The impact of depression on survival of Parkinson ’ s disease patients : a five-year study

Objective: The aim of this study is to evaluate the survival rate in a cohort of Parkinson’s disease patients with and without depression. Methods: A total of 53 Parkinson’s disease subjects were followed up from 2003-2008 and 21 were diagnosed as depressed. Mean time of follow up was 3.8 (SD 95% = 1.5) years for all the sample and there was no significant difference in mean time of follow up between depressed and nondepressed Parkinson’s disease patients. Survival curves rates were fitted using the Kaplan-Meier method. In order to compare survival probabilities according to the selected covariables the Log-Rank test was used. Multivariate analysis with Cox regression was performed aiming at estimating the effect of predictive covariables on the survival. results: The cumulative global survival of this sample was 83% with nine deaths at the end of the study – five in the depressed and four in the nondepressed group, and 55.6% died in the first year of observation, and none died at the fourth and fifth year of follow up. conclusion: Our finding point toward incremental death risk in depressed Parkinson’s disease patients.


Original article intrODUctiOn
Parkinson's disease (PD) is a chronic subcortical neurodegenerative disease which is best diagnosed by motor symptoms and sings.The non motor signs, however, are quite important as they progress contributing to the incapacities that ensue over the course of the disease 1 .Among the nonmotor symptoms in PD, depression is highly prevalent with rates around 35% 2 .
Several studies have shown that PD exerts a negative impact on the patient's survival, with a risk ranging from 1.5 to 2.9 as compared to the general population [3][4][5][6][7][8] .Likewise, depression has been reported as an independent variable contributing to increase mortality risk 9 .Indeed, a six-year follow up study with chronic depressed elderly pointed to an incremental mortality risk of 41% 10 .The severity of the depressive symptoms seems to hold a direct relationship with mortality in the elderly 10,11 .
Based on these data it would be reasonable to present the hypothesis that PD patients with depression would have a lower survival rate than the PD patients without depression.Conversely a previous review yielded only two studies with conflicting results.The early one did not find an association between depression and survival in PD 12 , whereas Hughes et al. 13 , reported that depressed PD patients presented a 1.64 (CI 1.26-2.99)risk of death as compared to controls.In order to provide more information on this issue, the aim of this study is to evaluate the survival rate in a cohort of PD patients with and without depression.

Patients
A consecutive series of PD patients (n = 100) were screened in three neurologic outpatient facilities from January 2003 to April 2006.Patients with dementia or with any other neurological or clinical disorders other than PD were not included in the study, as well as subjects with psychiatric disorders other than depression.Smokers and drug addicts were excluded.Patients using antidepressant medications at baseline or who were taking such medications until three months prior to the inclusion interview were also excluded from the study.In order to evaluate the cognitive status and to exclude dementia the Mini-Mental State Examination (MMSE) 14 and CAMDEX/ CAMCOG (Cambridge Examination for Mental Disor ders of the Elderly 15 (required score above 80) were used.We employed a validated Brazilian version of the CAMCOG 16 .

Neurological examination
All the patients were examined by a neurologist for a detailed diagnosis of PD according to the United Kingdom Parkinson's Disease Society Brain Bank (UK-PDS-BB) criteria 17 .PD staging and severity was ascertained using the Hoehn and Yahr stages (HY) 18 .This scale is used when patients were on the on period.All the patients had a normal CT scan.A psychiatrist evaluated the patients to determine a diagnosis of depression according to the DSM-IV criteria 19 and its severity as measured by the Montgomery Asberg Depression Rating Scale (MADRS) 20 and the Beck Depression Inventory (BECK) 21,22 .
With the use of standard clinical criteria, such as the UK Parkinson's disease brain bank criteria, accuracy of a clinical diagnosis of the disease can be improved significantly; however, up to 10% of the patients diagnosed with the disease in life will still have to be reclassified at post-mortem examination 23 .Diagnostic sensitivity and specificity of these criteria have been estimated as 98.6% and 91.1% respectively 24 .

Study design
The study started as a cross-sectional study aiming to compare frontal functions in depressed and nondepressed PD.The methodology of this study is described elsewhere 25 .
In 2008, the whole population was reassessed.Data on death and respective causes were collected in two complementary ways: an active search via telephone contact plus information search in the Mortality Information System, a database held by the Coordination of Vital Data of the Health Department of the State of Rio de Janeiro, Brazil.The data were captured by certificates reports from 2003 to 2007.To prevent mistakes regarding the presence of homonyms the data were compared with the information recorded in our own databank of the cohort.
In most cases, the cause of death was not specified.Some causes identified were from cardiovascular causes (like Acute Myocardial Infarction), infectious (pneumonia and septicemia) and pulmonary (obstructive pulmonary disease).

Ethics
The study was approved by the local Ethics Committee and all the patients signed the informed consent prior to any procedure.A written permission was issued by the Health State Department to access the mortality database.

Statistical analysis
Descriptive analysis of patient characteristics and initial cognitive tests were carried out to obtain frequency distributions, and the means and standard deviations.The date of inclusion into the cohort was considered as the baseline for the survival analysis of each patient.The primary endpoint was all causes mortality during the follow-up period and survival time was calculated since the cohort inclusion until the death date.All individuals who did not have death registry or who could not be contacted by telephone were censored at the end of data collection period.Follow-up losses were not considered in this study as analyses were based on secondary data, phone contact, and on clinical visits.
The annual mortality rates and survival rates were estimated using the Kaplan Meier method 26 .In order to compare Original article Silberman CD et al.   survival probabilities according to the selected covariables the Log-rank test was used.Next, a multivariate analysis with Cox regression was performed aiming at estimating the effect of predictive covariables on the survival.Statistical analysis was performed using SPSS17.0statistic software (SPSS Inc., USA).

reSUltS
A total of 53 PD subjects met the inclusion criteria for the study and 21 were diagnosed as depressed at the psychiatric examination.Baseline characteristics of the patients with and without depression are shown in table 1.The severity of PD by Hohen an Yahr stages and the presence of depression are shown in table 2.
Mean (standard deviation) time of follow up was 3.8 (1.5) years for all the sample and there was no significant difference in mean time of follow up between depressed and nondepressed PD patients.The cumulative global survival of this sample was 83% with nine deaths at the end of the study -five in the depressed and four in the nondepressed group (Table 3).Of note, 55.6% died in the first year of observation, and none died at the fourth and fifth year of follow up (Table 4).
The depressed group shows a higher rate of mortality than the nondepressed one as shown in figure 1.
Table 5 shows that the Hazard Ratio (HR) for deaths of PD patients with depression is 2.17 higher than for the nondepressed group, although not statistically significant (p = 0.15).Additionally, the better the cognitive status, the lower the death risk is (HR = 0.98), again not statistically significant (p = 0.495).
As age and cognitive status are considered confounding variables for examining mortality risk in patients with PD and depression, an analysis was run controlling for these covariables.In this analysis, the mortality HR reached 2.42 in depressed patients (p = 0.103).So, it remains to be studied the impact of having depression when a neurodegenerative disorder is already diagnosed.There are some limitations in our study which warrant some comments.The first one is the small sample size which possibly impacted in the lack of statistical significance.The absence of a group without PD and depression precluded a better study of the interaction of the two disease and its association with mortality.Moreover, as patients were not actively followed, the presence of follow-up and information biases could not be excluded.
In most cases, the cause of death was not specified (there is a serious problem with the completion of death certificates in Brazil).Some causes identified were from cardiovascular causes (like Acute Myocardial Infarction), infectious (pneumonia and septicemia) and pulmonary (obstructive pulmonary disease).

cOnclUSiOn
In summary, our finding points towards an incremental death risk in depressed PD patients.Further studies with larger samples are warranted to dissect whether this risk is present and irrespective of other variables, such as depression symptom severity and staging of PD, as well as whether treatment of depression is able to lower this risk.

inDiViDUal cOntriBUtiOnS
Cláudia Débora Silberman -Principal investigator.Contributed to conception, design analysis and interpretation of the data.Also contributed to drafting the article, revising it critically and approval of the final version to be published.Cláudia Soares Rodrigues -Responsible for all statistical calculations.She also contributed to: analysis and interpretation of data, revising the article critically; and had given the final approval of the version to be published.Eliasz Engelhardt -Contributed to conception, analysis and interpretation of the data; revising it critically for important intellectual content; and had given the final approval of the version to be published.Jerson Laks -Contributed to conception, design analysis and interpretation of the data.He also contributed to drafting the article, revising it critically and approval of the final version to be published.

acKnOWleDgMentS
To the Conselho Nacional de Pesquisa (CNPq) for supporting Jerson Laks, who is a Researcher 2 of CNPq.

DiScUSSiOn
The influence of depression on mortality of PD patients is still a matter of debate.PD alone was associated to a threefold increase of the mortality risk compared to non PD in elderly populations [3][4][5][6][7][8] .On the other hand, another study which observed a chronically depressed elderly population for 6 years found a 41% increase in the mortality rate compared to nondepressed subjects 10 .To the best of our knowledge, this is the first Brazilian study and the third study in the world over the last 18 years to address mortality rates in PD comparing depressed and nondepressed patients.Albeit not statistically significant, the HR for mortality in depressed PD patients was 2.45 times higher than in nondepressed ones when we controlled for cognitive status.Another study found that the HR for mortality in depressed PD patients was 2.66 (95% CI: 1.59-4.44)over 11 years of observation 13 .Despite the differences in the two studies, such as the presence of a control group, the sample size, and time of follow up, all these results are pointing to the same direction.
Of note in our study, half of the deaths occurred in the first year of observation (55.6%), a high rate which might be also associated with the higher age of patients, duration of disease, and worse economic and cultural status of the population 27,28 .A recent study in a large elderly male population 29 has presented convincing data with regards to the direct relationship between mortality and severity of depressive symptoms (dose-response relationship) even when controlled by factors as health status and age.Depression may increase mortality risk by a number of reasons.Firstly, comorbidity with clinical disorders is higher and depression also complicates the course of these disorders 30 .Secondly, a series of pathophysiological cascades with cytokines (e.g., IL6, alpha TNF) and lower levels of protective factors (e.g., BDNF, IGF1) 31 are triggered by depressive states.Inflammatory states are then a possible cause of higher mortality and neurodegeneration.All these factors also are present in PD.

table 1 .
Sociodemographic and clinical profile of PD patients with and without depression

table 2 .
Severity by Hohen and Yahr stages in patients with or without depression

table 3 .
Distribution of deaths in the sample with and without depression

table 4 .
Annual frequency and mortality rates Figure 1.Kaplan-Meier survival estimates.

table 5 .
Cox regression adjusted only by depression or by depression + age + MEEM