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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