Movement Disorders After Exposure to Antipsychotic Drugs in Patients With Depressive Disorders.

OBJECTIVES: The aims of the study were to explore the frequency of movement disorders (MDs) in depressive patients exposed to antipsychotic drugs (APDs) and to compare it with nonexposed depressive patients and APDs-treated schizophrenic patients. METHODS: Four hundred fifty-two depressive patients not exposed to APDs (group A), 156 depressives exposed to APDs (group B), and 75 patients with schizophrenia on APDs (group C) were recruited. Presence of MDs was explored by the Simpson-Angus and UKU scales (Registration: NCT02409823). RESULTS: Movement disorders were observed in 5%, 9%, and 13% of patients in groups A to C, respectively (P < 0.001, χ for linear trend). A logistic multivariate analysis revealed that male sex (odds ratio = 2.26, 95% confidence interval = 1.13-4.49, P < 0.01), exposure to first-generation (vs second-generation) APDs (odds ratio = 5.71, 95% confidence interval = 2.08-15.66, P < 0.01), and exposure to lithium (odds ratio = 3.99, 95% confidence interval = 1.74-9.14, P < 0.01) were independently and significantly associated with MDs. CONCLUSIONS: Male sex, use first-generation APDs, and exposure to lithium were associated with MDs in depression. Therefore, caution is advised with the use of these drugs in depressive patients. Prospective studies are needed to confirm these results.

Factors Related to Early Clinical Effects of Quetiapine Extended-Release: A Multinational, Prospective, Observational Study.

BACKGROUND AND OBJECTIVES: The first weeks of treatment with antipsychotics are important for the development of their long-term efficacy. The objective of this study was to identify factors related to early clinical effects and quality of life (QoL) improvements with quetiapine extended-release (XR). METHODS: Six hundred and sixty-five patients starting with quetiapine XR were followed up for 8 weeks (schizophrenia = 153, major depression = 200, bipolar depression = 252, other psychiatric conditions = 60). Clinical effects were assessed by the Clinical Global Impression of Change scale (CGI-C), QoL by the visual analog scale (VAS) of the EQ-5D (QoL-VAS), and adherence by the Moriksy scale. Adverse events were explored: movement disorders by the UKU and Simpson-Angus scales, weight gain by calibrated balances, and diurnal somnolence by the Epworth Somnolence Scale (ESS). RESULTS: The mean dose of quetiapine XR during follow-up was 195.6 ± 154.8 mg/day. CGI and QoL-VAS scores improved significantly at week 8 by 2.7 ± 0.1 points and 25.1 ± 0.9 points. Adverse events were observed in 34 and 26 % of patients at weeks 4 and 8, respectively. A significant reduction in ESS score was also observed at week 8. Factors independently associated with change in QoL-VAS ≥20 points (n = 292, 43 %) were female gender, more severe disease at baseline, higher antipsychotic dose during follow-up, and improvements in somnolence. Factors independently associated with clinically significant improvement (CGI-C ≥5, n = 610, 93 %) were greater change in QoL-VAS, less frequent movement disorders at baseline, and lack of adverse events during follow-up, especially somnolence. CONCLUSIONS: Results from this real-setting, large observational study in Central America suggest that disease severity at baseline, gender, antipsychotic dose, and occurrence of adverse reactions has a significant impact on the early clinical effects of quetiapine XR. Clinicaltrials.gov registration number NCT02409823.

Current Concepts in the Treatment of Multiple System Atrophy.

MSA is a progressive neurodegenerative disorder characterized by autonomic failure and a variable combination of poor levodopa-responsive parkinsonism and cerebellar ataxia (CA). Current therapeutic management is based on symptomatic treatment. Almost one third of MSA patients may benefit from l-dopa for the symptomatic treatment of parkinsonism, whereas physiotherapy remains the best therapeutic option for CA. Only midodrine and droxidopa were found to be efficient for neurogenic hypotension in double-blind, controlled studies, whereas other symptoms of autonomic failure may be managed with off-label treatments. To date, no curative treatment is available for MSA. Recent results of neuroprotective and -restorative trials have provided some hope for future advances. Considerations for future clinical trials are also discussed in this review.

A cross-sectional study on drug use in multiple system atrophy.

BACKGROUND: Drug use has rarely been studied in multiple system atrophy (MSA) while such patients receive many treatments based on weak evidence. OBJECTIVE: To analyze drug use from the database of the French MSA Reference Center, and to compare it with data from patients with Parkinson disease (PD). METHODS: Medication of 147 MSA and 180 age- and sex-matched PD patients was analyzed. Motor and autonomic symptoms were explored in MSA patients by the SCOPA-Autonomic and Unified MSA Rating Scale (UMSARS). RESULTS: MSA and PD patients received a mean of five different drugs. MSA patients were more frequently exposed to laxatives, antidiabetic medications, antihypotensives, muscarinic antagonists, alpha-adrenergic blockers, and antidepressants. Levodopa consumption was less in MSA-C (cerebellar) patients compared with MSA-P (parkinsonian) and PD patients. Dopamine agonists were more consumed by PD than MSA patients. MSA patients with more severe disability received more laxatives, anticoagulants, and antidepressants. MSA-P patients received more analgesics. "Probable" MSA patients received more antihypotensives and less alpha-adrenergic blockers. Patients with higher SCOPA-Autonomic scores were more frequently on antihypotensives or antidepressants. Drug associations leading to potential adverse interactions were uncommon (usually <5%). CONCLUSIONS: Some differences in drug use between MSA and PD patients were observed and expected, including those used for the relief of parkinsonian motor symptoms, autonomic dysfunction, and depression. Many of these drugs are frequently used in MSA in the absence of well-established, positive, benefit-risk evaluations, thus calling for better assessments. The reason why other medications, including anti-diabetic medications, were more consumed by MSA patients remains unclear and deserves further exploration.

Risk of heart failure following treatment with dopamine agonists in Parkinson's disease patients.

INTRODUCTION: Dopamine agonists (DAs) are frequently used to treat early or advanced Parkinson's disease (PD) patients. They have been shown to be efficacious for the treatment of motor symptoms and for delaying levodopa-induced dyskinesias. However, their utilization is limited by the risk of adverse drug reactions, some of which affect the cardiovascular system. Recently, the US FDA identified a possible association between exposure to pramipexole and the risk of heart failure. AREAS COVERED: This article begins by reviewing the pharmacodynamic and cardiovascular effects of DAs on PD patients. Pharmacoepidemiological studies about the association between DAs and heart failure are then evaluated. EXPERT OPINION: Four nested case-control studies were reviewed. In general, results showed higher heart failure risk following use of pramipexole or cabergoline. Although the effects of cabergoline may be explained by the induction of cardiac valve fibrosis, the basis for the significantly increased risk associated with pramipexole is unclear. It remains to be determined if these are dose-related effects, at what point they occur during the course of treatment, and if the risk is the same for all patients irrespective of other potential modifying factors, such as age and sex.

Emerging drugs for autonomic dysfunction in Parkinson's disease.

INTRODUCTION: Autonomic dysfunction, including orthostatic hypotension (OH), sialorrhea, sexual dysfunction, urinary dysfunction and constipation is a common feature of Parkinson's disease (PD). Even though its treatment has been recognized as a major unmet need in PD, there is a paucity of clinical trials to assess their treatment. AREAS COVERED: Evidence about the efficacy and safety of available treatments for autonomic dysfunction is summarized. Potential targets for upcoming therapies are then discussed in light of what is currently known about the physiopathology of each disorder in PD. Proof-of-concept trials and circumstantial evidence about treatments for autonomic dysfunction as well as upcoming clinical trials are discussed. Finally, critical aspects of clinical trials design are considered. EXPERT OPINION: Botulinum toxin (BTX) or glycopyrrolate might be used for sialorrhea whereas macrogol could be useful in constipation. There is preliminary evidence suggesting that fludrocortisone, domperidone, droxidopa or fipamezole may be effective for the treatment of OH. Tropicamide, clonidine or radiotherapy are under development for sialorrhea. Sildenafil may be effective for the treatment of erectile dysfunction; BTX or behavioral therapy for urinary incontinence and lubiprostone and probiotics for constipation. Sound clinical trials are needed in order to allow firm evidence-based recommendations about these treatments.

Rotigotine transdermal patch for the treatment of Parkinson's Disease.

Rotigotine, a non-ergot dopamine agonist, has been developed as a novel transdermal formulation. The rotigotine transdermal patch has received EMEA marketing authorization for the treatment of adult patients with early or advanced Parkinson's disease (PD) or with moderate to severe restless legs syndrome (RLS). FDA originally granted a marketing authorization for early PD, which was later suspended, and is now studying the authorization for RLS. The aim of this review is to review the pharmacokinetics, pharmacodynamics as well as the clinical efficacy and tolerability of the rotigotine transdermal patch in PD. Source material was identified using a PubMed search for the term 'rotigotine' and PD. Articles published up to January 2011 or abstract submitted to most relevant international neurology congresses were reviewed. The rotigotine transdermal patch is efficacious for the treatment of PD. Tolerability profile appears to be well within the range of that observed with other non-ergot dopamine agonists in PD. Application-site reactions were the most frequent adverse event, and they were considered mild to moderate in the majority of cases. The rotigotine transdermal patch offers a safe and efficacious alternative for the treatment of PD. Further studies should focus on the possibility that continuous dopamine stimulation by means of the transdermal patch has any influence on levodopa-related motor complications.

Drugs associated with restless legs syndrome: a case/noncase study in the French Pharmacovigilance Database.

BACKGROUND: Several case reports have suggested that drugs could induce restless legs syndrome. However, no systematic review of this adverse drug reaction (ADR) in a pharmacovigilance database has been published. OBJECTIVE: To assess the frequency of restless legs syndrome in the French Pharmacovigilance Database. METHODS: We selected all ADR reports from January 1, 1984 to December 31, 2009 coded as restless legs syndrome. Restless legs syndrome diagnosis was validated from case descriptions. Using a case/noncase approach, reporting odds ratio and 95% confidence interval were calculated for "suspected'' drugs with 2 or more observations. RESULTS: Twenty-six ADR reports were found. Four cases were excluded because of alternative diagnosis. Fourteen cases were women (64%). Median age was 57. Most frequently suspected drugs were antidepressants (reporting odds ratio, 15.9 [6.4-39.7]; amitriptyline, escitalopram, mianserine, mirtazapine, duloxetine), neuroleptics (17.8 [6.1-51.7]; thioridazine, loxapine, risperidone, aripiprazole) or tramadol (18.2 [6.3-52.8]). CONCLUSIONS: Restless legs syndrome is a very rare ADR that was more frequently reported in association with antidepressants, neuroleptics, or tramadol.

Prevalence and pharmacological factors associated with impulse-control disorder symptoms in patients with Parkinson disease.

BACKGROUND: Impulse-control disorders (ICDs) occur in patients with Parkinson disease (PD), especially in younger patients on dopamine therapies. OBJECTIVE: To assess the prevalence of ICD symptoms and its pharmacological correlations in a sample of French patients with PD and without PD (poststroke). METHODS: Outpatients with PD and without PD (poststroke) were screened for compulsive behaviors related to hypersexuality, compulsive shopping, pathological gambling, or compulsive eating by means of the Questionnaire for Impulse-Control Disorders--short version. Full medical history and Unified Parkinson's Disease Rating Scale scores were also recorded. Dose of dopamine agonists were converted to defined daily doses (DDDs), according to the World Health Organization Anatomical Therapeutic Chemical classification system classification system. RESULTS: Two hundred three patients with PD and 52 patients without PD were recruited (mean ± SD age, 67 ± 1 vs 69 ± 2, P= 0.4; males: 62% vs 55% P= 0.2). Symptoms of ICDs were reported by 0% of poststroke patients and 25% of the patients with PD (P < 0.001). Hypersexuality was reported by 10% of the patients with PD, compulsive shopping by 6%, pathological gambling by 3%, and compulsive eating by 14%. A logistic regression analysis found that age younger than 68 years (odds ratio [OR], 3.3; 95% confidence interval, 1.6-6.6) and exposure to dopamine agonists (OR, 20.3; 95% confidence interval, 2.7-65.0) or monoaminooxidase-B inhibitor (OR, 3.7; 95% confidence interval, 1.1-12.6) were significant factors associated with increased ICD frequency. Patients with ICD symptoms were exposed to higher dopamine doses than those without them (1.6 ± 0.1 vs 1.0 ± 0.1 daily-defined doses; P < 0.001). A dose-response pharmacodynamic model disclosed a significant nonlinear dose-response relationship between dopamine agonists and frequency of ICD symptoms (P < 0.01). CONCLUSIONS: Impulse-control disorder symptoms were more frequent in the patients with PD than in the poststroke patients with PD. Impulse-control disorder symptoms were related to younger age and exposure to monoaminooxidase-B inhibitors, and showed a nonlinear dose-response relationship with dopamine agonists.

Emerging analgesic drugs for Parkinson's disease.

INTRODUCTION: Pain affects between 40 and 85% of Parkinson's disease (PD) patients. It is a frequently disabling and overlooked feature, which can significantly reduce health-related quality of life. Unfortunately, there are no universally recommended treatments for this condition. AREAS COVERED: Evidence about the efficacy and safety of available analgesic treatments is summarized in this review. Potential targets for upcoming therapies are then discussed in light of what is currently known about the physiopathology of pain in PD. Protocols for efficacy and safety assessment of novel analgesic therapies are discussed. Finally, critical aspects of study protocol design such as patient selection or outcomes to be evaluated are discussed. EXPERT OPINION: Preliminary results indicate that duloxetine, cranial electrotherapy stimulation, rotigotine, subthalamic or pallidum nuclei stimulation or lesion or levodopa could be effective for treating pain in PD. Similarly, some case reports indicate that repetitive transcranial magnetic stimulation (rTMS) or apomorphine could be effective for relieving painful off-period dystonia. Clinical trials with rTMS or oxycodone/naloxone prolonged-release tablets for neuropathic pain or botulinum toxin for off-period dystonia are underway. Success of clinical trials about analgesic strategies in PD will depend on the selection of the right PD population to be treated, according to the type of pain, and the proper selection of study outcomes and follow-up of international recommendations.

Factors related to orthostatic hypotension in Parkinson's disease.

INTRODUCTION: Orthostatic hypotension (OH), a frequent feature of Parkinson's disease (PD) can contribute to falls and is usually related to the disease itself and/or to drugs. OBJECTIVES: To explore factors related to OH and to assess the concordance between abnormal blood pressure (BP) fall after standing and the presence of orthostatic symptoms. METHODS: Non-demented, non-operated idiopathic PD out-patients were questioned about the presence of orthostatic symptoms. Afterward, BP was measured 5-min after lying down and for 3-min after standing up. OH was defined as systolic and/or diastolic BP fall ≥ 20 and/or 10 mmHg after standing. Patients were further evaluated by the Unified PD Rating Scale (UPDRS) and their medications were recorded. RESULTS: 103 patients were included in this study (mean age = 66 ± 1 years, mean disease duration = 9 ± 1 years; mean UPDRS II+III in ON-state = 37 ± 2 points). Forty-one subjects (40%) reported the presence of orthostatic symptoms during the previous week and 38 (37%) had OH according to manometric definition. Independent factors related to OH, as assessed by logistic regression were age >68 years (OR, 95% CI=3.61, 1.31-9.95), polypharmacy (defined as intake of >5 medications, OR = 3.59, 1.33-9.69), amantadine (7.45, 1.91-29.07) or diuretics (5.48, 1.10-54.76), whereas the consumption of entacapone was protective (0.20, 0.05-0.76). The agreement between abnormal BP fall and presence of orthostatic symptoms was poor (kappa = 0.12 ± 0.1, p = 0.23). CONCLUSION: OH was significantly related to older age, polypharmacy and amantadine or diuretics intake, while entacapone exposure appeared to reduce the risk of OH. Low concordance between OH and orthostatic symptoms was observed.

Pregabalin beneficial effects on sleep quality or health-related quality of life are poorly correlated with reduction on pain intensity after an 8-week treatment course.

BACKGROUND: Pregabalin (PGB) has been shown to improve sleep quality and health-related quality of life (HRQoL) as well as pain intensity in patients with neuropathic pain. OBJECTIVE: The objective of the study was to explore the magnitude of the correlations between changes in pain intensity, sleep quality, and HRQoL after PGB treatment. METHODS: One hundred thirty-eight patients with neuropathic pain of any origin and without an adequate response to analgesics received an 8-week treatment course of PGB in an open-label fashion. Pain intensity, sleep quality, and HRQoL outcomes were evaluated at baseline and at week 8 by means of an 11-point (0-10) numerical rating scale (NRS), the Pittsburgh Sleep Quality Index (PSQI), and the EuroQol health-state visuoanalogic scale (EQ-5D VAS) score, respectively. RESULTS: At week 8, mean PGB dose was 166.7 ± 7.8 mg/d. Pain intensity NRS score, PSQI total score, and EQ-5D VAS score were improved by 66.5% ± 1.9%, 40.0% ± 3.6%, and 26.4% ± 4.7% (all P < 0.01), respectively. Correlations between percent change from baseline in pain NRS score and PSQI total score or EQ-5D VAS scores were r = 0.36 (P < 0.01, R = 0.11) and r = -0.20 (P < 0.02, R = 0.05), respectively. A multivariate logistic regression analysis disclosed that PSQI score change below the median (ie, a better outcome) was related to higher EQ-5D VAS score change (odds ratio, 2.15; 95% confidence interval, 1.09-4.25), whereas pain intensity NRS score change below the median was not (odds ratio, 1.58; 95% confidence interval,0.78-3.23). CONCLUSIONS: In our study, PGB-related improvements in sleep quality and HRQoL were marginally related to reductions in pain intensity in patients with neuropathic pain. Improvement in sleep quality was a significant predictor of better HRQoL, whereas pain intensity reduction was not.

Do Parkinson's disease patients disclose their adverse events spontaneously?

BACKGROUND: Underreporting of adverse drug reactions is common but has been rarely studied in Parkinson's disease (PD). OBJECTIVE: To compare the prevalence of adverse events (AEs) in relation to antiparkinsonian drugs in PD patients using two different data collection methods: patient's spontaneous reporting versus a predefined investigator-driven structured interview. Secondary objectives were to assess factors related to spontaneous reporting and to compare the rate of AE reporting in PD patients with that of a group of non-parkinsonian post-stroke patients. STUDY DESIGN: Cross-sectional study. PATIENTS: Ambulatory, cognitively intact PD or post-stroke outpatients. INTERVENTIONS: None. OUTCOME MEASURES: Patients were first asked by means of an an open question to disclose any unpleasant effects in connection with their current medications that had occurred during the previous week. Afterwards, a predefined questionnaire listing the most common AEs known to be related to antiparkinsonian drugs was used to question the same patients in a systematic manner about the presence of any AE during the same week. Chronological and semiological criteria were used to classify the reported AEs as "unrelated" or "possibly/plausibly related" to the antiparkinsonian treatment. RESULTS: A total of 203 PD and 52 post-stroke patients of comparable age and sex were recruited. Eighty-five PD and five post-stroke patients reported spontaneously at least one AE (42 vs. 10%, p < 0.01), while 203 PD and 47 post-stroke patients reported at least one AE following the structured questionnaire (100 vs. 90%, p < 0.001). In PD patients, there were a total of 112 spontaneously reported AEs as compared with 1,574 according to the structured questionnaire (7%). Spontaneous disclosure of AEs was associated with experiencing >2 AEs [OR = 1.2 (1.1-3.2)], logistic regression). Seventy-four percent of PD patients had ≥1 AE possibly/plausibly related to antiparkinsonian drugs. CONCLUSIONS: Results showed that only 7% of AEs were reported spontaneously by patients, thus underscoring the importance of systematically asking about AEs in PD patients.

Pramipexole for the treatment of early Parkinson's disease.

Pramipexole is a nonergolinic dopamine agonist, with high affinity for the D2 subfamily of dopamine receptors. Pramipexole is efficacious for the symptomatic treatment of early Parkinson's Disease (PD) and its early use, before that of levodopa can delay the emergence of levodopa-related motor complication. Dosage should be increased gradually from a starting dose of 0.375 mg/day up to a maximum of 4.5 mg/day in equally divided doses taken three times per day with pramipexole immediate-release or equivalent daily dosages once-daily with pramipexole extended-release. Pramipexole can also improve depressive symptoms and possibly health-related quality of life in PD. Nonetheless, its use is not devoid of tolerability problems. While peripheral adverse drug reactions, such as nausea, vomiting or orthostatic hypotension, can be effectively treated and usually pose few problems to most patients, neuropsychiatric events can seriously limit the use of pramipexole in some cases. Indeed, excessive daytime somnolence, impulse-control disorders, hallucinations or delusions can severely affect patients, causing important personal or social handicap. Patients should be informed about the risk of such neuropsychiatric complications and their presence should be actively detected at each consultation. More effort will have to be put into further studying the risk-benefit ratio of pramipexole and other dopamine agonists in the treatment of early PD.