A rapidly growing empirical literature on the treatment of major depressive disorder (MDD) in youth supports the efficacy of short-term treatment with depression-specific cognitive-behavioral therapy ...or medication management with a selective serotonin reuptake inhibitor. These studies also identify a substantial probability of partial response and of relapse, which might be addressed by more intensive, longer-term treatments.
Funded by the National Institute of Mental Health, the Treatment for Adolescents With Depression Study (TADS) is a multicenter, randomized, masked effectiveness trial designed to evaluate the short-term (12-week) and long-term (36-week) effectiveness of four treatments for adolescents with MDD: fluoxetine, cognitive-behavioral therapy, their combination, and, acutely, pill placebo. A volunteer sample of 432 subjects aged 12-17 years (inclusive) with a primary DSM-IV diagnosis of MDD who are broadly representative of patients seen in clinical practice will enter the study. The primary dependent measures rated blindly by an independent evaluator are the Children's Depression Rating Scale and, for responder analysis, a dichotomized Clinical Global Impressions-Improvement score. Consistent with an intent-to-treat analysis, all patients, regardless of treatment status, return for all scheduled assessments.
This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial.
When completed, TADS will improve our understanding of how best to initiate treatment for adolescents with MDD.
To determine if filgrastim (recombinant human methionyl granulocyte colony-stimulating factor) used in addition to standard inpatient antibiotic therapy accelerated recovery from infection associated ...with chemotherapy-induced neutropenia.
Randomized, double-blind, placebo-controlled trial.
Hematology and oncology wards of four teaching hospitals.
218 patients with cancer who had fever (temperature > 38.2 degrees C) and neutropenia (neutrophil count < 1.0 x 10(9)/L) after chemotherapy.
Patients were randomly assigned to receive filgrastim (12 micrograms/kg of body weight per day) (n = 109) or placebo (n = 107) beginning within 12 hours of empiric therapy with tobramycin and piperacillin. Patients received treatment and remained in the study until the neutrophil count was greater than 0.5 x 10(9)/L and until 4 days without fever (temperature < 37.5 degrees C) had elapsed.
Days of neutropenia and fever and days in the study (hospitalization); time to resolution of fever and febrile neutropenia; and frequency of the use of alternative antibiotics.
Compared with placebo, filgrastim reduced the median number of days of neutropenia (3.0 compared with 4.0 days of a neutrophil count of < 0.5 x 10(9)/L; P = 0.005) and the time to resolution of febrile neutropenia (5.0 compared with 6.0 days; P = 0.01) but not days of fever (3.0 days for both groups). The frequency of the use of alternative antibiotics was similar in the two groups (46% compared with 41%; P = 0.48). The median number of days patients were hospitalized while on study was the same (8.0 days; P = 0.09); however, filgrastim decreased the risk for prolonged hospitalization (> 11 days, 4th quartile) by half (relative risk, 2.1 95% CI, 1.1 to 4.1; P = 0.02). In exploratory subset analyses, filgrastim appeared to provide the greatest benefit in patients with documented infection and in patients presenting with neutrophil counts of less than 0.1 x 10(9)/L.
Filgrastim treatment used with antibiotics at the onset of febrile neutropenia in patients with cancer who have received chemotherapy accelerated neutrophil recovery and shortened the duration of febrile neutropenia.
Primer Sequence Ref Product size (bp) pmol per reaction APC exon 8 for ACC TAT AGT CTA AAT TAT ACC ATC 18 184 5 APC exon 8 rev GTC ATG GCA TTA GTG ACC AG 18 5 APC exon 15A for GTT ACT GCA TAC ACA TTG ...TGA C 18 371 2.5 APC exon 15A rev GCT TTT TGT TTC CTA ACA TGA AG 18 2.5 APC exon 15D for CTG CCC ATA CAC ATT CAA ACA C 18 382 2.5 APC exon 15D rev TGT TTG GGT CTT GCC CAT CTT 18 2.5 APC exon 15F for AAG CCT ACC AAT TAT AGT GAA CG 18 435 7.5 APC exon 15F rev AGC TGA TGA CAA AGA TGA TAA TG 18 7.5 MPZ exon 1 for CAG TGG ACA CAA AGC CCT CTG TGT A Yau (pers com) 389 7.5 MPZ exon 1 rev GAC ACC TGA GTC CCA AGA CTC CCA G Yau (pers com) 7.5 MPZ exon 2 for CTC ACT TCC TCT GTA TCC CTT ACT G Yau (pers com) 393 10 MPZ exon 2 rev GGA GGA CAA TGT AGT CAG GGT GAC A Yau (pers com) 10 MPZ exon 3 for TGA CAG CTG TGT TCT CAT TAG GGT C Yau (pers com) 453 7.5 MPZ exon 3 rev TCC GAG TGT ATG CCC TGC ATT GAG G Yau (pers com) 7.\n The order of the markers and exons is 5variant prime of APCto 3variant prime of APC. CGH is a promising alternative, but limitations in the size of deletions or duplications detectable by metaphase spreads must be overcome by the availability of arrayed DNA before the technique can be generally applicable. Since automated fragment analysis is already widely used in genetic diagnostic laboratories, the use of dosage quotient analysis offers a robust and accessible means to test for microdeletions and duplications.
To define the clinical and hematologic effects of subcutaneously administered bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF).
Single arm ...nonrandomized dose escalation study.
Twenty-one patients with advanced malignancy who were not receiving concurrent myelosuppressive therapy.
Subcutaneous administration of rhGM-CSF by once-daily injection to groups of two to four patients at doses of 0.3 to 30 micrograms/kg body weight.d for 10 consecutive days. Some patients received a second 10-day period of daily rhGM-CSF treatment after a 10-day nontreatment interval followed by alternate-day treatment. Clinical status and hematologic values were monitored frequently.
All doses of rhGM-CSF caused an immediate transient fall of 84% to 99% in circulating neutrophils, eosinophils, and monocytes. Continued daily dosing caused a leukocytosis of up to 10-fold with increases in numbers of circulating neutrophils, eosinophils, monocytes, and lymphocytes. There appeared to be a plateau in the increase in neutrophils in the dose range 3 to 15 micrograms/kg.d. Marrow aspirates showed increased proportions of promyelocytes and myelocytes. Alternate-day injection of 15 micrograms/kg maintained a leukocytosis. At doses up to 15 micrograms/kg.d, rhGM-CSF was well tolerated but adverse effects included bone pains, myalgias, rashes, and liver dysfunction. At doses exceeding 15 micrograms/kg.d, pericarditis was a dose-limiting toxicity. Idiopathic thrombocytopenic purpura was reactivated by rhGM-CSF in one patient.
Bacterially synthesized rhGM-CSF induces a leukocytosis in the dose range of 3 to 15 micrograms/kg.d. These doses are appropriate for phase II studies.
A Phase I study of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was undertaken in 21 patients with advanced malignancy or neutropenia. ...rhGM-CSF was administered once daily by i.v. bolus injection (0.3 to 3 micrograms/kg/day) or 2-h i.v. infusion (3 to 20 micrograms/kg day) for 10 days. rhGM-CSF at all i.v. doses caused an immediate transient decrease in circulating neutrophils, eosinophils, and monocytes. By 6 h after rhGM-CSF, circulating leukocyte levels were restored. Daily i.v. bolus dosing (0.3 to 3 micrograms/kg/day) did not elevate leukocyte levels except in one neutropenic patient. Daily 2-h i.v. infusions (10 to 20 micrograms/kg/day) caused a dose-dependent leukocytosis with increased levels of neutrophils (up to 4.3-fold), eosinophils (up to 18-fold), and monocytes (up to 3.5-fold). Marrow aspirates showed increased proportions of promyelocytes and myelocytes during rhGM-CSF administration. Retreatment after 10 days without rhGM-CSF resulted in a more marked leukocytosis at doses greater than or equal to 10 micrograms/kg/day. Platelet levels decreased for the first 3 days and then increased during the first course of rhGM-CSF administration. Two patients with chronic lymphocytic leukemia had a transient reduction in lymphocytosis. Serum cholesterol and albumin levels decreased, and vitamin B12 levels increased during rhGM-CSF treatment. At doses of up to 15 micrograms/kg/day, rhGM-CSF was relatively well tolerated by the patients, but adverse effects included bone pain, lethargy, fever, rash, and weight gain. A first dose reaction characterized by hypoxia and hypotension was identified at dose levels greater than or equal to 1 microgram/kg. Dosing i.v. was less potent at inducing a leukocytosis than previously observed for equivalent s.c. doses and was associated with a higher incidence of generalized rash and first dose reactions. The maximal tolerated dose of i.v. rhGM-CSF was 15 micrograms/kg/day. Phase II studies in which the derived effect is to raise leukocyte levels should be undertaken at rhGM-CSF doses of 3 to 15 micrograms/kg/day.
The colony-stimulating factors control the proliferation, differentiation, maturation, and activation of hemopoietic cells. The availability of large quantities of the hemopoietic growth factors as a ...result of the application of recombinant DNA technology permitted clinical trials to commence in 1987. Many clinical applications have been suggested. We review the findings of the preclinical and early clinical trials with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and granulocyte-macrophage colony-stimulating factor (rhGM-CSF).
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