Innovative Technologies in CNS Trials: Promises and Pitfalls for Recruitment, Retention, and Representativeness.

Objective: Recruitment of a sufficiently large and representative patient sample and its retention during central nervous system (CNS) trials presents major challenges for study sponsors. Technological advances are reshaping clinical trial operations to meet these challenges, and the COVID-19 pandemic further accelerated this development. Method of Research: The International Society for CNS Clinical Trials and Methodology (ISCTM; www.isctm.org) Innovative Technologies for CNS Trials Working Group surveyed the state of technological innovations for improved recruitment and retention and assessed their promises and pitfalls. Results: Online advertisement and electronic patient registries can enhance recruitment, but challenges with sample representativeness, conversion rates from eligible prescreening to enrolled patients, data privacy and security, and patient identification remain hurdles for optimal use of these technologies. Electronic medical records (EMR) mining with artificial intelligence (AI)/machine learning (ML) methods is promising but awaits translation into trials. During the study treatment phase, technological innovations increasingly support participant retention, including adherence with the investigational treatment. Digital tools for adherence and retention support take many forms, including patient-centric communication channels between researchers and participants, real-time study reminders, and digital behavioral interventions to increase study compliance. However, such tools add technical complexities to trials, and their impact on the generalizability of results are largely unknown. Conclusion: Overall, the group found a scarcity of systematic data directly assessing the impact of technological innovations on study recruitment and retention in CNS trials, even for strategies with already high adoption, such as online recruitment. Given the added complexity and costs associated with most technological innovations, such data is needed to fully harness technologies for CNS trials and drive further adoption.

Impact of an opioid prescribing alert system on patients with posttraumatic stress disorder.

BACKGROUND AND OBJECTIVES: Posttraumatic stress disorder (PTSD) is associated with higher rates of chronic pain and increased risk of developing Opioid use disorder. This paper evaluates the impact of PRIMUM, an electronic health record-embedded (EHR) clinical decision support intervention on opioid prescribing patterns for patients with diagnosis of PTSD. METHODS: Inpatient, emergency department (ED), urgent care, and outpatient encounters with ICD-10 codes F43.1 (PTSD), F43.10 (PTSD, unspecified), F43.11 (PTSD, acute), and F43.12 (PTSD, chronic) at Atrium Health between 1/1/2016 and 12/29/2018 were included in the study. RESULTS: A total of 3121 patients with a diagnosis of PTSD were seen in 37,443 encounters during the study period. Ten percent (n = 3761) of the encounters resulted in prescriptions for opioids and PRIMUM alerts were triggered in 1488 of these encounters. These alerts resulted in "decision influenced" for 17% of patients (n = 255) or no prescriptions for opioids or benzodiazepines for 5.8% (n = 86). The majority of the prescriptions were below 50 Morphine milligram equivalents (MME)/day, but there were 570 (15.5%) prescriptions for doses of 50-90 MME and 721 (19.6%) prescriptions for >90 MME/day. DISCUSSION AND CONCLUSION: The PRIMUM alert system helps improve patient safety. PRIMUM affected clinician decisions 17% of the time, and the effect was greater in patients with opioid overdose history and those presenting for early refills. SCIENTIFIC SIGNIFICANCE: The effectiveness of clinical support interventions for opioid prescribing for patients with PTSD has not been documented previously. Our findings provide novel evidence that the EHR can be used to improve patient safety among patients with PTSD in the context of substance use.

The Walking Wounded: Emerging Treatments for PTSD.

PURPOSE OF REVIEW: We review the published literature over the last 24 months in the treatment of PTSD for our military men and women. We examined the updated clinical practice guidelines published in June 2017 by the Veteran's administration and Department of Defense and contrasted the guidelines with the most recent literature. We also discuss new directions in PTSD research. RECENT FINDINGS: Psychotherapy remains one of the most effective treatments for PTSD; unfortunately, few participants remain in treatment to completion. Many of the emerging therapies target NMDA receptor antagonists, cannabinoid receptor modulators, glucocorticoid receptor agonists, non-SSRI antidepressants, and opioid receptor agonists. The newer therapies fall into the drug classes of anti-hypertensives, glutamate modulators, oxytocin, and medication targeting insomnia/hyperarousal. PTSD symptoms are often chronic in our veteran population. While current treatments are helpful, there are often significant residual symptoms. We reviewed the most recent improvements in treatment and discuss therapies that are in the research phase.

Update on optimal use of lisdexamfetamine in the treatment of ADHD.

Lisdexamfetamine (LDX) has been a recent addition to the treatment armamentarium for Attention Deficit Hyperactivity Disorder (ADHD). It is unique among stimulants as it is a prodrug, and has been found to be safe and well-tolerated medication in children older than 6 years, adolescents and adults. It has a smooth onset of action, exerts its action up to 13 hours and may have less rebound symptoms. LDX has proven to be effective in the treatment of ADHD in placebo controlled trials, and improved performance in simulated academic and work environments have been noticed. Both stimulant-naïve and stimulant-exposed patients with ADHD appear to benefit from LDX. It has also shown some promise in improving emotional expression and executive function of patients with ADHD. Adverse effects such as decrease in sleep, loss of appetite and others have been reported with LDX use, just as with other stimulant formulations. Since most such studies exclude subjects with preexisting cardiac morbidity, prescribing precautions should be taken with LDX in such subjects, as with any other stimulant. Study subjects on LDX have been reported to have low scores on drug likability scales, even with intravenous use; as a result, LDX may have somewhat less potential for abuse and diversion. There is a need for future studies comparing other long acting stimulants with LDX in ADHD; in fact clinical trials comparing LDX with OROS (osmotic controlled-release oral delivery system) methylphenidate are currently underway. Furthermore, the utility of this medication in other psychiatric disorders and beyond ADHD is being investigated.

Clinical utility of the risperidone formulations in the management of schizophrenia.

Risperidone is one of the early second-generation antipsychotics that came into the limelight in the early 1990s. Both the oral and long-acting injectable formulations have been subject to numerous studies to assess their safety, efficacy, and tolerability. Risperidone is currently one of the most widely prescribed antipsychotic medications, used for both acute and long-term maintenance in schizophrenia. Risperidone has better efficacy in the treatment of psychotic symptoms than placebo and possibly many first-generation antipsychotics. Risperidone fares better than placebo and first-generation antipsychotics in the treatment of negative symptoms. Risperidone's long acting injectable preparation has been well tolerated and is often useful in patients with medication nonadherence. Risperidone has a higher risk of hyperprolactinemia comparable to first-generation antipsychotics (FGAs) but fares better than many second-generation antipsychotics with regards to metabolic side effects. In this article, we briefly review the recent literature exploring the role of risperidone formulations in schizophrenia, discuss clinical usage, and highlight the controversies and challenges associated with its use.

Biological markers in schizophrenia: An update.

Biological markers are quantitative measures that allow clinicians to diagnose and assess the disease process, monitor response to treatment and may, to some extent, assist with prognostic assessments (1). Biological markers can modify the way clinicians approach, treat and care for patients. This has significant diagnostic and treatment-related implications, especially for chronic disabling disorders with complex etiopathogenesis, such as schizophrenia. Years of research have yielded a variety of relatively consistent findings in different domains including neuroanatomy, functional and molecular neuroimaging, neurophysiology, genetics and biochemistry. These attributes can complement clinical findings with improved diagnostic validity, and to some extent, assist the clinician in early initiation of efficacious treatment and predicting prognosis. On the contrary, many of these potential biological markers may require expensive testing and enhanced technological expertise. Considering the issues with sensitivity and specificity and an overlap with other neuropsychiatric disorders, their role in routine clinical care continues to be ambiguous.

Management of tics and Tourette's disorder: an update.

IMPORTANCE OF THE FIELD: Tic disorders are fairly prevalent neuropsychiatric disorders. While a proportion of children may not present to the clinician's office for management of tic disorders, another proportion may present with severe symptoms that impair social and occupational functioning. A combination of psychosocial interventions and pharmacological approaches are required in these cases. While alpha-2 agonists and dopamine antagonists constitute the mainstay of pharmacological agents for tic disorders, advances in neurobiology and psychopharmacology have discovered newer avenues for treatment of tic disorders. AREAS COVERED IN THIS REVIEW: Apart from reviewing evidence based literature and recent updates on alpha-2 agonists and dopamine antagonists in treating tic disorders, the review also includes novel treatment approaches such as glutamate modulators, nicotinic agents, antiandrogens and botulinum injection. In addition, a brief overview of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS) and habit reversal training is also provided. WHAT THE READER WILL GAIN: A clear and concise review of the therapeutic options and advances in management of tic disorders. TAKE HOME MESSAGE: In addition to psychosocial interventions, alpha-2 agonists and dopamine antagonists constitute the mainstay of treatment approaches for treating tic disorders. Additional treatment options such as ropinirole, pramipexole and tetrabenazine may be useful if patients do not respond to the primary agents. Severe intractable cases might need a referral to specialist centers to consider the possibility of using ECT, TMS or DBS.