.

Rakesh Jain, MD, MPH

Recent AdvancesIn

Neurobiology &TreatmentOf

Major Depression

Associate Clinical ProfessorDepartment of Psychiatry & Beh. Sciences

University of Texas Medical SchoolHouston, Texas

Assistant Clinical ProfessorDepartment of Psychiatry

Texas Tech Medical SchoolMidland, Texas

Director, Psychiatric Drug ResearchAdult, Child and AdolescentR/D Clinical Research, Inc

Lake Jackson, Texas

MajorDepression

BioPsycho

Social

A 20th Century Clinician’s View of Depression (“so yesterday… !”)

For the 21st Century’s Clinician – A New Way to Look at Depression

Schloesser RJ, et.al.2008.Neuropsychopharmacology Reviews 33:110-133

CellularCell growth/survival/death

Cell morphology:dendritic remodeling

MolecularSusceptibility genes

Protective genesTranscription factors

mRNA

SystemsCritical neuronal circuitry

BehaviorCognitive/Affective/Sensorymotor

Environment

Neurotransmission:Neurotransmitters andNeuropeptidesSynaptic connectivity

Environmental factors(including external

environment:psychosocial stressors,

sleep deprivation, internal environment

gonadal/HPA steriods)

PKC & MARCKSGSK-3 & substrates

CREB & BDNFERK 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

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):673-680.

0

5

10

15

20

25

30

35

Risk Factors

Moo

d an

d F

eelin

g Q

ues

tion

naire

(M

FQ

) D

epre

ssio

n S

core

s Controls (nonmaltreated) History of maltreatment5-HTTLPR s/s BDNF val66metLow social support

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):1135-1143.

32-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

% o

f S

tudy

Mem

bers

With

the

Con

ditio

n

≥2 (n=98)

70

60

50

40

30

20

10

0

0 (n=502)1 (n=253)

Schloesser RJ, et al. Neuropsychopharmacology. 2008;33(1):110-133.Reprinted with permission from Macmillan Publishers Ltd.

Cingulate gyrusThalamus

Hippocampus

Amygdala

Nucleusaccumbens

Prefrontalcortex (PFC)

Limbic Structures and Paralimbic Cortex

Anterior cingulate cortex (ACC)

Schloesser RJ, et.al.2008.Neuropsychopharmacology Reviews 33:110-133

`

Macro and Microscopic Structures Involved in Mood Disorders

Compromised neurotrophic support may alter synaptic structure in mood disorders

1. Manji HK, et al. Biol Psychiatry. 2003;53:707-742.2. Nestler EJ, et al. Neuron. 2002;34:13-25.

Hippocampal Pyramidal Neurons

Micrograph1Depression Reduced dendritic

arborizationGraphic representation2

Normaldendritic arborization

Correlation Between Hippocampal Volume and Duration of Untreated Depression*

Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.

38 Female Outpatients With Recurrent Depression in Remission

Days of Untreated Depression

Tota

l Hip

poca

mpa

l Vol

ume

(mm

3 )

R2=.28 *P=.0006n=38

0 1000 2000 3000 40003000

3500

4000

4500

5000

5500

6000

*Significant inverse relationship between total hippocampal volume and the length of time depression went untreated.

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):683-695.Reprinted with permission from John Wiley & Sons, Inc.

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):107-116.Reprinted with permission from Elsevier Limited.

Comparison of 15 Subjects With MDD and 14 Healthy ControlsRegions showing a negative correlation between gray matter concentration and depression severity

p<0.05

Adjusted VBM Responses, Medial Orbital PFC (Brodmann Area 11)

MA

DR

S S

core

-0.1 -0.05 0 0.05 0.115

17

19

21

23

25

27

29

31

Adjusted VBM Responses, Dorsolateral PFC (Brodmann Area 46)

MA

DR

S S

core

-0.1 -0.05 0 0.05 0.115

17

19

21

23

25

27

29

31

r=-0.53 r=-0.57

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):732-741.Reprinted with permission from Elsevier Limited.

Inflammatory Cytokine Levels Were Associated With Symptom Severity

in Patients With MDDComparison 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):2522-2530.

Da

ily M

ea

n V

AS

Sco

re (

mm

)

A. Concentration

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.4058P=.05

B. Guilt

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.6711P=.004*

C. Sadness

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.5139P=.02

Da

ily M

ea

n V

AS

Sco

re (

mm

)

D. Self-Esteem

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.735P=.002*

Daily Mean Log IL-6 (pg/mL)

E. Suicidal Thoughts

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.7785P=.0007*

Daily Mean Log IL-6 (pg/mL)

F. Tiredness

0 0.5 1.0 1.5 2.0 2.50

20

40

60

80

100

120

R2=0.566P=.02

Daily Mean Log IL-6 (pg/mL)

Implications of Residual Symptoms

Adapted from Lespérance F, et al. Circulation. 2002;105(9):1049-1053.

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 HospitalizationC

ardi

ac D

eath

-Fre

e S

urvi

val (

%) BDI <5

BDI 5 to 9

BDI 10 to 18

BDI ≥19

100

90

80

70

600 365 730 1095 1460 1825

N=896

Depression and MI – Importance of Depression and its Optimum

Treatment

Jonge P, et.al. Am J Psychiatry 2007;164:1371-1378; 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

Cellular and Molecular Changes in MDD

The Tripartite Synapse:The Role of Astroglia in Signaling

Halassa MM, et al. Trends Mol Med. 2007;13(2):54-63.Reprinted with permission from Elsevier Limited.

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):732-741. Reprinted with permission from Elsevier Limited.

P=.005

OFC=orbitofrontal cortex.Adapted from Rajkowska G, et al. Biol Psychiatry. 1999;45(9):1085-1098.

Decreased Glial Density in Dorsolateral PFC and OFC in Patients With MDD

Dorsolateral PFCBrodmann Area 9

Nu

mb

er

of

Glia

l Nu

cle

i/mm

3 x1

0-3

140

120

100

80

60Control With Depression

Caudal OFCBrodmann Area 474

P=.006

Nu

mb

er

of

Glia

l Nu

cle

i/mm

3 x1

0-3

130

110

90

70

Control With Depression

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 oflayer VI ACC pyramidalneurons in 12 depressedsuicide subjects vs 7 sudden-death controls

Branch Order

Nu

mb

er

of

Bra

nch

es

A ControlsDepressed suicides

0

1

2

3

4

5

1 2 3 4 5

*

1 2 3 4 5Branch Order

Tota

l Bra

nch

Le

ng

th (

µm

)

B ControlsDepressed suicides

0

10

30

40

50

60

20

70

*

Reduced Neuronal Size in OFC of Patients With MDD

Adapted from Rajkowska G. Prog Brain Res. 2000;126:397-412.Reprinted with permission from Elsevier Limited.

IIIIII

IIII

II

II

III

IV

V

VI

White Matter

Layer

Pia200

500

Dis

tanc

e fr

om P

ia (

µm

)

Control With Depression

I

Rostral OFC

[3H] 8-OH-DPAT

Integrated Mind-Body Perspective of MDD—

Treatment Implications

• 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

DSM-IV diagnostic criteria

Treatment May Improve Cerebral Activityin Patients With MDD

Fitzgerald PB, et al. Hum Brain Mapp. 2008;29(6):683-695.Reprinted with permission from John Wiley & Sons, Inc.

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=0.65P=.02

r=0.52P=.01

Adapted from Brunoni AR, et al. Int J Neuropsychopharmacol. 2008;11(8):1169-1180.

Cha

nge

in B

DN

F (

Effe

ct S

ize)

BDNF Change vs Depression Improvement BDNF Change vs Days of Treatment

2.0

1.5

1.0

0.5

0.0

-0.5

0 2 4 6Cohen’s d for Depression

Study analyzed (weighted by inverse variance)

2.0

1.5

1.0

0.5

0.0

-0.5

0 20 40 60Period of Treatment (Days)

80

Study analyzed (weighted by inverse variance)

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):788-796.Reprinted with permission from Macmillan Publishers Ltd.

12 Weeks of Cognitive Therapy

0.15

0.10

0.05

0.00

-0.052 4 6 8 10 12

Time (Seconds)

BO

LD

Sig

na

l (%

Ch

an

ge

)

Time (Seconds)

BO

LD

Sig

na

l (%

Ch

an

ge

) 0.30

0.15

0.10

0.05

2 4 6 8 10 12 14 16 180.00

0.20

0.25

PrePostControl

a. Emotional b. Cognitive

Is it you?UGLY

Put the digits in numerical order7 4 3 1 5

Patients with depression (n=9)

Controls (n=24)

Neurobiology of Exercise – A Complex Cascade

Dishman RK et al. (2006), Obesity 14(3):345-356; 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 DiseaseStructure

Executive ControlsPrefrontal & Cingulate Cortex

Emotional ControlsAmygdala, Prefrontal Cortex

External InputVisual

OlfactoryAcousticGustatory

Somatosensory

ANS&

Endocrine Systems

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

MuscleCardiovascular Consequences

Metabolic ConsequencesLiver, WAT, Pancreas

Thermal Consequences

Behavior•Social•Sexual•Coping•Addictive•Escape•Fight & Flight•Stress•Sleep•IngestiveMotor Controls

Motor CortexStriatum, Brainstem,

Cerebellum, Spinal Cord

Motivational ControlsReward, Wanting, SelectionHypothalamus, Accumbens, VTA

Cognitive ControlsHippocampus, Cortex

NeuralPrimary Afferents

“Exercise”

Internal Feedback

“Consequences of exercise”

Humoral Factors

CNS

Energy Balance

RepairPlasticityProtection

NeurogenesisTranscription

NA, 5-HT,GABA, Glutamate,

GlycineBDNF/TrkBERK/CREB

NFKB

Fitness & Hippocampal Volume – Further Reason to bring Exercise into our Rx Plan

Erikson Ki, et.al. Hippocampus. 2009. (ahead of publication)

Scatterplots showing increase in fitness (VO2 peak) is related to increase in hippocampal volume cm3

Correlations significant for both left and right (even after including age, sex, years of education as covariates)

Track…Track…Track…Monitor…Monitor…Monitor

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) levelsSutcigil L, et.al. Clinical and Developmental Immunology.2007.

BT AT

40

35

30

25

20

15

10

5

0

30

25

20

15

10

5

0BT AT

9876543210

BT AT

IL-1

2 (

pg

/ml)

HD

RS

IL-4

(p

g/m

l)

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

R2 =.376P=.0062

R2 =

- .353P=.0012

Treatment Guidelines

oIf no response and clinical severity warrants, consider the following: • Increase in dose of medication• Increase in intensity of psychotherapy• ECT

oIf 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 Response4-8 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

oIf patient is currently receiving medication, consider:• Changing

antidepressant• Adding or changing to

psychotherapy• ECT

oIf patient is currently receiving psychotherapy, consider:• Adding or changing to

medication

No Response

oIf patient is currently receiving medication, consider:• Changing

antidepressant• Adding or changing to

psychotherapy• ECT

oIf patient is currently receiving psychotherapy, consider:• Adding or changing to

medication

Partial Response

oIf patient is currently receiving medication, consider:• Changing dose• Augmenting antidepressant• Changing antidepressant• Adding or changing to psychotherapy• ECT

oIf 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

First-Line Antidepressants: Guidelines

CANMAT APA

SNRIs Desvenlafaxine, duloxetine, venlafaxine

Desvenlafaxine, duloxetine, venlafaxine

SSRIs Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

TCAs Amitriptyline, doxepin, imipramine, nortriptyline, protriptyline, maprotiline trimipramine

Serotonin modulators Nefadozone, trazodone

Norepinephrine-serotonin modulator

Mirtazapine Mirtazapine

MAOIs Moclobemide Isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine

DNRI Bupropion Bupropion

APA = American Psychiatric Association; TCA = tricyclic antidepressant; MAOI = monoamine axidase inhibitor; DNRI = dopamine norepinephrine reuptake inhibitorAmerican Psychiatric Association. Am J Psychiatry. 2010;[in press]. Lam RW, et al. J Affect Disord. 2009;117(Suppl 1):S26-S43.

TMAP Depression Algorithms: Strategies for the Treatment of Major Depression (Non-psychotic)

2008 version

Stage 0 Patient Assessment &Discussion of Treatment Option

(cont.)TMAP Guidelies, accessed 5.25.08 https://www.dshs.state.tx.us/mhprograms/pdf/timamdd1algo.pdf

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

Stage 1 A

SSRIs, BUP SR/XLMRT, SNRIs

(cont.)

Response

Continuation

If Non-response, move to Stage 2

PartialResponse

Augment with one of the following- SSRI,

SNRI, BUP, MRT, BUS, or T3 (choose different MOA from

Stage 1)

Stage 1

TMAP Depression Algorithms: Strategies for the Treatment of Major Depression

(Non- Psychotic) 2008 version

TMAP Depression Algorithms: Strategies for the Treatment of Major Depression

(Non- Psychotic) 2008 version

TMAP Guidelies, accessed 5.25.08 https://www.dshs.state.tx.us/mhprograms/pdf/timamdd1algo.pdf; BUP = bupropion; MRT = mirtazapine; BUS= buspirone; T3 = liothyronine; MOA = mechanism of action

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

‘Enhanced’ Care:An Update for the 21st

Century Clinician

Enhanced Care is Effective, Has long term benefits, and is Generalizeble Across

Different Clinical Settings

Unutzer J, et.al JAMA 2002;288:2836-2845; Hunkeler EM, et.al. BMJ 2006:332:259-263

Results from IMPACT studyImpact Intervention n= 906Usual Care n= 895

Longer Term Benefits

Works Across Settings

Algorithm-Based Care has better Outcomes as compared to Treatment as Usual

Trivedi MH, et.al. Arch Gen Psychiatry 2004;61:669-680.

Patient Self-Report of Depressive Symptoms in Algorithm-Based vs.

Usual Care

Clinical Ratings of Depressive Symptoms in Algorithm-Based vs.

Usual Care

Patients Discontinue Medication for Many Reasons – Some Stop

Without Consulting You

Bull SA, et al. JAMA. 2002;288:1403-1409. Lin EH, et al. Med Care. 1995;33:67-74.

Patient-Reported Reasons forDiscontinuation of Antidepressant Therapy

Disliked side effects 62%

Did not need medication 56%

Feeling better 50%

Felt medication was not working 32%

MD told me to stop 12%

Ran out of pills 11%

Friend told me to stop 7%

Weight gain 5%

Forgot to take pills 5%

In another study, 70% of patients who reported stopping their antidepressant medication did so without consulting their healthcare professional .

Antidepressant Discontinuation Rates

Product Product disc. rate due to AE

Placebo disc. rate

Desvenlafaxine 50 mg (Pristiq) 4.1% 3.8%

Escitalopram 10-20 mg (Cipralex) 5.9% 2.2%

Bupropion 150-300 mg (Wellbutrin SR) 6% 3%

Duloxetine 40-120 mg (Cymbalta) 10% 4%

Venlafaxine 75-225 mg (Effexor XR) 12% 6%

Citalopram 20-40 mg (Celexa) 15.9% 7.7%

Mirtazapine 15-45 mg (Remeron) 16% 7%

Paroxetine 20-60 mg (Paxil) 21% N/A

AE = adverse event; SR = sustained release; N/A = not availableCelexa 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.

Why is Achieving Remission, even in the

short run, so Important in Major Depression?

The Kupfer Curve: The Life Story of Depression

Kupfer DJ, Frank E. Am J Psychiatry. 1987;144(1):86-88.

What Is Remission?

A Researcher’s Definition:

A Clinician’s Definition:A Patient’s Definition:

What is thescore on rating

instrument?Are the symptoms

gone?

Are the symptoms gone? Am I functioning well? Do I feel optimistic and

self-confident?

Zimmerman M et al. Am J Psychiatry. 2006.163(1):148-150.

It Depends on Whom You Ask

Remission’s Importance: Its Impact on Patient’s Lives

Impacts Physical Functioning1,2

Impacts Social Functioning1,2

Impacts Children’s Mental Well-being3

Impacts Occupational Functioning1,2

Impacts Marital Functioning4

Increased relapse risk; faster relapse5,6

1Sobocki P et al. Int J Clin Pract. 2006;60(7):791-798; 2Keller MB. JAMA. 2003;289(23):3152-3160 ; 3Weissman MM et al. JAMA. 2006;295(12):1389-1398; 4Bromberger JT et al. J Nerv Ment Dis. 1994;182(1):40-44; 5Thase M et al. Am J Psychiatry. 1992;149(8):1046-1052; 6Judd LL et al. J Affect Disord. 1998;50(2-3):97-108.

Does Treatment With Antidepressants, If It Leads to Remission, Have Any Impact

on Brain Volume?

1 = BA25 – Subcallosal gyrus2 = BA24 – Subgenual PFC3 = BA32 – Paracingulate gyrus

HAM-D >7 (n = 26)

HAM-D <7 (n = 13)

586.8 mm3 712.7 mm3a

Subgenual PFC

aP<0.05; PFC, prefrontal cortexYucel K et al. Psychiatry Res. 2009;173(1):71-76.

‘Dual’ Action vs. Single Action Anti-depressants

Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications; 2000:254.

Interactions between serotonin and norepinephrine neurons

Current Shortcomings in the Treatment of the Full Spectrum of Depressive Symptoms

Greco T, et al. J Gen Intern Med. 2004;19(8):813-818

a naturalistic, randomized trial of 573 primary care patients on SSRIs followed for 9 months

Danish University Studies: Comparison of Clomipramine (Dual-Action) vs SSRI

Danish University Antidepressant Group. Psychopharmacology (Berl). 1986;90:131-138. Danish University Antidepressant Group. J Affect Disord. 1990;18:289-299.

19%

46%

0

5

10

15

20

25

30

35

40

45

50

Paroxetine30 mg/d(N = 27)

Clomipramine150 mg/d(N = 33)

30%

60%

0

10

20

30

40

50

60

Citalopram40 mg/d(N = 52)

Clomipramine150 mg/d(N = 50)

% r

emis

sio

n

Nelson JC, Mazure CM, Jatlow PI, et al. Biol Psychiatry 2004;55:296-300

%

Response

16.7

35.7

7.7

0

5

10

15

20

25

30

35

40

45

50

55

Remission

0.0

7.1

53.8 DMI

FLXDMI + 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

Week

Pat

ient

With

Sym

ptom

Res

olut

ion

(som

atic

-gen

eral

item

sco

re =

0),

%

0

5

10

15

20

25

30

35

40

*†

*†

*‡

*

*

*

**

Placebo (N = 932)SSRI (N = 3217)Venlafaxine (N = 3273)

1 2 3 4 6 8

*‡

Thase ME et al. Br J Psychiatry;178:234-241, 2001

Venlafaxine : Meta-analysis indicates the possibility of SNRI superior to SSRI in Remission Rates

Baseline HAM-D > 19

Rem

issi

on R

ate,

%

0

5

10

15

20

25

30

35

40

45

50PlaceboSSRIDuloxetine

All Randomized Patients

*† **

*

Duloxetine, SSRI, placebo: Focus on Remission

* P < 0.05 vs placebo

† P +0.013 vs SSRIs

Thase ME et al. Poster presented at the 156th Annual meeting, APA, San Francisco, May 2003

Data are from the intent-to-treat population.*p<0.05, †p<0.01, ‡p<0.001 for desvenlafaxine vs. placeboThase ME, et al. Manuscript submitted.

n=112

n=100

n=151

n=98

n=73

n=82 n=105n=73

‡

††

*

Desvenlafaxine Remission Rate(Pooled Data: HAM-D17 Remission Rate, FOT)

% p

atie

nts

3633

32

36

2326

2325

0

10

20

30

40

50

50 mg 100 mg 200 mg 400 mg

Desvenlafaxine

Placebo

Meta-analysis of TCAs vs SSRIs: 25 Studies

Anderson IM. Depress Anxiety. 1998;7(suppl 1):11-17.

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):177-188.

Odds RatioIV, Random, 95% CI

1 2Favors SNRIs

0.2 0.5 5Favors SSRIs

600

300

400

200

1.51

0.50

-0.5-1

-1.5

100

500

Number of Patients in Each Trial (N)

In (

odds

rat

io)

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

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):459-469; Burgdorf J, Panksepp J. Neurosci Biobehav Rev. 2006;30(2):173-187.

Valence

Arousal PANA

−PA −NA

Presence of fitness decrements

Absence of fitness decrements

Presence of fitness increments

Absence of fitness increments

How Are You Feeling Right Now?

Killingsworth MA, Gilbert DT. Science. 2010;330(6006):932.

0 = very bad - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 100 = very good

35 45 55 65 75 85 95

rest/sleep

working

home computer

grooming, self careother

watching television

relaxing, nothing special

shopping, errandspreparing food

eatingwalking, 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

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

StatementsNoneof the Time Rarely

Someof the Time Often

All of the Time

I’ve been feeling optimistic about the future 1 2 3 4 5

I’ve been feeling useful 1 2 3 4 5

I’ve been feeling relaxed 1 2 3 4 5

I’ve been feeling interested in other people 1 2 3 4 5

I’ve had energy to spare 1 2 3 4 5

I’ve been dealing with problems well 1 2 3 4 5

I’ve been thinking clearly 1 2 3 4 5

I’ve been feeling good about myself 1 2 3 4 5

I’ve been feeling close to other people 1 2 3 4 5

I’ve been feeling confident 1 2 3 4 5

I’ve been able to make up my own mind about things 1 2 3 4 5

I’ve been feeling loved 1 2 3 4 5

I’ve been interested in new things 1 2 3 4 5

I’ve been feeling cheerful 1 2 3 4 5

www.healthscotland.com/documents/1467.aspx; Tennant R et al. Health Qual Life Outcomes. 2007:5:63. www.hqlo.com/content/pdf/1477-7525-5-63.pdf. Accessed June 2, 2011.

The Warwick-Edinburgh Mental Well-Being Scale (WEMWBS)

© NHS Health Scotland, University of Warwick and University of Edinburgh, 2006, all rights reserved.

And the Results Are…WEMWBS – Population Sample

Tennant R et al. Health Qual Life Outcomes. 2007:5:63.

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):810-816.

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

LanguishingFloundering

Clinical Practice and Wellness Measurement WHO-5

• WHO (Five) Well-Being Index (1998 version)

www.cure4you.dk/354/WHO-5_English.pdf. Accessed June 2, 2011.

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 □4 □3 □2 □1 □0

I have felt calm and relaxed □5 □4 □3 □2 □1 □0

I have felt active and vigorous □5 □4 □3 □2 □1 □0

I woke up feeling fresh and rested □5 □4 □3 □2 □1 □0

My daily life has been filled with things that interest me

□5 □4 □3 □2 □1 □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.

RemissionNot 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.

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

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.

GABAModulation

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