Effect of next-step antidepressant treatment on suicidal ideation: findings from the VAST-D trial.

BACKGROUND: Major depressive disorder (MDD) contributes to suicide risk. Treating MDD effectively is considered a key suicide prevention intervention. Yet many patients with MDD do not respond to their initial medication and require a 'next-step'. The relationship between next-step treatments and suicidal thoughts and behaviors is uncharted. METHOD: The VA Augmentation and Switching Treatments for Depression trial randomized 1522 participants to one of three next-step treatments: Switching to Bupropion, combining with Bupropion, and augmenting with Aripiprazole. In this secondary analysis, features associated with lifetime suicidal ideation (SI) and attempts (SA) at baseline and current SI during treatment were explored. RESULTS: Compared to those with SI only, those with lifetime SI + SA were more likely to be female, divorced, or separated, unemployed; and to have experienced more childhood adversity. They had a more severe depressive episode and were more likely to respond to 'next-step' treatment. The prevalence of SI decreased from 46.5% (694/1492) at baseline to 21.1% (315/1492) at end-of-treatment. SI during treatment was associated with baseline SI; low positive mental health, more anxiety, greater severity and longer duration of current MDD episode; being male and White; and treatment with S-BUP or C-BUP as compared to A-ARI. CONCLUSION: SI declines for most patients during next-step medication treatments. But about 1 in 5 experienced emergent or worsening SI during treatment, so vigilance for suicide risk through the entire 12-week acute treatment period is necessary. Treatment selection may affect the risk of SI.

Xanthine oxidase inhibitor urate-lowering therapy titration to target decreases serum free fatty acids in gout and suppresses lipolysis by adipocytes.

OBJECTIVE: Linked metabolic and cardiovascular comorbidities are prevalent in hyperuricemia and gout. For mechanistic insight into impact on inflammatory processes and cardiometabolic risk factors of xanthine oxidase inhibitor urate-lowering therapy (ULT) titration to target, we performed a prospective study of gout serum metabolomes from a ULT trial. METHODS: Sera of gout patients meeting the 2015 ACR/EULAR gout classification criteria (n = 20) and with hyperuricemia were studied at time zero and weeks 12 and 24 of febuxostat or allopurinol dose titration ULT. Ultrahigh performance liquid chromatography-tandem mass spectroscopy acquired the serum spectra. Data were assessed using the Metabolon and Metaboloanalyst software. Lipolysis validation assays were done in febuxostat and/or colchicine-treated 3T3-L1 differentiated adipocytes. RESULTS: Serum urate decreased from time zero (8.21 ±1.139 SD) at weeks 12 (5.965 ± 1.734 SD) and 24 (5.655 ±1.763 SD). Top metabolites generated by changes in nucleotide and certain amino acid metabolism and polyamine pathways were enriched at 12 and 24 weeks ULT, respectively. Decreases in multiple fatty acid metabolites were observed at 24 weeks, linked with obesity. In cultured adipocytes, febuxostat significantly decreased while colchicine increased the lipolytic response to ß-adrenergic-agonism or TNF. CONCLUSION: Metabolomic profiles linked xanthine oxidase inhibitor-based ULT titration to target with reduced serum free fatty acids. In vitro validation studies revealed that febuxostat, but not colchicine, reduced lipolysis in cultured adipocytes. Since soluble urate, xanthine oxidase inhibitor treatment, and free fatty acids modulate inflammation, our findings suggest that by suppressing lipolysis, ULT could regulate inflammation in gout and comorbid metabolic and cardiovascular disease.

Impact of Concurrent Posttraumatic Stress Disorder on Outcomes of Antipsychotic Augmentation for Major Depressive Disorder With a Prior Failed Treatment: VAST-D Randomized Clinical Trial.

OBJECTIVE: To determine whether concurrent posttraumatic stress disorder (PTSD) should affect whether to augment or switch medications when major depressive disorder (MDD) has not responded to a prior antidepressant trial. METHODS: Patients at 35 Veterans Health Administration medical centers from December 2012 to May 2015 with nonpsychotic MDD (N = 1,522) and a suboptimal response to adequate antidepressant treatment were randomly assigned to 3 "next step" treatments: switching to bupropion, augmenting the current antidepressant with bupropion, and augmenting with the antipsychotic aripiprazole. Blinded ratings with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) determined remission and response by 12 weeks and relapse after remission. Survival analyses compared treatment effects in patients with concurrent PTSD diagnosed with the Mini-International Neuropsychiatric Interview (n = 717, 47.1%) and those without PTSD (n = 805, 52.9%). RESULTS: Patients diagnosed with PTSD showed more severe depressive symptoms at baseline and were less likely to achieve either remission or response by 12 weeks. Augmentation with aripiprazole was associated with greater likelihood of achieving response (68.4%) than switching to bupropion (57.7%) in patients with PTSD (relative risk [RR] = 1.26; 95% CI, 1.01-1.59) as well as in patients without PTSD (RR = 1.29; 95% CI, 1.05-1.97) (78.9% response with aripiprazole augmentation vs 66.9% with switching to bupropion). Treatment comparisons with the group receiving augmentation with bupropion were not significant. There was no significant interaction between treatment group and PTSD on remission (P = .70), response (P = .98), or relapse (P = .15). CONCLUSIONS: Although PTSD was associated with poorer overall outcomes, the presence of concurrent PTSD among Veterans in this trial did not affect the comparative effectiveness of medications on response, remission, or relapse after initial remission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01421342.