Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations.

Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three "next-step" strategies: switching to another antidepressant (bupropion-SR) or augmenting the current antidepressant with either another antidepressant (bupropion-SR) or with an atypical antipsychotic (aripiprazole). The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed "efficacy-effectiveness" trial.

Celecoxib and mucosal protection: translation from an animal model to a phase I clinical trial of celecoxib, irinotecan, and 5-fluorouracil.

PURPOSE: Chemotherapy-induced diarrhea occurs secondary to mucosal inflammation and may be cyclooxygenase-2 mediated. Cyclooxygenase-2 inhibitors may ameliorate chemotherapy-induced mucosal toxicity and enhance its antitumor effect. We investigated this hypothesis in the Ward colorectal cancer rat model and in a phase I clinical study. EXPERIMENTAL DESIGN: In the Ward rat model, irinotecan was given daily x 3 or weekly x 4 with or without celecoxib. In the phase I clinical study, we planned to escalate the dose of irinotecan in the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) with a fixed dose of celecoxib. Irinotecan was escalated in four dose levels: 180, 200, 220, and 260 mg/m2. Celecoxib was administered as 400 mg, twice daily starting on day 2 of cycle 1. Pharmacokinetics of irinotecan, SN-38, and SN-38G were obtained on days 1 and 14. A standard 3+3 dose escalation scheme was used. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured using high-pressure liquid chromatography. RESULTS: Celecoxib ameliorated diarrhea, weight loss, and lethality and resulted in synergistic antitumor effect in the rat model. Twelve patients with advanced cancers were enrolled and evaluable for dose-limiting toxicity (DLT). Diarrhea was the cause for discontinuation in one. Grade 2 and 3 diarrhea occurred in three and two patients, respectively. One patient had DLT at dose level 2 (grade 3 diarrhea). Two had a DLT at DL3 (G3 emesis and myocardial infarct). Celecoxib had limited influence on the pharmacokinetics of irinotecan in this data set. CONCLUSIONS: Maximum tolerated dose of irinotecan in FOLFIRI schedule with celecoxib is 200 mg/m2.

A Phase II study of St. John's Wort for smoking cessation.

OBJECTIVES: To examine the feasibility and efficacy of St. John's Wort (SJW) for smoking cessation. DESIGN: This one-arm Phase II study utilized an exact two-stage group sequential design with a 1-week run-in period between the start of SJW treatment and the designated quit date. A total of 37 smokers (ages 18-65 years, smoking > or = 10 cigarettes/day) were started on SJW. Thirteen failed to make a verified quit attempt on the predesignated date and were taken off study resulting in 24 evaluable subjects. SETTING: Smokers completed clinic visits at a cancer center with interval telephone calls and mailings. INTERVENTION: Standardized SJW, 450 mg capsules taken orally twice daily along with cessation counseling messages. MAIN OUTCOME MEASURES: Subjects completed validated surveys and a focused physical examination at baseline. Evaluable subjects were defined as those subjects who made a confirmed quit attempt on their "quit date" 1 week following initiation of SJW. Smoking status was determined through self-report and bioverification using carbon monoxide (CO) testing. RESULTS: Among evaluable subjects, the 12-week quit rate was 37.5% (9/24). Quitters had no significant change in weight from baseline to 12-weeks cessation. Use of SJW was generally well tolerated. CONCLUSIONS: Based upon these results (which suggest that SJW may be effective in maintaining smoking cessation) and the high compliance and few AEs, we conclude that SJW demonstrates feasibility for use in smoking cessation. If SJW proves to be effective in larger controlled studies, it could represent a less expensive, more readily accessible and well-tolerated agent to promote tobacco cessation.

A Phase I study of weekly intravenous oxaliplatin in combination with oral daily capecitabine and radiation therapy in the neoadjuvant treatment of rectal adenocarcinoma.

PURPOSE: We conducted a Phase I study to determine the maximum tolerated dose (MTD) of neoadjuvant capecitabine, oxaliplatin, and radiation therapy (RT) in Stage II to III rectal adenocarcinoma. METHODS AND MATERIALS: Capecitabine was given orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given i.v. once weekly x 5 (for 5 weeks) starting the first day of RT. RT was given daily except on weekends and holidays at 1.8 Gy per fraction x 28. Escalation for capecitabine or oxaliplatin was to occur in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Endorectal tumor biopsy samples were obtained before and on Day 3 of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase, DNA repair, and apoptosis. RESULTS: Twelve patients were enrolled on this study. Two of 6 patients at dose level (DL) 1 (capecitabine 825 mg/m2 orally (p.o.) given twice daily (b.i.d.); oxaliplatin 50 mg/m2/week) had a dose-limiting diarrhea. One of 6 patients at DL (-)1 (capecitabine 725 mg/m2 p.o., b.i.d.; oxaliplatin 50 mg/m2/week) experienced-dose-limiting diarrhea. Three of 11 patients who underwent resection had a complete pathologic response. No remarkable variations in rectal tumor biologic endpoints were noted on Day 3 of treatment in comparison to baseline. However, a higher apotosis index was observed at baseline and on Day 3 in complete pathologic responders (no statistical analysis performed). CONCLUSIONS: Capecitabine 725 mg/m2 p.o., twice daily in combination with oxaliplatin 50 mg/m2/week and RT 50.4 Gy in 28 fractions is the recommended dose for future studies.