Cognitive Dysfunction in Major Depression: Impactful Education for Impactful Outcomes

Rakesh Jain, MD, MPH Clinical Professor Department of Psychiatry Texas Tech Health Sciences Center School of Medicine Midland, Texas

Faculty Disclosure •  Dr. Rakesh Jain: Paid Speaker—Addrenex, Alkermes,

Allergan (Actavis/Forest), Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Rhodes Pharmaceuticals, Shionogi, Shire, Sunovion, Takeda, Tris Pharmaceuticals; Advisory Board—Addrenex, Alkermes, Forum, Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Takeda; Research—AstraZeneca, Allergan (Actavis/Forest), Lilly, Lundbeck, Otsuka, Pfizer, Shire, Takeda; Spouse: Consultant—Lilly, Otsuka, Pamlab.

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 erythropoietin, galantamine,

lisdexamfetamine, minocycline, modafinil, N-acetylcysteine, omega-3 polyunsaturated fatty acids, S-adenosyl methionine, scopolamine, statins, and thiazolidinediones 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.

Learning Objectives •  Apply validated assessment tools, such as CPFQ, to

routine practice in order to adequately identify and monitor cognitive dysfunction and other symptoms of major depressive disorder (MDD)

•  Describe the latest data on available therapies for MDD, including mechanisms of action, receptor affinity, and the relevance to targeted symptom control

•  Utilize the latest evidence to make informed MDD treatment decisions that accommodate specific patient needs and optimize outcomes in patients experiencing cognitive dysfunction

Introduction

The Course of Major Depression – and Why Early and Sustained Control is Critical

MDD = major depressive disorder.Sibille E, et al. Int J Neuropsychopharmacol. 2013;16(8):1893-1909.

Relapse

Impr

ovem

ent S

cale

S

ever

ity S

cale

Sym

ptom

Num

bers

Recurrence

Acute

Subchronicity

Chronicity

Remission Remission

(4–5 yr) (1–2 yr)

MDD Episodes Treatment Phases

First Episode Second Episode Third Episode

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

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. www.who.int/mental_health/management/depression/wfmh_paper_depression_wmhd_2012.pdf. Accessed January 13, 2017. 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 January 13, 2017.

Fatigue

Eating changes

Insomnia

Sexual dysfunction

Headaches

Sadness Anxiety

Irritability

Lack of enjoyment Suicidal ideation Hopelessness

Guilt

Physical

Difficulties with: Attention and concentration

Short- and long-term memory

Cognitive Emotional

MDD is like a 3-legged stool (all 3 legs are important)

Cognitive Symptom Complex is Number 2 among All Symptoms of MDD in Causing Impairment

STAR*D = Sequenced Treatment Alternatives to Relieve Depression.Fried EI, et al. PLoS ONE. 2014;9(2):e90311.

Relative importance coefficients of depressive symptoms on overall impairment 25 5 0 20 15 10

Data from 3703 depressed outpatients in the first treatment stage of the STAR*D study

Sad Mood

Self-blame

Concentration

Weight

Sex

Late Insomnia

Hypersomnia

Interest Loss

Early Insomnia Suicidal Ideation

Fatigue

Middle Insomnia

Agitated

Age

Slowed

Appetite

20.7

0.1

0.4

0.7

0.9

1.3

2.1

2.5

3.0

3.6

6.1

6.4

8.8

13.1

13.8

16.5

The Impact of Individual Depressive Symptoms on Impairment of Psychosocial Functioning –

Importance of Cognitive Dysfunction

*P < .05; **P < .01; ***P < .001. b = unstandardized regression coefficient; se = standard error; t = t-value. Fried EI, et al. PLoS ONE. 2014;9(2):e90311.

Results of linear regression analysis (heterogeneity model)

Predictors b se t

Early insomnia 0.50 0.11 4.53 ***

Middle insomnia 0.01 0.15 0.08

Late insomnia 0.26 0.11 2.32 *

Hypersomnia 0.54 0.15 3.64 ***

Sad mood 2.27 0.18 12.79 ***

Appetite 0.25 0.12 2.14 *

Weight 0.13 0.11 1.17

Concentration 1.61 0.14 11.21 ***

Self-blame 0.68 0.10 6.61 ***

Suicidal ideation 0.84 0.15 5.50 ***

Interest loss 1.24 0.12 10.40 ***

Fatigue 1.08 0.12 8.78 ***

Slowed 0.84 0.14 5.93 ***

Agitated 0.02 0.13 0.13

Age 0.04 0.01 4.07 ***

Sex –0.31 0.25 –1.25

Work Impairment Home Management

Private Activities

s1 s2 s3 s4 s5 s6 s7

Early Insomnia Middle Insomnia Late Insomnia Hypersomnia Sad Mood Appetite Weight

s8 s9 s10 s11 s12 s13 s14

Concentration Self-blame Suicidal Ideation Interest Loss Fatigue Slowed Agitated

D1

s1 s2 s14

s3 s13

s4 s12

s11

s9

s5

s8 s7

s6 s10

D2

s1 s2 s14

s3 s13

s4 s12

s11

s9

s5

s8 s7

s6 s10

D4

s1 s2 s14

s3 s13

s4 s12

s11

s9

s5

s8 s7

s6 s10

Clinician Knowledge Base in Regards to Cognition and Depression

McAllister-Williams RH, et al. J Affect Disord. 2017;207:346-352.

1 Cognitive dysfunction in depression occurs in thinking, memory, executive function, and concentration

2 Cognitive dysfunction in depression is independent of depressive symptoms

3 Problems with thinking, concentration, and memory have a clinically significant impact on a patient’s life, at presentation, during treatment, and after response to treatment

4 Cognitive dysfunction in depression is associated with impaired occupational function, even when depressive symptoms may have improved or remitted

5 Cognitive dysfunction in depression is associated with impaired social function

6 Cognitive dysfunction in depression is associated with impaired marital function

7 Cognitive dysfunction in depression is associated with impaired parental function

8 Cognitive dysfunction in depression reduces the patient’s confidence

9 Cognitive dysfunction in depression adds to the economic burden on the individual (eg, reduced earning potential because of difficulty in gaining or maintaining employment, or reduced ability to manage household finances)

10 Cognitive dysfunction in depression is associated with increases costs to society (eg, reduced productivity, increased use of health care resources, and family or relationship difficulties that may lead to divorce or family break-up)

11 More than 30% of patients experience persistent cognitive symptoms despite remission of depressive symptoms

12 Recovery of cognitive function is less likely following repeated episodes of depression

13 Further research is required to understand the burden of cognitive dysfunction in depression

Res

pons

es (%

)

66

20

100

0

40

90

60

80

Statement Number (GP / Psychiatrist Responses)

S1 S2 S3 S4 S5 S6 S7 S8 S9 S10 S11 S12 S13

Agree Disagree Don’t Know / Uncertain

GP

Psych

GP

Psych

GP

Psych

GP

Psych

GP

Psych

GP

Psych

GP

Psych

GP

Psych

GP

Psych

GP

Psych

GP

Psych

GP

Psych

GP

Psych

Points Worthy of Note – (1 of 2)

Cognitive Dysfunction is:

v  Common v  Commonly missed v  Commonly underestimated in

importance v  Under-represented even in

DSM-5 criteria (receives only 1 criteria out of 9)

Point Worthy of Note (2 of 2)

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

emotional and physical symptoms of MDD

Can SSRIs Induce Cognitive Dysfunction? Results from a Survey

117 MDD patients (mean +/- SD age: 43.4 +/- 12.6 years; women: N = 78 [66.7%]) met criteria for response according to the HANDS (score < 9).HANDS = Harvard Department of Psychiatry/National Depression Screening Day; SSRI = selective serotonin reuptake inhibitor. Fava M, et al. J Clin Psychiatry. 2006;67(11):1754-1759.

Even Response to an antidepressant is not a guarantee of cognitive symptom improvement. In fact, they may worsen cognitive symptoms in a fair number of patients.

“It is likely that these symptoms are both side effects of the antidepressants as well as residual symptoms of MDD.”

60

10

0

Prop

ortio

n of

R

espo

nder

s (%

)

30

Apathy

20

50

40

Word-Finding

Difficulty

Sleepiness

Tiredness

Inattentiv

eness

Forgetfulness

Mental

Slowing

7.7

32.5

24.8

Any Impairment Mild Moderate to Severe

12.8

52.3

39.5

8.6

48.8

40.2

9.4

35.9

26.5

19.5

53.1

33.6

9.5

35.4

25.9

6.0

31.9

25.9

** *

Many Antidepressants Can Actually Harm Cognition – Clinicians Beware

SARI = serotonin antagonist and reuptake inhibitor;SNRI = serotonin-norepinephrine reuptake inhibitors;NDRI = norepinephrine-dopamine reuptake inhibitors;NaSSA = noradrenergic and specific serotonergic antidepressant;PTD = post-traumatic brain injury depression.Failla MD, el al. J Head Trauma Rehabil. 2016;31(6):E62-E73.

Prospective cohort study of 154 with assessments at 6 and 12 months post-

injury. On and off antidepressants, and with and without MDD

Type Generic 6 mo 12 mo

SSRI Fluoxetine 1 3

Citalopram 7 5

Sertraline 3 4

Escitalopram 15 9

Paroxetine 3 2

SARI Trazodone 4 3

SNRI Duloxetine 1 4

Venlafaxine 6 2

NDRI Bupropion 1 1

NaSSA Mirtazapine 1 1

50

35

0

15

6 Months

No PTD, No Antidepressant

12 Months

10

Cog

nitiv

e C

ompo

site

(M

ean

T Sc

ore)

PTD, No Antidepressant

No PTD, Antidepressant PTD, Antidepressant

45

30

40

25 20

5

Neurobiology of MDD: A Brief Examination of Emergent Data and

Clinical Goal Setting in MDD

In MDD, Network Efficiency is Impaired Increased in Affective Processing and Decreased in Cognitive Processing

42 MDD and 42 age, education-matched controls were selected to investigate network efficiency abnormalities of the MDD patients’ cortical and subcortical regions.Ye M, et al. BMC Psychiatry. 2016;16(1):450.

Nodal efficiency was found to increase in affective processing regions (ie, amygdala, thalamus, hippocampus),

Decrease in cognitive control-related regions, which included dorsolateral prefrontal cortex and anterior cingulate cortex

MDD and Cognition: A Downward Spiral with Strong Neurobiological Underpinnings

CEN = central executive network; DMN = default mode network; SN = salience network.Wang X, et al. Harv Rev Psychiatry. 2016;24(3):188-201.

Cognitive-vulnerability factors for MDD and corresponding neural mechanisms in intrinsic networks using a dual process framework. The study authors propose that the dynamic alteration and imbalance among the intrinsic networks, both in the resting-state and the rest-task transition stages, contribute to the development of cognitive vulnerability and MDD.

Dynamic Switching

Externally Direction Action

Internally Directed Action

Expectancies are not violated

Cognitive- resource depletion

Inadequately adjust biased associative processing

Downward spiral

Dysphoric mood

Negative cognitive/ affective response

Aberrant DMN

Associative- processing

bias Resting state

Stimuli

Rest-task transition CEN

Ineffectively activate

DMN

Dominance

SN Impaired switching

Pyr

DR / MnR mPFC Cortex

Thalamus

Hippocampus Amygdala

Glu

5-HT 5-HT

5-HT

Glu

Glu GABA

GABA

VTA LC

GABA 5-HT3

5-HT

5-HT4

5-HT3

5-HT2A 5-HT1B 5-HT1A AMPA mGluR II/III GABAA

GABAB

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

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.

A 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)

A Focused Examination of the Impact of Cognitive Symptoms

and Impairments in MDD

Cognitive Dysfunction across Psychiatric Disorders

+ = 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.

Attention and / or

Vigilance

Working Memory

Executive Function

Episodic Memory

Semantic Memory

Visual Memory

Verbal Memory

Procedural Memory

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

Patients with Depression Often Report Experiencing Cognitive Symptoms

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.

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) Attention 2) Memory 3) Executive Function 4) Psychomotor Speed

We Could Just Rely on Standard Depression Rating Scales,

BUT…

They Underestimate Cognitive Difficulties

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

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

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

PHQ

MADRS HAM-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

BDI

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

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

Massachusetts General Hospital Cognitive and Physical Functioning

Questionnaire (CPFQ)

An excellent instrument to detect and monitor Cognitive Dysfunction

Massachusetts General Hospital CPFQ

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

•  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

Massachusetts General Hospital CPFQ

http://mghcme.org/academy-uploads/CPFQ_Rating_Scale.pdf. Accessed January 16, 2017.

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

Partial Responder, and Remitted Patients

1. Memory problems 2. Poor concentration 3. Expressing thoughts 4. Word finding 5. Slow thinking 6. Problem solving

Are you bothered by significant problems with ...

Key is: Routine, Routine, Routine Assessment !

Examining Treatment Options: Focus on Both Non-pharmacologic and

Pharmacologic Treatment Options

First, Let’s Examine the Non-pharmacologic Treatment Options

Why Physical Exercise Matters in Reversing Cognitive Challenges

Kandola A, et al. Front Hum Neurosci. 2016;10:373.

”Many psychiatric and neurological disorders have been associated with hippocampal dysfunction, which may underlie the expression of certain symptoms common to these disorders, including (aspects of) cognitive dysfunction.”

Major Depression causes the following damage / NEGATIVE changes in the hippocampus: 1.  Macro Changes

1.  Gray matter changes 2.  White matter changes

2.  Micro Changes 1.  Neurogenesis 2.  Synaptic plasticity 3.  Vasculature 4.  Neurotrophic factors

Aerobic Exercise causes the following damage / POSITIVE changes in the hippocampus: 1.  Macro Changes

1.  Gray matter changes 2.  White matter changes

2.  Micro Changes 1.  Neurogenesis 2.  Synaptic plasticity 3.  Vasculature 4.  Neurotrophic factors

“Running Away from Your Problems” Physical Exercise and Cognition

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

Changes in spatial working memory outcomes over 12 weeks of exercise. Participants randomized to receive high dose exercise (16 KKW) performed significantly better on the spatial working memory 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 is indicative of effective completion of the task. In contrast, participants in the low dose exercise group 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 Boxes 4 Boxes 8 Boxes

Spatial Working Memory Performance by Group

Strategy

-2

2

-6

How Antidepressants and Exercise May Work on Depression and Cognition

AD = antidepressant. Mateus-Pinheiro A, et al. Clin Epigenetics. 2011;3:5.

Normal epigenetic regulation of hippocampal neurogenesis promotes the stable generation of newborn neurons in the dentate gyrus, maintaining the homeostatic brain function

ADs administration may restore the regulatory function of epigenetic regulation thus allowing the recovery from depressive symptomatology

Impaired epigenetic regulation of hippocampal neurogenesis due to environmental stressors results in reduced formation of new neurons possibly accounting for the behavioral and cognitive deficits associated to depression

2 Points Worthy of Note

1. Non-pharmacologic 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

Question to Ponder: How Can an Antidepressant Have

Pro-Cognitive Effects?

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

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-cognitive regions of the brain

Through impacting glutamate / GABA balance

Drug Duloxetine Escitalopram Fluoxetine Paroxetine Vortioxetine

Study Design/ Cognitive Domain

Elderly N = 194 8 wks

Adults N = 37 24 wks

Elderly N = 18 4 wks

Adults N = 36 24 wks

Elderly N = 119 1 year

Elderly N = 123 1 year

Elderly N = 304 8 wks

Composite cognitive score ü(v)

Attention ü(v) ü(v) ü(v) ü(v) Working memory ü(v) ü(v) Executive function ü(v) ü(v) Processing speed ü(v) ü(v) ü

Memory ü(v) ü(v) ü(v) ü Verbal learning ü(v) ü(v) ü

Effects of Antidepressants on Cognitive Function in MDD

(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.

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

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

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

“Hot”

Cognition “Cold”

Cognition

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

Mechanism of Action of Various Antidepressants

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.

Vortioxetine

5-HT1A

5-HT1B

5-HT1D

5-HT3

Vilazodone

SERT

2 pharmacologic targets (reuptake inhibition)

NAT

SNRI 1 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 SERT SERT

5-HT7

SSRI and Bupropion Treatment Can Improve Cognition

Soczynska JK, et al. Psychiatry Res. 2014;220(1-2):245-250.

Escitalopram and bupropion XL significantly improved immediate as well as delayed verbal and nonverbal memory, global function (all P < .001), and work productivity (P < .045), with no significant between-group differences.

Mean Pre and Post-treatment Memory Composite Scores, Depression Severity, and Functional Outcomes by Antidepressant Type

Bupropion-XL (n = 19) Escitalopram (n = 19) Main effect of time

Drug by time interaction

Baseline Endpoint Baseline Endpoint P-value P-value

Mean (SD) Mean (SD) Mean (SD) Mean (SD)

Clinical measures

HDRS-17 23.3 (4.0) 8.6 (6.3) 23.4 (4.2) 10.5 (7.8) <0.001 0.414

CGI-S 4.8 (0.8) 2.1 (1.0) 4.7 (0.6) 2.4 (1.2) <0.001 0.342

CGI-I 3.1 (0.9) 1.7 (0.8) 3.3 (1.1) 2.1 (1.4) <0.001 0.482

MEI-SF 26.9 11.5 50.2 3.8 29.9 14.3 45.7 26.0 <0.001 0.316

Memory composite scores (T scores)

Immediate verbal memory 49.6 (8.2) 53.3 (7.8) 47.5 (9.7) 52.5 (11.9) 0.001 0.583

Delayed verbal memory 50.6 (10.2) 53.6 (7.1) 51.0 (10.1) 54.6 (9.3) 0.001 0.741

Immediate nonverbal memory 51.7 (9.5) 60.0 (7.8) 51.7 (10.7) 59.5 (9.7) <0.001 0.951

Delayed nonverbal memory 52.0 (9.9) 58.4 (7.6) 51.1 (9.3) 57.0 (9.5) <0.001 0.832

Working memory 49.7 (6.7) 52.0 (6.5) 50.1 (10.2) 50.0 (9.6) 0.257 0.197

Functional outcomes

SDS total 19.6 (7.7) 12.4 (9.1) 19.5 (8.1) 13.4 (8.9) <0.001 0.603

SDS-work 6.9 (3.3) 4.3 (3.4) 6.2 (3.3) 4.7 (3.7) <0.001 0.276

SDS-social 6.8 (2.8) 4.9 (3.4) 7.2 (2.6) 5.2 (3.3) <0.001 0.885

SDS-family 6.9 (2.2) 4.0 (3.1) 6.5 (2.5) 4.5 (3.1) <0.001 0.264

EWPS total 62.8 (30.6) 46.1 (26.1) 49.7 (21.0) 46.1 (26.1) 0.045 0.237

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

*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.

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

DSST RAVLT acquisition RAVLT delayed recall

Stan

dard

ized

Effe

ct S

ize

vs

Pla

cebo

Vortioxetine 5 mg/day (n = 156) Duloxetine 60 mg/day (n = 151)

* * *

* †

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

Week 8: FAS, ANCOVA, Cohen’s d

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

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.

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).

DSST Vortioxetine 5 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%

Examining the Evidence for Direct Impact on Cognitive Symptoms in MDD

Independent effect indicated by a priori specification, cognition as primary; pathoanalysis; subgroup analysis in non-responders and non-remitters. 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.

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

“Cognitive Remission” Emerging Concept, Emerging Agents

Bortolato B, et al. BMC Med. 2016;14:9.

Ascending level of evidence for Cognitive Symptom Improvement

Vortioxetine 5-HT3/5HT7 receptor antagonist; partial agonist at the 5-HT1B receptor; agonist at 5 HT1A receptor; inhibitor of the 5-HT transporter

Lisdexamfetamine dimesylate

D-amphetamine prodrug; enhances the efflux of dopamine and norepinephrine in the CNS

Erythropoietin Readily crosses the BBB and increases the production of BDNF

Minocycline Promotes hippocampal neurogenesis; Antiapoptotic effects; Anti-inflammatory activity; Antioxidant; Modulates glutamatergic transmission; Stabilizes the microglia

Thiazolidinediones Antagonist of PPAR-gamma; increased the production of BDNF; has anti-inflammatory and antioxidant activities

S-adenosyl methionine Major methyl-donor; essential for the synthesis of several neurotransmitters; involved in the synthesis of glutathione

Omega-3 PUFAs Anti-inflammatory and antioxidant activities; increases the production of BDNF; diminishes microglia-related neuro-inflammation

Modafinil Pleotropic agent that targets several neurotransmitter systems (eg, 5-HT, GABA, glutamate, orexin, and histamine)

Galantamine Rapidly reversible acetylcholinesterase inhibitor and a potent modulator of the nicotinic receptor; affects monoamines, GABA and glutamate neurotransmitter systems

Scopolamine Potent muscarinic antagonist; modulates 5-HT, neuropeptide Y, dopaminergic, and glutamatergic systems

N-acetylcysteine Pleotropic agent that modulates glutamate transmission; antioxidant; anti inflammatory effect; anti-apoptotic activity; increases glutathione

Statins Increases BDNF; antioxidant; anti inflammatory; inhibits the enzyme IDO; modulates the microglia

We Clinicians Should Re-examine Our Own Understanding of Cognitive Symptoms in MDD

Darcet F, et al. Pharmaceuticals. 2016;9(1).

Those cognitive signs can persist even after remission or recovery of MDD symptoms.

An early onset of cognitive symptoms in depression has been reported before the clinical diagnosis.

Normal State

Response

Remission

Recovery

Magnitude of:

First Episode Relapse Recurrence

– Depressive Symptoms

– Cognitive Symptoms

Stakeholders Need to Come to a Consensus

Rush AJ, et al. Neuropsychopharmacology. 2006;31(9):1841-1853.

Previous and Current “Gold” Standard: For MDD, remission is the recommended goal of

treatment

But, is this the new Gold Standard? v  Absence of significant MDD symptoms for ≥ 2 months

v  Improvement in Function, Work Productivity, and Cognition

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

Take-Home Messages 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 2017