Focus on Addressing Cognitive Symptoms

Provided by In collaboration with Sponsored byan 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, MDMary Sue and Mike Shannon Chair for

Healthy Minds, Children & FamiliesProfessor, School of Human EcologyProfessor, Department of PsychiatrySchool of Medicine and Public HealthUniversity of WisconsinMadison, WI

Sattaria S. Dilks, DNP, APRN, FAANPProfessor and Co-Coordinator Graduate Program College of Nursing McNeese State University Lake Charles, LA

Cindy Parsons, DNP, PMHNP-BC, FAANPStaff AssistantDepartment of Nursing University of TampaTampa, 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

QoL = quality of life.McIntyre RS. J Clin Psychiatry. 2013;74:14-18.

Symptom reductionBefore 1990

Response

Remission~2000

Improved function

Functional remission~2010

Improved QoL

Cognitive remission2014

Strategies for Addressing Cognitive

Symptoms in MDD

What Does Failure to Remit Look Like in Those Who Respond to an Antidepressant?

*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.

0 20 40 60 80 100

Midnocturnal InsomniaSad Mood

Concentration/Decision-MakingEnergy

RestlessnessHypersomnia

Sleep-Onset InsomniaGeneral Interest

Early-morning InsomniaNegative Self-view

Slowed DownIncreased Weight

Decreased AppetiteIncreased AppetiteDecreased Weight

Suicidal Ideation

81.670.870.6

64.663

60.457.5

5549

38.935.635.5

3127.8

25.117.1

Proportion of responders who had symptoms at baseline that persisted at exit*

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

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.

Vilazodone

SERT

5-HT

1A

Vortioxetine

SERT

5-HT

1A

5-HT3

5-HT7

5-HT 1B5-HT10

Other multimodal drugs in development: brexpiprazole, amitifadine

Vortioxetine Effect on Cognitive Performance

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.

Primary end point: composite z-score (DSST / RAVLTacq / RAVLTdelay)at Week 8 vs placebo (FAS, MMRM)

Secondary Analyses in Test Hierarchy

Difference From Placebo

Vortioxetine 10 mg

Vortioxetine20 mg

DSST 4.20* 4.26*

RAVLTacq 1.02† 0.59†

RAVLTdelay 0.71‡ 0.65‡

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

EEG = electroencephalography; PCPA = 4-chloro-DL-phenylalanineMork A, et al. ECNP 2013. Poster P.2.e.002.

Occupancy (%)SERT 88 >90 95

*P<.05, †P<.01, ‡P<.001 vs control; §P<.05 vs PCPA

Pref

eren

ce S

core

(%)

Alte

ratio

n (%

)Escita

lopramContro

lPCPA

Vortioxetine

Duloxetine

Escitalopram

Control

PCPA

Vortioxetine

Duloxetine

Episodic Memory (novel object recognition test) Spatial Memory (spontaneous alteration)§

§

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

Long-term Safety and Tolerability of Vortioxetine

TEAEs = treatment-emergent adverse events.Filippov G, et al. ENCP 2013. Poster P.2.b.011.

52-Week, Long-term, Open-Label, Flexible-Dose Extension Study of Vortioxetine 15 or 20 mg/day

TEAEs reported by at least 5 patients (N=71)

Preferred Term 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%)

Similar long-term adverse event profile

to that observed during short-term treatment

Safety and Tolerability of Vilazodone

Frampton JE. CNS Drugs. 2011;25:615-627.

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).

Increased Appetite

Inci

denc

e (%

of p

atien

ts)

Weight Increased

Abnormal Dreams

Somnolence

Upper Respiratory Tract In

fection

Nasopharyngitis

Insomnia

Dry Mouth

Dizziness

HeadacheNausea

Diarrhea

Back PainAnxiety

VomitingFatigue

Placebo (n=433)Vilazodone (n=436)

20

15

30

25

10

5

0

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

Influence on Emotional Symptoms

Influence on Cognitive

Impairment

Psychiatric Disorders Targeted

Cognitive behavioral therapy ↑ ± Mainly depression (anxiety disorders)

Cognitive remediation therapy ±/↑ ↑ Mainly schizophrenia (depression)

Deep-brain stimulation or electroconvulsive therapy ↑ ±/↓ Major depression

Repetitive transcranial magnetic stimulation ±/↑ ±/↑ 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 inTreatment Is a Powerful Remission Tool

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.

35

-1.5

30

25

20

15

10

5

0

-5-1.0 -0.5 0.0 0.5 1.0

Change of Attunement During First Clinical Interview

Impr

ovem

ent (

HRS

D T

1–T2

) Β=.46, P=.009

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