focus on addressing cognitive symptoms provided by in collaboration with sponsored by an educational...
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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