Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology

Inhibitors of MAO-A and MAO-B are in clinical use for the treatment of psychiatric and neurological disorders respectively. Elucidation of the molecular structure of the active sites of the enzymes has enabled a precise determination of the way in which substrates and inhibitor molecules are metabolized, or inhibit metabolism of substrates, respectively. Despite the knowledge of the strong antidepressant efficacy of irreversible MAO inhibitors, their clinical use has been limited by their side effect of potentiation of the cardiovascular effects of dietary amines (cheese effect). A number of reversible MAO-A inhibitors which are devoid of cheese effect have been described in the literature, but only one, moclobemide, is currently in clinical use. The irreversible inhibitors of MAO-B, selegiline and rasagiline, are used clinically in treatment of Parkinson’s disease, and a recently introduced reversible MAO-B inhibitor, safinamide, has also been found efficacious. Modification of the pharmacokinetic characteristics of selegiline by transdermal administration has led to the development of a new drug form for treatment of depression. The clinical potential of MAO inhibitors together with detailed knowledge of the enzyme’s binding site structure should lead to future developments with these drugs

Activity-based diary for Parkinson's disease

The objective of this study was to develop a Parkinson's disease diary that evaluates a patient's difficulties in performing activities as a substitute for the amount of "on"- and "off"-time and to assess its clinimetric qualities. In this study, 84 patients with Parkinson's disease kept a diary for 2 or 3 periods of 5 days. Daily, five items were recorded across 11 time periods. Patients simultaneously recorded "on-off" in the traditional way. The diary was easily understood, and median recording time was 5-10 minutes a day. Clinimetric analysis showed that the diary could be reduced successfully to 3 days, in which five items (walking, transfers, manual activities, dyskinesias, and sleep) with four response options (no, slight, moderate, and severe difficulty) were assessed seven times daily. Sumscores of the first three items accurately predicted being "on" or "off" in 93% of the cases, making separate scoring of "on" and "off" unnecessary. The diary was internally consistent and showed good reproducibility. Construct validity with external measures was adequate, and comparisons between patients grouped by disease severity and by degree of fluctuations revealed significant differences in the expected directions. Taken together, this Parkinson's disease diary has a sound clinimetric basis, provides information on the extent of perceived disability, and thereby accurately reflects the severity of "off"-periods and the variability of motor fluctuation

Double-blind trial of levodopa/carbidopa/entacapone versus levodopa/carbidopa in early Parkinson's disease

We performed a 39-week, randomized, double-blind, multicenter study to compare the efficacy, safety, and tolerability of levodopa/carbidopa/ entacapone (LCE, Stalevo) with levodopa/carbidopa (LC, Sinemet IR) in patients with early Parkinson's disease (PD). Four hundred twenty-three patients with early PD warranting levodopa were randomly assigned to treatment with LCE 100/25/200 or LC 100/25 three-times daily. The adjusted mean difference in total Unified Parkinson's disease Rating Scale (UPDRS) Parts II and III between groups using the analysis of covariance model (prespecified primary outcome measure) was 1.7 (standard error = 0.84) points favoring LCE (P = 0.045). Significantly greater improvement with LCE compared with LC was also observed in UPDRS Part II activities of daily living (ADL) scores (P = 0.025), Schwab and England ADL scores (blinded rater, P = 0.003; subject, P = 0.006) and subject-reported Clinical Global Impression (CGI) scores (P = 0.047). There was no significant difference in UPDRS Part III or investigator-rated CGI scores. Wearing-off was observed in 29 (13.9%) subjects in the LCE group and 43 (20.0%) in the LC group (P = 0.099). Dyskinesia was observed in 11 (5.3%) subjects in the LCE group and 16 (7.4%) in the LC group (P = 0.367). Nausea and diarrhea were reported more frequently in the LCE group. LCE provided greater symptomatic benefit than LC and did not increase motor complications. © 2008 Movement Disorder Society

Neurostimulation for Advanced Parkinson Disease and Quality of Life at 5 Years

Importance: Deep brain stimulation of the subthalamic nucleus (STN-DBS) improves quality of life (QOL) in patients with advanced Parkinson disease (PD). However, controlled studies with more than 3 years of follow-up are lacking.Objective: To investigate the long-term effects of STN-DBS on QOL compared with standard-of-care medication (MED).Design, setting, and participants: In this prospective, observational, quasi-experimental, longitudinal nonrandomized controlled trial, 183 patients were screened for eligibility and 167 were enrolled from March 1, 2011, to May 31, 2017, at 3 European university centers. Propensity score matching for demographic and clinical characteristics was applied to 108 patients with PD (62 in the STN-DBS group and 46 in the MED group), resulting in a well-balanced, matched subcohort of 25 patients per group. Data analysis was performed from September 2022 to January 2023.Exposure: Treatment for PD of STN-DBS or MED.Main outcomes and measures: Assessments included Parkinson's Disease Questionnaire 8 (PDQ-8), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-activities of daily living (ADL) and motor complications, and levodopa-equivalent daily dose. Within-group longitudinal outcome changes, between-group differences, and correlations of change scores were analyzed.Results: The study population in the analysis included 108 patients (mean [SD] age, 63.7 [8.3] years; 66 [61.1%] male). At 5-year follow-up, PDQ-8 and ADL worsened only in the MED group (PDQ-8 change, -10.9; 95% CI, -19.0 to -2.7; P = .01; ADL change: -2.0; 95% CI, -3.1 to -0.8; P = .002), whereas both outcomes remained stable in the STN-DBS group (PDQ-8 change, -4.3; 95% CI, -13.2 to 4.7; P = .34; ADL change, -0.8; 95% CI, -2.5 to 1.0; P = .38). Changes in PDQ-8 and ADL correlated moderately (rs = .40, P = .008). Furthermore, STN-DBS outcomes were favorable for motor complications (median difference in change scores between STN-DBS and MED, -2.0; 95% CI, -4.0 to -1.0; P = .003), mobility (-1.0; 95% CI, -2.0 to 0; P = .03), and levodopa-equivalent daily dose reduction (-821.4; 95% CI, -1111.9 to -530.8; P < .001).Conclusions and relevance: This study provides evidence of differences in QOL outcomes at 5-year follow-up between STN-DBS (stable) and MED (worsened), mainly driven by the favorable effect of STN-DBS on mobility (class IIb evidence). The association between changes in QOL and ADL, but not motor impairment or complications, highlights the relative importance of ADL outcomes for long-term DBS assessments.Trial registration: German ClinicalTrials Registry: DRKS00006735

Selecting deep brain stimulation or infusion therapies in advanced Parkinson's disease: an evidence-based review

Motor complications in Parkinson's disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine