Depressive subtypes and their biological differentiation

Transcription

1 Depressive subtypes and their biological differentiation Femke Lamers, PhD ISCTM Washington DC,19 February 2014

2 Disclosures Employee of: VU medical center/ggz ingeest, Amsterdam Research support from: EU (FP7 grant) Consultant for: - Stockholder in: - Honoraria from: -

3 Heterogeneity of MDD Outline Subtypes of depression: Results from data-driven analysis Clinical correlates Biological correlates Course differences Meaning of findings with respect to treatment Recent developments in treatment/rcts

4 Heterogeneity of MDD is hindering research Current classification systems based on descriptive phenomenology, not on etiology and pathophysiology Phenomenological heterogeneity etiological heterogeneity? Hindering research on MDD: Inconsistent findings Small effect sizes

5 MDD subtypes in literature Starting points for subtyping: 1. Symptom-based: Melancholia, Psychotic (delusional) depression, Atypical depression, Anxious depression 2. Etiology-based: Adjustment disorder with depressed mood, Early trauma, Reproductive depression, Perinatal depression, Organic & druginduced depression 3. Time of onset based: Early vs. late onset, Seasonal affective disorder Meta-review - Baumeister & Parker, J Affect Dis, 2012;139(2):126-40

6 MDD subtypes in literature (2) Meta-review - Baumeister & Parker, J Affect Dis, 2012;139(2):126-40

7 NESDA study Netherlands Study of Depression and Anxiety Naturalistic cohort study with assessments at baseline & after 2, 4, 6, 9 years 2,981 subjects (1979,1002 ), years Recruited in community, primary + specialized care Includes - controls (n=652) - depression patients (MDD, dysthymia) - anxiety patients (Panic, Social Phobia, Agora, GAD) (Penninx et al. Int J Meth Psychiatr Res 2008;17: /

8 Subtype identification sample Baseline data N=818 persons with a 1 month dx of depression or minor depression Input for data-driven analysis (latent class analysis): CIDI symptoms & selection of IDS symptoms: lack of responsiveness, quality of mood, mood worst in morning, early morning awakening, interpersonal sensitivity, leaden paralysis

9 LCA NESDA - Results CIDI IDS Severe Melancholic (46.3%) Severe Atypical (24.6%) Moderate (29.1%) (Lamers et al J Clin Psych 71: )

10 Correlates depression subtypes Severe Melancholic N=379 Severe Atypical N=201 Moderate N=238 P-value Female sex 65.4 % 73.1 % 63.4 %.08 Age of onset, median Duration (nr of months) <.001 Subthreshold manic symptoms 10.3 % 9.5 % 4.6 %.04 1st degree family history MDD 86.4 % 83.8 % 72.9% <.001 Comorbid panic disorder 31.1 % 37.3 % 16.8 % <.001 Comorbid social phobia 36.9 % 35.3% 20.2 % <.001 Comorbid GAD 37.2 % 31.3 % 18.5 % <.001 Neuroticism (NEO-FFI) <.001

11 Melancholic Environmental stress & smoking Psychosocial functioning Severe Melancholic Severe Atypical A vs M OR (95%CI) Childhood trauma index, median ( ) Negative life events, median ( ) Life style Current smoking, % 52.8% 36.8% 0.57 ( )

12 BMI Atypical - More metabolic disturbances * 25.4 Atypical vs. Melancholic (ref) 20 OR (95%CI) 15 Metabolic syndrome 2.17 ( ) 10 Waist circumference 2.30 ( ) 5 Triglycerides 1.93 ( ) 0 Severe Melancholic Severe Atypical Moderate *p<.05

13 Differences in biological measures? HPA axis (Stetler et al., Psychosom Med, 2011) Depression (Hiles et al., Brain, Behavior & Immun, 2012; Dowlati et al., Biol Psych, 2010; Howren et al., Psychosom Med, 2009)

14 Groups: Methods Biological measures NESDA Melancholic depression Atypical depression Controls Outcomes: Salivary cortisol (cortisol awakening curve) Inflammatory markers: C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor necrotic factor- (TNF- )

15 Cortisol (nmol/l) Cortisol (nmol/l) Cortisol in MDD & subtypes Current MDD (n=701) Remitted MDD (n=579) Controls (n=308) Control n=393 Melancholic n=66 Atypical n= awakening 30 min 45 min 60 min Vreeburg et al. Arch Gen Psychiatry 2009;66: Lamers et al., Mol Psych, 2013; 18(6):692-9 Stable Melancholic vs. Stable Atypical Stable Melancholic vs. Control AUCi p=ns; AUCg p=.001 AUCi p=ns; AUCg p=.002

16 Inflammation in MDD & subtypes CRP (mg/l) TNF-α (pg/ml) IL-6 (pg/ml) controls remitted MDD current MDD 0 controls remitted MDD current MDD 0 controls remitted MDD current MDD Vogelzangs et al. Trans Psych, 2012;2,e79 2 * 1.2 * 1.2 * 1.5 * * * Control Melancholic Atypical 0 Control Melancholic Atypical 0 Control Melancholic Atypical * p<.01 Lamers et al., Mol Psych, 2013; 18(6):692-9

17 Findings cortisol & inflammation other studies (Penninx et al., BMC Medicine, 2013;11;129)

18 Course differences melancholic/atypical? 2, 4 & 6 yr FU data Suicidal thoughts Onset diabetes atypical depression vs moderate depression p=0.01, Lamers et al, in progress

19 Two different clinical entities? MELANCHOLIC DEPRESSION Pathophysiology: environmental stress (?), smoking, hyperactivity HPA-axis ATYPICAL DEPRESSION Pathophysiology: increased inflammation/ MetSyn/ obesity Different genes? Different treatment? Different genes? Different treatment?

20 Inflammatory + metabolic dysregulations impair treatment response Adjusted risk of 2-year chronicity of depression among antidepressant users (N=315) 2-year chronicity of depression OR 95%CI p High CRP High interleukin Abdominal obesity Hypertriglyceridemia Low HDL cholesterol Hypertension Hyperglycemia Vogelzangs et al. Neuropsychopharm. in press

21 Anti-inflammatory agents as tx? 60 outpatients with treatment-resistant depression on antidepressants (n=37) or medication-free (n=23) 12-week RCT: - 3 infusions of TNF-antagonist infliximab - placebo Raison et al, JAMA Psychiatry 2013:70(1):31-41

22 NSAIDs as add-on tx? 40 MDD patients (HAM-D 18) 6-wk RCT : - sertraline + Cox-2 inhibitor (Celecoxib) - sertraline + placebo Abassi et al. J Affect Dis 2012;141:

23 NSAIDs as add-on tx? Meta-analysis adjunctive celecoxib tx in MDD Na et al. Prog Neuropsychopharmacol Biol Psychiatry, 2014:48:79-85

24 Take-home messages Atypical and melancholic depression represent two groups with different background characteristics, including biological differences Take MDD heterogeneity into account! Inflammation (=atypical depression(?)) seems to be associated with poorer treatment response and seems an important target for treatment

25 thanks to: