Discontinuation of psychotropic medication: a synthesis of evidence across medication classes.

Pharmacotherapy is an effective treatment modality across psychiatric disorders. Nevertheless, many patients discontinue their medication at some point. Evidence-based guidance for patients, clinicians, and policymakers on rational discontinuation strategies is vital to enable the best, personalized treatment for any given patient. Nonetheless, there is a scarcity of guidelines on discontinuation strategies. In this perspective, we therefore summarize and critically appraise the evidence on discontinuation of six major psychotropic medication classes: antidepressants, antipsychotics, benzodiazepines, mood stabilizers, opioids, and stimulants. For each medication class, a wide range of topics pertaining to each of the following questions are discussed: (1) Who can discontinue (e.g., what are risk factors for relapse?); (2) When to discontinue (e.g., after 1 year or several years of antidepressant use?); and (3) How to discontinue (e.g., what's the efficacy of dose reduction compared to full cessation and interventions to mitigate relapse risk?). We thus highlight how comparing the evidence across medication classes can identify knowledge gaps, which may pave the way for more integrated research on discontinuation.

Web Search Query Volume Correlates With Prescription Volumes of Antidepressants and Antipsychotics in the Netherlands and United Kingdom: An Explorative Study.

BACKGROUND: The significant increase in Internet availability has resulted in a rise in search queries on health-related topics. Previous research has demonstrated the potential for analyzing web search query volume for nonpsychotropic prescription drugs, while studies on psychotropic drugs remain scarce. The aims of this study were to expand upon this scarce knowledge by investigating the relationship between web search query volumes and prescription volumes of antidepressants and antipsychotics in the United Kingdom and the Netherlands and to gain insight in topics of concern, such as withdrawal symptoms and discontinuation. METHODS: Data were obtained for the United Kingdom and the Netherlands from January 2010 until January 2021. Prescription volume data for 5 antidepressants (paroxetine, fluoxetine, sertraline, citalopram, venlafaxine) and 5 antipsychotics (quetiapine, olanzapine, clozapine, aripiprazole, and risperidone) were obtained. Web search query volumes and data on related search queries of these substances were acquired from Google Trends. Descriptive statistics and Pearson correlation analyses were performed. RESULTS: A strong, positive, and statistically significant correlation between web search query volume and prescription volume was observed for most included substances in both the Netherlands and the United Kingdom. The search queries related to the included antidepressants and antipsychotics indicate important topics of concern for specific substances, such as withdrawal symptoms and discontinuation. CONCLUSIONS: Web search data from Google Trends could potentially be used as a proxy for prescribing trends of antidepressants and antipsychotics and to gain insight in topics of concern of users of these substances. These findings highlight the importance of providing reliable patient information, particularly regarding adverse effects, withdrawal, and discontinuation.

Inter-observer variability in library plan selection on iterative CBCT and synthetic CT images of cervical cancer patients.

INTRODUCTION: In the Library-of-Plans (LoP) approach, correct plan selection is essential for delivering radiotherapy treatment accurately. However, poor image quality of the cone-beam computed tomography (CBCT) may introduce inter-observer variability and thereby hamper accurate plan selection. In this study, we investigated whether new techniques to improve the CBCT image quality and improve consistency in plan selection, affects the accuracy of LoP selection in cervical cancer patients. MATERIALS AND METHODS: CBCT images of 12 patients were used to investigate the inter-observer variability of plan selection based on different CBCT image types. Six observers were asked to individually select a plan based on clinical X-ray Volumetric Imaging (XVI) CBCT, iterative reconstructed CBCT (iCBCT) and synthetic CTs (sCT). Selections were performed before and after a consensus meeting with the entire group, in which guidelines were created. A scoring by all observers on the image quality and plan selection procedure was also included. For plan selection, Fleiss' kappa (κ) statistical test was used to determine the inter-observer variability within one image type. RESULTS: The agreement between observers was significantly higher on sCT compared to CBCT. The consensus meeting improved the duration and inter-observer variability. In this manuscript, the guidelines attributed the overall results in the plan selection. Before the meeting, the gold standard was selected in 76% of the cases on XVI CBCT, 74% on iCBCT, and 76% on sCT. After the meeting, the gold standard was selected in 83% of the cases on XVI CBCT, 81% on iCBCT, and 90% on sCT. CONCLUSION: The use of sCTs can increase the agreement of plan selection among observers and the gold standard was indicated to be selected more often. It is important that clear guidelines for plan selection are implemented in order to benefit from the increased image quality, accurate selection, and decrease inter-observer variability.

Dosimetry and Monte Carlo modelling of the Papillon+ contact X-ray brachytherapy device.

PURPOSE: This study aimed to develop and validate a Monte Carlo (MC) model for the Papillon+ contact x-ray brachytherapy (CXB) device, producing 50 kilovolt (kV) X-rays, specifically focusing on its application with a 25 mm diameter rectal applicator for contact therapy. MATERIAL AND METHODS: The validation process involved depth dose and transverse dose profile measurements using EBT3 gafchromic films positioned in a plastic water low energy range phantom. The half-value layer (HVL) was further measured and derived from the simulated X-ray spectra. RESULTS: Excellent agreement within ±2% was achieved between the measured and simulated on-axis depth dose curves for the 25 mm rectal applicator. Transverse dose profile measurements showed a high level of agreement between the simulation and measurements, on average 3.1% in contact with the applicator at the surface of the phantom and on average 1.7% at 10 mm depth. A close agreement within 5.5% was noticed concerning the HVL between the measurement and simulation. The simulated gamma spectra and 2D-dose distribution demonstrated a soft X-ray energy spectrum and a uniform dose distribution in contact with the applicator. CONCLUSIONS: An MC model was successfully developed for the Papillon+ eBT device with a 25 mm diameter rectal applicator. The validated model, with its demonstrated accuracy in depth dose and transverse dose profile simulations, is a valuable tool for quality assurance and patient safety and, in a later phase, may be used for treatment planning, dose calculations and tissue inhomogeneity corrections.

ESTRO-ACROP guideline: Recommendations on implementation of breath-hold techniques in radiotherapy.

The use of breath-hold techniques in radiotherapy, such as deep-inspiration breath hold, is increasing although guidelines for clinical implementation are lacking. In these recommendations, we aim to provide an overview of available technical solutions and guidance for best practice in the implementation phase. We will discuss specific challenges in different tumour sites including factors such as staff training and patient coaching, accuracy, and reproducibility. In addition, we aim to highlight the need for further research in specific patient groups. This report also reviews considerations for equipment, staff training and patient coaching, as well as image guidance for breath-hold treatments. Dedicated sections for specific indications, namely breast cancer, thoracic and abdominal tumours are also included.

Anatomical evaluation of deep-learning synthetic computed tomography images generated from male pelvis cone-beam computed tomography.

Background and purpose: To improve cone-beam computed tomography (CBCT), deep-learning (DL)-models are being explored to generate synthetic CTs (sCT). The sCT evaluation is mainly focused on image quality and CT number accuracy. However, correct representation of daily anatomy of the CBCT is also important for sCTs in adaptive radiotherapy. The aim of this study was to emphasize the importance of anatomical correctness by quantitatively assessing sCT scans generated from CBCT scans using different paired and unpaired dl-models. Materials and methods: Planning CTs (pCT) and CBCTs of 56 prostate cancer patients were included to generate sCTs. Three different dl-models, Dual-UNet, Single-UNet and Cycle-consistent Generative Adversarial Network (CycleGAN), were evaluated on image quality and anatomical correctness. The image quality was assessed using image metrics, such as Mean Absolute Error (MAE). The anatomical correctness between sCT and CBCT was quantified using organs-at-risk volumes and average surface distances (ASD). Results: MAE was 24 Hounsfield Unit (HU) [range:19-30 HU] for Dual-UNet, 40 HU [range:34-56 HU] for Single-UNet and 41HU [range:37-46 HU] for CycleGAN. Bladder ASD was 4.5 mm [range:1.6-12.3 mm] for Dual-UNet, 0.7 mm [range:0.4-1.2 mm] for Single-UNet and 0.9 mm [range:0.4-1.1 mm] CycleGAN. Conclusions: Although Dual-UNet performed best in standard image quality measures, such as MAE, the contour based anatomical feature comparison with the CBCT showed that Dual-UNet performed worst on anatomical comparison. This emphasizes the importance of adding anatomy based evaluation of sCTs generated by dl-models. For applications in the pelvic area, direct anatomical comparison with the CBCT may provide a useful method to assess the clinical applicability of dl-based sCT generation methods.

Quality assurance and safety of hippocampal avoidance prophylactic cranial irradiation in the multicenter randomized phase III trial (NCT01780675).

Objective: NCT01780675, a multicenter randomized phase III trial of prophylactic cranial irradiation (PCI) versus PCI with hippocampal sparing in small cell lung cancer (SCLC) investigated neurocognitive decline and safety. As part of quality assurance, we evaluated if hippocampal avoidance (HA)-PCI was performed according to the NCT01780675 trial protocol instructions, and performed a safety analysis to study the incidence and location of brain metastases for patients treated with HA-PCI. Methods: This retrospective analysis evaluated the quality of the irradiation given in the randomized controlled trial (RCT) comparing SCLC patients receiving PCI with or without hippocampal avoidance, using intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT). The dose distribution for each patient receiving HA-PCI was retrieved and analyzed to evaluate if the treatment dose constraints were met. A questionnaire was sent out to all participating sites, and data on radiotherapy technique, pre-treatment dummy runs, phantom measurements and treatment electronic portal imaging device (EPID) dosimetry were collected and analyzed. As part of the safety analysis, the follow-up magnetic resonance imaging (MRI) or computerized tomography (CT) scans on which cranial disease progression was first diagnosed were collected and matched to the radiotherapy planning dose distribution. The matched scans were reviewed to analyze the location of the brain metastases in relation to the prescribed dose. Results: A total of 168 patients were randomized in the NCT01780675 trial in 10 centers in the Netherlands and Belgium from April 2013 until March 2018. Eighty two patients receiving HA-PCI without evidence of brain metastases were analyzed. All patients were treated with 25 Gy in 10 fractions. Dummy runs and phantom measurements were performed in all institutions prior to enrolling patients into the study. The radiotherapy (RT) plans showed a median mean bilateral hippocampal dose of 8.0 Gy, range 5.4-11.4 (constraint ≤ 8.5 Gy). In six patients (7.3%) there was a protocol violation of the mean dose in one or both hippocampi. In four of these six patients (4.9%) the mean dose to both hippocampi exceeded the constraint, in 1 patient (1.2%) only the left and in 1 patient (1.2%) only the right hippocampal mean dose was violated (average median dose left and right 8.9 Gy). All patients met the trial dose constraint of V 115% PTV ≤ 1%; however the D max PTV constraint of ≤ 28.75 Gy was violated in 22.0% of the patients. The safety analysis showed that 14 patients (17.1%) developed cranial progression. No solitary brain metastases in the underdosed region were found. Two out of 11 patients with multiple brain metastasis developed metastasis in the underdosed region(s). Conclusions: The radiotherapy quality within the HA-PCI trial is performed according to the protocol guidelines. The dose constraints to the hippocampi are met in the vast majority of cases. In all patients, the volume of the brain for which a higher dose was accepted, is according to the trial. However, within this volume there are small areas with higher doses than advised.

A quality assurance tool for helical tomotherapy using a step-wedge phantom and the on-board MVCT detector.

The purpose of this study was to develop and evaluate filmless quality assurance (QA) tools for helical tomotherapy by using the signals from the on-board megavoltage computed tomography (MVCT) detector and applying a dedicated step-wedge phantom. The step-wedge phantom is a 15 cm long step-like aluminum block positioned on the couch. The phantom was moved through the slit beam and MVCT detector signals were analyzed. Two QA procedures were developed, with gantry fixed at 0°: 1) step-wedge procedure: to check beam energy consistency, field width, laser alignment with respect to the virtual isocenter, couch movement, and couch velocity; and 2) completion procedure: to check the accuracy of a field abutment made by the tomotherapy system after a treatment interruption. The procedures were designed as constancy tool and were validated by measurement of deliberately induced variations and comparison with a reference method. Two Hi-Art II machines were monitored over a period of three years using the step-wedge procedures. The data acquisition takes 5 minutes. The analysis is fully automated and results are available directly after acquisition. Couch speed deviations up to 2% were induced. The mean absolute difference between expected and measured couch speed was 0.2% ± 0.2% (1 standard deviation SD). Field width was varied around the 10 mm nominal size, between 9.7 and 11.1 mm, in steps of 0.2 mm. Mean difference between the step-wedge analysis and the reference method was < 0.01 mm ± 0.03 mm (1 SD). Laser (mis)alignment relative to a reference situation was detected with 0.3 mm precision (1SD). The step-wedge profile was fitted to a PDD in water. The PDD ratio D20/D10, measured at depths of 20 cm and 10 cm, was used to check beam energy consistency. Beam energy variations were induced. Mean difference between step-wedge and water PDD ratios was 0.2% ± 0.3% (1SD). The completion procedure was able to reveal abutment mismatches with a mean error of -0.6 mm ± 0.2 mm (1SD). The trending data over a period of three years showed a mean deviation of 0.4% ± 0.1% (1 SD) in couch speed. The spread in field width was 0.15 mm (1 SD). The sagittal and transverse lasers showed a variation of 0.5 mm (1 SD). Beam energy varied 1.0% (1 SD). A mean abutment mismatch was found of -0.4 mm ± 0.2 mm (1 SD) between interrupted treatments. The on-board MVCT detector, in combination with the step-wedge phantom, is a suitable tool for a QA program for helical tomotherapy. The method allowed frequent monitoring of machine behavior for the past three years.

R117H-CFTR function and response to VX-770 correlate with mRNA and protein expression in intestinal organoids.

INTRODUCTION: Variability in disease severity and CFTR modulator responses exists between patients with identical CFTR genotypes. Here, we characterized transcription, translation and function of R117H-CFTR using intestinal organoids and correlated them with in vitro responses to ivacaftor (VX-770). METHODS: Organoids were generated from individuals possessing at least one R117H-CFTR allele. The forskolin-induced swelling (FIS) assay was used to measure CFTR function and response to VX-770 treatment. R117H-CFTR protein and mRNA expression levels were determined in parallel and Pearson's correlation coefficients were assessed. RESULTS: Variability in R117H-CFTR FIS responses was observed and correlated significantly with mRNA and protein expression. Response to VX-770 treatment in organoids correlated with mRNA and protein expression as well. CONCLUSIONS: Our results indicate that gene expression, protein expression and CFTR function are strongly correlated in organoids from people with CFTR-R117H-7T/9T, which may suggest that CFTR gene expression may have consequences for CF diagnosis, prognosis and therapeutic benefit.

Radiotherapy quality assurance for mesorectum treatment planning within the multi-center phase II STAR-TReC trial: Dutch results.

BACKGROUND: The STAR-TReC trial is an international multi-center, randomized, phase II study assessing the feasibility of short-course radiotherapy or long-course chemoradiotherapy as an alternative to total mesorectal excision surgery. A new target volume is used for both (chemo)radiotherapy arms which includes only the mesorectum. The treatment planning QA revealed substantial variation in dose to organs at risk (OAR) between centers. Therefore, the aim of this study was to determine the treatment plan variability in terms of dose to OAR and assess the effect of a national study group meeting on the quality and variability of treatment plans for mesorectum-only planning for rectal cancer. METHODS: Eight centers produced 25 × 2 Gy treatment plans for five cases. The OAR were the bowel cavity, bladder and femoral heads. A study group meeting for the participating centers was organized to discuss the planning results. At the meeting, the values of the treatment plan DVH parameters were distributed among centers so that results could be compared. Subsequently, the centers were invited to perform replanning if they considered this to be necessary. RESULTS: All treatment plans, both initial planning and replanning, fulfilled the target constraints. Dose to OAR varied considerably for the initial planning, especially for dose levels below 20 Gy, indicating that there was room for trade-offs between the defined OAR. Five centers performed replanning for all cases. One center did not perform replanning at all and two centers performed replanning on two and three cases, respectively. On average, replanning reduced the bowel cavity V20Gy by 12.6%, bowel cavity V10Gy by 22.0%, bladder V35Gy by 14.7% and bladder V10Gy by 10.8%. In 26/30 replanned cases the V10Gy of both the bowel cavity and bladder was lower, indicating an overall lower dose to these OAR instead of a different trade-off. In addition, the bowel cavity V10Gy and V20Gy showed more similarity between centers. CONCLUSIONS: Dose to OAR varied considerably between centers, especially for dose levels below 20 Gy. The study group meeting and the distribution of the initial planning results among centers resulted in lower dose to the defined OAR and reduced variability between centers after replanning. TRIAL REGISTRATION: The STAR-TReC trial, ClinicalTrials.gov Identifier: NCT02945566. Registered 26 October 2016, https://clinicaltrials.gov/ct2/show/NCT02945566).

Influence of daily setup measurements and corrections on the estimated delivered dose during IMRT treatment of prostate cancer patients.

PURPOSE: To evaluate the impact of marker-based position verification, using daily imaging and an off-line correction protocol, by calculating the delivered dose to prostate, rectum and bladder. METHODS: Prostate cancer patients (n=217) were treated with IMRT, receiving 35 daily fractions. Plans with five beams were optimized taking target coverage (CTV, boost) and organs-at-risk (rectum and bladder) into account. PTV margins were 8mm. Prostate position was verified daily using implanted fiducial gold markers by imaging the first segment of all the five beams on an EPID. Setup deviations were corrected off-line using an adapted shrinking-action-level protocol. The estimated delivered dose, including daily organ movements, was calculated using a version of PLATO's dose engine, enabling batch processing of large numbers of patients. The dose was calculated +/- inclusion of setup corrections, and was evaluated relative to the original static plan. The marker-based measurements were considered representative for all organs. RESULTS: Daily organ movements would result in an underdosage of 2-3Gy to CTV and boost volume relative to the original plan, which was prevented by daily setup corrections. The dose to rectum and bladder was on average unchanged, but a large spread was introduced by organ movements, which was reduced by including setup corrections. CONCLUSIONS: Without position verification and setup corrections, margins of 8mm would be insufficient to account for position uncertainties during IMRT of prostate cancer. With the daily off-line correction protocol, the remaining variations are accommodated adequately.

Impact of brachytherapy technique (2D versus 3D) on outcome following radiotherapy of cervical cancer.

Purpose: The purpose of this study was to analyze the effect of 2D conventional brachytherapy (CBT) compared to 3D MRI-guided brachytherapy (IGBT) with and without the use of interstitial needles on local control, overall survival, and toxicity in patients treated for cervical cancer with radiation or chemoradiation. Material and methods: A retrospective analysis was performed of biopsy-proven FIGO IB-IVA cervical cancer patients, treated with primary radiation or chemoradiation, followed by brachytherapy (BT) between January 1997 and July 2016. Endpoints were local control, overall survival, and toxicity. Results: Of 126 patients included, 35 have been treated with CBT, 31 with IGBT without needles (IC), and 60 with IGBT with needles (ICIS). External beam radiotherapy (EBRT) had mostly been delivered concurrently with chemotherapy (weekly cisplatin). Overall local control was 93% after 1 year, and 88% after 3 years. Overall 3-year survival was 75%, and 5-year survival was 66%. The 3D technique (IGBT cohorts) showed a trend for an improved local control and overall survival (p = 0.05) compared to the 2D technique (CBT cohort). A decrease in toxicity was observed from 17% (2D cohort) to 12% (3D cohort). The use of interstitial needles was associated with a higher high-risk clinical target volume (HR-CTV) dose (11.3 Gy vs. 9.9 Gy) and a lower D2cc bladder dose (10.9 Gy vs. 14.7 Gy, both p < 0.01). Conclusions: In cervical cancer treatment, the use of a 3D brachytherapy technique (MRI-guided with or without interstitial needles) showed a trend towards an increased local control and improved overall survival with reduced toxicity, compared to the conventional 2D brachytherapy technique. The use of interstitial needles allowed dose sculpting, resulting in delivery of higher doses to the HR-CTV, while reducing radiation doses to organs at risk, such as the bladder.

Heart position variability during voluntary moderate deep inspiration breath-hold radiotherapy for breast cancer determined by repeat CBCT scans.

Voluntary moderate deep inspiration breath hold (vmDIBH) in left-sided breast cancer radiotherapy reduces cardiac dose. The aim of this study was to investigate heart position variability in vmDIBH using CBCT and to compare this variability with differences in heart position between vmDIBH and free breathing (FB). For 50 patients initial heart position with respect to the field edge (HP-FE) was measured on a vmDIBH planning CT scan. Breath-hold was monitored using an in-house developed vertical plastic stick. On pre-treatment CBCT scans, heart position variability with respect to the field edge (ΔHP-FE) was measured, reflecting heart position variability when using an offline correction protocol. After registering the CBCT scan to the planning CT, heart position variability with respect to the chest wall (ΔHP-CW) was measured, reflecting heart position variability when using an online correction protocol. As a control group, vmDIBH and FB computed tomography (CT) scans were acquired for 30 patients and registering both scans on the chest wall. For 34 out of 50 patients, the average HP-FE and HP-CW increased over the treatment course in comparison to the planning CT. Averaged over all patients and all treatment fractions, the ΔHP-FE and the ΔHP-CW was 0.8±4.2mm (range -9.4-+10.6mm) and 1.0±4.4mm (range -8.3-+10.4mm) respectively. The average gain in heart to chest wall distance was 11.8±4.6mm when using vmDIBH instead of FB. In conclusion, substantial variability in heart position using vmDIBH was observed during the treatment course.

Charge modification of the endothelial surface layer modulates the permeability barrier of isolated rat mesenteric small arteries.

We hypothesized that modulation of the effective charge density of the endothelial surface layer (ESL) results in altered arterial barrier properties to transport of anionic solutes. Rat mesenteric small arteries (diameter approximately 190 microm) were isolated, cannulated, perfused, and superfused with MOPS-buffered physiological salt solutions. MOPS-solutions were of normal ionic strength (162 mM, MOPS), low ionic strength (81 mM, LO-MOPS), or high ionic strength (323 mM, HI-MOPS), to modulate ESL charge density (normal, high, or low ESL charge, respectively). Osmolarity of MOPS, LO-MOPS, and HI-MOPS was kept constant at 297 mosmol/l, using additional glucose when necessary. Perfusate solutions were supplemented with 1% BSA. Arteries were cannulated with a double-barreled theta-pipet on the inlet side and a regular pipet on the outlet side. After infusion of FITC-labeled dextran of 50 kDa (FITC-Delta50) and the endothelial membrane dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, the dynamics of arterial dye filling were determined with confocal microscopy. ESL thickness, as determined from the initial exclusion zone for FITC-Delta50 on the luminal endothelial surface, was 6.3 +/- 1.4 microm for LO-MOPS, 2.7 +/- 1.0 microm for MOPS, and 1.1 +/- 1.3 microm for HI-MOPS. At low ionic strength, FITC-Delta50 permeated into the ESL with a total ESL permeation time (tauESL) of 26 min, and at normal ionic strength with a tauESL of 20 min. No apparent exclusion of FITC-Delta50 from the ESL could be observed at high ionic strength. In conclusion, we demonstrate that the modulation of solvent ionic strength influences the thickness and barrier properties of the ESL.

Localization of the permeability barrier to solutes in isolated arteries by confocal microscopy.

Endothelial cells are covered by a surface layer of membrane-associated proteoglycans, glycosaminoglycans, glycoproteins, glycolipids, and associated plasma proteins. This layer may limit transendothelial solute transport. We determined dimension and transport properties of this endothelial surface layer (ESL) in isolated arteries. Rat mesenteric small arteries (diameter approximately 150 microm) were isolated and cannulated with a double-barreled -pipette on the inlet side and a regular pipette on the outlet side. Dynamics and localization of intra-arterial fluorescence by FITC-labeled dextrans (FITC-Deltas) and the endothelial membrane dye DiI were determined with confocal microscopy. Large FITC-Delta (148 kDa) filled a core volume inside the arteries within 1 min but was excluded from a 2.6 +/- 0.5-microm-wide region on the luminal side of the endothelium during 30 min of dye perfusion. Medium FITC-Delta (50.7 kDa) slowly penetrated this ESL within 30 min but did not permeate into the arterial wall. Small FITC-Delta (4.4 kDa) quickly passed the ESL and accumulated in the arterial wall. Prolonged luminal fluorochrome illumination with a bright mercury lamp destroyed the approximately 3-microm exclusion zone for FITC-Delta 148 within a few minutes. This study demonstrates the presence of a thick ESL that contributes to the permeability barrier to solutes. The layer is sensitive to phototoxic stress, and its damage could form an early event in atherosclerosis.