CAPA 2015 Annual Conference

Transcription

1 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 ϒ Live meetings at AAPA State Chapters and AANP State Organizations ϒ Three Clinical Case Challenges posted on mycme.com ϒ 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 Catherine R. Judd, MS, PA-C Department of Psychiatry Psychoneuroendocrine Group UT Southwestern Medical Center Dallas, TX Cherri L. Penne-Myers, PA-C Physician Assistant Newport Beach, CA 1

2 Learning Objectives At the conclusion of this activity, participants will be better able to: ϒ 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 ϒ Identify patients who might benefit from new pharmacologic treatment options The Impact of Cognitive Symptoms in MDD Cognitive Symptoms in MDD ϒ Among the core symptom domains included in the diagnostic criteria for a major depressive episode 1 ϒ >30% of patients who otherwise respond to antidepressant therapy report residual cognitive symptoms (forgetfulness, inattentiveness, mental slowing, apathy, and word-finding difficulty) 2 ϒ 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: Fava M, et al. J Clin Psychiatry. 2006;67:

3 Cognitive Symptoms in MDD (cont d) ϒ May predate onset of MDD episode ϒ Distinct neurobiology ϒ Heritable ϒ Some deficits may improve with antidepressant therapy ϒ Differences in antidepressant effects on cognition ϒ Often persist after treatment ϒ Impact quality of life and functional outcomes Trivedi M, Greer TL. J Affect Disord. 2014;152: Key Domains of Cognitive Function in MDD ATTENTION DOMAIN: Real-life manifestations: MEMORY DOMAIN: Real-life manifestations: EXECUTIVE FUNCTION DOMAIN: Real-world manifestations: PSYCHOMOTOR SPEED DOMAIN: Real-world manifestations: The ability to focus on several possible objects or trains of thought Difficulty with concentration, focus, attention Includes visual and verbal memory, episodic memory (time and places), semantic memory (meaning of things) Forgetfulness, word-finding difficulties Includes inhibition, working memory, mental flexibility, verbal fluency, planning, and problem-solving Indecisiveness: inability to prioritize, multi-task, make decisions, or plan The time to perform motor actions that arise from mental activity (eg, reaction time, information-processing speed, and slowed speech) Slow processing, slow speech, slow response The Diagnostic and StatisticalManual 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-D 17 = Hamilton Depression Scale. McIntyre RS, et al. Compr Psychiatry. 2015;56:

4 Decline in Gray Matter Volume in Patients with MDD Compared to Healthy Controls ϒ 3-year prospective study comparing 38 patients with 30 healthy controls ϒ Significant decline in gray matter density was noted in the hippocampus, amygdala, ACC, and DMPFC ϒ Threshold was set at P<.001 Frodl TS, et al. Arch Gen Psychiatry. 2008;65: 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 Poster P.1.j.006. Determinants of Cognitive Symptoms in Depression ϒ Patient s current age/age at onset ϒ Depression severity at onset ϒ Childhood adversity ϒ Level of educational attainment ϒ Frequency/duration of depressive episodes ϒ MDD subtype ϒ Medical/psychiatric comorbidity ϒ Remission status ϒ Treatment McIntyre RS, et al. Compr Psychiatry. 2015;56:

5 Measurement of Cognitive Impairment Clinical Trials ϒ Domains measured/measurement tools utilized vary across trials ϒ Objective testing: neuropsychologic battery ϒ Mini-Mental State Examination, Montreal Cognitive Assessment not sensitive enough for use in MDD ϒ 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 ϒ Significant deficits in executive function, memory, and attention 700 MDD and 700 control subjects (24 studies) ϒ 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: Raising the Bar: Evolving Treatment Goals for MDD Cognitive remission Improved QoL 2014 Functional remission Improved function ~2010 Remission Response ~2000 Symptom reduction QoL = quality of life. McIntyre RS. J Clin Psychiatry. 2013;74: Before

6 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 * 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 *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-SR 16. Presence of symptoms was indicated by a QIDS-SR 16 domain score 1. McClintock SM, et al. J Clin Psychopharmacol. 2011;31: MDD-Related Cognitive Dysfunction Tends to Be Persistent ϒ Up to to 50% of individuals with MDD have a suboptimal therapeutic response 1 ϒ 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-up 2 1. Baune BT, et al. Psychiatry Res. 2010;176: Nierenberg AA, et al. Psychol Med. 2010;40:

7 Traditional Antidepressants: Effects on Cognition ϒ Any improvements in cognition were secondary to improvements in mood symptoms ϒ 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 ϒ Some antidepressants worsen cognitive deficits ϒ 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: ; Fava M, et al. J Clin Psychiatry. 2006;67: ;Greer TL, et al. CNS Drugs. 2010;24: ; Herrera-Guzman I. J Affect Disord.2010;123: ;McClintock SM, et al. J Clin Psychopharmacol.2011; 31: ; Trivedi MH, Daly EJ. Dialogues Clin Neurosci. 2008;10: ; Millan MJ, et al. Nat Rev Drug Discov. 2012;11: 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; Richelson E. Int J Neuropharmacol. 2013;16: Mork A, et al. ENCP Poster P.2.e.002. Vortioxetine Effect on Cognitive Performance Primary end point: composite z-score (DSST / RAVLT acq / RAVLT delay ) at Week 8 vs placebo (FAS, MMRM) Secondary Analyses in Test Hierarchy Difference From Placebo Vortioxetine 10 mg Vortioxetine 20 mg DSST 4.20* 4.26* RAVLT acq RAVLT delay NCT *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:

8 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) Preference Score (%) Alteration (%) Occupancy (%) SERT 88 >90 95 EEG = electroencephalography; PCPA = 4-chloro-DL-phenylalanine Mork A, et al. ECNP Poster P.2.e.002. * P<.05, P<.01, P<.001 vs control; P<.05 vs PCPA 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 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) Similar long-term adverse event profile to that observed during short-term treatment 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%) TEAEs = treatment-emergent adverse events. Filippov G, et al. ENCP Poster P.2.b.011. Safety and Tolerability of Vilazodone Incidence (% of patients) Vilazodone (n=436) Placebo (n=433) 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:

9 Investigational Compounds With Potential Procognitive Effect ϒ Modafinil Considered an effective augmentation strategy for both acute unipolar or bipolar depressive episodes 1 4-week, open-label study in 35 patients with a history of MDD 2 ϒ Donepezil Partial response of depressive symptoms; some improvement of cognitive function Available evidence to date does not suggest a clear benefit as adjunctive therapy to antidepressants for cognitive enhancement 3 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: DeBattista C, et al. J Clin Psychopharmacol. 2004;24: Reynolds CF 3rd. Arch Gen Psychiatry. 2011;68: Investigational Compounds With Potential Procognitive Effect (cont d ) ϒ Ketamine May have neuroprotective effects, including in an ECT treatment context 1,2 Additional clinical trials are ongoing ϒ S-adenosyl-methionine (SAME-E) Superior to placebo and comparable to tricyclic antidepressants for MDD symptoms 3 Preliminary evidence shows improved recall information and a trend toward a greater enhancement in word-finding in depressed patients treated with oral, adjunctive SAM-E 4 1. Hudetz JA, Pagel PS. J Cardiothorac Vasc Anesth. 2010;24: MacPherson RD, Loo CK. J ECT. 2008;24: Papakostas GI, et al. J Clin Psychiatry. 2009;70(suppl 5): Levkovitz Y, et al. Eur Psychiatry. 2012;27: Investigational Compounds With Potential Procognitive Effect (cont d) ϒ Erythropoietin (EPO) Single high dose may enhance memory/executive function 1 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 placebo 2 in patients with TRD ϒ 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: Miskowiak KW, et al. Biol Psychiatry Dec Madhoo M, et al. Neuropsychopharmacology. 2014;39:

10 Alternative Therapeutic Strategies to Address Cognitive Symptoms Therapeutic Approach Influence on Emotional Symptoms Influence on Cognitive Impairment Cognitive behavioral therapy ± Cognitive remediation therapy ±/ Deep-brain stimulation or electroconvulsive therapy Repetitive transcranial magnetic stimulation Currently available pharmacotherapy Improved drugs (alone and in combination with above strategies) Psychiatric Disorders Targeted Mainly depression (anxiety disorders) Mainly schizophrenia (depression) ±/ Major depression ±/ = improvement; = worsening; ± = no marked change. Millan ML, et al. Nat Rev Drug Discov. 2012;11: ±/ Mainly depression (autism, schizophrenia) Schizophrenia, depression, bipolar disorder, anxiety disorders Dependent on mechanism of action Targeting Cognitive Deficits in MDD: Cognitive Remediation ϒ Potential aim: to exercise specific pathways with the goal of remediating specific areas of cognitive function ϒ Methods: using behavioral strategies to improve a range of neuropsychologic domains, such as memory and executive functioning ϒ 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: Measurement-Based Care for MDD ϒ 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): American Psychiatric Association. Accessed March 30,

11 Establishing a Therapeutic Alliance Early in Treatment Is a Powerful Remission Tool Improvement (HRSD T1 T2) Β=.46, P= Change of Attunement During First Clinical Interview HRSD = Hamilton Rating Scale for Depression. Geerts E, et al. J Affect Disord. 1996;40: Krupnick JL, et al. J Consult Clin Psychol. 1996;64: Summary ϒ Cognitive symptoms of MDD are especially difficult to treat and frequently persist even when patients are otherwise responsive to an antidepressant ϒ Traditional antidepressants frequently failed to adequately address cognition ϒ 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 ) ϒ Alternative approaches especially cognitive therapy may be helpful ϒ The goal of MDD remains: remission of all symptoms, including cognition ϒ 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 ϒ As with any chronic disease, the patient-provider relationship is paramount for good outcomes 11