Depression Predisposes Parkinson Disease, Associated With Worse Disease Severity

Using data from more than 430,000 participants with 14.1 years of follow-up, findings from a recently published study showed that depression is common in patients with Parkinson disease (PD), with prevalence increasing 10 years before PD diagnosis. Additionally, depression severity in PD was associated with cortical and subcortical volume loss, as well as increased risk of dementia and mortality.¹

Prior to the study, depression had been reported as a risk factor, prodromal feature, and late consequence of PD. In the analysis, investigators identified a total of 2632 individuals with incident PD from 434,023 participants in the UK biobank, excluding those who had PD at baseline (n = 930), had a psychiatric comorbidity other than depression (n = 873), used an antipsychotic medication (n = 9) or were missing important covariate data (n = 45). The goal of the study was to evaluate the timing, neuroatonomy, and prognostic implications of depression in PD.

Led by James Badenoch, a clinical research fellow at King’s College London, 20.5% (n = 539) of the individuals with incident PD were diagnosed with depression at some point. After controlling for age, sex, socioeconomic status, education, life-time smoking status, social isolation, and family history of PD, findings showed that diagnosis of depression was associated with an increased risk of developing PD during the follow-up period (rate ratio [RR], 1.53; 95% Ci, 1.37-1.72; P <.001).

Depression symptom severity also increased in the years prior to PD diagnosis. All told, average depression score was highest in the 1 year preceding PD diagnosis (RR, 1.98; 95% CI, 1.54-2.42) compared with matched controls (RR, 1.36; 95% CI, 1.20-1.52). Depression occurring prior to PD diagnosis was also associated with an increased risk of subsequent incident dementia (RR, 1.49; 95% CI, 1.07-2.05) after controlling for age, sex, education, socioeconomic status, and smoking. The risk of dementia was highest among patients who developed depression more than 5 years prior to PD onset (RR, 1.73; 95% CI, 1.16-2.58).

"Our findings of increased incident dementia risk and mortality provide high-quality longitudinal evidence that depression in PD indicates an adverse prognosis, without the risk of recall bias inherent in disease cohort studies. This amplifies previous evidence associating depression in PD with a range of prognostic outcomes in smaller cohorts, including motor complications, care home admission, disability and mild cognitive impairment," Badenoch et al wrote.

The study authors added, "Our finding that increased mortality risk continued to widen up to the end of follow-up suggests that larger and longer cohort studies are required to reveal the true magnitude of this effect."

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Results from the study showed that depression severity in PD was associated with reduced grey matter volume in 18 brain regions, distributed bihemispherically and predominantly comprising subcortical structures including the thalamus and amygdala but also several other cortical regions such as frontal pole, occipital pole, and temporal gyrus. These findings were observed after adjusting for intracranial volume, MRI center, age, and interval from PD diagnosis to enrollment in the study.

Patients who had depression prior to their PD diagnosis had an increased morality risk as well. This was observed (RR, 1.40; 95% CI, 1.09-1.80) after adjusting for age, sex, education, socioeconomic status, cardiovascular disease, obesity, diabetes mellitus, and smoking. The risk of mortality was highest among individuals who developed depression in the 3 years immediately prior to PD onset (RR, 4.01; 95% CI, 2.22-7.24).

Survival analyses showed that depression developing within a few years prior to PD diagnosis was associated with poorer prognosis in terms of incident dementia and all-cause mortality, whereas more long-standing depression or depression developing following PD diagnosis did not show the same prognostic associations. "This suggests that prodromal depression might be signaling the presence of specific patterns of underlying disease biology that expedite these outcomes,” the study authors wrote. “However, we could have been underpowered to find an association between postdiagnostic depression and poorer prognosis."

They added, “The regional brain volume associations suggest two possible mechanisms: the distributed grey matter atrophy might suggest that depression is indexing neurodegenerative intensity more broadly, whereas the association with limbic structures such as the amygdala raises the possibility that depression might be a consequence of neurodegeneration in a specific brain network that regulates affect. This is consistent with structural neuroimaging studies of major depressive disorder (outside of PD), where limbic regions including the amygdala and distributed cortical regions (mainly cingulate) have been implicated."

REFERENCE
1. Badenoch JB, Paris A, Jacobs BM, Noyce AJ, Marshall CR, Waters S. Neuroanatomical and prognostic associations of depression in Parkinson’s disease. Neuro, Neurosurg, and Psych. Published online April 3, 2024. doi:10.1136/jnnp-2023-333007