Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson's disease psychosis: an expert consensus.

Patients with Parkinson's disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent's pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2-6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.

Importance of time to ON versus wearing OFF in total daily OFF time experienced by patients with Parkinson's disease.

Most patients with Parkinson's disease (PD) receiving levodopa (LD)/DOPA decarboxylase inhibitors develop motor fluctuations with an increasing amount of OFF time, negatively impacting patient quality of life. Herein, we review the evidence supporting the substantial, yet underappreciated contribution of delays in time to ON (including delayed ON and no ON) to total daily OFF time. Most clinical studies use patient diaries that do not capture time to ON and wearing OFF separately as related to LD dosing, and consequently, most OFF time has generally been attributed to wearing OFF. Hence, most treatment regimens focus on reducing wearing OFF by changing LD dosing/formulations and/or using "ON-extenders" (eg, catechol-o-methyltransferase inhibitors, monoamine oxidase-B inhibitors, extended-release amantadine, and adenosine A2A receptor antagonists). However, the literature describing approved treatments for PD that has focused on delays in time to ON is sparse and suggests this type of OFF may comprise more than twice the amount of total daily OFF time as wearing OFF. Here, we advocate for the importance of measuring and adequately addressing delays in time to ON and build support for the consistent inclusion of the time to ON measurement in future clinical trials.

Clinical Use of On-Demand Therapies for Patients with Parkinson's Disease and OFF Periods.

On-demand therapies for Parkinson's disease (PD) provide rapid, reliable relief for patients experiencing OFF periods; however, practical guidelines on the use of these therapies are not generally available. This paper reviews the use of on-demand treatments. Motor fluctuations occur in nearly all patients with PD after long-term use of levodopa. As the goal of PD treatment is to provide good ON time, on-demand treatments that have a more rapid reliable onset than the slower-acting oral medications provide rapid relief for OFF periods. All current on-demand treatments bypass the gastrointestinal tract, providing dopaminergic therapy directly into the blood stream by subcutaneous injection, through the buccal mucosa, or by inhalation into the pulmonary circulation. On-demand treatments are fast acting (10- to 20-min onset), with maximum, reliable, and significant responses reached within 30 min after administration. Oral medications pass through the gastrointestinal tract and thus have slower absorption owing to gastroparesis and competition with food. On-demand therapies, by providing fast-acting relief, can have a positive impact on a patient's quality of life when patients are experiencing OFF periods.

How to manage the initiation of apomorphine therapy without antiemetic pretreatment: A review of the literature.

Introduction: Pretreatment with the antiemetic trimethobenzamide has been recommended practice in the United States (US) to address the risk of nausea and vomiting during initiation of apomorphine treatment. However, trimethobenzamide is no longer being manufactured in the US, and despite the recent update to the US prescribing information, there may be uncertainty regarding how to initiate apomorphine. Methods: To better understand why antiemetic pretreatment was recommended and if it is necessary when initiating apomorphine therapy, we performed a literature review of subcutaneous apomorphine therapy initiation with and without antiemetic pretreatment in patients with PD. Results: Three studies were identified as providing relevant information on antiemetic prophylaxis with initiation of injectable apomorphine. The first study demonstrated that nausea was significantly more common in patients who received 3-days of trimethobenzamide pretreatment compared with those who did not, while the primary endpoint of second study found no significant effect on the binary incidence of nausea and/or vomiting on Day 1 of apomorphine treatment. In the third study, which used a slow titration scheme for apomorphine, transient nausea was reported in just 23.1% of the antiemetic nonusers. Conclusions: Based on the reviewed trials and our clinical experience, we suggest that subcutaneous apomorphine therapy can be initiated using a slow titration scheme without antiemetic pretreatment.

Expert Consensus on the Use of On-Demand Treatments for OFF Episodes in Parkinson's Disease: A Modified Delphi Panel.

Background: On-demand treatments can treat OFF episodes in Parkinson's disease, however, there is limited information regarding when to prescribe them. Objective: Develop expert consensus to determine appropriate clinical factors for considering on-demand treatments. Methods: Using a RAND/UCLA modified Delphi panel method, a panel developed consensus on the use of on-demand treatments for OFF episodes. Results: The panel agreed on-demand treatments were appropriate when OFF episodes were associated with greater functional impact and interfered with basic daily activities. The panel also agreed on-demand treatment may be appropriate for patients with morning akinesia and/or delayed ON of first levodopa dose and >1 type of OFF episode (eg, early morning OFF or wearing OFF regardless of frequency). Conclusions: Experts agreed on-demand treatment is appropriate for many patients with OFF episodes. The greater the functional impact of OFF episodes, the more likely experts agreed that on-demand treatment is appropriate to prescribe.

Posterior Reversible Encephalopathy Syndrome Presenting as Opsoclonus-Myoclonus.

Opsoclonus-myoclonus may be caused by various neurological conditions and toxic-metabolic states, but typically occurs as a parainfectious or paraneoplastic manifestation. The development of opsoclonus-myo-clonus has been variably attributed to lesions in the pons or cerebellum. Herein the authors describe a case of opsoclonus-myoclonus due to posterior reversible encephalopathy syndrome in which magnetic resonance imaging revealed lesions in the region of the cerebellar dentate nuclei. Clinical and radiological resolution of the opsoclonus-myoclonus and of the posterior reversible encephalopathy syndrome followed antihyperten-sive therapy.

Tardive Dyskinesia in Older Persons Taking Antipsychotics.

Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by the use of dopamine receptor-blocking agents (DRBAs), a category of medications that includes first- and second-generation antipsychotics (APs) and agents such as metoclopramide that are used for the treatment of nausea and gastrointestinal dysmotility. While TD can affect people of all ages, older age is associated with increased risk of TD and also with the emergence of TD occurring after shorter treatment durations and lower dosages of DRBAs. TD is characterized by involuntary movements that include the face, limbs, and trunk, and is associated with increased comorbidities, social stigmatization, and impaired physical and mental health. Once present, TD tends to persist despite AP dose adjustment or discontinuation. Even with the use of US Food and Drug Administration (FDA)-approved medications for TD, symptoms may persist. Because the leading hypothesis for the pathophysiology of TD has been dysregulation of dopamine transmission due to treatment with DRBAs, APs that avoid postsynaptic dopamine receptor blockade may provide an alternative therapeutic approach for patients who require an AP. In this review, we discuss the risks, burdens, prevention, and management of TD, with a focus on older people.

Effects of Gocovri (Amantadine) Extended-Release Capsules on Motor Aspects of Experiences of Daily Living in People with Parkinson's Disease and Dyskinesia.

INTRODUCTION: Gocovri, a bedtime-administered delayed-release/extended-release capsule formulation of amantadine, is the only drug approved by the US Food and Drug Administration as levodopa-adjunctive therapy for the treatment of OFF episodes and/or dyskinesia in Parkinson's disease (PD). Part II of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) assesses patient-perceived disability on experiences of daily living affected by PD motor symptoms. We analyzed Gocovri-related changes in MDS-UPDRS Part II ratings in two placebo-controlled clinical trials. METHODS: Baseline to week 12 changes in MDS-UPDRS Part II total and item scores were compared for Gocovri and placebo using pooled data from phase 3 trials (EASE LID and EASE LID 3). RESULTS: Baseline mean MDS-UPDRS Part II total score was 15.1 for Gocovri (n = 100) and 15.3 for placebo (n = 96) groups. At week 12, the least squares mean change from baseline was -3.4 for the Gocovri group and -1.4 for placebo (treatment difference, -2.0; 95% CI -3.3 to -0.7; P = 0.004). For Gocovri, change from baseline exceeded a published minimal clinically important difference threshold of 3.05. Gocovri-related treatment differences over placebo were driven primarily by improvement in the scale items of freezing (-0.4; P < 0.0001), tremor (-0.4; P = 0.002), getting out of bed/car/deep chair (-0.3; P = 0.002), and eating tasks (-0.2; P = 0.016). CONCLUSION: In addition to improvement in dyskinesia, Gocovri-treated participants experienced improvement in motor aspects of experiences of daily living. Analyses suggest that Gocovri may specifically improve freezing, tremor, getting out of bed/car/deep chair, and eating tasks. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02136914, NCT02274766.

Capturing Initial Understanding and Impressions of Surgical Therapy for Parkinson's Disease.

Background: Deep Brain Stimulation (DBS) is an underutilized surgical therapy for Parkinson's Disease (PD). Both physician and patient hesitancies have been described as potential barriers to DBS, but the specifics of patient perceptions of DBS have not been well-characterized in the general PD population. Objective: To characterize the understanding and impressions of surgical therapy in PD patients prior to formal surgical evaluation. Methods: A 30-question survey assessing impressions of surgical therapy for PD and understanding of DBS for PD was administered to PD patients seen at an urban movement disorders clinic. Results: One hundred and two patients completed the survey. When asked if they would undergo a hypothetical risk-free, curative brain surgery for PD, 98 patients responded "yes." Patients were more agreeable to "reversible," "minimally-invasive," and "incisionless" surgery. 51.2% thought DBS is an "effective" treatment for PD, 76.6% thought it was "invasive," and 18.3% thought it was "reversible." 45.2% reported fear of being awake during DBS surgery. Regarding costs, 52.4% were concerned that DBS was "very expensive" or "not covered by insurance." Initial source of information and perceived treatment effectiveness were not associated with concerns about DBS effectiveness or threats to normality. Negative perceptions of past surgery were associated with concerns about DBS altering mood and personality. Conclusion: Overall, patients expressed concerns regarding procedural efficacy, invasiveness, cost, and irreversibility-independent of the original source of information. Future studies are required to allow us to better understand the impact of these initial findings on DBS hesitancy and underutilization.

AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location.

OBJECTIVE: To report the clinical and immunological features of a novel autoantigen related to limbic encephalitis (LE) and the effect of patients' antibodies on neuronal cultures. METHODS: We conducted clinical analyses of 10 patients with LE. Immunoprecipitation and mass spectrometry were used to identify the antigens. Human embryonic kidney 293 cells expressing the antigens were used in immunocytochemistry and enzyme-linked immunoabsorption assay. The effect of patients' antibodies on cultures of live rat hippocampal neurons was determined with confocal microscopy. RESULTS: Median age was 60 (38-87) years; 9 were women. Seven had tumors of the lung, breast, or thymus. Nine patients responded to immunotherapy or oncological therapy, but neurological relapses, without tumor recurrence, were frequent and influenced the long-term outcome. One untreated patient died of LE. All patients had antibodies against neuronal cell surface antigens that by immunoprecipitation were found to be the glutamate receptor 1 (GluR1) and GluR2 subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Human embryonic kidney 293 cells expressing GluR1/2 reacted with all patients' sera or cerebrospinal fluid, providing a diagnostic test for the disorder. Application of antibodies to cultures of neurons significantly decreased the number of GluR2-containing AMPAR clusters at synapses with a smaller decrease in overall AMPAR cluster density; these effects were reversed after antibody removal. INTERPRETATION: Antibodies to GluR1/2 associate with LE that is often paraneoplastic, treatment responsive, and has a tendency to relapse. Our findings support an antibody-mediated pathogenesis in which patients' antibodies alter the synaptic localization and number of AMPARs.

Early Recognition and Treatment of Tardive Dyskinesia in Patients With Mood Disorders and Schizophrenia.

​​​​Early Recognition and Treatment of Tardive Dyskinesia in Patients With Mood Disorders and Schizophrenia Click to enlarge page​​.

Earlier Diagnosis of Tardive Dyskinesia.

Because the symptoms of tardive dyskinesia (TD) have an insidious onset and fluctuating nature, and the risk of TD associated with second-generation antipsychotic (SGA) treatment has been underestimated, it has been challenging for clinicians to make an early and accurate TD diagnosis. More patients are at risk of developing this potentially permanent, disabling condition than ever before because of the widespread use of SGAs; therefore, prevention of TD, if possible, is of utmost importance. Clinicians must use reliable screening tools and diagnostic criteria to assess patients for TD, rule out other abnormal movement conditions, and make an accurate TD diagnosis.

Treatment Strategies for Tardive Dyskinesia.

Tardive dyskinesia (TD), a condition of potentially irreversible abnormal involuntary movements that is associated with dopamine receptor blocking agents (DRBAs), produces significant impairment of functioning and quality of life for patients. Contrary to expectations, TD has not vanished despite the introduction of SGAs. Instead, changing prescription practices and increased off-label prescription of DRBAs have placed more patients than ever at risk of this potentially dangerous and disabling condition. This activity provides an overview of treatment strategies for TD as part of an individualized management plan, including DRBA medication adjustment and antidyskinetic treatment.

Prevalence of Dyskinesia and OFF by 30-Minute Intervals Through the Day and Assessment of Daily Episodes of Dyskinesia and OFF: Novel Analyses of Diary Data from Gocovri Pivotal Trials.

BACKGROUND: Parkinson's disease (PD) patients using levodopa commonly develop dyskinesia and OFF episodes that reduce quality of life. OBJECTIVE: Evaluate prevalence of troublesome dyskinesia and OFF through the day, assessed by 30-minute intervals, as well as the mean number and duration of troublesome dyskinesia and OFF episodes, transitions between PD states, and effects of Gocovri® (amantadine) extended release capsules on these episodes. METHODS: Evaluate diary data from pooled Gocovri phase 3, placebo-controlled trials-analyzed for 17 hours following wake-up-at baseline and week 12. RESULTS: Diaries were evaluable for 162 patients. At baseline, 67% of patients woke up OFF, with prevalence decreasing to 13% at 2 hours and then remaining relatively steady at ∼12% (range, 6-17%) across half-hour intervals thereafter. Troublesome dyskinesia prevalence rose steadily from 5% to 24% over the first 2 hours, then fluctuated between 20% and 44% through the rest of the waking day. At baseline, patients experienced a mean of 3.0 daily episodes of troublesome dyskinesia (average duration 2.0 hours each), and 2.2 daily episodes of OFF (average duration 1.1 hour each). At week 12, Gocovri-treated patients showed greater reductions than placebo in troublesome dyskinesia and OFF episodes per day (treatment difference: -1.0 episodes and -0.4 episodes, respectively) and average episode duration (treatment difference: -0.6 hours and -0.3 hours, respectively). Mean duration of individual episodes of ON without troublesome dyskinesia (Good ON) increased by 5.0 hours for Gocovri, compared with 2.0 hours for placebo. Patients taking Gocovri experienced 2.2 fewer transitions between states than patients taking placebo. CONCLUSIONS: Troublesome dyskinesia and OFF occurred in the morning and throughout the waking day. Gocovri-treated patients experienced fewer, shorter episodes of both troublesome dyskinesia and OFF, thereby increasing the duration of continuous Good ON episodes and reducing the frequency of transitions between motor states.