Eiko Fried KU Leuven

1. Depression is more than the sum-score of its symptoms:A novel network approach to understanding depression Eiko Fried KU Leuven

2. Major Depression (MD) • Prevalence • Most common psychiatric disorder • Recurrence • 50-75% suffer from more than on episode • Previous episodes reduce treatment efficacy • Disability • Greatest impactof all biomedicaldiseases on disability • Closelyrelatedtosuicideand a varietyoflife-threateningconditions (coronaryheartdisease, diabetes) • 60% reportsevereorverysevereimpairmentoffunctioning • Costs • US: > $30 billion per year

3. Let's conduct a typical depression study

4. Hypothesis • People with Major Depression (MD) have different genes comparedtohealthycontrols

5. Procedure • Depression • Select questionnairetoassessdepressionsymptoms • 21-item BDI

6. Procedure • Depression • Select questionnairetoassessdepressionsymptoms • 21-item BDI • Buildsum-score ofsymptoms • Distinguishbetweenhealthycontrolsand MD participantsbased on threshold • Genetics • Examineparticipants' genomes

7. Sample • 500 depressedindividuals, 500 healthycontrols • MD group: meanof 14 points • Healthygroup: meanof 7 points

8. Results • Nodifferences at all betweengenomesofdepressedgroupandcontrolgroup

9. Results • Nodifferences at all betweengenomesofdepressedgroupandcontrolgroup

10. Previousstudies • Hek et al., 2013 • See • See also: • Lewis et al., 2010; Shi et al., 2011; Wray et al., 2012; ...

11. Discussion • Hek et al., 2013 • Jeffrey Lieberman, president of the American Psychiatric Association : progress "has been largely limited by technology"

12. Proceed to publish this typical depression study "Null findings due to technology and sample size"

13. Other problems in depression research • Antidepressants are only marginally efficacious compared to placebos, and only work "at the upper end of the very severely depressed category […] even there, differences are small." (Kirsch et al., 2008; Pigott et al., 2010; Turner et al., 2008) • Diagnostic and Statistical Manual (DSM-5) field trials: "questionable" inter-rater reliability of ~0.3 (Regier et al., 2013)

14. Other problems in depression research • Antidepressants are only marginally efficacious compared to placebos, and only work "at the upper end of the very severely depressed category […] even there, differences are small." (Kirsch et al., 2008; Pigott et al., 2010; Turner et al., 2008) • Diagnostic and Statistical Manual (DSM-5) field trials: "questionable" inter-rater reliability of ~0.3 (Regier et al., 2013) • Dramatic lack of progress in key research areas. Hypothesis: sample size and technology are probably not the main reasons. Instead, the main problem is our understanding of what depression is.

15. LIPS lecture today • Main goal: explaindramatic lack ofprogress in MD research • Problematicassumptionsofdepressionresearch • Depression as a naturalkind • Depression asthecommoncauseofitssymptoms • Network approachtoMD

16. Assumption 1:MD is a natural kind

17. Infectious diseases • Robert Koch, 1905: discovery that specific diseases have specific causative agents (tuberculosis & syphilis) • Diseasesunderstoodasnaturalkinds: • Natural kindsareunchangingandahistoricentitieswith sharp boundariesthathave a specificsetofproperties (e.g., symptoms) bothnecessaryandsufficientforclassification • This type ofclassificationiscalledessentialism • An essence is "some kind of underlying, intrinsic property, something that lies within kind members, making them the kind of thing that they are" (Wilson et al., 2007; p. 3)

18. Infectious diseases • Measles: infection of the respiratory system caused by a specific virus, accompanied by specific symptoms like red eyes, fever, generalized rash, and Koplik's spots. Natural kind perspective: measles exists outside the human classification system as real thing. • Gold: atomic number 79, and everything with this atomic number is gold. Specific properties ("essence"), and sharp boundary to all things that are not gold.

19. General paresis • 1910: discovery of syphilitic bacteria in brains of deceased patients diagnosed with "general paralysis of the insane" • Neuropsychiatricsyndromeoflate-stage syphilis • Clear "essence" identified for a mental disorder • Disease model applied to the rest of medicine, including psychiatry • 1912, Alfred Roche: • "The main example of a happy final definition of a disease condition […] has been general paresis. The success achieved here has perhaps been a misfortune in its side effects because it nourished the illusion that something similar might soon be repeated."

20. General paresis • 1959, Kurt Schneider: • "General paresis […] became the model for forming disease entities. It was thought it would continue thus, it was hoped that with time more and more such disease entities would emerge from the multifarious conditions of the mentally ill. In fact, however, this did not happen." • Diseasemodel still considered valid today, but nofurther "essences" detectfor mental disorders

21. Mental disorders as natural kinds • The hypothesisof mental disordersasnaturalkindshasbeenpresentthroughoutthehistoryofpsychiatry • Gerald Klerman, chief of the US national mental health agency, 1978: • "there is a boundary between the normal and the sick" • "there are discrete mental disorders" • Aim of developing specific treatments for particular disorders, and of finding specific underlying biological abnormalities • Think back toourstudy! • Notion of categorical nature of mental disorders also reflected in more recent developments like the DSM-5

22. Mental disorders as natural kinds • This ismorethan just a belief or a tacitassumption—itisreflected in everydayresearchpractices • Disparate depressionsymptomsaddedtosum-scores, thresholdsdistinguishbetweendepressedgroupandcontrolgroup • The search for potential causes then proceeds as if depression is a natural kind, similar to measles • Definition of MD as disease entity has discouraged attention to specific depression symptoms and their dynamic interactions

23. Assumption 1:evidence?

24. 1. Dimensional vs. categoricalview

25. 1. Dimensional vs. categoricalview

26. 1. Dimensional vs. categoricalview • Overwhelmingpsychometricandtaxometricevidence in favorof dimensional view • Manypeoplehavefewproblems, andthentherearepeoplewith minor, moderate, severe, andverysevereproblems. Thereisnozoneofrarity. • Idea of comparingdepressedvs control groupbased on a threshold is problematic

27. 1. Dimensional vs. categoricalview Subthreshold • The presence of subthreshold depression is often clinically significant, with depression-like levels of functional impairment, psychiatric and physical comorbidities, and increased risk of future depressive episodes

28. 1. Dimensional vs. categoricalview • Whilecategorical definitions may be necessary for practical purposes, they have fostered reductionist thinking about depression. • "What causes it"? • "What are genetic predispositions for it"?

29. 1. Dimensional vs. categoricalview • "Essentialist Bias": belief that mental disordersarenaturalkindsisprevalentamongbothlaypeopleandmedical professionals(Pieter Adriaens & Andreas de Block) • Categorical belief in cliniciansdiminisheswithexperience • Categorical belief in cliniciansassociatedwithlessempathy • Implicitessentialistworldviewdevelopsearly in human cognition, applies to numerous domains of classification such as chemical elements, species, and emotions • Richard Dawkins: "The Tyranny of the Dichotomous Mind"

30. 1. Dimensional vs. categoricalview • Summary: studying 2 groups—"healthy" vs. "depressed"—ignoresthe dimensional natureofdepression

31. 2. Heterogeneity of MD • A naturalkindhas a clearlydefinedessenceand a numberofnecessaryandsufficientproperties. • Formedicaland mental disorders, thesepropertiesare (amongothers) symptoms.

32. 2. Heterogeneity of MD • DSM-5 diagnosis of depression • Diminishedinterestorpleasure • Depressedmood • Increaseordecrease in eitherweightorappetite • Insomniaorhypersomnia • Psychomotor agitationorretardation • Fatigueorlossofenergy • Worthlessnessorinapproriateguilt • Problems concentratingormakingdecisions • Thoughtsofdeathorsuicidalideation

33. 2. Heterogeneity of MD • DSM-5 diagnosis of depression • Diminishedinterestorpleasure • Depressedmood • Increaseordecrease in eitherweightorappetite • Insomniaorhypersomnia • Psychomotor agitationorretardation • Fatigueorlossofenergy • Worthlessnessorinapproriateguilt • Problems concentratingormakingdecisions • Thoughtsofdeathorsuicidalideation

34. 2. Heterogeneity of MD • DSM-5 diagnosis of depression • Diminishedinterestorpleasure • Depressedmood • Increaseordecrease in eitherweightorappetite • Insomniaorhypersomnia • Psychomotor agitationorretardation • Fatigueorlossofenergy • Worthlessnessorinapproriateguilt • Problems concentratingormakingdecisions • Thoughtsofdeathorsuicidalideation > > >

35. 2. Heterogeneity of MD • DSM-5 diagnosis ofdepression • Diminishedinterestorpleasure • Depressedmood • Increaseordecrease in eitherweightorappetite • Insomniaorhypersomnia • Psychomotor agitationorretardation • Fatigueorlossofenergy • Worthlessnessorinapproriateguilt • Problems concentratingormakingdecisions • Thoughtsofdeathorsuicidalideation • Diagnosis: 5 / 9 symptoms and at least 1 core symptom • 2 depressedpatientsmay not share a singlesymptom > >

36. 2. Heterogeneity of MD • HAMD: anxiety, genital symptoms, hypochondriasis, insights into the depressive illness • CESD: frequent crying, talking less, perceiving others as unfriendly • BDI: irritability, pessimism, punishment feelings • Huge sample of "depressed" individualswithmassively different problems; potential explanationwhywecannot find biomarkersorefficacioustreatment • Contrastswiththeideaof MD asnaturalkind

37. 2. Heterogeneity of MD • Research study on a sample of 3,700 depressed patients • Goal: countuniquesymptomprofiles • (e.g., "sadmood, suicidalideation, fatigue, insomnia, lossofinterest") • Results: • 1,030 unique symptom profiles in 3,700 patients (3.6 patients per profile) • 83.9% of the profiles were endorsed by five or fewer individuals • 48.6% of the profiles were endorsed by only one individual • The most common symptom profile exhibited a frequency of only 1.8%

38. 3. Comorbidity • The high comorbidity rates of depression with other disorders such as generalized anxiety disorder and PTSD pose another problem for the notion of discrete diseases • Associations of genetic markers with particular mental disorders are small at best, and often not specific to one diagnosis • Dysregulations of glutamate neurotransmission implicated in the etiology of MD, schizophrenia, OCD,andanxietydisorders

39. Assumption 2:MD as common cause for its symptoms

40. Common cause framework • Goes back toinfectiousdiseasesaswell • Disordersitselfare "invisible" (latent)—wecannotobservemeaslesdirectly M

41. Common cause framework • Goes back toinfectiousdiseasesaswell • Disordersitselfare "invisible" (latent)—wecannotobservemeaslesdirectly • Wecanonlyobservethesymptomsofmeasles • Wecanusesymptomstoindicatethepresenceofmeasles s1 M s2 s3

42. Common cause framework • Goes back toinfectiousdiseasesaswell • Disordersitselfare "invisible" (latent)—wecannotobservemeaslesdirectly • Wecanonlyobservethesymptomsofmeasles • Wecanusesymptomstoindicatethepresenceofmeasles • This worksbecausemeaslescausesmeaslessymptoms s1 M s2 s3

43. Common cause framework • The CC frameworkisresponsibleforsymptomchecklists in therestofmedicineandpsychiatry • Weusesymptomliststodeterminethepresenceof an underlyingdisease • The CC frameworkexplainswhysymptomscluster: theyhavethe same causalorigin • Fever, generalizedrash, Koplik'sspots measles! s1 M s2 s3

44. Common cause framework • What does this mean for symptoms? • Symptoms are equivalent & interchangeable indicators of underlying disease ("Assumption of symptom equivalence") • Symptom number, not symptom nature is relevant • Symptoms are "locally independent"; since they are derived from the same common cause, their correlations are spurious 72 W 74 73

45. Common cause framework • What does this mean for symptoms? • Symptoms are equivalent & interchangeable indicators of underlying disease ("Assumption of symptom equivalence") • Symptom number, not symptom nature is relevant • Symptoms are "locally independent"; since they are derived from the same common cause, their correlations are spurious 72 W 74 73

46. Common cause framework • This "measurement detour" of latent variables is very common in psychology because the things we are often interested in cannot be observed directly • Mathematicalintelligence • Measured mathematical IQ via 3 questions • Tests interchangeable • Number of items solved is important • Correlation among items spurious q1 I q2 q3

47. Common cause framework • Depression: useratingscaletomeasuredepressionsymptoms • Most commonscales: • HAMD (1960) • BDI (1961) • CESD (1977)

48. Common cause framework • Depression: useratingscaletomeasuredepressionsymptoms • Most commonscales: • HAMD (1960) • BDI (1961) • CESD (1977) • Add symptomstosum-score. Itdoesn't matter whatparticularsymptomspatientshave (symptomsareinterchangeable) aslongastheyhaveenough. The DSM-5, forinstance, considers 5 (but not 4 or 6) symptomsenoughtowarrant a diagnosis. • Bynowyouunderstandwhythisisproblematic.

49. Assumption 2:evidence?

50. 1. Heterogeneity of symptoms • Itisoddthatonecommoncausetriggers a hugevarietyofvery different problems • HAMD: anxiety, genital symptoms, hypochondriasis, insights into the depressive illness • CESD: frequent crying, talking less, perceiving others as unfriendly • BDI: irritability, pessimism, punishment feelings • Itisoddaswellthatonecommoncausetriggerssymptomaticopposites (insomniavshypersomnia; appetitelossvsgain; psychomotoragitationvsregardation)