Standardized effect size (Cohen’s d) of vortioxetine (10 mg and 20 mg) on objective neuropsychological measures (McIntyre et al., 2014).
Several lines of evidence indicate that subjective measures of cognition at baseline minimally correlate with objective measures of cognition. Moreover, results from patient reported outcomes research indicate that measures that include patient perspective of cognitive function are prioritized as critical therapeutic objectives toward recovery in MDD (Zimmerman et al., 2006). Subjectively experienced cognitive function, as measured by PDQ, significantly improved in the vortioxetine treatment group on the total score as well as each of the subdomain scores (i.e. planning/organization, attention/concentration, prospective and retrospective memory). The latter results indicate that vortioxetine is improving both objective and subjective measures of cognitive function independent of their effect on depressive symptom severity.
The results of the McIntyre et al. (2014) study were replicated and extended in a similar trial that primarily evaluated vortioxetine’s effect on measures of cognition (i.e. DSST) in younger adults (i.e. 18–65) with recurrent, moderate-to-severe MDEs (i.e. MADRS score ≥ 26 at screening and baseline). In addition to meeting criteria for an MDE, eligible subjects also needed to report subjective cognitive function (slow thinking, difficulty focusing and learning or remembering new information). The primary efficacy parameter was change from baseline on the total score of the DSST. Additional secondary measures were the Groton Maze Learning Task, One-Back Task, Stroop Test, TMT (Part A and B), SRT and CRT, PDQ, and Cognitive and Physical Functioning Questionnaire (CPFQ). Along with measures of cognition, additional secondary measures were improvement in depression symptom severity as well as functional status, as measured by the University of California San Diego Performance-Based Skills Assessment (UPSA) and the Work Limitations Questionnaire (WLQ). Methodological approaches that aim to evaluate patient functional status are five-fold: (1) patient reported; (2) clinician reported; (3) informant reported; (4) in vivo evaluation (directly in ecosystem of interest); and (5) performance-based skills assessment. The UPSA has been validated, shown to be sensitive to change, is available in more than 20 languages, requires approximately 30 minutes for completion, and is demonstrated to be an easy to administer, repeat measure. The UPSA evaluates five domains: communication, finance, planning, transportation, and household chores. The UPSA brief (i.e. UPSA B) evaluates communication in finance only and has been shown to have a high level of correlation with UPSA (approximately 0.9) as well as with general cognitive measures (approximately 0.5) and negative symptoms (approximately 0.3) in adults with schizophrenia (Olsson, Helldin, Hjarthag, & Norlander, 2012; Patterson, Goldman, McKibbin, Hughs, & Jeste, 2001).
After eight weeks of flexible treatment with vortioxetine (10–20 mg) a significant change from baseline on the primary cognition measure (i.e. DSST) was observed in the vortioxetine-treated sample compared with the placebo-treated group. Duloxetine-treated subjects did not exhibit a significant change relative to placebo on the DSST. Path analysis indicated that 75.7 percent of vortioxetine’s effect on DSST was a direct effect while the direct effect for duloxetine on DSST was 48.7 percent. Significant benefit was also seen for vortioxetine and duloxetine on the PDQ total score. The estimated direct effect of vortioxetine on PDQ was 43 percent while for duloxetine it was 45 percent.
At the end of eight weeks of treatment, a significant benefit was seen in the vortioxetine-treated subjects on the UPSA composite total score versus placebo, but not in the duloxetine-treated subjects. It was determined that 97 percent of the effect of vortioxetine on UPSA was a direct effect compared to 67 percent for duloxetine. Moreover, it was determined that vortioxetine-treated subjects exhibited a significant improvement relative to the placebo group on the UPSA-B total score while the duloxetine-treated subjects exhibited a non-significant change from placebo.
A relatively small percentage of subjects completed the WLQ as subjects must have been employed for 14 days before baseline. This observation of low instrument completion makes the results of this particular instrument (which were non-significant for both groups) non-interpretable.
The results of the two studies with vortioxetine provide replicated, direct evidence of clinically significant effects on objective measures of cognitive function; an effect which is largely a direct effect and not attributable to depressive symptom improvement. The replication of studies indicates that along with an advantage for vortioxetine on measures of cognition, vortioxetine treatment was also associated with significant improvement in measures of function while duloxetine treatment was not. The results of the foregoing vortioxetine studies with duloxetine as a reference, along with results in the two foregoing geriatric studies, indicate that although vortioxetine and duloxetine have similar beneficial effects on depression symptom severity, there are significant differences between these two agents in their ability to improve measures of cognition. More specifically, duloxetine is capable of improving measures of learning and memory while vortioxetine improves a broader range of measures (i.e. executive function, learning and memory, processing speed, attention and concentration). Moreover, vortioxetine exerts a beneficial effect on self-rated measures of cognition and measures of functionality (Mahableshwarkar, Zajecka, Jacobson, Chen, & Keefe, 2014).
The link between improved measures of cognitive function and overall function/recovery underscores the importance of improving cognitive function in adults with MDD. For example, it has been reported that in adults with MDD who failed to recover successfully six months post discharge from hospital, measures of cognition are inferior to those with MDD who fully recover. Recent results from the International Mood Disorders Collaborative Project (IMDCP) representing collaboration between the Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, Toronto, Ontario, Canada, and the Cleveland Clinic, Cleveland, Ohio, USA, provide further evidence of the link between cognitive dysfunction and workplace function. The IMDCP analyzed results that included adults (n = 260; age 18–87) with DSM-IV-TR-defined MDD who were utilizing tertiary outpatient/inpatient services for MDD. Cognition was evaluated with the 18-item Attention Deficit/Hyperactivity Disorder Self-Report Scale (ASRS). The ASRS evaluates two domains: inattention and hyperactivity-impulsivity. The inattention subscale was used to evaluate subjective symptoms over the past six months. The ASRS includes measures of organization/planning, memory, attention, and information/processing speed. The primary question addressed is to what extent does the overall depression symptom severity (as measured by HAM-D-17) explain variance in workplace performance (as measured by the Endicott Work Productivity Scale (EWPS)). The EWPS assesses the degree of difficulty in accomplishing work objectives as well as changes in behavior related to work productivity, including absenteeism and presenteeism. It was determined that total depression symptom severity accounted for a relatively low percentage of variance on the EWPS (approximately 18%) while self-reported measures of cognition (i.e. ASRS) accounted for 58 percent of the variance on the EWPS scale. Taken together, results indicate that measures of cognition disproportionally account for the variance on functional outcomes when compared to total depressive symptom severity (McIntyre et al., 2010).
Psychostimulants
A robust and replicated body of controlled evidence indicates that psychostimulants as a class are not broadly effective in mitigating depressive symptoms in adults with MDD (Abbasowa, Kessing, & Vinberg, 2013). Notwithstanding, the pharmacodynamic profile of psychostimulants suggests that this class of agents would be predicted to be differentially effective in the cognitive domain in adults with MDD. In keeping with that view, a randomized, double-blind, placebo-controlled parallel multi-center study evaluated and compared the effect of lisdexamfetamine with placebo in adults with full or partial remission of depressive symptoms in MDD. Executive function was evaluated with a self-rated scale, BRIEF-A, which is a psychometrically validated executive function assessment tool. This study enrolled 143 adults (18–55 years of age) with mild depressive symptoms (MADRS score ≤ 18). The primary endpoint was change from baseline to week nine in BRIEF-A self-report. The secondary assessment included the BRIEF-A informant report as well as outcomes on MADRS. At the end of the study the lisdexamfetamine-treated subjects who had partially-to-fully remitted MDD and executive dysfunction exhibited greater improvement compared with placebo as measured by the BRIEF-A self-report scale. In addition to improvements in cognitive function, significant improvements in depressive symptoms were also reported. These results, which await replication, provide an important strategic approach (i.e. the domain-specific targeting of symptoms and dysfunction in MDD rather than the traditional “broad spectrum” approach) (Madhoo et al., 2014).
Modafinil has psychostimulant-like properties and has been demonstrated, with in vitro and in vivo studies, to block the reuptake of dopamine. Trial evidence in MDD suggests that modafinil, like psychostimulants, is not broadly “antidepressant”; notwithstanding, modafinil does exert a significant effect, relative to placebo, on measures of fatigue, and psychomotor performance. Modafinil’s beneficial effects on cognitive function have been demonstrated in healthy controls (Goss, Kaser, Costafreda, Sahakian, & Fu, 2013). The effect of modafinil on measures of cognitive function in younger individuals with MDD has not been sufficiently studied.
Neurostimulation
Electroconvulsive therapy (ECT) has well-established adverse effects on autobiographical memory. Notwithstanding, the totality of evidence indicates that ECT exerts a beneficial effect on measures of cognitive performance in adults with MDD. For example, a systematic review and meta-analysis of 84 studies comprising 2,981 patients was inclusive of 24 cognitive variables analyzed. It was concluded, somewhat surprisingly, that no standardized retrograde amnesia tests were identified. Significant decrease in cognitive performance was observed from 0 to 3 days following ECT treatment in 72 percent of variables. Effect sizes ranged from −1.10 to −0.21 four to 15 days post-ECT; all but one confidence interval included zero (or showed positive effect sizes). No negative effect sizes were observed after 15 days, with 57 percent of variables showing positive effects sizes, ranging from 0.35 to 0.75 (Semkovska & McLoughlin, 2010).
A compelling rationale exists for evaluating other neuromodulatory modalities with a specific emphasis on the beneficial effects on measures of cognitive function (e.g. rTMS). Preliminary evidence also indicates that deep brain stimulation (DBS) may have beneficial effects on measures of cognition (Bergfeld, Mantione, Hoogendoorn, & Denys, 2013; Demirtas-Tatlidede, Vahabzadeh-Hagh, & Pascual-Leone, 2013).
Aerobic exercise
The results from several original studies as well as systematic reviews and meta-analysis have documented the unequivocal effect of exercise in adults with MDD (Cooney et al., 2013; Mammen & Faulkner, 2013). Refinement of the dose, type, duration, appropriate subsample, and likelihood of benefit of exercise in MDD are areas of current and future emphasis (Rethorst et al., 2013a, 2013b; Trivedi et al., 2011). The beneficial effects of aerobic exercise on cognitive measures in older adults with MDD are suggested by available literature (Legrand, 2014; Pei et al., 2013). There are, however, no available studies that have primarily evaluated disparate modalities of exercise on measures of cognition in younger adults with MDD. Such a study would need to embrace many of the methodological principles enumerated in Table 19.1.
Method factors to determine direct effect of cognition in adults with MDD
I. Path analysis II. Subgroup analysis (i.e. outcomes in cognitive measures in non-responders/non-remitters) III. Correlation with depressive severity improvement (i.e. dissociation of cognitive change from depressive symptom change at endpoint) IV. Temporality of improvement V. Placebo control |
Cognitive remediation
Cognitive remediation (CR) uses behavioral strategies to exert a beneficial effect across a broad range of interpersonal/social skills. The beneficial effects of CR have been documented in schizophrenia, autism, and traumatic brain injury, as well as other brain disorders (Elgamal, McKinnon, Ramakrishnan, Joffe, & MacQueen, 2007; Naismith, Redoblado-Hodge, Lewis, Scott, & Hickie, 2010; Thorsen, Johansson, & Loberg, 2014). Results from a single center study enrolling adults with MDD (n = 33) sought to determine whether CR would result in improvement in neurocognition and general functioning compared with a wait-list control group. Neurocognition was evaluated with the Symbol Coding Task, Continuous Performance Test, Controlled Oral Word Association Test, Animal Naming Tests, Hopkins Verbal Learning Test, Letter–Number Sequencing, TMT (Part B), and Stroop. Interpersonal function was assessed with Social Skills Performance Assessment (SSPA) as well as general functioning with the Longitudinal Interval Follow-Up Evaluation – Range of Impaired Functioning Tool (LIFE-RIFT) and the adaptive skills were evaluated with the Advanced Finances Test. Cognitive remediation was conducted for 90 minutes each session, weekly, for ten weeks. The sessions had three participants per group and consisted of three components: computer-based drill-based exercises, strategic self-monitoring, and “bridging.” In addition, the participants were given homework activities (Bowie et al., 2013). At endpoint a significant time-by-group interaction was noted for attention and information processing speed as well as verbal learning and memory. Time-by-treatment effects were significant for executive function as well. There were, however, no significant time-by-treatment group interactions on the SSPA or the Advanced Finances Test.
Other
Intranasal insulin
In addition to being critical to glucose homeostasis, insulin is a critical brain neuropeptide involved in both central nervous system (CNS) physiology and pathophysiology. For example, insulin, via engagement of its CNS canonical receptor, inhibits the pro-apoptotic pathway and is critical to neuroplasticity, neurogenesis, anti-inflammation, anti-amyloid, neuronal differentiation, growth, and survival. Insulin and its receptor are identified throughout the brain with a topographical distribution differentially expressed in brain circuits critical to cognitive and emotional processing (McIntyre et al., 2012).
Available evidence indicates that intra nasally delivered insulin is capable of improving measures of cognitive function in adults with mild cognitive impairment, and APOE4 negative Alzheimer’s disease (AD) (Chapman et al., 2013). It has also been determined that in younger euthymic adults with non-diabetic bipolar disorder (BD) adjunctively administered intranasal insulin improves measures of executive function (i.e. TMT (Part B)) without hazardously affecting peripheral glucose homeostasis (McIntyre et al., 2012). Clinical trials are currently underway to determine whether adjunctive intranasal insulin could improve measures of both “cold” and “hot” cognition in younger adults (i.e. 18–65) with MDD (www.clinicaltrials.gov).
Conclusion
Taken together, cognitive dysfunction is common. It is tautological to state that cognitive dysfunction is common in MDD given the fact that it is a criterion item. What is more relevant is that cognitive dysfunction persists in the absence of active symptoms across other domains (e.g. mood, vegetative). It is abundantly clear that cognitive dysfunction not only is a principal quality of life detractor in affected individuals, but also is a principal determinant of functional outcome in work and other domains.
The first step toward mitigating cognitive dysfunction in MDD is through prevention of multiple-episode course, and attention to psychiatric comorbidity (e.g. substance abuse disorders) and medical comorbidity (e.g. obesity, diabetes mellitus, thyroid dysfunction). The non-specific effects of mechanistically different modalities of treatment on depressive symptom severity provide the basis for reasonably expecting improvements in the domain of cognition co-linearly with improvements in other domains. Avoidance of antidepressant medications and/or deferral to later in the algorithm seems axiomatic recommendation (e.g. antidepressants with anticholinergic properties). It also would be pragmatic to avoid, where possible, concomitant medications that interfere with cognitive function (e.g. benzodiazepines). Cognitive dysfunction should be systematically evaluated and measured in adults with MDD (see other chapters in this book) to provide decision support and a sharpening of the focus as it relates to the therapeutic targets.
Available evidence indicates that only two commercially available antidepressants have demonstrated replicated evidence of a direct effect on cognitive function in individuals with MDD. In the case of duloxetine, the beneficial effects were seen in a single study on measures of learning and memory in younger adults and in two studies in older adults (i.e. >65). Replicated evidence indicates that duloxetine is not effective across other modalities of cognitive function. Vortioxetine has demonstrated efficacy across the four principal domains of cognitive function (i.e. learning and memory, attention and concentration, executive function, and processing speed) in both younger and older adults with MDD.
In individuals receiving antidepressant therapy who continue to evince cognitive dysfunction, a reasonable expectation of possible benefit from a psychostimulant would be expected in discrete domains of cognitive function (i.e. executive function). A similar therapeutic expectation may be extrapolated to modafinil. The evidentiary base supporting other modalities (e.g. neuromodulation, cognitive remediation, aerobic exercise) is promising and would provide preliminary evidence of possible benefit. Notwithstanding, further studies in these modalities would be required before strong assertions of their efficacy could be made. It is expected that manual-based CBT, or mindfulness-based meditation processes would be beneficial to “hot” cognition; hitherto, evidence for cold cognition has not been established. During the next decade, possible beneficial effects of other sundry strategies will be elucidated (e.g. methyl folate, insulin, S-adenosyl methionine (SAME), anti-inflammatory) (Tables 19.2 and 19.3).
Treatments with demonstrated direct effect on disparate measures of cognitive function in individuals with MDD
| Author | Study design, sample characteristics | Treatment rx | Neuropsychological measures | Outcome |
|---|---|---|---|---|
| VORTIOXETINE | ||||
| Theunissen et al., 2013 | Randomized, double-blind, placebo-controlled, three-way crossover n = 24 Mean age: 31 yr | Vortioxetine (10 mg) Active comparator: mirtazapine (30 mg) Placebo | Critical-tracking test, Divided-attention task, Word-learning task Other: Driving test, Psychomotor vigilance task | Vortioxetine did not cause impairment in driving, cognitive, and psychomotor performances following the initial dose and subsequent doses. However, mirtazapine was found to impair cognitive and psychomotor performance on day 2 |
| Katona et al., 2012 | 8-week, randomized, double-blind, placebo-controlled n = 452 Age: 60–65 | Vortioxetine (5 mg) Related posts: HPA axis and cognitive dysfunction in mood disorders
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 Hot and cold cognition in major depressive disorder
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 A novel treatment targeting cognitive dysfunction in mood disorders
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