‫ירידה קוגניטיבית‪:‬‬ ‫הליקוי הנסתר של החולה הדיכאוני‬ ‫פרופ' גיל זלצמן‬ ‫מנהל המרכז לבריאות הנפש גהה‬ ‫ויו"ר האיגוד לפסיכיאטריה ביולוגית‬ Gil Zalsman Ethical Disclosure No Conflict of interest for this presentation No direct or indirect fee paid by Lundbeck for this presentation Advisor for: • JNJ RND: Protocol Number: # ESKETINSUI2001, Phase: 2a, Study Drug Number: JNJ54135419 • Elminda ltd Israel • Prophase LLC, NY Grants: 1. AFSP young investigator grant-2005-2007 (Zalsman) 2. PHS grants MH62185 and MH48514 (J.J. Mann) 3. The National Institute for Psychobiology in Israel Grants 29/98, 9b/99 (Zalsman) Organizations: 1. ECNP board member 2. EPA- section chair 3. ISBP-president ‫• דכאון היא מחלה כרונית עם רמיסיות נדירות‬ ‫וחלקיות‬ “Kindling” Phenomenon Risk (odds ratio) 10 Likelihood of recent life stress precipitating depression Risk (odds ratio) of depression onset per month 8 Female participants only N=2,395 6 4 2 0 0 1 2 3 4 5 6 7–8 Number of previous depressive episodes 9–11 Kendler KS, et al. Am J Psychiatry. 2000;157:1243–1251. Copyright © 2000 American Psychiatric Association. All rights reserved. Rush et al., STAR*D, AJP 2006 MDD: one N=3612 to four TX N=123 Zimmerman et al. AJP 2006 The ultimate goal of treatment in depression is full functional recovery Treatment goals in depression have evolved Full functional recovery Symptoms are essentially absent Remission Some symptoms may persist Response Many symptoms remain Definition varies between studies but commonly defined as MADRS score of <10 or HAM-D17 score of <7 Reduction of symptoms by >50% using, for example, MADRS or HAM-D MADRS, Montgomery-Åsberg Depression Rating Scale; HAM-D, Hamilton Depression Rating Scale; HAM-D17, Hamilton Depression Rating Scale 17-item version 8 Not officially defined; measures should include clinician rating, self-report and performance testing to assess both symptoms and functioning ‫• ליקוי קוגניטיבי הוא חלק משמעותי מהסנדרום‬ ‫הדכאוני‬ A Variety of Symptom Clusters Contribute to Functional Impairment In schizophrenia Positive symptoms1 Delusions Disorganized thought Disorganized speech Hallucinations symptoms1 Negative Flat or blunted affect and emotion Poverty of speech (alogia) Inability to experience pleasure (anhedonia) Lack of desire to form relationships (asociality) Lack of motivation (avolition) 1. 2. Lack of insight2 Functional impairment1 Ability to work Coping with household tasks Establishing social relationships Cognitive impairment1 Episodic memory Inappropriate affect Executive function Working memory Tandon R et al. Schizophr Res. 2009;110(1-3):1-23. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000. 1 Depression symptoms interact in a complex way Emotional Chronic debilitating disorder Sadness Anxiety Irritability Lack of enjoyment Suicidal ideation Hopelessness Guilt Difficulties with: Attention & concentration Short- & long-term memory Decision making Planning & organisation Mental sharpness Word-finding Thinking speed judgement Fatigue Eating changes Insomnia Headaches Physical Stomach problems Chest pain 11 Cognitive 11 ‫• קוגניציה מתחלקת לשני סוגים עיקריים‬ The CBT Model: Thoughts, emotions and behaviours interact What we THINK affects how we act and feel Thoughts What we FEEL affects what we do and think Emotions Behaviours Back et al., The CBT concept 13 What we DO affects how we think and feel Cognition in MDD (Guy Goodwin, ECNP 2013) • Hot processing= emotional processing- focus of CBT • Cold processing=non-emotional cognitive distortion: executive Functioning, learning, memory. “Cold” processing is critical for functioning Domains of cognition DOMAIN DESCRIPTION Attention The ability to focus and sustain attention Memory / learning Including episodic memory (relating to past or future events), verbal memory / learning and visuo-spatial memory / learning Executive functioning The ability to monitor and regulate cognitive processes, employing attention, planning, working memory, mental flexibility, inhibition, task initiation and monitoring, multi-tasking and decision-making Psychomotor speed The speed at which the brain controls the body to perform physical tasks 15 ‫• עוצמת הליקוי קוגניטיבי היא משמעותית במהלך‬ ‫המחלה וההחלמה‬ The course of the cognitive dysfunction is different from the course of mood symptoms despite them being integral parts of the same disorder Illustration of how the profile of cognitive dysfunction, the risk of relapse and symptom improvement might relate Remission Symptom reduction Normality Relapse New episode II Depressive symptoms I III Low Acute phase Cognitive function Hammar & Årdal. Front Hum Neurosci 2009;3:26 17 I • Does the cognitive impairment occur before the mood symptoms? II • Is the time course of cognitive normalization delayed in relation to remission? III • Is long-lasting cognitive impairment a predictor for enhanced relapse risk or for new episodes? Synder 2013, Meta-anlysis ‫‪Synder‬‬ ‫‪2013‬‬ ‫‪weighted mean‬‬ ‫‪effect size‬‬ ‫כל המחקרים פרט לשניים‬ ‫הראו על נחיתות מובהקת‬ ‫של החולה הדכאוני‬ ‫במדדים קוגניטיביים לעומת ביקורת‬ ‫• אנחנו כמעט לא מודדים את הליקוי הקוגניטיבי‬ Assessing cognitive dysfunction using depression rating scales HAM-D MADRS ● Retardation (slowness of thought and speech, impaired ability to concentrate, decreased motor activity) ● Difficulties in concentrating and sustaining thought, which reduces ability to read or hold a conversation Beck Depression Inventory Patient Health Questionnaire ● I have greater difficulty in making decisions than I used to ● Trouble concentrating on things, such as reading the newspaper or watching TV Standard depression scales do not assess all the cognitive domains HAM-D, Hamilton Depression Rating Scale; MADRS, Montgomery-Åsberg Depression Rating Scale ‫• הליקוי הקוגניטיבי משמש בתפקיד חשוב‬ ‫בפרוגנוזה ובסכנה האובדנית‬ “Typical” suicide victim in Israeli schools 2003-2011(n=70) • Low graded school • Academic difficulties • Trigger: interpersonal discord M/P humiliation (60%) 24 ‫ממצאים במחקר המוח‬ 1. 2. Top down Bottom up Internal thoughts 1 Mindfulness is blocking of 1 (relaxation) feelings Depression is blocking of 2 (rumination) 2 Bar M, trends in cognitive sciences 2007 External sensations Bar M. 2007 “The thought pattern typical of mood disorder involves rumination around a narrow focus. Even if this thought pattern is associative, it is limited in scope.” Williams M., 2009    Rumination )and not distraction( is typical to the suicidal depressed patient Distortion in gambling games Bed judgment and problem solving skills McIntyre et al., 2013 (Review, Depression & Anxiety) ‫• הליקוי הקוגניטיבי יכול להשאר גם אחרי החלמה‬ ‫מלאה או חלקית מהדכאון‬ Cognitive dysfunction is highly prevalent as a residual symptom of depression Percentage of time that patients met DSM-IV criteria per symptom cluster Time (%) 100 During MDE During remission 80 60 40 20 0 Depressed mood/ diminished interest Cognitive problems Lack of energy Sleeping problems Worthlessness/ guilt • Remission=presence of DSM-IV residual symptoms during non-major depressive episodes • DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th edition; MDE=major depressive episode Conradi et al. Psychol Med 2011;41:1165–1174 31 Eating problems Death ideations Psychomotor problems Subjective cognitive symptoms after treatment 60 Proportion of patientsa in full or partial remission after 3 months of treatment reporting cognitive and physical impairment Patients (%) 50 40 30 20 10 0 Items from the Cognitive and Physical Functioning Questionnaire an=117 Fava M et al. J Clin Psychiatry 2006;67:1754-9 32 Objective cognitive dysfunction persists even in remission Attention Effect size Increased deficit (relative to control) RVIP 0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1 p=0.0009 Memory DMTS PRM Executive function SOC p=0.05 SWM IED p=0.02 p=0.003 p<0.00001 Remitted patients continued to show deficits in executive function, memory and attention Meta-analysis of CANTAB studies in remitted patients with MDD (6 studies: 168 patients, 178 control individuals) RVIP, Rapid Visual Information Processing; DMTS, Delayed Matching-to-Sample; PRM, Pattern Recognition Memory; SOC, Stockings of Cambridge; SWM, Spatial Working Memory; IED, Intra-Extra Dimensional Set-Shift; CANTAB, Cambridge Neuropsychological Test Automated Battery; MDD, major depressive disorder 33 Rock PL et al. Psychol Med 2014;44:2029-40 33 Cognitive symptoms interfere with work functioning Patients (%) Percentage of depressed patients (n=164) reporting that depressive symptoms interfered with work functioning “very much” or “so much that I had to stop working” 70 60 50 40 30 20 10 0 52% Anergia Low mood Tension Cognitive difficulty Insomnia Guilt Pain Appetite Suicidal 52% of depressed patients report that cognitive symptoms severely interfere with their occupational functioning Anergia = lack of motivation, low energy, physically slowed down, sleepy during day; Tension = anxious / tense / nervous, irritability / anger; Cognitive difficulty = trouble concentrating, trouble with memory 34 Adapted from Lam RW et al. Depress Res Treat 2012;2012:630206 34 Cognitive Symptoms Adversely Affect Life Functioning Independent of Reduced Depressive Symptoms MDD patients 6 months post-hospital discharge Number of participants 12 10 Cognitive impairments were strongly associated with impaired life functioning at 6 months 8 6 4 2 0 1 2 3 4 5 6 MSIF score (1 = normal functioning, 7 = totally disabled) 35 7 MSIF, Multidimensional Scale of Independent Functioning. Jaeger J, et al. Psychiatry Res. 2006;140:39-48. Greer TL, et al. CNS Drugs. 2010;24:267-284. McIntyre RS, et al. Depress Anxiety. 2013;30:515-527. ‫• תכשירים חדשים מנסים לטפל בליקוי הקוגניטיבי‬ ‫בדכאון‬ Functional overlap between aminergic systems: features of depression NE 5-HT Anxiety Irritability Energy Interest Motivation Mood Emotion Cognitive function Impulsivity Sex Appetite Aggression Drive Dopamine 5-HT, serotonin; NE, norepinephrine FromStahl S. In: Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. Cambridge, UK: Cambridge University Press; 2000:135-97 37 Vortioxetine: Activity at receptors and transporter inhibitor agonist partial 38 agonist antagonist Westrich et al. 2013* * abstract, sponsored 39 ‫ביקור חולדה במרכז‬ ‫כמדד להעדר דכאון וחרדה‬ ‫‪SB=5HT7 selective anatagonist‬‬ ‫‪40‬‬ 5HT-7 : faster AD effect? 41 Vortioxetine and venlafaxine substantially improved MADRS total score at Week 8 (primary endpoint) Estimated change in MADRS total scores from baseline to Week 8 (ANCOVA, FAS, LOCF) Mean change from baseline in MADRS total score 0 -5 Vortioxetine (n=209) Venlafaxine (n=215) -10 -15 -20 0 1 2 3 4 5 6 7 8 Week Wang et al. Poster presented at CINP 2014 42 Katona et al., 2012* Int. Clinical Psychopharmacology *sponsored by Lundbeck Digit DSST=digit symbol substitution test RAVLT=Rey Auditory Verbal Learning test DSST= a neuropsychological test digit-symbol pairs (e.g. 1/,2/┴ ... 7/Λ,8/X,9/=) followed by a list of digits.[2][3][4] Vortioxetine improved cognitive performance in depressed elderly patients (≥65 years) Vortioxetine improved (objective) cognitive performance in both the DSST and RAVLT – exploratory endpoints, Week 8 (FAS, ANCOVA, Cohen’s d) Standardised effect size vs placebo 0.40 0.30 Vortioxetine 5 mg/day (n=156) Duloxetine 60 mg/day (n=151) * * * ** * 0.20 0.10 0.00 DSST Executive function Psychomotor speed *p<0.05, **p<0.01 vs placebo; nominal p-values n-values are APTS ANCOVA=analysis of covariance; APTS=all patients treated set; DSST=Digit Symbol Substitution Test; FAS=full analysis set; RAVLT=Rey Auditory Verbal Learning Test RAVLT acquisition Attention 45 45 RAVLT delayed recall Memory Katona et al. Int Clin Psychopharmacol 2012;27(4):215–223 ‫מסקנות‬ ‫•‬ ‫•‬ ‫•‬ ‫•‬ ‫•‬ ‫•‬ ‫סימפטומים קוגניטיביים הם חלק מהסינדרום הדכאוני‬ ‫והם נפוצים במצב החריף וגם ברמיסיה‬ ‫התסמינים הקוגניטיביים מסכנים באובדנות‬ ‫התסמינים הקוגניטיביים יכולים להתמיד גם אחרי טיפול‬ ‫נוגד דכאון‬ ‫התסמינים הקוגניטיביים יכולים להיות מחסום בפני‬ ‫רמיסיה תפקודית – מעגל שלילי‬ ‫הערכת מצב קוגניטיבי היא חשובה כחלק מהערכת המצב‬ ‫הדכאוני‬ ‫דור חדש של תרופות מנסה להתמודד עם חסרים אלו‬ ‫‪46‬‬ ‫האיגוד הישראלי לפסיכיאטריה ביולוגית‬ ‫הכנס השנתי ה‪ 19-‬שיתקיים בימים ‪ 19-17‬במרץ‪2015 ,‬‬ ‫ב"מלון בטבע"‪ ,‬קיבוץ הגושרים‬