Analyses of Safety Profile and Homologous Antibody Responses to a Mammalian Cell-Based, MF59-Adjuvanted, A/H5N1, Pandemic Influenza Vaccine across Four Phase II/III Clinical Trials in Healthy Children, Adults, and Older Adults.

Modern cell culture-based technology eliminates vaccine manufactures reliance on embryonated chicken eggs, which may become compromised during an avian influenza pandemic. Four studies (total N = 6230) assessed the immunogenicity and safety of mammalian cell-based, MF59®-adjuvanted, A/H5N1 vaccine (aH5N1c; AUDENZ™) as two doses administered on Days 1 and 22 in children (NCT01776554), adults (NCT01776541; NCT02839330), and older adults (NCT01766921; NCT02839330). Immunogenicity of formulations at 7.5 µg and 3.75 µg antigen per dose were assessed by hemagglutination inhibition and microneutralization assays on Days 1, 22, 43, and 183 or 387. Solicited local and systemic adverse events (AEs) were recorded for 7 days after each vaccination. Unsolicited AEs were collected for 21 days after each vaccination, and serious and other selected AEs were recorded for one year. Antibody responses after two 7.5 µg doses met CBER licensure criteria in all age groups. Overall, an age-related response was evident, with the highest responses observed in children <3 years old. In children, antibody titers met seroconversion criteria 12 months after vaccination. MF59 allowed for antigen dose sparing. Solicited AEs were mild to moderate in nature, of short duration, and less frequent after the second dose than the first, demonstrating a favorable risk-benefit profile.

MF59-adjuvanted influenza vaccine (FLUAD®) elicits higher immune responses than a non-adjuvanted influenza vaccine (Fluzone®): A randomized, multicenter, Phase III pediatric trial in Mexico.

The poor immune response elicited by trivalent influenza vaccines (TIVs) in children can be enhanced by the addition of adjuvants. This observer-blind, randomized Phase III trial assessed the immunogenicity and safety of the MF59-adjuvanted trivalent influenza vaccine FLUAD® (aTIV) and a non-adjuvanted TIV, in healthy children (aged 6 to <72 months) from 3 centers in Mexico, during the 2014-2015 season. The primary objectives were to assess the non-inferiority of aTIV to TIV, measured by geometric mean titers (GMTs), and the safety of aTIV and TIV. Seroconversion was one of several secondary objectives. In total, 287 children were enrolled. The non-inferiority criteria for GMTs and seroconversion were met for aTIV for all 3 vaccine strains. Lower bounds of the 95% confidence intervals for all 3 aTIV:TIV vaccine ratios were >2, showing that the immunogenicity of aTIV was superior to that of TIV for all 3 strains. Solicited adverse events (AEs) were experienced more frequently with aTIV than TIV by younger children (aged 6 to <36 months), but were more frequent with TIV than aTIV in older children (aged 36 to <72 months) who had been vaccinated previously. More unsolicited AEs were associated with aTIV than the TIV. All AEs were of mild or moderate severity. No deaths, serious AEs, or AEs leading to premature withdrawal were reported. Overall, aTIV was highly immunogenic and was well tolerated in healthy children 6 to <72 months of age. These results indicate that aTIV may be a beneficial addition to national pediatric vaccination programs.

An on-site dosimetry audit for high-energy electron beams.

BACKGROUND AND PURPOSE: External dosimetry audits are powerful quality assurance instruments for radiotherapy. The aim of this study was to implement an electron dosimetry audit based on a contemporary code of practice within the requirements for calibration laboratories performing proficiency tests. This involved the determination of suitable acceptance criteria based on thorough uncertainty analyses. MATERIALS AND METHODS: Subject of the audit was the determination of absorbed dose to water, D w, and the beam quality specifier, R 50,dos. Fifteen electron beams were measured in four institutes according to the Belgian-Dutch code of practice for high-energy electron beams. The expanded uncertainty (k = 2) for the D w values was 3.6% for a Roos chamber calibrated in 60Co and 3.2% for a Roos chamber cross-calibrated against a Farmer chamber. The expanded uncertainty for the beam quality specifier, R 50,dos, was 0.14 cm. The audit acceptance levels were based on the expanded uncertainties for the comparison results and estimated to be 2.4%. RESULTS: The audit was implemented and validated successfully. All D w audit results were satisfactory with differences in D w values mostly smaller than 0.5% and always smaller than 1%. Except for one, differences in R 50,dos were smaller than 0.2 cm and always smaller than 0.3 cm. CONCLUSIONS: An electron dosimetry audit based on absorbed dose to water and present-day requirements for calibration laboratories performing proficiency tests was successfully implemented. It proved international traceability of the participants value with an uncertainty better than 3.6% (k = 2).

Appraisal of cooperation with a palliative care case manager by general practitioners and community nurses: a cross-sectional questionnaire study.

AIMS: To investigate how general practitioners and community nurses value the support that they receive from a nurse case manager with expertise in palliative care, whether they think the case manager is helpful in realizing appropriate care and what characteristics of the patient and case management are associated with this view. BACKGROUND: For sustainable palliative care in an ageing society, basic palliative care is provided by generalists and specialist palliative care is reserved for complex situations. Acceptance of and cooperation with specialist palliative care providers by the general practitioner and community nurse is pivotal. DESIGN: Cross-sectional questionnaire study. METHODS: Questionnaire data from 168 general practitioners and 125 community nurses were analysed using chi-square tests, univariate and multivariate logistic regression. Data were gathered between March 2011-December 2013. RESULTS: Of general practitioners, 46% rated the case manager as helpful in realizing care that is appropriate for the patient; for community nurses this was 49%. The case manager did not hinder the process of care and had added value for patients, according to the general practitioners and community nurses. The tasks of the case manager were associated with whether or not the case manager was helpful in realizing appropriate care, whereas patient characteristics and the number of contacts with the case manager were not. CONCLUSION: General practitioners and community nurses are moderately positive about the support from the case manager. To improve cooperation further, case managers should invest in contact with general practitioners and community nurses.

Case management in primary palliative care is associated more strongly with organisational than with patient characteristics: results from a cross-sectional prospective study.

BACKGROUND: Case managers have been introduced in Dutch primary palliative care; these are nurses with expertise in palliative care who offer support to patients and informal carers in addition to the care provided by the general practitioner and home care nurses. This study aims to describe support and investigate what characteristics of patients and the organizational setting are related to the number of contacts and to the number of times topics are discussed between the case manager and patients and/or informal carers. METHODS: Prospective study following cancer patients (n = 662) receiving support from a palliative care case manager in Dutch primary care, using registration forms filled out by the case manager after contact with the patient and/or informal carer. In backward linear regression, the association was studied between patient or organizational characteristics and the number of contacts and the number of times conversation topics were discussed. RESULTS: Organizational characteristics add more to explained variability in data than patient characteristics. Case managers provide support in a flexible manner with regard to the number, mode, persons present, and duration of contacts. Support covered all domains of palliative care, with most attention given to physical complaints, life expectancy and psychological aspects. CONCLUSIONS: Support offered by the case managers is prompted by characteristics of the organization for which they work. This is contradictory to the idea of patient centered care highly valued in palliative care.

Involvement of a Case Manager in Palliative Care Reduces Hospitalisations at the End of Life in Cancer Patients; A Mortality Follow-Back Study in Primary Care.

BACKGROUND: Case managers have been introduced in primary palliative care in the Netherlands; these are nurses with expertise in palliative care who offer support to patients and informal carers in addition to the care provided by the general practitioner (GP) and home-care nurse. OBJECTIVES: To compare cancer patients with and without additional support from a case manager on: 1) the patients' general characteristics, 2) characteristics of care and support given by the GP, 3) palliative care outcomes. METHODS: This article is based on questionnaire data provided by GPs participating in two different studies: the Sentimelc study (280 cancer patients) and the Capalca study (167 cancer patients). The Sentimelc study is a mortality follow-back study amongst a representative sample of GPs that monitors the care provided via GPs to a general population of end-of-life patients. Data from 2011 and 2012 were analysed. The Capalca study is a prospective study investigating the implementation and outcome of the support provided by case managers in primary palliative care. Data were gathered between March 2011 and December 2013. RESULTS: The GP is more likely to know the preferred place of death (OR 7.06; CI 3.47-14.36), the place of death is more likely to be at the home (OR 2.16; CI 1.33-3.51) and less likely to be the hospital (OR 0.26; CI 0.13-0.52), and there are fewer hospitalisations in the last 30 days of life (none: OR 1.99; CI 1.12-3.56 and one: OR 0.54; CI 0.30-0.96), when cancer patients receive additional support from a case manager compared with patients receiving the standard GP care. CONCLUSIONS: Involvement of a case manager has added value in addition to palliative care provided by the GP, even though the role of the case manager is 'only' advisory and he or she does not provide hands-on care or prescribe medication.

Palliative care case managers in primary care: a descriptive study of referrals in relation to treatment aims.

BACKGROUND: Three important elements of the World Health Organization (WHO) definition of palliative care are: 1) it includes patients who may have cure or life prolongation as treatment aims besides palliative care; 2) it is not exclusively for cancer patients; and 3) it includes attention to the medical, psychological, social, and spiritual needs of the patients and their families. Case managers (nurses with expertise in palliative care) may assist generalist primary care providers in delivery of good palliative care. OBJECTIVES: This study investigates the referral of patients to case managers in primary care with regard to the three elements mentioned: diagnosis, treatment aims, and needs as reflected in reasons given for referral. METHODS: In this cross-sectional survey in primary care among case managers and referrers to case management, case managers completed questionnaires for 687 patients; referrers completed 448 (65%). RESULTS: Most patients referred have a combination of treatment aims (69%). Life expectancy and functional status of patients are lower for those with a treatment aim of palliation. Almost all (96%) of those referred are cancer patients. A need for psychosocial support is frequently given as a reason for referral (66%) regardless of treatment aim. CONCLUSIONS: Referrals to case managers reflect two of three elements of the WHO definition. Mainly, patients are referred for support complementary to medical care, and relatively early in their disease trajectory. However, most of those referred are cancer patients. Thus, to fully reflect the definition, broadening the scope to reach other patient groups is important.

The palliative performance scale applied in high-care residential hospice: a retrospective study.

BACKGROUND: The Palliative Performance Scale (PPS) is a tool that is widely used to predict end of life. In Ontario, Canada, the PPS is used to mark the terminal phase of life and eligibility for terminal care. OBJECTIVE: The aim of this retrospective study was to confirm that a PPS level of 40% can be used as a marker for the terminal phase of life. METHOD: PPS levels from 78 patients were calculated based on the intake reports made at admission to an inpatient hospice. RESULTS: Although 77 patients passed away within a period of 3 months, PPS levels at admission varied from 10% to 70%. Fifty-six percent of all patients had a PPS level of 40% or less. Regarding survival, three significant PPS profiles, consisting of two or more PPS levels could be distinguished.

Dissecting the immune response to MF59-adjuvanted and nonadjuvanted seasonal influenza vaccines in children less than three years of age.

INTRODUCTION: Annual seasonal influenza epidemics are particularly dangerous for the very young, the elderly and chronically ill individuals, in whom infection can cause severe morbidity, hospitalization and death. Existing, nonadjuvanted influenza vaccines exhibit a suboptimal immunogenicity and efficacy in immunologically naive subjects such as young children. METHODS: This phase II, randomized clinical trial was conducted to evaluate the antibody and cell-mediated responses to a trivalent influenza vaccine administered without adjuvant (TIV) or adjuvanted with MF59 (ATIV) in previously nonvaccinated children less than 3 years of age. RESULTS: The MF59-adjuvanted vaccine was well tolerated, and induced higher titers of hemagglutination inhibition antibodies able to recognize strains different from the one used in the vaccine (heterovariant) than TIV. The presence of the adjuvant MF59 induced a larger expansion of vaccine-specific CD4 T cells. Interestingly, the adjuvant MF59 did not modify the cytokine profile of the elicited T cells, characterized by the production of IL-2 and TNF-α, and did not bias the response toward either Th1 or Th2. The advantage of ATIV over TIV was more pronounced for the virus strains that had not circulated in the years that preceded this study and for the heterovariant strains. CONCLUSION: These data highlight the relevant role played by the oil-in-water adjuvant MF59 in enhancing the immunogenicity of inactivated influenza vaccines in immunologically naive individuals.

Target volume delineation in breast conserving radiotherapy: are co-registered CT and MR images of added value?

INTRODUCTION: In breast conserving radiotherapy differences of target volume delineations between observers do occur. We evaluated whether delineations based on co-registered computed tomography (CT) and magnetic resonance (MR) imaging may result in an improved consistency between observers. We used the delineation conformity index (CI) to compare clinical target volumes of glandular breast tissue (CTV breast) and lumpectomy cavity (LC) on both imaging modalities. METHODS AND MATERIALS: Four observers delineated CTV breast and LC on co-registered CTMR images in ten breast cancer patients. CIs were determined for CT and CTMR. Furthermore, the Cavity Visualization Score (CVS) of LC was taken into account. RESULTS: The mean CI for CTV breast (CICT;CTV: 0.82 and CICT-CTMR;CTV: 0.80) and LC (CICT;LC: 0.52 and CICT-CTMR;LC: 0.48) did not differ significantly (p=0.07 and p=0.33, respectively). Taking CVS into account for the LC, with a CVS ≥ 4 the mean CI was 0.62 for both CICT;LC and CICT-CTMR;LC. CONCLUSION: The mean volume of the delineated glandular breast tissue based on CT was significantly larger compared to the volume based on CTMR. For patients with a CVS ≥ 4, the mean CIs of the LC were higher compared to CVS<4 for volumes delineated on both CT as well as CTMR images. In our study cohort no significant differences between the CIs of the CTV breast and the LC delineated on CTMR co-registered images were found compared to the CIs on CT images only. Adding MR images does not seem to improve consistency of the delineation of the CTV breast and the LC, even though the volumes were copied from CT images. Since we included only ten patients, caution should be taken with regard to the results of our study.

The selective glycine uptake inhibitor org 25935 as an adjunctive treatment to atypical antipsychotics in predominant persistent negative symptoms of schizophrenia: results from the GIANT trial.

Using a selective glycine uptake inhibitor as adjunctive to second-generation antipsychotic (SGA) was hypothesized to ameliorate negative and/or cognitive symptoms in subjects with schizophrenia. Subjects with predominant persistent negative symptoms (previously stabilized ≥3 months on an SGA) were enrolled in a randomized, placebo-controlled trial to investigate adjunctive treatment with Org 25935, a selective inhibitor of type 1 glycine transporter, over 12 weeks in a flexible dose design. Org 25935 was tested at 4 to 8 mg twice daily and 12 to 16 mg twice daily versus placebo. Primary efficacy outcome was mean change from baseline in Scale for Assessment of Negative Symptoms composite score. Secondary efficacy end points were Positive and Negative Syndrome Scale total and subscale scores, depressive symptoms (Calgary Depression Scale for Schizophrenia), global functioning (Global Assessment of Functioning scale), and cognitive measures using a computerized battery (Central Nervous System Vital Signs). Responder rates were assessed post hoc. A total of 215 subjects were randomized, of which 187 (87%) completed the trial. Both dose groups of Org 25935 did not differ significantly from placebo on Scale for Assessment of Negative Symptoms, Positive and Negative Syndrome Scale (total or subscale scores), Global Assessment of Functioning, or the majority of tested cognitive domains. Org 25935 was generally well tolerated within the tested dose range, with no meaningful effects on extrapyramidal symptoms and some reports of reversible visual adverse effects. Org 25935 did not differ significantly from placebo in reducing negative symptoms or improving cognitive functioning when administered as adjunctive treatment to SGA. In our study population, Org 25935 appeared to be well tolerated in the tested dose ranges.

Left-sided breast cancer radiotherapy with and without breath-hold: does IMRT reduce the cardiac dose even further?

PURPOSE: In radiotherapy for left-sided breast cancer, Active Breathing Control enables a decrease of cardiac and Left Anterior Descending (LAD) coronary artery dose. We compared 3D-Conformal (3D-CRT) to Intensity Modulated Radiotherapy (IMRT) treatment plans based on free-breathing (FB) and breath-hold (BH). We investigated whether IMRT enables an additional decrease of cardiac dose in radiotherapy plans with and without BH. METHODS AND MATERIALS: Twenty patients referred for whole breast irradiation were included. The whole breast, heart and LAD-region were contoured. Four treatment plans were generated: FB_3D-CRT; FB_IMRT; BH_3D-CRT; BH_IMRT. Several doses were obtained from Dose Volume Histograms and compared. Results were compared statistically using the Wilcoxin Signed Rank Test. For heart and LAD-region, a significant dose reduction was found in BH (p<0.01). For both BH and FB, a significant dose reduction was found using IMRT (p<0.01). By using IMRT an average reduction of 5% was noted in the LAD-region for the volume receiving 20Gy. In 5 cases, the LAD-region remained situated in the vicinity of the radiation portals even in BH. Nevertheless, with IMRT the LAD dose was reduced in these cases. CONCLUSION: IMRT results in a significant additional decrease of dose in the heart and LAD-region in both breath-hold and free-breathing.

Palliative care case management in primary care settings: a nationwide survey.

BACKGROUND: In case management an individual or small team is responsible for navigating the patient through complex care. Characteristics of case management within and throughout different target groups and settings vary widely. Case management is relatively new in palliative care. Insight into the content of care and organisational characteristics of case management in palliative care is needed. OBJECTIVES: To investigate how many case management initiatives for palliative care there are in the Netherlands for patients living at home; to describe the characteristics of these initiatives with regard to content and organisation of care. SETTING: Primary care. DESIGN AND PARTICIPANTS: A nationwide survey of all 50 coordinators of networks in palliative care in the Netherlands was conducted. Additional respondents were found through snowball sampling. We looked at 33 possible initiatives using interviews (n=33) and questionnaires (n=30). RESULTS: We identified 20 initiatives for case management. All stated that case management is supplemental to other care. In all initiatives the case managers are registered nurses and most possess higher vocational education and/or further training. All initiatives seek to identify the multidimensional care needs of the patients and the relatives and friends who care for them. Almost all provide information and support and refer patients who need care. Differences are found between the organisations offering the case management, their target groups, the names of the initiatives and whether direct patient care is provided by the case manager. CONCLUSIONS: In the Netherlands, case management in palliative care is new. Several models of delivery were identified. Research is needed to gain insight into the best way to deliver case management. By describing characteristics of case management in palliative care, an important first step is made in identifying effective elements of case management.

What is case management in palliative care? An expert panel study.

BACKGROUND: Case management is a heterogeneous concept of care that consists of assessment, planning, implementing, coordinating, monitoring, and evaluating the options and services required to meet the client's health and service needs. This paper describes the result of an expert panel procedure to gain insight into the aims and characteristics of case management in palliative care in the Netherlands. METHODS: A modified version of the RAND®/University of California at Los Angeles (UCLA) appropriateness method was used to formulate and rate a list of aims and characteristics of case management in palliative care. A total of 76 health care professionals, researchers and policy makers were invited to join the expert panel, of which 61% participated in at least one round. RESULTS: Nine out of ten aims of case management were met with agreement. The most important areas of disagreement with regard to characteristics of case management were hands-on nursing care by the case manager, target group of case management, performance of other tasks besides case management and accessibility of the case manager. CONCLUSIONS: Although aims are agreed upon, case management in palliative care shows a high level of variability in implementation choices. Case management should aim at maintaining continuity of care to ensure that patients and those close to them experience care as personalised, coherent and consistent.

Haemostatic and cranial computed tomography characteristics in patients with acute and delayed coagulopathy after isolated traumatic brain injury.

PRIMARY OBJECTIVE: To investigate whether the development of coagulopathy at different stages after isolated traumatic brain injury (TBI) is associated with distinct cranial computed tomography characteristics. RESEARCH DESIGN: Retrospective cohort study in 226 patients with moderate-to-severe isolated TBI who were categorized as subjects without coagulopathy or with acute temporary, acute sustained or delayed coagulopathy. METHODS AND PROCEDURES: Coagulopathy was defined as an activated partial thromboplastin time >40 seconds and/or prothrombin time (PT) >1.2 and/or platelet count <120*10(9)l(-1). Cranial CT scans were assigned to the six-point Traumatic Coma Data Bank (TCDB) CT-classification. MAIN OUTCOMES AND RESULTS: Coagulopathy occurred in 44% of patients in the first 24-hours post-trauma. Patients with acute, sustained coagulopathy showed a prolonged PT (1.64 ± 0.89) when compared to patients without (1.03 ± 0.07), acute temporary (1.27 ± 0.22) or delayed coagulopathy (1.08 ± 0.06; p < 0.05). Patients with acute temporary or delayed coagulopathy had the worst TCDB CT classification scores, while mortality rates were the highest in patients with sustained or delayed coagulopathy. CONCLUSIONS: Not only the mere presence of coagulopathy, but also the course of haemostatic alterations following neurotrauma may hold predictive value for patient outcome, irrespective of the severity level of cerebral injury.

MRI- versus CT-based volume delineation of lumpectomy cavity in supine position in breast-conserving therapy: an exploratory study.

PURPOSE: To examine magnetic resonance imaging (MRI) and computed tomography (CT) for lumpectomy cavity (LC) volume delineation in supine radiotherapy treatment position and to assess the interobserver variability. METHODS AND MATERIALS: A total of 15 breast cancer patients underwent a planning CT and directly afterward MRI in supine radiotherapy treatment position. Then, 4 observers (2 radiation oncologists and 2 radiologists) delineated the LC on the CT and MRI scans and assessed the cavity visualization score (CVS). The CVS, LC volume, conformity index (CI), mean shift of the center of mass (COM), with the standard deviation, were quantified for both CT and MRI. RESULTS: The CVS showed that MRI and CT provide about equal optimal visibility of the LC. If the CVS was high, magnetic resonance imaging provided more detail of the interfaces of the LC seroma with the unaffected GBT. MRI also pictured in more detail the interfaces of axillary seromas (if present) with their surroundings and their relationship to the LC. Three observers delineated smaller, and one observer larger, LC volumes comparing the MRI- and CT-derived delineations. The mean ± standard deviation CI was 32% ± 25% for MRI and 52% ± 21% for CT. The mean ± standard deviation COM shift was 11 ± 10 mm (range 1-36) for MRI and 4 ± 3 mm (range 1-10) for CT. CONCLUSIONS: MRI does not add additional information to CT in cases in which the CVS is assessed as low. The conformity (CI) is lower for MRI than for CT, especially at a low CVS owing to greater COM shifts for MRI, probably caused by inadequate visibility of the surgical clips on magnetic resonance (MR) images. The COM shifts seriously dictate a decline in the CI more than the variability of the LC volumes does. In cases in which MRI provides additional information, MRI must be combined with the CT/surgical clip data.

Magnetic resonance imaging- versus computed tomography-based target volume delineation of the glandular breast tissue (clinical target volume breast) in breast-conserving therapy: an exploratory study.

PURPOSE: To examine MRI and CT for glandular breast tissue (GBT) volume delineation and to assess interobserver variability. METHODS AND MATERIALS: Fifteen breast cancer patients underwent a planning CT and MRI, consecutively, in the treatment position. Four observers (two radiation oncologists and two radiologists) delineated the GBT according to the CT and separately to the MR images. Volumes, centers of mass, maximum extensions with standard deviations (SD), and interobserver variability were quantified. Observers viewed delineation differences between MRI and CT and delineation differences among observers. RESULTS: In cranio-lateral and cranio-medial directions, GBT volumes were delineated larger using MRI when compared with those delineated with CT. Center of mass on MRI shifted a mean (SD) 17% (4%) into the cranial direction and a mean 3% (4%) into the dorsal direction when compared with that on the planning CT. Only small variations between observers were noted. The GBT volumes were approximately 4% larger on MRI (mean [SD] ratio MRI to CT GBT volumes, 1.04 [0.06]). Findings were concordant with viewed MRI and CT images and contours. Conformity indices were only slightly different; mean conformity index was 77% (3%) for MRI and 79% (4%) for CT. Delineation differences arising from personal preferences remained recognizable irrespective of the imaging modality used. CONCLUSIONS: Contoured GBT extends substantially further into the cranio-lateral and cranio-medial directions on MRI when compared with CT. Interobserver variability is comparable for both imaging modalities. Observers should be aware of existing personal delineation preferences. Institutions are recommended to review and discuss target volume delineations and to design supplementary guidelines if necessary.

Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression.

OBJECTIVE: To evaluate the clinical value of early partial symptomatic improvement in predicting the probability of response during the short-term treatment of bipolar depression. METHODS: Blinded data from 10 multicenter, randomized, double-blind, placebo-controlled trials in bipolar I or II depression were used to determine if early improvement (≥20% reduction in depression symptom severity after 14 days of treatment) predicted later short-term response or remission. Sensitivity, specificity, efficiency, and positive and negative predictive values (PPV, NPV) were calculated using an intent to treat analysis of individual and pooled study data. RESULTS: 1913 patients were randomized to active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1456 to placebo. In the pooled positive studies, early improvement predicted response and remission with high sensitivity (86% and 88%, respectively), but rates of false positives were high (53% and 59%, respectively). Pooled negative predictive values for response/remission (i.e. confidence in knowing the drug will not result in response or remission) were 74% and 82%, respectively, with low rates of false negatives (14% and 12%, respectively). CONCLUSION: Early improvement in an individual patient does not appear to be a reliable predictor of eventual response or remission due to an unacceptably high false positive rate. However, the absence of early improvement appears to be a highly reliable predictor of eventual non-response, suggesting that clinicians can have confidence in knowing when a drug is not going to work during short-term treatment. Patients who fail to demonstrate early improvement within the first two weeks of treatment may benefit from a change in therapy.

Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients.

OBJECTIVE: New evidence indicates that treatment response can be predicted with high sensitivity after 2 weeks of treatment. Here, we assess whether early improvement with antidepressant treatment predicts treatment outcome in patients with major depressive disorder (MDD). DATA SOURCES: Forty-one clinical trials comparing mirtazapine with active comparators or placebo in inpatients and outpatients (all-treated population, N = 6907; intent-to-treat population, N = 6562) with MDD (DSM-III-R or DSM-IV Criteria) were examined for early improvement (>or= 20% score reduction from baseline on the 17-item Hamilton Rating Scale for Depression [HAM-D-17] within 2 weeks of treatment) and its relationship to treatment outcome. STUDY SELECTION: Data were obtained from a systematic search of single- or double-blind clinical trials (clinical trials database, Organon, a part of Schering-Plough Corporation, Oss, The Netherlands). All included trials (a total of 41) employed antidepressant treatment for more than 4 weeks and a maximum of 8 weeks. The studies ranged from March 1982 to December 2003. Trials were excluded if there were no HAM-D-17 ratings available, no diagnosis of MDD, or if the study was not blinded. Trials were also excluded if HAM-D-17 assessments were not available at week 2, week 4, and at least once beyond week 4. DATA SYNTHESIS: Early improvement predicted stable response and stable remission with high sensitivity (>or= 81% and >or= 87%, respectively). Studies utilizing rapid titration vs. slow titration of mirtazapine demonstrated improved sensitivity for stable responders (98%, [95% CI = 93% to 100%] vs. 91% [95% CI = 89% to 93%]) and stable remitters (100%, [95% CI = 92% to 100%] vs. 93% [95% CI = 91% to 95%]). Negative predictive values for stable responders and stable remitters were much higher (range = 82%-100%) than positive predictive values (range = 19%-60%). CONCLUSIONS: These results indicate that early improvement with antidepressant medication can predict subsequent treatment outcome with high sensitivity in patients with major depressive disorder. The high negative predictive values indicate little chance of stable response or stable remission in the absence of improvement within 2 weeks. A lack of improvement during the first 2 weeks of therapy may indicate that changes in depression management should be considered earlier than conventionally thought.