Showing papers in "Innovations in clinical neuroscience in 2017"

Virtual Reality and Medical Inpatients: A Systematic Review of Randomized, Controlled Trials.

Abstract: Objective: We evaluated the evidence supporting the use of virtual reality among patients in acute inpatient medical settings. Method: We conducted a systematic review of randomized controlled trials conducted that examined virtual reality applications in inpatient medical settings between 2005 and 2015. We used PsycINFO, PubMed, and Medline databases to identify studies using the keywords virtual reality, VR therapy, treatment, and inpatient.Results: We identified 2,024 citations, among which 11 met criteria for inclusion. Studies addressed three general areas: pain management, eating disorders, and cognitive and motor rehabilitation. Studies were small and heterogeneous and utilized different designs and measures. Virtual reality was generally well tolerated by patients, and a majority of studies demonstrated clinical efficacy. Studies varied in quality, as measured by an evaluation metric developed by Reisch, Tyson, and Mize (average quality score=0.87; range=0.78-0.96). Conclusion: Virtual reality is a promising intervention with several potential applications in the inpatient medical setting. Studies to date demonstrate some efficacy, but there is a need for larger, well-controlled studies to show clinical and cost-effectiveness.

Trazodone for Insomnia: A Systematic Review.

Abstract: OBJECTIVE: While trazodone is approved for the treatment of depression, the off-label use of this medication for insomnia has surpassed its usage as an antidepressant. In this systematic review, we examined the evidence for the efficacy and safety of trazodone for insomnia. METHODS: A literature search was conducted using MEDLINE/PubMed databases from the past 33 years (1983-2016) and the keywords insomnia, trazodone, sedative, treatment, and hypnotics. The results were restricted to English language and human subjects. All randomized clinical trials, meta-analyses, observational studies, and placebo-controlled trials regarding trazodone for the treatment of primary or secondary insomnia were reported, per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The study selection process yielded a total of 45 studies. RESULTS: Evidence for the efficacy of trazodone has been repeatedly demonstrated for primary insomnia, as well as secondary insomnia, including for symptoms that are a result of depression, dementia, and being a healthy man. Earlier studies (1980-2000) focused on utilizing trazodone at high doses (≥100mg/d) for the treatment of insomnia among the depressed population; however, since the 2000s, the utility of trazodone has been expanded to treat secondary insomnia among the non-depressed population as well. The side effects are dose-dependent, and the most common is drowsiness. CONCLUSION: A review of the literature suggests that there are adequate data supporting the efficacy and general safety of the low-dose use of trazodone for the treatment of insomnia.

Positive and Negative Syndrome Scale (PANSS) Training: Challenges, Solutions, and Future Directions.

Abstract: Rater training and the maintenance of the consistency of ratings are critical to ensuring reliability of study measures and sensitivity to changes in the course of a clinical trial. The Positive and Negative Syndrome Scale (PANSS) has been widely used in clinical trials of schizophrenia and other disorders and is considered the "gold standard" for assessment of antipsychotic treatment efficacy. The various features associated with training and calibration of this scale are complex, reflecting the intricacy and heterogeneity of the disorders that the PANSS is used to evaluate. In this article, the authors review the methods for ensuring reliability of the PANSS as well as a proposed trajectory for its use in the future. An overview of the current principles, implementation, technologies, and strategies for the best use of the PANSS; tips for how to achieve consistency among raters; and optimal training practices of this instrument are presented.

Using the positive and negative syndrome scale (PANSS) to define different domains of negative symptoms: Prediction of everyday functioning by impairments in emotional expression and emotional experience

Abstract: Background: Reduced emotional experience and expression are two domains of negative symptoms. The authors assessed these two domains of negative symptoms using previously developed Positive and Negative Syndrome Scale (PANSS) factors. Using an existing dataset, the authors predicted three different elements of everyday functioning (social, vocational, and everyday activities) with these two factors, as well as with performance on measures of functional capacity. Methods: A large (n=630) sample of people with schizophrenia was used as the data source of this study. Using regression analyses, the authors predicted the three different aspects of everyday functioning, first with just the two Positive and Negative Syndrome Scale factors and then with a global negative symptom factor. Finally, we added neurocognitive performance and functional capacity as predictors. Results: The Positive and Negative Syndrome Scale reduced emotional experience factor accounted for 21 percent of the variance in everyday social functioning, while reduced emotional expression accounted for no variance. The total Positive and Negative Syndrome Scale negative symptom factor accounted for less variance (19%) than the reduced experience factor alone. The Positive and Negative Syndrome Scale expression factor accounted for, at most, one percent of the variance in any of the functional outcomes, with or without the addition of other predictors. Implications: Reduced emotional experience measured with the Positive and Negative Syndrome Scale, often referred to as "avolition and anhedonia," specifically predicted impairments in social outcomes. Further, reduced experience predicted social impairments better than emotional expression or the total Positive and Negative Syndrome Scale negative symptom factor. In this cross-sectional study, reduced emotional experience was specifically related with social outcomes, accounting for essentially no variance in work or everyday activities, and being the sole meaningful predictor of impairment in social outcomes.

Negative Symptom Dimensions of the Positive and Negative Syndrome Scale Across Geographical Regions: Implications for Social, Linguistic, and Cultural Consistency.

Abstract: Objective: Recognizing the discrete dimensions that underlie negative symptoms in schizophrenia and how these dimensions are understood across localities might result in better understanding and treatment of these symptoms. To this end, the objectives of this study were to 1) identify the Positive and Negative Syndrome Scale negative symptom dimensions of expressive deficits and experiential deficits and 2) analyze performance on these dimensions over 15 geographical regions to determine whether the items defining them manifest similar reliability across these regions. Design: Data were obtained for the baseline Positive and Negative Syndrome Scale visits of 6,889 subjects across 15 geographical regions. Using confirmatory factor analysis, we examined whether a two-factor negative symptom structure that is found in schizophrenia (experiential deficits and expressive deficits) would be replicated in our sample, and using differential item functioning, we tested the degree to which specific items from each negative symptom subfactor performed across geographical regions in comparison with the United States. Results: The two-factor negative symptom solution was replicated in this sample. Most geographical regions showed moderate-to-large differential item functioning for Positive and Negative Syndrome Scale expressive deficit items, especially N3 Poor Rapport, as compared with Positive and Negative Syndrome Scale experiential deficit items, showing that these items might be interpreted or scored differently in different regions. Across countries, except for India, the differential item functioning values did not favor raters in the United States. Conclusion: These results suggest that the Positive and Negative Syndrome Scale negative symptom factor can be better represented by a two-factor model than by a single-factor model. Additionally, the results show significant differences in responses to items representing the Positive and Negative Syndrome Scale expressive factors, but not the experiential factors, across regions. This could be due to a lack of equivalence between the original and translated versions, cultural differences with the interpretation of items, dissimilarities in rater training, or diversity in the understanding of scoring anchors. Knowing which items are challenging for raters across regions can help to guide Positive and Negative Syndrome Scale training and improve the results of international clinical trials aimed at negative symptoms.

Neuroendocrine, Autonomic, and Metabolic Responses to an Orexin Antagonist, Suvorexant, in Psychiatric Patients with Insomnia.

Abstract: Aim: The aim of this study was to investigate the neuroendocrine, autonomic, and metabolic system responses to suvorexant in psychiatric subjects with insomnia. Design: This prospective study was conducted in Kusatsu Hospital in Hiroshima, Japan and included 40 psychiatric inpatients treated with suvorexant from December 2014 to April 2016. Methods: Questionnaire of Pittsburgh Sleep Quality Index (PSQI), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9) scores were checked at baseline, Week 2, and Week 4, and fasting serum levels of prolactin, insulin, cortisol, noradrenaline, white blood cell count, and average pulse rate were measured at baseline and Week 4 and Week 8 after suvorexant initiation. Sequential change of the values were compared against baseline respectively. Results: Subjective sleep quality scores were significantly decreased at Weeks 2 and 4, and sleep duration, habitual sleep efficacy, and global scores were significantly decreased at Week 4 from baseline. Total scores on the Generalized Anxiety Disorder-7 and the Patient Health Questionnaire-9 significantly decreased at Week 4 from baseline. The levels of cortisol and white blood cell count were decreased, significantly at Week 8, and the levels of pulse rate were significantly decreased at Week 4 from baseline. The levels of noradrenaline decreased, although not significantly. The prolactin levels remained unchanged, and no trend was found in the insulin levels. Conclusion: Suvorexant treatment resulted in overall improvement in the quality of sleep and the severity of anxiety and depression. This dual orexin antagonist may be related to autonomic functions and neuroendocrine systems, especially in the hypothalamus-pituitary-adrenal axis in psychiatric subjects.

Outcomes Assessment in Clinical Trials of Alzheimer's Disease and its Precursors: Readying for Short-term and Long-term Clinical Trial Needs.

Abstract: An evolving paradigm shift in the diagnostic conceptualization of Alzheimer's disease is reflected in its recently updated diagnostic criteria from the National Institute on Aging-Alzheimer's Association and the International Working Group. Additionally, it is reflected in the increased focus in this field on conducting prevention trials in addition to improving cognition and function in people with dementia. These developments are making key contributions towards defining new regulatory thinking around Alzheimer's disease treatment earlier in the disease continuum. As a result, the field as a whole is now concentrated on exploring the next-generation of cognitive and functional outcome measures that will support clinical trials focused on treating the slow slide into cognitive and functional impairment. With this backdrop, the International Society for CNS Clinical Trials and Methodology convened semi-annual working group meetings which began in spring of 2012 to address methodological issues in this area. This report presents the most critical issues around primary outcome assessments in Alzheimer's disease clinical trials, and summarizes the presentations, discussions, and recommendations of those meetings, within the context of the evolving landscape of Alzheimer's disease clinical trials.

MicroRNAs as Biomarkers for Psychiatric Conditions: A Review of Current Research.

Abstract: Neural-derived exosomes can be used as diagnostic markers to screen for various psychiatric conditions. These intravenously injected exosomes carry the potential to cross the blood brain barrier and deliver miRNA molecules specifically to neurons, microglia, and oligodendrocytes in the brain, resulting in specific gene knockdown. Here the authors review and discuss the current research on microRNA molecules and the therapeutic roles they may potentially play in treating depression, bipolar disorder, and schizophrenia.

Methadone Treatment of Opiate Addiction: A Systematic Review of Comparative Studies.

Abstract: Opiate misuse is a chronic relapsing disease that has become an epidemic in the United States. Methadone is the mainstay of treatment for opiate addiction and has been researched widely. Recently, new avenues of treatment have been researched and developed. The objective of this review is to study methadone in comparison to other pharmacological options available or being considered for opiate addiction treatment through a methodical search and review of evidence provided by recent clinical trials conducted in this regard. There is a paucity of high quality randomized controlled trials focusing on the comparison between buprenorphine and methadone for treatment of opiate use disorder. Buprenorphine should be researched more for patient retention and satisfaction, as well as for its prospect for better outcomes in neonatal abstinence syndrome to generate more decisive recommendations. Current data suggest monitoring of liver enzymes with the use of buprenorphine/naloxone for better liver outcomes. In light of the analyzed data, the authors conclude that methadone should still be considered the preferred treatment mode in comparison to slow-release oral morphine and heroin.

Performance-based and Observational Assessments in Clinical Trials Across the Alzheimer's Disease Spectrum.

Abstract: Assessment of the earlier stages of Alzheimer's disease requires different strategies than those previously developed for fully syndromal Alzheimer's disease . This challenge is further magnified in very early stages, where symptomatology may be minimal and functional deficits very subtle to absent. This paper reviews strategies for performance-based assessment of the early stages of Alzheimer's disease, including assessments of cognition, functional capacity, and social cognition. Meetings with an International Society for CNS Clinical Trials and Methodology working group served as the basis for this paper and its companion. The current state of the art of detection and staging-oriented assessments is presented, and information is provided regarding the practicality and validity of these approaches, with a special focus on their usefulness in clinical trials for new medication development.

Sensitivity of the Positive and Negative Syndrome Scale (PANSS) in Detecting Treatment Effects via Network Analysis.

Abstract: Objective: The Positive and Negative Syndrome Scale is a primary outcome measure in clinical trials examining the efficacy of antipsychotic medications. Although the Positive and Negative Syndrome Scale has demonstrated sensitivity as a measure of treatment change in studies using traditional univariate statistical approaches, its sensitivity to detecting network-level changes in dynamic relationships among symptoms has yet to be demonstrated using more sophisticated multivariate analyses. In the current study, we examined the sensitivity of the Positive and Negative Syndrome Scale to detecting antipsychotic treatment effects as revealed through network analysis. Design: Participants included 1,049 individuals diagnosed with psychotic disorders from the Phase I portion of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Of these participants, 733 were clinically determined to be treatment-responsive and 316 were found to be treatment-resistant. Item level data from the Positive and Negative Syndrome Scale were submitted to network analysis, and macroscopic, mesoscopic, and microscopic network properties were evaluated for the treatment-responsive and treatment-resistant groups at baseline and post-phase I antipsychotic treatment. Results: Network analysis indicated that treatment-responsive patients had more densely connected symptom networks after antipsychotic treatment than did treatment-responsive patients at baseline, and that symptom centralities increased following treatment. In contrast, symptom networks of treatment-resistant patients behaved more randomly before and after treatment. Conclusions: These results suggest that the Positive and Negative Syndrome Scale is sensitive to detecting treatment effects as revealed through network analysis. Its findings also provide compelling new evidence that strongly interconnected symptom networks confer an overall greater probability of treatment responsiveness in patients with psychosis, suggesting that antipsychotics achieve their effect by enhancing a number of central symptoms, which then facilitate reduction of other highly coupled symptoms in a network-like fashion.

Immersive Virtual Reality Therapy with Myoelectric Control for Treatment-resistant Phantom Limb Pain: Case Report.

Abstract: Objective: Phantom limb pain is a condition frequently experienced after amputation. One treatment for phantom limb pain is traditional mirror therapy, yet some patients do not respond to this intervention, and immersive virtual reality mirror therapy offers some potential advantages. We report the case of a patient with severe phantom limb pain following an upper limb amputation and successful treatment with therapy in a custom virtual reality environment. Methods: An interactive 3-D kitchen environment was developed based on the principles of mirror therapy to allow for control of virtual hands while wearing a motion-tracked, head-mounted virtual reality display. The patient used myoelectric control of a virtual hand as well as motion-tracking control in this setting for five therapy sessions. Pain scale measurements and subjective feedback was elicited at each session. Results: Analysis of the measured pain scales showed statistically significant decreases per session [Visual Analog Scale, Short Form McGill Pain Questionnaire, and Wong-Baker FACES pain scores decreased by 55 percent (p=0.0143), 60 percent (p=0.023), and 90 percent (p=0.0024), respectively]. Significant subjective pain relief persisting between sessions was also reported, as well as marked immersion within the virtual environments. On followup at six weeks, the patient noted continued decrease in phantom limb pain symptoms. Conclusions: Currently available immersive virtual reality technology with myolectric and motion tracking control may represent a possible therapy option for treatment-resistant phantom limb pain.

Bridging the Measurement Gap Between Research and Clinical Care in Schizophrenia: Positive and Negative Syndrome Scale-6 (PANSS-6) and Other Assessments Based on the Simplified Negative and Positive Symptoms Interview (SNAPSI).

Abstract: There is currently a "measurement gap" between research and clinical care in schizophrenia. The main reason behind this gap is that the most widely used rating scale in schizophrenia research, the 30-item Positive and Negative Syndrome Scale (PANSS), takes so long to administer that it is rarely used in clinical practice. This compromises the translation of research findings into clinical care and vice versa. The aim of this paper is to discuss how this measurement gap can be closed. Specifically, the main points of discussion are 1) the practical problems associated with using the full 30-item PANSS in clinical practice; 2) how the brief, six-item version of the Positive and Negative Syndrome Scale (PANSS-6) was derived empirically from the full 30-item PANSS and what the initial results obtained with PANSS-6 entail; and 3) how PANSS-6 ratings, guided by the newly developed, 15-25-minute, stand-alone Simplified Negative and Positive Symptoms Interview (SNAPSI), might help bridge the measurement gap between research and clinical care in schizophrenia. The full 30-item PANSS is often used in research studies, but is too time consuming to allow for routine clinical use. Recent studies suggest that the much briefer PANSS-6 is a psychometrically valid measure of core positive and negative symptoms of schizophrenia and that the scale is sensitive to symptom improvement following pharmacological treatment. SNAPSI is a brief interview that yields the information needed to rate PANSS-6 (and other brief rating scales). We believe that PANSS-6 ratings guided by SNAPSI will help bridge the measurement gap between research and clinical care in schizophrenia.

The Role and Treatment Implications of Peripheral and Central Processing of Pain, Pruritus, and Nausea in Heightened Somatic Awareness: A Review.

Abstract: Pain, pruritus, and nausea are complex sensory and emotional physiological symptoms that can vary widely between people and even within an individual, depending on the context and meaning of the symptom and the psychological state of the person. This article reviews the acute neural transmission of pain, pruritus, and nausea symptoms, which can begin in the periphery and/or viscera. The subsequent multiple pathways in the central nervous system that become involved in the processing of these symptoms are also discussed. The authors describe human brain imaging studies that have revealed consistent cortical and subcortical networks activated by these symptoms, including sensory, limbic, and associative regions. In particular, the authors discuss information revealed by the studies regarding the primary somatosensory cortex, secondary somatosensory cortex, anterior cingulate cortex, insula, prefrontal cortex and thalamus, are the brain areas most commonly activated by noxious stimuli. Finally, the authors describe treatment options for chronic presentations of these symptoms, which are, in part, based on central nervous processing of these sensations.

It's Time For Combination Therapies: in Multiple Sclerosis.

Abstract: The treatment of multiple sclerosis continues to evolve. However, even with the introduction of B-cell depleting monoclonal antibodies, disability progression continues unabated since B-cell therapies are unable to cross the blood brain barrier and thus are unable to address the disease that lurks within the brain. In this commentary, the author explores the research and practice of using B-cell depleting monoclonal antibody therapies in MS. The author provides discussion on the blood brain barrier as the primary limitation to the effectiveness of MS therapies. The author briefly reviews the pathophysiological role of B-cells in MS and the implications that B-cell migration to the brain has on MS disease progression and treatment. The author discusses potential drug development strategies for MS that combine blood brain barrier crossing molecules with peripherally acting B-cell depleting monoclonal antibodies.

Redefining Acute Relapses in Multiple Sclerosis: Implications for Phase 3 Clinical Trials and Treatment Algorithms.

Abstract: Relapses in multiple sclerosis are defined as periods of clinical worsening and radiological progression. Magnetic resonance imaging data, however, are not always supportive of "clinical worsening," and clinical symptoms of worsening may not always be present in cases of acute relapse. In the pharmaceutical domain, this discordance between "clinical worsening" and "radiological progression" has never been fully elucidated, and no Phase 3 clinical study has addressed this conundrum. Thus, the true number of acute relapse cases enrolled in Phase 3 clinical studies remains unclear. Breach of the blood-brain barrier solely, as determined by magnetic resonance imaging, may be more a more accurate definition of an acute relapse in multiple sclerosis. Increasingly, magnetic resonance imaging data push the boundaries of science and carry significant advantages in sensitivity, data storage, retrieval, and unbiased analyses, if warranted retrospectively. Magnetic resonance imaging data can also be standardized, shared, and exploited by pharmaceutical companies to develop more effective drugs and therapeutic endpoints. Neurology is awakening to big data concepts and how such concepts are evolving the field. Magnetic resonance imaging data is one of the pillars of this evolution. In this commentary, the author reviews the current standard of determining acute relapse in both clinical practice and clinical research, and discusses its limitations. The author then proposes a more modern definition of acute relapse in multiple sclerosis and includes a supportive discussion on the current and emerging roles magnetic resonance imaging and "big data" are playing in the prevention, diagnosis, and treatment of multiple sclerosis.

Are Shorter Versions of the Positive and Negative Syndrome Scale (PANSS) Doable? A Critical Review

Abstract: The Positive and Negative Syndrome Scale (PANSS) is a well-established assessment tool for measuring symptom severity in schizophrenia. Researchers and clinicians have been interested in the development of a short version of the PANSS that could reduce the burden of its administration for patients and raters. The author presents a comprehensive overview of existing brief PANSS measures, including their strengths and limitations, and discusses some possible next steps. There are two available scales that offer a reduced number of original PANSS items: PANSS-14 and PANSS-19; and two shorter versions that include six items: Brief PANSS and PANSS-6. The PANSS-6 has been tested quite extensively in established trials and appears to demonstrate high sensitivity to change and an established cut off definition for remission. Prospective testing in new antipsychotic treatment trials is still required for these shorter versions of PANSS. In addition, they need to be supplemented with interview guides, as well as provide conversion formulas to translate total scores from the short PANSS versions to the PANSS-30. Both short versions of the PANSS are essentially designed to evaluate response to antipsychotic treatment. Future PANSS scale development needs to address specific measurement of treatment-responsive positive symptoms by including treatment-sensitive items, as well as illness-phase specific PANSS tools.

A Developmental History of the Positive and Negative Syndrome Scale (PANSS)

Abstract: Psychometric instruments are products of their time-Their designs and initial purposes are influenced and shaped by the contemporary treatment regimens, context, and cultural and conceptual biases of their developers. In this review article, the authors explore the history of the most influential schizophrenia research tools that have been created over the past several decades. The authors describe the scientific concepts, cultural influences, and challenges of past and present researchers as they strive to develop better assessment tools for schizophrenia. Starting with Moore's Scheme for the Quantitative Measurement of Abnormal Emotional Condition, developed in the early 1900s, and concluding with Kay, Fiszbein, and Opler's Positive and Negative Syndrome Scale, developed in the 80s, the authors describe several scales and illustrate how each scale led to and influenced the development of a later scale. The authors hope that a better understanding of schizophrenia assessment tool evolution and limitations will assist in the development of new instruments that better address the global needs for the evaluation, research, and treatment of psychosis.

Human Embryonic Stem Cells in the Treatment of Autism: A Case Series.

Abstract: Background: Autism spectrum disorder is a neurodevelopmental disorder accompanied by weak immune system and neuroinflammation. Multiple factors contribute to etiology of autism spectrum disorder including genetic disorders, environmental substances/toxins, imbalanced immune system, encephalitis, and viral infections. Autism spectrum disorder is an incurable disease; however, it can be managed by educational and medical interventions. Human embryonic stem cell therapy has been shown to improve blood perfusion in the brain; thus, this therapy may be effective in improving motor skills, social skills, and cognition in patients with autism spectrum disorder. Method: Three pediatric patients with autism spectrum disorder were administered human embryonic stem cell therapy. Their treatment plan comprised 3 to 4 therapy sessions (T1, T2, T3, T4) that were 4 to 6 weeks in length, with 4- to 8-month gap phases separating each therapy session. Results: The patients showed improvements in eye coordination, writing, balancing, cognition, and speech and showed reduced hypersensitivity to noises and smells. Conclusion: The use of human embryonic stem cell therapy may be a safe and effective treatment for patients with autism spectrum disorder. Studies with larger sample sizes are needed to support the use of human embryonic stem cell therapy in this patient population.

Ketamine Therapy for Treatment-resistant Depression in a Patient with Multiple Sclerosis: A Case Report.

Abstract: Objective: Depression is a common condition among patients with multiple sclerosis and often becomes resistant to oral antidepressants. We report a patient with multiple sclerosis who developed severe treatment-resistant depression and who was successfully treated with intravenous ketamine over the period of two years. Methods: Ketamine treatment protocol included an initial series of six treatments administered every other day, followed by a maintenance schedule. Ketamine was administered intravenously at 0.5mg/kg of ideal body weight over 40 minutes. Depression symptoms were measured using Beck Depression Index. Results: The patient's Beck Depression Index score prior to initiating ketamine treatment was 38, corresponding to severe depression. Response to treatment, defined as 50-percent reduction in Beck Depression Index score, was observed after five treatments. For this patient, the maintenance schedule ranged from a weekly treatment to one treatment every three weeks. During the two-year observation period, this patient was able to maintain a stable non-depressed mood and had no worsening of her MS symptoms. Conclusion: Ketamine may be an alternative treatment for resistant depression and may have a special use in patients with multiple sclerosis.

Behavioral and Stereological Analysis of the Effects of Intermittent Feeding Diet on the Orally Administrated MDMA ("ecstasy") in Mice.

Abstract: Background: 3,4-methylenedioxy-methamphetamine or MDMA (also known as "ecstasy" or "molly") is a commonly abused drug that affects behavior and can lead to neuronal damage. Intermittent feeding is an effective dietary protocol that promotes neuroprotection and improves behavioral outcomes in animal models of neurotoxicity and neurodegenerative diseases. In this study, we investigated the behavioral and histological outcomes of the effect of intermittent feeding on the orally administered MDMA in mice. Methods: The animals (male albino mice) were divided into four groups: ad libitum (AL), intermittent feeding (IF) (food given every other day), and AL and IF control groups. After five weeks, AL and IF groups were given a single oral dose of 20 or 60mg/kg MDMA. Behavior was assessed with the elevated plus-maze and the open field tests. Each of the treatment groups were then divided in to two groups: AL-AL (AL diet throughout), AL-IF (IF after MDMA administration), IF-IF (IF diet throughout), IF-AL (AL after MDMA administration). The second behavioral assessment was performed on ninth and 12th day after MDMA administration. The brains were then prepared with cresyl fast violet stain for stereology of the CA1 area of hippocampus. Results: The AL groups showed enhanced locomotion and anxiety compared to the IF (p<0.001); however, IF groups showed significantly (p<0.05) more locomotor activity and less anxiety recovery at ninth and 12th days compared to the AL animals. The neuronal numerical density was significantly (p<0.05) higher in the hippocampus in the AL-IF groups compared to the AL-AL. Conclusion: IF regimen can significantly modify various behavioral characteristics induced by MDMA and promotes faster recovery from MDMA's anxiogenic effects. Additionally, IF regimen had neuroprotective effects on the neurons of the CA1 area of the hippocampus after a single oral dose of MDMA. We believe the results of our study support the need for further research examining the behavior modifying and neuroprotective potential of the IF regminen for the treatment of drug addiction in humans.

Understanding Antipsychotic Drug Treatment Effects: A Novel Method to Reduce Pseudospecificity of the Positive and Negative Syndrome Scale (PANSS) Factors.

Abstract: The Positive and Negative Syndrome Scale (PANSS) is the most widely used efficacy measure in acute treatment studies of schizophrenia. However, interpretation of the efficacy of antipsychotics in improving specific symptom domains is confounded by moderate-to-high correlations among standard (Marder) PANSS factors. The authors review the results of an uncorrelated PANSS score matrix (UPSM) transform designed to reduce pseudospecificity in assessment of symptom change in patients with schizophrenia. Based on a factor analysis of five pooled, placebo-controlled lurasidone clinical trials (N=1,710 patients), a UPSM transform was identified that generated PANSS factors with high face validity (good correlation with standard Marder PANSS factors), and high specificity/orthogonality (low levels of between-factor correlation measuring change during treatment). Between-factor correlations were low at baseline for both standard (Marder) PANSS factors and transformed PANSS factors. However, when measured change in symptom severity was measured during treatment (in a pooled 5-study analysis), there was a notable difference for standard PANSS factors, where changes across factors were found to be highly correlated (factors exhibited pseudospecificity), compared to transformed PANSS factors, where factor change scores exhibited the same low levels of between-factor correlation observed at baseline. At Week 6-endpoint, correlations among PANSS factor severity scores were moderate-to-high for standard factors (0.34-0.68), but continued to be low for the transformed factors (-0.22-0.20). As an additional validity check, we analyzed data from one of the original five pooled clinical trials that included other well-validated assessment scales (MADRS, Negative Symptom Assessment scale [NSA]). In this baseline analysis, UPSM-transformed PANSS factor severity scores (negative and depression factors) were found to correlate well with the MADRS and NSA. The availability of transformed PANSS factors with a high degree of orthogonality/specificity, but which retain a high degree of concurrent and face validity, can reduce pseudospecificity as a measurement confound, and should facilitate the drug development process, permitting a more accurate characterization of the efficacy of putative new agents in targeting specific symptom domains in patients with psychotic illness.

Disparity between General Symptom Relief and Remission Criteria in the Positive and Negative Syndrome Scale (PANSS): A Post-treatment Bifactor Item Response Theory Model.

Abstract: Objective: Total scale scores derived by summing ratings from the 30-item PANSS are commonly used in clinical trial research to measure overall symptom severity, and percentage reductions in the total scores are sometimes used to document the efficacy of treatment. Acknowledging that some patients may have substantial changes in PANSS total scores but still be sufficiently symptomatic to warrant diagnosis, ratings on a subset of 8 items, referred to here as the "Remission set," are sometimes used to determine if patients' symptoms no longer satisfy diagnostic criteria. An unanswered question remains: is the goal of treatment better conceptualized as reduction in overall symptom severity, or reduction in symptoms below the threshold for diagnosis? We evaluated the psychometric properties of PANSS total scores, to assess whether having low symptom severity post-treatment is equivalent to attaining Remission. Design: We applied a bifactor item response theory (IRT) model to post-treatment PANSS ratings of 3,647 subjects diagnosed with schizophrenia assessed at the termination of 11 clinical trials. The bifactor model specified one general dimension to reflect overall symptom severity, and five domain-specific dimensions. We assessed how PANSS item discrimination and information parameters varied across the range of overall symptom severity (θ), with a special focus on low levels of symptoms (i.e., θ<-1), which we refer to as "Relief" from symptoms. A score of θ=-1 corresponds to an expected PANSS item score of 1.83, a rating between "Absent" and "Minimal" for a PANSS symptom. Results: The application of the bifactor IRT model revealed: (1) 88% of total score variation was attributable to variation in general symptom severity, and only 8% reflected secondary domain factors. This implies that a general factor may provide a good indicator of symptom severity, and that interpretation is not overly complicated by multidimensionality; (2) Post-treatment, 534 individuals (about 15% of the whole sample) scored in the "Relief" range of general symptom severity, but more than twice that number (n = 1351) satisfied Remission criteria (37%). 2 in 3 Remitted patients had scores that were not in a low symptom range (corresponding to Absent or Minimal item scores); (3) PANSS items vary greatly in their ability to measure the general symptom severity dimension; while many items are highly discriminating and relatively "pure" indicators of general symptom severity (delusions, conceptual disorganization), others are better indicators of specific dimensions (blunted affect, depression). The utility of a given PANSS item for assessing a patient depended on the illness level of the patient. Conclusion: Satisfying conventional Remission criteria was not strongly associated with low levels of symptoms. The items providing the most information for patients in the symptom Relief range were Delusions, Preoccupation, Suspiciousness Persecution, Unusual Thought Content, Conceptual Disorganization, Stereotyped Thinking, Active Social Avoidance, and Lack of Judgment and Insight. Lower scores on these items (item scores ≤2) were strongly associated with having a low latent trait θ or experiencing overall symptom relief. The inter-rater agreement between Remission and Relief subjects suggested that these criteria identified different subsets of patients. Alternative subsets of items may offer better indicators of general symptom severity and provide better discrimination (and lower standard errors) for scaling individuals and judging symptom relief, where the "best" subset of items ultimately depends on the illness range and treatment phase being evaluated.

What Can I Do About a Negative Online Review

Abstract: This ongoing column is dedicated to providing information to our readers on managing legal risks associated with medical practice. We invite questions from our readers. The answers are provided by PRMS, Inc. (www.prms.com), a manager of medical professional liability insurance programs with services that include risk management consultation, education and onsite risk management audits, and other resources to healthcare providers to help improve patient outcomes and reduce professional liability risk. The answers published in this column represent those of only one risk management consulting company. Other risk management consulting companies or insurance carriers might provide different advice, and readers should take this into consideration. The information in this column does not constitute legal advice. For legal advice, contact your personal attorney. Note: The information and recommendations in this article are applicable to physicians and other healthcare professionals, so \"clinician\" is used to indicate all treatment team members.

Narcolepsy in Adolescence-A Missed Diagnosis: A Case Report.

Abstract: Narcolepsy is an uncommon sleep cycle disorder with a usual onset in adolescence, but it is often misdiagnosed and underdiagnosed. Rarely is the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis seen in patients. The clinical characteristics of narcolepsy are often confused with many psychiatric and neurologic disorders. Lack of clinical awareness about narcolepsy leads to frequent prescriptions of antiepileptics and psychotropics, which can adversely affect the quality of life of children and adolescents. We report a case of an adolescent male who presented with all four cardinal symptoms of narcolepsy and had been misdiagnosed with epilepsy, psychosis, and depression. We discuss various issues regarding narcolepsy in children and adolescents.

A Case of Psychosis in a Patient with Secondary Adrenal Insufficiency: A Possible Etiological Role of a Hypocortisolemic-induced Increase in Proinflammatory Cytokines

Abstract: Adrenal insufficiency is divided into three types based on the etiology of its development. In primary adrenal insufficiency, pathology resides in end-organ failure at the level of the adrenal cortex, while in secondary and tertiary adrenal insufficiency, impairment rests in the pituitary gland and hypothalamus, respectively. Regardless of etiology, adrenal insufficiency results in a hypocortisolemic condition. While the relationship between neuropsychiatric symptoms, especially psychosis, and hypercortisolemia has been extensively documented, the development of hypocortisolemia-induced psychosis is less common. We present a case of secondary adrenal insufficiency caused by a pituitary tumor. During the course of evaluation and treatment, the patient developed a psychotic episode. We will briefly review the condition of adrenal insufficiency and propose how hypocortisolemia can result in psychosis.

Precursors to the PANSS: The BPRS and its progenitors.

Abstract: The systematic assessment of signs and symptoms of psychopathology has roots that date back to rating scale development that began in the 1950s. This article reviews some of those rating scales. The focus is on the Brief Psychiatric Rating Scale, which is the most important precursor of the Positive and Negative Symptom Rating Scale.