Mayo School of Continuous Professional Development Psychiatry Clinical Reviews Depression What Matters and Why? William V. Bobo, M.D., M.P.H. October 6-8, 2016 Intercontinental Chicago Magnificent Mile Chicago, IL
Disclosure Relevant Financial Relationships Research support: AHRQ, Mayo Foundation Off-Label/Investigational Uses None 2016 MFMER 3540366-2
Global burden of mental health and substance use disorders Mental health and substance use disorders affect an estimated 450 million people worldwide. World Health Organization. Investing in Mental Health, 2003 2016 MFMER 3540366-3
Burden of depression in the U.S. and worldwide Estimated lifetime prevalence: 16.9% Estimated 12-month prevalence: 3.2% without comorbid chronic medical illness; 9.3%-23.0% with comorbid chronic medical disease Major depression is fourth-highest cause of disability worldwide By 2020, major depression will be the second-highest cause of disability worldwide Moussavi S et al. Lancet. 2007;370:851-858 Kessler RC et al. Int. J. Methods Psychiatr. Res. 1998;7:33-55 2016 MFMER 3540366-4
Major depressive disorder (DSM-5) Criterion A. Five or more: Depressed mood* Anhedonia* Appetite/weight change Changes in sleep duration Observable psychomotor change Fatigue/loss of energy Feeling worthless, excessive guilt Poor concentration, decision making Suicidality/thoughts of death Criteria B-E: Impairment in >1 life domain Not caused by substance(s) or medical condition(s) Depression not better explained by psychotic illness(es) No evidence of manic or hypomanic episodes American Psychiatric Association, 2013 2016 MFMER 3540366-7
DSM-5 Field Trials in the U.S. and Canada, Part II: Test-Retest Reliability of Selected Categorical Diagnoses Intra-class kappa Regier DA et al. Am. J. Psychiatry. 2013;170:59-70. 2016 MFMER 3540366-8
Clinical heterogeneity and treatment outcome 60% of patients do not fully recover following a single antidepressant trial Personalized treatment approach is therefore needed No single set of assessments predict antidepressant treatment outcome with sufficient validity for routine clinical use Serially conducted therapeutic trials (systematic trialand-error) is the main approach Trivedi MH et al. Am. J. Psychiatry. 2006;163:28-40. Holsboer F. Nat. Rev. Neurosci. 2008;9:638-646. Thase ME. Dialogues. Clin. Neurosci. 2014;16:539-544. Rush AJ et al. Arch. Gen. Psychiatry. 2008;65:870-80. 2016 MFMER 3540366-9
Clinical subtyping in patients with MDD Melancholic depression Psychotic depression Atypical depression Anxious depression (MDD with anxious distress) Seasonal affective disorder (MDD with seasonal pattern) Perinatal depression (MDD with peripartum onset) Single episode, recurrent, chronic Mild, moderate, severe American Psychiatric Association. DSM-5. 2013 Rush AJ. J. Clin Psychiatry. 2007;68 suppl 8:4-10 2016 MFMER 3540366-10
Criteria for clinically significance of MDD subtypes: Unique genetic or neurobiological characteristics Prognostic implications Treatment implications Rush AJ. J. Clin. Psychiatry. 2007;68 (suppl 8):4-10. 2016 MFMER 3540366-11
Clinical importance of psychotic depression Risk factor for bipolar depression 5x the rate of suicide in hospitalized patients with MDE + delusions, vs. MDE without delusions Combination pharmacotherapy (AD + APD) is mainstay Few specific combinations have been studied ECT is especially advocated Very few direct comparisons with combination pharmacotherapy Farahani A, Correll CU. J. Clin Psychiatry 2012;73:486-96. Roose SP et al. Am J Psychiatry 1983;140:1159-62. Parker G, et al. J. Affect. Disord. 1992;24:17-24. Petrides G et al. J ECT. 2001;17:244-253. 2016 MFMER 3540366-12
Pharmacological treatment for psychotic depression Systematic review of 12 RCTs (929 participants) Primary intervention Control Χ 2 =0.0, df=1, I 2 =0.0% Χ 2 =0.2, df=1, I 2 =0.0% Χ 2 =2.1, df=3, I 2 =0.0% Χ 2 =2.8, df=4, I 2 =0.0% APD vs. PLC RR 1.1 (0.7,1.7) AD + APD vs. PLC RR 1.9 (1.2,2.8) AD + APD vs. PLC + APD RR 1.8 (1.4,2.4) AD + APD vs. PLC + AD RR 1.4 (1.1,1.8) 0.2 0.4 0.6 0.8 1 2 4 6 8 10 Favors control Risk Ratio (Clinical Response) Favors primary intervention Wijkstra J et al. Cochrane Datab. Syst. Rev. 2015;CD004044. 2016 MFMER 3540366-13
ECT Remission Rates: Psychotic vs Nonpsychotic Depression Multi-site randomized trial 253 psychotic and non-psychotic MDD patients Bitemporal ECT at 50% above seizure threshold, up to 12 treatments HDRS total score 40 35 30 25 20 15 10 5 0 37.6 * Psychotic 6.9 Δ -30.8 33.7 8.6 Non-psychotic Δ -25.1 Remission rates: Psychotic: 95% Non-psychotic: 83% * Pooled t-test, p<0.0001 Baseline End Petrides G et al. J. ECT. 2001;17:244-253. 2016 MFMER 3540366-14
Misdiagnosis of psychotic major depression Population studies -- prevalence estimates for MDD + hallucinations and/ or delusions: 14 19% of patients with MDD Lifetime population prevalence >2% Samples of hospitalized depressed patients -- up to 25% meeting criteria for psychotic depression (PD) 63% misdiagnosis rate, usually due to missing the psychosis, rather than the mood disorder Rothschild AJ et al. J. Clin. Psychiatry. 2008;69:1293. Ohayon MM et al. Am. J. Psychiatry. 2002;159:1855. Johnson J, et al. J. Nerv. Ment. Dis. 1984;172:521. Coryell W et al. J. Clin. Psychiatry. 2008;69:1293. 2016 MFMER 3540366-15
Psychotic depression: clinical features and questions Delusions are more common than hallucinations or having both delusions and hallucinations (11% vs. 7% vs. 1% of patients with MDE) Pathological guilt Worthlessness Hopelessness Nihilistic thoughts Persecutory themes Fidelity Somatic delusions Ohayon MM, Schatzberg AF. Am. J. Psychiatry. 2002;159:1855-1861. 2016 MFMER 3540366-16
Psychotic depression: clinical probes Are you a good person? Do you feel guilty? Do you deserve to feel this way? Do you feel worthless? Why? Do you feel you are the cause of problems for others? What problems? Why? Have you done things that are unpardonable? Do you feel you (need to be) punished for something you have done? Are you being watched or monitored (spied upon/followed) by anyone? Are you being singled out for any reason? Are you feeling threatened by anyone? Are others trying to do you harm? Do you have something physically wrong with you? Can you explain your concerns to me? What evidence do you have? www.blackdoginstitute.org.au. Rothschild AJ. Biol. Psychiatry. 2003;53:680-690. Zimmerman M, Matia JI. J. Clin. Psychiatry. 1999;60:311. Coryell W. J. Clin. Psychiatry. 1998;69 suppl 1:22-27. 2016 MFMER 3540366-17
Clinical importance of seasonal depression Classical description Recurrent (by definition) Onset usually in Fall, resolution by late Spring Full inter-episode recovery Missed diagnoses Geography prevalence <2% in Florida, 10% in New England Subsyndromal worsening 2-3 times more common Residual subsyndromal depression also common Rosen LN et al. Psychiatry Res. 1990;31:131. Magnusson A. Acta Psychiatr. Scand. 2000;101:176. Bauer MS, Dunner DL. Compr. Psychiatry. 1993;34:159. Westrin A, Lam R. Ann. Clin. Psychiatry. 2007;19:239. 2016 MFMER 3540366-18
The efficacy of light therapy (luminotherapy) in the treatment of mood disorders -1.2-0.8-0.4 0 0.4 0.8 1.2 Favors control Effect Size (Cohen s d) Favors primary intervention Seasonal depression (bright light) Non-seasonal depression (bright light) Non-seasonal depression (adjunctive bright light) Cohen s d=0.84 Cohen s d=0.53 Cohen s d=-0.01 Golden RN et al. Am. J. Psychiatry. 2005;162:656-662. 2016 MFMER 3540366-19
Seasonal depression: missed diagnosis Outcomes of Depression International Network (ODIN) project Diagnostic surveys to assess prevalence and RF s for depression in Europe (n=1,250 respondents) Screen (+) for seasonal depression: n=66 (5.3%) Confirmed (+) for seasonal depression: n=25 (2.4%) Previous diagnosis: n=1 (4%) Previous antidepressant treatment: n=15 (60%) Previous luminotherapy: n=0 (0%) Michalak EE et al. Br. J. Psychiatry. 2001;179:31-34. 2016 MFMER 3540366-20
Forms of depression possibly related to sensitivity to fluctuating gonadal steroid levels Premenstrual dysphoric disorder (PMDD) 5 of 11 symptoms last week of luteal phase, remission within a few days of onset of menstrual flow Post-partum depression (MDD with peripartum onset) Onset of mood symptoms during pregnancy or in the first 4 weeks following delivery Both are risk factors for depression in menopause transition. Epperson CN et al. Am. J. Psychiatry. 2012;169:465. Gehlert S et al. Psychol. Med. 2009;39:129. Bobo WV, Yawn B. Mayo Clin Proc. 2014;89:835. Barth C et al. Front. Neurosci. 2015. 2016 MFMER 3540366-21
Depression in women during midlife: risk of CV mortality A Severe depressive symptoms and/or AD use and their relationship to cardiac events in the Nurses' Health Study, 1991-2000 Risk of CV death: HR 1.49, 95% CI 1.11-2.00 B Whang W et al. J AM Coll Cardiol. 2009;53:950-958. 2016 MFMER 3540366-23
Depression Subtypes in Predicting Antidepressant Response: A Report From the ispot-d Trial A. B. Arnow BA et al. Am. J. Psychiatry. 2015;172:743-750. 2016 MFMER 3540366-24
Features of depression that (may) predict poorer response to antidepressants Chronic (rather than episodic) depression (15-25%) Dysthymic disorder Major depression + dysthymic disorder Chronic major depression Mild depression Clinically significant anxiety Clinically significant (subsyndromal) symptoms Comorbid syndromal anxiety (especially if chronic, e.g., GAD) Holzel L et al. J. Affect. Disord. 2011;129:1-13. Kocsis J. J. Clin Psychiatry. 2003;59:885-892. Fava M et al. Am. J. Psychiatry. 2008;165:342-351. Vohringer P, Ghaemi SN. Clin. Ther. 2011;33:B49-B61. 2016 MFMER 3540366-27
Difference in Treatment Outcome in Outpatients With Anxious Versus Non-anxious Depression in STAR*D A. Time to response B. Time to remission Log-rank statistic=22.7, p<0.0001. Log-rank statistic=41.7, p<0.0001. Fava M et al. Am. J. Psychiatry. 2008;165:342-351. 2016 MFMER 3540366-28
Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis Meta-analysis of 6 randomized trials of FDA-approved AD s for MDD Fournier JC et al. JAMA. 2010;303:47-53. 2016 MFMER 3540366-29
Persisting depression/anxiety and high stress-reactivity with super-imposed major depressive episodes Mania Mild but chronic (and disabling) depression and anxiety/worry Mood Time MDE Nierenberg AA, Ellard KK. Epidemiol. Psychiatr. Sci. 2015;165:342-351. 2016 MFMER 3540366-30
Formulation on the fly: rumination and disengagement Rumination Very common residual symptom Contributes to chronicity and therapy resistance Contents can be anxious, depressive, or both Passive coping Disengagement, isolation, inactivity, excessive distraction, substance use, other escape behavior Leads to feelings of guilt, further reduction in self esteem, increased sense of helplessness Watkins ER. Cogn. Behav. Ther. 2009;38:8-14. Donaldson C, Lam D. Psychol. Med. 2004;34:1309-18. Holtzheimer PE, Mayberg HS. Trends Neurosci. 2011;34:1. Feder A et al. Nat. Rev. Neurosci. 2009;10:446-457. 2016 MFMER 3540366-31
Applications in the clinic Need to actively screen for: Psychosis (especially delusions) Seasonal pattern of onset/resolution and relative exacerbation/alleviation of persisting symptoms Comorbid anxiety disorders and symptoms Chronic, mild depressive disorders can respond to antidepressants, but hard to achieve remission with medication alone Formulation on the fly behaviorally targetable factors that sustain misery but are amenable to change 2016 MFMER 3540366-32