SAS1 2016-942-MDD-Takeda FINAL-recording - Cloud …€¦ · Sobocki P, et al. J Ment Health Policy...
Transcript of SAS1 2016-942-MDD-Takeda FINAL-recording - Cloud …€¦ · Sobocki P, et al. J Ment Health Policy...
Provided by North American Center forContinuing Medical Education, LLC,
an HMP Communications Holdings Company
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
Fatigue or loss of energy
Fatigue or loss of energy
Indecisiveness or
diminished ability to think
Indecisiveness or
diminished ability to think
Indecisiveness or
diminished ability to think
Significant appetite or
weight changes
Significant appetite or
weight changes
Significant appetite or
weight changes
Worthlessnessor guilt
Worthlessnessor guilt
Worthlessnessor guilt
Suicidal ideationSuicidal ideationSuicidal ideation
Insomnia or
hypersomnia
Insomnia or
hypersomnia
Insomnia or
hypersomnia
Psychomotor agitation or retardation
Psychomotor agitation or retardation
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
Point Worthy of Note
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
Point Worthy of Note
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
Percentage of time that patients met DSM-IV criteria per symptom cluster
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)
Slide 38
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
2 Points Worthy of Note
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
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
2 Points Worthy of Note
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