1. Eiko Fried University of Leuven, Belgium 1 "The differential impact of individual depression symptoms on impairment of psychosocial functioning"

2. Major Depressive Disorder (MDD) Prevalent (Kessler et al., 2003) Recurrent (McClintock et al., 2010) Costly (Lopez et al., 2006) 2Introduction

3. Depression symptoms DSM-5 MDD diagnosis: 1.Diminished interest or pleasure 2.Depressed mood 3.Increase or decrease in either weight or appetite 4.Insomnia or hypersomnia 5.Psychomotor agitation or retardation 6.Fatigue or loss of energy 7.Worthlessness or inapproriate guilt 8.Problems concentrating or making decisions 9.Thoughts of death or suicidal ideation 3Introduction

4. Depression symptoms DSM-5 MDD diagnosis: 1.Diminished interest or pleasure 2.Depressed mood 3.Increase or decrease in either weight or appetite 4.Insomnia or hypersomnia 5.Psychomotor agitation or retardation 6.Fatigue or loss of energy 7.Worthlessness or inapproriate guilt 8.Problems concentrating or making decisions 9.Thoughts of death or suicidal ideation 4Introduction > > >

5. Disease model 5Introduction

6. Disease model Depression is a latent disorder 6Introduction D D s1 s2 s3 s4 s5

7. Disease model Depression is a latent disorder Depression is the common cause of its symptoms 7Introduction s1 s2 s3 s4 s5 D D

8. Disease model Depression is a latent disorder Depression is the common cause of its symptoms Measure MDD symptoms and use them to indicate presence of depression 8Introduction s1 s2 s3 s4 s5 D D

9. Disease model Consequences: Symptoms are passive indicators Symptoms are interchangeable: irrelevant what particular symptoms a person has (DSM: 5/9) – Symptom number, not symptom nature matters This disease model justifies adding up symptoms to sum-scores 9Introduction s1 s2 s3 s4 s5 D D

10. Disease model Common-cause model implausible considering the pronounced symptomatic variability among MDD patients > 1500 unique symptom profiles qualifying for DSM-5 MDD diagnosis Alternative: understand symptoms as distinct entities worth studying individually Prior research: symptoms differ from each other in important aspects – Symptoms have different risk factors (Fried et al., 2013) – Symptoms differ in their genetic background (Kendler et al., 2013; Myung et al., 2012) – Symptoms and their impact on impairment psychosocial functioning (Fried & Nesse, 2014) 10Introduction

11. Depression & impairment Majority of MDD patients: moderate to severe impairment (Kessler et al., 2003) Impairment long-lasting and affects various domains of living (e.g., home, workplace, friendships) (Hays et al., 1995; Hirschfeld et al., 2002) Unknown whether individual symptoms differ in their impact on impairment 11STAR*D: impaired functioning

12. Methods NIMH dataset: "Sequenced Treatment Alternatives to Relieve Depression" (STAR*D) Enrollment stage: 3,703 MDD outpatients – Cross-sectional – Age M ~ 41, ~ 60% female – No antidepressants Goal: test the impact of MDD symptoms on impairment – Depression symptoms (QIDS-16) (e.g., insomnia & hypersomnia) – Psychosocial impairment (WSAS); example question: "Because of my depression, my ability to work is impaired" 12STAR*D: impaired functioning

13. Question 1 Do symptoms have differential effects on impairment? H1 - heterogeneity model: IMPAIRMENT ~ S 1 + S 2 + S 3... AGE + SEX vs. H0 - homogeneity model: IMPAIRMENT ~ S 1 + S 2 + S 3... AGE + SEX 13STAR*D: impaired functioning differential impact equal impact

14. Question 1 H1 - heterogeneity model: IMPAIRMENT ~ S 1 + S 2 + S 3... AGE + SEX H0 - homogeneity model: IMPAIRMENT ~ S 1 + S 2 + S 3... AGE + SEX  ² diff = 394.5, df diff = 13 p < 0.001 R² = 41% 14STAR*D: impaired functioning Do symptoms have differential effects on impairment? – Yes.

15. Question 2 How much variance of impairment does each individual symptom explain? Relative importance analysis Impairment, total variance = 100% 15STAR*D: impaired functioning

16. Question 2 How much variance of impairment does each individual symptom explain? Relative importance analysis Impairment, total variance = 100%Variance explained by symptoms R ² = 41% 16STAR*D: impaired functioning

17. Question 2 How much variance of impairment does each individual symptom explain? Relative importance analysis 100% S1 20% S2 10% S4 40% S3 30% Impairment, total variance = 100% 17STAR*D: impaired functioning

18. 18 Symptoms vary dramatically in their explained variance of impairment Coefficients within compound symptoms differ from each other – Slowed vs. agitated p < 0.05 < <

19. Question 3 Do symptoms vary in their associations across 5 impairment subdomains? – work, home, social activities, private activities, close relationships – Yes –  ² diff = 299.8 (df diff = 56); p < 0.001 19STAR*D: impaired functioning

20. 20 D1: work; D2: home; D3: social act.; D4: private act.; D5: relationships fatigue interest loss

21. 21 D1: work; D2: home; D3: social act.; D4: private act.; D5: relationships s5: sad mood s8: concentration probl.

22. Results question 3 sad mood and concentration problems were among the four most debilitating symptoms in all domains Comparably strong impacts: – early insomnia >> work self-blame >> close relationships interest loss >> social activities fatigue >> home management Comparably weak impacts: – interest loss >> work fatigue >> close relationships sad mood >> home management conc. problems >> social activities & close relationships 22STAR*D: impaired functioning

23. Conclusions Some depression symptoms are much more impairing than others – Two MDD patients with similar symptom sum-scores potentially suffer from different levels of impairment Analyses of individual symptoms reveal important clinical information that are obfuscated by analyses of sum-scores 23STAR*D: impaired functioning

24. Implications Main problems of modern psychiatry – Antidepressants only marginally efficacious compared to placebos (Kirsch et al., 2008; Pigott et al., 2010; Turner et al., 2008) – "Questionable" reliability of MDD diagnosis in DSM-5 field trials (Regier et al., 2013) – In the largest GWAS study with > 34,000 subjects, no single locus was significantly associated with depression diagnosis (Hek et al., 2013; see also: Lewis et al., 2010; Shi et al., 2011; Wray et al., 2012) Current psychiatric research and practice lumps individuals suffering from a wide range of disparate symptoms into one undifferentiated category, obfuscating dramatic differences between patients diagnosed with MDD. 24STAR*D: impaired functioning

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