PracticeUpdate Conference Series European Congress of Psychiatry 2019

ISSN 2208-150X (Print) ISSN 2208-1518 (Online)

27 TH EUROPEAN CONGRESS OF PSYCHIATRY 6–9 APRIL 2019 • WARSAW, POLAND

THE BEST OF EPA 2019 Gut Microbiota Affect and Are Affected by Depression • Five Patient Characteristics Predict Recurrence of Major Depressive Disorder • To Date, Only Hydrocortisone Shows Promise for Pharmacologic Prevention of PTSD • Nutraceuticals Might Be Effective Adjunctive Therapy for Bipolar Disorder

MDD can turn people into shadows of their former selves

Up to 30% of MDD patients don’t respond to traditional antidepressants, 1,2 and even among those that do, as many as two- thirds don’t recover fully and continue to experience residual symptoms. 1,3 What’s more, the proportion of MDD patients who achieve remission decreases significantly after each treatment failure, from 31%with a second treatment to 13% with a fourth.* 3 It’s time to step out of the shadow of MDD. To find out more visit www.majordepressivedisorder.com

*From a report comparing acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Remission was defined as a score of ≤5 on the Quick Inventory of Depressive Symptomatology– Self-Report (QIDS-SR16) (equivalent to ≤7 on the 17-item Hamilton Rating Scale for Depression [HRSD17]) 3 References: 1. Al-Harbi K et al. Patient Prefer Adherence 2012; 6: 369-388. 2. Keller MB. J Clin Psychiatry 2005; 66(Suppl 8): 5-12. 3. Rush AJ et al. Am J Psychiatry 2006; 163(11): 1905-1917. Date of preparation: May 2019 EM-11146

© EPA 2019

Contents

EPA 2019 • 6–9 April 2019 • Warsaw, Poland BY THE PRACTICEUPDATE EDITORIAL TEAM

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3 Gut Microbiota Affect and Are Affected by Depression 4 Five Patient Characteristics Predict Recurrence of Major Depressive Disorder 5 Trazodone OAB Proves Non-Inferior to Venlafaxine XR for Major Depressive Disorder 6 Positive Emotions Following Stroke Predictive of Functional Recovery 7 Hypertension Linked With Increased Risk of Anxiety and Depression 8 Adolescent Sleep Problems Typically Precede Anxiety Symptoms

10 Baseline Depression Severity Does Not Affect Benefits of Antidepressant Therapy 11 Lurasidone Safe, Effective for Major Depressive Disorder With Mixed Features 12 Risk Profiles Can Identify Seniors’ Likelihood for Suicidal Ideation and Attempts 12 Mood Disorders With Comorbid Disease Linked With Elevated Mortality Risk in the Elderly 14 Symptom Remission May Not Equate to Functional Recovery in Depression

15 To Date, Only Hydrocortisone Shows 16 Early Antidepressant Response Not 18 Nutraceuticals Might Be Effective Adjunctive Therapy for Bipolar Disorder 19 Insomnia Associated With Reduced Health- Related Quality of Life 20 Consider Psychiatric Referrals for Patients With Unexplained Somatic Complaints Promise for Pharmacologic Prevention of PTSD Sufficiently Predictive of Later Response In Major Depression

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PRACTICEUPDATE PRIMARY CARE BOARD PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise.

Editor-in-Chief

David Rakel MD, FAAFP Professor and Chair, Department of Family & Community Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico

PracticeUpdate ® is a registered trademark of Elsevier Inc. ©2019 Elsevier Inc. All rights reserved. ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. PracticeUpdate Conference Series is a collection of key research from leading international conferences, reviewed by the PracticeUpdate editorial and advisory board, made available in print format. These news highlights and more are also available online at PracticeUpdate.com PracticeUpdate and the PracticeUpdate Conference Series are commercially supported by advertising, sponsorship, and educationalgrants. Individualaccess toPracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER The PracticeUpdate Conference Series provides highlights of key international conferences for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in thispublication, includinganyclaimsrelated to the products,drugs,orservicesmentionedherein.Becauseofrapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. Theproductionanddistributionof thispublication issponsored by Janssen. It contains content published in accordance with theeditorialpoliciesofElsevier’sPracticeUpdate.com.Content was produced by Elsevier with no involvement by Janssen. All content printed in this publication can be found on PracticeUpdate.com SALES Robert Bayliss r.bayliss@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja ISSN 2208-150X (Print) • ISSN 2208-1518 (Online)

Associate Editors

Tricia C. Elliott MD, FAAFP Vice President, Academic Affairs, Chief Academic Officer, Designated Institutional Official, John Peter Smith Health Network; Adjunct Professor, Family Medicine, University of Texas Medical Branch, Texas

Peter Lin MD, CCFP Director, Primary Care Initiatives, Canadian Heart Research Centre; Medical Director, LinCorp Medical Inc, Ontario, Canada

Advisory Board

Robert Bonakdar MD, FAAFP, FACN Director of Pain Management, Scripps Center for Integrative Medicine, La Jolla, California

Dennis J. Butler PhD Professor Emeritus of Family Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin

Frederick Chen MD, MPH Chief of Family Medicine, Harborview Medical Center; Professor of Family Medicine University of Washington, Seattle, Washington

Irene Mace Hamrick MD, FAAFP, AGSF Associate Professor, Clinical Health Sciences, Department of Family Medicine, University of Wisconsin; Director of Geriatrics Services, Department of Family Medicine, University of Wisconsin, Madison, Wisconsin

Dipesh Navsaria MPH, MSLIS, MD Associate Professor of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Jonathan Temte MD, PhD Professor, University of Wisconsin School of Medicine and Public Health, Department of Family Medicine and Community Health, Madison, Wisconsin

Editorial Contributors

Michael Allen MD Chief Resident – Family Medicine, Jennie Sealy Hospital, UTMB Health John Sealy Hospital, Galveston, Texas

Andrea Dotson MD, MSPH NRSA Primary Care Research Fellow, University of North Carolina, Department of Family Medicine, Cecil G. Sheps Center for Health Services Research, Chapel Hill, North Carolina

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Gut Microbiota Affect and Are Affected by Depression Evidence on psychobiotics shows a promising avenue of research.

E vidence is accumulating that the state of the gut microbiome affects and reflects overall health, including psychiatric health, according to a presentation at EPA 2019. There is increasing evidence of two-way communication between the brain and the enteric nervous system. Indeed, that primary nervous system is “far more immediately aware of what’s going on in the [gut]” than is the brain, Ted Dinan, MD, PhD of University College Cork in Ireland told Elsevier’s PracticeUpdate . This brain-gut-microbiota axis of commu- nication is complex. It involves the vagus nerve and spinal pathways, short-chain fatty acids, the hypothalamic-pituitary-adrenal axis, tryptophan, and the neurotransmitters GABA, norepinephrine, dopamine, and serotonin. Making use of this knowledge is a challenge, Dr. Dinan said. “We need greater understanding of how microbes communicate with the brain; we have only rudimentary understanding.” Although Dr. Dinan stressed that evidence for the gut microbiome’s role in psychiatric illness is limited, results of his and other scientists’ research, including early studies in animals, is intriguing. “We’ve learned a lot from looking at germ-free animals,” he said. “They have no microbiota. As a result, their brains don’t develop normally;

Dr. Dinan and others believe that psycho- biotics can be considered a new class of psychotropic drugs. He cautioned, how- ever, that there is no proof of this as of yet that we should all consume nutritional supplements. One reason is that we do not yet know much about which species are beneficial. “That’s a fundamental question,” he said. “There is no consensus on that, no con- sensus on what the missing microbes are. … The key to healthy aging is maintaining diversity in microbiota,” and that is best done through a varied diet that includes foods high in prebiotics. Some examples of these foods are Jerusalem artichokes, onions, leek bulbs, jicama, wheat and potatoes that have been cooked and cooled. “In my view,” he concluded, “psychobiotics are probably not effective for severe depression – but nobody has done trials. As a practicing psychiatrist, I would like to see live biotherapeuticals developed for treating mild to moderate depression. There have been no new medications; the field has stagnated. Whether [psychobiotics] are capable of acting like and, in some circumstances, replacing antidepressants, remains to be seen.”

their serotonin system doesn’t develop normally; their blood-brain barrier doesn’t develop normally.” Dr. Dinan and colleague conducted fecal microbiota transplants in rats, using feces from depressed patients or healthy controls. The rats who received a transplant from depressed patients developed a depressive phenotype, which included alterations in corticosterone release and tryptophan metabolism. They also developed a pro- inflammatory phenotype. These experiences with animal models translate to humans. “We were one of the first groups to show that in patients attending my clinic for depression, gut microbiota differed in these patients,” Dr. Dinan said. “It was less diverse than one sees in healthy subjects.” Dr. Dinan and his colleagues have also published results from human stud- ies – for instance, “Our paper about Bifidobacterium longum 1714 showed that it reduced anxiety, decreased cortisol, and altered EEG patterns when ingested by healthy volunteers. … There are marked differences in the gut microbiota between patients with major depression and healthy controls. Patients with major depression show decreased microbial diversity.”

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Five Patient Characteristics Predict Recurrence of Major Depressive Disorder Specific symptomatology, patient age and duration of illness were among themost relevant predictors.

T he chances of a patient having recurring episodes of major depressive disorder can be predicted by five sociodemographic and clinical findings, according to an abstract featured at EPA 2019. In their abstract, Gianluca Serafini, MD, PhD, from the University of Genoa in Italy, and colleagues remarked that, although specific predictors of depression relapse/recurrence have been iden- tified, evidence for which predictors are the most relevant is currently inconsistent across various studies. The researchers conducted their own nat- uralistic cohort study to identify the most relevant sociodemographic and clinical predictors of major depressive disorder recurrence. The 508 subjects in their study all had euthymic- type major depressive disorder and were outpatients. Their mean age was 54.1 ± 16.2 years. The subjects who were experiencing their first episode of major depressive disorder comprised 53.9% of the cohort, and 46.1% of the cohort had experienced recurrent depressive episodes. The investigators performed a detailed data col- lection, and they traced illness histories through clinical files and lifetime computerized medical records. The analysis showed that, compared with patients who had a single episode of major depres- sive disorder, patients with recurrent episodes

differed significantly with regard to a plethora of characteristics: age, age at first treatment, gender, working status, family history of mental disorders, typical depressive characteristics at first episode, psychotic symptoms at first episode, duration of untreated illness, melancholic characteristics, seasonality, and comorbid cardiovascular/endo- crinologic conditions. The researchers narrowed the field of possibly relevant characteristics through multivariate analyses that adjusted for age, gender, educational level and working status. Results showed that recurrence was associated with five characteristics: typical depressive features at first episode (beta coefficient = 4.635, P ≤ .001), melancholic features (beta coefficient = 4.011, P ≤ .05), age at first treatment (beta coefficient = –9.723, P ≤ .005), duration of untreated illness (beta coefficient = –5.630, P ≤.05), and current age (beta coefficient = 14.702, P ≤ .001). Dr. Serafini and colleagues state in their abstract that, “the predictors of recurrence of major depressive episodes identified in the current study may aid in the stratification of patients who could benefit from more intensive maintenance treatments for major depressive disorder.” They also caution that “clinicians should rapidly identify cases that are not likely to recur in order to avoid unnecessary treatments [that] are commonly considered as the standard of care.”

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Trazodone OAB Proves Non-Inferior to Venlafaxine XR for Major Depressive Disorder Significant improvements were seenwith trazodone in just 1 week. A once daily formulation of trazodone (trazo- done OAD) was shown to be non-inferior to venlafaxine extended release (venlafaxine XR) for the treatment of major depressive dis- order in a 2-month trial. The study results were presented at EPA 2019. In a double-blind, parallel-design study, research- ers led by Enrica Salvatori of Angelini S.p.A. in Rome, Italy randomized 324 patients with major depressive disorder to treatment with trazodone OAD 300 mg (n=166) or venlafaxine XR 75 mg (n=158) once daily. The primary efficacy endpoint of the study was to demonstrate the non-infe- riority of trazodone OAD, based on a change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) total score from baseline to final visit on Day 56. Both treatments were found to be effective. Based on an intent-to-treat analysis, the mean reduction in HAM-D total score was –12.9 ± 6.82 with trazodone OAD and –14.7 ± 6.56 with venlafaxine XR. Similarly, using a per-protocol analysis, mean reduction in HAM-D was –15.4 ± 5.32 with trazodone OAD and –16.4 ± 5.39 with venlafaxine XR. In both cases, trazodone OAD was found to be non-inferior to venlafaxine XR. Notably, patients treated with trazodone OAD achieved a statistically significant reduction in the HAM-D total score after only 7 days of treatment. Among patients treated with trazodone OAB, the most frequent adverse events reported were dizziness and somnolence. Among those treated with venlafaxine XR, they were nausea and headache. In both groups, adverse events were usually mild-to-moderate in severity. In their poster, the authors concluded that, “this trial confirmed that trazodone OAD and venla- faxine XR represent an effective and relatively safe therapeutic option for patients with [major depressive disorder]; moreover, trazodone OAD was able to reduce [major depressive disorder] symptoms after only 7 days of treatment, provid- ing a fast onset of action.”

In a comment on the study for Elsevier’s PracticeUpdate , Dennis Butler, PhD, Professor Emeritus of Family Medicine at the Medical College of Wisconsin in Milwaukee, pointed out that “an oft-repeated belief about recurrence of major depressive disorder is that 50% of patients with a first episode will have a second episode and 85% of those with a second episode will have a third. The percentages tumble to near 100% after that. “Since the majority of depressed patients are diagnosed and treated in primary care, it’s tempting to take the results of this study and start identifying patients from your panel who have the risk factors,” he continued. “However, being able to proactively predict which patients will have another bout of depression is still a challenge. Among the key factors identified from the multivariate analysis, it does appear that delays in seeking treatment for a first episode and duration of the depressive episode were powerful influences on the likelihood of recurrence. “The importance of this research lies in the emphasis on the need for maintenance therapy and patient education,” concluded Dr. Butler. “Most first- episode patients would prefer to only have one episode of depression, and many will resist ‘dire’ predictions about recurrence. Make sure to encourage your first-episode depressed patients to return for routine re-evaluation and provide them with symptom checklists which can be completed at regular intervals.” " The importance of this research lies in the emphasis on the need for maintenance therapy and patient education. "

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Positive Emotions Following Stroke Predictive of Functional Recovery Primary care physicians should screen post-stroke patients for low emotional states and refer for psychological support, if needed.

S creening patients for positive emotions should be undertaken following a stroke, as this can have an impact on both functional independence and functional recovery, according to a poster presentation at EPA 2019. Importantly, the predictive value of patients’ emotional state was significant even in the absence of clinical depression. “Stroke is a major global health problem with tre- mendous disease burden,” lead author Jesjeet Singh Gill, MBBS, of the University of Malaya in Malaysia told Elsevier’s PracticeUpdate . “Post-stroke depression is well-[known] to be associated with post-stroke functional recovery. However, positive emotions, another domain of mood, [have not been] given much scientific atten- tion. Positive emotions are thought to be vital in promoting recovery process in medical illness.” Dr. Gill pointed out that while two previous studies (by Ostir et al and Seale et al) have examined the relationship between positive emotions and recov- ery of function following stroke, it has never been evaluated in a Malaysian population. Dr. Gill and his colleagues Dr. Low Jong Sern (Penang Hospital) and Dr. Amarpreet Kaur (University of Malaya) recruited 136 patients dur- ing the 6 to 12 weeks after they experienced a stroke. These patients’ positive emotional states were assessed using the Positive Emotion Rating Scale (PERS). They were also evaluated for the presence of depression using the Montgomery- Åsberg Depression Rating Scale-Self (MADRS-S) or the Malay version of the MADRS-S. In addition,

patients’ functional status was assessed using the Modified Barthel Index (MBI). Overall, 65.4% of patients had a good positive emotional state, with the remaining 34.6% having a poor positive emotional state. In addition, a total of 23.5% of the patients met the clinical criteria for depression. Patients who had a length of inpatient hospital stay <5 days were 7.3 times more likely to have a good positive emotional state and 12.3 times less likely to have depression. Similarly, patients with fewer than three medical comorbidities were 4.3 times less likely to have depression. Dr. Gill told Elsevier’s PracticeUpdate that longer hospital stays were likely a marker of more severe stroke. Total PERS and MADRS-S scores were significantly associated with both functional independence and functional recovery. Multiple regression analysis revealed, however, that only PERS was significantly independently associated with both functional independence and functional recovery. Other factors significantly associated with post- stroke function were length of hospital stay, MBI at discharge, presence of a spouse and age. “Positive emotions screening should be consid- ered in post-stroke patients upon discharge [from hospital] and during follow-up, in order to detect those [patients who] are at risk,” said Dr. Gill. “Early intervention, such as medications that promote positive emotions or positive psychotherapy, can be provided if poor positive emotions are detected early.”

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Hypertension Linked With Increased Risk of Anxiety and Depression Systematic screening and earlymanagement of thesemental health disorders is needed in the hypertensive population. P atients with hypertension are more likely than those without it to suf- fer from anxiety and depression,

according to an analysis of patients from a general healthcare practice in Tunisia. The findings were presented in a poster at EPA 2019. The researchers highlight the need to screen for anxiety and depres- sion among patients with hypertension. “Anxiety and depression are common psychiatric comorbidities in patients diagnosed with hypertension, which may worsen the course of this disease,” write the investigators in their poster, which was presented by Nada Ghazouani, a psychiatry resident at the Medical School of Tunis in Tunisia. “The objective of our study was to evaluate the prevalence of anxiety and depression during hyperten- sion in a Tunisian cohort.” " This exploratory study is a welcome reminder to clinicians that depression, anxiety and hypertension can and do co-occur. " The investigators conducted a cross-sec- tional, comparative study of 200 patients recruited from a basic health center in the governorate of Mannouba, Tunisia. Among these patients, 100 had hyper- tension and 100 were controls who were matched with respect to age and gender. Anxiety and depression were assessed in both groups of patients using the Hospital Anxiety and Depression Scale (HADS). Overall, a greater proportion of patients with hypertension had anxiety, as deter- mined by an anxiety score >10, compared with control subjects (58% vs 22%, P < .0001). Similarly, depression, which was defined as a depression score >10,

was more frequently seen among those with hypertension than those without (27% vs 8%, P < .001). In addition, 24% of patients with hyper- tension had both an anxiety disorder and depression, compared with only 6% of controls (P < .001). “Our results emphasize the high preva- lence of anxiety disorders and depression in patients diagnosed with hypertension compared to a control group,” write the investigators in their poster. “Nevertheless, these disorders are still underdiagnosed in this population, which highlights the need for a systematic screening and an early management of these comorbidities.” In a comment on the study for Elsevier’s PraticeUpdate , Dennis Butler, PhD, Professor Emeritus of Family Medicine at the Medical College of Wisconsin in Milwaukee, noted that, “In the early days of psychosomatic medicine, a predom- inant theory was that anxiety caused hypertension. As research on essential hypertension evolved, attention shifted to examining how stress and distress con- tributed to hypertension. The subsequent

development of effective hypertensive agents then shifted clinicians’ attention to the importance of diet and exercise. Discussion of psychological factors played a less prominent role in encounters. “This exploratory study is a welcome reminder to clinicians that depression, anxiety and hypertension can and do co-occur,” he continued. “Further, it is safe to say that depression and anxiety do not contribute to the effective management of hypertension but certainly can interfere. “There does need to be further research in this area,” concluded Dr. Butler, “but such findings lend support to models of practice that incorporate mental health professionals in primary care to confirm psychiatric disorders and offer psycholog- ical and behavioral health interventions. This research does not support making causal statements about the relationship between depression/anxiety and hyper- tension, but it does remind us to help patients see the relationship between psyche and soma.”

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Adolescent Sleep Problems Typically Precede Anxiety Symptoms The findings suggest that addressing sleep problems early onmay help prevent the development of anxiety.

B oth sleep problems and anxiety are common complaints among adolescents and new research suggests that the sleep problems might actually come first, suggesting they may even play a causative role in the development of anxiety. Altanzul Narmandakh, a PhD student at the University of Groningen in The Netherlands, joined with three colleagues to investigate the association between anxiety and sleep issues among Dutch adolescents. They operated from the premise that sleep problems and anxiety symptoms increase considerably during adolescence. The bidirec- tional association between sleep problems and anxiety symptoms has been explored in other studies, but those studies have not distinguished differences occurring between persons from dif- ferences occurring within individuals over time. Narmandakh et al believe that this could have led to erroneous conclusions regarding underlying causal mechanisms. They therefore undertook to investigate the bidi- rectional association between sleep problems and anxiety symptoms during adolescence and young adulthood, with a particular focus on distinguish- ing between within-person and between-person effects. Their data came from the Tracking Adolescents’ Individual Lives Survey (TRAILS), a prospective cohort study of Dutch adolescents that includes six waves of data spanning 15 years. Sleep prob- lems and anxiety symptoms were measured by self-report questionnaires. The investigators looked at data from 2230 ado- lescents with a mean age at baseline of 11.1 years. These subjects were assessed every 2 to 3 years up until young adulthood (mean age 25.6 years).

Among the study participants, those who reported sleep problems were significantly more likely to report elevated anxiety than those who did not report sleep problems (beta coefficient = 0.58, P < .001). Over the 15 years of an individual sub- ject’s participation, that individual’s sleep problems and anxiety were cross-sectionally associated at all waves (beta coefficient = 0.014–0.018, P < .001). The study also showed that an individual’s experience of poor sleep predicted greater anxiety symptoms after 2 years at some assessment waves, but the reverse association was not statistically significant. Narmandakh and colleagues concluded in their abstract that their findings “tentatively suggest that adolescent sleep problems may precede anxiety symptoms, and … that anxiety might be prevented by alleviating sleep problems. “Anxiety symptoms and sleep problems become more prevalent among adolescents, and the authors of this study advance a hypothesis that sleep problems can precede and may cause anxiety problems,” Dennis Butler, PhD, Professor Emeritus of Family Medicine at the Medical College of Wisconsin in Milwaukee, told Elsevier’s PracticeUpdate in a comment on the study.

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“This hypothesis goes contrary to traditional thinking about the origin of anxiety disorders and how they develop. Most anxiety disorders have a strong relationship to a family history of anxiety or to personality (trait anxiety) and exist as a base- line condition or are exacerbated by situational variables. The predominant evidence about sleep problems and anxiety in children and adolescents finds that excessive worry and anxiety interferes with sleep onset and to disrupted sleep. “Sleep problems among adolescents are ubiqui- tous, and current findings are demonstrating an alarming increase in sleep deprivation among teens, which interferes with school and work per- formance,” continued Dr. Butler. “The increase is attributed to lifestyle, physical devel- opment, pressure to achieve (think homework), or simply adolescent difficulty with self-regulation. It is possible that the current study has uncovered that for some adolescents, sleep problems are a pro- dromal symptom of an emerging anxiety problem. The researchers do not indicate if the measured anxiety reached a clinical diagnostic level, but their findings do reveal a concerning pattern among the identified group. Sleep problems and anxiety

" It is possible that the current study has uncovered that for some adolescents, sleep problems are a prodromal symptom of an emerging anxiety problem. "

worsened in tandem for this group over a 15-year period. “This study reinforces the importance of more specifically evaluating sleep problems when interacting with teens in the primary care setting,” concluded Dr. Butler. “If teens report sleep prob- lems, ask more specifically about the cause. Are they up late studying, using social media, playing video games, or worrying and fretting? Behavioral and pharmacologic interventions for disruptive anxiety are most effective when started in a timely manner.”

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Baseline Depression Severity Does Not Affect Benefits of Antidepressant Therapy Study evaluates available data on five new-generation antidepressant medications.

D oes degree of severity of major depression affect the benefits derived from antide- pressants? The answer is no, according to research led by Andrea Cipriani, MD, PhD, from the University of Oxford in the United Kingdom. Dr. Cipriani stated in his abstract that the role of baseline severity as an effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This can be observed in the case of major depressive disorder, where clinical practice guidelines for prescribing antidepressants vary. For instance, the National Institute for Health and Care Excellence (NICE) and the American Psychiatric Association recommend pharmacother- apy for even mild degrees of depression, whereas the Canadian Network for Mood and Anxiety Treatments (CANMAT) and the Royal Australian and New Zealand College of Psychiatrists do not necessarily support this approach. In their study, Dr. Cipriani and colleagues examined whether the baseline severity of major depres- sive disorder modifies the efficacy of various antidepressants. They did this through individual participant data (IPD) meta-analysis. The researchers identified all placebo-controlled, double-blind, randomized trials of new-generation antidepressants in the acute-phase treatment of major depression conducted in Japan. They requested the studies’ IPD through the public- private partnerships between the relevant academic societies and the pharmaceutical companies. They examined how baseline depression severity could modify the effects of antidepressants, using six increasingly complex, competing, mixed-effects models for repeated measures. The researchers identified 11 eligible trials and obtained IPD from six. In a related journal article, they specify that participants were largely in their 30s and 40s, there were slightly more females than males, and the average baseline Hamilton Rating

Scale for Depression (HDRS) was approximately 22 to 23. The trials lasted 6 to 8 weeks. The six trials compared duloxetine, escitalopram, mirtazapine, paroxetine, or bupropion against pla- cebo (n=2464). The best-fitting model revealed no interaction between baseline severity and treat- ment (coefficient = –0.04, 95% confidence interval –0.16 to 0.08, P = .49). Several sensitivity analyses confirmed these findings. In their journal article, the researchers note that the findings reflect earlier research on the use of fluoxetine and venlafaxine as well as cognitive behavior therapy for depression. Their analysis did not include tricyclic antidepressants or monoamine oxidase inhibitors, however, so the findings may not be generalizable to those classes. In the abstract, Dr. Cipriani and colleagues con- clude that “we may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.” In a comment on the study for Elsevier’s PracticeUpdate , Dennis Butler, PhD, Professor Emeritus of Family Medicine at the Medical College of Wisconsin in Milwaukee, pointed out

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Lurasidone Safe, Effective for Major Depressive DisorderWith Mixed Features Study of 12 weeks also showed lurasidone treatment to be well-tolerated, with onlyminor metabolic changes observed. T he atypical antipsychotic lurasidone has shown efficacy and tolera- bility in patients with major depressive disorder with mixed features in a recent study presented at this meeting. Typically, lurasidone is used for treating patients with schizophrenia, bipolar disorder or bipolar depression. Stephen Stahl, MD, PhD, from the University of California in San Diego and colleagues reported in their conference abstract that their study evaluated the efficacy and tolerability of longer term treatment with lurasidone in patients with major depressive disorder with mixed features. The study took place in the United States and enrolled patients with major depressive disorder who presented with two or three manic symptoms and who had completed 6 weeks of a double-blind, placebo-controlled treat- ment with lurasidone in dosages of 18.5 to 56 mg per day. The research reported by Dr. Stahl and colleagues was a 12-week, open-label extension study. Patients already on lurasidone continued taking it while the original placebo group was switched to lurasidone. The primary efficacy measure was the Montgomery-Åsberg Depression Rating Scale (MADRS). A total of 48 patients entered the open-label extension study, with different groups having a different mean MADRS score at the beginning of the open-label phase of the trial. The mean score was 15.0 for those who continued on lurasidone (n=29) and 24.1 for those who switched from lurasidone to placebo (n=19). The remaining 9 patients (18.8%) discontinued the trial prematurely. Among patients who remained on the lurasidone, the mean change in total MADRS scores from baseline to week 12 was –4.1 (observed cases) and –3.3 (last observation carried forward). For those switched from placebo to lurasidone, the mean change in MADRS score was –11.2 (observed cases) and –9.7 (last observation carried forward). In the study, adverse events affecting at least 5% of patients were akathisia (10.4%); diarrhea (8.3%); upper respiratory infection (8.3%); and headache, sedation, nausea, or fatigue (6.3% each). Regarding metabolic parameters, median changes from the beginning of the open-label extension to the end of the 12 weeks in the lurasidone- lurasidone group were: cholesterol –6.5mg/dL, triglycerides –3.5mg/dL and hemoglobin (Hb)A1c +0.15%. For those switched from placebo to lurasidone, cholesterol increased by 1.5 mg/dL, triglycerides by 20.0 mg/dL and HbA1c by 0.30%. The study cohort experienced no clinically significant changes in body weight. Treatment-emergent mania or hypomania as an adverse event occurred in 2 patients (4.2%). Stahl and colleagues concluded that treatment with lurasidone (18.5–56 mg daily) was generally safe and well-tolerated for up to 12 weeks in patients with major depressive disorder with mixed features. They also stated that they observed continued improvement in depressive symptoms.

that determining the appropriate point to initiate antidepressant therapy among patients suffering from depressive symptoms remains an important clinical quandary. “Some guidelines discourage the use of medication for mild depression, and certainly some clinicians express reluctance to prescribe medication for milder forms of depression,” he pointed out. In addition, “patient beliefs about being able to over- come depression through willpower or lifestyle changes are also a barrier to the use of medication for less severe forms of depression. “Although this statistically sophisticated review only had a half dozen studies with data on the acute phase of depression treatment,” he noted, “the results strongly indicated that antidepressants were effective regardless of depression severity. While this research might affect future treatment guidelines and recommendations, it should be balanced with the very extensive problem of patient non-adherence to medication regimens. Patients with mild symptoms would seem to be among the most likely to discontinue medication treatment since, by definition, mild symptoms are those which do not cause significant disruption in their lives.”

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Risk Profiles Can Identify Seniors’ Likelihood for Suicidal Ideation and Attempts Depression, substance abuse, trauma-related disorders, declines in vision and psychosocial problems are among themost reliable indicators.

R isk profiles can identify older adults in care homes most likely to ideate about or attempt suicide, according to Australian research- ers who presented their results at this meeting. Identifying risk factors can be used to target inter- ventions to those who need it most, conclude the study authors. George Kuruvilla, MBBS, of Eastern Health in Melbourne, Australia and colleagues stated in their abstract that older adults disproportionately die by suicide. This is further emphasized by a statement from the Australian government in 2018 indicating that while depression affects 10% to 15% of older adults in Australia overall, the rate jumps to about

30% when looking specifically at those living in residential homes for the aged. In fact, the highest rates of suicide in men are seen in those aged 85 and older. In a cohort of older adults admitted to a mental health unit for aged persons, Dr. Kuruvilla and col- leagues investigated the unique and overlapping psychosocial risk factors associated with late-life suicide ideation and attempts. Their retrospec- tive case-control study included 135 individuals who had attempted suicide. These subjects were compared against controls on five characteristics: demographic data, clinical disorders, personality disorders, general medical conditions and psycho- social problems. Dr. Kuruvilla and his team found that, compared with controls, older suicide ideators and attempters had higher rates of depressive disorders, psycho- social problems and past suicide attempts. They also found differences between those who ideated about suicide and those who actively attempted

" …the males in this study were more likely to report suicidal ideation and women were more likely to attempt suicide. This is opposite of the patterns for all other age groups. "

MoodDisordersWithComorbidDisease LinkedWith ElevatedMortality Risk in the Elderly Early detection, better

A mong elderly people, the presence of a mood disorder and comorbid physical or mental illness may be associated with an increased 3-year mortality risk, according to research out of Taiwan. In their poster, Chun-Lin Chen, MD and Yi-Yu Pan, MD of Far Eastern Memorial Hospital in New Taipei City, Taiwan pointed out that, “there is a lack of clarity in the literature regarding the longitudi- nal risk factors associated with mortality in elderly people with mood disorders, including bipolar disorder and major depressive disorder.” Drs. Chen and Pan used the National Health Insurance Research Database in Taiwan to identify 26,570 elderly patients who were diagnosed with and treated for

mood disorders in 2008 and who were followed up for 3 consecutive years. The investigators conducted survival analyses to examine the risk factors associated with mortality over this follow-up period. Overall, 5854 patients were diagnosed with bipolar disorder and 20,716 were diagnosed with major depressive disor- der. In total, 4048 patients died within the 3-year follow-up period. This included 1003 patients with bipolar disorder and 3045 with major depressive disorder. Among these patients with mood disor- ders, the presence of comorbid dementia was associated with an approximate 40% increase in mortality risk. Other comorbid conditions associated with an increase risk of mortality were diabetes mellitus and renal disease.

control and risk prevention of physical andmental illness are important among older patients.

PRACTICEUPDATE CONFERENCE SERIES • EPA 2019 12

it. Ideators were more likely to be male, to require carer support and to have substance-related disorders. Attempters were often widowed, had trauma- and stressor-related disorders, suffered from diseases of the eye and lacked social connectedness; in addition, attempters were more likely to be female and to be without carer support. The researchers stated in their abstract that these results support “risk profiles that can be utilized in inpatient settings to identify older adults at risk of suicide ide- ation and attempts.” They comment that “post-discharge programs can focus on a variety of risk factors, such as depression, substance abuse, trauma-related disor- ders, factors associated with decline in vision and psychosocial problems.” They also emphasized that social connected- ness and carer support are particularly important psychosocial factors. In a comment on the study for Elsevier’s PracticeUpdate , Dennis Butler, PhD, Professor Emeritus of Family Medicine at the Medical College of Wisconsin in Milwaukee, explained that the findings are primarily relevant to psychiatrists, as primary care physicians should not be the first line of care among older adults with psychiatric conditions requiring residen- tial placement. In their poster, the investigators con- cluded that, “elderly patients treated for mood disorders were at a fairly high risk of mortality over a 3-year follow-up period. While comorbid mental and phys- ical illnesses generally contributed to an elevated risk, diagnoses of hypertension and hyperlipidemia were shown to be negatively associated with the mortality risk. Early detection, better control, and risk prevention for physical and mental illnesses are important to improve prog- nosis of mood disorder in elderly patients.” Dennis Butler, PhD, Professor Emeritus of Family Medicine at the Medical College of Wisconsin in Milwaukee, commented on the study for Elsevier’s PraticeUpdate . He pointed out that, “what’s especially con- cerning about the findings of this survival analysis is that the study group of elderly patients with mood disorders were being Interestingly, having a diagnosis of hyper- tension or hyperlipidemia was associated with a lower risk of mortality.

“As noted by the authors, rates of suicide among older adults are among the high- est of any group in Australia, a pattern which is also occurring in the United States” he continued. “One finding that should serve to affect who primary care physicians screen for suicidality was that that the males in this study were more likely to report suicidal ideation and women were more likely to attempt sui- cide. This is opposite of the patterns for all other age groups.”

Nevertheless, he noted, “there are val- uable findings that can contribute to the care of the older adult in the primary care settings. Inadequate caregiver support and lack of social interaction contribute to isolation, despair and hopelessness in this population. The findings regarding the negative impact of declining vision are also noteworthy. For many elderly patients, physiological aging is not grace- ful but is marked by numerous functional losses. Decline or loss of vision after a lifetime of sight is both a functional and symbolic loss.

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" It could be very valuable to follow this study with a multivariate analysis of which factors other than comorbid physical conditions were predictive of increased mortality risk. "

symptoms. And the severe complications which can accompany these conditions can deflect attention away from consist- ent management of mood disorders in the elderly (and others). “It could be very valuable to follow this study with a multivariate analysis of which factors other than comorbid physical conditions were predictive of increased mortality risk,” he suggested. “The pres- ence of a solid social support system, provision of an established routine, and creating a living environment low in emo- tional upheaval are all associated with improved quality of life among elderly with psychiatric disorders.”

treated and still had an elevated mortality risk. Epidemiologic research has consist- ently established that the presence of a major psychiatric disorder is predictive of not only poorer quality of life but a signifi- cantly shortened lifespan. “The dynamics of having a psychiatric disorder and life-challenging comorbid condition in late life can get quite compli- cated quickly,” he explained. “First, mood disorders are characterized by symptoms that can interfere with adherence and cooperation with medical care, including indecisiveness, anhedonia, pessimism, etc. In contrast, worsening of medical conditions such as dementia, diabetes and renal disease exacerbate psychiatric

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EPA 2019 • PRACTICEUPDATE CONFERENCE SERIES 13

Symptom Remission May Not Equate to Functional Recovery in Depression Functional deficits related to cognitive and depressive symptoms may persist.

P atients with major depressive disorder who meet the criteria for remission of depressive symptoms may still face functional impairment, according to research presented at EPA 2019. While many physicians assume that patients for whom antidepressant therapy has led to remission of depressive symptoms of major depressive dis- order can return to a normal level of functioning, research conducted by Antonios Chatzimanolis, MD, a practicing psychiatrist in Athens, Greece, and colleagues suggest this might not always be the case. Dr. Chatzimanolis and colleagues noted in their abstract that almost half of patients diagnosed with major depressive disorder who meet symptom- based definitions of remission, as measured by commonly used rating scales, do not consider their condition to be truly in remission and continue to experience functional impairment. As a result, it is important to evaluate functional recovery in multiple domains, including school, work and home life, among patients being treated for depression. The investigators conducted a non-interventional, cross-sectional multi-site study of 335 outpatients

in routine clinical practice in Greece who had been diagnosed with major depressive disorder and who had experienced a clinical response to antidepressant therapy. Remission of depression was defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) score ≤12, and functional recovery was defined as a Sheehan Disability Scale total score (SDS) ≤6. Cognitive symptoms were assessed using the Perceived Deficits Questionnaire-Depression (PDQ-D). Overall, 198 patients (53.7%) were evaluated as being remitted and 135 (40.3%) were functionally recovered. Among the patients who met the crite- ria for remission, only 113 (57%) also met the criteria for functional recovery. Functional recovery correlated significantly with MADRS total score (P < .001, beta-coefficient = –0.155) and with PDQ-D total score (P = .045, beta-coefficient = –0.039). The authors concluded that functional recovery remains an unmet need among a proportion of patients whose depressive symptoms have remit- ted. Lack of functional recovery appears to be linked to both depressive and cognitive symptoms. In a comment on the study for Elsevier’s PraticeUpdate , Dennis Butler, PhD, Professor Emeritus of Family Medicine at the Medical College of Wisconsin in Milwaukee, said, “As many of my mentors so often proclaimed, ‘treat the patient, not the lab!’ As this study confirms, that dictum also applies to the treatment of depressed patients whose scores on common depression screening

" Symptom checklists have their limitations and do not assess functionality. So, the study authors are onto something. It is necessary to ask patients about their current functioning. " PRACTICEUPDATE CONFERENCE SERIES • EPA 2019 14