Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review describes symptoms and pathophysiology of Parkinson's diseases (PD) and restless legs syndrome (RLS), and discusses the relationship between clinical outcome of DA agonists and their receptor-binding and pharmacokinetics. Oral DA agonists are divided into 2 classes; the ergots and the non-ergots. Both classes are in general equally effective against PD motor symptoms. Ergots (apart from bromocriptine) stimulate the DA D(1) subreceptor and increase dyskinesia. Furthermore, valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis appear to represent a class effect of 8beta-aminoergolines as cabergoline and pergolide The side effects profile therefore seems more beneficial for non-ergots than ergots. The main improvement of motor functions by DA agonists is related to D(2) agonism. However, in monotheraphy, the selective D(2)-receptor DA agonist sumanirole seemed less effective than ropinirole which is selective for D(2)-like DA-receptors (D(2), D(3) and D(4)). Given as adjunctive to L-dopa both drugs had equal efficacy on motor-symptoms, indicating that D(2)-receptor activity must be accompanied with stimulation of other DA receptors for optimizing the efficacy on motor symptoms. Striatal D(3) receptor loss may be more important than D(2) receptor loss for reduced response to dopaminergic treatment. D(3) stimulation may also be beneficial for the non-motor symptom depression/mood in PD and for neuron-protection. This makes D(3)-receptors a potential therapeutic target in PD. 5-HT(1A)-receptor agonism and alpha(2) adrenergic antagonism may contribute to prevention of dyskinesia. However, 5-HT-receptor activity is also associated with side effects. 5-HT(2B) agonism (and possibly 5-HT(1B) agonism) is associated with fibrotic reactions, and valvular heart disease (VHD). By interfering with the CYP450 system DA agonists may contribute to drug-drug interactions. Lack of CYP2D6 activity is also suggested as important for etiology and CNS-symptoms of PD. Based on current knowledge D2-like receptor activities (preferences for the D(3) receptor) seem most beneficial. 5-HT(1A)-receptor agonism (prevention of dyskinesia), 5-HT(2B) antagonism or no 5-HT(2B)-receptor activity also seems beneficial. Development of DA agonists containing these properties, without interfering with CYP2D6 may be beneficial.
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PMID:Receptor-binding and pharmacokinetic properties of dopaminergic agonists. 1869 Nov 32

Non-motor symptoms, such as psychiatric symptoms and autonomic dysfunction, are common co-morbid conditions in Parkinson's disease (PD) and major contributors to poor quality of life and disability. Within the group of neuropsychiatric conditions, depressive symptoms are the most common condition. Despite their frequency and importance, depressive symptoms can be difficult to assess and diagnose and thus depression in PD is frequently unrealized. Diagnostic challenges include the overlap of depressive symptoms with motor and non-motor symptoms of PD, such as dementia and apathy. Furthermore, there are no definite standards to assess and diagnose depression in PD leading also to the lack of exact data on the epidemiology of this non-motor symptom in PD. Depending on the diagnostic test and the study design the prevalence of depression in PD is reported between 7 and 72% of PD patients with approximately 40% in most cross-sectional studies. In contrast, the pathogenesis and long-term course of depression in PD remain elusive. Current hypothesis, however, includes that depressive symptoms are part of the core condition of PD when regarded as an entity. The present review summarizes the current knowledge on epidemiology, pathogenesis and diagnosis of depression in PD and proposes on this data base a standard procedure for screening and diagnosis of depressive symptoms in PD.
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PMID:[Depression in Parkinson's disease. Part 1: epidemiology, signs and symptoms, pathophysiology and diagnosis]. 1901 23

The aim of this article was to determine which aspects of Huntington's disease (HD) are most important with regard to the health-related quality of life (HrQOL) of patients with this neurodegenerative disease. Seventy patients with HD participated in the study. Assessment comprised the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive and functional capacity sections, and the Beck Depression inventory. Mental and physical HrQOL were assessed using summary scores of the SF-36. Multiple regression analyses showed that functional capacity and depressive mood were significantly associated with HrQOL, in that greater impairments in HrQOL were associated with higher levels of depressive mood and lower functional capacity. Motor symptoms and cognitive function were not found to be as closely linked with HrQOL. Therefore, it can be concluded that, depressive mood and greater functional incapacity are key factors in HrQOL for people with HD, and further longitudinal investigation will be useful to determine their utility as specific targets in intervention studies aimed at improving patient HrQOL, or whether other mediating variables. As these two factors had a similar association with the mental and physical summary scores of the SF-36, this generic HrQOL measure did not adequately capture and distinguish the true mental and physical health-related HrQOL in HD.
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PMID:Health-related quality of life in Huntington's disease: Which factors matter most? 1909 81

Purpose. To assess the impact of clinical variables on social skills and behaviors in Parkinson's disease (PD) patients and patient versus examiner estimates of social functioning. Methods. Twenty-eight patients with PD and 32 controls with chronic disease were assessed with a battery of neuropsychologic, personality, mood, and social function tests. Results. Patients' estimates of their own social functioning were not significantly different from examiners' estimates. The impact of clinical variables on social functioning in PD revealed depression to be the strongest association of social functioning in PD on both the patient and the examiner version of the Social Adaptation Self-Evaluation Scale. Conclusions. PD patients appear to be well aware of their social strengths and weaknesses. Depression and motor symptom severity are significant predictors of both self- and examiner reported social functioning in patients with PD. Assessment and treatment of depression in patients with PD may improve social functioning and overall quality of life.
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PMID:The Impact of Clinical and Cognitive Variables on Social Functioning in Parkinson's Disease: Patient versus Examiner Estimates. 2094 89

Parkinson's disease (PD) is a common age-associated neurodegenerative disorder. Motor symptoms are the cardinal component of PD, but non-motor symptoms, such as dementia, depression, and autonomic dysfunction are being increasingly recognized. Motor symptoms are primarily caused by selective degeneration of substantia nigra dopamine (SNDA) neurons in the midbrain; non-motor symptoms may be referable to well-described pathology at multiple levels of the neuraxis. Development of symptomatic and disease-modifying therapies is dependent on an accurate and comprehensive understanding of the pathogenesis and pathophysiology of PD. Gene expression profiling has been recently employed to assess function on a broad level in the hopes of gaining greater knowledge concerning how individual mechanisms of disease fit together as a whole and to generate novel hypotheses concerning PD pathogenesis, diagnosis, and progression. So far, the majority of studies have been performed on postmortem brain samples from PD patients, but more recently, studies have targeted enriched populations of dopamine neurons and have begun to explore extra-nigral neurons and even peripheral tissues. This review will provide a brief synopsis of gene expression profiling in parkinsonism and its pitfalls to date and propose several potential future directions and uses for the technique. It will focus on the use of microarray experiments to stimulate hypotheses concerning mechanisms of neurodegeneration in PD, since the majority of studies thus far have addressed that complicated issue.
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PMID:Current status and future directions of gene expression profiling in Parkinson's disease. 2105 69

The mechanisms underlying pain in Parkinson's disease (PD) are unclear. Although a few studies have reported that PD patients may have low pain threshold and tolerance, none could accurately assess whether there was a correlation between sensory thresholds and demographic/clinical features of PD patients. Thus, tactile threshold, pain threshold, and pain tolerance to electrical stimuli in the hands and feet were assessed in 106 parkinsonian patients (of whom 66 reported chronic pain) and 51 age- and sex-matched healthy subjects. Linear regression models determined relationships between psychophysical parameters and demographic/clinical features. Female gender, severity of disease, medical disease associated with painful symptoms, and dyskinesia were more frequently observed in PD patients experiencing pain, even though dyskinesia did not reach significance. Pain threshold and pain tolerance were significantly lower in PD patients than in control subjects, whereas the tactile threshold yielded comparable values in both groups. Multivariable linear regression analyses yielded significant inverse correlations of pain threshold and pain tolerance with motor symptom severity and Beck depression inventory. Pain threshold and pain tolerance did not differ between PD patients with and without pain. In the former group, there was no relationship between pain threshold and the intensity/type of pain, and number of painful body parts. These findings suggest that pain threshold and pain tolerance tend to decrease as PD progresses, which can predispose to pain development. Female gender, dyskinesia, medical conditions associated with painful symptoms, and postural abnormalities secondary to rigidity/bradikinesia may contribute to the appearance of spontaneous pain in predisposed subjects.
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PMID:Spontaneous pain, pain threshold, and pain tolerance in Parkinson's disease. 2108 24

Motor symptoms in Parkinson's disease (PD) are caused by a severe loss of pigmented dopamine-producing nigro-striatal neurons. Symptomatic therapies provide benefit for motor features by restoring dopamine receptor stimulation. Studies have demonstrated that delaying the introduction of dopaminergic medical therapy is associated with a rapid decline in quality of life. Nonmotor symptoms, such as depression, are common in early PD and also affect quality of life. Therefore, dopaminergic therapy should typically be initiated at, or shortly following, diagnosis. Monamine oxidase-B inhibitors provide mild symptomatic benefit, have excellent side effect profiles, and may improve long-term outcomes, making them an important first-line treatment option. Dopamine agonists (DAs) provide moderate symptomatic benefit but are associated with more side effects than levodopa. However, they delay the development of motor complications by delaying the need for levodopa. Levodopa (LD) is the most efficacious medication, but its chronic use is associated with the development of motor complications that can be difficult to resolve. Younger patients are more likely to develop levodopa-induced motor complications and they are therefore often treated with a DA before levodopa is added. For older patients, levodopa provides good motor benefit with a relatively low-risk of motor complications. Using levodopa with a dopa-decarboxylase inhibitor lessens adverse effects, and further adding a catechol-O-methyl transferase inhibitor can improve symptom control.
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PMID:Improving symptom control in early Parkinson's disease. 2118 Jun 28

The accumulation of alpha-synuclein in Lewy bodies and Lewy neurites of different neuronal populations is one of the neuropathological hallmarks in Parkinson disease (PD). Overexpression of human wildtype or mutant alpha-synuclein affects the generation of new neurons in the adult dentate gyrus (DG) of the hippocampus in models of PD. Hippocampal dysfunction with reduced neurogenesis plays an important role in the pathogenesis of depression, an important non-motor symptom in PD. Moreover, effective antidepressant treatment is still an unmet need in PD. The present study explored if impaired hippocampal neurogenesis in the A53T transgenic animal model of PD may be restored by chronic oral application of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. First, we determined the expression pattern of transgenic mutant A53T synuclein in developing DG neurons and showed early expression of the transgene linked to a severely impaired neurogenesis. After chronic fluoxetine treatment we observed an increased adult neurogenesis in the hippocampus of more than threefold in treated A53T mice compared with controls. The pro-neurogenic effect of chronic fluoxetine application is predominantly related to an increased proliferation of neural precursor cells in the DG, and to a lesser extent by induction of differentiation into mature neurons. Analysis of the underlying mechanisms revealed an induction of brain-derived and glial cell-derived neurotrophic factor levels as a result of fluoxetine treatment. This study underlines the large potential of SSRI-dependent mechanisms to stimulate adult hippocampal neurogenesis in alpha-synuclein models and may lead to novel means to improve neuropsychiatric symptoms in PD.
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PMID:Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic A53T synuclein mouse model. 2221 40

Background. Apathy and impulsivity in Parkinson disease (PD) are associated with clinically significant behavioral disorders. Aim. To explore the phenomenology, distribution, and clinical correlates of these two behaviors. Methods. In PD participants (n = 99) without dementia we explored the distribution of measures of motivation and impulsivity using univariate methods. We then undertook factor analysis to define specific underlying dimensions of apathy and impulsivity. Regression models were developed to determine the associated demographic and clinical features of the derived dimensions. Results. The factor analysis of apathy (AES-C) revealed a two-factor solution: "cognitive-behavior" and "social indifference". The factor analysis of impulsivity (BIS-11) revealed a five-factor solution: "inattention"; "impetuosity"; "personal security"; "planning"; and "future orientation". Apathy was significantly associated with: age, age of motor symptom onset (positive correlation), disease stage, motor symptom severity, and depression. Impulsivity was significantly associated with: age of motor symptom onset (negative correlation), gambling and anxiety scores, and motor complications. We observed an overlap of apathy and impulsivity in some participants. Conclusion. In PD, apathy and impulsivity have specific phenomenological profiles and are associated with particular clinical phenotypes. In spite of this, there is some overlap of behaviors which may suggests common aspects in the pathology underlying motivation and reward processes.
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PMID:An exploration of apathy and impulsivity in Parkinson disease. 2282 14

Autoimmune myasthenia gravis (MG) comprises a broad spectrum of non-motor symptoms. Patients with MG sometimes have psychiatric symptoms, such as depression and anxiety, which impair their quality of life. However, these symptoms are not principally immune-mediated. Moreover, some patients with MG have additional autoimmune disorders. The clinical manifestations of these diseases are also considered non-motor symptoms, even though the autoimmune mechanisms underlying the association between MG and these disorders are not fully understood. In this review, we clarify that the non-motor symptoms of autoimmune disorders are attributed to abnormal T-cell clones from thymomas. We review the clinical characteristics of patients with MG and associated thymomas who exhibit non-motor symptoms based on previously reported cases and our multicenter cooperative study. CD8+ T-cell cytotoxicity against hematopoietic precursor cells in the bone marrow and unidentified autoantigens in hair follicles result in the development of pure red cell aplasia, immunodeficiency, and alopecia areata. In contrast, neuromyotonia, limbic encephalitis, myocarditis, and taste disorders are autoantibody-mediated disorders, as is MG. Autoantibodies to several types of voltage-gated potassium channels and related molecules can evoke various neurological and cardiac disorders. Approximately 25% of patients with MG and associated thymomas experience at least one non-motor symptom. Non-motor symptoms affect many target organs and result in a broad disease spectrum, ranging from the impairment of quality of life to lethal conditions.
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PMID:[Non-motor symptoms in myasthenia gravis: attributed to T-cell clones from thymoma]. 2356 96


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