Depressive subtypes and their biological differentiation Femke Lamers, PhD ISCTM Washington DC,19 February 2014 Disclosures • Employee of: VU medical center/GGZ inGeest, Amsterdam • Research support from: EU (FP7 grant) • Consultant for: - • Stockholder in: - • Honoraria from: - Outline • Heterogeneity of MDD • 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 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 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 & drug- induced 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 MDD subtypes in literature (2) Meta-review - Baumeister & Parker, J Affect Dis , 2012;139(2):126-40 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 ♂), 18-65 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;17:121-140/ www.nesda.nl) 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 LCA NESDA - Results 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 CIDI IDS Severe Melancholic (46.3%) Severe Atypical (24.6%) Moderate (29.1%) (Lamers et al. 2010 J Clin Psych 71:1582-1589) Correlates depression subtypes Severe Melancholic Severe Atypical Moderate P-value N=379 N=201 N=238 Female sex 65.4 % 73.1 % 63.4 % .08 Age of onset, median 25 22 28 .002 Duration (nr of months) 18.7 18.2 9.6 <.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) 44.4 44.4 38.7 <.001 Melancholic – Environmental stress & smoking Severe Severe A vs M Melancholic Atypical OR (95%CI) Psychosocial functioning Childhood trauma index, median 0.4 0.2 0.86 (0.74-1.00) Negative life events, median 1 0.6 0.87 (0.73-1.04) Life style Current smoking, % 52.8% 36.8% 0.57 (0.39-0.84) Atypical - More metabolic disturbances 30 28.3 * 25.3 25.4 25 Atypical vs. Melancholic (ref) 20 OR (95%CI) 15 Metabolic syndrome 2.17 (1.38-3.42) BMI 10 Waist circumference 2.30 (1.59-3.35) 5 Triglycerides 1.93 (1.25-2.99) 0 Severe Severe Moderate Melancholic Atypical *p<.05 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) Methods Biological measures NESDA Groups: • 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-) Cortisol in MDD & subtypes Current MDD (n=701) Remitted MDD (n=579) Controls (n=308) Control n=393 Melancholic n=66 Atypical n=82 24 24 22 22 /l) 20 20 nmol 18 18 16 16 Cortisol ( Cortisol Cortisol (nmol/l) Cortisol 14 14 12 12 0 15 30 45 60 awakening 30 min 45 min 60 min Vreeburg et al. Arch Gen Psychiatry 2009;66:617-626 Lamers et al., Mol Psych, 2013; 18(6):692-9 Stable Melancholic vs. Stable Atypical AUCi p=NS; AUCg p=.001 Stable Melancholic vs. Control AUCi p=NS; AUCg p=.002 Inflammation in MDD & subtypes CRP (mg/l) TNF-α (pg/ml) IL-6 (pg/ml) 2 1.2 1.2 1 1 1.5 0.8 0.8 1 0.6 0.6 0.4 0.4 0.5 0.2 0.2 0 0 0 controls remitted MDD current MDD controls remitted MDD current MDD controls remitted MDD current MDD Vogelzangs et al. Trans Psych, 2012;2,e79 1.2 2 * 1.2 * * * 1 1 1.5 * * 0.8 0.8 1 0.6 0.6 0.4 0.4 0.5 0.2 0.2 0 0 0 Control Melancholic Atypical Control Melancholic Atypical Control Melancholic Atypical * p<.01 Lamers et al., Mol Psych, 2013; 18(6):692-9 Findings cortisol & inflammation other studies (Penninx et al., BMC Medicine, 2013;11;129) 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 Two different clinical entities? MELANCHOLIC ATYPICAL DEPRESSION DEPRESSION Pathophysiology: Pathophysiology: environmental stress (?), increased inflammation/ smoking, hyperactivity MetSyn/ obesity HPA-axis ↓ ↓ Different genes? Different genes? Different treatment? Different treatment? 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 1.33 0.83-2.14 .23 High interleukin-6 2.18 1.35-3.52 .001 Abdominal obesity 0.92 0.56-1.52 .75 Hypertriglyceridemia 1.78 1.01-3.14 .05 Low HDL cholesterol 2.08 1.09-3.99 .03 Hypertension 0.70 0.40-1.23 .22 Hyperglycemia 2.44 1.25-4.79 .01 Vogelzangs et al. Neuropsychopharm. in press 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 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;141:308-312 NSAIDs as add-on tx? • Meta-analysis adjunctive celecoxib tx in MDD Na et al. Prog Neuropsychopharmacol Biol Psychiatry, 2014:48:79-85 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 thanks to: Email: [email protected] www.nesda.nl .