In relationship between the affective disorders and Parkinson’s disease (PD) it was found that comorbidity was higher than expected in the majority of the studies. Patients with PD are at increased risk of developing depression and, conversely, recent studies have shown that patients with depressive disorders have increased risk of incident PD. However, the temporal associations between the disorders are not fully elucidated. From this review it could be learned that the temporal aspects strongly suggest that a neurobiological association exists between affective disorder and PD. This is illustrated with hitherto unpublished data. Some of these issues may be investigated in case register studies, e.g. by linkage of registers of somatic and psychiatric illness, and suggestions for future research are given. For GP’s, psychiatrists, geriatricians, and neurologists these new findings will lead to a better understanding and better treatment for patients with complicated comorbid conditions. Here timing is important!
Parkinson’s disease (PD) is a movement disorder. However, often the diagnosis of PD can be preceded or followed by psychiatric symptoms [1-4]. And non-motor symptoms have been recognised as important in recent papers [5,6].
Several findings suggest that the major affective disorders are brain disorders. With the new imaging techniques, computerised tomography (CT-scan), magnetic resonance imaging (MRI) and functional magnetic resonance imaging (f-MRI) neuropathological studies can be conducted on the living brain [
The epidemiological comorbidity between major affective disorders and other psychiatric disorders such as anxiety disorders (panic attack, panic disorder, social phobias, obsessive compulsive disorder (OCD), and others), and drugand alcohol-dependency has been investigated in several studies during the latest decade. For a recent review see Kessler [
Theoretically, it is possible that major affective disorders may share some common pathophysiological mechanisms with PD. For this reason, we wanted to review the epidemiological literature regarding comorbidity between affective disorders and PD to investigate the temporal relationship between the disorders in order to elucidate aetiological causality.
Burke et al. suggested the term “comorbid” in psychiatric epidemiology meaning the presence of more than one specific disorder in a person, in a defined period of time [
The temporal association of symptoms are of great importance in everyday clinical situations [
The questions in focus in this review will be:
1) Temporal associations: are there differences in the course of the illness (affective/neurological), depending on whether symptoms of depression are primary or secondary to the neurological disorder? What are the rates of co-occurrence?
2) The use of rating scales in epidemiological studies in identifying risk factors for developing depression in patients with PD. Time relationship is important the choice of rating scale.
3) What is learned from family studies and data from genetic studies, and temporal relationship?
4) And the quintessence: is the comorbid affective disorder a psychological reaction to the distress caused by a severely disabling neurological disease, PD, or is it secondary to the neuro-pathophysiological process of PD itself? Can time-relationship tell us anything on these matters?
To what extent comorbid affective disorder is the result of treatment of PD, was not dealt with in this paper.
Data for the overview of the literature for this paper were identified by computerised searches of the Medline and Embase databases. In Medline the search terms were: Explode of “Depressive disorder” and “Bipolar disorder” (search of the listed terms and their sub-headings and thereby covering “Affective disorders” as well) and combined with explode of “Parkinson disease”. The search included all published articles from 1966 to September 2010. An additional search of the term “Depression” was performed. In the Embase the search included all published articles from 1986 to 2010, and the keywords concerning affective disorders were slightly different (manio-depressive, endogenous depression) but the procedure was the same. The searches were combined with the keywords “Temporal relations”, “Temporal”, and “Time”.
Additional articles were identified through manually searching the reference list of retrieved articles. Reviews were consulted and additional manual search was pursued to augment the computer-generated study-base of literature. Books on neurological diseases, e.g. symposia summaries, were consulted to obtain additional information.
The Cochrane Library was consulted for additional references. This search gave no additional references since it was primarily or maybe only based on Medline searches.
We found more than 700 articles; primarily on comorbidity. It soon turned out that there was not published much on bipolar disorder and PD. Many results come from family studies done in the 1990-ies and the 2000- ies.
The predominant feature of PD involves disturbances of motor control. The mean age of onset has been reported to be 55 years (two-thirds of the patients were between the ages of 50 and 69) [20,21]. Emotional symptoms have been described since James Parkinson’s first description of the disorder in 1817 [
The amount of papers on the subject of depression in PD is extensive. Several reviewers have investigated the subject, and in the last decade numerous major reviews were isolated with different foci [10,13,23-35]. These can be divided into reviews on neurobiology [10,13,24- 26,30-32], epidemiology [10,23,25,28,33,35], and treatment [10,27,29,34].
As a contribution to the revision of the DSM-III-R [
These questions are dealing with the temporal association between affective disorders and the impairment of motor function in patients with PD. McNamara mentioned that these issues were at that moment (1992) unsolved.
Cummings [
The incidence of depression in a population of PD patients has been estimated to be 1.86% per year [
In a review by Tom and Cummings [
Guze and Barrio [
To investigate whether patients with Parkinson’s disease were at an increased risk of developing major depression compared with patients with other medical illnesses with a comparable degree of disability, Nilsson et al. [
In the same study female patients with PD were found to have an estimated intensity of depression of 3.29 (95% CI: 2.00 - 5.40) compared with male patients with PD. The intensity was elevated for female patients with PD compared with female patients with diabetes or with osteoarthritis. These findings support the hypothesis that depression in patients with Parkinson’s disease is a consequence of some kind of brain dysfunction [
Nilsson et al. also conducted another case register study of hospitalised patients in Denmark [
The duration between a diagnosis of depression and a diagnosis of PD was 5.4 years on average (95% CI for mean 4.5 - 6.2 years; std. error 0.43), in accordance with others [
There have been contradictory results about the presence of depression in PD and the patient’s age at onset of PD. Some found no relationship [51,52], and others found a tendency of patients with PD and depression to be younger at the time of onset of PD symptoms (PD prior to age 55) than non-depressive PD patients [44,53,54]. It has been suggested that PD with depression might constitute a subtype of PD, in which patients are characterised by younger age at onset of PD, less impairment, and a higher frequency of positive family history of PD [
Concerning the duration of PD and the rate of depression in PD, most investigators have found no relationship [51,52,55-60]. This is interesting because depression might occur both early and late in PD, and early recognition is in both instances important because of the impact
on quality of life and even worsening of motor symptoms, that seems to decline faster if depression is present.
Instead of using a mere calendar time since onset of PD, some investigators have also considered staging of PD. As an indicator of the course of the illness, the Hoehn and Yahr staging scale (HY) [
Activities of Daily Living (ADL) [
with non-depressed PD patients [
Asymmetric left-sided Parkinson’s disease was found to be associated with greater rates of symptoms of anxiety and atypical depression in one study only [
In the quantification of mood changes in PD, the Beck Depression Inventory (BDI) (a self-report symptom rating scale) [
The BDI was constructed for measuring the severity of depression in patients with idiopathic depression. Measuring the severity of depressive symptoms in PD with the BDI, the somatic items included in the scale raise questions about its ability to differentiate depression from manifestations of the disease (in this case PD). Most authors discuss this, and two different groups reported that the BDI scores were found to reflect the severity of depressive symptoms in PD and that it was possible to separate them from symptoms of PD [74-76]. Others found that depression scores in PD, as measured by BDI, were significantly higher than in normal controls, but did not differ from those in control groups of arthritis patients [
Very few community-based studies have been published. In general the prevalence of depression has been found to be lower in these studies than in studies conducted in tertiary centres (university clinics). Thus, in a community-based cross-sectional study from Rogaland County in Norway, 7.7% met the diagnostic criteria for major depression using DSM-III-R among 245 patients with PD. Based on MADRS scores for assessment of severity of symptoms, 5.1% of the PD patients were found moderately to severely depressed and another 45.5% had mild depressive symptoms, [
Only one recently published epidemiological paper with relevant data exist about mania or bipolar disorder and PD [
Additionally, in our review of the literature we found ten case-stories in nine journal articles [82-90]. Some reports deal with manic attacks in PD without relation to drug treatment [82-84,86,87], and some deal with probable drug-induced manic attacks in PD patients treated with apomorphine or levodopa [85,88,89]. Only one case story presents a bipolar affective patient who subsequently developed PD. A severe manic episode occurred after initiating levodopa. The manic episode was treated successfully with clozapine, and levodopa dose was even raised afterwards [
In our group, in a hospital discharge registry study, based on the Danish population (approximately 5.1 million people), we found in a group of 2007 incident, hospitalised manic or bipolar patients, followed for up to 17 years, that the risk of a subsequent diagnosis of PD was not significantly elevated compared to control groups [
In
It has been suggested that there may be a variant of PD in which depression is more common, characterised by greater bradykinesia, rigidity, younger age of onset, and a greater probability of a positive family history for PD [28,44]. The effect of a family history of affective disorder on the risk of developing PD later on has, as far as we know, not been investigated. One twin study was found, although small in sample size (basically case stories) [
One study [
study) a sub group of 329 participants were identified as patients who had ever been treated by a psychiatrist for depression (patient self report). Data on the family history in first-degree relatives were collected, including psychiatric disease, dementia, and PD (self report). A tendency of increased risk of PD (however, not significant) was reported in families of those patients with bipolar depression (odds ratio 1.87, 95% CI: 0.65 - 5.34, NS), but not in families of patients with unipolar depression (odds ratio 0.67, 95% CI: 0.37 - 1.20, NS), suggesting that an association within families might be limited to bipolar disorders only (see later). In general, no clear relationship to family history of affective disorder, or a personal history of previous depressive episodes have been found [25,30].
A familial autosomal dominant form of parkinsonism and severe depression with an early onset, rapid progression leading to an early death, and in some families, additionally respiratory problems (alveolar hypoventilation), were summarised from five distinct families by Bhatia et al. [
The frequency and clinical correlates of neuropsychiatric symptoms in patients with PD, with and without dementia, and in those with dementia with Lewy bodies (DLB) has been investigated by Aarsland et al. [
In a large population based historical cohort study it was found that depressive and anxiety disorders may share familial susceptibility factors with PD [
This has only been scarcely studied.
In a population based study by Fahim et al. [
It seems from these studies that mania and hypomania are rare in PD, but also that patients who previously had signs of mania or hypomania may experience an acute exacerbation when given dopaminergic drugs [
The contemporary neurobiological literature on PD and affective disorders show that the prevalence of depression in PD is elevated compared with the general population. In several cases up to a mean of 40 - 43 percent of patients with PD has been found to suffer from depression [
It has to be emphasised that the reverse association, the risk for patients with affective disorder of developing a neurological disorder, has been only scarcely investigated. In patients with affective disorders we located three studies [46-48], all done in 2000-ies and in three different populations [
Most case-control studies quoted in this review were small in sample sizes and most frequently conducted in tertiary centres (university clinics) with the risk of introducing a selection bias [44,47,52,57,64]. The majority of the studies had a relatively short follow-up time, at least compared to the long lasting conditions in focus here; (all cases of PD last in fact for life). Survival analysis was only rarely used. A special topic to be very careful about, concerning comorbidity is Berkson’s fallacy or bias; in which persons with two conditions are more likely to be hospitalised or seek treatment. This could lead to artefact associations [100,101], and should be avoided by for example symmetric exclusion criteria for cases and controls, or careful selection of control subjects independently of exposure status and in some cases a stratified analysis. Survival analysis is the proper way to analyse time relationships in comorbidity studies.
PD has been investigated concerning depressive disorders and comorbidity. Comorbidity between bipolar disorder and neurological diseases remains to be illuminated, in all areas of interest, but from the available data there seems to be strong evidence in favour of a neurobiological connection between the two disorders of yet unknown nature. A hypothesis of a excitotoxin mechanism in the basal ganglia has been proposed for affective disorders [
One could speculate, whether the underlying and yet unknown mechanism in depression, comorbid with neurological disorders, is a cascade-like process that could be triggered in several different ways (or in different points of the evolving process) and lead to the same endpoint, namely depression [
An important finding, using PET-scanning, was a paralimbic frontal lobe glucose hypometabolism in patients with depression associated with PD compared with non-depressed patients with PD [
Another elegant imaging support was found using transcranial midbrain sonography. Walther et al. [
From the literature search several landmark theoretical papers on PD and depression were found, both concerning clinically relevant [
CT-scans, MRI and functional brain imaging like PET, have in lesion-and-deficit studies supported an association between lesions disrupting frontostriatal or paralimbic pathways and depressed mood [10,116]. In both PD and Huntington’s disease (HD), orbitofrontal circuit dysfunction appears to be linked to depression. The orbitofrontal circuit is carrying projections from the basal ganglia to the orbitofrontal cortex, a neocortical part of the limbic system [
Recently an algorithm for clinical prediction of PD according to the neuropathological stage (Braak stages) has been published [
The use of psychometric rating scales is an important matter in these studies. It has been mentioned in a paper concerning MS, that the Montgomery-Åsberg Depression scale (MADRS) has some advantages in a comorbidity study with neurological patients, because it has less items with physical symptoms (i.e. measuring merely psychological problems) [
It could not be recommended to use sub-scales of the existing depression rating scales, since the validation of the sub-scale is a difficult task, and comparisons between studies become almost impossible.
A new alternative for a self rating scale, the Major Depression Inventory (MDI), has been suggested by Bech et al. [
was found superior to the analogue Zung scale [
Both The BDI and the HDRS partly rely on somatic symptoms (e.g., fatigue or loss of energy, weight loss, insomnia, concentration difficulties, etc.), which are also part of the neurological deficits. The MDI could be an alternative. Both BDI and HDRS have recently been evaluated as tools for measuring Depression in patients with PD [79,124].
All rating scales are dependent on experienced users and training of the personnel using them. The more experienced—the earlier the affective disorder will be detected.
From family studies it was learned that predominantly younger PD patients have a family history of depression. For bipolar disorder the opposite was the case. No relationship was found except that treatment with dopamine containing drugs can give rise to exacerbation [
The overall goal of this review was to discuss comorbidity between affective disorder and PD. It can from our review be concluded that comorbidity between PD and affective disorder was higher than expected in the majority of the studies. However, the temporal associations between the disorders are not fully elucidated.
There is some evidence that the course of PD for patients with PD and a comorbid depression is impaired compared to patients with PD without comorbid affective disorder. The reverse situation, whether the course of affective disorders is altered by the comorbid neurological condition (PD), has been less well investigated. In depressed patients (major depression) with accompaning medical (non CNS) illnesses (DSM-III, axis I, II, or III—other than affective disorder), the course and recovery rate were less favourable, in the populations investigated, than in “pure depression” [
As stated in the introduction several scenarios concerning PD and affective disorder comorbidity may theoretically occur:
1) PD and affective disorders (depression or mania) co-occur, i.e. both disorders present themselves at the same point of time.
2) Affective symptoms or disorder (depressive or manic) may be the first to occur, i.e. precursor of PD. Hence, in this scenario, there would be no time interval between the two disorders.
3) Affective symptoms or disorder (depressive or manic) may be a predictor of a subsequent diagnosis of PD. Hence, in this scenario; there would be a symptom-free interval between the two disorders.
4) Neurological symptoms and signs of PD may be the first to occur, i.e. precursor of affective disorder. Hence, in this scenario, there would be no time interval between the two disorders.
5) Neurological symptoms and signs of PD may be a predictor of subsequent affective disorder. Hence, in this scenario, there would be a free time interval between the two disorders.
At least for some cases the scenario 3 is the most probable explanation and likewise scenario 5 is the most probable for some cases of patients with PD. From this review it could be learned that the temporal aspects strongly suggest a neurobiological association exists between affective disorder and PD.
It is therefore necessary to investigate these aspects further in “large scale” epidemiological comorbidity studies with the proper rating scales. There is a need for prospective longitudinal studies including large cohorts of patients with affective disorder and large cohorts of patients with neurological disorders [
Some of these relationships have been investigated in case register studies, e.g. by linkage of the Danish National Hospital Register including somatic disorders (Lands Patient Registeret, LPR), and the Danish Psychiatric Central Register (PCR) including psychiatric disorders as done in the studies from our research institute. Recently we extended the studies with linkage with a prescription database, from the Danish Medicines Agency. This was primarily done to control for the effect of treatment given to the patients in studying the comorbid conditions [127,128].
In 1817 James Parkinson noted a relationship between mood disorders and “The Shaking Palsy” [
For general practitioners, psychiatrists, geriatricians, and neurologists these new findings will lead to a better understanding of the diseases and eventually a better treatment of patients with complicated comorbid conditions. For clinicians it is important to realise that a depressive disorder in old age is of course not a neurological condition, but that eventually some of our patients with depression will develop a neurological disease such as Parkinson’s disease, and treatment of this condition may be initiated earlier if the physician remembers this possibility. This could have great impact for many elderly patients. Already St. Augustine realised that time is a difficult concept to understand. The quintessence being: “Timing is important!”
The author thanks Ms. Christine Sweeney Hansen for language corrections. The Theodore and Vada Stanley Foundation (USA) supported this study. Professor Lars Vedel Kessing, Rigshospitalet, Copenhagen made numerous suggestions on an earlier draft of this paper, for which he is gratefully thanked.