in interventions to reduce smoking in this population by Louise Gagnon,

Correspondent, The Chronicle

the annual meeting of the Society for research on Nicotine and tobacco in Chicago found alcohol use, but not depression, emerged as a factor that could be addressed in interventions to reduce smoking in pregnant women. “We were looking at various risk factors related to smoking during pregnancy that could possibly be controlled,” said Amy Loree, PhD, a clinical psychologist at the vA Connecticut Health Care System and yale university School of Medicine in New Haven, Conn. “We wanted to focus on particular variables that could be amenable to smoking cessation interventions.” Despite the decline in smoking in the general population, prenatal smoking has been stable over the past 10 years, noted Dr. Loree. According to the u.S. Public Health Service guideline treating tobacco use and Dependence: 2008 update, the use of nicotine replacement therapy (Nrt) is not recommended as a means to promote abstinence during pregnancy (Am J Prev Med Aug. 2008; 35(2):158–176). Moreover, Nrt has been found to yield poor compliance among pregnant women. eSeArCH PreSeNteD At

Dr. Loree and co-investigators looked at data from the National Survey on Drug use and Health over the period 2004 through 2013. the survey included data on 8,895 pregnant women. Of that number, 3,252 pregnant women had smoked within the past year. Some of the variables studied included perceived general health, nicotine dependence, alcohol and illicit drug use, distress and psychopathology, criminal justice involvement, and engagement in risky behaviours. Of the 3,252 pregnant women who had smoked within the past year, there were 1,920 current smokers, meaning they had smoked in the past 30 days, and 1,332 former smokers, who had smoked within the past year, but not in the past 30 days. investigators used no past 30-day cigarette use as a proxy for smoking cessation during pregnancy. Of those who currently smoked, about one-third smoked between six and 16 cigarettes daily and two-thirds were considered nicotine dependent within the past month. “Women who continued to smoke during their pregnancy were more economically disadvantaged, but that is not an intervention that we can target,” she noted. Smoking history and early onset of smoking are also factors that are not modifiable, but factors such as alcohol use or anxiety and depression are factors that can be modified through interventions, explained

Indication and clinical use: Pr

FAMPYRA™ (fampridine) sustained release tablets are indicated for the symptomatic improvement of walking in adult patients with multiple sclerosis (MS) with walking disability (EDSS 3.5–7). Not indicated in patients < 18 years of age. The initial prescription should be for no more than 4 weeks, and assessment for improvement in walking should be carried out within that timeframe. Renal function should be checked in elderly patients before starting treatment and monitored regularly. Contraindications: • Patients with known hypersensitivity to the drug fampridine or to any ingredient in the formulation or component of the container • Patients concurrently taking compounded 4-aminopyridine or other forms of fampridine • Patients with mild, moderate or severe renal impairment (creatinine clearance )80mL/min) • Patients with prior history or current presentation of seizure • Patients taking medicinal products that are inhibitors of the renal Organic Cation Transporter 2 (OCT2), such as cimetidine and quinidine Relevant warnings and precautions: • Doses should be taken 12 hours apart • Determine renal function before treatment and regular monitoring during treatment • Seizure risk • Carcinogenesis and mutagenesis • Caution in cardiovascular symptoms of rhythm and conduction cardiac disorders FM-CAN-0148a

• • • • • • •

Dr. Loree. investigators found binge drinking (Or=0.33) to be a modifiable risk factor associated with smoking cessation. they did not find that emotional distress nor depression emerged as a modifiable risk factor. “there was not a significant difference [in depression and emotional distress] between women who had quit smoking [during pregnancy] and women who had not quit smoking [during pregnancy],” said Dr. Loree.

ROLE OF DEPRESSION AS SMOKING TRIGGER ‘MERITS MORE CONSIDERATION’ While distress and depression did not emerge as a significant risk factor related to continuing smoking among pregnant women, further examination of the role of distress and depression as a significant trigger for smoking in pregnancy “merits more consideration,” said Dr. Loree. “We thought depression would emerge as a modifiable risk factor,” she said. indeed, other research in this area has shown that after controlling for other variables, distress or depression is associated with decreased likelihood of quitting. A recent analysis found pregnant women who were current smokers were significantly more likely to have more symptoms of depression than pregnant women who had recently quit, suggesting interventions should —please turn to page 16 address reducing

Low white blood cell counts and infections Neurological, dizziness and balance disorder Dizziness and fatigue Urinary tract infections Exacerbation of trigeminal neuralgia Use during pregnancy Not recommended for use during breastfeeding

For more information: Please consult the Product Monograph at www.biogen.ca/product_portfolio. aspx?ID=14979 for important information relating to warnings and precautions, adverse reactions, drug interactions, missed dose and dosing information that has not been discussed in this piece. The Product Monograph can also be obtained by contacting Biogen Canada Inc. at: 1-866-359-2502. †MS-F203 and MS-F204 were phase III, randomized, parallel-group, placebo-controlled trials.

MS-F203: n=301 (n=229 FAMPYRA 10 mg twice daily, n=72 placebo), 21-week study (1-week post-screening, 2-week single-blind placebo run-in, 14-week double-blind treatment, 4-week no-treatment follow-up). MS-F204: n=239 (n=120 FAMPYRA 10 mg twice daily, n=119 placebo), 14-week study (1-week post-screening, 2-week single-blind placebo run-in, 9-week double-blind treatment, 2-week no-treatment follow-up). Patients in these two trials had a mean disease duration of 13 years and EDSS score of 6. The primary measure of efficacy in both trials was walking speed (in feet per second) as measured by the Timed 25-foot Walk Test, using a responder analysis. Reference: FAMPYRA™ Product Monograph. Biogen Canada Inc. Mississauga, ON. November 26, 2014. © Biogen Canada Inc 2016. FAMPYRA™ is marketed by Biogen International, GmbH under license from Acorda Therapeutics, Inc. FAMPYRA™ is manufactured under license from Alkermes Pharma Ireland Ltd, (APIL), utilizing APIL’s MatriX Drug Absorption System (MXDASTM) technology. FAMPYRA™ is a trademark of Acorda Therapeutics, Inc.

fampridine Sustained release tablets

MDD

Non-pharmacologic vs. pharmacologic Tx for adults with

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Associate Editor, The Chronicle

AMeriCAN COLLege of Physicians (ACP) has released guidelines that present the evidence and provide clinical recommendations of the comparative effectiveness of treatment with second-generation antidepressants (SgA) versus non-pharmacologic treatment for major depressive disorder (MDD) in adults. the ACP’s primary recommendation, published in the journal Annals of Internal Medicine (Mar. 1, 2016; 164(5):350–359), is that “clinicians select between either cognitive behavioural therapy (Cbt) or SgAs to treat patients with MDD after discussing treatment effects, adverse effect profiles, cost, accessibility, and preferences with the patient (grade: strong recommendation; moderatequality evidence).” the authors reviewed randomized, controlled trials from 1990 through 2015 on psychotherapies (including Cbt, interpersonal therapy, and pscyhodynamic therapies), complementary and alternative medicines (CAM) (including acupunture, omega-3 fatty acids, S-adenosyl-L-methionine, and St. John’s wort), exercise, and SgAs. He

CLINICIANS FAVOUR PHARMACOLOGIC Tx “i think when it comes to the treatment of MDD the majority of clinicians tend to go the pharmacological

treatment route because that is easy to do to just prescribe a second generation antidepressant,” said Dr. Amir Qaseem, director of the Department of Clinical Policy at ACP and the lead author. “but that is why there has been more and more evidence that has been coming out that has been talking about various non-pharmacological treatments. that is what we evaluated—many different ones but there was only evidence [to support] cognitive behavioural therapy.” Only low-quality evidence showed no difference in effectiveness or adverse effects between SgAs and

the other psychotherapies, CAM, and exercise, noted the investigators. “i think that will be [a] game changer that we are saying that Cbt is as good as SgAs,” said Dr. Qaseem, adding that this may surprise some physicians. “i think it is a good reasonable approach [to start treating with] Cbt because both work as well and logically you should start with something that is going to have less adverse effects versus something that is associated with adverse effects when treating a patient with depression.”

CBT PROBABLY HAS FEWER ADVERSE EFFECTS THAN SGAS the authors state that adverse effects commonly associated with SgAs included constipation, diarrhea, dizziness, headache, insomnia, nausea, sexual adverse events, and somnolence. the researchers found that “Cbt has no more—and probably fewer—adverse effects than SgAs.” Adverse effects were also associated with St. John’s wort including gastrointestinal symptoms, dizziness or confusion, and fatigue or sedation. it has also been linked with drug-to-drug interactions and it has been known to induce cytochrome P450 isoenzyme 3A4. the guidelines note that while low-quality evidence showed that St. John’s wort may be as effective as SgAs for treating MDD, it is not regulated by the u.S. food and Drug Administration and therefore there is no current —please turn to page 16 standard in place regarding

ACP guidelines provide invitation for clinicians to reflect on the evidence

—Continued from page 3

unanimity of opinion despite careful analysis and best intent. thus, what is the clinician left with as the goals of treatment to help optimize patient care? Perhaps it is best to recall the great Canadian physician Sir William Osler, who said that in order to be a good clinician, it is not enough to read books nor is it enough to listen to patients; but to be a good clinician, one must do both. these guidelines by the ACP are helpful, thoughtful, and challenging. they provide a clear review of the evidence. this is an important hallmark of contemporary psychiatry differentiating from practice decades ago. that they do not reach the same conclusions as other guidelines is in some respects paradoxically a good thing, further inviting clinicians to reflect on the evidence and what’s best for patient care. in my view, patients are best served by clinicians who are aware of these practice guidelines, consider them carefully and then adapt them to the needs and exigencies of the patient’s situation. While evidence-based medicine is one of the great advances in the last several decades, as clinicians we are always faced with an ‘n-of-one.’ it is our responsibility to provide the best care to the patient as the situation determines. Most

12 n June 2016

patients, if possible, should be afforded the right evidence-based medication in the context of a therapeutic relationship that is supportive and evidence-based, addressing relevant issues in a useful, pragmatic, and planned method. this is the meta-value of these guidelines even, and/or perhaps especially, when they differ from other guidelines; encouraging clinicians to reflect on what our assumptions are, what we do clinically, and given the evidence, what we should do to provide optimal care.

REFERENCES

1. Mcintyre J: usefulness and limitations of treatment guidelines in psychiatry. World Psychiatry Oct. 1 2002; (3):186–189. 2. Kennedy SH, Lam rW, et al: Canadian Network for Mood and Anxiety treatments (CANMAt) 2016 Clinical guidelines for the Management of Adults with Major Depressive Disorder. Section 3. Pharmacological treatments. Submitted May 2016 3. Parikh Sv, Quilty L, ravitz P, rosenbluth M, et al: Canadian Network for Mood and Anxiety treatments (CANMAt) 2016 Clinical guidelines for the Management of Adults with Major Depressive Disorder. Section 2: Psychological treatments. Submitted May 2016

Photo by Santa Monica Psychotherapy by Bliusa via Wikimedia Commons and by Tom Varco, Wikimedia Commons

by Emily Innes-Leroux,

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Surveying the current

Neurology literature Infarct volume, hyperglycemia linked to poor neurological outcomes for pediatric stroke patients

Cervical dystonia associated with head tremor, laryngeal dystonia, psychiatric comorbidities

Women with migraine at greater risk of cardiovascular mortality

Recently come across something from the peer-review literature that you consider to be interesting or impactful? Share it with your colleagues. E-mail your clippings, along with your comments, to: health@chronicle.org

to be associated with poor neurological outcomes in children with arterial ischemic stroke in a study published online ahead of print in JAMA Neurology (May 23, 2016). NfArCt vOLuMe AND HyPergLyCeMiA Were fOuND

researchers conducted a study to determine the prevalence of abnormal blood pressure, blood glucose levels, and temperature in pediatric patients with acute arterial ischemic stroke and to explore any association between these measures and neurological outcome. the investigators performed a retrospective review of children aged 29 days to 18 years with their first arterial ischemic stroke between Jan. 2009 and Dec. 2013 at a tertiary academic children’s hospital. Ninety-eight children with stroke were identified by an international Classification of Diseases, Ninth revision, code search and medical record review. blood pressure, blood glucose, and temperature data were collected for five days after the stroke. the investigators found that hypertension was present in 64 (65.3%) patients, hypotension in 67 (68.4%), hyperglycemia in 17 (18.1%), and fever in 37 (37.8%). the strongest association with poor neurological outcome was an infarct size of 4% or greater of brain volume (odds ratio, 5.6; 95% Ci, 2.0-15.4; p=.001). Hyperglycemia was also independently associated with poor neurological outcome (odds ratio, 3.9; 95% Ci, 1.2-12.4; p=.02). Hypertension and fever were not significantly associated with infarct size, poor outcome, or death. Hypertension was not documented in 24 of 87 surviving children (27.6%) at three month follow-up and was not associated with poor neurological outcome. the authors concluded, “prospective studies that systematically record blood pressure, blood glucose, and temperature data are required to further assess the associations between these potentially modifiable physiological parameters and pediatric stroke outcome.” —Read more at http://ow.ly/Ibfr301dcz7

eAD treMOr, LAryNgeAL DyStONiA, AND PSyCHiAtriC

comorbidities are more common in female patients with cervical dystonia (CD), according to a study published in Neurology Genetics (June 2016; 2(3):e69) that aimed to characterize the clinical and genetic features of CD.

the investigators included 1,000 participants enrolled in the Dystonia Coalition biorepository with initial manifestation as CD in the study. Data intake included demographics, family history, and the global Dystonia rating Scale. the researchers screened the participants for sequence variants (Svs) in gNAL, tHAP1, and exon 5 of tOr1A. the majority of participants were Caucasian (95%) and female (75%). the mean age at onset and disease duration were 45.5 ± 13.6 and 14.6 ± 11.8 years, respectively. At the time of assessment, 68.5% had involvement limited to the neck, shoulder(s), and proximal arm(s), whereas 47.4% had dystonia limited to the neck. the remaining 31.5% of the individuals exhibited more extensive anatomical spread. A head tremor was noted in 62% of the patients. Head tremor and laryngeal dystonia were more common in females. Psychiatric comorbidities, mainly depression and anxiety, were reported by 32% of the participants and were more common in females. family histories of dystonia, parkinsonian disorder, and tremor were present in 14%, 11%, and 29% of the patients, respectively. Pathogenic or likely pathogenic Svs in tHAP1, tOr1A, and gNAL were identified in eight participants (0.8%). two individuals harboured novel missense Svs in exon 5 of tOr1A. Synonymous and noncoding Svs in tHAP1 and gNAL were identified in 4% of the cohort. —Find more information at http://ow.ly/oU8G301dfx3

eSuLtS Of A LArge , PrOSPeCtive COHOrt StuDy

in women with more than 20 years of followup indicate a consistent link between migraine and cardiovascular disease events, including cardiovascular mortality (BMJ May 31, 2016; 353:i2610).

researchers used a cohort of 115,541 female nurses in the u.S. aged 25 to 42 years at baseline, who were free of angina and cardiovascular disease. the investigators found that 17,531 (15.2%) women reported a physician’s diagnosis of migraine. Over 20 years of follow-up, 1,329 major cardiovascular disease events occurred and 223 women died from cardiovascular disease. After adjustment for potential confounding factors, migraine was associated with an increased risk for major cardiovascular disease (hazard ratio 1.50, 95% confidence interval 1.33 to 1.69), myocardial infarction (1.39, 1.18 to 1.64), stroke (1.62, 1.37 to 1.92), and angina/coronary revascularization procedures (1.73, 1.29 to 2.32), compared with women without migraine. furthermore, migraine was associated with a significantly increased risk for cardiovascular disease mortality (hazard ratio 1.37, 1.02 to 1.83). Associations were similar across subgroups of women, including by age (<50/≥50), smoking status (current/past/never), hypertension (yes/no), postmenopausal hormone therapy (current/not current), and oral contraceptive use (current/not current). the authors say the findings suggest that women with migraine should be evaluated for their vascular risk. —Read more at http://ow.ly/T75Y301dwbD June 2016 n 13

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Link between CVD and schizophrenia needs more awareness —Continued from page 1

“the life expectancy of people with schizophrenia is significantly shorter than the life expectancy seen in their general counterpart,” said Dr. turin Chowdhury, scholarship director and assistant professor in the Department of family Medicine at the university of Calgary. Although CvD is not the sole reason for the increase in mortality risk among people who have schizophrenia, Dr. turin Chowdhury stressed that CvD is a comorbidity that should be monitored by health care providers. “this review was planned to summarize the literature around the issue of CvD among the patients with schizophrenia,” said Dr. turin Chowdhury. “What we aimed to do with this review was to present the burden, risk factors, and early detection of risk factors—leading to the prevention of CvD among patients with schizophrenia.” findings in this report present an overall picture of CvD among the schizophrenia patients and highlight the disease burden, noted Dr. turin Chowdhury “Also, we have highlighted the importance of prevention and control of the CvD risk factors.” Dr. turin Chowdhury recommends that physicians consider the following CvD risk factors that pertain to schizophrenia patients: (a) behavioural factors, such as substance abuse, smoking, unhealthy eating patterns, and sedentary behaviour; (b) Management factors, such as side effects of antipsychotics and other medications, inequalities in quality of medical care, fragmentation of physical and mental health care; and (c) Socio-economic status-related factors, such as lower socioeconomic status. All these factors need to be kept in mind while planning a treatment regiment for these patients. “Patients with schizophrenia should be followed much 14 n June 2016

more closely by their health care providers to identify the appearance of conventional CvD risk factors,” said Dr. turin Chowdhury, who added that this will give clinicians an opportunity to intervene against CvD in an earlier stage, reducing future risk of CvD. “Also, monitoring of the risk factors [progression of their risk factors if already present] by the health care providers is an important part of their treatment,” he said.

PREVENTION OF CVD “Prevention of CvD in schizophrenia can reduce disease burden and increase longevity. Modifiable risk factors of CvD, such as smoking, sedentary and unhealthy lifestyle, unhealthy diet habits, metabolic syndrome and obesity can be controlled in people with schizophrenia in the same way as in the general population,” said Dr. turin Chowdhury. Conventional life style modification alone, however, may not be enough because people with schizophrenia have additional risk factors such as dealing with the effects of antipsychotics, he said. “A close working relation between the patient and the health care provider is very crucial. Apart from the attending physician, [a] cardiologist, dietitian, and exercise therapist play important roles in schizophrenia care and should either be consulted on a regular basis or be part of the multiprofessional team to work closely with these patients,” he said. RECOMMENDATIONS Health care providers should be aware of the side effects of antipsychotics and cautiously choose the regimen that causes the least harm to the cardiovascular system of each patient, the authors advised. the authors wrote that regular monitoring of carotid intima-media thickness, ankle-brachial index, or Doppler echocardiography might be beneficial for early diagnosis of CvD in schizophrenia. they concluded that there is a need for consensus guidelines for early detection and prevention of CvD in this group of patients.

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Stopping second antipsychotic found to be safe for most schizophrenic patients n Second antipsychotic raises concern regarding additive, as well as synergistic, side effects, notes study’s author

by John Evans,

Associate Editor, The Chronicle

rANDOMiZeD, PLACebO-CONtrOLLeD

study published in the Journal of Clinical Psychiatry (Jan. 2016; 77(1):e14-e20) has found that the majority of included patients with schizophrenia who were switched from two antipsychotic drugs to one did not experience any clinical deterioration. these findings suggest that clinicians adding a second antipsychotic to a schizophrenic patient’s therapy should plan to re-assess patients periodically over the next several months from when they started the second drug to see if they are benefiting, said one of the study’s authors. there is a lack of robust evidence supporting the use of multiple antipsychotic drugs at once to treat schizophrenia, but the practice is still widespread, said study author Dr. gary remington, speaking with tHe CHrONiCLe Of NeurOLOgy + PSyCHiAtry. Dr. remington is the lead for the subspecialty clinics in the Schizophrenia Program at the Centre for Addiction and Mental Health (CAMH) in toronto. “the drugs that we currently have available for use only produce a partial response in a number of individuals,” said Dr. remington. As a result, many doctors will reach for a second antipsychotic to try and improve outcomes. However, the mechanism of action of all currently available antipsychotic drugs is the same, he said. they share in common dopamine D2 blockade, which in turn attenuates the psychotic symptoms in psychosis thought to reflect a hyperdopaminergic state. “but there is that idea that somehow if you find the right combination you can perhaps enhance the

effects of the first drug by adding a second drug.” However, adding a second drug raises a concern regarding additive, as well as synergistic, side effects, Dr. remington said. “the antipsychotics are notorious for their side effect profile—everything ranging from motor to metabolic side effects. So there is certainly evidence that when adding two antipsychotics you risk causing more side effects than you would with a single agent alone.” using multiple therapies also adds costs to the health care system and potentially the patient, he said.

DETERIORATION AFTER SWITCHING TO MONOTHERAPY RARE to evaluate the impact of switching patients with schizophrenia from two to one antipsychotic drug, a group of 35 patients with DSM-iv diagnosed schizophrenia or schizoaffective disorder receiving two antipsychotics at stable dosages were randomly assigned to an antipsychotic polypharmacy (APP) group to continue on their current drug regimen (n=17), or to an antipsychotic monotherapy arm (APM) in which their secondary antipsychotic was discontinued (n=18). Patients were assessed weekly for the first month, then every two weeks for two months. Outcomes were measured with the brief Psychiatric rating Scale (bPrS) total score, and measures were also taken using the Clinical global impressions (Cgi) scale, Simpson-Angus Scale, and barnes Akathisia Scale. A total of five patients withdrew from the study due to clinical deterioration—one in the APP group (5.8%), and four in the APM group (22.2%). However, no other indication of clinical worsening was observed in the APM group on either the bPrS or Cgi scale.

the authors concluded that most patients receiving multiple antipsychotic therapies could be safely transitioned to a single drug, with the risk of clinical deterio-

The antipsychotics are notorious for their side effect profile— everything ranging from motor to metabolic side effects. So there is certainly evidence that when adding two antipsychotics you risk causing more side effects than you would with a single agent alone.

—Dr. Gary Remington, lead for the subspecialty clinics in the Schizophrenia Program at CAMH in Toronto.

ration greatest in the first few months. these findings were “encouraging and reassuring to us in that they fit with our current position that polypharmacy really is not substantiated based on evidence. And here with this double-blind trial we confirmed that,” said Dr. remington. “but it was also a bit unsettling to find that one in five individuals did seem to show deterioration with the removal of the second antipsychotic.”

SOME PATIENTS DO WORSEN As a caveat to that, Dr. remington noted that in the study patients’ second medication was discontinued abruptly, rather than —please turn to page 17

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CBT outcomes depend on severity of depression and expertise of clinician

—Continued from page 12

the contents and potency of the medication. “[the patient] does not know the content, [they] do not know the potency of the medication. What ends up happening, is once there is no quality control, [they] do not know what [they] are taking,” said Dr. Qaasem. “it needs to be regulated and then maybe we will be able, based on the current evidence, to make a recommendation. but until it is regulated, i would [recommend to] go the route of Cbt and SgAs.” Dr. roger Mcintyre, professor in the Division of Adult Psychiatry and Health Systems in the Department of Psychiatry at the university of toronto, told tHe CHrONiCLe that these guidelines are very reasonable and provide general overview. However, he said, clinicians are still left with the difficult reality that clinicians often see patients who are not represented in the studies the guidelines are based on. He noted that there are many “stakeholders in depression” including academic psychiatrists, commuDr. McIntyre nity psychiatrists, family physicians, general practitioners, nurse practitioners, and people who work in policy and reimbursement. for some, the brevity is beneficial to provide a general perspective on the literature; others—himself included—might be seeking more precision.

THE DEVIL IS IN THE DETAILS However, he noted “i think you do need more details. And i think the reason is that a blanket statement that Cbt is just as effective as an antidepressant is true, but also false. it is true as a general statement, but if you dig into that there are many sub-types of depression that clearly are better suited for pursuing a medication first.” Dr. Mcintyre said when it comes to that recommendation “the devil is in the details.” He agreed it is reasonable to conclude that Cbt is as effective as SgAs at treating patients with a mild-to-moderate MDD, but it would not be pragmatic to use Cbt as a first-line therapy for patients with severe MDD. “i would not conclude that Cbt would not be appropriate for someone with severe depression, because the evidence suggests that it could be entirely appropriate for someone with severe depression,” said Dr. Mcintyre. “[However, i think] most experienced clinicians would agree that someone who is so severely depressed to the point that they are so tired they cannot stay awake, they are sleeping all the time, and their mind is so impaired by psycho motor retardation and lack of cognitive abilities they cannot engage in psychotherapy, then they cannot participate in the process.”

CBT: NOT EASILY ACCESSIBLE, AVAILABLE, OR AFFORDABLE Dr. rajamannar ramasubbu, professor in the Department of Psychiatry at the university of Calgary, agrees with Dr. Mcintyre that Cbt might not be the optimal treatment for patients with severe depression. He added that there is no good evidence to indicate the effectiveness of Cbt for patients who have MDD in combination with extreme hopelessness or lack of motivation. “When you are talking to the patients we have to understand that if the patient has lack of motivation or hopelessness it is hard for the patient to participate or engage [in Cbt] even if the patient desires to do that,”

16 n June 2016

said Dr. ramasubbu. Another limitation of Cbt in Canada, according to Dr. ramasubbu, is that it is not easily accessible available, or affordable. Cbt also has various formats, noted Dr. ramasubbu, including one-on-one Cbt, group Cbt, telephone-based Cbt, web-based Cbt, and self help Cbt books. He said the severity of depression needs to be taken into consideration when determining what type of Cbt a patient should receive. Dr. “if your patient is technologicalRamasubbu ly advanced, is literate, and has motivation then they can participate in web-based, telephone-based [Cbt], or use self help Cbt books. but group based or individual [Cbt is better suited] for patients who may need more intensive Cbt than other people,” said Dr. ramasubbu. A limitation with the ACP guidelines—and guidelines in general—was that the primary recommendation was based only on moderate-quality evidence, said Dr. ramasubbu. “in general, evidence-based guidelines for depression is crucial for evidence-based decision-making in the clinical practice and also evidencebased policy at the government level and at the public health level. but the problem that we always face is that there is no good evidence to make evidence-based guidelines. We need more research addressing clinical practice and personalized medicine in psychiatry.” Dr. Ari Zaretsky, psychiatrist-in-chief, Sunnybrook Health Sciences Centre, and associate professor in both the Division of brain and therapeutics and Psychotherapies, Humanities and educational Scholarships in the Department of Psychiatry at the university of toronto, said he liked that the guidelines were brief and that they highlighted the role of psychotherapies for depression, particularly Cbt. “My hope would be that clinicians will continue to emphasize the value of treatments like Cbt for patients and not focus on pharmacotherapy alone in the treatment of depression,” said Dr. Zaretsky. He added that the current “cost containment environment” in medicine has created the danger for favouring pharmacological treatments over pharmacotherapy for

major depression, even for mild-moderate depression.

OUTCOMES DETERMINED BY CBT EXPERTISE Dr. Zaretsky said the problem with the guidelines was that it does not address the fact that the research trials upon which these guidelines were based were efficacy studies conducted by experts in Cbt. “[the results do] not scale-

A blanket statement that CBT is just as effective as an antidepressant is true, but also false. It is true as a general statement, but if you dig into that there are many sub-types of depression that clearly are better suited for pursuing a medication first.

—Dr. Roger McIntyre, professor in the Department of Psychiatry at the University of Toronto.

up, [it] does not necessarily generalize to what you would get in the community. the Cbt conducted in the majority of research studies are conducted by ‘masters of Cb’.” “When a highly experienced Cbt therapist provides the treatment for even moderate-to-severe depression they can get outcomes that are comparable to antidepressant pharmacotherapy in some research studies. but i think that interpreting those findings requires special caution.” “the outcomes are very determined by your expertise. that is the downside or the concern about how you apply these guidelines, because if community therapists market themselves as trained in Cbt when they have minimal training then patients will select Cbt, forego effective treatment with medication and perhaps not get better,” said Dr. Zaretsky.

Tension reduction: cause for smoking when pregnant

—Continued from page 11

depressive symptoms and increasing readiness to quit (Matern Child Health J Dec. 9, 2015). Another recently published longitudinal investigation found tension reduction was the chief reason that pregnant women continued to smoke, and half of the study subjects had depressive symptoms (J Eval Clin Pract Jun. 2016 ;22(3):403–410).

SELF-REPORTED SMOKING SHOULD BE VERIFIED WITH BIOLOGICAL MEASURES A limitation of some research efforts in smoking and pregnancy can be the exclusive use of self-reports, noted Dr. Loree. Many women may not want to disclose their smoking status or be completely accurate in reporting their smoking behaviour. ideally, self-reported smoking should be verified with biological measures. “Women who are smoking during pregnancy may not admit to it because they fear judgement,” said Dr. Loree. “there can be a discord between self-reported smoking and actual confirmed measures of smoking. you tend to get a higher rate [of smoking] if you perform biological collection rather than just ask subjects if they are smoking.” biological collection can include measures such as samples of urine or salivary cotinine and expired carbon monoxide. various suggestions have been proposed about the appropriate cut-point of expired carbon monoxide to detect smoking in pregnancy. increasingly, intervention programs that target pregnant women with the goal to achieve smoking cessation will likely integrate various technologies as platforms to deliver smoking cessation programs, pointed out Dr. Loree. “[Mobile] phones and computers can be used to reach people and respond to issues like transportation to attend [a smoking cessation program],” she said.

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Light therapy is an affordable Tx option for MDD

—Continued from page 7

revealed that the combination therapy was superior to placebo in MADrS response (β=1.70; df = 1; p= 0.005) and remission (β=1.33; df = 1; p=0.02), with numbers needed to treat of 2.4 (95% Ci, 1.6 to 5.8) and 3.5 (95% Ci, 2.0 to 29.9), respectively. “it was interesting to find out that the light treatment was more effective than the sham-placebo [arm] and that the combination treatment was even better in terms of the effects compared to shamplacebo for the treatment of adults with non-seasonal MDD,” said Dr. Lam. “in our study the antidepressant alone, which consisted of fluoxetine . . . was not found to be more effective than placebo. that result was not so unusual because it was not a huge study. typically in smaller studies like these you sometimes do not see the effects against placebo even with effective treatments like antidepressants,” he added. the fact that both light monotherapy and the combination treatment were effective suggests that the addition of bright light treatment might be beneficial in treating people with non-seasonal depression, said Dr. Lam. “i think use of light therapy for the treatment of depression is clinically applicable and that is because we know that single treatments such as antidepressants or psychotherapy are not effective for treating everyone with depression,” he said. “it is really important to find more treatment options for depression and in particular treatments that can be combined, because we know that many people will not respond well to just one treatment.” EFFICACY, SIDE EFFECTS OF LIGHT THERAPY “generally speaking the side effects from light therapy are milder than those of antidepressants,” he said. “What we found in this study was that the light therapy was well tolerated. there were no unusual side effects as the result of light therapy

for the treatment of non-seasonal depression that we have not found with treating people with SAD.” Data suggests, however, that the incidence of diarrhea was more common in the light monotherapy group, explained Dr. Lam. “interestingly, in the combined bright light therapy and antidepressant group there were no side effects that were any higher than placebo,” he said. “it looked like even though the fluoxetine by itself and the light by itself had side effects that were more frequent than placebo, the combination might actually mitigate the side effects of each of those treatments. it was an interesting finding that needs to be confirmed.”

LIGHT THERAPY IS INEXPENSIVE, EASY TO USE the benefit of light therapy is that it is inexpensive, easy to use, widely available and it does not have many side effects, said Dr. Lam. “Light therapy can also be easily combined with other treatments like antidepressants or psychotherapy for treating people with depression. As an added benefit, with light therapy you do not have to worry about drug interactions,” he said. Surveys have shown that psychiatrists in the u.S. are using light therapy predominately for treating people with SAD, said Dr. Lam. “i think psychiatrists are not using light therapy for the treatment of non-seasonal depression because perhaps the evidence has not been supportive,” he said. “the results of our study show that light therapy can be helpful and it could be considered as a treatment for people with non-seasonal related depression.” AVAILABILITY AND RESOURCES Dr. Lam noted that the light devices used in the study are widely available and can be purchased at various stores and cost between $100 and $300. “there are some good websites that offer a lot of good information on how to use these light devices, how to get light boxes and what to look for in a light device,” he said. “Websites such as www.ubcsad.ca and www.cet.org can be useful for clinicians and the public.”

Schizophrenia: second antipsychotic needs monitoring

—Continued from page 15

being titrated as would normally happen in clinical practice. “So there is a possible bias that may have skewed toward an increase in people not doing as well when we took away the second medication.” “We certainly know that you can see people worsen during that time period where medication is being discontinued, especially through factors such as withdrawal side effects that would be fostered if you abruptly discontinued the second medication,” Dr. remington said. “So it is an at-risk period and we set the stage for the worst-case scenario by abruptly stopping the second medication.” ADVICE ON ANTIPSYCHOTIC POLYPHARMACY Overall, Dr. remington says his advice to clinicians who feel that the next step they need to take for their patients with schizophrenia is to try adding a second antipsychotic drug is twofold: “the first is to circumscribe the time period so that they do not just add the second medication and not check periodically to see if the individual is doing any better or not.” Secondly, “[clinicians] should also attempt to quantify the change [in their patients’ symptoms] so that they can say in two months whether or not that drug warrants continuation based on an identifiable shift in symptoms.” that some patients in the study did worsen after discontinuing their second drug supports the idea that schizophrenia is really a heterogenous group of disorders, and sub-typing patients by clinical response might be valuable for future research, said Dr. remington.

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“It is difficult to accept death in this society because it is

unfamiliar. In spite of the fact that it happens all the time, we never see it.” —Dr. Elisabeth Kübler-Ross, Swiss-American psychiatrist (1926-2004)

Dr. James Rutka

How did you react to be appointed an officer of the Order of Canada? i was surprised, obviously, and thrilled at the same time that i was given this prestigious award. the process by which someone becomes appointed to the Order of Canada is a little mysterious and you never know how it happens and you never know who is behind the nomination process. i certainly did not [know] in my case, but i was delighted when i received the news. And when the announcement came my family and i were actually travelling in france and we were in Paris. We had a wonderful evening out to celebrate the very special occasion.

How did you become interested in mentoring Ukrainian surgeons? i am of ukrainian heritage to begin with. My mother and father are from ukrainian families, though they themselves were born here in Canada. their parents, my grandparents, came from the ukraine at the turn of the century. even though my parents sent us to public schools throughout our educational system, we were very familiar with ukrainian culture and heritage . . . So my ukrainian heritage made it an easy choice for me to get involved. An opportunity arose when an associate professor in the Department of Psychiatry at the [university of toronto], Dr. Myroslava romach—she is of ukrainian heritage too—[as a Children of Chornobyl Canadian fund board member] steered a gift toward SickKids of $1 million to kick start this project . . . She approached me to see if i would be interested in helping her with her [program] to mentor ukrainian neurosurgeons in ukraine. i told her i could certainly do it insofar as surgery and neurosurgery were concerned, and she said

18 n June 2016

there have been a number. in pediatric neuro-oncology for example, through the work that has been done at the Labatt Centre, we have identified how important genetic analysis of the tumour is. take, for example, one tumour called medulloblastomas, which is the most common pediatric malignant brain tumour. Previously it was thought that this was a single tumour type. A neuropathologist would look at it under a microscope and say ‘yes this is medulloblastoma.’ but now, through genetic analysis, [we have] shown that in fact while they all look the same under the microscope they segregate into four separate sub-classes of tumour. that is important because each subclass may require a different treatment. And when you have targeted treatment—it is our strong belief and we have seen this play out in clinical trials—patients will do better.

that was a reasonable place to start. As part of the neurosurgical effort, we would travel to ukraine each year. We would travel to a couple of centres in Kiev and another city called Lviv . . . and we would help them with their educational programs. We would teach, we would lecture, we would consult, and then we would help them with neurosurgical procedures that they felt required our expertise. So i would perform surgical procedures over there as well.

What drew you to being involved in advancing treatment for pediatric brain tumours? i have been involved in research since 1984 when i started my PhD at the university of California San francisco. i was midway through my residency in neurosurgery when i started studying the basics of neurooncology research and after my PhD was completed i finished my neurosurgery residency and then started my own laboratory at SickKids. in those days, in 1990, i was given a lab bench and desk that amounted to about 200 square feet, which is rather a small amount. Over the years, through some hard work, good fortune, bringing people together, finding support from SickKids and from philanthropy, . . . we have grown this effort from 200 square feet of space to now almost 20,000 square feet. Along the way we have gone from having a single person on the bench, to having over 100 students, post-doctoral fellows, research assistants, and principal investigators working on the problem of brain tumours, not just pediatric brain tumours, but adult brain tumour as well at the Arthur and Sonia Labatt brain tumour research Centre at SickKids.

What have been some of the results of you and your team’s research?

What are your current brain cancer research projects? We are now concentrating on delivery strategies for getting very targeted reagents—whether they are drugs, nanoparticules, antibodies, or amalgamations of these reagents— targeted directly to the most invasive and aggressive parts of these tumours using a variety of approaches. One of these is called magnetic resonance image (Mri)-guided focused ultrasound. What that technique allows us to do is to break down the blood-brain barrier. the blood-brain barrier exists in the brain to prevent the passage of toxic compounds that would be harmful to the brain. unfortunately, as a result, most chemotherapeutics are excluded from crossing the blood-brain barrier. Mri-guided focused ultrasound is a fairly new technique that allows us to bypass the obstacle of the blood brain barrier to deliver targeted therapeutics at high concentrations to brain tumours. We have been successful with this approach in several of our experimental studies. And just recently, at Sunnybrook Hospital [in toronto], it was announced that the blood-brain barrier was overcome in [a human] patient for the first time in Canada [using Mri-guided focused ultrasound]. We now have the opportunity to see these novel approaches being taken to clinical trials. this is exciting, because we now know that we will [likely] be able to get the drugs or the nanoparticles directly to the tumour. in the past we never knew if our therapies were hitting the target. —Who’s making a difference near you? Tell The Chronicle, so we can tell our readers. Write us at health@chronicle.org

Courtesy of Dr. James Rutka

r. James Rutka has been appointed as an officer of the Order of Canada for his contributions to advancing treatment for pediatric brain tumours and for his international leadership in neurosurgery. The Canadian Cancer Society also named him as the 2015 co-recipient of the Robert L. Noble prize—an Award of Excellence. Dr. Rutka is a professor and chair of the Division of Surgery at the University of Toronto, a neurosurgeon at The Hospital for Sick Children (SickKids), and co-director and principal investigator at The Arthur and Sonia Labatt Brain Tumour Research Centre. He is also the chair of the Ukraine Paediatric Fellowship Program at SickKids. He spoke with tHe CHrONiCLe’s Emily Innes-Leroux about his involvement with helping train Ukrainian neurosurgeons and his achievements in brain cancer research.

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â&#x20AC;&#x153;demonstrated improved functional outcomesâ&#x20AC;? She calls it â&#x20AC;&#x153;helping her at workâ&#x20AC;?

Choose PRISTIQ:

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References: 1.Â Boyer P, et al. EfďŹ cacy, safety, and tolerability of ďŹ xed-dose desvenlafaxine 50 and 100 mg/day for major depressive disorder in a placebo-controlled trial. Int Clin Psychopharm 2008;23:243â&#x20AC;&#x201C;253. 2. Sheehan DV, Rush AJ, et al., editors. Handbook of psychiatric measures. 2000.

â&#x20AC;˘ Interstitial lung disease and eosinophilic pneumonia with venlafaxine â&#x20AC;˘ Seizures â&#x20AC;˘ Narrow angle glaucoma â&#x20AC;˘ Mania/hypomania â&#x20AC;˘ Serotonin syndrome or neuroleptic malignant syndrome-like reactions For More Information: Please consult the product monograph at http://pďŹ zer.ca/ en/our_products/products/monograph/226 for important information relating to adverse reactions, drug interactions and dosing information which have not been discussed in this piece. The product monograph is also available by calling 1-800-463-6001.

PRISTIQ ÂŽ Wyeth LLC, owner/ Pfizer Canada Inc, Licensee ÂŠ 2016 Pfizer Canada Inc. Kirkland, Quebec H9J 2M5

CA0115PRI005E

Clinical Use: â&#x2C6;&#x2019; Severe agitation-type adverse events coupled with self-harm or harm to others â&#x20AC;˘ PRISTIQ is not indicated for use in children under the age of 18 â&#x2C6;&#x2019; Suicidal ideation and behavior; rigorous monitoring â&#x20AC;˘ The short-term efďŹ cacy of PRISTIQ has been demonstrated in placebo-controlled trials of up to 8 weeks â&#x20AC;˘ The efďŹ cacy of PRISTIQ in maintaining an antidepressant â&#x20AC;˘ Discontinuation symptoms: should not be discontinued abruptly. Gradual dose reduction is response for up to 26 weeks, following response during recommended 20 weeks of acute, open-label treatment, was demonstrated in a placebo-controlled trial Other Relevant Warnings and Precautions: Contraindications: â&#x20AC;˘ Concomitant use with venlafaxine not recommended â&#x20AC;˘ Concomitant use with monoamine oxidase inhibitors â&#x20AC;˘ Allergic reactions such as rash, hives or a related (MAOIs) allergic phenomenon or within the preceeding 14 days â&#x20AC;˘ Bone fracture risk with SSRI/SNRI â&#x20AC;˘ Hypersensitivity to venlafaxine hydrochloride â&#x20AC;˘ Increases in blood pressure and heart rate (measurement prior to and regularly during treatment) Most Serious Warnings and Precautions: â&#x20AC;˘ Increases cholesterol and triglycerides â&#x20AC;˘ Behavioural and emotional changes, (consider measurement during treatment) including self-harm: SSRIs and other newer â&#x20AC;˘ Hyponatremia or Syndrome of Inappropriate antidepressants may be associated with: Antidiuretic Hormone (SIADH) with SSRI/SNRI â&#x2C6;&#x2019; Behavioural and emotional changes including an â&#x20AC;˘ Potential for GI obstruction increased risk of suicidal ideation and behaviour â&#x20AC;˘ Abnormal bleeding SSRI/SNRI