Objective:Pharmacogenomic studies of antipsychotics have typically examined effects of individual polymorphisms. By contrast, polygenic risk scores (PRSs) derived from genome-wide association studies ...(GWAS) can quantify the influence of thousands of common alleles of small effect in a single measure. The authors examined whether PRSs for schizophrenia were predictive of antipsychotic efficacy in four independent cohorts of patients with first-episode psychosis (total N=510).Method:All study subjects received initial treatment with antipsychotic medication for first-episode psychosis, and all were genotyped on standard single-nucleotide polymorphism (SNP) arrays imputed to the 1000 Genomes Project reference panel. PRS was computed based on the results of the large-scale schizophrenia GWAS reported by the Psychiatric Genomics Consortium. Symptoms were measured by using total symptom rating scales at baseline and at week 12 or at the last follow-up visit before dropout.Results:In the discovery cohort, higher PRS significantly predicted higher symptom scores at the 12-week follow-up (controlling for baseline symptoms, sex, age, and ethnicity). The PRS threshold set at a p value <0.01 gave the strongest result in the discovery cohort and was used to replicate the findings in the other three cohorts. Higher PRS significantly predicted greater posttreatment symptoms in the combined replication analysis and was individually significant in two of the three replication cohorts. Across the four cohorts, PRS was significantly predictive of adjusted 12-week symptom scores (pooled partial r=0.18; 3.24% of variance explained). Patients with low PRS were more likely to be treatment responders than patients with high PRS (odds ratio=1.91 in the two Caucasian samples).Conclusions:Patients with higher PRS for schizophrenia tended to have less improvement with antipsychotic drug treatment. PRS burden may have potential utility as a prognostic biomarker.
IMPORTANCE: Previous evidence has implicated corticostriatal abnormalities in the pathophysiology of psychosis. Although the striatum is the primary target of all efficacious antipsychotics, the ...relationship between its functional connectivity and symptomatic reduction remains unknown. OBJECTIVE: To explore the longitudinal effect of treatment with second-generation antipsychotics on functional connectivity of the striatum during the resting state in patients experiencing a first episode of psychosis. DESIGN, SETTING, AND PARTICIPANTS: This prospective controlled study took place at a clinical research center and included 24 patients with first-episode psychosis and 24 healthy participants matched for age, sex, education, and handedness. Medications were administered in a double-blind randomized manner. INTERVENTIONS: Patients were scanned at baseline and after 12 weeks of treatment with either risperidone or aripiprazole. Their symptoms were evaluated with the Brief Psychiatric Rating Scale at baseline and follow-up. Healthy participants were scanned twice within a 12-week interval. MAIN OUTCOMES AND MEASURES: Functional connectivity of striatal regions was examined via functional magnetic resonance imaging using a seed-based approach. Changes in functional connectivity of these seeds were compared with reductions in ratings of psychotic symptoms. RESULTS: Patients had a median exposure of 1 day to antipsychotic medication prior to being scanned (mean SD = 4.5 6.1). Eleven patients were treated with aripiprazole and 13 patients were treated with risperidone.As psychosis improved, we observed an increase in functional connectivity between striatal seed regions and the anterior cingulate, dorsolateral prefrontal cortex, and limbic regions such as the hippocampus and anterior insula (P < .05, corrected for multiple comparisons). Conversely, a negative relationship was observed between reduction in psychosis and functional connectivity of striatal regions with structures within the parietal lobe (P < .05, corrected for multiple comparisons). CONCLUSIONS AND RELEVANCE: Our results indicated that corticostriatal functional dysconnectivity in psychosis is a state-dependent phenomenon. Increased functional connectivity of the striatum with prefrontal and limbic regions may be a biomarker for improvement in symptoms associated with antipsychotic treatment.
Diffusion tensor imaging (DTI) is used extensively in neuroscience to noninvasively estimate white matter (WM) microarchitecture. However, the diffusion signal is inherently ambiguous because it ...infers WM structure from the orientation of water diffusion and cannot identify the biological sources of diffusion changes. To compare inferred WM estimates to directly labeled axonal elements, we performed a novel within-subjects combination of high-resolution ex vivo DTI with two-photon laser microscopy of intact mouse brains rendered optically transparent by Clear Lipid-exchanged, Anatomically Rigid, Imaging/immunostaining compatible, Tissue hYdrogel (CLARITY). We found that myelin basic protein (MBP) immunofluorescence significantly correlated with fractional anisotropy (FA), especially in WM regions with coherent fiber orientations and low fiber dispersion. Our results provide evidence that FA is particularly sensitive to myelination in WM regions with these characteristics. Furthermore, we found that radial diffusivity (RD) was only sensitive to myelination in a subset of WM tracts, suggesting that the association of RD with myelin should be used cautiously. This combined DTI-CLARITY approach illustrates, for the first time, a framework for using brain-wide immunolabeling of WM targets to elucidate the relationship between the diffusion signal and its biological underpinnings. This study also demonstrates the feasibility of a within-subject combination of noninvasive neuroimaging and tissue clearing techniques that has broader implications for neuroscience research.
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Poly (ethylene glycol) methyl ether-block-poly (Ɛ-caprolactone) copolymers are useful biomedical materials owing to their amphiphilic nature, biodegradability, biocompatibility and also due to their ...semi-crystalline form having a low glass transition temperature. Due to their slow drug release profile, PEG-PCL copolymers are excellent candidates for sustained delivery applications over a period of time of more than a year. This unique property has provoked their relevance specially in the area of anticancer drug delivery applications in the form of various nanoaggregates like microspheres, nanogels, nanospheres, polymersomes, micelles, etc. A large variety of anticancer drugs/bioactives have been encapsulated in PEG-PCL copolymers for developing effective anticancer drug delivery systems and also for producing controlled drug release profiles. In recent times, PEG-PCL copolymers based nanoparticles have shown tremendous advancements as anticancer drug delivery vehicles owing to their higher drug loading capacities of the hydrophobic drugs, enhanced bioavailability, keeping away from being overpowered by way of phagocytes, decreased blasted discharge, and also in increasing the scattering time of drug within the blood stream during their systemic inoculation. These nano-formulated drug delivery systems can be used for the delivery of anticancer drugs at a specific site in a targeted approach. The developed nano-formulations possess promising potential in the treatment of cancer with improved anticancer efficacy and reduced toxicity invivo. In the current review, our main focus is to highlight the development and synthesis of different types of PEG-PCL copolymers (both conventional and greener approaches) along with the physico-chemical characterization techniques used primarily for the PEG-PCL co-polymeric systems. We have also summarized the uses of PEG-PCL co-polymeric nano formulations with various anticancer drugs as drug delivery platforms in the area of anticancer chemotherapy.
In the current review we highlight the development and synthesis of PEG-PCL copolymers along with the physico-chemical characterization techniques used primarily for their characterization. Also, we showed nanoformulations of PEG-PCl copolymeric systems with anticancer drugs for anticancer applications. Display omitted
•Development and synthesis of different types of PEG-PCL copolymers (both conventional and greener approaches).•The physico-chemical characterization techniques used primarily for the PEG-PCL co-polymeric systems.•The preparation and characterization of PEG-PCL nanoparticles through diverse methods.•PEG-PCL co-polymeric nano formulations with various anticancer drugs as drug delivery platforms.
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Objective:Up to 70% of patients with treatment-resistant schizophrenia do not respond to clozapine. Pharmacological augmentation to clozapine has been studied with unimpressive results. The authors ...examined the use of ECT as an augmentation to clozapine for treatment-refractory schizophrenia.Method:In a randomized single-blind 8-week study, patients with clozapine-resistant schizophrenia were assigned to treatment as usual (clozapine group) or a course of bilateral ECT plus clozapine (ECT plus clozapine group). Nonresponders from the clozapine group received an 8-week open trial of ECT (crossover phase). ECT was performed three times per week for the first 4 weeks and twice weekly for the last 4 weeks. Clozapine dosages remained constant. Response was defined as ≥40% reduction in symptoms based on the psychotic symptom subscale of the Brief Psychiatric Rating Scale, a Clinical Global Impressions (CGI)-severity rating <3, and a CGI-improvement rating ≤2.Results:The intent-to-treat sample included 39 participants (ECT plus clozapine group, N=20; clozapine group, N=19). All 19 patients from the clozapine group received ECT in the crossover phase. Fifty percent of the ECT plus clozapine patients met the response criterion. None of the patients in the clozapine group met the criterion. In the crossover phase, response was 47%. There were no discernible differences between groups on global cognition. Two patients required the postponement of an ECT session because of mild confusion.Conclusions:The augmentation of clozapine with ECT is a safe and effective treatment option. Further research is required to determine the persistence of the improvement and the potential need for maintenance treatments.
The Mental Health Centers for Intervention Development and Applied Research (CIDAR) program prioritized research to provide an evidence base for biomarker development. At the Zucker Hillside Hospital ...(ZHH), our CIDAR grant supported research on a comprehensive investigation of treatment response and outcome in first episode schizophrenia. Results provide evidence that baseline neuroimaging, neurocognitive, and genetic measures are significantly associated with clinical response to treatment, and that our currently available interventions can effectively treat aspects of psychotic illness, as well as potentially reduce comorbidity associated with illness. Future research may include combining modalities to more robustly predict response and identify treatment targets, as well as to further develop more effective intervention strategies for these devastating and disabling disorders.
Antipsychotic drugs and obesity Correll, Christoph U; Lencz, Todd; Malhotra, Anil K
Trends in molecular medicine,
02/2011, Volume:
17, Issue:
2
Journal Article
Peer reviewed
Open access
Mechanisms underlying antipsychotic cardiometabolic adverse effects are incompletely understood. This hampers the identification of high-risk patients, low-risk antipsychotics and ...preventive/ameliorative treatments. Recent clinical, molecular and genetic data suggest that: (i) antipsychotic-naïve samples provide the greatest power for mechanistic studies; (ii) weight and metabolic effects can be discordant, pointing to overlapping and distinct mechanisms; (iii) antipsychotics affect satiety and energy homeostasis signaling; (iv) the specific peptides mediating these effects are unknown but probably overlap with those involved in idiopathic obesity; and (v) single nucleotide polymorphisms in genes encoding known neurotransmitter receptors and metabolic proteins are promising pharmacogenomic targets for countering adverse affects. However, sophisticated molecular studies and genome-wide association studies, ideally in antipsychotic-naïve/first episode samples, are needed to further advance the field.
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CONTEXT Cardiometabolic effects of second-generation antipsychotic medications are concerning but have not been sufficiently studied in pediatric and adolescent patients naive to antipsychotic ...medication. OBJECTIVE To study the association of second-generation antipsychotic medications with body composition and metabolic parameters in patients without prior antipsychotic medication exposure. DESIGN, SETTING, AND PATIENTS Nonrandomized Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) cohort study, conducted between December 2001 and September 2007 at semi-urban, tertiary care, academic inpatient and outpatient clinics in Queens, New York, with a catchment area of 4.5-million individuals. Of 505 youth aged 4 to 19 years with 1 week or less of antipsychotic medication exposure, 338 were enrolled (66.9%). Of these patients, 272 had at least 1 postbaseline assessment (80.5%), and 205 patients who completed the study (60.7%). Patients had mood spectrum (n = 130; 47.8%), schizophrenia spectrum (n = 82; 30.1%), and disruptive or aggressive behavior spectrum (n = 60; 22.1%) disorders. Fifteen patients who refused participation or were nonadherent served as a comparison group. INTERVENTION Treatment with aripiprazole, olanzapine, quetiapine, or risperidone for 12 weeks. MAIN OUTCOME MEASURES Weight gain and changes in lipid and metabolic parameters. RESULTS After a median of 10.8 weeks (interquartile range, 10.5-11.2 weeks) of treatment, weight increased by 8.5 kg (95% confidence interval CI, 7.4 to 9.7 kg) with olanzapine (n = 45), by 6.1 kg (95% CI, 4.9 to 7.2 kg) with quetiapine (n = 36), by 5.3 kg (95% CI, 4.8 to 5.9 kg) with risperidone (n = 135), and by 4.4 kg (95% CI, 3.7 to 5.2 kg) with aripiprazole (n = 41) compared with the minimal weight change of 0.2 kg (95% CI, −1.0 to 1.4 kg) in the untreated comparison group (n = 15). With olanzapine and quetiapine, respectively, mean levels increased significantly for total cholesterol (15.6 mg/dL 95% CI, 6.9 to 24.3 mg/dL P < .001 and 9.1 mg/dL 95% CI, 0.4 to 17.7 mg/dL P = .046), triglycerides (24.3 mg/dL 95% CI, 9.8 to 38.9 mg/dL P = .002 and 37.0 mg/dL 95% CI, 10.1 to 63.8 mg/dL P = .01), non–high-density lipoprotein (HDL) cholesterol (16.8 mg/dL 95% CI, 9.3 to 24.3 mg/dL P < .001 and 9.9 mg/dL 95% CI, 1.4 to 18.4 mg/dL P = .03), and ratio of triglycerides to HDL cholesterol (0.6 95% CI, 0.2 to 0.9 P = .002 and (1.2 95% CI, 0.4 to 2.0 P = .004). With risperidone, triglycerides increased significantly (mean level, 9.7 mg/dL 95% CI, 0.5 to 19.0 mg/dL; P = .04). Metabolic baseline-to-end-point changes were not significant with aripiprazole or in the untreated comparison group. CONCLUSIONS First-time second-generation antipsychotic medication use was associated with significant weight gain with each medication. Metabolic changes varied among the 4 antipsychotic medications.
Abstract Recent data suggests that a history of childhood maltreatment is associated with reductions in hippocampal volume in healthy adults. Because this association is also evident in adults with ...psychiatric illness, it has been suggested that reductions in hippocampal volume associated with childhood maltreatment may be a risk factor for psychiatric illness. Such an interpretation suggests that healthy adults with a history of childhood maltreatment are more resilient to the effects of maltreatment. Current models of resilience suggest, however, that resiliency should be measured across multiple domains of functioning. The present study sought to investigate childhood maltreatment in relationship to hippocampal volumes in healthy adults and to address the question of whether the putative resiliency extends to other domains of functioning. Sixty-seven healthy Caucasian adults were assessed for a history of childhood emotional abuse, emotional neglect and physical abuse and received high resolution structural MR imaging scans. Participants with and without histories of abuse or neglect were compared on measures of total hippocampal volume, general cognitive ability and subclinical psychopathology. Our results suggest that childhood emotional abuse is associated with reduced hippocampus volume in males, but not in females. However, emotional abuse was associated with higher levels of subclinical psychopathology in both males and females. These data suggest that while females may be more resilient to the neurological effects of childhood maltreatment, they are not more resilient to the psychiatric symptoms associated with childhood maltreatment. Further research is needed to elucidate the mechanisms involved in these different levels of resilience.
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