Enabling Discovery, Development, and Translation of Treatments for Cognitive Dysfunction in Depression Workshop Summary (2015) / Chapter Skim
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4 Challenges and Potential Solutions to Enable Development of Successful Treatments
4 Challenges and Potential Solutions to Enable Development of Successful Treatments
Pages 25-42
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. • Subjective and objective measures of cognition both have value in assessing treatment effects, yet both also have disadvantages and of ten do not correlate with one another (Areán, Fava, Harvey)
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Neuropsychological tests may also be useful to detect early signs of depression or predict response to treatment. Amit Etkin described the International Study to Predict Optimized Treatment in Depression (iSPOT-D)
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The battery included tests of psychomotor function, decision speed, verbal memory, working memory, cognitive flexibility, attention, response inhibition, information processing speed, executive function, emotion identification reaction time, and emotion bias reaction time. The study showed that a subgroup of depressed patients that could be discriminated based on cognitive test performance had poorer treatment outcomes, suggesting that a composite biomarker based on the antidepressant outcome and test performance could be used to predict treatment outcome (Etkin et al., 2014)
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. In comparison to healthy controls, depressed patients find it much more difficult to perform this task; however, after just one dose of the noradrenergic reuptake inhibitor reboxetine, patients show an improved ability to recognize happy facial expressions.
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. In both healthy controls and depressed patients in remission, vortioxetine treatment improved both subjective and objective measures of cognition and resulted in decreased neural activity across the brain regions that are affected in depression, that is, a reduced activation of the DLPFC and increased deactivation of parts of the DMN.
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is an example of this approach. The CONNECT study compared vortioxetine and duloxetine, both active agents, against a placebo with results demonstrating that both treatments significantly improved depressive symptoms based on the MADRS scale, but only vortioxetine was found to be efficacious in improving cognitive function in depressive patients (Mahableshwarkar et al., 2015)
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For example, for a trial of an augmentation therapy, enrichment with patients who have residual cognitive symptoms may make the most sense. Stratifying patients into narrow groups for clinical trials may, in addition to improving the efficiency of the trial, help deal with pseudospecificity, said Richard Keefe.
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Other changes in design that were mentioned by several participants included assessing changes over time rather than only at baseline and end of study, and identifying signals that can be assessed in 1 week or 48 hours to enable faster trials, particularly in Phases I and II. Adaptive approaches such as those used in the I-SPY2 TRIAL for breast cancer therapies might also be useful for testing treatments for cognitive impairment in depression, said Thomas Insel (Barker et al., 2009)
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Cognition Versus Function Naturally, cognitive measures are widely used in studies to assess the effects of a treatment on cognition, but the need to find measures that are clinically meaningful to patients has prompted many investigators to consider functional measures as an alternative or adjunct. Harvey and colleagues conducted a study of clinically stable patients with schizophrenia, schizoaffective disorder, bipolar disorder, and depression, using a battery of neuropsychological tests assessing eight cold cognitive domains.
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. A recent meta-analysis of studies using objective measures of impaired cognition in depression showed that several tests -- including the Stroop task, Trail Making Test B (TMT-B)
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and grreater functio onal impairmeent, whereas objective imp mpairment corrrelated only o with funnctional impaiirment, but noot severity. Inn the lisdexam mfetamin ne study meentioned earlier, both seelf- and infoormant-reportted measures showed significant s impprovement, bbut a computeerized cognitiive test baattery did not (Madhoo et al., a 2014)
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Moreover, she and Harvey added that in depression, even so-called objective measures are affected by amotivation and anhedonia, and that this can confound the results. Co-Primary Measures Harvey noted that in both Alzheimer's disease and schizophrenia trials, regulators have asked for co-primary measures in addition to cognitive performance, and both performance-based and interview-based measures have been used to determine functional capacity.
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. Harvey concluded that validated performance-based measures of functional capacity that are related to everyday outcomes are optimal for assessing treatment outcomes.
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Innovative Tools for Assessment Many participants spoke of the need to embrace innovation for the assessment and treatment of cognitive impairment in depression. Assessment can benefit from increased use of technology, ranging from the development of touchscreen computerized tests of hot cognition with domains including emotional processing, social cognition, motivation, and reward to the use of ubiquitous computing tools.
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In designing these tools, developers have been cognizant of the need not only to accurately assess cognition, but also to engage patients in the activity through games and provide outcome measures that are meaningful to patients. Many of these tools offer an additional advantage in that they can be adapted to individual performance at baseline or as the trial progresses, analyzing data in real time and optimizing information from previous trials.
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It will use an eextensive rannge of mag gnetic resonaance imaging g and cognitivve testing, allong with addditional clinical testin ng and biomaarkers, at mulltiple frequennt intervals ovver the course of threee months. Thee goal is thatt these biomaarkers could be used inn a range of follow-on f trialls.2 FIGUR RE 4-2 In-deptth assessment of o cognition inn depression annd frequent monnitoring of o changes in severity.
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Future Directions in Assessment In addition to the need to embrace innovation, a major issue that arose during workshop discussions was the need for alignment on appropriate assessments to use in clinical trials. Two approaches to assessment that seemed diametrically opposed emerged: (1)
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He argued that something more proximal to brain changes is important because so many factors (work, social life, etc.) influence functional measures.
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