Dissociable effects of dopaminergic medications on depression symptom dimensions in Parkinson disease
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SUBMITTER: Costello H
PROVIDER: S-EPMC11310074 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundDepression in Parkinson's disease (PD) is common, disabling and responds poorly to standard antidepressant medication. Motivational symptoms of depression, such as apathy and anhedonia, are particularly prevalent in depression in PD and predict poor response to antidepressant treatment. Loss of dopaminergic innervation of the striatum is associated with emergence of motivational symptoms in PD, and mood fluctuations correlate with dopamine availability. Accordingly, optimising dopaminergic treatment for PD can improve depressive symptoms, and dopamine agonists have shown promising effects in improving apathy. However, the differential effect of antiparkinsonian medication on symptom dimensions of depression is not known.AimsWe hypothesised that there would be dissociable effects of dopaminergic medications on different depression symptom dimensions. We predicted that dopaminergic medication would specifically improve motivational symptoms, but not other symptoms, of depression. We also hypothesised that antidepressant effects of dopaminergic medications with mechanisms of action reliant on pre-synaptic dopamine neuron integrity would attenuate as pre-synaptic dopaminergic neurodegeneration progresses.MethodsWe analysed data from a longitudinal study of 412 newly diagnosed PD patients followed over five years in the Parkinson's Progression Markers Initiative cohort. Medication state for individual classes of Parkinson's medications was recorded annually. Previously validated "motivation" and "depression" dimensions were derived from the 15-item geriatric depression scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging.ResultsLinear mixed-effects modelling was performed across all simultaneously acquired data points. Dopamine agonist use was associated with relatively fewer motivation symptoms as time progressed (interaction: β=-0.07, 95%CI [-0.13,-0.01], p=0.015) but had no effect on the depression symptom dimension (p=0.6). In contrast, monoamine oxidase-B (MAO-B) inhibitor use was associated with relatively fewer depression symptoms across all years (β=-0.41, 95%CI [-0.81,-0.01], p=0.047). No associations were observed between either depression or motivation symptoms and levodopa or amantadine use. There was a significant interaction between striatal DAT binding and MAO-B inhibitor use on motivation symptoms: MAO-B inhibitor use was associated with lower motivation symptoms in patients with higher striatal DAT binding (interaction: β=-0.24, 95%CI [-0.43,-0.05], p=0.012). No other medication effects were moderated by striatal DAT binding measures.ConclusionsWe identified dissociable associations between dopaminergic medications and different dimensions of depression in PD. Dopamine agonists may be effective for treatment of motivational symptoms of depression. In contrast, MAO-B inhibitors may improve both depressive and motivation symptoms, albeit the latter effect appears to be attenuated in patients with more severe striatal dopaminergic neurodegeneration, which may be a consequence of dependence on pre-synaptic dopaminergic neuron integrity.
| S-EPMC10327242 | biostudies-literature
Project description:BackgroundDistortions in metacognition-the ability to reflect on and control other cognitive processes-are thought to be characteristic of poor mental health. However, it remains unknown whether such shifts in self-evaluation are due to specific alterations in metacognition and/or a downstream consequence of changes in decision-making processes.MethodsUsing perceptual decision making as a model system, we employed a computational psychiatry approach to relate parameters governing both decision formation and metacognitive evaluation to self-reported transdiagnostic symptom dimensions in a large general population sample (N = 995).ResultsVariability in psychopathology was unrelated to either speed or accuracy of decision formation. In contrast, leveraging a dimensional approach, we revealed independent relationships between psychopathology and metacognition: a symptom dimension related to anxiety and depression was associated with lower confidence and heightened metacognitive efficiency, whereas a dimension characterizing compulsive behavior and intrusive thoughts was associated with higher confidence and lower metacognitive efficiency. Furthermore, we obtained a robust double dissociation-whereas psychiatric symptoms predicted changes in metacognition but not decision performance, age predicted changes in decision performance but not metacognition.ConclusionsOur findings indicate a specific and pervasive link between metacognition and mental health. Our study bridges a gap between an emerging neuroscience of decision making and an understanding of metacognitive alterations in psychopathology.
| S-EPMC6117452 | biostudies-literature
Project description:While depression is a leading cause of disability, prior investigations of depression have been limited by studying correlates in isolation. A data-driven approach was applied to identify out-of-sample predictors of current depression from adults (N = 217) sampled on a continuum of no depression to clinical levels. The current study used elastic net regularized regression and predictors from sociodemographic, self-report, polygenic scores, resting electroencephalography, pupillometry, actigraphy, and cognitive tasks to classify individuals into currently depressed (MDE), psychiatric control (PC), and no current psychopathology (NP) groups, as well as predicting symptom severity and lifetime MDE. Cross-validated models explained 20.6% of the out-of-fold deviance for the classification of MDEs versus PC, 33.2% of the deviance for MDE versus NP, but -0.6% of the deviance between PC and NP. Additionally, predictors accounted for 25.7% of the out-of-fold variance in anhedonia severity, 65.7% of the variance in depression severity, and 12.9% of the deviance in lifetime depression (yes/no). Self-referent processing, anhedonia, and psychosocial functioning emerged as important differentiators of MDE and PC groups. Findings highlight the advantages of using psychiatric control groups to isolate factors specific to depression.
| S-EPMC8042639 | biostudies-literature
Project description:ObjectivesBoth depression and apathy, alone and in combination, have been shown to negatively affect cognition in patients with Parkinson's disease (PD). However, the influence of specific symptom dimensions of depression and apathy on cognition is not well understood. The current study investigated the relationship between symptom dimensions of depression and apathy, based on factors identified in Kirsch-Darrow et al. (2011), and memory and executive function in PD.MethodsA sample of 138 non-demented individuals with PD (mean age=64.51±7.43 years) underwent neuropsychological testing and completed the Beck Depression Inventory, 2nd Edition, and Apathy Scale. Separate hierarchical regression models examined the relationship between symptom dimensions of depression and apathy ("pure" depressive symptoms, "pure" apathy, loss of interest/pleasure [anhedonia], and somatic symptoms) and three cognitive domain composites: immediate verbal memory, delayed verbal memory, and executive function.ResultsAfter adjusting for general cognitive status and the influence of the other symptom dimensions, "pure" depressive symptoms were negatively associated with the delayed verbal memory composite (p<.034) and somatic symptoms were positively associated with the executive function composite (p<.026). No symptom dimensions were significantly related to the immediate verbal memory composite.ConclusionsFindings suggest that specific mood symptoms are associated with delayed verbal memory and executive function performance in non-demented patients with PD. Further research is needed to better understand possible mechanisms through which specific symptom dimensions of depression and apathy are associated with cognition in PD. (JINS, 2018, 24, 269-282).
| S-EPMC5820218 | biostudies-literature
Project description:Depression is common in Parkinson's disease and is associated with cognitive impairment. Dopaminergic medications are effective in treating the motor symptoms of Parkinson's disease; however, little is known regarding the effects of dopaminergic pharmacotherapy on cognitive function in depressed Parkinson patients. This study examines the neuropsychological effects of dopaminergic pharmacotherapy in Parkinsonian depression. We compared cognitive function in depressed and non-depressed Parkinson patients at two time-points: following overnight withdrawal and after the usual morning regimen of dopaminergic medications. A total of 28 non-demented, right-handed patients with mild to moderate idiopathic Parkinson's disease participated. Ten of these patients were depressed according to DSM IV criteria. Results revealed a statistically significant interaction between depression and medication status on three measures of verbal memory and a facial affect naming task. In all cases, depressed Parkinson's patients performed significantly more poorly while on dopaminergic medication than while off. The opposite pattern emerged for the non-depressed Parkinson's group. The administration of dopaminergic medication to depressed Parkinson patients may carry unintended risks.
| S-EPMC3805794 | biostudies-literature
Project description:BackgroundMajor depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions.MethodsUsing three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism.ResultsThe IMD clinical dimension and the inflammatory index were positively correlated (r = 0.19, p = 0.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids.ConclusionThe IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.
| S-EPMC9241382 | biostudies-literature
Project description:ObjectivePeople with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated α-syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD-affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphé nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert.MethodsHigh-performance liquid chromatography and novel enzyme-linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 α-syn deposition) and six age-matched controls were tested.ResultsPD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups.InterpretationThese results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced PD with dementia.
| S-EPMC4603378 | biostudies-literature
Project description:ObjectiveA recent study observed a 2-fold greater risk of Parkinson disease (PD) in relation to the β2-adrenoreceptor antagonist propranolol and a markedly lower risk of PD for the β2-adrenoreceptor agonist salbutamol. We examined whether confounding by clinical indication for these medications, that is, tremor and smoking-related pulmonary conditions, explained these associations.MethodsIn a large, population-based case-control study of United States Medicare beneficiaries in 2009 with diagnosis codes, procedure codes, and prescription data (48,295 incident PD cases, 52,324 controls), we examined the risk of PD in relation to use of selected β antagonists (propranolol, carvedilol, metoprolol), the β2 agonist salbutamol, and other medications used for the same clinical indications (primidone, inhaled corticosteroids). We adjusted for demographics, smoking, and overall use of medical care. We then examined the effect of also adjusting for clinical indication and applying medication exposure lagging.ResultsPropranolol appeared to increase PD risk (odds ratio [OR] = 3.62, 95% confidence interval [CI] = 3.31-3.96). When we adjusted for tremor or abnormal involuntary movement prior to the PD diagnosis/reference date and lagged propranolol exposure, the association was 0.97 (95% CI = 0.80-1.18). Primidone, also used for tremor, was similarly sensitive to this adjustment and lagging. β Antagonists not indicated for tremor appeared to reduce PD risk (carvedilol: OR = 0.77, 95% CI = 0.73-0.81; metoprolol: OR = 0.94, 95% CI = 0.91-0.97) and were insensitive to adjustment for indications and lagging. Neither salbutamol nor inhaled corticosteroids were consistently associated with PD risk.Interpretationβ2-adrenoreceptor agonists and antagonists do not appear to alter PD risk. Ann Neurol 2018;84:691-701.
| S-EPMC6881195 | biostudies-literature
Project description:BackgroundMajor depressive disorder (MDD) is a prevalent psychiatric disorder characterized by substantial clinical and neurobiological heterogeneity. Conventional studies that solely focus on clinical symptoms or neuroimaging metrics often fail to capture the intricate relationship between these modalities, limiting their ability to disentangle the complexity in MDD. Moreover, patient neuroimaging data typically contains normal sources of variance shared with healthy controls, which can obscure disorder-specific variance and complicate the delineation of disease heterogeneity.MethodsWe employed contrastive principal component analysis to extract disorder-specific variations in fMRI-based resting-state functional connectivity (RSFC) by contrasting MDD patients (N=233) with age-matched healthy controls (N=285). We then applied sparse canonical correlation analysis to identify latent dimensions in the disorder variations by linking the extracted contrastive connectivity features to clinical symptoms in MDD patients.ResultsTwo significant and generalizable dimensions linking distinct brain circuits and clinical profiles were discovered. The first dimension, associated with an apparent "internalizing-externalizing" symptom dimension, was characterized by self-connections within the visual network and also associated with choice reaction times of cognitive tasks. The second dimension, associated with personality facets such as extraversion and conscientiousness typically inversely associated with depression symptoms, is primarily driven by self-connections within the dorsal attention network. This "depression-protective personality" dimension is also associated with multiple cognitive task performances related to psychomotor slowing and cognitive control.ConclusionsOur contrastive RSFC-based dimensional approach offers a new avenue to dissect clinical heterogeneity underlying MDD. By identifying two stable, neurophysiology-informed symptom dimensions in MDD patients, our findings may enhance disease mechanism insights and facilitate precision phenotyping, thus advancing the development of targeted therapeutics for precision mental health.
| S-EPMC11482755 | biostudies-literature
Project description:Motor complications are a consequence of the chronic treatment of Parkinson's disease (PD) and include motor fluctuations (wearing-off phenomenon) and levodopa-induced dyskinesia. Both can have a significant impact on functionality and quality of life; thus, proper recognition and management is essential. The phenomenology and temporal relationship of motor complications to the schedule of levodopa dosing can be helpful in characterizing them. There are several therapeutic approaches to motor complications, including pharmacological and surgical options. The authors summarize the different types of motor complications according to phenomenology and the currently available medical treatments, including ongoing trials for the management of this condition.
| S-EPMC5990008 | biostudies-literature