Depression in Parkinson's Disease: Assessment Methods and Risk Factors

Dissanayaka, Nadeeka (2008). Depression in Parkinson's Disease: Assessment Methods and Risk Factors PhD Thesis, School of Medicine, The University of Queensland.

       
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Author Dissanayaka, Nadeeka
Thesis Title Depression in Parkinson's Disease: Assessment Methods and Risk Factors
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2008-07
Thesis type PhD Thesis
Supervisor A/Prof George Mellick
Prof Peter Silburn
Dr John O'Sullivan
Prof Michael Roberts
Total pages 490
Total colour pages 6
Total black and white pages 484
Subjects 320000 Medical and Health Sciences
Formatted abstract
Depression and anxiety are common non-motor symptoms of Parkinson’s disease (PD) which have
a major detrimental effect on patients’ quality of life. Identifying depression in PD is complicated
and a validated strategy to recognise depression in PD for large-scale research studies has not yet
been established. The determinants of depression in PD are considered complex and debatable. This
thesis first explored the methods used to assess current and lifetime depression in PD, with the view
of establishing a validated user-rated strategy to identify the PD-associated depression phenotype.
Secondly, the thesis investigated the determinants of depression in PD by examining the influence
of PD specific, genetics and other factors to the risk of depression in PD.
PD patients were recruited from neurology outpatient clinics in Brisbane. A pilot study was
conducted to identify an optimal user-rated depression rating scale, and to develop and validate a
user-rated method to recognise lifetime (‘current’ and ‘previous’) depression in PD. The Diagnostic
and Statistical Manual Edition IV (DSM-IV) criteria was used as the gold standard to identify
depression. A user-rated research survey was developed to obtain risk-factor data of potential
relevance to depression in PD. Reproducibility of this survey was examined by conducting a second
pilot study and the questions with poor reproducibility were revised. Following an exploratory
analysis using an existing dataset, two independent association studies were conducted to examine
the risk factors for depression in PD. A third pilot study was conducted using a case-series of 78 PD
patients using the DSM-IV criteria to identify depression. Finally, a large association study of 304
PD patients, using the validated user-rated method of identifying lifetime depression, was
performed to examine the determinants of depression in PD. The severity of PD was determined by
the Unified PD Rating Scale (UPDRS). DNA was extracted from blood samples collected from all
participants. Genomic studies were conducted to examine the association between depression in PD
and common genetic variations (eg: htSNPs and VNTRs) of the serotonin (SLC6A4) and dopamine
(SLC6A3) transporter gene loci. In these genetic studies, depressed subjects were age and gender
matched to never depressed subjects. The results generated from both genetic and non-genetic
studies were also utilised to explore the determinants of anxiety in PD, independent of depression.
Appropriate statistical analyses were performed for each aspect of the thesis. In brief, receiver
operating characteristic curves were drawn to obtain the optimal rating scale setting PD specific cutoff
scores. Measures of sensitivity, specificity, positive and negative predictive values were
obtained to examine the validity of depression assessment methods. Kappa and interclass
correlation coefficient (ICC) values were calculated to examine the test-retest reliability of the userrated risk-factor research survey. Binary logistic regression models were constructed adjusting for
age and gender for the case-control association studies.
From the three rating scales (the Hamilton Depression Rating Scale, HAMD-17; the Hamilton
Depression Inventory, HDI-17; and the Geriatric Depression Scale, GDS-15), the GDS-15 was
determined to be the optimal user-rated scale in PD. An optimal cut-off of 6/7 was identified to
discriminate ‘current’ depressive disorder. A combination of the GDS-15 and the screening
questions introduced in this thesis could be used to identify a ‘lifetime’ history of depression
(sensitivity=0.97; specificity=0.65). The user-rated risk-factor research survey developed in this
thesis showed high reproducibility with kappa/ICC values >0.50 for the majority of the questions.
In the final association analysis, seventy percent of the PD patients met the criteria for a lifetime
history of depression; 41% fulfilled the criteria for anxiety. Anxiety disorders were more common
in the depressed compared to never-depressed group (OR=9.19, 95%CI=4.15-20.36, p<0.01).
UPDRS impairment in activities of daily living (UPDRS-II-ADL) score was higher in the depressed
group (OR=1.09, 95%CI=1.02-1.08, p=0.02). Exposure to chemicals was related to depression
(OR=2.80, 95%CI=1.38-5.71, p<0.01). Memory problems (OR=7.17, 95%CI=2.32-22.20, p<0.01)
were also more frequent in depressed PD subjects. None of the genetic variations or combinations
of these variations (haplotypes) showed association with depression or anxiety in PD.
Based on the validated depression recognition method and risk-factor surveys, this thesis showed
that number of factors were associated with depression in PD. Impairment in ADL increased the
risk for depression; however depression could also impair ADL. Examining the relationship
between subsections of the UPDRS-II-ADL and depression may aid to better understand these
connections in the future. This thesis highlighted the complexity of PD suggesting that both motor
and non-motor conditions (such as depression, anxiety and memory problems) equally contribute to
the presentation of the disease. For the first time this thesis showed that exposure to chemicals is
more prevalent in depressed PD compared to the non-depressed PD. This result may suggests a
possible interaction between depression and increased risk for PD conferred by toxin exposure;
literature already suggests that high exposure to chemicals increases the risk for PD. Identifying the
specific chemicals that increase the risk for depression in PD may provide biochemical clues to the
pathways connecting depression and PD. The thesis showed that serotonin and dopamine
transporter genes are unrelated to depression and anxiety in PD suggesting alternative avenues for
future genetic studies. This thesis further highlighted the complexity of depression and anxiety in
PD and suggested novel implications for future research and clinical practice.
Keyword Parkinson’s disease, depression, anxiety, risk factors, rating scales, surveys, validity, test-retest repeatability, SLC6A4, SLC6A3
Additional Notes Page numbers for couloured printing p70 (p38 Figure 2.1 in the thesis) p134 (p102 Fig. 8.1) p136 (p104 Fig. 8.2) p154 (p122 Fig. 8.3) p155 (p123 Fig. 8.4) p489 Total number of landscape pages=31 Landscape pages 60, 79, 93, 100, 101, 116, 117, 138, 151, 152, 156, 455-458 (inclusive), 462-478 (inclusive)

 
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Created: Tue, 02 Dec 2008, 13:54:29 EST by Miss Nadeeka Dissanayaka on behalf of Library - Information Access Service