In this large population of older Americans, we observed an association between depression and a higher subsequent risk of PD. The association was stronger for depression diagnosed in closer proximity to clinical PD diagnosis, but was also detected even for depression diagnosed more than 15 years prior to PD diagnosis. The depression-PD association was not explained or modified by the other PD risk factors that we took into account.
A link between depression and PD has been investigated previously, in case-control, 1, 3, 6–9
historical cohort, 4, 5
and prospective cohort 2
studies. All but one 7
of these studies showed a positive association between depression and a higher subsequent risk of PD. Some known PD protective factors, such as smoking, 17
may serve as self-medication among depressed individuals 18
and therefore might alter the association of depression with PD. However, few studies have explored whether smoking or other PD risk factors might have confounded or modified the depression-PD relationship. 3,8
Our multivariate and subgroup analyses showed that this association was neither confounded nor modified by these PD risk or protective factors.
Depression is one of the common non-motor symptoms of PD; but few data are available to describe its temporal relationship to PD, especially for depression occurring prior to PD diagnosis. 1, 3
Shiba et al. found that depressive disorder was associated with a 1.9-fold risk of PD, but the risk elevation was limited to depressive disorder diagnosed within 5 years of PD onset. 1
Similarly, an Indian study reported a higher risk of PD among depressed patients diagnosed within 10 years prior to PD onset but not earlier (OR=1.5). 3
Another two studies found a significant association between antidepressant use and the subsequent risk of PD or antiparkinson drugs use within a short time after antidepressant prescription (six months and two years respectively) but not earlier. 11,12
Our study is larger than most of the previous studies, and we evaluated the depression-PD relationship over a longer period of time.
One explanation for these findings is that depression might be a very early marker of PD pathogenesis, before a significant involvement of dopaminergic neurons in the substantia nigra. 19,20
It is however still under debate when PD-related pathologies begin, with most evidence pointing to a time window within 10 years of the diagnosis. 21,22
If the 10-year time window is accurate, our finding may suggest that depression is also etiologically related to PD or, more likely, that it shares common mechanistic pathways with PD. For example, both PD and depression are characterized by impaired monoaminergic neurotransmission. 23
Another example is chronic inflammation, which may underlie both depression and PD. 24, 25
It is possible that use of antidepressants or antipsychotics may increase the risk of PD 11,12
which may partially account for our observation for depression. However, it is more plausible that the findings on antidepressants were explained by the presence of depression as an early marker of PD 12
. Finally, it is important to note that the depression and PD relationship is not specific. Depression belongs to a group of non-motor symptoms that many of which may predate the onset of PD. 26
On the other hand, depression has been related to many chronic conditions such as diabetes as a risk factor or consequence. 27
Major strengths of our study include the large sample size, long period of exposure assessment, and detailed information on potential confounders and effect modifiers. The analyses were however retrospective in nature. Selection bias cannot be ruled out if depressed individuals with PD were less likely to participate in the follow-up survey compared to depressed individuals without PD; if true the observed odds ratios are likely underestimated. Recall bias could also be a concern as PD patients might be more likely to recall or report depression than the PD-free participants. Although we could not directly evaluate potential impacts from this bias, our additional analysis excluding individuals with poor health status who might be more likely to over report depression, showed similar results. In such a large cohort, we had to rely on the self-report to identify depression and PD diagnoses as well as the years of first diagnoses. Misdiagnosis and under reporting are therefore unavoidable. Our ongoing verification study of PD diagnosis showed that 88% of PD cases were validated with information from their treating neurologists. Although we did not validate self-reported depression, nor did we have data on antidepressant use, in other validation studies self-reported diagnosis of depression was deemed fairly reliable compared to medical record review or specialist interview 16
and self-reports have been used in other longitudinal studies 24
In summary, we noted an association between depression and PD which is independent of other risk factors for PD. The significant association with depression diagnosed 15 years previously suggests that depression may be a very early symptom of PD or share common etiological factors with PD.