Kinderen van ouders met een bipolaire of psychotische stoornis; vroeg identificatie en behandeling

Transcription

1 Kinderen van ouders met een bipolaire of psychotische stoornis; vroeg identificatie en behandeling Manon Hillegers Kinder-en jeugdpsychiatrie/psychologie Erasmus MC-Sophia kinderziekenhuis Symposium Vroegdetectie in GGZ 28 juni 2018

2 Disclosure belangen spreker Manon H.J. Hillegers (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties met bedrijven Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding Aandeelhouder Andere relatie, namelijk Geen / Zie hieronder Bedrijfsnamen Grants: ZonMW, NWO, NARSAD, EU FP7, DoY

3 Psychiatrische stoornissen komen in families voor!

4 Heritability Estimations BD en SZ komen in families voor Grote genetische contributie aan risico Bienvenu et al., 2010

5 Burden of illness Jongeren jaar Rank Cause Total DALYs x 1000 ( %) 1 Depressive Disorders 193 (8.2%) 2 Road accidents 127 (5.4%) 3 Schizophrenia 96 (4.1%) 4 Bipolar Disorder 88 (3.8%) 5 Violence 81 (3.5%) 6 Alcohol use 71 (3.0%) 7 HIV/AIDS 70 (3.0%) 8 Self-inflicting injuries 67 (2.8%) 9 Tuberculosis 60 (2.6%) 10 Respiratory infections 60 (2.6%) Gore et al,

6 Prodrome of Bipolar disorders Malhi et al. Bipolar Disord, 2014;16(5)

7 Ontwikkeling van jeugd naar jongvolwassenheid 75% van de psychische stoornissen manifesteert voor het 24 e levensjaar (Kessler, 2005) 2/3 van de volwassen patienten heeft al tijdens jeugd psychiatrische klachten

8 Potential impact of early intervention strategies Potential Impact of Early Intervention Strategies -Better course, Same outcome -Better course, Better outcome

9 Why offspring studies? Mental disorders run in families Cumulative incidence of admission with schizophrenia and bipolar disorder in offspring by age.

10 Worldwide Bipolar Offspring studies Study Authors Recruitment Strategy Sample Description Parent Diagnosis Psychiatric Comorbidity Offspring Assessment Follow-up yrs Flourish Canadian Study Duffy et al Genetic study multiplex families & mood outpatient 229 HR & 87 C 5-25 years at baseline Mostly BDI + 1 st degree affected relatives Unilineal & low rate of comorbidity in proband ( 25%) Clinician- administered SADS-L (parent) & KSADS blind best estimate consensus 15 yrs Dutch Bipolar Offspring Study Wals, Reichart, Hillegers, Mesman et al 2001 Support group-& mood outpatient 140 offspring from 86 families BD I 74% and BD II 26% Co-parent 30% Clinician- administered KSADS 12 yrs Amish Study Egeland et al Genetic study multiplex families 210 HR & 110 C most 10 years Mostly BDI Unilineal & low rate of comorbidity in proband Clinician- administered CARE interview & blind consensus 16 yrs BIOS Pittsburgh Birmaher et al, 2009 Ads (51%) & other studies 288 HR & 251 C 6-18 years BDI & II 48% other parents with disorder and high rates comorbidity in proband Trained rater SCID (parent) & K-SADS (offspring) reviewed by a clinician 8 yrs Multi-site US- Australian Nurnberger et al., 2011 Genetic study multiplex families & mood outpatient 141 HR and 91 C years Mostly BDI + 1 st degree affected relatives Unilineal unclear comorbidity rates in probands Clinician- administered DIGS/FIGS (parent) and modified KSADS-blind consensus review - Switserland Lausanne Vandeleur et al., 2012 Presig et al., 2016 Genetic study Unipolar and bipolar 139 HR BD I, BD II or SCZBD BD: 12% MDD: 26% K-SADS-E 10 year Given the high heritability and complexity of BD, study the offspring of affected parents can help to map changes related to illness development at multiple levels

11 Topics Today: Dutch Bipolar and Schizophrenia Offspring studies 1. Psychopathology development 2. Early signs of mood disorders 3. Short movie 4. Life events, coping, social and family functioning 5. SZ offspring 6. Future plans: MARIO PROJECT & early detection and intervention

12 Mick yr Family Mother: bipolar I disorder Father: unipolar depression Uncle (FM): bipolar disorder (suicide) Sister +4 years Participant Dutch Bipolar offspring study

13 The Dutch Bipolar Offspring study Design:12-year follow-up T1 T2 T3 T children 86 families yr (M=16 yr) 108 children 70 families yrs (M=28 yr) ~80% Wals, Reichart, Hillegers & Mesman,

14 The Dutch bipolar offspring study: 12-year follow-up -Psychopathology- T1 (%) T4 (%) Any mood disorder Major depressive disorder 6 17 Dysthymic disorder 6 8 Depressive disorder NOS Bipolar Spectrum disorders 4 13 Bipolar disorder (BD I, BD II) 3 11 Schizoaffective disorder - 1 Cyclothymia 1 1 Adjustment disorder - Mood 1 4 Psychosis - - Anxiety disorders Disruptive behavioral disorders 6 7 Attention deficit disorder 5 5 Substance abuse disorder 6 23 Other disorders** Any disorder Wals, Reichart, Hillegers & Mesman,

15 Mesman, E., Nolen, W. A., Reichart, C. G., Wals, M., & Hillegers, M. H. J. (2013). American Journal of Psychiatry, 170(5),

16 Survival Analyse years from 1 st mood episode to 1 st (hypo)manic episode No prepubertal mania onset Mean age of onset 14.6 yrs First (hypo)manic episode 5.3 yrs after depressive mood episode Mesman, E., Nolen, W. A., Reichart, C. G., Wals, M & Hillegers, M. H. J. (2013). American Journal of Psychiatry, 170(5),

17 Survival Analyse first mood episode - Mood disorders in general (n=58, 54%) Mean age of onset 17,2 19 recurrent unipolar depression Including BD: 33% recurrent mood disorder 67% comorbid disorders 71% between T3 and T4 received mental health support After age of 25, only 4 new onsets of mood disorders

18 UP BD BD? UP Familial Load and risk for MD in offspring Familial Load for mood disorders is significantly associated with mood disorders in offspring and not with non-mood disorders in offspring A high Familial Load for mood disorders is associated with an early expression of mood disorders in the offspring.

19 Conclusions and questions Dutch Bipolar offspring is at high risk to develop bipolar spectrum disorders 13% and debuts with a mild depression. Only 3% developed Bipolar I disorder, but 54 % a mood disorder. Mood disorders were often recurrent (33%) and complex (67% comorbidity, 71% treated) and run in families with early onset. Can we identify early predictive symptoms for bipolar disorder? Is this different from depressive disorder development? Can we identify Mick s risk profile and predict outcome?

20 -Early symptoms of Bipolar disorder-

21 MENTAL ILLNESS FROM A DEVELOPMENTAL PERSPECTIVE Early manisfestations of mental illnesses are often: mild non-specific & unstable overlap typical (pre)pubertal behavior change over time dimensional approach is needed!

22

23 Staging model Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 Childhood Adolescence Adulthood?????? Bipolar disorder Other disorder? After Duffy, 2010 and Berk, 2007

24

25 Prodromal features of Bipolar Disorder Prodromal features of (hypo)mania onset at baseline: transition from MD to BD Mesman et al. 2017

26 Prodromal features of (hypo)mania onset: transition from MD to BD 95% CI Comparison A: MD BD OR Lower Upper p Depression scale, 21 items Mania scale, 4 items 4.34* Anxiety scale, 23 items Externalizing scale, 12 items Substance scale, 6 items Residual scale, 12 items Constant R 2 Nagelkerke:.58, Model Χ 2 (2) = , p =.016. Mesman et al. 2017

27 Prodromal features of (hypo)mania onset: transition from MD to BD 5 discriminating symptoms % Mania sympt Depr sympt Mesman et al. 2017

28 Prodromal features of mood disorders Transition from non-mood disorders to any mood

29 Prodromal features of mood disorders 95% CI Comparison B: NoMD AnyMD OR Lower Upper p Depression scale, 21 items 1.79** Mania scale, 4 items Anxiety scale, 23 items Externalizing scale, 12 items Substance scale, 6 items Residual scale, 12 items Constant R 2 Nagelkerke:.28, Model Χ 2 (1) = , p =.008 Mesman et al. 2017

30 Prodromal features of mood disorders: 4 discriminating symptoms % NoMD -> MD NoMD=NoMD Recurrent thoughts of death Marked feeling of tension Marked selfconsciousness Compulsions Mesman et al. 2017

31 In line with recent studies: Pittsburgh BIOS: subsyndromal manic symptoms are a strong predictor for subsequent (hypo)mania onset, especially close to onset. COBY study outcome of bipolar youth showed that 45% of the subjects diagnosed with a BD-NOS made the transition into BD-I or II within 58 weeks. Canadian offspring study: 48% of the offspring developing BD met criteria of BD NOS prior to (hypo)mania onset None of the Dutch offspring of the NoMD category developing BD reported (sub)threshold manic symptoms at the baseline assessment already, suggesting indeed a more proximal role for subsyndromal manic symptomatology.

32 The early course of mood disorders among bipolar offspring: a proposed model (sub)threshold general anxiety symptoms (sub)threshold depressive symptoms (mild) depressive episode (sub)threshold manic symptoms threshold (hypo)manic episode Distal: Compulsions Tension Self-consciousness Thoughts of death Proximal: Suicidal ideation Sleep disturbances Elated mood Racing thoughts (Axelson et al., 2015; Correll et al., 2014a; Duffy, 2010; Duffy et al., 2014, Mesman et al. 2017).

33 Dimensional Predictors of Bipolar Spectrum Disorders in At-Risk Youths BIOS study Boris Birmaher Older parental mood disorder onset Younger parental mood disorder onset No symptoms Anxiety/depression only Anxiety/depression + affective lability Anxiety/depression + affective lability + proximal manic symptoms Hafeman et al., American Journal of Psychiatry, 2016

34 Clinical Implications-BIOS RISK CALCULATOR Offspring of parents with BP are at high risk to develop BP if their parents had early onset mood symptoms and specially, if the children have depression/anxiety, subsyndromal manic symptoms and/or mood lability. These children may benefit from early interventions The risk calculator may facilitate the individual risk (clinical and research implications) Not all children of parents with BP develop BP Many children of bipolar parents have other disorders Substance abuse increases after developing BP

35

36 Is het mogelijk de eerste tekenen van BD te detecteren met een screenings instrument? Aanvang BD prodrome tijdens adolescentie Begint met aspecifieke klachten: angst, prikkelbaarheid, slaapstoornissen Eerste epsiode is vrijwel altijd depressie Onderscheid met normale gedragsveranderingen tijdens pubertijd moeilijk 5. Skjelstad DV et al; Symptoms and signs of the initial prodrome of bipolar disorder: A systematic review. Journal of Affective Disorders 2010: 126: Duffy A; The Early Course of Bipolar Disorder in Youth at Familial Risk. J Can Acad Child Adolesc Psychiatry 2009: 18:3 7. Duffy A; The Early Natural History of Bipolar Disorder: What We Have Learned From Longitudinal High-Risk Research. The Canadian Journal of Psychiatry 2010: 55 :8

37 Samenvatting resultaten 7U7D als screener Externe validatie van Seven Up, Seven Down: AUC s tussen.70 en.80 (redelijk tot goed) Nagenoeg gelijk aan 73-item versie: MAKKELIJK TOEPASBAAR GOEDE SCREENER IN HR POPULATIE VOOR UD EN BD 7U7D op baseline als voorspeller: Significante voorspeller van stemmingsstoornissen (UD en BD) in HR popuatie; vooral de 7D Niet duidelijk onderscheidend BD tov UD. 7U Score >2 geassocieerd met BD uitkomst Wat hadden we Mick kunnen bieden aan preventieve interventie?

38 -SHORT MOVIE-

39

40 -Life events, coping, social and family functioning -

41 Course of cumulative life event load per year for mood affected and unaffected offspring Onset of severe symptoms >15y Life events are a risk factor in the early stage of MD enhanced by passive coping styles and a avoidant temperament For more details: The role of life events and psychological factors in the onset of first and recurrent mood episodes in bipolar offspring: results form the Dutch Bipolar Offspring Study S.M. Kemner*, E. Mesman*, W.A. Nolen, M.J.C. Eijckemans and M.H.J. Hillegers Psychological Medicine (2015)

42 Social functioning Has growing up in a family with a bipolar parent a negative impact on social functioning of the offspring? Competence scales of CBCL, YSR and YASR Teacher Report Form (TRF) Four adaptive functioning scales Sum of the scales Examples of questions: How well do you get along with your close friends? My spouse or partner and I enjoy similar activities Compared to others, how well do you get along with your father? I achieve what I am capable of Reichart et al., 2007

43 Social functioning ( Baseline T1, year) Offspring with mood disorder other disorder no disorder general population 0 score by child score by parent score by teacher No differences at early age Reichart et al., 2007

44 Social functioning (T3, year ) 16 Offspring with 12 * * bipolar disorder depression 8 other disorder no disorder 4 0 score by adolescent general population Impairment in social functioning appears to be the result of the disorder and not of the family environment Reichart et al., 2007

45 passive reactive coping styles and harmavoidant temperament

46 Conclusions life events, coping, social and family functioning - Life events are especially a risk factor in the onset of mood disorders, though less so in recurrent episodes - This effect is enhanced by passive reactive coping styles and harm-avoidant temperament in bipolar offspring - The number of previous episodes is a significant contributor to the risk of recurrent episodes - Impaired social and family functioning seems to be the result of psychopathology development in the offspring - These results point towards potential early intervention strategies for bipolar offspring. S.M. Kemner*, E. Mesman*, W.A. Nolen, M.J.C. Eijckemans and M.H.J. Hillegers Psychological Medicine (2015)

47 Cross diagnostic approach Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 Childhood Adolescence Adulthood RISK: Familial load Environment; stress, infection Anxiety Behavio r problem s Sleep Minor Mood disorder Disruptiv e behavior Major mood Bipolar disorder Psychotic disorder Cognitive vulnerabilities Biological vulnerabilities Brain development

48 Bipolar and Schizophrenia offspring studies Almost no SZ offspring studies: low reproductive rates of SZ patients (Bundy et al., 2011) restricted the number of SZ-offspring participants included. US & Canada: Keshevan older offspring; Maziade et al., 2008 adolescent SZ and BP-offspring, included only densely affected families and did not have a control group. Spanish group (Castro-Fornieles, Sugranyes, Romero): BD, SZ and control offspring Denmark Copenhagen en Aarhus Via7/11 (Nordertoft, von Plessen, Thorup) The Netherlands Dutch Bipolar and Schizophrenia Offspring study (BDSOS)

49 BRIDGE study Baseline: 191 children 8-18 yrs Psychopathology: K-SADS CBCL/YSR/TRF Imaging smri; fmri Cognition

50 Diagnosis and comorbidity (% offspring) >1 Comorbid diagnosis 1 comorbid diagnosis SZo BDo Co 1 diagnosis No diagnosis * SZo&BDo>Co * SZo&BDo<Co Psychopathology and structural brain abnormalities in offspring of schizophrenia and bipolar patients # 50

51 Type of diagnosis (% diagnosis) SZo BDo Co Other disorders PDD/Asperger ADHD Anxiety disorder Major depression disorder Any mood diagnosis * SZo>BDo * SZo<BDo Psychopathology and structural brain abnormalities in offspring of schizophrenia and bipolar patients # 51

52 Estimated intracranial volume (ml) Intracranial Volume * # 52 Co SZo BDo Psychopathology and structural brain abnormalities in offspring of schizophrenia and bipolar patients SZo have a smaller intracranial volume than BDo and Co which might suggest that aberrant neurodevelopmental development plays a role.

53 SAMENVATTING & take home messages Offspring of a parent with a bipolar or psychotic disorder are especially at risk for mood disorders Early predictive symptoms of mood disorder development can be identified and include sleep, anxiety and mild manic symtoms. Stressful life events are especially a risk factor in the onset of mood disorders and this effect is enhanced by passive reactive coping styles and harm-avoidant temperament A focus of preventive intervention is: Awareness in families and clinicians early identifcation of problems (screening) Enhancing coping skills

54 -MARIO project-

55 Huidige situatie ~400,000 Kinderen van Ouders met een StemmingsStoornis (KOSS) Ouder met een stemmingsstoornis is belangrijkste risico factor voor depressie 50-60% van KOSS ontwikkelt voor 35 ste levensjaar een depressie ( > ) 2013: Wettelijk verplichte kind check In de praktijk niet breed ingevoerd

56 Project doelen 1 Ontwikkeling van depressie in KOSS begrijpen via langlopend onderzoek 2 Depressie in KOSS vroeg herkennen door screening in de praktijk 3 Door preventieve interventie, depressie in KOSS voorkomen

57 Waarom dit MARIO-project? KOSS zijn de patiënten van de toekomst DE risicogroep binnen de psychiatrie Nu is er geen coherente aanpak op beter begrip en vroege interventie

58 Future plans: early identification and preventive interventions Very Mood profile (2265) Cheerful Grumpy Sad Tired Three context-dependent and distinct mood profiles in the general population n= Somewhat PA family PA friends PA classmates 2 NA family Not mei 27 mei 29 mei 31 jun 02 jun 04 jun 06 jun 08 jun happy prototypical depressed NA friends NA classmates In preparation: Hiemstra et al.,

59 SMARTPHONES Smartphone applicaties veelbelovend: - 96% smartphone - Game elementen vergroten hun motivatie - Grote schaal aangeboden - Geen reistijd en niet afh. afstand ziekenhuis

60 STEMMING IDENTIFICEREN

61 INTERVENTIE OP EMOTIES DOOR VERSTERKING COPING Opzet interventie Serious game ACTIVEREN EN VERBREDEN COPING Ieder team heeft 8 spelers Individuele en team challenges (per dag en week) Punten te verdienen per challenge en registratie gevoelens Elkaar motiveren via (gereguleerde) chatfunctie

62 Thank you for your attention Acknowledgements: all participating families Dutch Bipolar Offspring Study team Esther Mesman Willem Nolen Sanne Kemner Gijsje Snijders Catrien Reichart Marjolein Wals Frank Verhulst Hans Ormel Hemmo Drexhage DBSOS study team Nikita Setiaman Heleen Baalbergen Merel Prikken Martijn Koevoets Guusje Collin Martijn vd Heuvel Hugo Schnack Neeltje van Haren René Kahn ESM/IRIS study team Loes Keijsers, Marieke Hiemstra, & HKU 13-16, 2016

63 Opinions/experiences of Dutch Bipolar offspring study participants Question Is it ethical to do an offspring study? It was approved by ethical committee Nevertheless questions remained Aren t they too young? What are their experiences? More focus on possible problems?

64 Opinions/experiences of offspring participants Method Questionnaire ((fully)agree/(fully)not agree) Examples By participation in this study I started to think more about bipolar disorder. I am angry with my parents that they asked me to participate in this study. 130 questionnaires at T3 125 completed Psycho-educational effect? Protective?

65 Opinions/experiences of offspring participants Usefulness Found it useful 99% Would recommend it to others 86% Information Started to think more about bipolar disorder 67% Better informed about bipolar disorder 56% More understanding for their parents 52% Own situation Participation was confronting 45% Do worry getting bipolar disorder themselves 15% Don t think they have/will develop bipolar 70% disorder