Single-subject classification of schizophrenia using event-related potentials obtained during auditory and visual oddball paradigms.

In the search for the biomarkers of schizophrenia, event-related potential (ERP) deficits obtained by applying the classic oddball paradigm are among the most consistent findings. However, the single-subject classification rate based on these parameters remains to be determined. Here, we present a data-driven approach by applying machine learning classifiers to relevant oddball ERPs. Twenty-four schizophrenic patients and 24 matched healthy controls finished auditory and visual oddball tasks while high-density electrophysiological recordings were applied. The N1 component in response to standards and target as well as the P3 component following targets were submitted to different machine learning algorithms and the resulting ERP features were submitted to further correlation analyses. We obtained a classification accuracy of 72.4 % using only two ERP components. Latencies of parietal N1 components to visual standard stimuli at electrode positions Pz and P1 were sufficient for classification. Further analysis revealed a high correlation of these features in controls and an intermediate correlation in schizophrenia patients. These data exemplarily show how automated inference may be applied to classify a pathological state in single subjects without prior knowledge of their diagnoses and illustrate the potential of machine learning algorithms for the identification of potential biomarkers. Moreover, this approach assesses the discriminative accuracy of one of the most consistent findings in schizophrenia research by means of single-subject classification.

A Randomized, Placebo-Controlled Laboratory Classroom Study of the Efficacy and Safety of Dasotraline in Children With ADHD.

OBJECTIVE: To evaluate the efficacy of dasotraline 2 mg/day for treatment of ADHD in children weighing ≤30 kg. METHOD: Children (ages 6-12) with ADHD were randomized to 14 days of once-daily evening doses of dasotraline 2 mg (n = 47) or placebo (n = 48). Efficacy was assessed at Baseline and day-15 in seven, 30-minutes classroom sessions on each day (8:00 a.m. to 8:00 p.m.; 12-24 hours post-dose). The primary endpoint was change from Baseline at Day-15 in the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) combined score averaged over the seven, serial timepoints. RESULTS: Treatment with dasotraline was associated with significant improvement versus placebo in the primary SKAMP-combined score (least squares mean [SE] change from Baseline at Day-15: -3.67 [0.775] vs. +1.57 [0.773]; p < .001; effect size, 1.04). CONCLUSION: Dasotraline 2 mg/day was found to be efficacious and generally well tolerated in this placebo-controlled, laboratory classroom study of children ages 6 to 12 years with ADHD. CLINICALTRIALS.GOV IDENTIFIER: NCT03231800.

Cerium Oxide Nanoparticles Improve Outcome after In Vitro and In Vivo Mild Traumatic Brain Injury.

Mild traumatic brain injury results in aberrant free radical generation, which is associated with oxidative stress, secondary injury signaling cascades, mitochondrial dysfunction, and poor functional outcome. Pharmacological targeting of free radicals with antioxidants has been examined as an approach to treatment, but has met with limited success in clinical trials. Conventional antioxidants that are currently available scavenge a single free radical before they are destroyed in the process. Here, we report for the first time that a novel regenerative cerium oxide nanoparticle antioxidant reduces neuronal death and calcium dysregulation after in vitro trauma. Further, using an in vivo model of mild lateral fluid percussion brain injury in the rat, we report that cerium oxide nanoparticles also preserve endogenous antioxidant systems, decrease macromolecular free radical damage, and improve cognitive function. Taken together, our results demonstrate that cerium oxide nanoparticles are a novel nanopharmaceutical with potential for mitigating neuropathological effects of mild traumatic brain injury and modifying the course of recovery.

Comparative utility of aripiprazole and haloperidol in schizophrenia: post hoc analysis of two 52-week, randomized, controlled trials.

BACKGROUND: Since their introduction, second-generation antipsychotics (SGAs) have become the drugs of choice for the treatment of schizophrenia. However, recent findings have questioned the benefits of SGAs over first-generation antipsychotics (FGAs). OBJECTIVE: This post hoc analysis sought to compare the utility of the SGA aripiprazole with the FGA haloperidol in patients with early-phase schizophrenia (ES) or chronic schizophrenia (CS). METHOD: Data were pooled from two identical 52-week, randomized, active comparator trials (31-98-217 and 31-98-304) of aripiprazole 20-30 mg/day versus haloperidol 7-10 mg/day. Patients in the efficacy sample were classified as having ES if they were

Biliary hyperkinesia, a new diagnosis or misunderstood pathophysiology of dyskinesia: A case report.

INTRODUCTION: Biliary colic, characterized by intermittent right upper quadrant abdominal pain is a common complaint in the United States population. Patients whose pain is undiagnosed by ultrasound generally undergo hepatobiliary iminodiacetic acid scan with cholecystokinin stimulation (HIDA-CCK) to assess function of the gallbladder and biliary tree. Traditionally, two outcomes are possible based on a measured ejection fraction of the gallbladder: either dyskinesia or normal function is diagnosed. Biliary dyskinesia, or hypokinesia of the gallbladder, is accepted as an ejection fraction less than 35%, while an accepted normal functioning gallbladder ejection fraction is greater than 35%. CASE: We report a case of a fifteen-year-old female who had functional gallbladder disease per Rome IV criteria due to intermittent biliary colic, with exception to the ejection fraction measurement which was elevated at 96.5%. She underwent laparoscopic cholecystectomy with complete symptom resolution. DISCUSSION: As demonstrated in the literature reviewed here, these subsets of patients, who present with normal to high ejection fractions, have undergone laparoscopic cholecystectomy with resolution of pain in several case studies. CONCLUSION: Many unknown variables still exist due to lack of prospective studies, most notably the pathophysiology and definitive indications for surgical treatment. As such, we propose that surgical options should not be limited to those who display the traditional findings of biliary dyskinesia, but also patients who demonstrate typical symptoms with normal to elevated ejection fraction, following work up to rule out the extensive differential diagnoses for right upper quadrant abdominal pain.

DTNBP1 genotype influences cognitive decline in schizophrenia.

OBJECTIVE: Intellectual decline is common in schizophrenia and predicts functional outcome. While many patients undergo intellectual decline that typically predates the onset of symptoms, few studies have investigated the underlying mechanism through which this occurs. The current study assessed the relationship between intellectual decline in schizophrenia and genetic variation in dysbindin-1 (DTNBP1). METHODS: We assessed cognitive decline in 183 Caucasian patients with schizophrenia using a proxy measure of premorbid IQ with which current general cognitive ability (g) was compared. We then tested for a relationship between the risk haplotype identified in previous work (CTCTAC) and intellectual decline. RESULTS: We found that carriers of the CTCTAC haplotype, demonstrated a significantly greater decline in IQ as compared with non-carriers (p=0.05). CONCLUSIONS: These data suggest that DTNBP1 influences the severity of intellectual decline in schizophrenia and may represent one underlying cause for heterogeneity in cognitive course.

Electrophysiological indices of automatic and controlled auditory information processing in first-episode, recent-onset and chronic schizophrenia.

BACKGROUND: Deficits in amplitudes of auditory event-related potentials (ERP) indexing preattentive, automatic (mismatch negativity, MMN) and controlled, attention-dependent (N2, P3) auditory information processing have been well described in chronic schizophrenia. Normal MMN, but deficient N2 and P3 have been reported in first-episode patients. No study has investigated these ERPs concurrently in first-episode patients; thus, reported differences in MMN, N2 and P3 generation may reflect differences in patient samples rather than genuine differences in abnormal generation of these ERPs. METHODS: We recorded MMN, N2 and P3 in 26 first-episode patients, 25 recent-onset patients within 1.5 to 5 years after first admission, 25 chronic patients and 39 healthy controls. RESULTS: Recent-onset and chronic, but not first-episode patients showed reduced MMN. However, among first-episode patients those with low premorbid educational achievement demonstrated significantly reduced MMN. All patient groups showed pronounced N2 deficits and, to a variable extent, abnormalities in P3 generation. CONCLUSIONS: Abnormalities in N2 and P3 generation appear to reflect premorbid neuropathology, whereas MMN deficits may index both ongoing disease processes associated with illness progression as well as premorbid neurocognitive impairment. ERPs may provide tools to assess static and progressive neuropathology in schizophrenia. These findings need confirmation in longitudinal studies.

Ziprasidone-induced cognitive enhancement in schizophrenia: specificity or pseudospecificity?

OBJECTIVE: Ziprasidone may improve cognition in schizophrenia; however, this could be related to clinical symptom improvement, reflecting "pseudospecificity". We tested the hypothesis that ziprasidone improves cognition in the absence of clinical improvement. METHODS: We conducted a 12-week, open-label study of ziprasidone in 10 schizophrenia patients who met non-response criteria (<20% reduction in BPRS scores over 12 weeks). We conducted comprehensive cognitive testing and assessed change from baseline to end of study. RESULTS: We detected significant improvement on three measures of episodic memory (p<0.01) in these clinically non-responsive patients. Trend-level improvements were noted on tests involving processing speed and executive function. CONCLUSIONS: These data suggest that ziprasidone has cognitive benefits unrelated to an influence on other disease parameters.

A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition.

OBJECTIVE: In the prefrontal cortex, the enzyme catechol O-methyltransferase (COMT) is critical in the metabolic degradation of dopamine, a neurotransmitter hypothesized to influence human cognitive function. The COMT gene contains a functional polymorphism, Val158Met, that exerts a fourfold effect on enzyme activity. The current study investigated whether prefrontal cognition varies with COMT genotype. METHOD: Val158Met was genotyped in 73 healthy volunteers. A task of prefrontal cognition, the Wisconsin Card Sorting Test, was also administered. RESULTS: Subjects with only the low-activity met allele made significantly fewer perseverative errors on the Wisconsin Card Sorting Test than did subjects with the val allele. CONCLUSIONS: These data are consistent with those of previous studies, suggesting that a functional genetic polymorphism may influence prefrontal cognition.

No evidence for phenotypic variation between probands in case-control versus family-based association studies of schizophrenia.

Traditional case-control genetic association studies utilizing unrelated probands are often used interchangeably with family-based designs to detect genes for complex psychiatric disorders. This strategy may be limited, however, if significant phenotypic variation exists between probands enrolled in these two types of studies. The present study compared 37 probands enrolled in a case-control study of schizophrenia with 37 age-, sex-, and ethnically matched probands enrolled in a family-based study of schizophrenia. Age of onset of illness was compared as well as performance on a battery of cognitive tests assessing attention, working memory, executive function, and verbal memory. Results revealed no significant differences in age of onset between the two groups or on any measure of cognitive performance. These data do not support reports of significant phenotypic variation between probands in case-control and family-based studies, and suggest that studies utilizing family-based approaches may be used to replicate reports of association made with case-control designs in schizophrenia.

Genetic factors and neurocognitive traits.

Genetic contributions to phenotypic variation in general intelligence have been studied extensively. Less research has been conducted on genetic contributions to specific cognitive abilities, such as attention, memory, working memory, language, and motor functions. However, the existing data indicate a significant role of genetic factors in these abilities. Stages of information processing, such as sensory gating, early sensory registration, and cognitive analysis, also show evidence of genetic contributions. Recent molecular studies have begun to identify candidate genes for specific cognitive functions. Future research, identifying endophenotypes based on cognitive profiles of neuropsychiatric disorders, may also assist in the detection of genes that increase susceptibility to major psychiatric disorders.

Use of augmentation agents for treating depression: analysis of a psychiatric electronic medical record data set.

OBJECTIVE: This study evaluated the relationship between patient characteristics and augmentation strategies for the treatment of major depressive disorder. METHODS: This retrospective, cross-sectional study used data from a psychiatric electronic medical record database for patients with depression without psychosis or psychotic features who initiated augmentation therapy between January 2001 and June 2011. Medical records were evaluated to identify factors predicting use of specific augmentation agents, and a multivariate logistic regression model was used to assess clinical and demographic predictors of augmentation strategy. RESULTS: Of 3,209 patients initiating augmentation therapy for depression, 75% received augmentation with an antidepressant combination and 11% received augmentation with second-generation antipsychotics. Baseline clinical severity (Clinical Global Impressions-Severity score) most strongly and consistently predicted augmentation with second-generation antipsychotics. CONCLUSIONS: Treatment of patients in specialty settings with depression was often augmented with an antidepressant combination, whereas those with severe depression had an increased likelihood of augmentation with second-generation antipsychotics.

Evidence for impaired visual prediction error in schizophrenia.

BACKGROUND: Mismatch negativity (MMN) is regarded a prediction error signal that is deficient in schizophrenia in the auditory modality. If, however, MMN reflects a general computational signal of the cortex, then MMN should be also deficient in the visual modality in schizophrenia patients. METHODS: Twenty-two schizophrenia patients and 24 matched healthy controls finished a visual oddball task while high-density electroencephalogram was recorded. Visual mismatch negativity was computed as a surrogate marker of prediction error. RESULTS: Visual MMN, as measured over posterior extra-striate cortical areas, was significantly reduced in schizophrenia at about 300 ms post stimulus. Standardized mean difference was -.98, corresponding to a large effect size. CONCLUSIONS: A posterior visual MMN deficit in schizophrenia is demonstrated for the first time. Our results tentatively suggest a supra-modal MMN deficit in schizophrenia and thus argue in favor of reduced prediction error estimation in schizophrenia.

Association between second-generation antipsychotic medication half-life and hospitalization in the community treatment of adult schizophrenia.

OBJECTIVE: To examine the effect of antipsychotic medication half-life on the risk of psychiatric hospital admission and emergency department (ED) visits among adults with schizophrenia. METHODS: Retrospective claims-based cohort study of adult Medicaid patients with schizophrenia who were prescribed second-generation antipsychotic monotherapy following hospital discharge between 1/1/04 and 12/31/06. Cox proportional hazards models were applied to compare adjusted hazards of mental disorder admission among patients treated with oral antipsychotics that have either a long [risperidone (t(1/2) = 20 h), olanzapine (t(1/2) = 30 h), aripiprazole (t(1/2) = 75 h)] (n = 1479) or short [quetiapine (t(1/2) = 6 h), ziprasidone (t(1/2) = 7 h)] (n = 837) half-life. Day-level models controlled for baseline background characteristics and antipsychotic adherence over time as measured by gaps in the prescription record. Similar analyses examined either hospitalization or ED visits as separate endpoints. RESULTS: A significantly lower rate of hospitalization/ED visits was evident for long (0.74/patient-year) vs short (1.06/patient-year) half-life antipsychotics (p < 0.001). The unadjusted rate of hospitalization alone was significantly lower for long (0.38/patient-year) vs short (0.52/patient-year) half-life antipsychotics (p = 0.005). Compared with short half-life antipsychotic drugs, the adjusted hazard ratio associated with long half-life medications was 0.77 (95% CI = 0.67-0.88) for combined hospitalization/ED visits and 0.80 (95% CI = 0.67-0.96) for hospitalization. The corresponding number needed to treat with long, rather than short, half-life medications to avoid one hospitalization was 16 patients for 1 year and to avoid one hospitalization or ED visit was 11 patients for 1 year. LIMITATIONS: This study demonstrated an association between antipsychotic medication half-life and hospitalization, not a causal link. Patients using long half-life medications had fewer comorbid mental health conditions and took fewer psychiatric medications at baseline. Other unmeasured differences may have existed between groups and may partially account for the findings. CONCLUSIONS: In schizophrenia management, longer-acting second-generation antipsychotics were associated with a lower risk of hospital admission/ED visits for mental disorders.

Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment.

The preferential dopamine D(3)-agonist pramipexole (4.25±0.38 mg/day) or placebo were added for up to 12 weeks to ongoing antipsychotic treatment for 24 adult patients with DSM-IV schizophrenia or schizoaffective disorder. Pramipexole was generally well-tolerated (82% trial-completion), and yielded greater decreases in PANSS-total scores (drug/placebo=2.1; p=0.04), with similar decreases in PANSS positive and negative scores and 6.7-fold greater reduction of serum prolactin concentrations compared to placebo. There were no differences in ratings of mood, cognition or extrapyramidal symptoms, all of which were low at intake.

Impact of cost-sharing on treatment augmentation in patients with depression.

OBJECTIVES: Many patients with depression do not respond to first-line antidepressant therapy and may require augmentation with another concurrent treatment such as a second antidepressant, a stimulant, a mood stabilizer, or a second-generation antipsychotic (SGA). The objective of this study was to examine the relationship between patient cost-sharing and the use of augmentation among a sample of commercially insured patients. STUDY DESIGN: Retrospective observational study of adult patients diagnosed with depression and receiving antidepressant therapy (n = 48,807). METHODS: Logistic regression models estimated the likelihood of augmentation as a function of patient cost-sharing amounts. An alternative-specific conditional logit model of the likelihood of each augmentation class, varying the cost-sharing prices faced for each class, was also estimated. All models controlled for sociodemographic characteristics, physical and mental comorbidities, health plan type, and year of index antidepressant therapy initiation. RESULTS: The range of mean copayments paid by patients for augmentation therapy was from $27.05 (antidepressant) to $38.81 (SGA). A $10- higher cost-sharing index for all augmentation classes was associated with lower odds of augmentation (adjusted odds ratio = 0.85; 95% confidence interval 0.79-0.91). Doubling the costsharing amount for each augmentation class was associated with a smaller percentage of patients utilizing each class of augmentation therapy. CONCLUSIONS: Employers and payers should consider the relationship between cost-sharing and medication utilization patterns of patients with depression.

Comparison of second-generation antipsychotic treatment on psychiatric hospitalization in Medicaid beneficiaries with bipolar disorder.

OBJECTIVE: To compare second-generation antipsychotics on time to and cost of psychiatric hospitalization in Medicaid beneficiaries with bipolar disorder. METHODS: Retrospective study using healthcare claims from 10 US state Medicaid programs. Included beneficiaries were aged 18-64, initiated a single second-generation antipsychotic (aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone) between 1/1/2003-6/30/2008 (initiation date=index), and had a medical claim with an ICD-9-CM diagnosis code for bipolar disorder. A 360-day post-index period was used to measure time to and costs of psychiatric hospitalization (inpatient claims with a diagnosis code for a mental disorder [ICD-9-CM 290.xx-319.xx] in any position). Cox proportional hazards models and Generalized Linear Models compared time to and costs of psychiatric hospitalization, respectively, in beneficiaries initiating aripiprazole vs each other second-generation antipsychotic, adjusting for beneficiaries' baseline characteristics. RESULTS: Included beneficiary characteristics: mean age 36 years, 77% female, 80% Caucasian, aripiprazole (n=2553), mean time to psychiatric hospitalization or censoring=85 days; olanzapine (n=4702), 81 days; quetiapine (n=9327), 97 days; risperidone (n=4377), 85 days; ziprasidone (n=1520), 82 days. After adjusting for baseline characteristics, time to psychiatric hospitalization in beneficiaries initiating aripiprazole was longer compared to olanzapine (hazard ratio [HR]=1.52, p<0.001), quetiapine (HR=1.40, p<0.001), ziprasidone (HR=1.33, p=0.032), and risperidone, although the latter difference did not reach significance (HR=1.18, p=0.13). The adjusted costs of psychiatric hospitalization in beneficiaries initiating aripiprazole were significantly lower compared to those initiating quetiapine (incremental per-patient per-month difference=$42, 95% CI=$16-66, p<0.05), but not significantly lower for the other comparisons. LIMITATIONS: This study was based on a non-probability convenience sample of the Medicaid population. Analyses of administrative claims data are subject to coding and classification error. CONCLUSIONS: Medicaid beneficiaries with bipolar disorder initiating aripiprazole had significantly longer time to psychiatric hospitalization than those initiating olanzapine, quetiapine, or ziprasidone, and significantly lower adjusted costs for psychiatric hospitalization than those initiating quetiapine.

Correlates of medication adherence among patients with bipolar disorder: results of the bipolar evaluation of satisfaction and tolerability (BEST) study: a nationwide cross-sectional survey.

OBJECTIVE: To identify and describe correlates of medication adherence in a large, national sample of outpatients with bipolar disorder. METHOD: Data were collected via a self-report, Web-based survey in January and February of 2008 from US patients aged 18-65 years who reported a diagnosis of bipolar disorder and current use of psychotropic medication. Patients with a Composite International Diagnostic Interview-bipolar disorder (CIDI-bipolar disorder) score ≥ 7, indicating a high risk of bipolar disorder, were included in the analyses. Medication adherence was assessed via the Morisky Medication Adherence Scale, with scores ≥ 2 being considered nonadherent. The primary analysis was a multivariate binomial logistic regression with adherence as the dependent variable. Covariates included patient demographics, physical health measures including Medical Outcomes Study 8-item Short-Form Health Survey physical summary score, number of manic and depressive episodes, 24-item Behavior and Symptom Identification Scale (BASIS-24), Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS), Satisfaction With Antipsychotic Medication scale (SWAM), and current psychiatric medication use. RESULTS: Nearly half (49.5%) of the 1,052 bipolar patients in the analysis were classified as being nonadherent. Adherence was positively associated with college degree, higher SWAM total score, and monotherapy treatment. Adherence was negatively associated with female sex, alcohol use, BASIS-24 total score, and LUNSERS total score. CONCLUSIONS: Nonadherence is common among patients with bipolar disorder. By addressing tolerability issues and treatment satisfaction, which are both significant correlates of adherence, health care providers may be able to improve adherence and, ultimately, treatment outcomes.

Adherence and outcomes associated with copayment burden in schizophrenia: a cross-sectional survey.

OBJECTIVE: Assess the association of schizophrenia patients' perceived copayment burden with medication adherence and outcomes. METHODS: Patients with schizophrenia (aged 18+) completed self-reported questionnaires. Analyses included those currently using a second-generation antipsychotic (SGA) with no exposure to clozapine or depot formulation antipsychotics. Adherence was assessed using the Morisky Medication Adherence Scale (MMAS). Outcomes included emergency room (ER) use, hospitalization, attempted suicide, missed work due to health, and experiencing severe psychological distress. Logistic regression was used to adjust for demographics, health characteristics, psychotropic medication use, and insurance status. RESULTS: Of 351 schizophrenia patients, 39% perceived copayment burden. These patients were less than half as likely to have complete adherence [OR = 0.427; 95% CI:0.257, 0.711; p = 0.001] Copayment burden was associated with greater likelihood of ER use, [OR = 2.157; 95% CI:(1.322, 3.520); p = 0.002], hospitalization [OR = 2.512; 95% CI: (1.475, 4.277); p < 0.001], attempted suicide[OR = 2.385; 95% CI: (1.156, 4.920); p = 0.019], severe psychological distress [OR = 1.833; 95% CI:1.092, 3.075; p = 0.022] and greater likelihood of missing work [OR = 7.193; 95% CI: 2.554, 20.256; p < 0.001]. CONCLUSIONS: Copayment burden is associated with poorer medication adherence and outcomes. Formularies that reduce copayment burden for SGAs may positively affect medication adherence and outcomes among schizophrenia patients. LIMITATIONS: Patient data were self-reported, which may have introduced additional bias in the study measures. Also, the use of a cross-sectional design precludes causal inference and the use of the current sampling methodology (both interview and Internet panel) might impact the ability to generalize the results to the broader population.

Acute dopamine depletion with branched chain amino acids decreases auditory top-down event-related potentials in healthy subjects.

Cerebral dopamine homeostasis has been implicated in a wide range of cognitive processes and is of great pathophysiological importance in schizophrenia. A novel approach to study cognitive effects of dopamine is to deplete its cerebral levels with branched chain amino acids (BCAAs) that acutely lower dopamine precursor amino acid availability. Here, we studied the effects of acute dopamine depletion on early and late attentive cortical processing. Auditory event-related potential (ERP) components N2 and P3 were investigated using high-density electroencephalography in 22 healthy male subjects after receiving BCAAs or placebo in a randomized, double-blind, placebo-controlled crossover design. Total free serum prolactin was also determined as a surrogate marker of cerebral dopamine depletion. Acute dopamine depletion increased free plasma prolactin and significantly reduced prefrontal ERP components N2 and P3. Subcomponent analysis of N2 revealed a significant attenuation of early attentive N2b over prefrontal scalp sites. As a proof of concept, these results strongly suggest that BCAAs are acting on basic information processing. Dopaminergic neurotransmission seems to be involved in auditory top-down processing as indexed by prefrontal N2 and P3 reductions during dopamine depletion. In healthy subjects, intact early cortical top-down processing can be acutely dysregulated by ingestion of BCAAs. We discuss the potential impact of these findings on schizophrenia research.