Verification of successful maintenance by serum drug level during a guided antipsychotic reduction to reach minimum effective dose (GARMED) trial.

BACKGROUND: Inconsistent results regarding the risk of relapse and better subjective outcomes of previous antipsychotic dose reduction trials in patients with remitted psychosis have not been verified using therapeutic drug monitoring (TDM). This study examined plasma drug concentrations of a dose-tapering trial which exhibited the potential of successful maintenance under lower antipsychotic dosages. METHODS: A 2-year open-label randomized prospective trial recruited remitted patients to undergo guided antipsychotic tapering. Blood samples were collected at baseline, annually, and after each dose reduction. Plasma aripiprazole/dehydroaripiprazole concentrations were determined using LC-MS/MS. The relationship between the dose and serum drug levels was examined using Spearman's correlation. Divided at 120 ng/mL, relapse rate, global function, quality of life, and psychopathology were compared between high- and low- drug level groups. RESULTS: A total of 126 blood samples were collected, after excluding13 samples due of non-adherence. The correlation coefficients between dosage and drug level were 0.853 (aripiprazole) and 0.864 (dehydroaripiprazole), and the dose and concentration plots were parallel along the tapering trajectories, except patients with non-adherence. The concentration-to-dose ratio of aripiprazole in this cohort, 17.79 ± 7.23 ng/mL/mg, was higher than that in Caucasian populations. No significant differences were observed in the clinical outcomes between the high- and low-level groups. Remarkably, 12 of 15 patients maintained remission at plasma aripiprazole concentrations of <120 ng/mL. CONCLUSIONS: The lower-than-expected doses reached in our antipsychotic tapering trial were substantiated to provide adequate prophylactic effects by TDM results in a subset of patients treated with aripiprazole, even considering the differences in pharmacogenomics between ethnicities.

Reparametrized Firth's Logistic Regressions for Dose-Finding Study With the Biased-Coin Design.

Finding an adequate dose of the drug by revealing the dose-response relationship is very crucial and a challenging problem in the clinical development. The main concerns in dose-finding study are to identify a minimum effective dose (MED) in anesthesia studies and maximum tolerated dose (MTD) in oncology clinical trials. For the estimation of MED and MTD, we propose two modifications of Firth's logistic regression using reparametrization, called reparametrized Firth's logistic regression (rFLR) and ridge-penalized reparametrized Firth's logistic regression (RrFLR). The proposed methods are designed by directly reducing the small-sample bias of the maximum likelihood estimate for the parameter of interest. In addition, we develop a method on how to construct confidence intervals for rFLR and RrFLR using profile penalized likelihood. In the up-and-down biased-coin design, numerical studies confirm the superior performance of the proposed methods in terms of the mean squared error, bias, and coverage accuracy of confidence intervals.

Efficient Study Design and Analysis of Longitudinal Dose-Response Data Using Fractional Polynomials.

Correctly characterising the dose-response relationship and taking the correct dose forward for further study is a critical part of the drug development process. We use optimal design theory to compare different designs and show that using longitudinal data from all available timepoints in a continuous-time dose-response model can substantially increase the efficiency of estimation of the dose-response compared to a single timepoint model. We give theoretical results to calculate the efficiency gains for a large class of these models. For example, a linearly growing Emax dose-response in a population with a between/within-patient variance ratio ranging from 0.1 to 1 measured at six visits can be estimated with between 1.43 and 2.22 times relative efficiency gain, or equivalently, with 30% to a 55% reduced sample size, compared to a single model of the final timepoint. Fractional polynomials are a flexible way to incorporate data from repeated measurements, increasing precision without imposing strong constraints. Longitudinal dose-response models using two fractional polynomial terms are robust to mis-specification of the true longitudinal process while maintaining, often large, efficiency gains. These models have applications for characterising the dose-response at interim or final analyses.

Guided antipsychotic reduction to reach minimum effective dose (GARMED) in patients with remitted psychosis: a 2-year randomized controlled trial with a naturalistic cohort.

BACKGROUND: Patients with remitted psychosis face a dilemma between the wish to discontinue antipsychotics and the risk of relapse. We test if an operationalized guided-dose-reduction algorithm can help reach a lower effective dose without increased risks of relapse. METHODS: A 2-year open-label randomized prospective comparative cohort trial from Aug 2017 to Sep 2022. Patients with a history of schizophrenia-related psychotic disorders under stable medications and symptoms were eligible, randomized 2:1 into guided dose reduction group (GDR) v. maintenance treatment group (MT1), together with a group of naturalistic maintenance controls (MT2). We observed if the relapse rates would be different between 3 groups, to what extent the dose could be reduced, and if GDR patients could have improved functioning and quality of life. RESULTS: A total of 96 patients, comprised 51, 24, and 21 patients in GDR, MT1, and MT2 groups, respectively. During follow-up, 14 patients (14.6%) relapsed, including 6, 4, and 4 from GDR, MT1, and MT2, statistically no difference between groups. In total, 74.5% of GDR patients could stay well under a lower dose, including 18 patients (35.3%) conducting 4 consecutive dose-tapering and staying well after reducing 58.5% of their baseline dose. The GDR group exhibited improved clinical outcomes and endorsed better quality of life. CONCLUSIONS: GDR is a feasible approach as the majority of patients had a chance to taper antipsychotics to certain extents. Still, 25.5% of GDR patients could not successfully decrease any dose, including 11.8% experienced relapse, a risk comparable to their maintenance counterparts.

Weight-based oxytocin infusion for preventing uterine atony during caesarean delivery in non-labouring patients: A dose-response study.

Postpartum haemorrhage remains a significant cause of maternal morbidity and mortality with the commonest reason being uterine atony. For prevention of uterine atony during caesarean delivery, oxytocin is advocated as a first line drug. There is however no published data regarding utility of a weight-based oxytocin infusion. The present study evaluated dose-response relationship for oxytocin infusion when used as weight-based regimen. A total of 55 non-labouring patients without risk factors for uterine atony and scheduled for caesarean delivery under spinal anaesthesia were enrolled. Randomization was done to receive oxytocin infusion in a dose of 0.1, 0.15, 0.2, 0.25 or 0.3 IU kg-1  h-1 (n = 11 each), initiated at the time of cord clamping and continued until the end of surgery. Successful outcome was defined as attaining an adequate uterine response at 4 min of initiation of infusion and maintained till end of surgery. Oxytocin associated hypotension, tachycardia, ST-T changes, nausea/vomiting, flushing and chest pain were also observed. A significant linear trend for adequate intraoperative uterine tone was seen with increasing dose of weight-based oxytocin infusion (P < 0.001). The effective dose in 90% population (ED90) was 0.29 IU kg-1  h-1 (95% CI = 0.25-0.42). Amongst the oxytocin associated side effects, a significant linear trend was seen between increasing dose of oxytocin infusion and hypotension as well as nausea/vomiting (p = 0.016 and 0.023 respectively). Thus, oxytocin infusion during caesarean delivery may be used as per the patient's body weight.

Exercise Frequency and Fracture Risk in Older Adults-How Often Is Enough?

PURPOSE OF REVIEW: Due to older people's low sports participation rates, exercise frequency may be the most critical component for designing exercise protocols that address fracture risk. The aims of the present article were to review and summarize the independent effect of exercise frequency (ExFreq) on the main determinants of fracture prevention, i.e., bone strength, fall frequency, and fall impact in older adults. RECENT FINDINGS: Evidence collected last year suggests that there is a critical dose of ExFreq that just affects bone (i.e., BMD). Corresponding data for fall-related fracture risk are still sparse and inconsistent, however. The minimum effective dose (MED) of ExFreq that just favorably affects BMD at the lumbar spine and femoral neck has been found to vary between 2.1 and 2.5 sessions/week. Although this MED cannot necessarily be generalized to other cohorts, we speculate that this "critical exercise frequency" might not significantly vary among adult cohorts.

Identification of the minimum effective dose for normally distributed data using a Bayesian variable selection approach.

The identification of the minimum effective dose is of high importance in the drug development process. In early stage screening experiments, establishing the minimum effective dose can be translated into a model selection based on information criteria. The presented alternative, Bayesian variable selection approach, allows for selection of the minimum effective dose, while taking into account model uncertainty. The performance of Bayesian variable selection is compared with the generalized order restricted information criterion on two dose-response experiments and through the simulations study. Which method has performed better depends on the complexity of the underlying model and the effect size relative to noise.

Phase II dose-response trials: A simulation study to compare analysis method performance under design considerations.

Phase II trials are intended to provide information about the dose-response relationship and to support the choice of doses for a pivotal phase III trial. Recently, new analysis methods have been proposed to address these objectives, and guidance is needed to select the most appropriate analysis method in specific situations. We set up a simulation study to evaluate multiple performance measures of one traditional and three more recent dose-finding approaches under four design options and illustrate the investigated analysis methods with an example from clinical practice. Our results reveal no general recommendation for a particular analysis method across all design options and performance measures. However, we also demonstrate that the new analysis methods are worth the effort compared to the traditional ANOVA-based approach.

The minimum dose of dexmedetomidine required for cessation of postspinal anesthesia shivering: A prospective observational study.

BACKGROUND AND AIMS: Shivering is a common postanesthesia adverse event with multiple etiologies. Dexmedetomidine, a centrally acting alpha-2 adrenergic agonist, is known to reduce the shivering threshold. However, the minimum dose at which dexmedetomidine causes cessation of shivering is unknown. The aim of this prospective observational study was to find the minimum dosage of dexmedetomidine required for abolition of post-spinal anesthesia (SA) shivering. MATERIAL AND METHODS: Thirty patients having shivering after SA were enrolled, who received dexmedetomidine in the dosage of 1 mcg/kg over 10 min. The time-to-cessation of shivering and the dose of dexmedetomidine required were expressed as mean ± standard deviation. RESULTS: The mean time-to-cessation of shivering after starting dexmedetomidine infusion was 155.88 ± 15.16 s for Grade 3 shivering and 177.71 ± 10.87 s for Grade 4 shivering. Till that time, the mean dose of dexmedetomidine which had been infused was 0.258 ± 0.024 mcg/kg in Grade 3 shivering and 0.295 ± 0.018 mcg/kg in Grade 4 shivering. CONCLUSION: The minimum dose of dexmedetomidine required for abolition of shivering was 0.258 ± 0.024 mcg/kg for patients with Grade 3 shivering and 0.295 ± 0.018 mcg/kg for patients with Grade 4 shivering, which is much less than the commonly administered dose.

A hybrid method to estimate the minimum effective dose for monotone and non-monotone dose-response relationships.

This article proposes a new multiple-testing approach for estimation of the minimum effective dose allowing for non-monotonous dose-response shapes. The presented approach combines the advantages of two commonly used methods. It is shown that the new approach controls the error rate of underestimating the true minimum effective dose. Monte Carlo simulations indicate that the proposed method outperforms alternative methods in many cases and is only marginally worse in the remaining situations.

Weight-based versus fixed dose oxytocin infusion for preventing uterine atony during cesarean section in laboring patients: A randomized trial.

OBJECTIVE: We compared efficacy of weight-based (0.4 IU/kg/h) versus fixed-dose (34 IU/h) oxytocin infusion during cesarean section. METHODS: The oxytocin infusion in either group (n = 32 each) was initiated upon cord clamping. Primary outcome measure was adequacy of uterine tone at 4 min after initiating oxytocin infusion. Oxytocin associated side effects were also observed. RESULTS: Significantly less oxytocin was used with the weight-based versus fixed-dose regimen (16.3 [11.2-22.4] IU vs 20.4 [15.8-26.9] IU; P = 0.036). Incidence of adequate uterine tone was clinically greater but not significantly different with the weight-based versus fixed-dose regimen (81.3% vs 71.9%; P = 0.376). The weight-based regimen was associated with clinically lesser, although not statistically significant need for rescue oxytocin (25% vs 46.9%; P = 0.068) and additional uterotonic (9.4% vs 15.6%; P = 0.708); as well as oxytocin associated side effects (hypotension [34.4% vs 46.9%; P = 0.309], nausea/vomiting [18.8% vs 40.6%; P = 0.055], and ST-T changes [0% vs 3.1%; P = 1.000]). CONCLUSION: Weight-based oxytocin was not significantly different from the fixed-dose regimen in terms of uterotonic efficacy or associated side-effects, despite significantly lower doses being used. Use of weight-based oxytocin infusion (0.4 IU/kg/h) can be considered in clinical practice. TRIAL REGISTRATION: Clinical Trial Registry of India (ctri.nic.in, number. CTRI/2021/01/030642).

The minimum effective dose (ED90) of prophylactic oxytocin infusion during cesarean delivery in patients with and without obesity: an up-down sequential allocation dose-response study.

BACKGROUND: Obesity is associated with greater oxytocin requirement during labor induction or augmentation. There are scant data exploring the intra-operative requirement during cesarean delivery in patients with obesity, and none comparing it with those without obesity. We evaluated the minimum effective dose (ED90) of an oxytocin infusion to achieve adequate uterine tone during cesarean delivery in patients with and without obesity. METHODS: Patients (body mass index ≥30 kg/m2 represented patients with obesity) undergoing cesarean delivery using subarachnoid block were included. This prospective dual-arm dose-finding study used a 9:1 biased sequential allocation design. Oxytocin infusion was initiated at 13 IU/h at cord clamping in the first patient of each group. Uterine tone was graded as satisfactory or unsatisfactory by the obstetrician four minutes after initiation of the infusion. The dose of oxytocin infusion for subsequent patients was determined according to the response of the previous patient in the group. Oxytocin-associated side effects were evaluated. Dose-response data for the groups was evaluated using log-logistic function and ED90 estimates derived from fitted equations using the delta method. RESULTS: The ED90 of oxytocin was significantly higher for patients with obesity (n = 40) compared with those without obesity (n = 40) [25.7 IU/h, 95% CI 18.6 to 32.9) vs. 16.6 IU/h, 95% CI 14.9 to 18.3)]; relative ratio 1.55 [95% CI 1.09 to 2.01] (P = 0.019). CONCLUSIONS: Patients with obesity require a higher intra-operative oxytocin infusion dose rate to achieve a satisfactorily contracted uterus after fetal delivery when compared with patients without obesity.

KD-409, a Respiratory Syncytial Virus FG Chimeric Protein without the CX3C Chemokine Motif, Is an Efficient Respiratory Syncytial Virus Vaccine Preparation for Passive and Active Immunization in Mice.

Although respiratory syncytial virus (RSV) vaccine development initiatives have existed for half a century, no candidate has been approved for application at all ages from neonates to children. Developing an effective and safe RSV vaccine for pediatric use is challenging owing to RSV-associated disease and vaccine-enhanced disease (VED). We aimed to design an RSV vaccine, KD-409, by structurally incorporating the F ectodomain and G protein central conserved domain without the CX3C chemokine motif and test its efficacy and safety. KD-409 formed rosette particles or trimmers. KD-409 immunization of mice mainly induced anti-RSV F protein IgG. The induced anti-F antibodies had a higher IgG2a/IgG1 ratio than pre-fusion F, suggesting that they induced Th1-dominant immunity. Active and passive immunities were assessed by analyzing the viral titers in BALB/c mice intranasally challenged with RSV after intramuscular KD-409 immunization and pups derived from mothers who were intramuscularly vaccinated with KD-409 twice, respectively. KD-409 was more effective than post-fusion F and had a lower minimum effective dose than pre-fusion F. Thus, KD-409 demonstrated great potential as a novel RSV vaccine candidate, outperforming existing RSV F-based candidates. Our findings provide a promising strategy to overcome RSV-associated acute lower respiratory infections without the risk of VED associated with traditional approaches.

Efficacy and safety of low dose desmopressin orally disintegrating tablet in women with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study.

PURPOSE: Previous studies suggest a lower dose of desmopressin orally disintegrating tablet may be effective in females compared to males with nocturia. We confirm the efficacy and safety of 25 µg desmopressin orally disintegrating tablet compared to placebo in female patients. MATERIALS AND METHODS: In this 3-month, randomized, double-blind, parallel group study 25 µg desmopressin once daily was compared to placebo in women with nocturia (2 or more nocturnal voids). The co-primary efficacy end points were change from baseline in mean number of nocturnal voids and proportion of patients achieving at least a 33% reduction from baseline in the mean number of nocturnal voids (33% responders). RESULTS: The full analysis set comprised 261 patients (age range 19 to 87 years). Desmopressin significantly reduced the mean number of nocturnal voids and increased the odds of a 33% or greater response compared to placebo during 3 months, assessed by longitudinal analysis (-0.22, p = 0.028 and OR 1.85, p = 0.006, respectively). Desmopressin increased the mean time to first nocturnal void by 49 minutes compared to placebo at 3 months (p = 0.003). The response to desmopressin was seen by week 1 of treatment and was sustained throughout the trial. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated. Serum sodium levels remained greater than 125 mmol/L throughout the trial and 3 transient decreases to less than 130 mmol/L were recorded. CONCLUSIONS: At a dose of 25 µg, desmopressin orally disintegrating tablet is an effective and well tolerated treatment for women with nocturia. Treatment provides rapid and sustained improvement in nocturia and quality of life.

Dose-tapering trajectories in patients with remitted psychosis undergoing guided antipsychotic reduction to reach minimum effective dose.

BACKGROUND: Patients with remitted psychosis wish to reduce antipsychotic doses yet facing increased risks of relapse. Examining dose-tapering processes may provide insights to re-evaluate the risk-to-benefit balance. We aimed to depict and subgroup tapering trajectories, and explore factors associated with different dose-reduction patterns. METHODS: A 2-year open-label randomized prospective comparative trial from August 2017 to September 2022 in Taiwan. Patients with a history of schizophrenia-related psychotic disorders under stable medications and symptoms were eligible, randomizing a proportion to conduct guided dose reduction. We depicted the trajectories of individual patients and named subgroups based on dose-tapering patterns. Predictors of baseline characteristics for designated subgroups were examined by logistic regression analysis; changes in outcomes were compared by paired t-test. RESULTS: Fifty-one patients undergoing guided dose reduction, 18 (35.3%) reduced 4 steps consecutively (sequential reducers, SR), 14 (27.5%) reduced 1 to 3 steps (modest reducers, MR), 3 (5.9%) re-escalated to previous level (alert reducers, AR), 7 (13.7%) returned to baseline level (baseline returners, BR), 6 (11.7%) relapsed (failed reducers, FR) and 3 (5.9%) withdrew without relapse (early exits, EE). Patients with a history of relapse assumed a conservative dose-tapering pace; only the SR subgroup exhibited significant improvements in functioning and quality of life while failing to identify variables for predicting who would become SR or FR. CONCLUSIONS: Guided dose reduction comprises dynamic processes with differences between individual trajectories. The proposed naming of dose-tapering patterns/subgroups provides a framework depicting patients undergoing dose-tapering. Longer-term observation and more flexible tapering approaches are anticipated to reveal favorable outcomes.

Minimal Effective Dose of Beans Required to Elicit a Significantly Lower Glycemic Response Than Commonly Consumed Starchy Foods: Predictions Based on In Vitro Digestion and Carbohydrate Analysis.

Beans elicit lower glycemic responses (GRs) than other starchy foods, but the minimum effective dose (MED) to reduce GR is unknown. We sought to determine the MED of beans compared to common starchy foods. Overnight-fasted healthy volunteers consumed »c (phase 1, n = 24) or ½c (phase 2, n = 18) of black, cranberry, great northern, kidney, navy and pinto beans and corn, rice, pasta and potato (controls), with blood glucose measured before and for 2 h after eating. GRs (incremental areas under the curves, iAUCs) after beans were consumed were compared to those of controls by ANOVA followed by Dunnett's test. To qualify for MED, beans had to elicit an effective reduction in GR, defined as a statistically significant reduction in iAUC of ≥20% (i.e., a relative glycemic response, RGR, ≤80). Outcomes from in vitro digestion were compared with in vivo RGR. Both doses of all six beans effectively reduced GR versus all four starchy controls, except for »c and ½c cranberry and pinto vs. corn, »c great northern and navy vs. corn and »c navy and pinto vs. potato. MED criteria were met for 18 comparisons of the »c servings, with four of the remaining six met by the ½c servings. The overall mean ± SEM RGR vs. controls was similar for the »c and ½c servings: 53 ± 4% and 56 ± 3%, respectively. By multiple regression analysis, RGR = 23.3 × RDS + 8.3 × SDS - 20.1 × RS + 39.5 × AS - 108.2 (rapidly digested starch, p < 0.001; slowly digested starch, p = 0.054; resistant starch, p = 0.18; available sugars, p = 0.005; model r = 0.98, p = 0.001). RGR correlated with in vitro glucose release (r = 0.92, p < 0.001). The MED of beans is » cup. For n = 30 comparisons (n = 24 beans vs. controls, n = 6 controls vs. each other), an effective reduction in GR was predicted from in vitro carbohydrate analysis with 86% sensitivity and 100% specificity.

Minimum effective dose of oxytocin bolus during the caesarean section for patients at high vs low risk of uterine atony: A non-randomized, dual-arm, dose-finding prospective trial.

Background and Aims: There are scanty data for oxytocin dose in patients at high risk of uterine atony. We aimed to compare the effective dose (ED) 90 of oxytocin for adequate uterine tone during the caesarean section in patients at high-risk vs low-risk uterine atony. Methods: This dose-finding study was undertaken after ethical approval in non-labouring women aged >18 years with pre-defined risk factors for uterine atony (high-risk group) vs those without such factors (low-risk group) (n = 39 each). Starting dose of oxytocin in the first patient of low-risk and high-risk groups was 1 and 3 IU, respectively. Achieving adequate uterine tone at 3 min of oxytocin bolus was designated 'success', while inadequate tone constituted 'failure'. If the response was 'failure', the dose of oxytocin was increased for the next patient by 0.5 or 0.2 IU (high- and low-risk groups, respectively). In case of a successful response, the dose for the next patient was decreased with a probability of 1/9 using the same dosing intervals or otherwise kept unchanged. Results: The ED90 (95% CI) of oxytocin bolus was 4.7 (3.3-6.0) IU for the high-risk group and 2.2 (1.3-3.2) IU for the low-risk group (P = 0.044). Oxytocin-associated tachycardia (P = 0.247) and hypotension (P = 0.675) were clinically greater for the high-risk vs low-risk group but statistically similar. Conclusion: Non-labouring patients with high-risk factors for uterine atony require a greater dose of initial oxytocin bolus to achieve adequate uterine tone during the caesarean section compared to those without risk factors.

Expected loss functions as additional measures to assess performance of multiple testing procedures for combination drug dose finding.

There are several measures that are commonly used to assess performance of a multiple testing procedure (MTP). These measures include power, overall error rate (family-wise error rate), and lack of power. In settings where the MTP is used to estimate a parameter, for example, the minimum effective dose, bias is of interest. In some studies, the parameter has a set-like structure, and thus, bias is not well defined. Nevertheless, the accuracy of estimation is one of the essential features of an MTP in such a context. In this paper, we propose several measures based on the expected values of loss functions that resemble bias. These measures are constructed to be useful in combination drug dose response studies when the target is to identify all minimum efficacious drug combinations. One of the proposed measures allows for assigning different penalties for incorrectly overestimating and underestimating a true minimum efficacious combination. Several simple examples are considered to illustrate the proposed loss functions. Then, the expected values of these loss functions are used in a simulation study to identify the best procedure among several methods used to select the minimum efficacious combinations, where the measures take into account the investigator's preferences about possibly overestimating and/or underestimating a true minimum efficacious combination. The ideas presented in this paper can be generalized to construct measures that resemble bias in other settings. These measures can serve as an essential tool to assess performance of several methods for identifying set-like parameters in terms of accuracy of estimation.

Protocol of guided antipsychotic reduction to reach minimum effective dose (GARMED) in patients with remitted psychosis based on pragmatic design.

AIMS: Patients with psychosis intend to discontinue antipsychotic treatment for various reasons. As antipsychotic discontinuation involves a high risk of relapse, maintenance treatment is recommended by mainstream opinion even when remission is attained. To optimize the risk-to-benefit ratio of long-term antipsychotic treatment, we proposed an operationalized guided dose-reduction algorithm to serve as an intermediate approach as to achieve the lowest effective antipsychotic dose and better functioning for patients with remitted psychosis. METHODS: Outpatients with a history of schizophrenia-related psychotic disorders currently under stable medications and symptoms are eligible to register in this protocol. Patients intending for dose reduction are randomized into 2:1, guided dose reduction group (GDR) versus maintenance treatment group (MTG1). Eligible patients who do not intend to reduce antipsychotics serve as naturalistic maintenance controls (MTG2). The GDR patients reduce no more than 25% of their baseline antipsychotic dose, with at least a 6-month stabilization period before reducing another 25% of their last dose. The timing of the next dose reduction will be determined by shared decision-making with the patient. Following a dose reduction, the patients will receive three consecutive monthly monitoring; otherwise, they receive treatment as usual. DISCUSSION: By employing this pragmatic-based protocol, patients are empowered to evaluate their readiness for next dose reduction attempt. We would like to test in real-world situations if stable patients can reduce antipsychotics not at the expense of an increased risk of relapse, so as to optimize the balance between risk-to-benefit ratios of long-term antipsychotic treatment.

Minimum Effective Dose to Achieve Biochemical Correction with Adeno-Associated Virus Vector-Mediated Gene Therapy in Mice with Pompe Disease.

Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA), resulting in skeletal muscle weakness and cardiomyopathy. Muscle weakness progresses despite currently available therapy, which has prompted the development of gene therapy with adeno-associated virus (AAV) type 2 vectors cross-packaged as AAV8 (2/8). Preclinical studies of gene therapy demonstrated that the minimum effective dose (MED) for biochemical correction with AAV2/8-LSPhGAA was ∼2 × 1011 vector genomes (vg)/kg body weight. The current study examined the transduction of AAV2/8-LSPeGFP vector in adult GAA-KO mice with Pompe disease, and correlated that degree of transduction with the biochemical correction achieved by the same dose of AAV2/8-LSPhGAA. The MED was found to be ∼2 × 1011 vg/kg, with all hepatocytes variably transducing at this dose. At this dose, liver GAA significantly increased, while liver glycogen significantly decreased. The 2 × 1011 vg/kg dose was sufficient to significantly decrease diaphragm glycogen. However, the heart, diaphragm, and quadriceps all required a fourfold higher dose to achieve correction of GAA deficiency in association with significant clearance of stored glycogen, which correlated with increased serum GAA activity. These data indicate that AAV2/8-LSPeGFP transduced all hepatocytes when the 2 × 1011 vg/kg dose was administered, which correlated with partial biochemical correction from the equivalent dose of AAV2/8-LSPhGAA. Altogether, these data support the conclusion that substantial transduction of the liver is required to achieve biochemical correction from AAV2/8-LSPhGAA.