sas1 2016-942-mdd-takeda final-recording - cloud …€¦ · sobocki p, et al. j ment health policy...

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Supported by an educational grant from Takeda Pharmaceuticals U.S.A., Inc. and Lundbeck.

Rakesh Jain, MD, MPHClinical Professor

Department of Psychiatry

Texas Tech Health Sciences Center

School of Medicine

Midland, Texas

Faculty

Dr. Jain: Consultant—Addrenex, Allergan, Lilly, Lundbeck, Merck, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Takeda (Spouse: Lilly, Otsuka, Pamlab); Speakers Bureau—Addrenex, Allergan, Lilly, Lundbeck, Merck, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Takeda; Research Support—AstraZeneca, Allergan, Lilly, Lundbeck, Otsuka, Pfizer, Shire, Takeda.

Faculty Disclosure

The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). The off-label use of buspirone, erythropoietin,

lisdexamfetamine, lithium, modafinil, tranylcypromine, and triiodothyronine for the treatment of major depressive disorder will be discussed.

Applicable CME staff have no relationships to disclose relating to the subject matter of this activity.

This activity has been independently reviewed for balance.

Disclosure

Describe the prevalence and quality of life impact of cognitive symptoms in patients with major depressive disorder (MDD)

Routinely utilize assessment tools to identify cognitive symptoms in patients with MDD

Outline the receptor pharmacology of available MDD agents and the evidence-based impact on therapeutic decision-making

Optimize outcomes in patients with MDD who are experiencing cognitive symptoms

Learning Objectives

Introduction and Taking a Measure of Major Depression’sImpact

Unipolar depression is the leading cause of global disease burden among mental, neurological, and substance use disorders

The total annual cost of depression in Europe was estimated at €118 billion in 2004, which corresponds to a cost of €253 per inhabitant

$44 billion cost to US employers in 1 year

DALY = disability-adjusted life-year; COPD = chronic obstructive pulmonary disease.Collins PY, et al. Nature. 2011;475(7354):27-30. Sobocki P, et al. J Ment Health Policy Econ. 2006;9(2):87-98. Stewart WF, et al. JAMA. 2003;289(23):3135-3144.

Depression is Associated with Significant Economic Costs

Mental Health

Disorders

23%

Cancer

16%

16%

Other Conditions

45%

CardiovascularDisease

Burden of Disease: Leading Individual Disease/Disorder Contributors

2.96

3.01

3.07

3.07

3.65

4.08

6.76

10.3

0 5 10 15

8. Cerebrovascular disease

7. Alzheimer's disease / dementia

6. Hearing loss: adult onset

5. Trachea / bronchus / lung cancer

4. COPD

3. Alcohol-use disorders

2. Ischaemic heart disease

1. Unipolar depression

Total DALYs: USA and Canada (%)Data courtesy of World Health Organization

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013. World Federation for Mental Health. Depression: A Global Crisis. October 10, 2012. http://wfmh.com/wp-content/uploads/2013/11/2012_wmhday_english.pdf. Accessed on January 5, 2016. Fehnel SE, et al. CNS Spectr. 2016;21(1):43-52. Hammar A, et al. Front Hum Neurosci. 2009;3:26. Bair MJ, et al. Arch Intern Med. 2003;163(20):2433-2445. Clayton A. Effects of Psychiatric Illness and Medication on Sexual Function. July 20, 2004. www.medscape.org/viewarticle/482059_3. Accessed on January 5, 2016.

Depression is a Clinically Heterogeneous Disorder with Emotional, Physical, and Cognitive Symptoms

FatigueEating changes

InsomniaSexual dysfunction

HeadachesStomach problems

Chest pain

SadnessAnxiety

IrritabilityLack of enjoymentSuicidal ideationHopelessness

Guilt

Physical

Difficulties with:Attention and concentration

Short- and long-term memoryDecision-making

Planning and organizationMental flexibility

Word-findingThinking speed

CognitiveEmotional

MDE = major depressive episode.Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Textbook Revision). Arlington, VA: American Psychiatric Association; 2000.

Symptom Dimensions of MDE

Fatigue or loss of energy



Indecisiveness or

diminished ability to think

Indecisiveness or


Indecisiveness or


Significant appetite or

weight changes


weight changes


weight changes

Worthlessnessor guilt



Suicidal ideationSuicidal ideationSuicidal ideation

Insomnia or

hypersomnia

Insomnia or

hypersomnia

Insomnia or

hypersomnia

Psychomotor agitation or retardation



• ALL symptoms are important!

• Symptoms are often under-recognized and underappreciated every day in clinical practice

• Each one of these symptoms, by themselves, or in combinations, can become Residual Symptoms

* Depressed Mood

* Anhedonia

Point Worthy of Note

Cognitive Dysfunction is under-represented even in DSM-5 criteria

(receives only 1 criteria out of 9)

Patient Perception of Burden from Individual Symptoms ofMajor Depression

*MDD diagnosis was based on DSM-III-R criteria and symptoms were assessed by the National Institute of Mental Health Diagnostic Interview Schedule. MDD = major depressive disorder.Chen LS, et al. Am J Psychiatry. 2000;157(4):573-580.

Patient Perspective on the Most Common Diagnostic Symptoms of MDD: An Unequal Distribution

From a 13-year study following a general population sample in the Baltimore Epidemiologic Catchment Area (N = 1920)

Proportion of MDD patients with symptoms during MDEs (n = 100)*

1.00.20.0 0.80.60.4

Depressed mood

Appetite problems

Sleep problems

Tiredness

Slowness/restlessness

Lost of interest

Worthlessness

Trouble thinking

Thoughts of death

McIntyre RS, et al. Depress Anxiety. 2013;30(6):515-527. Hammar A, et al. Front Hum Neurosci. 2009;3:26.

Cognitive Symptoms of Depression Have a Negative Impact on All Aspects of a Patient’s Life

Cognitive dysfunction and general functioning are linked; both have an impact on clinical outcomes

Find it difficult to maintain job performance

Loss of focus

Loss of productivity

Struggle with a variety of attention

related tasks

Unable to fully participate in

family life

Exhibit social irritability

Have problems meeting expectations from society

Find it difficult to participate in social life

Experience household and financial strainWork/

School LifeWork/

School LifeFamily/

Personal LifeFamily/

Personal Life

Social LifeSocial Life

Work/ School Life

Family/ Personal Life

Social Life

Sally


Cognitive Dysfunction is impairing, and often “lost” in the mix with

emotional and physical symptoms of MDD

Neurobiology of MDD: A Brief Examination ofEmergent Data andClinical Goal Setting in MDD

B. Depressed Individuals

ACC = anterior cingulate cortex; AMN = autobiographic memory network; AN = affective network; CCN = cognitive control network; dACC = dorsal ACC; dlPFC = dorsolateral prefrontal cortex; omPFC = orbitomesial PFC; rACC = rostral ACC. Rayner G, et al. Neurosci Biobehav Rev. 2015;61:53-65.

Cognition Related Brain Networks Underpin Symptoms of Major Depression

2 distinct neurocognitive networks, the AMN and the CCN, are central to the symptomatology of depression

Study integrated findings from 59 functional neuroimaging studies

of adults with unipolar depression using a narrative approach

A. Healthy Controls

High activation– CCN

Suppressed activation– AN

Deactivation– AMN

Hyperactivation – AMN

Activation – AN

Deactivation – CCN

How We Humans Create CognitionA Neuropsychiatric Perspective

BasalGanglia

Trivedi MH, et al. J Affect Disord. 2014;152-154:19-27. Millan MJ, et al. Nat Rev Drug Discov. 2012;11(2):141-168.

PFCOFC

Amygdala

Temporal lobe(semantic memory:

storage and retrieval)

DorsolateralPFC

FrontalLobe

ACC

BasalGanglia

Thalamus ParietalCortex

AssociationCortex

PORC

PRHC

Cerebellum

Episodic andsemantic memory

(space, time,and context)

HippocampusDGCA3CA1Sub

I/IIV/VI

ERHC

PRTC PFC Basal Ganglia Thalamus

Segregation,convergence,and crosstalk

Dorsolateral PFC

ACCOFC

Dorsolateralcaudate nucleusNucleus accumbensVentromedial caudate

VA and MD

MDVA and MD

GPiandSNr

PRTC = parietal cortex; PFC = prefrontal cortex; ACC = anterior cingulate cortex; OFC = orbital prefrontal cortex; PORC = postrhinal cortex; PRHC = perirhinal cortex; GP = internal globus pallidus; SNr = substantia nigra pars reticulata; VA = ventral anterior thalamic nucleus; MD = medial dorsal thalamic nucleus.

Axial Sections

DLPFC OFC ACC FG

• Working memory

• Executive function

• Strategic planning

• Decision-making

• Emotional processing

• Cognitive flexibility

• Reward processing

• Adaptive learning

• Attention

• Emotional processing

• Emotional encoding

• Social cognition

• Social cognition

• Facial recognition

27% decrease 19% decrease 8%-11% decrease 11% decrease

n = 102, MDD; n = 34, controls. FG = fusiform gyrus.Grieve SM, et al. Neuroimage Clin. 2013;3:332-339.

MDD is Associated with Reductions in Volume in Areas of the Brain Associated with

Higher Cognitive Functions

Kellough JL, et al. Behav Res Ther. 2008;46(11):1238-1243. Levens SM, et al. J Exp Psychol Gen. 2010;139(4):654-664.

Depressed Patients Display Negative Biases in Attention, Working, and Verbal Memory

Eye-tracking studies show that depressed patients preferentially

attend to negatively-valenced stimuli while healthy controls show no such

biases

Depressed patients are slower to disengage from sad stimuli during affective working memory tasks and faster to disengage from happy stimuli while

healthy controls display the opposite bias

Pyr

DR / MnRmPFC

CortexThalamus

HippocampusAmygdala

Glu

5-HT5-HT

5-HT

Glu

Glu

VTA LC

5-HT3

5-HT

5-HT4

5-HT3

5-HT2A

5-HT1B

5-HT1A

AMPA

mGluR II/III

GABAA

GABAB

5-HT = serotonin; DR = dorsal raphe; GABA = gamma-aminobutyric acid; Glu = glutamate; LC = locus coeruleus; mGluR = metabotropic glutamate receptor; MnR = median raphe; mPFC = medial prefrontal cortex; VTA = ventral tegmental area. Amargós-Bosch M, et al. Cereb Cortex. 2004;14(3):281-299. Puig MV, et al. Cereb Cortex. 2004;14(12):1365-1375.

Serotonin, Through Multiple 5-HT Receptor Subtypes, Control a Large Number of Mood Related Functions


The neurobiology of Cognitive Dysfunction in MDD is well characterized, and it

involves macrostructures (such as brain networks)

to microstructures (individual receptors)

HAM-D = Hamilton Rating Scale for Depression; MADRS = Montgomery-Åsberg Depression Rating Scale. Zimmerman M, et al. J Affect Disord. 2012;142(1-3):77-81. Zimmerman M, et al. J Clin Psychiatry. 2012;73(6):790-795.

The Ultimate Treatment Goal in Depression is Full Functional Recovery

Treatment goals in depression have evolvedTreatment goals in depression have evolved

ResponseMany symptoms remain

RemissionSome symptoms may persist

Full Functional RecoverySymptoms are essentially absent; patient returns to premorbid functional status

Reduction of symptoms (eg, 50% of MADRS or HAM-D score)

1970sReduction of symptoms (eg, 50% of MADRS or HAM-D score)

Reduction of symptoms (eg, 50% of MADRS or HAM-D score)

1970s1970sDefinition varies between studies, but commonly defined as MADRS score ≤10, or HAM-D17 score ≤7

1990sDefinition varies between studies, but commonly defined as MADRS score ≤10, or HAM-D17 score ≤7

1990s

Expectations not yet formallydefined; measures shouldinclude clinician ratings,self-reports, and performancetesting to assess symptomsand functioning

Current

Expectations not yet formallydefined; measures shouldinclude clinician ratings,self-reports, and performancetesting to assess symptomsand functioning

Current

Nearly half of depressed patients who achieve “remission” do not consider themselves to be in remission

John

A Focused Examination ofthe Impact of CognitiveSymptoms andImpairments in MDD

+ = consistently present but not pronounced; ++ = a common marked characteristic; +++ = a core, severe, and virtually universal characteristic of the disorder; () = an intermediate magnitude of effect; ↑ = increased; 0 / + = poorly documented; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GAD = generalized anxiety disorder; OCD = obsessive-compulsive disorder; PTSD = posttraumatic stress disorder.

Millan MJ, et al. Nat Rev Drug Discov. 2012;11(2):141-168.

Cognitive Dysfunction across Psychiatric Disorders

Attention and / or

Vigilance

Working Memory

Executive Function

EpisodicMemory

Semantic Memory

Visual Memory

Verbal Memory

ProceduralMemory

Processing Speed

Major Depression

+(+) ++ ++ ++ + + +(+) + ++(+)

Bipolar Disorder

++(+) ++ ++ ++ + + ++ 0 ++

Schizophrenia +++ +++ +++ +++ ++ +(+) +++ + ++

ASD +++ + +++ ++ + + +(+) 0 / + +++

ADHD +++ ++ +++ 0 / + + ++ ++ + ++

OCD +++(↑) +(+) ++ + 0 / + + 0 / + ++ ++

PTSD +++(↑) +(+) +(+) ++ + + ++(+) 0 +

Panic disorder +++(↑) + 0 / + + 0 / + 0 / + + 0 ++

GAD + + 0 0 + + + 0 0

Parkinson’s Disease

++ ++(+) ++ + 0 / + + + +++ +++

Alzheimer’s Disease

+(+) +(+) +(+) +++ +++ +++ ++(+) + +

Conradi HJ, et al. Psychol Med. 2011;41(6):1165-1174.

All 3 Domains of Depression (Emotional, Cognitive, and Physical)

are Highly Prevalent Residual Symptoms of Depression

Percentage of time that patients met DSM-IV criteria per symptom cluster



Tim

e (%

)

During MDE

During remission

*P < .05, **P < .01, ***P < .001; aDue to missing data, sample size varied from 75 to 77; bDue to missing data, sample size varied from 60 to 63. Zimmerman M, et al. J Affect Disord. 2012;142(1-3):77-81.

Incidence of Residual Symptoms Self-Reported Remission Rates

CUDOS Symptom Mild Severity Threshold Moderate Severity Threshold

Self-Reported Remission (n = 77)a

Self-Reported Not in Remission (n = 63)b

Self-Reported Remission (n = 77)a

Self-Reported Not in Remission (n = 63)b

n % n % n % n %

Depressed mood 10 13.2 38 60.3*** 2 2.6 11 17.5**

Loss of interest 13 17.1 23 37.1** 3 3.9 9 14.5*

Poor appetite 3 4.0 12 19.0** 1 1.3 7 11.1*

Increased appetite 15 19.7 18 29.0 7 9.2 3 4.8

Insomnia 14 18.4 25 39.7** 8 10.5 9 14.3

Hypersomnia 4 5.3 17 27.0*** 2 2.6 6 9.5

Psychomotor agitation 6 7.9 20 32.3*** 0 0.0 7 11.3**

Psychomotor retardation 9 11.8 26 41.9*** 4 5.3 8 12.9

Low energy 19 25.0 36 57.1*** 7 9.2 16 25.4*

Guilt 6 7.9 20 33.3*** 2 2.6 13 21.7***

Worthlessness 6 7.9 20 32.3*** 1 1.3 14 22.6***

Impaired concentration 13 17.3 31 50.0*** 5 6.7 20 32.3***

Indecisiveness 5 6.6 20 32.3*** 2 2.6 6 9.7

Death wishes 1 1.3 6 9.7* 0 0.0 3 4.8

Suicidal thoughts 1 1.3 3 4.8 1 1.3 2 3.2

Hopelessness 5 6.6 11 17.5* 1 1.3 3 4.8

Depressive symptoms in remitted depressed outpatients according to HAM-D17 who do and do not consider themselves to be in remission

Conradi HJ, et al. Psychol Med. 2011;41(6):1165-1174.

Depressive Symptoms Persist during Periods of Remission and Subsequent Depressive Episodes

Mean proportion of time symptoms are present during 3-year follow-up period (N = 267)

Me

an P

rop

ort

ion

of

Tim

e D

SM

-IV

Sym

pto

m C

lust

er is

Pre

sen

t

1.00

0.80

0.60

0.40

0.20

0.00

Weeks of Follow-up

Lack of energySleeping problems

Worthlessness/guiltEating problemsPsychomotor problemsDeath ideations

Cognitive problemsCore symptoms: depressed mood/↓ interest

Importance of all 3 sets of residual symptoms is highlighted:Emotional Symptoms • Cognitive Symptoms • Physical Symptoms

Disease StateAcute EpisodeSeverity of affective symptoms>1/3 suffer in remission

Disease Course Variables

Number of depressive episodes

Number of hospitalizations

Course of illness

Age of onset

Years with illness

Function

Poor reintegration at work

Employment

Social function

Readiness for cognitive therapies

NEUROCOGNITIVE FUNCTION

GENERAL DAILY FUNCTION

CLINICAL CHARACTERISTICS

Ability to perform tasks and meet psychosocial demand

Baune BT, et al. Psychiatry Res. 2010;176(2-3):183-189. Beblo T, et al. Neuropsychol Rev. 2011;21(4):337-359.

Inter-relationship between Cognitive Function and General Function in Depression

Fehnel SE, et al. CNS Spectr. 2016;21(1):43-52. McIntyre RS, et al. Depress Anxiety. 2013;30(6):515-527. Trivedi MH, et al. J Affect Disord. 2014;152-154:19-27.

Patients with Depression Often Report Experiencing Cognitive Symptoms

Lose train of thought

Not listening

Forgetful

Loss of short- and long-term memory

Attention deficit

Concentration difficulties

Lack of focus

Key Domains of Cognitive Function

Patient descriptors

Scientific terminology

Real-life terminology

Procrastinate

Lacking confidence

Indecisive

Brain is cloudy

Slow motion

Tired/Lethargic

2 Points Worthy of Note

1. Cognitive Dysfunction can be present during “active” disease, as well as a residual symptom

2. Also, the 4 areas of Cognitive Dysfunction to note in MDD are

1) Attention2) Memory3) Executive Function4) Psychomotor Speed

A Focused Examination ofthe Impact of CognitiveSymptoms andImpairments in MDD

Now That We Appreciate That Cognitive Dysfunctionis Common and Impactful,How Do We Screen for It in Everyday Clinical Practice? Some Practical Tips

Zimmerman M, et al. J Clin Psychiatry. 2012;73(6):790-795. Zimmerman M, et al. J Affect Disord. 2012;142(1-3):77-81.

There are Multiple Ways to Measure Clinical Outcomes in Depression

In clinical practice, physicians and patients take a less empirical approach, often with differing priorities

1. Response

2. Reduction in cognitive symptoms

3. Reduction in anxiety symptoms

Key Treatment Priorities

Criteria for Remission

Decrease in negative affect symptoms

Increase in positive affect symptoms

Return to normal function

Physician Patient

1. Remission

2. Avoidance of relapse

3. Improvements in social function

We Could Just Rely onStandard DepressionRating Scales, BUT… They Underestimate Cognitive Difficulties

HAM-D = Hamilton Rating Scale for Depression; MADRS = Montgomery-Åsberg Depression Rating Scale; BDI = Beck Depression Inventory; PHQ = Patient Health Questionnaire.

Assessing Residual Cognitive and Physical Symptoms are Poorly Done by Most Depression Rating Scales

Standard depression scales do not assess all cognitive or physical symptom domains

PHQPHQ

MADRSMADRSHAM-DHAM-D

● Retardation (slowness of thought and speech, impaired ability to concentrate, decreased motor activity)

● Difficulties in concentrating and sustaining thought, which reduces ability to read or hold a conversation

BDIBDI

● I have greater difficulty in making decisions than I used to

● Trouble concentrating on things, such as reading the newspaper or watching TV

DSST = Digit Symbol Substitution Test; RAVLT = Rey Auditory Verbal Learning Test. Katona C, et al. Int Clin Psychopharmacol. 2012;27(4):215-223. McIntyre RS, et al. Int J Neuropsychopharmacol. 2014;17(10):1557-1567. Mahableshwarkar AR, et al. Neuropsychopharmacology. 2015;40(8):2025-2037.

Selection of Neuropsychological Tests Involves Cognitive Domains Known to Be Affected in MDD

Primary endpoint

(composite score)

DSSTA measure of executive function, working memory,

processing speed, and visuospatial attention

RAVLTA measure of verbal learning and memory

STROOP(a measure of mental [attentional] vitality and

cognitive flexibility/response inhibition)

Trail Making B(a measure of executive control and cognitive

flexibility / set-shifting)

Trail Making A(a measure of attention, visual searching, and

mental processing speed)

Choice Reaction time task(a measure of visual attention and vigilance)

Simple Reaction time task(a measure of psychomotor

function / speed of processing)

Executive Function Psychomotor Speed Attention Memory

2 Excellent Supplemental Scales to Measure Cognitive Dysfunction:Perceived Deficits Questionnaire (PDQ-5)

Massachusetts General HospitalCognitive and Physical Functioning Questionnaire (CPFQ)

DP1 This is the selction chosen by LUNDBECK..How do we handle the fact that a post hoc analyiss of the Focus data indicates that the change in DSST is driven by changes on all aspectsDanae Papapetrou, 10/20/2014

Fehnel SE, et al. CNS Spectr. 2016;21(1):43-52.

PDQ-5

The following questions describe problems people may have with their memory, attention, or concentration. Please select the best response based

on your experiences during the past 7 days.

• Patient-reported

• Total score 0–20

– The higher the score, the more frequent the symptoms

Self-rated scale, sensitive to treatment, short, easy to use clinically

7 items, 4 specifically assess cognition Motivation/interest/enthusiasm Wakefulness/alertness Energy Focus/sustain attention Remember/recall information Find words Sharpness/mental acuity

Each item rated 1 (greater than normal) to 6 (totally absent) Higher scores indicate greater impairment

Fava M, et al. Psychother Psychosom. 2009;78(2):91-97.

Massachusetts General Hospital CPFQ

http://mghcme.org/academy-uploads/CPFQ_Rating_Scale.pdf. Accessed on January 5, 2016.

Massachusetts General Hospital CPFQ

Sally’s First Appointment

Sally’s First Appointment (continued)

We Can Elevate Our Clinical Practices by Inquiring about the Following Symptoms in

Symptomatic, Partial Responder, and Remitted Patients

1. Memory problems 2. Poor concentration3. Expressing thoughts 4. Word finding5. Slow thinking 6. Problem solving

Dear Patient, Are You Having

Trouble with…

Routine, Routine, Routine Assessment for Residual Symptoms is Appropriate

Kalkstein S, et al. Curr Top Behav Neurosci. 2010;4:373-390. Nuechterlein KH, et al. Am J Psychiatry. 2008;165(2):203-213. Sabbe B. Proceedings of the Belgian Royal Academies of Medicine. 2012;1:77-88.

Real World, Clinical Examples of Questions We Clinicians Can Ask Our Patients…

Some Representative Cognitive Domains What is It? Real-World Example

Attention/vigilance• Responding correctly to targets while not

responding to distractors during a series of rapidly presented stimuli

• Being able to read a book or pay attention to a movie

Working memory• Maintaining and manipulating information in

mind for brief (approximately 5-20 seconds)periods of time

• Remembering a phone number just given to you

Verbal learning and memory

• Remembering verbal information over longer periods of time (minutes to years)

• Remembering the items someone told you to purchase at the supermarket

Visual learning and memory

• Remembering visual information over longer periods of time (minutes to years)

• Remembering where you put something in a closet

Reasoning andproblem solving

• The ability to apply strategies effectively• Arriving on time for work even though your

bus schedule has changed

Speed of processing

• Responding quickly and accurately when executing relatively simple tasks

• Using a touch-screen computer to serve customers at a fast-food restaurant

Social cognition• Effectively processing social information,

such as facial expressions and emotions and the meaning of social interactions

• Knowing by looking at someone whether they are angry at you or not; being able to take someone else’s perspective in a conversation

Examining Treatment Options: Focus on BothNonpharmacologic and Pharmacologic TreatmentOptions

First, Let’s Examine the NonpharmacologicTreatment Options

Baune BT, et al. Psychiatry Res. 2014;219(1):25-50. McIntyre RS, et al. CNS Drugs. 2015;29(7):577-589.

Nonpharmacologic Treatments to Improve Cognitive Dysfunction in MDD

The following treatments have demonstrated positive studies in improving cognitive dysfunction in MDD• Neuropsychological Educational Approach to

Remediation (NEAR), a computerized cognitive retraining package (PSSCogReHab)

• Psychodynamic psychotherapy • Sahaj Yoga Meditation • Electroconvulsive Therapy• Physical Exercise

At a cellular level, preliminary research suggests that cognitive training may influence spinedensity, synaptogenesis, and vascular supply to the brain. Additionally, it may promote glial andmetabolic activity, brain-derived neurotrophic factor and hippocampal neurogenesis.

Greer TL, et al. Eur Neuropsychopharmacol. 2015;25(2):248-256.

“Running Away from Your Problems”Physical Exercise and Cognition

Changes in spatial working memory outcomes over 12 weeks of exercise. Participants randomizedto receive high dose exercise (16 KKW) performed significantly better on the spatial workingmemory task with respect to generation of fewer errors on the most complex problems (8 boxes)(P < .04), and showed trends (P < .06) on the 4 box problems as well as the strategy score, which isindicative of effective completion of the task. In contrast, participants in the low dose exercisegroup generated more errors (P < .04) and showed less efficient use of strategy over time (P < .04).

4 KKW

16 KKW

8

-8

4

6

0

-4

Between Errors

6 Boxes4 Boxes 8 Boxes

Spatial Working Memory Performance by Group

Strategy

-2

2

-6

Rel

ativ

e A

bu

nd

ance

MD

S D

ime

ns

ion

2

ex = exercise; HFD = high fat diet; ND = no diet.Kang SS, et al. Mol Neurodegener. 2014;9:36.

Diet and Exercise Change Gut Microbiota – and Both Positively and Independently Impact Cognition

Impact of Diet and Exercise are “orthogonal” – ie, independent of each other

Mice Study. Examining groups of rats exposed to HFD vs not, and mice allowed to freely exercise vs not. Gut microbiota was

studied, along with measures of cognition

Multidimensional analysis of diet and exercise reveals orthogonal changes in the gut microbiome. This analysis in multidimensional space demonstrates clear segregation of each of the 4 groups of mice with no overlap between groups.

MDS Dimension 1

0.0005

0.0015

0.0020

0.0010

0

Freezing Context (%)

40 806020

OTU79-Clostridiales;RuminococcaceaeCR2 = .0983P = .0489

0.002

0.006

0.008

0.004

040 806020

OTU39-Clostridiales;RuminococcaceaeA

R2 = .1117P = .0351

Rel

ativ

e A

bu

nd

ance

0.004

0.008

0.0010

0.006

0

0.002

Freezing Context (%)

40 806020

OTU57-Clostridiales;LachnospiraceaeD

R2 = .1010P = .0457

0.001

0.002

0.003

040 806020

OTU82-Clostridiales;RuminococcaceaeB

R2 = .2144P = .0026

ND

ND+ex HFD+ex

HFD


1. Nonpharmacologic treatments for cognitive dysfunction are a growing body of literature

2. How much we exercise and what we eat, does matter – even from a cognitive perspective

Pharmacologic Treatment Options

Baune BT, et al. Psychiatry Res. 2014;219(1):25-50.

Question to Ponder: How Can an Antidepressant Have Pro-Cognitive Effects?

By positively impacting “hot” cognition

By positively impacting “cold” cognition

Through neurogenesis, particularly in the dentate region of the hippocampus

Through reducing cognitive bias that is inherent in major depression

Through altering glucose metabolism in various pro-cognitiveregions of the brain

Through impacting glutamate / GABA balance

Early Pharmacologic

Approaches 2 31American Psychiatric Association, Work Group on Major Depressive Disorder. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition. 2010. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf.Accessed on January 6, 2016.

Pharmacologic Approaches for the Treatment of Symptoms following Inadequate Response to SSRIs

Treatment-Resistant

Depression

Allows time for natural recovery to start and to carry

out further assessments

Initially, to another SSRI, or a better tolerated newer-

generation antidepressant

Then to an antidepressant of a

different pharmacologic

class that may be less well tolerated

Increase Dose Switch Switch

American Psychiatric Association, Work Group on Major Depressive Disorder. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition. 2010. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. Accessed on January 6, 2016.

Pharmacologic Approaches for the Treatment of Symptoms following Inadequate Response to SSRIs

(continued)

3 4Antidepressant

combination (mirtazapine with

SSRI or SNRI)

Atypical antipsychotic augmentation2Lithium

augmentation1Add CBT

Further Management

Switch to another

class

Augmentation

Early Pharmacologic Approaches

Increase dose

Residual Symptoms of Depression

Switch within class

5Neuro-modulation

*The top box represents the sertraline-venlafaxine pairwise comparison and the bottom box the sertraline-bupropion pairwise comparison. NNT = number needed to treat; SSRI = selective serotonin reuptake inhibitor. Papakostas GI, et al. Biol Psychiatry. 2008;63(7):699-704.

Within or Out of Class Treatment Switch in SSRI-Resistant Patients: Which is Superior?

A meta-analysis of 4 clinical trials (N = 1496) found a modest yet statistically significant advantage in remission rates when switched to a different class rather than another SSRI

Switch

Poirier and Boyer, 1999

Lenox-Smith et al, 2001

Thase et al, 2001

Rush et al, 2006

*

*

Favors across-class switchFavors within-class switch

Risk Ratio

-1 .5 1 5 10

Combined

NNT = 22

Remission defined as QIDS-SR16 score ≤5 at exit from the indicated treatment step, citalopram group also included those with an exit score of ≤7 on the 17-item HAM-D. Response defined as ≥50% reduction in QIDS-SR16 score from entry score at each step. QIDS-SR = Quick Inventory of Depressive Symptomatology Self-Report; STAR*D = Sequenced Treatment Alternatives to Relieve Depression. Trivedi MH, et al. Am J Psychiatry. 2006;163(1):28-40. Rush AJ, et al. N Engl J Med. 2006;354(12):1231-1242.

“Real-World” Efficacy of AntidepressantsEvidence from Second-Line Treatment in STAR*D

Switch 1

Response Remission

n = 2876 n = 239 n = 238 n = 250

Switch

At entry: 80% recurrent or chronic depression; mean episodes: 6; mean duration: 25 months

Response and remission rates in patients following switch from first-line treatment with citalopram

At entry: 80% of patients had recurrent or chronic depression;mean number of episodes: 6; mean duration: 25 monthsAt entry: 80% of patients had recurrent or chronic depression;mean number of episodes: 6; mean duration: 25 monthsAt entry: 80% of patients had recurrent or chronic depression;mean number of episodes: 6; mean duration: 25 months

05

1015202530354045

Initial AD Augment 1 Augment 2 Switch 3

AD = antidepressant; T3 = triiodothyronine.Nierenberg AA, et al. Psychol Med. 2010;40(1):41-50. Rush AJ, et al. Am J Psychiatry. 2006;163(11):1905-1917. Nierenberg AA, et al. Am J Psychiatry. 2006;163(9):1519-1530. McGrath PJ, et al. Am J Psychiatry. 2006;163(9):1531-1541.

“Real-World” Efficacy of AntidepressantsEvidence from Third-Line Treatment in STAR*D

n=2876

Pro

po

rtio

n o

f P

atie

nts

wit

h R

emis

sio

n (

%)

Switch

Augmentation

n=58

n=51

n=279

n=286

n=69

n=73

• Treatment augmentation with an atypical agent resulted in

– Response rate 44.2% vs 29.9% for placebo

– Remission rate 30.7% vs 17.2% for placebo

• Efficacy risk difference between augmentation with an atypical agent vs placebo translated into

– NNT of 9 for response

– NNT of 9 for remission

• Risk difference for discontinuation due to adverse events with atypical agent vs placebo resulted in an NNH of 17

N = 3500.NNH = number needed to harm.Nelson JC, et al. Am J Psychiatry. 2009;166(9):980-991.

Atypical Antipsychotic Augmentation of SSRI Treatment: A Meta-Analysis of Placebo-Controlled Trials

Atypical Antipsychotic Augmentation

• In a multicenter, randomized, double-blind, placebo-controlled studyof 362 patients with MDD, remission rates were 26.0% with adjunctivearipiprazole and 15.7% with adjunctive placebo (P = .011)

¯ At 6 weeks, the mean change in MADRS total score was significantly greaterin patients receiving adjunctive aripiprazole than in those receiving placebo

*P < .001.Berman RM, et al. J Clin Psychiatry. 2007;68(6):843-853.

Atypical Antipsychotic Augmentation of SSRI Treatment Adjunctive Aripiprazole

-12

-10

-8

-6

-4

-2

0Baseline 1 2 3 4 5 6

Placebo (n = 172) Ariprprazole (n = 181)

**

* * *

Me

an (

±SE

) C

han

ge

in M

AD

RS

To

tal

Sco

re f

rom

En

d o

f P

rosp

ecti

ve

Tre

atm

ent

Ph

ase

to E

nd

of

Ran

do

miz

ed T

reat

men

t P

has

e

Week

Atypical Antipsychotic Augmentation

*Defined as decreased sexual drive and functioning.Goethe JW, et al. J Clin Psychopharmacol. 2007;27(5):451-458.

Common Adverse Effects Responsible for Treatment Discontinuation

33.9 35.0

47.0

36.5

0

10

20

30

40

50

60

Gastrointestinal symptoms

Weight changes Decreasedsexuality*

Insomnia

Pat

ien

ts (

%)

Most Bothersome Side Effects (N = 406)

In an observational study, adverse events were the most common reason cited for SSRI discontinuation after 3 months

Angst J. Int Clin Psychopharmacol. 1998;13 Suppl 6:S1-S4. Thakurta RG, et al. Indian J PsycholMed. 2012;34(4):365-370. Atlantis E, et al. J Sex Med. 2012;9(6):1497-1507.

Sexual Dysfunction in Patients with Untreated MDD

• A meta-analysis of 12 studies revealed a bidirectional association between untreated depression and sexual dysfunction

- 6 studies (N = 3285) showed that depression increased the risk of sexual dysfunction by 50% to 70%

- 6 studies (N = 11,171) showed that sexual dysfunction increased the risk of depression by 130% to

210%

MDD Symptom Severity Correlateswith the Degree of Sexual Dysfunction

in Untreated MDD Patients

Sexual Dysfunctionin Depressed Patients vs

Healthy Controls

22

10

28

12

8

Tota

l Sex

ual F

unct

ion

Scor

e

20

26

16

14

18

24

Total Hamilton Depression Scale Score

2412 1614 3210 22 3020 2818 26

40

70

0

Popu

latio

n (%

)

30

60

10

20

50

Healthy Controls (n=291)

Untreated Depression (n=122)

Depression Treated with Medication (n=37)

Depression Treated without Medication (n=41)

Roiser JP, et al. CNS Spectr. 2013;18(3):139-149.

“Hot” and “Cold” Cognition:An Emerging Concept in Mental Health

Emotion-independent; logical thinking and executive control (executive, attention, perception, and psychomotor functions)

Emotional processing; response to negative feedback. Changes in the “hot” system are more likely to be associated with antidepressant response

McIntyre RS, et al. CNS Drugs. 2015;29(7):577-589.

What Do We Mean When We Say“Cognitive Problems in Depression”? Examining the Different Cognitive Domains

Cognition Examples

Hot cognition Rumination

Catastrophic reactions

Bias towards negative stimuli (internal/external)

Anhedonia (eg, anticipatory anhedonia)

Cold cognition Executive function

Information processing speed

Learning and memory

Attention/concentration

Social cognition Theory of mind

Mentalization

“Hot” CognitionVMPFC is linked to emotion-based cognition, with associations to emotional processing areas (eg, amygdala)

Connectivity between PFC andOther Brain Regions

“Cold”’ Cognition DLPFC is associated with non-emotional cognition, sensory, and motor areas (eg, basal ganglia and parietal cortex)

VMPFC = ventromedial prefrontal cortex.Wood JN, et al. Nat Rev Neurosci. 2003;4(2):139-147.

“Hot” and “Cold” Cognition Have Different Brain Pathways and Connectivity

Image provided by Roger S. McIntyre, MD, FRCPC

Cingulate HippocampalFormation

Parietal/OccipitalVisual-Association

Areas

Motor Structures DLPFC Posterior Parietal

Heteromodal Area

AmygdalaComplexVMPFC

Inferior TemporalVisual-Association

Areas

Drug Duloxetine Escitalopram Fluoxetine Paroxetine Vortioxetine

Study Design/Cognitive Domain

ElderlyN = 1948 wks

AdultsN = 3724 wks

ElderlyN = 184 wks

AdultsN = 3624 wks

ElderlyN = 1191 year

ElderlyN = 1231 year

ElderlyN = 3048 wks

Composite cognitive score (v)

Attention (v) (v) (v) (v)

Working memory (v) (v)

Executive function (v) (v)

Processing speed (v) (v)

Memory (v) (v) (v)

Verbal learning (v) (v)

(v) = function still remained lower than that of controls. Cassano GB, et al. J Clin Psychiatry. 2002;63(5):396-402. Herrera-Guzmán I, et al. Psychiatry Res. 2010;177(3):323-329. McIntyre RS, et al. Int J Neuropsychopharmacol. 2014;17(10):1557-1567. Katona C, et al. Int Clin Psychopharmacol. 2012;27(4):215-223. Raskin J, et al. Am J Psychiatry. 2007;164(6):900-909. Savaskan E, et al. Int J Neuropsychopharmacol. 2008;11(3):381-388.

Effects of Antidepressants on Cognitive Function in MDD

NAT = noradrenaline transporter; SERT = serotonin transporter; SNRI = serotonin-norepinephrine reuptake inhibitor.

Nutt DJ. J Psychopharmacol. 2009;23(4):343-345. Bang-Andersen B, et al. J Med Chem. 2011;54(9):3206-3221.

Mechanism of Action of Various Antidepressants

Vortioxetine

5-HT1A

5-HT1B

5-HT1D

5-HT3

Vilazodone

SERT

2 pharmacologic targets (reuptake inhibition)

NAT

SNRI1 target(reuptake inhibition)

SERT

SSRI

2 pharmacologic targets (receptor activity + reuptake inhibition)

6 pharmacologic targets

(receptor activity + reuptake inhibition)

Uptake inhibitor Agonist Partial agonist Antagonist

5-HT1A SERTSERT

5-HT7

*P < .05, †P < .01 vs placebo; nominal P-values; n numbers are APTS. ANCOVA = analysis of covariance; APTS = all-patients-treated set; DSST = Digit Symbol Substitution Test; FAS = full analysis set; RAVLT = Rey Auditory Verbal Learning Test. Katona C, et al. Int Clin Psychopharmacol. 2012;27(4):215-223.

Comparing 2 Different Mechanisms of Action: Antidepressants in Patients with Depression

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

DSST RAVLT acquisition RAVLT delayed recall

Sta

nd

ard

ized

Eff

ect

Siz

e vs

Pla

ceb

o

Vortioxetine 5 mg/day (n = 156)

Duloxetine 60 mg/day (n = 151)

* **

* †

Improvement from baseline compared with placebo at week 8 in patients ≥65 yearsDSST and RAVLT Exploratory Endpoints

Week 8: FAS, ANCOVA, Cohen’s d

BjEb1 i would indicate partial response as (v)Bjarke Ebert, 10/14/2014

Duloxetine was included as active reference for study validation, not for comparison of effect sizes. Katona C, et al. Int Clin Psychopharmacol. 2012;27(4):215-223.

Effects on Cognitive Function Cannot Be Solely Explained by Improvements in Mood

Path analysis showed that in addition to improving cognitive function indirectly through the alleviation of depressive symptoms, vortioxetine exerts direct effects on depression-related

cognitive impairments as measured by patient performance in relevant tests (DSST).

DSSTVortioxetine5 mg

HAM-D24

Direct effect

Indirect effect

Direct effect (DSST)

83%

Indirect effect

(HAM-D24)17%

Vortioxetine

Indirect effect

(HAM-D24)74%

Direct effect

(DSST)26%

Duloxetine

On RAVLT acquisition, vortioxetine had a 71% direct effect & duloxetine 65%On RAVLT delayed recall, vortioxetine had a 72% direct effect & duloxetine 66%

Independent effect indicated by a priori specification, cognition as primary; pathoanalysis; subgroup analysis in nonresponders and nonremitters. Level 1 replicated placebo-controlled trial evidence with demonstration of independent effect. Level 2 single placebo-controlled trial evidence with demonstration of independent effect. Level 3 uncontrolled evidence (eg, lacking placebo and case-series) with lack of demonstration of independent effect.

McIntyre RS, et al. Curr Opin Psychiatry. 2016;29(1):48-55. McIntyre RS, et al. CNS Drugs. 2015;29(7):577-589.

Examining the Evidence for Direct Impact on Cognitive Symptoms in MDD

Antidepressants and psychotropic agents that improve measures of cognition in individuals with MDD independent of improvements in measures of depressive symptom severity

Learning/Memory

Attention/Concentration

Executive Function

Processing Speed

Vortioxetine 1 1 1 1

Duloxetine 1

Lisdexamfetamine 2

Other (eg, SSRIs, SNRIs, and bupropion)

3 3 3 3

Modafinil 3 3 3 3

Erythropoietin 2 2 2 2


1. Pharmacologic treatments can impact cognitive dysfunction, and a growing body of literature is emerging on this topic

2. Receptor pharmacology of various agents appears to have some importance in addressing cognitive dysfunction

1. Residual symptoms, including Cognitive Dysfunction, are the rule, and not the exception in MDD

2. All 3 sets of residual symptoms are frequent – and they matter• Emotional• Cognitive• Physical

3. Mechanism of action of various antidepressants is important in both its efficacy and side effect profile

4. Fitting the appropriate intervention with the specific patient needs is state-of-the-art practice in 2016

Take-Home Messages

sas1 2016-942-mdd-takeda final-recording - cloud …€¦ · sobocki p, et al. j ment health policy...

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