Focus on Addressing
Cognitive Symptoms
Provided by
In collaboration with
Sponsored by
an educational grant from
Program Overview
Part of a 3-component activity for PAs and NPs on
achieving sustained remission in MDD
 Live meetings at AAPA State Chapters and AANP
State Organizations
 Three Clinical Case Challenges posted on
myCME.com
 Print monograph, a supplement to:
– JAAPA
– The Clinical Advisor
Content Development Faculty
Charles L. Raison, MD
Mary Sue and Mike Shannon Chair for
Healthy Minds, Children & Families
Professor, School of Human Ecology
Professor, Department of Psychiatry
School of Medicine and Public Health
University of Wisconsin
Madison, WI
Sattaria S. Dilks, DNP, APRN, FAANP
Professor and Co-Coordinator
Graduate Program
College of Nursing
McNeese State University
Lake Charles, LA
Cindy Parsons, DNP, PMHNP-BC,
FAANP
Staff Assistant
Department of Nursing
University of Tampa
Tampa, FL
Learning Objectives
At the conclusion of this activity, participants
will be better able to:
 Assess the impact of acute and residual
symptoms of cognitive dysfunction in MDD
on patient function, quality of life, risk for
relapse, and long-term outcomes
 Identify patients who might benefit from
new pharmacologic treatment options
The Impact of
Cognitive
Symptoms
in MDD
Cognitive Symptoms in MDD
 Among the core symptom domains included in the
diagnostic criteria for a major depressive episode1
 >30% of patients who otherwise respond to
antidepressant therapy report residual cognitive
symptoms (forgetfulness, inattentiveness, mental
slowing, apathy, and word-finding difficulty)2
 Prevalence:
– Among all adults with MDD: 30% - 40%1
– Among MDD patients >65 years: 50% - 60%2
1. Poletti S, et al. J Affect Disord. 2014;156:144-149. 2. Fava M, et al. J Clin Psychiatry. 2006;67:1754-1759.
Cognitive Symptoms in MDD (cont’d)
 May predate onset of MDD episode
 Distinct neurobiology
 Heritable
 Some deficits may improve with antidepressant
therapy
 Differences in antidepressant effects on cognition
 Often persist after treatment
 Impact quality of life and functional outcomes
Trivedi M, Greer TL. J Affect Disord. 2014;152:19-27.
4 Key Domains of Cognitive Function
in MDD
ATTENTION DOMAIN:
The ability to focus on several possible objects or trains
of thought
Real-life manifestations:
Difficulty with concentration, focus, attention
MEMORY DOMAIN:
Includes visual and verbal memory, episodic memory
(time and places), semantic memory (meaning of things)
Real-life manifestations:
Forgetfulness, word-finding difficulties
EXECUTIVE FUNCTION
DOMAIN:
Includes inhibition, working memory, mental flexibility,
verbal fluency, planning, and problem-solving
Real-world
manifestations:
Indecisiveness: inability to prioritize, multi-task, make
decisions, or plan
PSYCHOMOTOR SPEED
DOMAIN:
The time to perform motor actions that arise from
mental activity (eg, reaction time, information-processing
speed, and slowed speech)
Real-world
manifestations:
Slow processing, slow speech, slow response
The Diagnostic and Statistical Manual of Mental Disorders (5th ed.;DSM–5; American Psychiatric Association [APA], 2013.
Cognitive Symptoms in Measures of
Workplace Performance
Cognitive Measures Account for More Variability in
Workplace Functioning Than Total Depression Severity
N=260; HAM-D17 = Hamilton Depression Scale.
McIntyre RS, et al. Compr Psychiatry. 2015;56:279-282.
Decline in Gray Matter Volume in Patients
with MDD Compared to Healthy Controls
 3-year prospective study
comparing 38 patients
with 30 healthy controls
 Significant decline in
gray matter density
was noted in the
hippocampus, amygdala,
ACC, and DMPFC
 Threshold was set
at P<.001
Frodl TS, et al. Arch Gen Psychiatry. 2008;65:1156-1165.
Association Between Cognitive Function,
Disability, and QoL in Patients Treated for
Depression
Cognitive dysfunction group had significantly
greater impairments on the SDS
Conclusion: correlation between objectively measured cognitive
dysfunction and poorer patient-reported quality of life and disability
Kurlander JL, et al. ECNP 2013. Poster P.1.j.006.
Determinants of Cognitive Symptoms
in Depression
 Patient’s current age/age at onset
 Depression severity at onset
 Childhood adversity
 Level of educational attainment
 Frequency/duration of depressive episodes
 MDD subtype
 Medical/psychiatric comorbidity
 Remission status
 Treatment
McIntyre RS, et al. Compr Psychiatry. 2015;56:279-282.
Measurement of Cognitive
Impairment—Clinical Trials
 Domains measured/measurement tools utilized vary
across trials
 Objective testing: neuropsychologic battery
 Mini-Mental State Examination, Montreal Cognitive
Assessment not sensitive enough for use in MDD
 Subjective tests for clinical use
– Perceived Deficits Questionnaire (PDQ)
– MGH Cognitive and Physical Functioning
Questionnaire (CPFQ)
– British Columbia Cognitive Complaint
Inventory (BC-CCI)
Consistency of Cognitive Impairment in
MDD: Meta-analysis
 Significant deficits in executive function, memory,
and attention
– 700 MDD and 700 control subjects (24 studies)
 Significant deficits in executive function and attention
– 270 unmedicated MDD and 270 controls (8 studies)
“Cognitive impairment represents a core feature
of depression that cannot be considered an
epiphenomenon that is secondary to mood symptoms…”
Rock PL, et al. Psychol Med. 2014;44:2029-2040.
Raising the Bar: Evolving Treatment
Goals for MDD
Cognitive remission
Improved QoL
Functional remission
Improved function
Remission
~2000
Response
Symptom reduction
QoL = quality of life.
McIntyre RS. J Clin Psychiatry. 2013;74:14-18.
Before 1990
~2010
2014
Strategies for
Addressing
Cognitive
Symptoms
in MDD
What Does Failure to Remit Look Like in Those
Who Respond to an Antidepressant?
Proportion of responders who had symptoms at baseline that persisted at exit*
81.6
Midnocturnal Insomnia
Sad Mood
Concentration/Decision-Making
Energy
Restlessness
Hypersomnia
Sleep-Onset Insomnia
General Interest
Early-morning Insomnia
Negative Self-view
Slowed Down
Increased Weight
Decreased Appetite
Increased Appetite
Decreased Weight
Suicidal Ideation
70.8
70.6
64.6
63
60.4
57.5
55
49
38.9
35.6
35.5
31
27.8
25.1
17.1
0
20
40
60
80
*Percentages are reported as the remaining percent of those with each symptom at baseline that continued to
have the symptom at exit. Response was defined as ≥50% reduction in QIDS-SR16. Presence of symptoms was
indicated by a QIDS-SR16 domain score ≥1.
McClintock SM, et al. J Clin Psychopharmacol. 2011;31:180-186.
100
MDD-Related Cognitive Dysfunction
Tends to Be Persistent
 Up to to 50% of individuals with MDD have a
suboptimal therapeutic response1
 Among individuals deemed responsive to
antidepressant therapy (n=267), cognitive
problems, lack of energy, and sleeping
difficulties were present for nearly half the
time during remissions (39% to 44%) and most
of the time (85% to 94%) during depressive
episodes over 3 years of follow-up2
1. Baune BT, et al. Psychiatry Res. 2010;176:183-189. 2. Nierenberg AA, et al. Psychol Med. 2010;40:41-50.
Traditional Antidepressants:
Effects on Cognition
 Any improvements in cognition were secondary to
improvements in mood symptoms
 To date, no conventional antidepressant has shown significant
improvements in cognitive symptoms
– MDD patients who achieve remission of other symptoms
often have persistent cognitive deficits
 Some antidepressants worsen cognitive deficits
 Study limitations: small sample sizes; lack of replication; not
always placebo-controlled; cognitive function not primary
endpoint; largest studies conducted in the elderly, or in
populations with large age range
McIntyre RS, et al. Depress Anxiety. 2013;30:515-527; Fava M, et al. J Clin Psychiatry. 2006;67:1754-1759;Greer TL, et al. CNS Drugs.
2010;24:267-284; Herrera-Guzman I. J Affect Disord. 2010;123:341-350; McClintock SM, et al. J Clin Psychopharmacol. 2011;
31:180-186; Trivedi MH, Daly EJ. Dialogues Clin Neurosci. 2008;10:377-384; Millan MJ, et al. Nat Rev Drug Discov. 2012;11:141-168.
New Multimodal Antidepressants
Reuptake inhibitors + 5-HT receptor actions to
add to the efficacy and/or reduce adverse effects
Vilazodone
Vortioxetine
Other multimodal drugs in development: brexpiprazole, amitifadine
SERT = serotonin transporter.
Nutt DJ. J Psychopharmacol. 2009;23;343-345.
Richelson E. Int J Neuropharmacol. 2013;16:1433-1442.
Mork A, et al. ENCP 2013. Poster P.2.e.002.
Vortioxetine Effect on Cognitive
Performance
Primary end point: composite z-score (DSST / RAVLTacq / RAVLTdelay)
at Week 8 vs placebo (FAS, MMRM)
Secondary Difference From Placebo
Analyses
Vortioxetine Vortioxetine
in Test
10 mg
20 mg
Hierarchy
DSST
4.20*
4.26*
RAVLTacq
1.02†
0.59†
RAVLTdelay
0.71‡
0.65‡
NCT01422213
*P<.001; †P<.05; ‡P<.01; vs placebo.
DSST = Digit Symbol Substitution Test; RAVLT = Rey Auditory Verbal Learning Test; acq = acquisition;
delay = delayed recall; FAS = full analysis set; MMRM = mixed model for repeated measurements.
*Vortioxetine is not FDA approved for treatment of cognitive impairment.
McIntyre RS, et al. Int J Neuropsychopharmacol. 2014;17:1557-1567.
Preclinical Comparison of Vortioxetine,
SSRIs, and SNRIs in Cognitive Function
Study Assessed Cognitive Function Using Quantitative EEG Measurers and a Novel
Object Recognition Memory Task in Normal and 5-HT-Depleted Rats
Episodic Memory (novel object recognition test)
Spatial Memory (spontaneous alteration)
§
Alteration (%)
Preference Score (%)
§
Occupancy (%)
SERT
88
>90
*P<.05, †P<.01, ‡P<.001
vs control; §P<.05 vs PCPA
95
 Vortioxetine restored memory deficits induced by 5-HT depletion; escitalopram and duloxetine did not
 Results suggest a role for vortioxetine in modulating cortical networks recruited during cognitive behavior
EEG = electroencephalography; PCPA = 4-chloro-DL-phenylalanine
Mork A, et al. ECNP 2013. Poster P.2.e.002.
Long-term Safety and Tolerability of
Vortioxetine
52-Week, Long-term,
Open-Label, FlexibleDose Extension Study
of Vortioxetine 15 or
20 mg/day
Preferred Term
TEAEs reported by at least
5 patients (N=71)
Similar long-term
adverse event profile
to that observed during
short-term treatment
TEAEs = treatment-emergent adverse events.
Filippov G, et al. ENCP 2013. Poster P.2.b.011.
Patients (N, %)
Patients with TEAEs
56 (78.9%)
Nausea
22 (31.0%)
Dizziness
14 (19.7%)
Headache
14 (19.7%)
Nasopharyngitis
9 (12.7%)
Insomnia
7 (9.9%)
Accidental overdose
5 (7.0%)
Dry mouth
5 (7.0%)
Sinusitis
5 (7.0%)
Incidence (% of patients)
Safety and Tolerability of Vilazodone
30
25
Vilazodone (n=436)
Placebo (n=433)
20
15
10
5
0
Short-term tolerability of oral vilazodone in adult patients with MDD.
Incidence of treatment-emergent adverse events occurring in ≥5% of vilazodone patients.
40-mg, once-daily recipients in two 8-week, double-blind, placebo-controlled studies (pooled results).
Frampton JE. CNS Drugs. 2011;25:615-627.
Investigational Compounds With
Potential Procognitive Effect
 Modafinil
– Considered an effective augmentation strategy for both acute
unipolar or bipolar depressive episodes1
– 4-week, open-label study in 35 patients with a history of MDD2
• Partial response of depressive symptoms; some improvement of
cognitive function
 Donepezil
– Available evidence to date does not suggest a clear benefit as
adjunctive therapy to antidepressants for cognitive enhancement3
– Clinical trial to assess cognitive improvement for a large sample of
cognitively impaired MDD patients with combined treatment of
antidepressant/donepezil is ongoing
1. Goss AJ, et al. J Clin Psychiatry. 2013;74:1101-1107. 2. DeBattista C, et al. J Clin Psychopharmacol. 2004;24:87-90.
3. Reynolds CF 3rd. Arch Gen Psychiatry. 2011;68:51-60.
Investigational Compounds With
Potential Procognitive Effect (cont’d )
 Ketamine
– May have neuroprotective effects, including in an ECT
treatment context1,2
– Additional clinical trials are ongoing
 S-adenosyl-methionine (SAME-E)
– Superior to placebo and comparable to tricyclic antidepressants
for MDD symptoms3
– Preliminary evidence shows improved recall information and a
trend toward a greater enhancement in word-finding in
depressed patients treated with oral, adjunctive SAM-E4
1. Hudetz JA, Pagel PS. J Cardiothorac Vasc Anesth. 2010;24:131-142. 2. MacPherson RD, Loo CK. J ECT.
2008;24:52-56. 3. Papakostas GI, et al. J Clin Psychiatry. 2009;70(suppl 5):18-22. 4. Levkovitz Y, et al. Eur
Psychiatry. 2012;27:518-521.
Investigational Compounds With
Potential Procognitive Effect (cont’d)

Erythropoietin (EPO)
– Single high dose may enhance memory/executive function1
– Follow-up, randomized, double-blind, placebo-controlled study: sustained
improvements in verbal learning and memory after repeated EPO
administrations as adjunctive treatment (8 weekly infusions of 1 ml
recombinant EPO—doses of 40,000 UI) versus placebo2 in patients with TRD

Lisdexamfetamine (LDX)
– Randomized, double-blind, placebo-controlled, parallel-group study for
treating executive dysfunction in patients on antidepressant therapy with full
or partial remission of other symptoms
• In addition to improvement of any residual depressive symptomatology, patients treated with
LDX displayed greater executive improvement compared with placebo
1. Miskowiak KW, et al. Psychopharmacology (Berl). 2012;219:687-698. 2. Miskowiak KW, et al.
Biol Psychiatry. 2014 Dec 18. 3. Madhoo M, et al. Neuropsychopharmacology. 2014;39:1388-1398.
Alternative Therapeutic Strategies to
Address Cognitive Symptoms
Therapeutic Approach
Cognitive behavioral therapy
Cognitive remediation therapy
Deep-brain stimulation or
electroconvulsive therapy
Repetitive transcranial magnetic
stimulation
Influence on
Emotional
Symptoms
Influence on
Cognitive
Impairment
Psychiatric
Disorders
Targeted
↑
±
Mainly depression
(anxiety disorders)
±/↑
↑
Mainly schizophrenia
(depression)
↑
±/↓
Major depression
±/↑
±/↑
Mainly depression
(autism, schizophrenia)
Currently available
pharmacotherapy
↑
↑
Schizophrenia,
depression, bipolar
disorder, anxiety
disorders
Improved drugs (alone and in
combination with above strategies)
↑
↑
Dependent on
mechanism of action
↑ = improvement; ↓ = worsening; ± = no marked change.
Millan ML, et al. Nat Rev Drug Discov. 2012;11:141-168.
Targeting Cognitive Deficits in MDD:
Cognitive Remediation
 Potential aim: to exercise specific pathways
with the goal of remediating specific areas of
cognitive function
 Methods: using behavioral strategies to
improve a range of neuropsychologic domains,
such as memory and executive functioning
 Techniques: cognitive control training sessions,
computer games, group discussion, homework,
application to real-life situations
Bowie CR, et al. J Nerv Ment Dis. 2013;201:680-685.
Measurement-Based Care for MDD
 Systematically use measurement tools to
monitor progress and guide treatment choices
– Regularly scheduled visits
– Time-efficient, validated tools
– Regularly monitoring symptom improvement,
side effects, medication adherence
– Use a treatment algorithm with established
critical decision points
Trivedi MH. J Clin Psychiatry. 2009;70(suppl 6):26-31. American Psychiatric Association.
http://psychiatryonline.org/data/Books/prac/PG_Depression3rdEd.pdf. Accessed March 30, 2015.
Establishing a Therapeutic Alliance Early in
Treatment Is a Powerful Remission Tool
Improvement (HRSD T1–T2)
35
Β=.46, P=.009
30
25
20
15
10
5
0
-5
-1.5
-1.0
-0.5
0.0
0.5
1.0
Change of Attunement During
First Clinical Interview
HRSD = Hamilton Rating Scale for Depression.
Geerts E, et al. J Affect Disord. 1996;40:15-21. Krupnick JL, et al. J Consult Clin Psychol. 1996;64:532-539.
Summary
 Cognitive symptoms of MDD are especially difficult to
treat and frequently persist even when patients are
otherwise responsive to an antidepressant
 Traditional antidepressants frequently failed to
adequately address cognition
 New multimodal antidepressants appear to be
particularly efficacious in targeting the residual
symptoms of MDD, particularly in regard to cognitive
deficits, with favorable side-effect profiles
– However, not all patients may be candidates for these
therapies; individualization of therapy is key
Summary (cont’d )
 Alternative approaches—especially cognitive
therapy—may be helpful
 The goal of MDD remains: remission of all symptoms,
including cognition
 It is critical to continuously monitor therapeutic
response and make adjustments accordingly
– A number of validated instruments have been developed to
facilitate monitoring of response
 As with any chronic disease, the patient-provider
relationship is paramount for good outcomes