Comment by Dr. Pratap Chokka, Edmonton, Alberta
Antidepressant therapies have traditionally been evaluated for their effect on symptoms of depression and anxiety. However, symptomatic improvements may not result in functional gains in areas such as work performance and productivity, activities of daily living and quality of life. In the latest iteration of the Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder (MDD), functional recovery was recognized as a priority in the treatment of MDD in both the acute and maintenance phases of the disease (Lam et al. Ann Clin Psychiatry 2015;27:142-149). The group concluded that there was a need for evidence-based interventions that demonstrated an improvement in patient functioning.
Two new studies have examined the effect of vortioxetine (Trintellix) on functional outcomes, and the interrelationship of work productivity and cognition. Vortioxetine is a multimodal serotonergic agent that inhibits the 5-hydroxytryptamine (HT) transporter, is an agonist of the 5-HT1A receptor, a partial agonist of the 5-HT1B receptor, and is an antagonist of the 5-HT1D, 5-HT3 and 5-HT7 receptors (Bang-Andersen et al. J Med Chem 2011;54:3206-3221). The CANMAT guidelines on pharmacological treatment recommend vortioxetine as a first-line therapy for MDD (Kennedy et al. Can J Psychiatry 2016;61:540-560).
In published studies to date, vortioxetine 5-20 mg/day for 5-8 weeks produced significant reductions in depression scores, as assessed by the Hamilton Depression Rating Scale (HAM-D-24) or the Montgomery-Asberg Depression Rating Scale (MADRS) (Katona et al. Int J Neuropsychopharmacol 2012;15:589-600. Henigsberg et al. J Clin Psychiatry 2012;73:953-959. Boulenger et al. Int Clin Psychopharmacol 2012;26:1408-1416. Boulenger et al. Int Clin Psychopharmacol 2014;29:138-149. Mahableshwarkar et al. Psychopharmacology (Berl) 2015;232:2061-2070. Jacobsen et al. J Clin Psychiatry 2015;76:575-582). Treatment was well-tolerated, with 6% of vortioxetine-treated patients discontinuing due to adverse events (vs. 4% with placebo) (Trintellix Product Monograph, October 17, 2014). The most common adverse events were nausea, dry mouth and dizziness.
A pooled analysis of five 52-week extension studies reported that clinical gains are maintained or show ongoing improvement with vortioxetine during long-term maintenance (Vieta et al. Eur Neuropsychopharmacol 2017;27:877-884. Response and remission rates improved over time; at week 52, the overall response rate was 75.4% and the overall remission rate was 60.7%.
Of particular relevance to functional recovery is the effect of vortioxetine on cognitive functioning, which has been attributed to the drug’s pharmacologic interactions with 5-HT receptor subtypes, in particular 5-HT3 and 5-HT7 (Schatzberg et al. J Clin Psychiatry 2014;75:1411-1418; free full text at www.psychiatrist.com/JCP/article/_layouts/ppp.psych.controls/BinaryViewer.ashx?Article=/jcp/article/Pages/2014/v75n12/v75n1209.aspx&Type=Article). In the study by Katona and colleagues, elderly subjects (mean age 70.6 years) treated with vortioxetine 5 mg/day showed improved processing speed, verbal learning and memory on cognitive testing (Katona 2012). The reference agent, duloxetine 60 mg/day, was not significantly different from placebo on cognitive measures.
These results were supported by the FOCUS trial, an 8-week study of vortioxetine 10 or 20 mg/day in adult subjects aged 18-65 years with MDD (McIntyre et al. Int J Neuropsychopharmacol 2014;17:1557-1567; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC4162519/pdf/S1461145714000546a.pdf). Both doses of vortioxetine were superior to placebo across the range of cognitive tests, including the DSST (Digit Symbol Substitution Test of executive function); RAVLT (Rey Auditory Verbal Learning Test of learning and memory); TMT (Trail-Making Test of processing speed); Stroop (executive function); and SRT (Simple Reaction Time test of processing speed). A noteworthy finding was that improvements in cognitive function with vortioxetine occurred largely independently of the drug’s effects on symptoms of depression. There were also significant improvements in the patient-rated Perceived Deficits Questionnaire (PDQ-20).
Similar results were seen in a separate 8-week trial, named CONNECT, of a flexible dose of vortioxetine 10-20 mg in adult patients with MDD (Mahableshwarkar et al. Neuropsychopharmacology 2015;40:2025-2037). Vortioxetine was superior to placebo on the DSST, the UPSA (University of San Diego Performance-based Skills Assessment, which evaluates patient functioning), and the patient-reported PDQ (Perceived Deficits Questionnaire). These data indicate that vortioxetine benefits overall patient function as well as cognitive function. In contrast, duloxetine, the reference agent in the study, was superior to placebo on the PDQ, but not on the DSST or UPSA. This may indicate that vortioxetine has a direct effect on cognitive measures, whereas the cognitive effects seen with duloxetine occur indirectly through improvement in mood symptoms. The implication is that antidepressant therapies will have varying effects on daily functioning as well as on cognitive functioning.
Functional recovery – Work and productivity
It is well-established that MDD results in significant productivity losses through absenteeism (time away from work) and presenteeism (less productive while at work) (Lam et al. Can J Psychiatry 2016;61:510-523). An analysis of data from the Canadian National Population Health Survey found that among individuals aged 26-45 years, a major depressive episode was associated with a 2-3 fold increased risk of transitioning from working to nonworking status (hazard ratio 2.6) (Patten et al. Can J Psychiatry 2009;54:841-845). A separate database analysis of MDD patients treated in primary care across Canada, and Canadian subjects enrolled in the International Mood Disorders Collaborative Project (IMDCP), reported high rates of unemployment (30.3%) and disability (42.1%) in the MDD population (Rizvi et al. Can J Psychiatry 2015;60:14-22).
While absenteeism is often a focus of productivity research, several studies have shown that presenteeism, or lost productivity while at work, has a greater social and economic impact (Ammendolia et al. BMC Public Health 2016;16:1190). A U.S. study estimated presenteeism-related costs at USD$180 billion annually, compared to USD$118 billion due to absenteeism. As a result, research is now focusing on treatments and workplace interventions that will reduce presenteeism and improve productivity (Callander et al. J Occup Environ Med 2017;59:246-249).
A Canadian post-hoc analysis of IMDCP data found that subjective measures of cognitive dysfunction (e.g. inattention, difficulty concentrating) had a greater impact on workplace performance that the severity of depression symptoms (McIntyre et al. Compr Psychiatry 2015;56:279-282). The authors concluded that MDD treatments need to address issues of cognitive dysfunction to improve workforce participation and performance.
The association between improvements in cognitive function and work productivity was recently examined in the AtWoRC study (Assessment in work productivity and the relationship with cognitive symptoms in patients with MDD taking vortioxetine), conducted at 26 sites across Canada. The primary endpoint was a partial correlation between changes in patient-reported cognitive symptoms (PDQ-D-20) scores and self-reported work productivity loss (Work Limitations Questionnaire; WLQ) scores over 12 weeks of flexible 10-20 mg of vortioxetine treatment. All subjects were required to be employed or attending post-secondary or vocational school full-time.
The mean age of study participants was 40.8 years; 69.4% were female; the mean disease duration was 8.4 years (Chokka et al. International Society for Pharmacoeconomics and Outcomes Research [ISPOR] 2017; abstract). Subjects’ employment status was employed/independent (92.1%), full-time vocational (2.8%), or full-time post-secondary student (4.2%). Primary analysis at Week 12 indicated a significant and strong correlation between PDQ-D-20 and WLQ scores (r = 0.633; p<0.001), demonstrating that patients with perceived improvement in cognitive symptoms following treatment with vortioxetine also had improved workplace productivity. The proportion of patients with missed work days decreased from 57% at baseline, to 22% at week 12. Among those who missed work, the mean number of missed days declined from 12 to 7 days. The authors concluded that treating cognitive symptoms is important for functional outcomes in MDD patients. The study is ongoing, and results at 52 weeks will be presented.
These results suggest that the emerging goal of MDD management is to benefit all domains of functioning – cognitive and physical functioning, in addition to mood symptoms of depression and anxiety. This multimodal approach, with agents such as vortioxetine, will enable individuals with MDD to remain employed and productive, and may provide a more complete and sustained recovery from major depressive episodes.
Dr. Pratap Chokka: Depression has become the leading cause of disability in the workplace. When accounting for both absenteeism and presenteeism, $52 billion is lost in the Canadian economy as a result of the functional impairment associated with depression. A recent Conference Board of Canada Survey indicated that the cognitive dimension of depression is associated with high levels of workplace functional impairment.
Three placebo-controlled trials with vortioxetine resulted in a statistically significant improvement in the cognitive symptoms associated with depression, superior to placebo and duloxetine. The AtWorc study extended the placebo controlled studies and assessed the role of cognitive functioning and workplace productivity in working patients with depression. In this real-world study, vortioxetine, at a mean dose of approximately 15 mg/day, led to improvement of cognitive functioning, as assessed by the PDQ, which correlated with increased workplace productivity, as assessed by the WLQ. This was a significant and strong correlation that was independent of age, gender, disease severity, and duration. This translational study extends and supports the importance of treating the full dimensions of depression, including cognitive symptoms, to restore full functional recovery.