Dopamine D2/3 occupancy of ziprasidone across a day : a within-subject PET study

Rationale Ziprasidone is an atypical antipsychotic recommended to be administered twice daily. Objectives The purpose of this study was to investigate whether occupancy of the dopamine D2/3 receptors by ziprasidone is maintained across a day employing a within subject design. Methods Positron emission tomography (PET) scans with [11C]-raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [11C]-raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum. Results Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and −6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans. Conclusions The absence of ziprasidone striatal D2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D2/3 receptor occupancy (i.e. 60 %).peer-reviewe

Time course of improvement with antipsychotic medication in treatment-resistant schizophrenia

Background Improvements are greatest in the earlier weeks of antipsychotic treatment of patients with non-resistant schizophrenia. Aims To address the early time-line for improvement with antipsychotics in treatment-resistant schizophrenia. Method Randomised double-blind trials of antipsychotic medication in adult patients with treatment-resistant schizophrenia were investigated (last search June 2010). A series of meta-regression analyses were carried out to examine the effect of time on the average item scores in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) at three or more distinct time points within the first 6 weeks of treatment. Results Study duration varied from 4 weeks to 1 year and the definitions of treatment resistance as well as of treatment response were not necessarily consistent across 19 identified studies, resulting in highly variable rates of response (0–76%). The mean standardised baseline item score in the PANSS or BPRS was 3.4 (s.e. = 0.06) in the five studies included in the meta-regression analysis, with the average baseline Clinical Global Impression – Severity score being 5.2 (marked illness). For the pooled population treated with a range of antipsychotics (n = 1019), significant reductions in the mean item scores occurred during the first 4 weeks; improvements observed in later weeks were smaller and non-significant. In contrast, weekly improvement with clozapine was significant throughout (n = 356). Conclusions Our findings provide preliminary evidence that the majority of improvement with antipsychotics may occur relatively early. More consistent improvements with clozapine may be associated with a gradual titration. To further elucidate response patterns, future studies are needed to provide data over regular intervals during earlier stages of treatment.peer-reviewe

Determinants of Social Distancing Adherence

Introduction: Governments and public health authorities across many jurisdictions implemented social (physical) distancing measures to contain the spread of the 2019 novel coronavirus disease (COVID-19). Adherence to these measures is variable and likely influenced by various factors. This study aimed to 1) identify the individual sociodemographic, COVID-19 and social distancing related, and psychological determinants of social distancing adherence, and 2) explore regional differences in social distancing adherence in the United States (U.S.) and English-speaking Canada based on each region\u27s discrepant response to social distancing restrictions. Methods: A web-based repeated cross-sectional survey was conducted in 4,942 English-speaking participants from the four most populous U.S. states, specifically New York, California, Texas, and Florida, and Canada (www.covid19-database.com). The study was conducted at two timepoints, from May 1 to 5, 2020 (n = 1,019, Canadian participants only) and from July 6 to 10, 2020 (n = 3,923). Separate univariate models were computed for individual sociodemographic, COVID-19 and social distancing related, and psychological determinants of social distancing adherence. To determine the total variance explained, a univariate analysis including all of the determinants was performed. Regional differences in social distancing were compared between the four U.S. states and Canada, and between the U.S. as a whole and Canada. Results: Adherence to social distancing was higher in May (mean = 4.4/5.0±0.7) compared to July (mean = 4.3/5.0±0.7) [t (4940) = 6.96, p \u3c 0.001], likely a reflection of relaxing restrictions. There were no regional differences in adherence. Sociodemographic, COVID-19 and social distancing related, and psychological determinants explained 10, 36, and 23% of the variance of social distancing adherence, respectively. Higher perceived seriousness of COVID-19 [β (SE) = 0.39 (0.01), p \u3c 0.001, partial η2 = 0.22], lower risk propensity [β (SE) = -0.15 (0.01), p \u3c 0.001, partial η2 = 0.06], germ aversion [β (SE) = 0.12 (0.01), p \u3c 0.001, partial η2 = 0.03], age [β (SE) = 0.01 (0.00), p \u3c 0.001, partial η2 = 0.02], and greater social support [β (SE) = 0.03 (0.00), p \u3c 0.001, partial η2 = 0.02] had the largest effects on social distancing adherence. Conclusion: Public service initiatives to emphasize the serious consequences of infection and targeted interventions toward certain sociodemographic groups, such as younger adults and vulnerable individuals in greater need of social support, may help enhance the public\u27s adherence to social distancing measures during subsequent waves of COVID-19 and future pandemics

Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with first-episode psychosis

The glutamatergic and dopaminergic systems are thought to be involved in the pathophysiology of schizophrenia. Their interaction has been widely documented and may have a role in the neurobiological basis of the disease. The aim of this study was to compare, using proton magnetic resonance spectroscopy (1H-MRS), glutamate levels in the precommissural dorsal-caudate (a dopamine-rich region) and the cerebellar cortex (negligible for dopamine) in the following: (1) 18 antipsychotic-naïve subjects with prodromal symptoms and considered to be at ultra high-risk for schizophrenia (UHR), (2) 18 antipsychotic-naïve first- episode psychosis patients (FEP), and (3) 40 age- and sex- matched healthy controls. All subjects underwent a 1H-MRS study using a 3Tesla scanner. Glutamate levels were quantified and corrected for the proportion of cerebrospinal fluid and percentage of gray matter in the voxel. The UHR and FEP groups showed higher levels of glutamate than controls, without differences between UHR and FEP. In the cerebellum, no differences were seen between the three groups. The higher glutamate level in the precommissural dorsal-caudate and not in the cerebellum of UHR and FEP suggests that a high glutamate level (a) precedes the onset of schizophrenia, and (b) is present in a dopamine-rich region previously implicated in the pathophysiology of schizophrenia.peer-reviewe

the effect of ethnicity and immigration on treatment resistance in schizophrenia

Background: Treatment resistance is a common issue among schizophrenia patients undergoing antipsychotic treatment. According to the American Psychiatric Association (APA) guidelines, treatment-resistant status is defined as little or no symptom reduction to at least two antipsychotics at a therapeutic dose for a trial of at least six weeks. The aim of the current study is to determine whether ethnicity and migration are associated with treatment resistance. Methods: In a sample of 251 participants with schizophrenia spectrum disorders, we conducted cross-sectional assessments to collect information regarding self-identified ethnicity, immigration and treatment history. Ancestry was identified using 292 markers overlapping with the HapMap project. Using a regression analysis, we tested whether a history of migration, ethnicity or genetic ancestry were predictive of treatment resistance. Results: Our logistic regression model revealed no significant association between immigration (OR = 0.04; 95%CI = 0.35–3.07; p = 0.93) and treatment resistant schizophrenia. White Europeans did not show significant association with resistance status regardless of whether ethnicity was determined by self-report (OR = 1.89; 95%CI = 0.89–4.20; p = 0.105) or genetic analysis (OR = −0.73; 95%CI = −0.18–2.97; p = 0.667). Conclusion: Neither ethnicity nor migrant status was significantly associated with treatment resistance in this Canadian study. However, these conclusions are limited by the small sample size of our investigation. Keywords: Schizophrenia, Treatment resistance, Antipsychotics, Ethnicity, Migratio

The Effect of Task-Irrelevant Fearful-Face Distractor on Working Memory Processing in Mild Cognitive Impairment versus Healthy Controls: An Exploratory fMRI Study in Female Participants

In mild cognitive impairment (MCI), a risk state for Alzheimer’s disease, patients have objective cognitive deficits with relatively preserved functioning. fMRI studies have identified anomalies during working memory (WM) processing in individuals with MCI. The effect of task-irrelevant emotional face distractor on WM processing in MCI remains unclear. We aim to explore the impact of fearful-face task-irrelevant distractor on WM processing in MCI using fMRI. Hypothesis. Compared to healthy controls (HC), MCI patients will show significantly higher BOLD signal in a priori identified regions of interest (ROIs) during a WM task with a task-irrelevant emotional face distractor. Methods. 9 right-handed female participants with MCI and 12 matched HC performed a WM task with standardized task-irrelevant fearful versus neutral face distractors randomized and counterbalanced across WM trials. MRI images were acquired during the WM task and BOLD signal was analyzed using statistical parametric mapping (SPM) to identify signal patterns during the task response phase. Results. Task-irrelevant fearful-face distractor resulted in higher activation in the amygdala, anterior cingulate, and frontal areas, in MCI participants compared to HC. Conclusions. This exploratory study suggests altered WM processing as a result of fearful-face distractor in MCI

Antipsychotics, Metabolic Adverse Effects, and Cognitive Function in Schizophrenia

Cognitive impairment is a core symptom domain of schizophrenia. The effect of antipsychotics, the cornerstone of treatment in schizophrenia, on this domain is not fully clear. There is some evidence suggesting that antipsychotics may partially improve cognitive function, and that this improvement may vary depending on the specific cognitive domain. However, this research is confounded by various factors, such as age, duration/stage of illness, medication adherence, and extrapyramidal side effects that complicate the relationship between antipsychotics and cognitive improvement. Furthermore, antipsychotics—particularly the second generation, or “atypical” antipsychotics—can induce serious metabolic side effects, such as obesity, dyslipidemia and type 2 diabetes, illnesses which themselves have been linked to impairments in cognition. Thus, the inter-relationships between cognition and metabolic side effects are complex, and this review aims to examine them in the context of schizophrenia and antipsychotic treatment. The review also speculates on potential mechanisms underlying cognitive functioning and metabolic risk in schizophrenia. We conclude that the available literature examining the inter-section of antipsychotics, cognition, and metabolic effects in schizophrenia is sparse, but suggests a relationship between metabolic comorbidity and worse cognitive function in patients with schizophrenia. Further research is required to determine if there is a causal connection between the well-recognized metabolic adverse effects of antipsychotics and cognitive deficits over the course of the illness of schizophrenia, as well as, to determine underlying mechanisms. In addition, findings from this review highlight the importance of monitoring metabolic disturbances in parallel with cognition, as well as, the importance of interventions to minimize metabolic abnormalities for both physical and cognitive health

Can we accurately classify schizophrenia patients from healthy controls using magnetic resonance imaging and machine learning?:A multi-method and multi-dataset study

Machine learning is a powerful tool that has previously been used to classify schizophrenia (SZ) patients from healthy controls (HC) using magnetic resonance images. Each study, however, uses different datasets, classification algorithms, and validation techniques. Here, we perform a critical appraisal of the accuracy of machine learning methodologies used in SZ/HC classifications studies by comparing three machine learning algorithms (logistic regression [LR], support vector machines [SVMs], and linear discriminant analysis [LDA]) on three independent datasets (435 subjects total) using two tissue density estimates and cortical thickness (CT). Performance is assessed using 10-fold cross-validation, as well as a held-out validation set. Classification using CT outperformed tissue densities, but there was no clear effect of dataset. LR, SVMs, and LDA each yielded the highest accuracies for a different feature set and validation paradigm, but most accuracies were between 55 and 70%, well below previously reported values. The highest accuracy achieved was 73.5% using CT data and an SVM. Taken together, these results illustrate some of the obstacles to constructing effective disease classifiers, and suggest that tissue densities and CT may not be sufficiently sensitive for SZ/HC classification given current available methodologies and sample sizes

Test-retest variability of high resolution positron emission tomography (PET) imaging of cortical serotonin (5HT2A) receptors in older, healthy adults

<p>Abstract</p> <p>Background</p> <p>Position emission tomography (PET) imaging using [¹⁸F]-setoperone to quantify cortical 5-HT_2Areceptors has the potential to inform pharmacological treatments for geriatric depression and dementia. Prior reports indicate a significant normal aging effect on serotonin 5HT_2Areceptor (5HT_2AR) binding potential. The purpose of this study was to assess the test-retest variability of [¹⁸F]-setoperone PET with a high resolution scanner (HRRT) for measuring 5HT_2AR availability in subjects greater than 60 years old. Methods: Six healthy subjects (age range = 65–78 years) completed two [¹⁸F]-setoperone PET scans on two separate occasions 5–16 weeks apart.</p> <p>Results</p> <p>The average difference in the binding potential (BP_ND) as measured on the two occasions in the frontal and temporal cortical regions ranged between 2 and 12%, with the lowest intraclass correlation coefficient in anterior cingulate regions.</p> <p>Conclusion</p> <p>We conclude that the test-retest variability of [¹⁸F]-setoperone PET in elderly subjects is comparable to that of [¹⁸F]-setoperone and other 5HT_2AR radiotracers in younger subject samples.</p