Long-acting injectable versus daily oral antipsychotic treatment trials in schizophrenia: pragmatic versus explanatory study designs

Trial design characteristics related to the explanatory:pragmatic spectrum may contribute toward the inconsistent results reported in studies comparing long-acting injectable (LAI) versus daily oral antipsychotic (AP) treatments in schizophrenia. A novel approach examined the hypothesis that a more pragmatic design is important to show the advantages of LAI versus oral APs. A literature search identified comparative studies assessing the clinical efficacy/effectiveness of LAI versus oral APs in more than 100 schizophrenia patients, with 6-month or more duration/follow-up, and published between January 1993 and December 2013 (n=11). Each study\u27s design was rated using the six-domain ASPECT-R (A Study Pragmatic:Explanatory Characterization Tool-Rating). Nonparametric Wilcoxon rank-sum tests compared ratings of studies supporting (n=7) and not supporting (n=4) a LAI advantage. ASPECT-R total and domain scores were significantly higher (more pragmatic) in studies finding a LAI versus oral AP treatment advantage than those that did not. The rank order of this significance among domains was as follows: participant compliance assessment\u27 (P=0.005), medical practice setting/practitioner expertise\u27 (P=0.006), intervention flexibility\u27 (P=0.007), follow-up intensity/duration\u27 (P=0.009), primary trial outcomes\u27 (P=0.012), and participant eligibility\u27 (P=0.015). Findings support that more pragmatic, less explanatory design features are important to show advantages for LAI treatment. Explanatory studies may introduce features that obscure advantages related to adherence

Trends in Availability and Prices of Subsidized ACT over the First Year of the AMFm: Evidence from Remote Regions of Tanzania

Background: The Affordable Medicines Facility for malaria (AMFm) is a pilot supra-national subsidy program that aims to increase access and affordability of artemisinin combination therapy (ACT) in public sector clinics and private retail shops. It is unclear to what extent the AMFm model will translate into wide scale availability and price reductions in ACT, particularly for rural, remote areas where disparities in access to medicines often exist. This study is the first to rigorously examine the availability and price of subsidized ACT during the first year of the AMFm, measured through retail audits in remote regions of Tanzania. Methods: Periodic retail audits of Accredited Drug Dispensing Outlets (ADDOs) were conducted in two remote regions of Tanzania (Mtwara and Rukwa). Temporal and spatial variation in ACT availability and pricing were explored. A composite measure of ADDO remoteness, using variables, such as distance to suppliers and towns, altitude and population density, was used to explore whether ACT availability and price vary systematically with remoteness. Results: Between February 2011 and January 2012, the fraction of ADDOs stocking AMFm-ACT increased from 25% to 88% in Mtwara and from 3% to 62% in Rukwa. Availability was widespread, though diffusion throughout the region was achieved more quickly in Mtwara. No significant relationship was found between ACT availability and remoteness. Adult doses of AMFm-ACT were much more widely available than any other age/weight band. Average prices fell from 1529 TZS (1.03 USD) to 1272 TZS (0.81 USD) over the study period, with prices in Rukwa higher than Mtwara. The government recommended retail price for AMFm- ACT is 1,000 TZS ($0.64 USD). The median retail ACT price in the final round of data collection was 1,000 TZS. Conclusions: The AMFm led to large increases in availability of low priced ACT in Tanzania, with no significant variation in availability based on remoteness. Availability did remain lower and prices remained higher in Rukwa, which is a more remote region overall. Low availability of child and adolescent ACT doses could be due in part to lower quantities of non-adult packs imported into Tanzania. Future research will explore whether increased availability and affordability persists and whether it translates into higher ACT use in Tanzania

Trends in availability and prices of subsidized ACT over the first year of the AMFm: evidence from remote regions of Tanzania

Abstract Background The Affordable Medicines Facility for malaria (AMFm) is a pilot supra-national subsidy program that aims to increase access and affordability of artemisinin combination therapy (ACT) in public sector clinics and private retail shops. It is unclear to what extent the AMFm model will translate into wide scale availability and price reductions in ACT, particularly for rural, remote areas where disparities in access to medicines often exist. This study is the first to rigorously examine the availability and price of subsidized ACT during the first year of the AMFm, measured through retail audits in remote regions of Tanzania. Methods Periodic retail audits of Accredited Drug Dispensing Outlets (ADDOs) were conducted in two remote regions of Tanzania (Mtwara and Rukwa). Temporal and spatial variation in ACT availability and pricing were explored. A composite measure of ADDO remoteness, using variables, such as distance to suppliers and towns, altitude and population density, was used to explore whether ACT availability and price vary systematically with remoteness. Results Between February 2011 and January 2012, the fraction of ADDOs stocking AMFm-ACT increased from 25% to 88% in Mtwara and from 3% to 62% in Rukwa. Availability was widespread, though diffusion throughout the region was achieved more quickly in Mtwara. No significant relationship was found between ACT availability and remoteness. Adult doses of AMFm-ACT were much more widely available than any other age/weight band. Average prices fell from 1529 TZS (1.03 USD) to 1272 TZS (0.81 USD) over the study period, with prices in Rukwa higher than Mtwara. The government recommended retail price for AMFm- ACT is 1,000 TZS ($0.64 USD). The median retail ACT price in the final round of data collection was 1,000 TZS. Conclusions The AMFm led to large increases in availability of low priced ACT in Tanzania, with no significant variation in availability based on remoteness. Availability did remain lower and prices remained higher in Rukwa, which is a more remote region overall. Low availability of child and adolescent ACT doses could be due in part to lower quantities of non-adult packs imported into Tanzania. Future research will explore whether increased availability and affordability persists and whether it translates into higher ACT use in Tanzania.http://deepblue.lib.umich.edu/bitstream/2027.42/112716/1/12936_2012_Article_2494.pd

Do Price Subsidies on Artemisinin Combination Therapy for Malaria Increase Household Use?: Evidence from a Repeated Cross-Sectional Study in Remote Regions of Tanzania

Background: The Affordable Medicines Facility-malaria (AMFm) is a pilot program that uses price subsidies to increase access to Artemisinin Combination Therapies (ACTs), currently the most effective malaria treatment. Recent evidence suggests that availability and affordability of ACTs in retail sector drug shops (where many people treat malaria) has increased under the AMFm, but it is unclear whether household level ACT use has increased. Methods and Findings: Household surveys were conducted in two remote regions of Tanzania (Mtwara and Rukwa) in three waves: March 2011, December 2011 and March 2012, corresponding to 3, 13 and 16 months into the AMFm implementation respectively. Information about suspected malaria episodes including treatment location and medications taken was collected. Respondents were also asked about antimalarial preferences and perceptions about the availability of these medications. Significant increases in ACT use, preference and perceived availability were found between Rounds 1 and 3 though not for all measures between Rounds 1 and 2. ACT use among suspected malaria episodes was 51.1% in March 2011 and increased by 10.9 percentage points by Round 3 (p = .017). The greatest increase was among retail sector patients, where ACT use increased from 31% in Round 1 to 49% in Round 2 (p = .037) and to 61% (p<.0001) by Round 3. The fraction of suspected malaria episodes treated in the retail sector increased from 30.2% in Round 1 to 46.7% in Round 3 (p = .0009), mostly due to a decrease in patients who sought no treatment at all. No significant changes in public sector treatment seeking were found. Conclusions: The AMFm has led to significant increases in ACT use for suspected malaria, especially in the retail sector. No evidence is found supporting the concerns that the AMFm would crowd out public sector treatment or neglect patients in remote areas and from low SES groups

A Recurrent Network in the Lateral Amygdala: A Mechanism for Coincidence Detection

Synaptic changes at sensory inputs to the dorsal nucleus of the lateral amygdala (LAd) play a key role in the acquisition and storage of associative fear memory. However, neither the temporal nor spatial architecture of the LAd network response to sensory signals is understood. We developed a method for the elucidation of network behavior. Using this approach, temporally patterned polysynaptic recurrent network responses were found in LAd (intra-LA), both in vitro and in vivo, in response to activation of thalamic sensory afferents. Potentiation of thalamic afferents resulted in a depression of intra-LA synaptic activity, indicating a homeostatic response to changes in synaptic strength within the LAd network. Additionally, the latencies of thalamic afferent triggered recurrent network activity within the LAd overlap with known later occurring cortical afferent latencies. Thus, this recurrent network may facilitate temporal coincidence of sensory afferents within LAd during associative learning

What Is Causing the Reduced Drug-Placebo Difference in Recent Schizophrenia Clinical Trials and What Can be Done About It?

On September 18, 2007, a collaborative session between the International Society for CNS Clinical Trials and Methodology and the International Society for CNS Drug Development was held in Brussels, Belgium. Both groups, with membership from industry, academia, and governmental and nongovernmental agencies, have been formed to address scientific, clinical, regulatory, and methodological challenges in the development of central nervous system therapeutic agents. The focus of this joint session was the apparent diminution of drug-placebo differences in recent multicenter trials of antipsychotic medications for schizophrenia. To characterize the nature of the problem, some presenters reported data from several recent trials that indicated higher rates of placebo response and lower rates of drug response (even to previously established, comparator drugs), when compared with earlier trials. As a means to identify the possible causes of the problem, discussions covered a range of methodological factors such as participant characteristics, trial designs, site characteristics, clinical setting (inpatient vs outpatient), inclusion/exclusion criteria, and diagnostic specificity. Finally, possible solutions were discussed, such as improving precision of participant selection criteria, improving assessment instruments and/or assessment methodology to increase reliability of outcome measures, innovative methods to encourage greater subject adherence and investigator involvement, improved rater training and accountability metrics at clinical sites to increase quality assurance, and advanced methods of pharmacokinetic/pharmacodynamic modeling to optimize dosing prior to initiating large phase 3 trials. The session closed with a roundtable discussion and recommendations for data sharing to further explore potential causes and viable solutions to be applied in future trials

Acinic cell carcinoma in pregnancy: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>We report an observational study on the etiology and recurrence of acinic cell carcinoma of the parotid gland that seemed to be related to pregnancy. The medical literature has never reported such an association; therefore, our case report is probably the first to mention this observation.</p> <p>Case presentation</p> <p>This report is of a 25-year-old Arabic female patient from the United Arab Emirates, who, during her first pregnancy, developed acinic cell carcinoma of the right parotid gland that was managed with surgical excision in the form of superficial parotidectomy. During her second pregnancy, which occurred four years later, she had a recurrence of the same malignant neoplasm associated with ipsilateral malignant cervical lymphadenopathy. The patient was managed with total parotidectomy and neck dissection, as well as postoperative adjuvant radiotherapy. Our observation on this particular case of acinic cell carcinoma is that the initial onset of her neoplasm was during her first pregnancy, and the recurrence of the same malignant disease was during a subsequent pregnancy. This chronologic association raised our suspicion that there might be a possible etiologic effect of pregnancy or its associated hormonal or physiologic changes or both on the pathogenesis or etiology of acinic cell carcinoma.</p> <p>Conclusion</p> <p>Some association might exist between pregnancy and the pathogenesis or etiology of acinic cell carcinoma.</p

Adjunctive long-acting risperidone in patients with bipolar disorder who relapse frequently and have active mood symptoms

<p>Abstract</p> <p>Background</p> <p>The objective of this exploratory analysis was to characterize efficacy and onset of action of a 3-month treatment period with risperidone long-acting injection (RLAI), adjunctive to an individual's treatment regimen, in subjects with symptomatic bipolar disorder who relapsed frequently and had significant symptoms of mania and/or depression.</p> <p>Methods</p> <p>Subjects with bipolar disorder with ≥4 mood episodes in the past 12 months entered the open-label stabilization phase preceding a placebo-controlled, double-blind study. Subjects with significant depressive or manic/mixed symptoms at baseline were analyzed. Significant depressive symptoms were defined as Montgomery-Åsberg Depression Rating Scale (MADRS) ≥16 and Young Mania Rating Scale (YMRS) < 16; manic/mixed symptoms were YMRS ≥16 with any MADRS score. Subjects received open-label RLAI (25-50 mg every 2 weeks) for 16 weeks, adjunctive to a subject's individualized treatment for bipolar disorder (mood stabilizers, antidepressants, and/or anxiolytics). Clinical status was evaluated with the Clinical Global Impressions of Bipolar Disorder-Severity (CGI-BP-S) scale and changes on the MADRS and YMRS scales. Within-group changes were evaluated using paired <it>t </it>tests; categorical differences were assessed using Fisher exact test. No adjustment was made for multiplicity.</p> <p>Results</p> <p>162 subjects who relapsed frequently met criteria for significant mood symptoms at open-label baseline; 59/162 (36.4%) had depressive symptoms, 103/162 (63.6%) had manic/mixed symptoms. Most subjects (89.5%) were receiving ≥1 medication for bipolar disorder before enrollment. Significant improvements were observed for the total population on the CGI-BP-S, MADRS, and YMRS scales (p < .001 vs. baseline, all variables). Eighty-two (53.3%) subjects achieved remission at the week 16 LOCF end point. The subpopulation with depressive symptoms at open-label baseline experienced significant improvement on the CGI-BP-S and MADRS scales (p < .001 vs. baseline, all variables). Subjects with manic/mixed symptoms at baseline had significant improvements on the CGI-BP-S and YMRS scales (p < .001 vs. baseline, all variables). No unexpected tolerability findings were observed.</p> <p>Conclusions</p> <p>Exploratory analysis of changes in overall clinical status and depression/mania symptoms in subjects with symptomatic bipolar disorder who relapse frequently showed improvements in each of these areas after treatment with RLAI, adjunctive to a subject's individualized treatment. Prospective controlled studies are needed to confirm these findings.</p