Current challenges and opportunities for pharmacogenomics: perspective of the Industry Pharmacogenomics Working Group (I-PWG).

Pharmaceutical companies have increasingly utilized genomic data for the selection of drug targets and the development of precision medicine approaches. Most major pharmaceutical companies routinely collect DNA from clinical trial participants and conduct pharmacogenomic (PGx) studies. However, the implementation of PGx studies during clinical development presents a number of challenges. These challenges include adapting to a constantly changing global regulatory environment, challenges in study design and clinical implementation, and the increasing concerns over patient privacy. Advances in the field of genomics are also providing new opportunities for pharmaceutical companies, including the availability of large genomic databases linked to patient health information, the growing use of polygenic risk scores, and the direct sequencing of clinical trial participants. The Industry Pharmacogenomics Working Group (I-PWG) is an association of pharmaceutical companies actively working in the field of pharmacogenomics. This I-PWG perspective will provide an overview of the steps pharmaceutical companies are taking to address each of these challenges, and the approaches being taken to capitalize on emerging scientific opportunities.

An Exploratory Study Using Electronic Medical Records to Assess the Feasibility of Establishing Cohorts of Patients with Genetic Causes of Parkinson's Disease.

BACKGROUND: More efficient screening methods are needed to improve the ability to identify and follow genetic cohorts in Parkinson's disease (PD). OBJECTIVE: To explore the use of the electronic medical records (EMRs) to identify participants with PD. METHODS: Using an algorithm previously developed in collaboration with Maccabi Healthcare Services (MHS), approximately 5,200 participants with PD were identified, more than 3,200 were screened, and 837 participants were enrolled and genotyped for leucine-rich repeat kinase 2 (LRRK2) and beta-glucocerebrosidase (GBA) variants. Questionnaires were completed to ascertain Ashkenazi Jewish (AJ) ancestry and family history of PD. RESULTS: Among 837 participants with PD, 82% were 65 years and older and 72% had a family history of AJ ancestry. Among those with AJ ancestry, 15.6% reported having relatives with PD. The frequency of observed mutations for LRRK2 and GBA genes combined was approximately 15.4%. The frequency of observed LRRK2 mutation was 6.1% overall and 7.2% from those with AJ ancestry; and for GBA mutation was 9.3% overall and 11.2% from those with AJ ancestry. CONCLUSION: Although the frequency of observed mutations in this study was lower than anticipated, mutation carriers were enriched among those with a family history of AJ ancestry increasing nearly 2-3-fold, from 3% -7% (LRRK2) and 4% -11% (GBA). The identification (and selection) of PD patients through EMRs prior to genotyping is a viable approach, to establish a genetically defined cohort of patients with PD for clinical research.

Depression in Parkinson's disease: symptom improvement and residual symptoms after acute pharmacologic management.

OBJECTIVE: Parkinson's disease (PD) is frequently complicated by depression and there is a paucity of controlled research that can inform the management of this disabling nonmotor complaint. A randomized controlled trial of nortriptyline, paroxetine, and placebo for the treatment of depression in PD (dPD) was recently completed. The purpose of this article is to describe the baseline pattern of depressive symptom presentation in PD, the specific symptoms of dPD that improve with pharmacotherapy, and the residual symptoms that remain in patients who meet a priori criteria for response or remission after acute treatment (8 weeks). SETTING: The Departments of Psychiatry and Neurology at Robert Wood Johnson Medical School, New Jersey. PARTICIPANTS: : Fifty-two depressed patients (major depression or dysthymia based on Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria) with Parkinson's disease (by research criteria). DESIGN/INTERVENTION: A randomized controlled trial of nortriptyline, paroxetine, and placebo. MEASUREMENT: The four subscales (core mood, anxiety, insomnia, and somatic) and individual items from the Hamilton Rating Scale for Depression-17 were the focus of this study. These measures were assessed at baseline and Week 8. RESULTS: Baseline depressive symptoms were unrelated to motor functioning. Treatment response was associated with significant improvements in the core mood, anxiety, insomnia, and somatic symptoms seen in dPD. Residual symptoms, such as sadness and loss of interest, persisted in treatment responders in a milder form than was initially present. CONCLUSIONS: Antidepressants may influence all symptoms of dPD, including those that share great overlap with the physical disease process. Additional research regarding adjunctive interventions is needed to help optimize the management of dPD.

Telephone-based cognitive-behavioral therapy for depression in Parkinson disease.

BACKGROUND: Although face-to-face cognitive-behavioral therapy (CBT) was found to be beneficial for the treatment of depression in Parkinson disease (dPD) in a recent randomized-controlled trial, access to care was identified as a critical issue that needs to be addressed in order to improve the management of this nonmotor complication in PD. The purpose of this study was to examine the feasibility and effect of telephone-based CBT for dPD. METHODS: Twenty-one depressed people with PD participated in a National Institutes of Health-sponsored uncontrolled pilot trial of telephone-based CBT in an academic medical center from October 2009 to February 2011. The Hamilton Depression Rating Scale was the primary outcome. Treatment was provided to people with PD for 10 weeks, modified for delivery over the phone, and supplemented with 4 separate phone-based caregiver educational sessions. Assessments were completed at baseline and 5 (midpoint), 10 (end-of-treatment), and 14 weeks (follow-up) post-enrollment. RESULTS: Twenty (95%) people with PD completed the study treatment. Phone-based CBT was associated with significant improvements in depression, anxiety, negative thoughts, and coping. Mean Hamilton Depression Rating Scale change from baseline to week 10 was 7.91 points (P < .001, Cohen d = 1.21). CONCLUSIONS: Telephone-based CBT may be a feasible and helpful approach for treating dPD and warrants further exploration in randomized-controlled trials. Results were comparable to those observed in the few in-person cognitive-behavioral treatment studies for dPD conducted to date.

Sleep disturbances in Parkinson's disease.

Sleep disturbances are very common in patients with PD and are associated with a variety of negative outcomes. The evaluation of sleep disturbances in these patients is complex, as sleep may be affected by a host of primary sleep disorders, other primary medical or psychiatric conditions, reactions to medications, aging or the neuropathophysiology of PD itself. In this article, we review the evaluation of the common disturbances of sleep seen in PD. This includes the primary sleep disorders, the interaction of depression and insomnia, the impact that medications for PD have on sleep, as well as the role of factors such as nocturia, pain, dystonia, akinesia, difficulty turning in bed, and vivid dreaming. The treatment of sleep disturbances in PD is largely unstudied but recommendations based on clinical experience in PD and research studies in other geriatric populations can be made. Important principles include, diagnosis, treating the specific sleep disorder or co-occurring disorder, and control of the motor aspects of PD.

Treatment of insomnia in Parkinson's disease: a controlled trial of eszopiclone and placebo.

Parkinson's disease (PD) is a common neurodegenerative disease affecting up to 1 million individuals in the United States. Sleep disturbances, typically in sleep maintenance, are found in up to 88% of these individuals and are associated with a variety of poor outcomes. Despite being common and important, there are few data to guide clinical care. We conducted a 6-week, randomized, controlled trial of eszopiclone and placebo in 30 patients with PD and insomnia. Patients with other primary sleep disorders (PSG defined) were excluded. The primary outcome was total sleep time (TST), and secondary measures included wake after sleep onset (WASO), number of awakenings, and quality of sleep, among others. The groups did not significantly differ on TST, but significant differences, favoring eszopiclone, did emerge in number of awakenings (P = 0.035), quality of sleep (P = 0.018), and in physician-rated CGI improvement (P = 0.035). There was also a trend toward significance in WASO (P = 0.071). There were no significant differences between groups in measures of daytime functioning. The drug was well tolerated, with 33% of patients on eszopiclone and 27% of patients on placebo reporting adverse events. Although modest in size, this is the first controlled study of the treatment of insomnia in patients with PD. Eszopiclone did not increase TST significantly but was superior to placebo in improving quality of sleep and some measures of sleep maintenance, which is the most common sleep difficulty experienced by patients with PD. Definitive trials of the treatment of sleep disorders in this population are warranted.

The impact of antidepressant treatment on cognitive functioning in depressed patients with Parkinson's disease.

Depression is associated with more rapid cognitive decline in Parkinson's disease. The goal of this study was to examine the impact of the acute (8-week) and longer-term (24-week) antidepressant treatment on cognition in Parkinson's disease and to detail cognitive predictors of treatment response. Fifty-two depressed Parkinson's disease patients were enrolled in an NIH-funded randomized, controlled trial of nortriptyline, paroxetine, and placebo. Neuropsychological testing was performed at baseline and weeks 8 and 24. Higher baseline scores on measures of executive functioning, speed of processing, and verbal memory were associated with antidepressant response. Treatment responders did not exhibit larger gains in cognition than nonresponders. Findings warrant replication.

The role of inflammatory cytokines in cognition and other non-motor symptoms of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) affects patients' lives with more than just physical impairment. Many of the non-motor aspects of PD, such as cognitive impairment, depression, and sleep disturbances, are common and are associated with a variety of poor outcomes. However, at present, the pathophysiology and clinical management of these symptoms are poorly understood. OBJECTIVE: The authors sought to determine the associations between various illness-associated cytokines, cortisol, and the non-motor symptoms of PD. METHOD: The authors examined a panel of cytokines (IL-1ß, IL-6, IL-10, TNF-α) and cortisol in a cohort of 52 PD patients with depression. RESULTS: There were a number of significant correlations between the non-motor symptoms and TNF-α. Specifically, the authors found that TNF-α (but not IL-1ß, IL-6, IL-10, or cortisol) was significantly correlated with measures of cognition, depression, and disability. In regression analyses accounting for all variables, TNF-α was consistently significant in explaining variance in cognition, depression, sleep, and disability. CONCLUSION: These data are consistent with a growing body of literature that implicates inflammatory cytokines in neural and behavioral processes and further suggests that TNF-α may be involved in the production and/or maintenance of non-motor symptoms in PD.

The impact of treatment of depression on quality of life, disability and relapse in patients with Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease affecting up to one million individuals in the United States. Depression is found in 40 to 50% of these patients and is associated with a variety of poor outcomes for both patients and their families. Despite this, there are few evidence-based data to guide clinical care. This was an NIH-funded, randomized, controlled trial of paroxetine, nortriptyline, and placebo. It included an 8 week acute phase and a 16 week blind extension phase. This report details the impact of depression treatment on quality of life (QoL) and disability in the acute and extension phase of this study. Secondary outcomes included relapse, tolerability, safety, and the impact of depression treatment on PD physical functioning. Patients who had improvement in depression, compared with those who did not, had significant gains in measures of QoL and disability (PDQ-8, P = 0.0001; SF-36, P = 0.0001) at 8 weeks and maintained their gains in the extension phase. Patients who were on active drug were significantly less likely to relapse in the extension phase than those on placebo (P = 0.041). Though relatively modest in size, this trial provides the first controlled data on the impact of treatment of depression on QoL and disability in PD. It suggests that successfully treating depression in PD leads to important, sustained improvements in these outcomes and that patients who improve on antidepressants are less likely to relapse than are patients who initially improve on placebo.

Escitalopram reduces hot flashes in nondepressed menopausal women: A pilot study.

BACKGROUND: Hot flashes are one of the most troubling manifestations of menopause, affecting about 80% of women. Due to recent controversies about hormone replacement therapy, many women seek alternative treatments. The use of antidepressants to treat hot flashes and other menopausal symptoms has been an active area of investigation. However, the majority of past research in this area has included women with significant medical or psychiatric histories that may influence treatment response. This was the first study to examine the impact of escitalopram on hot flashes, mood, sleep, and quality of life in a sample of healthy nondepressed menopausal women. METHODS: This study enrolled 25 menopausal women who had no significant psychiatric or medical history. All women were treated with escitalopram (10 to 20 mg flexibly dosed) for 8 weeks. The active treatment phase was preceded by a single-blind placebo lead-in period. RESULTS: Over the course of the study, women reported significant decreases in both hot flash frequency and severity as well as improvements in dysphoria, anxiety, quality of life, and sleep. CONCLUSION: These preliminary findings suggest that escitalopram may be a feasible and effective option for treating hot flashes and other menopausal symptoms in healthy women who might not ordinarily consider antidepressant treatment.

Mobilizing pharmacogenomic analyses during clinical trials in drug development.

The utilization of pharmacogenomics (PGx) in drug development is increasing as pharmaceutical companies and regulatory agencies work to understand variation in response to medications. The implementation of PGx in clinical trials requires a number of considerations that begin early at the point of program development for a compound. This article will discuss the issues involved in mobilizing a PGx study during the conduct of a clinical trial, including the development of a PGx hypothesis, the identification of genetic markers for analysis, PGx platform selection and assay development, as well as challenges that arise in relation to global laws and regulations related to genetic research and logistical/timeline concerns in the execution of a PGx analysis.

Improving clinical trial sampling for future research - an international approach: outcomes and next steps from the DIA future use sampling workshop 2011.

Clinical trial samples collected for pharmacogenomic and future research are vital resources for the development of safe and effective drugs, yet collecting adequate, representative sample sets in global trials is challenging. The Drug Information Association (DIA) sponsored a workshop on future use sampling in September 2011, bringing together experts from regulatory agencies, academia and industry to discuss challenges to future use sample collection and identify actions to improve collection. Several common themes and associated action items emerged, including the need for international guidance on the collection of samples for future research; additional discussion related to coding, scope of research, and return of research results; and additional education about pharmacogenomic/future research and the importance of long-term storage of specimens.

Cognitive-behavioral therapy for depression in Parkinson's disease: a randomized, controlled trial.

OBJECTIVE: Despite the negative effects of depression in Parkinson's disease, there is currently no evidence-based standard of care. The purpose of this study was to examine the efficacy of individually administered cognitive-behavioral therapy (CBT), relative to clinical monitoring (with no new treatment), for depression in this medical population. METHOD: Eighty depressed (based on DSM-IV criteria) patients with Parkinson's disease participated in a randomized, controlled trial of CBT relative to clinical monitoring (1:1 ratio) in an academic medical center from April 2007 to July 2010. All patients continued to maintain stable medication regimens under the care of their personal physicians. The 17-item Hamilton Depression Rating Scale (HAM-D) total score was the primary outcome. CBT was modified to meet the unique needs of the Parkinson's disease population and provided for 10 weeks. Assessments were completed by blind raters at baseline and 5 (midpoint), 10 (end of treatment), and 14 weeks (follow-up evaluation) postrandomization. RESULTS: The CBT group reported greater reductions in depression (change in HAM-D score) than the clinical monitoring group. At week 10, the mean HAM-D score change was 7.35 for CBT relative to 0.05 for clinical monitoring. CBT was also superior to clinical monitoring on several secondary outcomes (i.e., Beck Depression Inventory scores, anxiety, quality of life, coping, Parkinson's disease symptom ratings). There were more treatment responders in the CBT group than the clinical monitoring group (56% versus 8%, respectively). CONCLUSIONS: CBT may be a viable approach for the treatment of depression in Parkinson's disease. Further research is needed to replicate and extend these findings.

Impulsive smoking in a patient with Parkinson's disease treated with dopamine agonists.

Impulse control disorders, including pathological gambling, binge eating, compulsive shopping and hypersexual behaviors, have frequently been reported as a side effect of dopaminergic medications for Parkinson's disease (PD). Here we describe a patient with PD who developed an unusual manifestation of impulsive behaviors, including cigarette smoking, associated with an increase in dopamine agonist medication. We postulate this to be related to an overstimulation of mesolimbic dopamine receptors responsible for reward-seeking behaviors. Further research is needed to examine impulsive cigarette smoking in PD.

Ramelteon for the treatment of insomnia in menopausal women.

OBJECTIVE: Sleep disturbances have been reported to be one of the most troubling manifestations of menopause. While hormone replacement therapy (HRT) has historically been considered a first-line treatment for menopausal insomnia, many women are now seeking alternative treatments due to concerns about the risks and side-effects of HRT. The goal of this study was to evaluate the effect of ramelteon, a selective melatonin receptor agonist, for the treatment of menopausal insomnia. STUDY DESIGN: A total of 20 healthy peri- and postmenopausal women with insomnia participated in this six-week, prospective, open-label trial of ramelteon (8 mg) at an academic medical centre. Participants completed sleep-wake diaries on a daily basis for six weeks. Self-report measures of sleep impairment, daytime functioning, quality of life and mood were also completed on a bi-weekly basis. RESULTS: Significant improvements in latency to sleep onset, total sleep time and sleep efficiency were observed in diary data while gains in sleep quality, sleep impairment, daytime functioning, quality of life and mood were found in self-report measures. There was no evidence of tolerance or rebound over the course of the trial. CONCLUSIONS: Overall, results suggest that ramelteon is an effective non-hormonal approach for the treatment of insomnia in menopause. Randomized-controlled trials are needed to further evaluate the efficacy of this intervention.

CBT for the treatment of depression in Parkinson's disease: a promising nonpharmacological approach.

Depression is very common in Parkinson's disease (PD) and linked with a faster progression of physical symptoms, greater cognitive decline and poorer quality of life. Nonpharmacological approaches, such as cognitive-behavioral therapy (CBT), for the treatment of depression in PD (dPD) have received little experimental attention despite strong demonstrated efficacy in other geriatric and medical populations. Depressed PD patients often differ from the depressed non-PD elderly in that they present with increased rates of both executive dysfunction and comorbid psychiatric diagnoses, may differ in their depressive symptom presentation and typically have caregivers who are highly involved in their treatment. Therefore, it is not possible to conclude that empirically validated treatments in the depressed aged will generalize to those with PD. In order to be most effective for PD patients, CBT should be tailored to their unique needs. Additional controlled research is needed to further explore the efficacy of CBT for dPD.