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. Rakesh Jain, MD, MPH Recent Advances In Neurobiology &Treatment Of Major Depression Associate Clinical Professor Department of Psychiatry & Beh. Sciences.

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Presentation on theme: ". Rakesh Jain, MD, MPH Recent Advances In Neurobiology &Treatment Of Major Depression Associate Clinical Professor Department of Psychiatry & Beh. Sciences."— Presentation transcript:

1 . Rakesh Jain, MD, MPH Recent Advances In Neurobiology &Treatment Of Major Depression Associate Clinical Professor Department of Psychiatry & Beh. Sciences University of Texas Medical School Houston, Texas Assistant Clinical Professor Department of Psychiatry Texas Tech Medical School Midland, Texas Director, Psychiatric Drug Research Adult, Child and Adolescent R/D Clinical Research, Inc Lake Jackson, Texas

2 MajorDepression Bio Psycho Social A 20 th Century Clinician’s View of Depression (“so yesterday… !”)

3 For the 21 st Century’s Clinician – A New Way to Look at Depression Schloesser RJ, et.al.2008.Neuropsychopharmacology Reviews 33: Cellular Cell growth/survival/death Cell morphology: dendritic remodeling Molecular Susceptibility genes Protective genes Transcription factors mRNA Systems Critical neuronal circuitry Behavior Cognitive/Affective/Sensorymotor Environment Neurotransmission: Neurotransmitters and Neuropeptides Synaptic connectivity Environmental factors (including external environment: psychosocial stressors, sleep deprivation, internal environment gonadal/HPA steriods) PKC & MARCKS GSK-3 & substrates CREB & BDNF ERK MAP kinase Bcl-2 family of proteins) HPA = Hypothalamic-Pituitary-Adrenal; PKC = protein kinase C; MARCKS = myristoylated alanine-rich C kinase substrate; GSK = glycogen synthase kinase; CREB = cAMP responsive element binding; BDNF = brain-derived neurotrophic factor; ERK = extracellular signal regulated kinase; MAP = mitogen activated protein

4 Another Issue in Attempting Optimization of Outcomes – Appreciating the Cumulative Effect of Risk Factors on Depression Study included 196 children (109 maltreated and 87 nonmaltreated controls) Adapted from: Kaufman J, et al. Biol Psychiatry. 2006;59(8): Risk Factors Mood and Feeling Questionnaire (MFQ) Depression Scores Controls (nonmaltreated)History of maltreatment 5-HTTLPR s/sBDNF val66met Low social support

5 Childhood Adversity Represents a Risk for Adulthood Disease Major depression (panel 1): z=4.94, P<.001. High-sensitivity C-reactive protein (hsCRP) level  3 mg/L (panel 2): z=3.24, P=.001. Clustering of metabolic risk markers (panel 3): z=4.58, P<.001.  1 age-related disease risks (panel 4): z=5.66, P<.001. Adapted from Danese A, et al. Arch Pediatr Adolesc Med. 2009;163(12): year prospective study. Panel 1: Major Depression Panel 2: hsCRP >3 mg/L Panel 3: Clustering of Metabolic Risk Markers Panel 4: ≥1 Disease Risk Number of Adverse Childhood Experiences % of Study Members With the Condition ≥2 (n=98) (n=502) 1 (n=253)

6 Schloesser RJ, et al. Neuropsychopharmacology. 2008;33(1): Reprinted with permission from Macmillan Publishers Ltd. Cingulate gyrus Thalamus Hippocampus Amygdala Nucleus accumbens Prefrontal cortex (PFC) Limbic Structures and Paralimbic Cortex Anterior cingulate cortex (ACC)

7 Schloesser RJ, et.al.2008.Neuropsychopharmacology Reviews 33: ` Macro and Microscopic Structures Involved in Mood Disorders

8 Compromised neurotrophic support may alter synaptic structure in mood disorders 1. Manji HK, et al. Biol Psychiatry. 2003;53: Nestler EJ, et al. Neuron. 2002;34: Hippocampal Pyramidal Neurons Micrograph 1 Depression Reduced dendritic arborization Graphic representation 2 Normal dendritic arborization

9 Correlation Between Hippocampal Volume and Duration of Untreated Depression * Sheline YI, et al. Am J Psychiatry. 2003;160(8): Female Outpatients With Recurrent Depression in Remission Days of Untreated Depression Total Hippocampal Volume (mm 3 ) R 2 =.28 *P=.0006 n= *Significant inverse relationship between total hippocampal volume and the length of time depression went untreated.

10 Decreased Activity in Dorsolateral PFC and Dorsal ACC in Patients With MDD Areas of increased activation in patients with MDD at rest red and decreased activation blue compared with controls Increased activity: lateral orbital PFC, ventromedial PFC, amygdala, thalamus, caudate Decreased activity: dorsolateral PFC, insula, pregenual and dorsal ACC, superior temporal gyrus Fitzgerald PB, et al. Hum Brain Mapp. 2008;29(6): Reprinted with permission from John Wiley & Sons, Inc.

11 There Was a Correlation Between Gray Matter Volumetric Changes in MDD and Clinical Symptoms MADRS=Montgomery-Asberg Depression Rating Scale. VBM=voxel-based morphometry. Vasic N, et al. J Affect Disord. 2008;109(1-2): Reprinted with permission from Elsevier Limited. Comparison of 15 Subjects With MDD and 14 Healthy Controls Regions showing a negative correlation between gray matter concentration and depression severity p<0.05 Adjusted VBM Responses, Medial Orbital PFC (Brodmann Area 11) MADRS Score Adjusted VBM Responses, Dorsolateral PFC (Brodmann Area 46) MADRS Score r=-0.53r=-0.57

12 Neuroendocrine, Autonomic, and Immune Dysregulation in MDD CRH=corticotropin-releasing hormone. NF-κB=nuclear factor kappa B. ACTH=adrenocorticotropic hormone. Miller AH, et al. Biol Psychiatry. 2009;65(9): Reprinted with permission from Elsevier Limited.

13 Inflammatory Cytokine Levels Were Associated With Symptom Severity in Patients With MDD Comparison of 5 Patients With MDD and 5 Matched Healthy Controls *Correlations of IL-6 with guilt, self-esteem, and suicidal thoughts remained significant after Bonferroni correction. VAS=Visual Analog Scale. Adapted from Alesci S, et al. J Clin Endocrinol Metab. 2005;90(5): Daily Mean VAS Score (mm) A. Concentration R 2 = P=.05 B. Guilt R 2 = P=.004* C. Sadness R 2 = P=.02 Daily Mean VAS Score (mm) D. Self-Esteem R 2 =0.735 P=.002* Daily Mean Log IL-6 (pg/mL) E. Suicidal Thoughts R 2 = P=.0007* Daily Mean Log IL-6 (pg/mL) F. Tiredness R 2 =0.566 P=.02 Daily Mean Log IL-6 (pg/mL)

14 Implications of Residual Symptoms

15 Adapted from Lespérance F, et al. Circulation. 2002;105(9): Depression Decreased Long-Term Survival After Myocardial Infarction (MI) Days Postdischarge After MI Long-Term Survival After MI in Relation to Beck Depression Inventory (BDI) Score During Hospitalization Cardiac Death-Free Survival (%) BDI <5 BDI 5 to 9 BDI 10 to 18 BDI ≥ N=896

16 Depression and MI – Importance of Depression and its Optimum Treatment Jonge P, et.al. Am J Psychiatry 2007;164: ; MI = myocardial infarction Event Rate: Non-responders = 25.6 % Untreated controls = 11.2 % Responders = 7.4 % data derived from MIND-IT study, participants had post-MI depression

17 Cellular and Molecular Changes in MDD

18 The Tripartite Synapse: The Role of Astroglia in Signaling Halassa MM, et al. Trends Mol Med. 2007;13(2): Reprinted with permission from Elsevier Limited.

19 Glia-Neuron Interaction May Influence Neurotrophic Factors 5-HT=serotonin. BDNF=brain-derived neurotrophic factor. CNS=central nervous system. GLU=glutamate. IDO=indoleamine 2,3 dioxygenase. IFN=interferon. IL=interleukin. NMDA=N-methyl-D-aspartate. QUIN=quinolinic acid. RNS=reactive nitrogen species. ROS=reactive oxygen species. TNF=tumor necrosis factor. TRP=tryptophan. Miller AH, et al. Biol Psychiatry. 2009;65(9): Reprinted with permission from Elsevier Limited.

20 P=.005 OFC=orbitofrontal cortex. Adapted from Rajkowska G, et al. Biol Psychiatry. 1999;45(9): Decreased Glial Density in Dorsolateral PFC and OFC in Patients With MDD Dorsolateral PFC Brodmann Area 9 Number of Glial Nuclei/mm 3 x ControlWith Depression Caudal OFC Brodmann Area 47 4 P=.006 Number of Glial Nuclei/mm 3 x ControlWith Depression

21 Altered ACC Pyramidal Cell Dendritic Arborization in MDD *Significant decrease in number of branches and total branch length at branch order 3 in depressed suicides. Adapted from Hercher C, et al. J Psychiatr Res. [Epub ahead of print]. Reprinted with permission from Elsevier Limited. Postmortem study of layer VI ACC pyramidal neurons in 12 depressed suicide subjects vs 7 sudden-death controls Branch Order Number of Branches A Controls Depressed suicides * Branch Order Total Branch Length (µm) B Controls Depressed suicides *

22 Reduced Neuronal Size in OFC of Patients With MDD Adapted from Rajkowska G. Prog Brain Res. 2000;126: Reprinted with permission from Elsevier Limited. III II I I III IV V VI White Matter Layer Pia Distance from Pia (µm) ControlWith Depression I Rostral OFC [3H] 8-OH-DPAT

23 Integrated Mind-Body Perspective of MDD— Treatment Implications

24 Depressed mood Decreased interest or pleasure Significant appetite or weight change Fatigue Insomnia or hypersomnia Psychomotor disturbances Worthlessness/guilt Impaired concentration Thoughts of death/suicide A Clinician’s View Of Major Depression: 16 out of 9 symptoms! (And, all are important to the Clinician) APA. DSM-IV-TR. 2000:352,356. Irritability Brooding Pain Tearfulness Anxiety or phobias Obsessive rumination Associated symptoms Excessive worry over physical health Excessive worry over physical health DSM-IV diagnostic criteria

25 Treatment May Improve Cerebral Activity in Patients With MDD Fitzgerald PB, et al. Hum Brain Mapp. 2008;29(6): Reprinted with permission from John Wiley & Sons, Inc.

26 Relationship Between Change in BDNF Levels, Duration of Treatment, and Treatment Response in Patients With MDD Meta-regression based on 10 case control and 13 clinical trial studies assessing 1504 subjects r=0.65 P=.02 r=0.52 P=.01 Adapted from Brunoni AR, et al. Int J Neuropsychopharmacol. 2008;11(8): Change in BDNF (Effect Size) BDNF Change vs Depression ImprovementBDNF Change vs Days of Treatment Cohen’s d for Depression Study analyzed (weighted by inverse variance) Period of Treatment (Days) 80 Study analyzed (weighted by inverse variance)

27 Impact of Cognitive Therapy on Amygdala and Prefrontal (Dorsolateral PFC) Activity in MDD Adapted from DeRubeis RJ, et al. Nat Rev Neurosci. 2008;9(10): Reprinted with permission from Macmillan Publishers Ltd. 12 Weeks of Cognitive Therapy Time (Seconds) BOLD Signal (% Change) Time (Seconds) BOLD Signal (% Change) Pre Post Control a. Emotionalb. Cognitive Is it you? UGLY Put the digits in numerical order Patients with depression (n=9) Controls (n=24)

28 Neurobiology of Exercise – A Complex Cascade Dishman RK et al. (2006), Obesity 14(3): ; VTA = ventral tegmental area; ROS = reactive oxygen species; WAT = white adipose tissue; NFKB = nuclear factor kappa B; ANS = autonomic nervous system ; CVD = cardiovascular disease Function Disease Structure Executive Controls Prefrontal & Cingulate Cortex Executive Controls Prefrontal & Cingulate Cortex Emotional Controls Amygdala, Prefrontal Cortex Emotional Controls Amygdala, Prefrontal Cortex External Input Visual Olfactory Acoustic Gustatory Somatosensory External Input Visual Olfactory Acoustic Gustatory Somatosensory ANS & Endocrine Systems ANS & Endocrine Systems DA ↓ Parkinson’s Disease ↑ ROS DA ↓ Parkinson’s Disease ↑ ROS Alzheimer’s Dementia Schizophrenia Depression Sleep Disorders Obesity Diabetes CVD Immune Disorder IBD, Constipation Colon Cancer Learning & Memory Immune Control Gastrointestinal Control Muscle Cardiovascular Consequences Cardiovascular Consequences Metabolic Consequences Liver, WAT, Pancreas Metabolic Consequences Liver, WAT, Pancreas Thermal Consequences Behavior Social Sexual Coping Addictive Escape Fight & Flight Stress Sleep Ingestive Behavior Social Sexual Coping Addictive Escape Fight & Flight Stress Sleep Ingestive Motor Controls Motor Cortex Striatum, Brainstem, Cerebellum, Spinal Cord Motor Controls Motor Cortex Striatum, Brainstem, Cerebellum, Spinal Cord Motivational Controls Reward, Wanting, Selection Hypothalamus, Accumbens, VTA Motivational Controls Reward, Wanting, Selection Hypothalamus, Accumbens, VTA Cognitive Controls Hippocampus, Cortex Cognitive Controls Hippocampus, Cortex Neural Primary Afferents Neural Primary Afferents “Exercise” Internal Feedback “Consequences of exercise” Internal Feedback “Consequences of exercise” Humoral Factors CNS Energy Balance Repair Plasticity Protection Neurogenesis Transcription NA, 5- HT,GABA, Glutamate, Glycine BDNF/TrkB ERK/CREB NFKB Repair Plasticity Protection Neurogenesis Transcription NA, 5- HT,GABA, Glutamate, Glycine BDNF/TrkB ERK/CREB NFKB

29 Fitness & Hippocampal Volume – Further Reason to bring Exercise into our R x Plan Erikson Ki, et.al. Hippocampus (ahead of publication) Scatterplots showing increase in fitness (VO 2 peak) is related to increase in hippocampal volume cm 3 Correlations significant for both left and right (even after including age, sex, years of education as covariates)

30 Track…Track…Track… Monitor…Monitor…Monitor

31 BT - before Treatment AT - after treatment Anti-depressant Treatment and Effects on Pro- & Anti-inflammatory Cytokines Hamilton Depression Rating Scale – scores before and after treatment Interleukin-12 (IL-12) levels Interleukin-4 (IL-4) levels Sutcigil L, et.al. Clinical and Developmental Immunology BTAT BTAT IL-12 (pg/ml) HDRS IL-4 (pg/ml)

32 Relationship between Depression, & Inflammatory Cytokines and Neurotrophic Factors Yoshimura R, et.al. Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 722–726 Positive co-relationship between depression and IL-6 Negative co-relationship between depression and BDNF R 2 =.376 P=.0062 R 2 = P=.0012

33 Treatment Guidelines

34 o If no response and clinical severity warrants, consider the following: Increase in dose of medication Increase in intensity of psychotherapy ECT o If no response and clinical severity warrants, consider the following: Increase in dose of medication Increase in intensity of psychotherapy ECT No Response o If patient is currently receiving medication, consider: Changing antidepressant Adding or changing to psychotherapy ECT o If patient is currently receiving psychotherapy, consider: Adding or changing to medication No Response o If patient is currently receiving medication, consider: Changing antidepressant Adding or changing to psychotherapy ECT o If patient is currently receiving psychotherapy, consider: Adding or changing to medication Acute Phase Treatment of Major Depressive Disorder Start of Trial: Medication and/or Psychotherapy Start of Trial: Medication and/or Psychotherapy 4-8 Weeks: Reassess Adequacy of Response APA Practice Guidelines Monitor:  Degree of danger to self or others  Symptomactic status  Functional status  Response to treatment  Side effects  Compliance  Signs of switch to mania  Other mental disorders, including alcohol and substance abuse  General medical comorbidities Monitor:  Degree of danger to self or others  Symptomactic status  Functional status  Response to treatment  Side effects  Compliance  Signs of switch to mania  Other mental disorders, including alcohol and substance abuse  General medical comorbidities No Response o If patient is currently receiving medication, consider: Changing antidepressant Adding or changing to psychotherapy ECT o If patient is currently receiving psychotherapy, consider: Adding or changing to medication No Response o If patient is currently receiving medication, consider: Changing antidepressant Adding or changing to psychotherapy ECT o If patient is currently receiving psychotherapy, consider: Adding or changing to medication Partial Response o If patient is currently receiving medication, consider: Changing dose Augmenting antidepressant Changing antidepressant Adding or changing to psychotherapy ECT o If patient is currently receiving psychotherapy, consider: Changing intensity of psychotherapy Changing type of psychotherapy Adding or changing to medication Full Response Go to Continuation Phase Treatment Full Response Go to Continuation Phase Treatment

35 First-Line Antidepressants: Guidelines CANMATAPA SNRIsDesvenlafaxine, duloxetine, venlafaxine SSRIsCitalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline TCAsAmitriptyline, doxepin, imipramine, nortriptyline, protriptyline, maprotiline trimipramine Serotonin modulatorsNefadozone, trazodone Norepinephrine- serotonin modulator Mirtazapine MAOIsMoclobemideIsocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine DNRIBupropion APA = American Psychiatric Association; TCA = tricyclic antidepressant; MAOI = monoamine axidase inhibitor; DNRI = dopamine norepinephrine reuptake inhibitor American Psychiatric Association. Am J Psychiatry. 2010;[in press]. Lam RW, et al. J Affect Disord. 2009;117(Suppl 1):S26-S43.

36 TMAP Depression Algorithms: Strategies for the Treatment of Major Depression (Non-psychotic) 2008 version Stage 0 Patient Assessment & Discussion of Treatment Option Patient Assessment & Discussion of Treatment Option (cont.) TMAP Guidelies, accessed https://www.dshs.state.tx.us/mhprograms/pdf/timamdd1algo.pdf Discuss EBPT as an option Discuss EBPT as an option EBPT = Evidence Based Psychotherapy. EBPT is an option before starting pharmacotherapy, or in combination with pharmacotherapy at any stage in the algorithm Stages 1-8 follow

37 Stage 1 A SSRIs, BUP SR/XL MRT, SNRIs SSRIs, BUP SR/XL MRT, SNRIs (cont.) Response Continuation If Non-response, move to Stage 2 Partial Response Augment with one of the following- SSRI, SNRI, BUP, MRT, BUS, or T 3 (choose different MOA from Stage 1) Stage 1 TMAP Depression Algorithms: Strategies for the Treatment of Major Depression (Non- Psychotic) 2008 version TMAP Guidelies, accessed https://www.dshs.state.tx.us/mhprograms/pdf/timamdd1algo.pdf; BUP = bupropion; MRT = mirtazapine; BUS= buspirone; T 3 = liothyronine; MOA = mechanism of actionhttps://www.dshs.state.tx.us/mhprograms/pdf/timamdd1algo.pdf

38 TMAP Advice on Critical Issues Visit Frequency – at 2, 4, 6, 9 and 12 weeks (more if indicated.) Assessment Frequency – each visit – core symptoms, functional impairment, side-effect severity. A scale, such as QIDS-16 should be administered. Criteria for Medication Change - many factors. QIDS-16 response criteria are as follows – non-response 9 or greater, partial response 6-8, full response/remission 5 or less Medication Switching – cross taper is recommended Medication Doses – ranges provided Documentation – uniform documentation is an important component of the algorithm

39 ‘Enhanced’ Care: An Update for the 21 st Century Clinician

40 Enhanced Care is Effective, Has long term benefits, and is Generalizeble Across Different Clinical Settings Unutzer J, et.al JAMA 2002;288: ; Hunkeler EM, et.al. BMJ 2006:332: Results from IMPACT study Impact Intervention n= 906 Usual Care n= 895 Longer Term Benefits Works Across Settings

41 Algorithm-Based Care has better Outcomes as compared to Treatment as Usual Trivedi MH, et.al. Arch Gen Psychiatry 2004;61: Patient Self-Report of Depressive Symptoms in Algorithm-Based vs. Usual Care Clinical Ratings of Depressive Symptoms in Algorithm-Based vs. Usual Care

42 Patients Discontinue Medication for Many Reasons – Some Stop Without Consulting You Bull SA, et al. JAMA. 2002;288: Lin EH, et al. Med Care. 1995;33: Patient-Reported Reasons for Discontinuation of Antidepressant Therapy Disliked side effects62% Did not need medication56% Feeling better50% Felt medication was not working32% MD told me to stop12% Ran out of pills11% Friend told me to stop7% Weight gain5% Forgot to take pills5% In another study, 70% of patients who reported stopping their antidepressant medication did so without consulting their healthcare professional.

43 Antidepressant Discontinuation Rates Product Product disc. rate due to AE Placebo disc. rate Desvenlafaxine 50 mg (Pristiq) 4.1%3.8% Escitalopram mg (Cipralex) 5.9%2.2% Bupropion mg (Wellbutrin SR) 6%3% Duloxetine mg (Cymbalta) 10%4% Venlafaxine mg (Effexor XR) 12%6% Citalopram mg (Celexa) 15.9%7.7% Mirtazapine mg (Remeron) 16%7% Paroxetine mg (Paxil) 21%N/A AE = adverse event; SR = sustained release; N/A = not available Celexa Canadian Product Monograph. Cipralex Canadian Product Monograph. Cymbalta Canadian Product Monograph. Effexor XR Canadian Product Monograph. Paxil Canadian Product Monograph. Pristiq Canadian Product Monograph. Remeron Canadian Product Monograph. Wellbutrin SR Canadian Product Monograph.

44 Why is Achieving Remission, even in the short run, so Important in Major Depression?

45 The Kupfer Curve: The Life Story of Depression Kupfer DJ, Frank E. Am J Psychiatry. 1987;144(1):86-88.

46 What Is Remission? A Researcher’s Definition: A Clinician’s Definition: A Patient’s Definition: What is the score on rating instrument? What is the score on rating instrument? Are the symptoms gone? Am I functioning well? Do I feel optimistic and self-confident? Are the symptoms gone? Am I functioning well? Do I feel optimistic and self-confident? Zimmerman M et al. Am J Psychiatry (1): It Depends on Whom You Ask

47 Remission’s Importance: Its Impact on Patient’s Lives Impacts Physical Functioning 1,2 Impacts Social Functioning 1,2 Impacts Children’s Mental Well-being 3 Impacts Occupational Functioning 1,2 Impacts Marital Functioning 4 Increased relapse risk; faster relapse 5,6 1 Sobocki P et al. Int J Clin Pract. 2006;60(7): ; 2 Keller MB. JAMA. 2003;289(23): ; 3 Weissman MM et al. JAMA. 2006;295(12): ; 4 Bromberger JT et al. J Nerv Ment Dis. 1994;182(1):40-44; 5 Thase M et al. Am J Psychiatry. 1992;149(8): ; 6 Judd LL et al. J Affect Disord. 1998;50(2-3):

48 Does Treatment With Antidepressants, If It Leads to Remission, Have Any Impact on Brain Volume? 1 = BA25 – Subcallosal gyrus 2 = BA24 – Subgenual PFC 3 = BA32 – Paracingulate gyrus HAM-D >7 (n = 26) HAM-D <7 (n = 13) mm mm 3a Subgenual PFC a P<0.05; PFC, prefrontal cortex Yucel K et al. Psychiatry Res. 2009;173(1):71-76.

49 ‘Dual’ Action vs. Single Action Anti-depressants

50 Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2000:254. Interactions between serotonin and norepinephrine neurons

51 Current Shortcomings in the Treatment of the Full Spectrum of Depressive Symptoms Greco T, et al. J Gen Intern Med. 2004;19(8): a naturalistic, randomized trial of 573 primary care patients on SSRIs followed for 9 months

52 Danish University Studies: Comparison of Clomipramine (Dual-Action) vs SSRI Danish University Antidepressant Group. Psychopharmacology (Berl). 1986;90: Danish University Antidepressant Group. J Affect Disord. 1990;18: % 46% Paroxetine 30 mg/d (N = 27) Clomipramine 150 mg/d (N = 33) 30% 60% Citalopram 40 mg/d (N = 52) Clomipramine 150 mg/d (N = 50) % remission

53 Nelson JC, Mazure CM, Jatlow PI, et al. Biol Psychiatry 2004;55: % Response Remission DMI FLX DMI + FLX Is the Combination of Serotonin and Norepinephrine superior to Either by Itself? Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study

54 Week Patient With Symptom Resolution (somatic-general item score = 0), % *†*† *†*† *‡*‡ * * * * * *‡*‡ Thase ME et al. Br J Psychiatry;178: , 2001 Venlafaxine : Meta-analysis indicates the possibility of SNRI superior to SSRI in Remission Rates

55 Baseline HAM-D > 19 Remission Rate, % All Randomized Patients *†*† * * * Duloxetine, SSRI, placebo: Focus on Remission * P < 0.05 vs placebo † P vs SSRIs Thase ME et al. Poster presented at the 156 th Annual meeting, APA, San Francisco, May 2003

56 Data are from the intent-to-treat population. *p<0.05, †p<0.01, ‡p<0.001 for desvenlafaxine vs. placebo Thase ME, et al. Manuscript submitted. n=112 n=100 n=151 n=98 n=73 n=82 n=105 n=73 ‡ † † * Desvenlafaxine Remission Rate (Pooled Data: HAM-D17 Remission Rate, FOT) % patients mg100 mg200 mg400 mg Desvenlafaxine Placebo

57 Meta-analysis of TCAs vs SSRIs: 25 Studies Anderson IM. Depress Anxiety. 1998;7(suppl 1):11-17.

58 Remission Rates with SSRIs vs. SNRIs Debate: What is the Latest? SNRI remission rates were 5.7% higher A meta-analysis of head-to-head SSRIs vs. SNRIs trials Remission as the outcome measured Machado M et al. J Clin Pharm Ther. 2010;35(2): Odds Ratio IV, Random, 95% CI 12 Favors SNRIs Favors SSRIs Number of Patients in Each Trial (N) In (odds ratio)

59 Is Remission Enough of a “high” standard for Us to set ??

60 Mental Well-Being is Much More Than Absence of Symptoms NA, negative affect; PA, positive affect. Reprinted by permission from John Wiley & Sons, Inc: Panksepp J et al. Addiction. 2002;97(4): ; Burgdorf J, Panksepp J. Neurosci Biobehav Rev. 2006;30(2): Valence ArousalPA NA −PA −NA Presence of fitness decrements Absence of fitness decrements Presence of fitness increments Absence of fitness increments

61 How Are You Feeling Right Now? Killingsworth MA, Gilbert DT. Science. 2010;330(6006): = very bad = very good rest/sleep working home computer grooming, self care other watching television relaxing, nothing special shopping, errands preparing food eating walking, taking a walk playing exercising not mind wandering pleasant mind wandering unpleasant mind wandering neutral mind wandering making love talking, conversation listening to music praying/worshipping/meditating taking care of your children reading doing housework listening to radio, news commuting, traveling

62 One Way to Measure That is via the Use of Scales Such as This… – This scale asks zero questions about depression or negative mental health traits and focuses only on the mental well-being constructs Statements None of the TimeRarely Some of the TimeOften All of the Time I’ve been feeling optimistic about the future I’ve been feeling useful I’ve been feeling relaxed I’ve been feeling interested in other people I’ve had energy to spare I’ve been dealing with problems well I’ve been thinking clearly I’ve been feeling good about myself I’ve been feeling close to other people I’ve been feeling confident I’ve been able to make up my own mind about things I’ve been feeling loved I’ve been interested in new things I’ve been feeling cheerful Tennant R et al. Health Qual Life Outcomes. 2007:5:63. Accessed June 2, The Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) © NHS Health Scotland, University of Warwick and University of Edinburgh, 2006, all rights reserved.

63 And the Results Are… WEMWBS – Population Sample Tennant R et al. Health Qual Life Outcomes. 2007:5:63.

64 Optimism Mitigates Biological Impact of Stress Double-blind, placebo-controlled study showed that acute psychological stress increased serum levels of IL-6 and negative mood in 59 healthy men. Further analysis of this sample investigated the relationship between dispositional optimism and stress-induced changes in immunity and mood. Brydon L et al. Brain Behav Immun. 2009;23(6):

65 Complete and Several Types of Incomplete States of Mental Health Slade M. BMC Health Serv Res. 2010;10:26. Incomplete mental illness Complete mental health Incomplete mental health Complete mental illness High subjective well-being symptoms Low subjective well-being symptoms Low mental illness symptoms High mental illness symptoms Struggling Flourishing Languishing Floundering

66 Clinical Practice and Wellness Measurement WHO-5 WHO (Five) Well-Being Index (1998 version) Accessed June 2, Over the Last Two Weeks All of the Time Most of the Time More than Half of the Time Less than Half of the Time Some of the Time At No Time I have felt cheerful and in good spirits □5□5 □4□4 □3□3 □2□2 □1□1 □0□0 I have felt calm and relaxed □5□5 □4□4 □3□3 □2□2 □1□1 □0□0 I have felt active and vigorous □5□5 □4□4 □3□3 □2□2 □1□1 □0□0 I woke up feeling fresh and rested □5□5 □4□4 □3□3 □2□2 □1□1 □0□0 My daily life has been filled with things that interest me □5□5 □4□4 □3□3 □2□2 □1□1 □0□0 Please indicate for each of the five statements which is closest to how you have been feeling over the last two weeks. Notice that higher numbers mean better well-being. Example: If you have felt cheerful and in good spirits more than half of the time during the last two weeks, put a tick in the box with the number 3 in the upper right corner.

67 Remission Not officially defined; varies between studies (e.g., HAM-D <7-10) Functional Recovery Changes in SDS scores? Pre-morbid functioning? Outcomes were here Outcomes are now here Ideal outcome should be here Defining Treatment Goals for Depression: An evolving concept? Response 50% improvement in a validated depression rating scale from baseline (e.g., HAM-D) Adapted from: Nierenberg & DeCecco. J Clin Psychiatry 2001;62 (Suppl 16):5-9.

68 Emergence of Functionality as Key to Anti- Depressant Effects – Focus on SDS and WHO-5 Guico-Pabia CJ, et al. Poster Presentation, American Academy of Nurse Practitioners, 2010

69 In Conclusion, Our View of Depression Is Evolving Repetitive mood episodes may result in enduring functional and structural alterations in the sensitive brain areas Disruption in corticolimbic circuitry may create neuroendocrine, neuroimmune, and sympathetic dysregulation Inadequate monoamine and neurotrophic signaling combined with excessive glutaminergic and inflammatory cytokine transmission may precipitate a “breakdown” in vulnerable glia-neuron units An altered glia-neuron relationship may then further impede corticolimbic processing GRP=glucose-regulated protein. NMB=neuromedin B. AVP=arginine vasopressin. MAP=mitogen-activated protein. DA=dopamine. CORT=cortisol. JAK-STAT=janus kinase and signal transducer and activator of transcription. Adapted from Anisman H. J Psychiatry Neurosci. 2009;34(1):4-20. GABA Modulation Apoptotic oxidative NE DA − − − − GRP/ NMB Neuroplasticity Growth Factors (eg, BDNF) JAK- STAT MAP kinase NFκB ACTH Depression Stressors Cytokine (eg, IL-1 , TNF-  ) CORT CRH/ AVP 5-HT


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