Continuation phase treatment outcomes for switching, combining, or augmenting strategies for treatment-resistant major depressive disorder: A VAST-D report.

BACKGROUND: This secondary analysis of the VA Augmentation and Switching Treatments for Depression study compared the continuation phase treatment outcomes of three commonly used second-step treatment strategies following at least one prior failed medication treatment attempt. METHODS: In total, 1522 outpatients with MDD were randomized to switching to bupropion-SR (S-BUP), combining with bupropion-SR (C-BUP), or augmenting with aripiprazole (A-ARI). Following 12 weeks of acute phase treatment, 725 entered the 24-week continuation treatment phase. Depressive symptom severity, relapse, "emergent" remission, anxiety, suicidal ideation, quality of life, health status, and side effects were compared. RESULTS: We did not find clinically significant differential treatment effects with the exception that A-ARI was associated with less anxiety than S-BUP or C-BUP. Participants who entered continuation treatment as remitters had milder depressive symptom severity and lower relapse rates than those not in remission; they also experienced more improvement on most other outcomes. A-ARI was associated with less anxiety, insomnia, and dry mouth but more somnolence, extrapyramidal effects, akathisia, abnormal laboratory values, and appetite and weight gain. CONCLUSIONS: Continuation treatment is a dynamic period. Regardless of the treatment, participants who entered continuation treatment at Week 12 in full remission continued to have better outcomes over the subsequent 24 weeks than those who were not in remission at the start of the continuation phase.

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.

Defining "Adequately Treated": A Post Hoc Analysis Examining Characteristics of Patients with Schizophrenia Successfully Transitioned from Once-Monthly Paliperidone Palmitate to Once-Every-3-Months Paliperidone Palmitate.

PURPOSE: Paliperidone palmitate once every 3 months (PP3M) is indicated in adults with schizophrenia adequately treated with once-monthly paliperidone palmitate (PP1M) for at least 4 months, in whom the last two consecutive doses are the same. The decision of when to transition to PP3M is based on the patient's symptom status while receiving PP1M. PATIENTS AND METHODS: In a double-blind relapse-prevention study (NCT01529515), patients who met Positive and Negative Syndrome Scale (PANSS) score stabilization criteria after 4 months of PP1M were eligible for transition to PP3M; those who continued to meet stabilization criteria after 12 weeks following an open-label PP3M dose were randomized to receive PP3M or placebo. We compared (post hoc) PANSS, Clinical Global Impression-Severity (CGI-S), and Personal and Social Performance (PSP) scores during the pre-randomization, open-label phase in patients in randomized versus non-randomized groups using analysis of variance or chi-square tests. RESULTS: Of 506 patients enrolled, 305 were randomized. After 4 months' PP1M treatment, PANSS and CGI-S scores were significantly lower and PSP scores significantly higher in randomized patients versus non-randomized patients (least squares means [95% CI]: 57.1 [55.7, 58.6] vs 62.2 [60.0, 64.3], 2.9 [2.8, 3.1] vs 3.3 [3.1, 3.4], and 67.0 [65.7, 68.3] vs 64.5 [62.6, 66.4], respectively); changes from baseline between groups differed significantly (all P ≤0.009). CONCLUSION: Confirming adequate stabilization with PP1M prior to transitioning to PP3M is critical in maximizing treatment response; clinicians should consider transitioning patients to PP3M only if patients respond well to PP1M for at least 4 months and their last two consecutive doses are the same.

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.

Anxious depression: clinical features and treatment.

Anxious depression has been conceptualized in at least two related but separate ways: 1) major depressive disorder with at least one comorbid Axis I anxiety disorder and 2) major depressive disorder with a high level of anxiety with or without one or more comorbid Axis I anxiety disorders. Using either definition, patients with anxious depression seem to have a more chronic course of illness, an increased incidence of suicidal thoughts and behavior, greater functional and occupational impairment, and poorer response to treatment. Multiple classes of medications are used to treat anxious depression, most commonly first- and second-generation antidepressants, atypical antipsychotics, and benzodiazepines. Certain patients with anxious depression may require lower starting doses, more gradual dose escalations, higher end point doses, longer duration of treatment, and/or early augmentation with other agents. Nonpharmacologic treatments such as targeted psychotherapy and preventative stepped-care approaches also may be effective. Well-conceived, randomized controlled treatment trials are necessary to make further gains in the management of patients with anxious depression.

Pediatric Headache Management and Use of the PedMIDAS.

BACKGROUND: Headache is a worldwide problem affecting people of all ages, races, and incomes. Childhood headache is a common condition affecting quality of life and prompting frequent medical visits. The Pediatric Migraine Disability Assessment tool (PedMIDAS) is a validated questionnaire recognized in the assessment of pediatric headache. Use of the PedMIDAS is supported in the 2014 American Academy of Neurology headache quality measurement set, which provides practice parameters for headache management. OBJECTIVE: The purpose of this quality improvement project is to introduce the PedMIDAS into the assessment of pediatric headache patients in a pediatric neurology practice in an attempt to standardize care and discern provider satisfaction. METHODS: Chart review (11-21-16 to 11-30-17) following provider/staff education regarding the PedMIDAS. RESULTS: The PedMIDAS was completed 23% of the time (404/1741). CONCLUSIONS: Although the PedMIDAS was only completed 23% of the time, providers surveyed regarding usefulness indicated the PedMIDAS is helpful with quantifying the disability experienced by pediatric headache patients. IMPLICATIONS FOR NURSING: Assessing disability through the use of the PedMIDAS is a beneficial practice change helping with evaluating headache interventions, differentiating headache frequency from disability, and clarifying the severity of pain related to headache that affects daily life.

Psychiatric issues in palliative care: recognition of depression in patients enrolled in hospice care.

Major depression is prevalent, difficult to assess, underrecognized, and undertreated in hospice settings. Furthermore, it is associated with significant morbidity and mortality. A retrospective chart review of 2716 patients receiving hospice care was conducted in order to determine the baseline rate of recognition of depression in patients with advanced, life-threatening illnesses by frontline hospice clinicians. Documentation of "depression" as either a diagnosis or problem was used as an estimate of how often these disorders were considered significant issues by the treating interdisciplinary team. Of the patients receiving home/long-term care, 10.8% (234/2168) had depression documented as a diagnosis or significant problem. The presence of recognized depression in this setting was associated with significant differences in gender, marital status, and terminal diagnoses. Total length of hospice care was also significantly longer. Of patients receiving inpatient care, 13.7% (75/548) had depression documented as a diagnosis or significant problem. Recognized depression in this setting was associated with significant differences in marital status, length of inpatient stay, and total time in hospice care. If documentation is representative of the care that the interdisciplinary teams provide, depression of any kind appears to be underrecognized in this population. In fact, it is on the low end of prevalence estimates in the literature. Improved depression assessment is needed in order to minimize the impact of depression on patients living with advanced, life-threatening illnesses.

Dosing strategies for switching from oral risperidone to paliperidone palmitate: Effects on clinical outcomes.

INTRODUCTION: There are currently no guidelines for switching patients from oral risperidone to paliperidone palmitate (Invega Sustenna®). Furthermore, the paliperidone long-acting injectable (LAI) package insert does not recommend bridging with oral antipsychotics, which may result in inadequate serum concentrations in patients on ≥4 mg/d risperidone. METHODS: This study evaluated the effects of suboptimal dosing and bridging in patients switched from oral risperidone to paliperidone LAI on hospitalization days, emergency department (ED)/mental health urgent care visits, and no-shows/cancellations to mental health appointments. Patients were categorized into optimal or suboptimal dosing based on their loading and maintenance paliperidone doses. Patients on risperidone ≥4 mg/d were categorized as bridged if they received risperidone for ≥7 days after the first paliperidone injection. RESULTS: There were no significant differences in outcomes between optimally and suboptimally dosed patients. There were statistically significant reductions in hospitalization days in patients who were bridged compared with patients who were not bridged. There were statistically significant reductions in hospitalization days and ED/mental health urgent care visits after switching to paliperidone LAI. DISCUSSION: The results of this study indicate that bridging patients who are on ≥4 mg/d risperidone, when converting to paliperidone LAI, is associated with reductions in hospitalization days. However, more research is required to determine the optimal dose and duration of the bridge. The results also indicate that switching patients from oral risperidone to paliperidone LAI, even if the dose is suboptimal, is associated with reductions in hospitalization days and ED/mental health urgent care visits.

Characteristics of U.S. Veteran Patients with Major Depressive Disorder who require "next-step" treatments: A VAST-D report.

OBJECTIVE: Finding effective and lasting treatments for patients with Major Depressive Disorder (MDD) that fail to respond optimally to initial standard treatment is a critical public health imperative. Understanding the nature and characteristics of patients prior to initiating "next-step" treatment is an important component of identifying which specific treatments are best suited for individual patients. We describe clinical features and demographic characteristics of a sample of Veterans who enrolled in a "next-step" clinical trial after failing to achieve an optimal outcome from at least one well-delivered antidepressant trial. METHODS: 1522 Veteran outpatients with nonpsychotic MDD completed assessments prior to being randomized to study treatment. Data is summarized and presented in terms of demographic, social, historical and clinical features and compared to a similar, non-Veteran sample. RESULTS: Participants were largely male and white, with about half unmarried and half unemployed. They were moderately severely depressed, with about one-third reporting recent suicidal ideation. More than half had chronic and/or recurrent depression. General medical and psychiatric comorbidities were highly prevalent, particularly PTSD. Many had histories of childhood adversity and bereavement. Participants were impaired in multiple domains of their lives and had negative self-worth. LIMITATIONS: These results may not be generalizable to females, and some characteristics may be specific to Veterans of US military service. There was insufficient data on age of clinical onset and depression subtypes, and three novel measures were not psychometrically validated. CONCLUSIONS: Characterizing VAST-D participants provides important information to help clinicians understand features that may optimize "next-step" MDD treatments.

Neonatal Gabapentin Withdrawal Syndrome.

INTRODUCTION: Gabapentin, an anticonvulsant, neuroleptic, and pain medication, is widely used in both adults and children for management of epilepsy, bipolar illness, and neuropathic pain. Gabapentin use has also been recommended for hyperemesis gravidarum and restless leg syndrome in pregnant mothers. OBJECTIVE: Although gabapentin use is deemed safe during pregnancy, no clinical reports of gabapentin withdrawal syndrome in a neonate have been described. RESULTS: We present a newborn who showed signs of withdrawal after prolonged in utero exposure to gabapentin. CLINICAL IMPLICATIONS: Clinicians should be aware of possible withdrawal symptoms from drugs such as gabapentin, administered to mothers during pregnancy. We also encourage the gradual tapering of gabapentin in neonates over weeks to months similar to the adult population.

Ease of screening for depression and delirium in patients enrolled in inpatient hospice care.

BACKGROUND: Major depression and delirium are prevalent, underrecognized, and undertreated in hospice and palliative care settings. Furthermore, they are both associated with significant morbidity and mortality. OBJECTIVE: A screening study of patients receiving inpatient hospice care was conducted in order to determine the ease of screening for depression and delirium in patients with advanced, life-threatening illnesses by hospice social workers and nurses, respectively. METHODS: A two-question depression screening tool was administered to 20 consecutive patients on admission to a hospice general inpatient care center by social work staff during their initial assessment. A delirium-screening tool was administered daily to 22 consecutive patients admitted to the ICC daily by nursing staff. Screening results were collected, as were patient and staff feelings about the burden of the screening process. RESULTS: Of the 20 patients screened on admission for depression by social work, 70% (14/20) screened positive. Of the 22 patients screened daily for delirium by nursing, 64% (14/22) screened positive at least once during their admission. Screening for both conditions was considered relatively easy to accomplish by the hospice staff. There were no significant associations between a positive screen of depression or delirium and patient gender, age, ethnicity, terminal diagnosis, or marital status. DISCUSSION: These results support the notion that depression and delirium are very common in hospice inpatients, and that screening for both is relatively easy and practical for hospice clinicians to conduct.

Augmentation with citalopram for suicidal ideation in middle-aged and older outpatients with schizophrenia and schizoaffective disorder who have subthreshold depressive symptoms: a randomized controlled trial.

OBJECTIVE: To examine the effects of citalopram augmentation of antipsychotics on suicidal ideation in middle-aged and older people with schizophrenia and subthreshold depressive symptoms. METHOD: In this placebo-controlled trial conducted from September 1, 2001, to August 31, 2007, 198 outpatients > or = 40 years old with DSM-IV-diagnosed schizophrenia or schizoaffective disorder and subthreshold depressive symptoms were randomly assigned to flexible-dose citalopram (n = 104) or placebo (n = 94) augmentation of their antipsychotic for 12 weeks. Depression was measured with the Hamilton Depression Rating Scale (HDRS) and Calgary Depression Rating Scale (CDRS). Primary suicidal ideation measures were the Clinical Global Impressions-Severity of Suicide scale (CGI-SS) and the InterSePT Scale for Suicidal Thinking (ISST); secondary outcomes were the Scale for Suicidal Ideation (SSI), Beck Hopelessness Scale (BHS), HDRS item 3, and CDRS item 8. RESULTS: Compared to placebo, at the final visit, citalopram was associated with lower BHS scores (4.21 vs 4.98; P < .05) and lower likelihood of having suicidal ideation on the ISST (17.7% vs 38.7%; P < .005) and HDRS item 3 (14.4% vs 22.6%; P < .05). Among the 114 participants with no baseline suicidal ideation, there were no significant differences between citalopram and placebo regarding "emergent" ideation on either primary outcome. Among the 55 participants with baseline suicidal ideation, fewer treated with citalopram had endpoint ideation on the ISST (28.6% vs 66.7%; P < .05). Significantly more depression responders than nonresponders went from having baseline suicidal ideation to no suicidal ideation on both the ISST (75.0% vs 31.4%; P < .05) and CGI-SS (84.6% vs 31.3%; P < .05). CONCLUSIONS: Treatment-emergent suicidal ideation was no more common with citalopram than placebo. In participants with baseline suicidal ideation, citalopram reduced suicidal ideation, especially in those whose depressive symptoms responded to treatment.