By Nimish J. Thakore, MD, and Erik P. Pioro, MD, PhD
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About half of all patients with amyotrophic lateral sclerosis (ALS) die within roughly three years after onset of weakness, and current treatments prolong survival only marginally. Until a treatment emerges that effectively slows or halts ALS progression, the focus of care is primarily to maximize function, comfort and quality of life.
Despite the fatal nature of ALS, it’s a common belief that affected patients tend not to become depressed. To further examine that belief, we recently conducted the largest single-center study of depression in ALS to date that used a validated instrument for depression evaluation. Here we recap the findings of our study, published in Neurology in March 2016, and explore their implications for clinical practice and future ALS research.
Study design and the Knowledge Program
We sought to examine the prevalence, associations and course of depression, as measured by the validated Patient Health Questionnaire–9 (PHQ-9), among 1,067 patients with ALS evaluated in Cleveland Clinic’s Neuromuscular Center over an eight-year period.
All patients had completed the PHQ-9 as part of the Knowledge Program© (KP), a system pioneered by Cleveland Clinic’s Neurological Institute in 2006 to electronically capture and store patient-reported outcomes (PROs) entered by patients using wireless tablet devices in waiting rooms. The PROs include generic measures, such as the PHQ-9 for depression and the validated quality-of-life instrument known as EQ-5D, as well as multiple disease-specific metrics. The information gathered via the KP is reported to the provider in the electronic medical record to inform clinical care.
Key findings on depression prevalence and associations in ALS
As reported in detail in our Neurology paper, we found that about one-third of the 1,067 ALS patients were at least moderately depressed at initial assessment, and approximately 5 percent were severely depressed. Overall, depression was substantially more prevalent in patients with ALS than in the general population.
Patients with more severe disease and prominent respiratory symptoms were the most depressed. Not unexpectedly, depression was associated with poorer quality of life. However, severity of depression did not increase with time despite worsening weakness (Figure 1).
Figure 1. Plots of ALS patients’ individual trajectories of serially measured PHQ-9 scores showed no overall worsening of depression over time. (Reprinted, with permission, from Thakore and Pioro, Neurology. 2016;86:1031-1038, © 2016 American Academy of Neurology.)
Key findings on depression’s effect on survival
Next we examined predictors of mortality using dates of death ascertained in 499 patients. Interestingly, we found a robust deleterious effect of depression after adjusting for other predictors of survival including age, gender, bulbar onset, prominent respiratory symptoms, disease severity (as measured by the revised ALS Functional Rating Scale), rate of progression and body weight. Median survival from onset of ALS was 11 months shorter in depressed patients than in their nondepressed counterparts (Figure 2), and univariate proportional hazards modeling showed that each 1-point increase in a patient’s initial PHQ-9 score (indicating greater depression severity) increased the risk of death during follow-up by 4.4 percent. There have been few prior reports of depression affecting survival in ALS, and all have studied much smaller cohorts (e.g., Arch Neurol. 1994;51:17-23).
Figure 2. Kaplan-Meier curves showing significantly shorter survival among patients with ALS who were at least moderately depressed (PHQ-9 score ≥ 10) versus those who were not depressed (PHQ-9 score < 10). (Reprinted, with permission, from Thakore and Pioro, Neurology. 2016;86:1031-1038, © 2016 American Academy of Neurology.)
Implications for both clinical care and research
These findings reinforce the importance of recognizing depression in patients with ALS and then treating it aggressively. Although we could not determine in our study whether survival improved in ALS after depression was treated, it is certainly reasonable to offer such treatment, if only to improve quality of life and help patients cope better as their disease progresses.
Additionally, the results of this study may influence the design of future ALS therapeutic trials so that the effect of depression is taken into account. For a number of proposed therapies for ALS, initial positive findings from registry studies (using historical controls) have proved to be at odds with negative results from subsequent randomized controlled trials (as in the recent DiPALS study), and it is possible that depression played a role in those discordant outcomes.
Why does depression affect survival?
Depression negatively affects survival in many chronic diseases, and our study adds ALS to the list. ALS is believed to be different, however, because it is characterized by severe and inexorable physical deterioration leading to death. The mechanism mediating this effect of depression on survival in ALS is unknown and demands further study. Possibilities include poorer general health, poorer adherence to treatment and even biological mechanisms. An obvious question for future studies is whether aggressive treatment of depression in ALS would extend survival.
Value and power of the Knowledge Program
PROs captured by the KP and reported to providers during clinical encounters with patients add a rich quantitative dimension to other available information. Although some may question the incremental value of such extra information in routine clinical care, our results demonstrate the tremendous prognostic importance of such PROs and prove the transformative value of the KP in caring for the individual patient. This study also showcases the KP’s value as a low-burden means of electronic capture and assembly of PROs to address clinically and scientifically meaningful questions.
Dr. Thakore is a neurologist in Cleveland Clinic’s Neuromuscular Center and Center for Regional Neurolosciences. Dr. Pioro is the Barry Winovich Endowed Chair in ALS Research and Director of the Section of ALS and Related Disorders in the Neuromuscular Center.