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Context: We previously used positron emission tomography (PET) measurement of brain metabolism with 18fluorodeoxyglucose to show that patients receiving selective serotonin reuptake inhibitors (SSRIs) who have a tryptophan depletion-induced return of depressive symptoms have an acute decrease in metabolism in orbitofrontal cortex, dorsolateral prefrontal cortex, and thalamus. Many patients with depression in remission while taking norepinephrine reuptake inhibitors (NRIs) (but not SSRIs) experience a return of depressive symptoms with depletion of norepinephrine and dopamine using alpha-methylparatyrosine (AMPT).Objective: To assess brain metabolic correlates of AMPT administration in patients with depression in remission while receiving NRIs.Design, Setting, and Participants: Randomized, controlled, double-blind trial in which 18 patients recruited in 1997-2000 from the general community who had depression in remission while taking NRIs had PET imaging in a psychiatric research unit following AMPT and placebo administration.Interventions: After initial medication with desipramine and follow-up until response, patients underwent active AMPT (five 1-g doses administered orally over 28 hours) and placebo (diphenhydramine hydrochloride, five 50- mg doses administered similarly) catecholamine depletion challenges in randomized order of assignment, after which PET imaging was performed on day 3 of each condition. Both study conditions were performed 1 week apart.Main Outcome Measures: Regional brain metabolism rates in patients with and without AMPT-induced return of depressive symptoms.Results: AMPT-induced return of depressive symptoms was experienced by 11 of the 18 patients and led to decreased brain metabolism in a number of cortical areas, with the greatest magnitude of effects in orbitofrontal (P =.002) and dorsolateral prefrontal (P =.03) cortex and thalamus (P =.006). Increased resting metabolism in prefrontal and limbic areas predicted vulnerability to return of depressive symptoms.Conclusions: Different neurochemical systems that mediate depression may have effects on a common brain circuitry. Baseline metabolism in successfully treated depressed patients may predict vulnerability to future episodes of depression. [ABSTRACT FROM AUTHOR]

Introduction: Chronic stress-related illnesses such as major depressive disorder and post-traumatic stress disorder share symptomatology, including anxiety, anhedonia, and helplessness. Across disorders, neurotoxic dysregulated glutamate (Glu) signaling may underlie symptom emergence. Current first-line antidepressant drugs, which do not directly target Glu signaling, fail to provide adequate benefit for many patients and are associated with high relapse rates. Riluzole modulates glutamatergic neurotransmission by increasing metabolic cycling and modulating signal transduction. Clinical studies exploring riluzole's efficacy in stress-related disorders have provided varied results. However, the utility of riluzole for treating specific symptom dimensions or as a prophylactic treatment has not been comprehensively assessed., Methods: We investigated whether chronic prophylactic riluzole (∼12-15 mg/kg/day p.o.) could prevent the emergence of behavioral deficits induced by unpredictable chronic mild stress (UCMS) in mice. We assessed (i) anxiety-like behavior using the elevated-plus maze, open-field test, and novelty-suppressed feeding, (ii) mixed anxiety/anhedonia-like behavior in the novelty-induced hypophagia test, and (iii) anhedonia-like behavior using the sucrose consumption test. Z-scoring summarized changes across tests measuring similar dimensions. In a separate learned helplessness (LH) cohort, we investigated whether chronic prophylactic riluzole treatment could block the development of helplessness-like behavior., Results: UCMS induced an elevation in anhedonia-like behavior and overall behavioral emotionality that was blocked by prophylactic riluzole. In the LH cohort, prophylactic riluzole blocked the development of helplessness-like behavior., Discussion/conclusion: This study supports the utility of riluzole as a prophylactic medication for preventing anhedonia and helplessness symptoms associated with stress-related disorders., Competing Interests: G.S. has served as consultant to Allergan, Alkermes, Aptiny, Axsome Therapeutics, Biogen, Biohaven Pharmaceuticals, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Cowen, EMA Wellness, Engrail Therapeutics, Clexio, Denovo Biopharma, Gilgamesh, Hoffman La-Roche, Intra-Cellular Therapies, Janssen, Levo, Lundbeck, Merck, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Seelos Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, Vistagen Therapeutics, and XW Laboratories and received research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Naurex, and the Usona Institute over the past 36 months. Dr. Sanacora holds equity in Biohaven Pharmaceuticals and is a co-inventor on a US patent (#8778979) held by Yale University and a co-inventor on US Provisional Patent Application No. 047162-7177P1 (00754) filed on August 20, 2018, by Yale University Office of Cooperative Research. Yale University has a financial relationship with Janssen Pharmaceuticals and may in the future receive financial benefits from this relationship. The University has put multiple measures in place to mitigate this institutional conflict of interest. Questions about the details of these measures should be directed to Yale University’s Conflict of Interest office. R.M.B. and V.C. are employees and stockholders of Biohaven Pharmaceuticals., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Glutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors., Methods: Patients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy., Results: We enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested., Conclusion: The combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors. Trial Registration ClinicalTrials.gov Identifier NCT03229278., (© 2022. The Author(s).)

For patients with amyotrophic lateral sclerosis who take oral riluzole tablets, approximately 50% experience alanine transaminase (ALT) levels above upper limit of normal (ULN), 8% above 3× ULN, and 2% above 5× ULN. BHV-0223 is a novel 40 mg rapidly sublingually disintegrating (Zydis) formulation of riluzole, bioequivalent to conventional riluzole 50 mg oral tablets, that averts the need for swallowing tablets and mitigates first-pass hepatic metabolism, thereby potentially reducing risk of liver toxicity. DILIsym is a validated multiscale computational model that supports evaluation of liver toxicity risks. DILIsym was used to compare the hepatotoxicity potential of oral riluzole tablets (50 mg BID) versus BHV-0223 (40 mg BID) by integrating clinical data and in vitro toxicity data. In a simulated population (SimPops), ALT levels > 3× ULN were predicted in 3.9% (11/285) versus 1.4% (4/285) of individuals with oral riluzole tablets and sublingual BHV-0223, respectively. This represents a relative risk reduction of 64% associated with BHV-0223 versus conventional riluzole tablets. Mechanistic investigations revealed that oxidative stress was responsible for the predicted ALT elevations. The validity of the DILIsym representation of riluzole and assumptions is supported by its ability to predict rates of ALT elevations for riluzole oral tablets comparable with that observed in clinical data. Combining a mechanistic, quantitative representation of hepatotoxicity with interindividual variability in both susceptibility and liver exposure suggests that sublingual BHV-0223 confers diminished rates of liver toxicity compared with oral tablets of riluzole, consistent with having a lower overall dose of riluzole and bypassing first-pass liver metabolism., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology.)

Orally administered riluzole extends survival in patients with amyotrophic lateral sclerosis, although it has significant shortcomings (eg, adverse events, dysphagic patients) that limit its utility. BHV-0223 is a Zydis-based orally disintegrating formulation of riluzole designed for sublingual administration that addresses the limitations of conventional tablets. This study assessed the bioequivalence between 40-mg BHV-0223 and standard 50-mg oral riluzole tablets, and the food effect on BHV-0223 pharmacokinetics in healthy volunteers. Overall, 133 healthy subjects received BHV-0223 and riluzole tablets under fasted conditions. Geometric mean ratios for the area under the plasma concentration-time curve (AUC) from time zero to time of last nonzero concentration (AUC 0-t ) (89.9%; confidence interval [CI], 87.3%-92.5%), AUC from time zero to infinity (AUC 0-∞ ) (89.8%; CI, 87.3%-92.4%), and maximum observed concentration (112.7%; CI, 105.5%-120.4%) all met bioequivalence criteria (80%-125%). Subsequently, 67 subjects received BHV-0223 under fed conditions. The geometric mean ratios of AUC 0-t (91.2%; CI, 88.1-94.3%), and AUC 0-∞ (92.0%; CI, 89.0-95.1%) were similar, but maximum observed concentration ratios were not within bioequivalence criteria. BHV-0223 was well tolerated. This study demonstrated that 40-mg sublingual BHV-0223 is bioequivalent to 50-mg oral riluzole tablets., (© 2019, The American College of Clinical Pharmacology.)

Background: Glypican 3 (GPC3), a plasma membrane heparan sulfate proteoglycan, is overexpressed on human hepatocellular carcinoma and may represent a promising biomarker. Several studies have reported peptides that selectively bind to GPC3 and could serve as scaffolds for imaging or therapeutic agents. Materials and Methods: We synthesized variants of two previously published peptides, DHLASLWWGTEL (TJ12P1) and RLNVGGTYFLTTRQ (L5), and evaluated their in vitro binding performance in paired isogenic cell lines, A431(GPC3 - ) and A431-GPC3 + (G1), as well as the liver cancer cell line HepG2. Using flow cytometry and biolayer interferometry (BLI), we compared the binding of the TJ12P1 and L5 peptide variants to the binding of corresponding scrambled peptides having the same amino acid composition, but in random sequence. Results: While both peptides bound to G1 and HepG2, they also bound to A431. The corresponding scrambled peptides demonstrated greater apparent binding to both G1 and A431 than their specific counterparts. BLI confirmed lack of binding at 0.5-1 μM for both peptides. Conclusions: We conclude that neither TJ12P1 nor L5 variant demonstrates selectivity for GPC3 at concentrations near the reported K D , and that the peptides lack potency or are nonspecific, making them inadequate for use as imaging agents.

The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a γ-secretase modulator (GSM), were tested in healthy young and elderly volunteers after single and multiple doses. BMS-932481 was orally absorbed, showed dose proportionality after a single dose administration, and had approximately 3-fold accumulation after multiple dosing. High-fat/caloric meals doubled the Cmax and area under the curve and prolonged Tmax by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased cerebrospinal fluid (CSF) Aβ39, Aβ40, and Aβ42 while increasing Aβ37 and Aβ38, thereby providing evidence of γ-secretase enzyme modulation rather than inhibition. In plasma, reductions in Aβ40 and Aβ42 were observed with no change in total Aβ; in CSF, modest decreases in total Aβ were observed at higher dose levels. Increases in liver enzymes were observed at exposures associated with greater than 70% CSF Aβ42 lowering after multiple dosing. Although further development was halted due to an insufficient safety margin to test the hypothesis for efficacy of Aβ lowering in Alzheimer's disease, this study demonstrates that γ-secretase modulation is achievable in healthy human volunteers and supports further efforts to discover well tolerated GSMs for testing in Alzheimer's disease and other indications., (Copyright © 2016 The Author(s).)

DCE MRI is an established component of multi-parametric MRI of the prostate. The sequence highlights the vascularization of cancerous lesions, allowing readers to corroborate suspicious findings on T2W and DW MRI and to note subtle lesions not visible on the other sequences. In this article, we review the technical aspects, methods of evaluation, limitations, and future perspectives of DCE MRI.

Importance: Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms., Objectives: To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia., Design, Setting, and Participants: A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity., Interventions: Oral avagacestat or placebo daily., Main Outcomes and Measure: Safety and tolerability of avagacestat., Results: Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures., Conclusions and Relevance: Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD., Trial Registration: clinicaltrials.gov Identifier: NCT00890890.

Background: This study examined the psychometric relationship between the Word and Picture versions of the Free and Cued Selective Reminding Test (FCSRT) and developed an equation for score conversion., Methods: 187 participants were administered the FCSRT-Picture and FCSRT-Word on two visits using a randomized counterbalanced design., Results: Participants had a mean age of 82.1 (sd=5.4) and mean education of 14.5 (sd=3.3) years. Mean FCSRT-Picture Free Recall score (mean 33.0, range: 17-44) was 7.9 points higher than the Word score (mean 25.1, range: 3-43). The Picture and Word FCSRT correlations for Free Recall and Total Recall were r=0.56, p<0.01 and r=0.46, p<0.01, respectively., Discussion: The Picture and Word versions of the FCSRT were moderately associated in a sample of cognitively normal older adults. The score mean differences and variability between FCSRT-Picture and FCSRT-Word indicate that their scores should not be considered equivalent.

Introduction: Efficacy of depression treatments, including adjunctive antipsychotic treatment, has not been explored for patients with worsening symptoms after antidepressant therapy (ADT)., Methods: This post-hoc analysis utilized pooled data from 3 similarly designed, randomized, double-blind, placebo-controlled trials that assessed the efficacy, safety, and tolerability of adjunctive aripiprazole in patients with major depressive disorder with inadequate response to ADT. The studies had 2 phases: an 8-week prospective ADT phase and 6-week adjunctive (aripiprazole or placebo) treatment phase. This analysis focused on patients whose symptoms worsened during the prospective 8-week ADT phase (worsening defined as >0% increase in Montgomery-Åsberg Depressive Rating Scale [MADRS] Total score). During the 6-week, double-blind, adjunctive phase, response was defined as ≥50% reduction in MADRS Total score and remission as ≥50% reduction in MADRS Total score and MADRS score ≤10., Results: Of 1065 patients who failed to achieve a response during the prospective phase, 160 exhibited worsening of symptoms (ADT-Worseners), and 905 exhibited no change/reduction in MADRS scores (ADT-Non-worseners). Response rates for ADT-Worseners at endpoint were 36.6% (adjunctive aripiprazole) and 22.5% (placebo). Similarly, response rates at endpoint for ADT-Non-worseners were 37.5% (adjunctive aripiprazole) and 22.5% (placebo). Remission rates at endpoint for ADT-Worseners were 25.4% (adjunctive aripiprazole) and 12.4% (placebo). For ADT-Non-worseners, remission rates were 29.9% (adjunctive aripiprazole) and 17.4% (placebo)., Conclusion: These results suggest that adjunctive aripiprazole is an effective intervention for patients whose symptoms worsen during antidepressant monotherapy. The results challenge the view that benefits of adjunctive therapy with aripiprazole are limited to partial responders to ADT.

Background: The efficacy of adjunctive aripiprazole in patients with major depressive disorder (MDD) with no improvement after 8 weeks of prior antidepressant monotherapy has not been evaluated., Methods: A post hoc analysis of three similarly designed, randomised, double-blind, placebo-controlled, phase III studies was conducted investigating the efficacy and safety of aripiprazole adjunctive to standard antidepressant treatment (ADT) in MDD patients with a prior inadequate response to one to three ADTs. Minimal improvement to antidepressant monotherapy was defined as a Clinical Global Impressions - Improvement (CGI-I) score of 3 and non-improvement as a CGI-I of 4 at weeks 6 and 8 of antidepressant monotherapy., Results: The end-point response rate for ADT minimal improvers receiving adjunctive aripiprazole was 38.8% vs. 26.6% for adjunctive placebo (p < 0.05; number needed to treat [NNT] = 9 [95% confidence interval: 4.8-27.7]), and for ADT non-improvers receiving adjunctive aripiprazole was 24.0% vs. 10.3% for adjunctive placebo (p < 0.05; NNT = 8 [95% confidence interval: 4.4-21.5]). ADT minimal improvers and non-improvers demonstrated significant improvements in response vs. ADT alone as early as after 1 and 2 weeks of adjunctive treatment, respectively. The end-point remission rate for ADT minimal improvers receiving adjunctive aripiprazole was 34.2% vs. 21.0% for adjunctive placebo (p < 0.05; NNT = 8), and for ADT non-improvers receiving adjunctive aripiprazole was 16.0% vs. 5.9% for adjunctive placebo (p < 0.05; NNT = 10). The most common adverse events for ADT minimal improvers and non-improvers receiving adjunctive aripiprazole were akathisia, restlessness and insomnia., Conclusion: Patients with minimal or no improvement after 8 weeks of antidepressant monotherapy significantly benefited from adjunctive aripiprazole treatment, supporting the efficacy of this treatment for MDD patients with all levels of response to ADT., (© 2014 John Wiley & Sons Ltd.)

Background: This post hoc analysis assessed the safety, tolerability and effectiveness of long-term treatment with aripiprazole adjunctive to either bupropion or selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD)., Methods: Data from de novo patients (did not participate in 2 previous studies) in a 52-week, open-label safety study of adjunctive aripiprazole after documented inadequate response to 1-4 antidepressant treatments (ADTs; SSRI, SNRI, or bupropion) were analyzed post hoc. Assessments included safety and tolerability, sexual functioning (Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI]) and Clinical Global Impressions-Severity (CGI-S)., Results: Forty-seven patients received bupropion plus aripiprazole and 245 received an SSRI/SNRI plus aripiprazole; 19 (40.4%) and 78 (31.8%), respectively, completed 52 weeks of treatment, and 46 and 242, respectively, received ≥1 dose of study medication (safety sample). Median time to discontinuation (any reason) was 184.0 days. Overall, 97.8% of patients in the bupropion group and 93.8% in the SSRI/SNRI group experienced ≥1 adverse event. The most common treatment-emergent adverse events were fatigue (26.1%) and somnolence (21.7%) with bupropion and fatigue (23.6%) and akathisia (23.6%) with an SSRI/SNRI. Mean change in body weight at week 52 (observed cases) was +3.1 kg for bupropion and +2.4 kg for an SSRI/SNRI. Treatment-emergent, potentially clinically relevant abnormalities in fasting glucose occurred in 8.3% of patients with bupropion and 17.4% with an SSRI/SNRI; for abnormalities in fasting total cholesterol, the incidence was 25.0% and 34.7%, respectively. Mean (SE) change from baseline in fasting glucose was 1.4 (1.9) mg/dL with bupropion and 2.7 (1.5) mg/dL with an SSRI/SNRI. Baseline MGH-SFI item scores indicated less severe impairment with bupropion versus an SSRI/SNRI; in both groups most MGH-SFI items exhibited improvement at week 52. Mean CGI-S improvement at week 52 (last observation carried forward) was -1.4 with bupropion and -1.5 with an SSRI/SNRI (efficacy sample)., Conclusions: There were no unexpected AEs with long-term adjunctive aripiprazole therapy when added to either bupropion or SSRIs/SNRIs, and symptom improvement was similar between ADT groups. Sexual functioning in patients with MDD on antidepressants was also modestly improved after adding aripiprazole., Trial Registration: ClinicalTrials.gov: NCT00095745 (November 9, 2004).

Background: There is a paucity of evidence for outcome predictors in patients with major depressive disorder (MDD) not responding to initial antidepressant therapy (ADT). This post-hoc analysis evaluated whether MDD severity affects response to adjunctive aripiprazole., Methods: Data from 3 randomized, double-blind, placebo-controlled trials of adjunctive aripiprazole in adults with MDD and inadequate response to 1 to 3 ADT trials were pooled and stratified based on Montgomery-Åsberg Depression Rating Scale (MADRS) total score (mild, ≤24; moderate, 25-30; severe, ≥31). Treatment differences in change in MADRS total score and rates of response (≥50% MADRS improvement) and remission (response with MADRS total score ≤10) were analyzed at endpoint. Adverse events were assessed within each subgroup., Results: Aripiprazole produced greater improvement than placebo in the MADRS total score regardless of MDD severity at baseline (between-treatment difference [95% CI]: mild, -2.5 [-4.0 to -1.1]; moderate, -3.2 [-4.9 to -1.6]; severe, -4.5 [-6.8 to -2.2]). Compared with placebo, adjunctive aripiprazole increased the likelihood of response in all subgroups (risk ratio [95% CI]: mild, 1.50 [1.15, 1.95]; moderate, 1.51 [1.09, 2.11]; severe, 1.95 [1.23, 3.10]). Common treatment-emergent adverse events included akathisia and restlessness., Limitations: The original studies were not designed to assess the efficacy of adjunctive aripiprazole by baseline severity, and this post-hoc analysis was not powered to evaluate differences in severity subgroups., Conclusions: In patients who failed to respond to initial ADT, adjunctive aripiprazole was more effective than placebo in mild, moderate, and severe MDD strata., Clinical Trial Registration: ClinicalTrial.gov: NCT00095823, NCT00105196, and NCT00095758., (Copyright © 2014. Published by Elsevier B.V.)

Objective: Data from the Einstein Aging Study (EAS) were used to prospectively evaluate the free recall score from the free and cued selective reminding test (FCSRT-FR) and logical memory I immediate recall (LM-IR) subtest of the Wechsler memory scale-revised for prediction of incident Alzheimer disease (AD) dementia among individuals from a community-based cohort with memory complaints., Methods: Analyses included 854 participants, age ≥70 years, who initially had no dementia, and had memory complaints. Clinic evaluations were completed annually and AD dementia was diagnosed using standard criteria (n = 86 cases; average follow-up 4.1 years). Time-dependent receiver operating characteristic analysis was used to evaluate the prognostic ability of FCSRT-FR and LM-IR for incident AD over various durations of follow-up., Results: For identifying those with memory complaints who will develop incident AD dementia over 2-4 years, the FCSRT-FR had better operating characteristics than LM-IR. APOE ε4 status, age, and education did not affect cut points; however, positive predictive values were higher among APOE ε4-positive individuals., Conclusions: For follow-up intervals of 2-4 years, the FCSRT-FR is more predictive than the LM-IR for identifying individuals with memory complaints who will develop incident AD. APOE ε4 status improves positive predictive value, but does not affect the choice of optimal cuts.

A hallmark of Alzheimer's disease (AD) pathology is the accumulation of brain amyloid β-peptide (Aβ), generated by γ-secretase-mediated cleavage of the amyloid precursor protein (APP). Therefore, γ-secretase inhibitors (GSIs) may lower brain Aβ and offer a potential new approach to treat AD. As γ-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of Aβ and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) Aβ levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notch-regulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF Aβ40 and Aβ42 levels similarly. Chronic administration in rats and dogs, and 28-day, single- and multiple-ascending-dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF Aβ40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF Aβ levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.

Over the past 30 years, many drugs have been studied as possible treatments for Alzheimer's disease, but only four have demonstrated sufficient efficacy to be approved as treatments, of which three are in the same class. This lack of success has raised questions both in the pharmaceutical industry and academia about the future of Alzheimer's disease therapy. The high cost and low success rate of drug development across many disease areas can be attributed, in large part, to late-stage clinical failures (Schachter and Ramoni, Nat Rev Drug Discov 2007;6:107-8). Thus, identifying in phase II, or preferably phase I, drugs that are likely to fail would have a dramatic impact on the costs associated with developing new drugs. With this in mind, the Alzheimer's Association convened a Research Roundtable on June 23 and 24, 2011, in Washington, DC, bringing together scientists from academia, industry, and government regulatory agencies to discuss strategies for improving the probability of phase II trial results predicting success when considering the go/no-go decision-making process leading to the initiation of phase III., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate the single dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the γ-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women., Methods: All subjects received double-blinded administration of a single 50 mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-β (Aβ)(1-40) concentratios and exploration of Notch biomarkers., Results: Avagacestat 50 mg capsule was well tolerated and rapidly absorbed among young and elderly subjects, with a median t(max) between 1 and 2 h post dose and an average half-life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,∞) values than those aged less than 75 years. An exploratory analysis of Aβ(1-40) serum concentrations showed a pattern of decreasing concentrations over the first 4-6 h followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly., Conclusions: The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer's disease., (© 2012 Bristol-Myers Squibb. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Objective: To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD)., Design: Randomized, double-blind, placebo-controlled,24-week phase 2 study., Setting: Global, multicenter trial., Patients: A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years,58.9% were APOE ε4 carriers, and baseline measures of disease severity were similar among groups., Intervention: Avagacestat, 25, 50, 100, or 125 mg daily,or placebo administered orally daily., Main Outcome Measures: Safety and tolerability of avagacestat., Results: Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups.Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and125-mg dose groups. Treatment-emergent serious adverse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal anddermatologic. Other adverse events occurring more frequentlyin patients undergoing treatment included reversibleglycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomaticmagnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients., Conclusions: Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for -secretase target engagement,but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses.This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD., Trial Registration: clinicaltrials.gov Identifier: NCT00810147

Background: The concentration of amyloid β (Aβ) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer's disease (AD) pathology, and has been used to evaluate the effectiveness of γ-secretase inhibition. Avagacestat is a selective γ-secretase inhibitor in development for the treatment of AD. The primary objective of this study was to assess the effects of single oral doses of avagacestat on the CSF Aβ concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability., Methods: This was a double-blind, placebo-controlled, randomized, single-dose study. Healthy male subjects were assigned to one of three sequential avagacestat dose panels (50, 200 and 400 mg) or placebo as single oral doses., Results: 34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF Aβ(1-38), Aβ(1-40) and Aβ(1-42) concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2 h, and a CSF t(max) of approximately 3 h. Adverse events were uncommon and occurred with similar frequency in the placebo and avagacestat groups., Conclusion: Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF Aβ concentrations, suggestive of γ-secretase inhibition. The results warrant further clinical study in patients with AD.

Background and Objectives: Avagacestat is an orally active γ-secretase inhibitor that selectively inhibits amyloid β (Aβ) synthesis in cell culture and animal models. The objective of the current study was to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple doses of avagacestat over 28 days in healthy young men and elderly men and women in a placebo-controlled, sequential-panel, ascending multiple-dose study., Methods: Thirty-three young men were assigned to four serial dose groups of avagacestat 15, 50, 100 or 150 mg (n = 6-7 per dose), or placebo (n = 2 per dose panel; 8 subjects total) once daily for 28 days. Elderly men and women were assigned to serial dose groups of avagacestat 50 mg and then 100 mg (n = 7 men, 6 women) or placebo (n = 2 men, 2 women) once daily for 14 days per dose level., Results: Avagacestat was rapidly absorbed, had a terminal elimination half-life of 38-65 h, and reached a steady-state concentration by day 10 of daily dosing. Exposure in young subjects increased in proportion to dose. There were no apparent differences in steady-state area under the plasma concentration-time curve between young and elderly subjects; however, elderly subjects demonstrated a higher maximum plasma concentration for avagacestat. Doses of avagacestat >50 mg/day reduced steady-state trough concentrations of CSF Aβ(1-38), Aβ(1-40) and Aβ(1-42) in a dose-dependent fashion over 28 days of daily dosing. There were no signs of potential Notch-related dose-limiting toxicities., Conclusion: The results support continued evaluation of avagacestat in an elderly target population with predementia and mild to moderate Alzheimer's disease.

To evaluate the efficacy of adjunctive aripiprazole in patients with minimal response to prior antidepressant therapy (ADT). Pooled data from three randomized, double-blind, placebo-controlled studies assessing the efficacy of adjunctive aripiprazole to ADT in patients with major depressive disorder who had a minimal response [< 25% reduction on the Montgomery-Åsberg Depression Rating Scale (MADRS)] to an 8-week prospective ADT. During the 6-week, double-blind adjunctive phase, response was defined as at least 50% reduction in the MADRS score and remission as at least 50% reduction in MADRS score and a MADRS score ≤ 10. Rates were examined using analysis of covariance and Cochran-Mantel-Haenszel tests. Kaplan-Meier curves were used to calculate time to response and remission. Of 1038 patients, 72% (n=746) exhibited a minimal response to ADT (ADT minimal responder). Time to response and remission were significantly shorter for ADT minimal responders receiving aripiprazole+ADT versus adjunctive placebo+ADT. ADT minimal responders on aripiprazole+ADT showed significantly greater improvements in MADRS score at endpoint compared with minimal responders on placebo+ADT (-10.3 vs. -6.5, P<0.0001). In addition, ADT minimal responders exhibited significantly higher response rates with aripiprazole+ADT than placebo+ADT (36 vs. 19%, respectively, P<0.0001) and higher remission rates (24 vs. 12%, respectively, P<0.0001). The numbers needed to treat with aripiprazole+ADT were six for response and eight for remission. Aripiprazole augmentation had a rapid and clinically meaningful effect in ADT minimal responders.

Background: γ-Secretase inhibitors (GSIs) are being investigated for their potential to modify the progression of Alzheimer disease based on their ability to regulate amyloid-β (Aβ) accumulation. BMS-708163 (avagacestat) is an oral GSI designed for selective inhibition of Aβ synthesis currently in development for the treatment of mild to moderate and predementia AD. In addition to the desired effect on Aβ synthesis, GSIs affect Notch processing, which is thought to mediate some toxic adverse effects reported with this drug class. Avagacestat produced up to 190-fold greater selectivity for Aβ synthesis than Notch processing in preclinical studies and may therefore produce less toxic adverse events than other less selective compounds. Presented here are the results of the first in-human study for this new GSI compound., Objective: The goal of this study was to assess the tolerability profile, pharmacokinetic properties, and effects on pharmacodynamic markers (Aβ, trefoil factor family 3 protein, dual specificity phosphatase 6, and hairy and enhancer of split-1) of single, oral doses of avagacestat in healthy, young, male volunteers., Methods: This was a multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study in 8 healthy young men (age, 18-45 years) per dosing panel. Each study participant was randomized to receive a single dose of placebo (n = 2) or avagacestat (n = 6 for each dose) as an oral solution in 1 of 9 sequential dose panels (0.3, 1.5, 5, 15, 50, 100, 200, 400, and 800 mg). For determination of avagacestat, blood samples were obtained before dosing and for up to 144 hours after dosing. For participants in the 800-mg avagacestat dose panel, additional samples were obtained at 216, 312, and 648 hours. For 40-amino acid isoform of Aβ (Aβ(1-40)) assessment, plasma samples were collected before avagacestat administration and up to 72 hours after dosing., Results: Avagacestat concentrations peaked quickly after oral administration and then had a biphasic decrease in concentrations with a prolonged terminal phase. Exposures were proportional with doses up to 200 mg. Avagacestat was well tolerated at single oral doses up to 800 mg, with a biphasic effect on plasma Aβ(1-40). Adverse events were predominately mild to moderate in severity with no evidence of dose dependence up to 200 mg., Conclusions: Results from this single-ascending dose study suggest that avagacestat was tolerated at a single-dose range of 0.3 to 800 mg and suitable for further clinical development., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Objective: To determine whether switching within or between antidepressant therapy (ADT) classes prior to the use of adjunctive antipsychotic treatment is associated with different outcomes in major depressive disorder (MDD)., Method: This was a post hoc analysis of pooled data from 3 similar, multicenter, randomized, double-blind, placebo-controlled registrational studies of aripiprazole adjunctive to ADT conducted between September 2004 and April 2008. The trials comprised the following 3 phases: a 7- to 28-day screening phase, an 8-week single-blind prospective treatment phase, and a 6-week double-blind, randomized phase. Patients were aged 18-65 years and met DSM-IV-TR criteria for MDD. Patients with an inadequate response to ADT during the screening phase entered the prospective treatment phase, during which they were switched to another ADT medication of either the same or a different class. Those patients with an inadequate response were then randomized to double-blind adjunctive aripiprazole or adjunctive placebo and followed for 6 weeks., Results: Mean improvement in Montgomery-Asberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole versus adjunctive placebo for both between-class (-9.2 vs -6.2, P < .001) and within-class (-9.8 vs -6.6, P < .001) switch groups. Relative risks for response were 1.6 (95% CI = 1.3-2.1) for those who switched between classes and 1.7 (95% CI = 1.2-2.2) for those who switched within class., Conclusions: Augmentation with aripiprazole, after either a between-class or within-class switch following initial ADT failure, is an effective option for patients with nonresponsive MDD. In contrast to current strategies employed in clinical practice, these results suggest that adjunctive aripiprazole is a logical strategy in patients unresponsive to ADT., Trial Registration: ClinicalTrials.gov identifiers: NCT00105196, NCT00095758, NCT00095823.

Objective: To evaluate the effect of adjunctive aripiprazole to antidepressant therapy (ADT) on functional outcomes, as assessed by the Sheehan Disability Scale (SDS)., Method: A post hoc analysis of pooled data from 3 similarly designed randomized, placebo-controlled trials was conducted (CN138-139 [September 2004-December 2006], CN138-163 [June 2004-April 2006], and CN138-165 [March 2005-April 2008]). Patients with DSM-IV major depressive disorder who had a prior inadequate response to ADT received adjunctive aripiprazole or placebo to standard ADT. The change from baseline to endpoint on total SDS score and on individual SDS domains and the distributional categorical shifts of patient-reported severity of functional impairment on the SDS were assessed., Results: Aripiprazole compared to placebo augmentation produced significant improvements in self-reported functioning levels in the SDS mean total score (-1.2 vs -0.7, P ≤ .001) and social life (-1.4 vs -0.7, P ≤ .001) and family life (-1.4 vs -0.7, P ≤ .001) domains. Additionally, a significant number of patients exhibited a shift from a severe/moderate level of impairment at baseline to a mild level of functional impairment after 6 weeks of adjunctive aripiprazole treatment compared with placebo in the SDS mean total score (P = .001) and social life (P ≤ .001) and family life (P = .001) scores., Conclusions: Aripiprazole augmentation of standard antidepressant therapy resulted in significant improvements in both total and individual domains of functioning, as assessed by the SDS, with significant categorical shifts from severe/moderate to mild levels of functioning compared with placebo augmentation., Trial Registration: ClinicalTrials.gov identifiers: NCT00095823, NCT00095758, and NCT00105196.

Objectives: To determine whether early symptom improvement with adjunctive aripiprazole in major depressive disorder (MDD) predicts overall symptom remission., Study Design: Post hoc pooled analysis of 3 randomized, double-blind studies evaluating efficacy, safety, and tolerability of adjunctive aripiprazole or placebo with standard antidepressant therapy (ADT) in inadequate responders to a prospective 8-week ADT and at least 1 historical ADT., Methods: A multivariate logistic regression model was developed to determine factors predicting remission most strongly at the end point. Remission was defined as a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 10 or less at end point., Results: Early improvement in depression symptoms was the most significant predictor of remission. In adjunctive aripiprazole and placebo groups, improvement of 20% or more in MADRS total score (week 2) was a significant predictor of remission. At week 2, high sensitivity and high negative predictive values (NPVs) were reported for remission in both treatment arms. In the adjunctive aripiprazole arm, early improvement predicted later MADRS remission with high sensitivity (88.0%) and a high NPV (91.5%). Positive predictive value was moderate in both the adjunctive aripiprazole (45.4%) and placebo (37.5%) arms; specificity was 55.0% with adjunctive aripiprazole and 71.5% with placebo., Conclusions: Week 2 was a clinically meaningful time point to identify early improvers, and lack of improvement early in treatment was a highly significant predictor of lack of later remission. Early assessment of changes in symptoms could prove useful in clinical practice and more appropriately target healthcare costs.

Advances in neonatology have made possible to increase the survival of preterm and/or serious diseases, but many of them suffer some consequences that can affect their behavior and development. Similarly a better understanding of central nervous system (CNS), has led to associate the negative effects that certain stimuli received from the environment can have on their development loss. All these data raise some changes to managed care to manage care of the newborn during their stay in neonatal units, and there is a new concept of care focused on development (CCD). And the creation of a new concept: caring focused on development. The CCD include a wide array of interventions that aim to minimize environmental stress is during the stay in the neonatal unit, facilitating its the adaptation to new environment. These interventions include several elements: the control of external stimuli (vestibular auditory visual and tactile), clustering of care activities, positioning and participation / integration of the family in care. Clinical practice shows that reducing or acting on certain environmental stimuli such as noise, light, smells, manipulation, pain and position, may reduce neurological sequel in premature infants, helping to better organization of their CNS through the reduction of stress behaviors.

Objectives: To evaluate the efficacy and safety of adjunctive aripiprazole compared with standard antidepressant therapy (ADT) for older patients with major depressive disorder (MDD) who demonstrated an incomplete response to standard antidepressant monotherapy., Methods: Data from three similar 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled for this post hoc analysis. Two age groups were defined: younger patients (aged 18-49 years) and older patients (aged 50-67 years). The older patient group was further divided into three subgroups: 50-55, 56-60, and 61-67 years. The efficacy endpoint was the mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from end of the prospective phase (Week 8) to endpoint (Week 14, last observation carried forward (LOCF)). Remission was defined as MADRS total score ≤10 at endpoint., Results: Four hundred and nine older patients (placebo, n = 198; aripiprazole, n = 211) and 679 younger patients (placebo, n = 341; aripiprazole, n = 338) were included in this analysis. Older patients receiving aripiprazole demonstrated significantly greater improvement in MADRS total score versus placebo at Week 14 (-10.0 vs. -6.4; p < 0.001; LOCF), similar to the improvement seen in younger patients. Remission rates were significantly higher with aripiprazole versus placebo in older (32.5% vs. 17.1%; p < 0.001) and younger (26.9% vs. 16.4%; p < 0.001) patients. Akathisia was the most common adverse event in both the older (17.1%) and younger (26.0%) patient groups., Conclusions: Adjunctive aripiprazole was effective in improving depressive symptoms in older patients, 50-67 years, with MDD who have had an inadequate response to standard antidepressant medication., (Copyright © 2010 John Wiley & Sons, Ltd.)

Objective: To assess the impact of adjunctive aripiprazole versus adjunctive placebo treatment on suicidality in patients with major depressive disorder., Method: Data were pooled from 2 identical aripiprazole augmentation studies. Patients with DSM-IV-TR-diagnosed major depressive disorder with an inadequate response to 8 weeks of prospective antidepressant treatment were randomly assigned to adjunctive placebo or adjunctive aripiprazole (2-20 mg/d) treatment for 6 weeks. Adverse events related to suicidality were identified in the adverse event database using the Medical Dictionary for Regulatory Activities-preferred term. Treatment-emergent suicidal ideation was defined using item 10 (suicidality) of the Montgomery-Åsberg Depression Rating Scale (MADRS) and item 18 (suicidality) of the Inventory of Depressive Symptomatology (IDS)., Results: In total, 737 patients were included in the safety database (aripiprazole n = 371; placebo n = 366). No suicides were reported. There were no treatment-emergent, suicide-related adverse events in the aripiprazole group; 2 patients in the placebo group had ≥ 1 adverse event related to suicide (both suicidal ideation). More placebo than aripiprazole patients > 25 years old experienced a 2-point (P < .01) or 1-point (P < .05) worsening of MADRS item 10 scores. For this age group, 2-point improvement in MADRS item 10 scores and 1-point improvement of IDS item 18 scores were significantly more common in aripiprazole patients than placebo patients (both P < .05)., Conclusions: This post hoc analysis demonstrated that adjunctive aripiprazole treatment in patients with depression with a history of an inadequate response to antidepressant medication is associated with a decreased rate of suicidality in a group of subjects not at significant risk. Prospective trials directly assessing suicidality are needed to further understand the benefits of an adjunctive antipsychotic in an at-risk population., Trial Registration: clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objective: To investigate the specific effect of adjunctive aripiprazole on sexual function in patients with major depressive disorder and a history of an inadequate response to antidepressant medication by controlling for improvement in depressive symptoms as measured by improvement in Montgomery-Asberg Depression Rating Scale (MADRS) total scores., Method: For this post hoc analysis, data were pooled from 3 multicenter, randomized, double-blind, placebo-controlled aripiprazole augmentation studies (CN138-139: June 2004-April 2006; CN138-163: September 2004-December 2006; and CN138-165: March 2005-April 2008). Outpatients who met DSM-IV-TR criteria for a major depressive episode that had lasted ≥8 weeks with an inadequate response to prospective antidepressant treatment were randomized to adjunctive aripiprazole or placebo for 6 weeks. Sexual functioning was assessed using the Massachusetts General Hospital Sexual Functioning Inventory (MGH-SFI). To assess whether adjunctive aripiprazole improves sexual functioning directly, rather than as an indirect effect of improvement in depression symptoms, the mean change in MGH-SFI item scores and overall improvement scores was assessed using analysis of covariance, with double-blind baseline and change in MADRS total score as covariates. Correlations between MGH-SFI items and MADRS total score and prolactin levels were also assessed., Results: The analysis included 1,092 subjects (n=737 female and n=355 male). In the total population, adjunctive aripiprazole demonstrated statistically significant greater improvements versus placebo on the MGH-SFI item "interest in sex" (-0.34 vs -0.18, P<.05). In males, no significant treatment differences were observed. In females, improvements in sexual functioning with adjunctive aripiprazole versus placebo were found on the MGH-SFI items "interest in sex" (-0.41 vs -0.21, P<.05) and "sexual satisfaction" (-0.44 vs -0.25, P<.05)., Conclusions: Aripiprazole adjunctive to antidepressant treatment can have some beneficial effects on sexual functioning in patients with major depressive disorder who respond inadequately to standard antidepressant treatment; the benefits in women were specific to sexual interest and satisfaction and were independent of the improvement in depressive symptoms., Trial Registration: clinicaltrials.gov Identifiers: NCT00095823, NCT00095758, and NCT00105196.

Background: Effective management of major depressive disorder often includes the long-term use of multiple medications, and the longer-term utility and safety of adjunctive aripiprazole has not been evaluated in a controlled setting., Patients and Methods: Patients (n = 706) completing one of two 14-week double-blind studies of aripiprazole augmentation, as well as de novo patients (n = 296) nonresponsive to current antidepressant therapy, were enrolled in this open-label study. Patients received open-label aripiprazole for up to 52 weeks., Results: Open-label treatment was completed by 323 patients (32.2%). At endpoint (n = 987), the mean dose of aripiprazole was 10.1 mg/day. Common (>15% of patients) spontaneously reported adverse events were akathisia (26.2%), fatigue (18.0%), and weight gain (17.1%). The incidence of serious adverse events was 4.0%. Four spontaneous reports of possible tardive dyskinesia were submitted (0.4%); all resolved within 45 days of drug discontinuation. Mean weight change was 4.4 kg; 36.6% experienced ≥7% increase in weight from baseline (observed case analysis, n = 303). No clinically relevant changes in other metabolic parameters were seen. At the end of open-label treatment, 221 patients (69.7%) had a Clinical Global Impression-Severity of Illness score of 1 (not at all ill) or 2 (borderline ill)., Conclusion: Long-term adjunctive aripiprazole therapy was well tolerated with an acceptable long-term safety and tolerability profile in patients with major depressive disorder who had not responded to treatment with one or more antidepressant therapies. Clinically significant weight gain was observed in about one-third of patients. Overall, the adverse event profile was consistent with that reported in the short-term trials and readily managed clinically.

Background: These analyses aimed to examine the pattern of improvement in depression symptoms with adjunctive aripiprazole., Methods: Data were pooled (724 subjects: n = 356 placebo, n = 368 aripiprazole) from 2 double-blind, 6-week aripiprazole studies. Pearson correlation coefficients (r) were calculated between changes on the Montgomery-Asberg Depression Rating Scale (MADRS) line items and selected Inventory of Depressive Symptomatology (IDS) line items using last observation carried forward. The magnitude of change was expressed as a between-group effect size (ES)., Results: At end point, adjunctive aripiprazole demonstrated significant improvement versus antidepressant therapy alone in 8 of the 10 MADRS items (MADRS total score Cohen effect size = 0.37) and 12 of the 30 IDS items (IDS total score Cohen ES = 0.18). Analysis of correlation data identified 5 MADRS items assessing mood, lassitude, inability to feel, self-worth, and suicidal thoughts that correlated with similar IDS items; these showed a similar pattern of rapid, sustained response to adjunctive aripiprazole and a similar ES. Other symptoms associated with depression (tension associated with feeling anxious, irritability, and lack of concentration) did not show statistically significant changes on either scale at end point. The IDS identified an additional 3 important depression-related symptoms (diminished libido, view of self, and interpersonal sensitivity) that showed significant rapid and sustained improvement with adjunctive aripiprazole., Conclusions: This cross-correlation analysis confirmed that improvement in core depressive symptoms with adjunctive aripiprazole was identified by both clinicians and patients. Clinically, these changes were maintained during the study. Theoretically, these findings lead to important questions regarding neurochemical changes produced by aripiprazole when used in combination with antidepressants.

Possible effects of the atypical antipsychotic aripiprazole on the pharmacokinetics of standard antidepressant therapies (ADTs) were assessed in two open-label, non-randomised studies in healthy subjects (Studies 1 and 2) and two placebo-controlled studies in patients with major depressive disorder (MDD) (Studies 3 and 4). Healthy subjects received venlafaxine 75 mg/day (Study 1; N = 38) or escitalopram 10 mg/ day (Study 2; N = 25) with the addition of aripiprazole 10-20 mg/day (10 mg/day fixed dose in Study 2) for 14 days. Patients with MDD (N = 498; Studies 3 and 4) received escitalopram (10-20 mg/day), fluoxetine (20-40 mg/day), paroxetine controlled-release (37.5-50 mg/day), sertraline (100-150 mg/day) or venlafaxine extended-release (150-225 mg/day) for 8 weeks plus placebo. Incomplete responders were randomised (1:1) to placebo or adjunctive aripiprazole 2-20 mg/day. Blood samples were collected for pharmacokinetic analysis of ADTs. Plasma concentration-time data from Studies 3 and 4 were combined for statistical analysis. In healthy subjects, point estimates [90% CI] for the ratios of geometric means of C( max) (venlafaxine 1.148 [1.083-1.217]; escitalopram 1.04 [0.99-1.09]) and AUC(TAU) (venlafaxine 1.183 [1.130-1.238]; escitalopram 1.07 [1.04-1.11]) indicated no meaningful increase in ADT exposure in the presence of aripiprazole. In patients, point estimates for mean plasma concentration ratios indicated no substantial effect of aripiprazole on any ADT escitalopram 0.970 [0.911-1.033], fluoxetine 1.177 [1.049-1.321], paroxetine 0.730 [0.598-0.892], sertraline 0.958 [0.887-1.035] or venlafaxine 0.966 [0.887-1.051]. Aripiprazole had no meaningful effects on the pharmacokinetics of standard ADTs in either healthy subjects or patients with MDD.

Background: Although antipsychotic agents have a long history of use in depression, their effectiveness in treating core symptoms of depression such as loss of interest has been questioned. Adjunctive aripiprazole is beneficial for the treatment of patients with major depressive disorder but its effects on specific symptoms have not been reported. The objective of this study was to examine the effects of aripiprazole on core symptoms of depression., Methods: This is a post-hoc, pooled analysis of two trials of aripiprazole augmentation of standard antidepressants (ADT) in patients with major depression. Patients with an inadequate response to ADT received adjunctive aripiprazole (n=373) or placebo (n=368) for 6 weeks. Change on four subscales of the 17-item Hamilton Depression Rating Scale (HAM-D17) that capture core depression symptoms was determined and change on individual HAM-D items also was assessed. The magnitude of within-group change for the subscales and individual items was expressed as effect size (ES) and between-group significance tested with ANCOVA. The magnitude of change was also examined comparing the response rates for aripiprazole and placebo on HAM-D17 and the four subscales. Change on three composite subscales - anxiety, insomnia and drive was also examined., Results: Within-group change on the four core subscales was substantial (ES=1.1-1.2) and similar to that for the 17-item HAM-D total score. Between-group comparisons indicated mean change and response rates were significantly greater with adjunctive aripiprazole than placebo for each core subscale (all p<0.01). Individual HAM-D17 items showing the greatest change from baseline with adjunctive aripiprazole: depressed mood (within-group ES=1.03) work and activities (ES=0.86), guilt (ES=0.77) and psychic anxiety (ES=0.67) are the same symptoms identified by each of the core subscales and each of these items differed significantly from change on that item with placebo (p<0.01). On three composite scales, adjunctive aripiprazole was significantly more effective than placebo with respect to mean change for anxiety, insomnia and drive (all p<0.001)., Conclusions: Aripiprazole augmentation of standard ADT results in significant, clinically meaningful changes in the core symptoms of depression. It is also associated with significant change in anxiety, insomnia, and drive components of the 17-item HAM-D.

In 2 identical multicenter, double-blind, placebo-controlled trials, an 8-week prospective treatment phase to ensure inadequate response to standard antidepressants was followed with 6 weeks of aripiprazole (2-20 mg/d) or placebo, plus a standard antidepressant. This pooled analysis involving 737 patients across the 2 studies evaluated the metabolic effects of adjunctive aripiprazole in patients with major depressive disorder. Outcomes included mean change from end of prospective treatment phase to endpoint in body weight, waist circumference, fasting levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides (TG), fasting plasma glucose, and glycosylated hemoglobin (hemoglobin A1C). Logistic regression determined whether baseline variables were associated with weight gain or whether weight change was associated with clinical outcome. Statistically significant increases occurred in mean body weight (adjunctive aripiprazole, +1.73 kg, vs adjunctive placebo, +0.38 kg; P < 0.001). Significantly more subjects receiving adjunctive aripiprazole had clinically relevant (> or = 7%) weight gain versus placebo (5.2% vs 0.6%; P < 0.001). More patients treated with adjunctive aripiprazole shifted body mass index category group from normal to overweight and from overweight to obese than those treated with adjunctive placebo. Body mass index, sex, age, Montgomery-Asberg Depression Rating Scale score, fasting TG, fasting glucose, and standard antidepressants were not clinically meaningful predictors of weight gain with adjunctive aripiprazole, and change in weight had no correlation with clinical outcome. Adjunctive aripiprazole produced no significant changes versus placebo in mean waist circumference, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TG, fasting plasma glucose, or hemoglobin A1C. Also, there was no apparent change in the incidence of National Cholesterol Education Program-defined abnormal metabolic measures after treatment with aripiprazole.

Introduction: Effective management of major depressive disorder (MDD) continues to be a challenging task for psychiatrists and primary care physicians. This trial evaluated the efficacy and safety of adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and independently replicated the positive findings of two similar trials., Methods: Patients (N=1,147) with MDD experiencing a major depressive episode and a history of inadequate response to antidepressant monotherapy were enrolled (week 0); 827 received single-blind adjunctive placebo plus open-label antidepressant (escitalopram, fluoxetine, paroxetine controlled release, sertraline, or venlafaxine extended release) for 8 weeks to confirm inadequate response to antidepressants; 349 patients with inadequate response were randomized (1:1) to double-blind, adjunctive placebo (n=172) or adjunctive aripiprazole (n=177; 2-20 mg/day). Primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) Total score from baseline (week 8) to endpoint (week 14)., Results: Clinically significant improvements in depressive symptoms as assessed by decreases in the MADRS Total score were greater with adjunctive aripiprazole (-10.1) than placebo (-6.4; P<.001). Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo (week 14, 36.8% vs 18.9%; P<.001). Completion rates with adjunctive aripiprazole and placebo were high (83% vs. 87%) and discontinuations due to adverse events were low (6.2% vs 1.7%)., Conclusion: For some patients with MDD who do not obtain adequate symptom relief with antidepressant monotherapy, adjunctive therapies can significantly improve depressive symptoms. As reported, adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo. This, and previous studies, have shown that discontinuations due to adverse events were low and completion rates were high, and has indicated that both antidepressant and aripiprazole in combination were relatively well-tolerated and safe. This is the third consecutive clinical trial, in the absence of a failed trial, to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to standard antidepressant monotherapy (ClinicalTrials.gov study NCT00105196).

Objective: To evaluate the safety and tolerability of aripiprazole adjunctive to standard antidepressant therapy (ADT) for patients with major depressive disorder (DSM-IV-TR criteria)., Method: Data from 2 identical studies of aripiprazole augmentation (8 weeks of prospective ADT treatment followed by 6 weeks of randomized double-blind adjunctive treatment) were pooled. The incidence of treatment-emergent adverse events (TEAEs) and weight, electrocardiogram (ECG), and laboratory measurements were assessed during the 6-week phase, including time course, severity, resolution, and predictors. The studies were conducted from June 2004 to April 2006 and September 2004 to December 2006., Results: The safety analysis included 737 outpatients (aripiprazole, n = 371; placebo, n = 366). The majority of patients completed the trials (aripiprazole, 86%; placebo, 88%). Common TEAEs (≥ 5% and twice the placebo rate) with aripiprazole were akathisia (25%), restlessness (12%), insomnia (8%), fatigue (8%), blurred vision (6%), and constipation (5%). Most TEAEs were of mild to moderate severity (aripiprazole, 89%; placebo, 95%). TEAE rates in the aripiprazole and placebo groups were not affected by ADT, age, or gender. Discontinuation due to TEAEs was low (aripiprazole, 3%; placebo, 1%). Mean weight change was higher with aripiprazole versus placebo (1.73 kg vs 0.38 kg, P < .001). At endpoint, clinical laboratory parameters, vital signs, and ECG indices (including QT(c) interval) were similar between groups. Akathisia with aripiprazole generally occurred in the first 3 weeks (76%), was of mild to moderate severity (92%), and led to discontinuation in 3 patients (0.8%). Within the aripiprazole group, age (18-40 years) was the only positive predictor for akathisia., Conclusions: In this short-term post hoc analysis, aripiprazole as augmentation to ADT demonstrated a safety and tolerability profile similar to that in monotherapy studies in other psychiatric populations. Controlled long-term safety and efficacy data of aripiprazole as adjunctive to ADT are warranted., Trial Registration: clinicaltrials.gov Identifiers: NCT00095823 (CN138-139) and NCT00095758 (CN138-163).

Objective: To evaluate the efficacy of adjunctive aripiprazole to standard antidepressant therapy (ADT) for patients with DSM-IV major depressive disorder with anxious/atypical features at baseline., Method: Data from 2 identical 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled to evaluate efficacy and safety in the 2 subgroups. The primary efficacy endpoint was mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of ADT treatment to end of randomized treatment (last observation carried forward). Anxious depression was defined by a Hamilton Rating Scale for Depression anxiety/somatization factor score ≥ 7, and atypical depression was defined by previously described criteria on the Inventory of Depressive Symptomatology-Self-Report. Both anxious and atypical subtypes were defined based on symptoms at entry into prospective ADT (week 0). Patients were enrolled between June 2004 and April 2006 in one study and from September 2004 to December 2006 in the other (total randomized population, N = 742; anxious/nonanxious population, N = 740; atypical/nonatypical population, N = 737)., Results: Completion rates were between 84% and 90% and comparable across all subgroups, with low discontinuations due to adverse events. Patients receiving adjunctive aripiprazole demonstrated significantly greater improvement in MADRS total score versus patients receiving adjunctive placebo, starting at week 1 or week 2 and continuing through to endpoint (anxious: -8.72 vs. -6.17, p ≤ .001; nonanxious: -8.61 vs. -4.97, p ≤ .001; atypical: -9.31 vs. -5.15, p ≤ .001; nonatypical: -8.08 vs. -6.22, p < .05). At endpoint, remission rates were also significantly higher with adjunctive aripiprazole versus adjunctive placebo (p < .05) in all subgroups. Treatment emergent adverse event profile was similar in all subgroups and comparable to the total population. Reporting of akathisia and weight gain on aripiprazole treatment did not differ between subgroups., Conclusion: Adjunctive aripiprazole is an effective treatment for patients with major depression presenting with either anxious or atypical features., Trial Registration: clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758., (Copyright 2008 Physicians Postgraduate Press, Inc.)

Major depressive disorder (MDD) is a disabling psychiatric condition for which effective treatment remains an outstanding need. Antidepressants are currently the mainstay of treatment for depression; however, almost two-thirds of patients will fail to achieve remission with initial treatment. As a result, a range of augmentation and combination strategies have been used in order to improve outcomes for patients. Despite the popularity of these approaches, limited data from double-blind, randomized, placebo-controlled studies are available to allow clinicians to determine which are the most effective augmentation options or which patients are most likely to respond to which options. Recently, evidence has shown that adjunctive therapy with atypical antipsychotics has the potential for beneficial antidepressant effects in the absence of psychotic symptoms. In particular, aripiprazole has shown efficacy as an augmentation option with standard antidepressant therapy in two, large, randomized, double-blind studies. Based on these efficacy and safety data, aripiprazole was recently approved by the FDA as adjunctive therapy for MDD. The availability of this new treatment option should allow more patients with MDD to achieve remission and, ultimately, long-term, successful outcomes.

Objective: Major mental disorders are associated with an increased risk for obesity-related cardiovascular mortality, leading to interest in risk-reduction approaches that target weight and risk-related plasma lipids, including use of antipsychotic agents with low metabolic risk. This multicenter, randomized, double-blind study compared the metabolic effects of aripiprazole versus olanzapine in overweight persons with schizophrenia or schizoaffective disorder who were previously on olanzapine treatment., Method: In total, 173 subjects with DSM-IV-TR-defined schizophrenia or schizoaffective disorder were randomly assigned to receive aripiprazole (N = 88) or olanzapine (N = 85) for 16 weeks in a study conducted from March 30, 2004, to August 8, 2006. Primary and secondary endpoints were mean weight change from baseline and percentage change from baseline in fasting triglyceride levels, respectively., Results: At week 16, weight decreased significantly with aripiprazole versus olanzapine (-1.8 vs. +1.41 kg; p < .001). Significant differences in percentage change in triglyceride levels were observed with aripiprazole (decreases) versus olanzapine (increases) at all time-points. In addition, significantly more subjects receiving aripiprazole had clinically relevant (> or = 7%) weight loss versus olanzapine (11.1% vs. 2.6%; p = .038), and a lower percentage of subjects receiving aripiprazole had clinically relevant weight gain (2.5% vs. 9.1%; p = .082). Mean percentage changes in fasting total cholesterol and high-density lipoprotein cholesterol at week 16 were significantly different with aripiprazole versus olanzapine, with no significant effects on glycemic laboratory measures. Mean Clinical Global Impressions-Improvement (CGI-I) scores for both groups were in the range of "no change" to "minimal improvement." CGI-I endpoint scores were statistically significantly better with olanzapine (mean +/- SE = 3.09 +/- 0.16) versus aripiprazole (mean +/- SE = 3.74 +/- 0.15; p < .001), and more subjects discontinued aripiprazole (N = 32/88; 36%) than olanzapine (N = 22/85; 26%)., Conclusion: Significant improvements in weight and lipids observed during discontinuation of olanzapine and switch to aripiprazole treatment occurred with limited evidence of negative psychiatric effects, relative to uninterrupted continuation of olanzapine treatment. The results suggest that the potential value of therapeutic substitutions involving specific antipsychotic medications should be considered in overall efforts to reduce cardiovascular risk in this population.

Background: While electroconvulsive therapy (ECT) in major depression is effective, cognitive effects limit its use. Reducing the width of the electrical pulse and using the right unilateral electrode placement may decrease adverse cognitive effects, while preserving efficacy., Methods: In a double-masked study, we randomly assigned 90 depressed patients to right unilateral ECT at 6 times seizure threshold or bilateral ECT at 2.5 times seizure threshold, using either a traditional brief pulse (1.5 ms) or an ultrabrief pulse (0.3 ms). Depressive symptoms and cognition were assessed before, during, and immediately, two, and six months after therapy. Patients who responded were followed for a one-year period., Results: The final remission rate for ultrabrief bilateral ECT was 35 percent, compared with 73 percent for ultrabrief unilateral ECT, 65 percent for standard pulse width bilateral ECT, and 59 percent for standard pulse width unilateral ECT (all P's<0.05 after covariate adjustment). The ultrabrief right unilateral group had less severe cognitive side effects than the other 3 groups in virtually all primary outcome measures assessed in the acute postictal period, and during and immediately following therapy. Both the ultrabrief stimulus and right unilateral electrode placement produced less short- and long-term retrograde amnesia. Patients rated their memory deficits as less severe following ultrabrief right unilateral ECT compared to each of the other three conditions (P<0.001)., Conclusions: The use of an ultrabrief stimulus markedly reduces adverse cognitive effects, and when coupled with markedly suprathreshold right unilateral ECT, also preserves efficacy. (ClinicalTrials.gov number, NCT00487500.).

Nonresponse to one or more antidepressants is common and an important public health problem. This study evaluated the efficacy and safety of adjunctive aripiprazole or placebo to standard antidepressant therapy (ADT) in patients with major depressive disorder who showed an inadequate response to at least 1 and up to 3 historical and 1 additional prospective ADT. The study comprised a 7-28-day screening, an 8-week prospective treatment, and a 6-week randomization phase. During prospective treatment, patients experiencing a major depressive episode (17-item Hamilton Rating Scale for Depression total score > or = 18) received single-blind adjunctive placebo plus clinicians' choice of ADT (escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release). Subjects with inadequate response were randomized to adjunctive placebo (n = 190) or adjunctive aripiprazole (n = 191) (starting dose 5 mg/d, dose adjustments 2-20 mg/d, mean end-point dose of 11.0 mg/d). The primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale total score from end of prospective treatment phase to end of randomized treatment phase (last observation carried forward). Mean change in Montgomery-Asberg Depression Rating Scale total score was significantly greater with adjunctive aripiprazole than placebo (-8.5 vs -5.7; P = 0.001). Remission rates were significantly greater with adjunctive aripiprazole than placebo (25.4% vs 15.2%; P = 0.016) as were response rates (32.4% vs 17.4%; P < 0.001). Adverse events occurring in 10% of patients or more with adjunctive placebo or aripiprazole were akathisia (4.2% vs 25.9%), headache (10.5% vs 9.0%), and fatigue (3.7% vs 10.1%). Incidence of adverse events leading to discontinuation was low (adjunctive placebo [1.1%] vs adjunctive aripiprazole [3.7%]). Aripiprazole is an effective and safe adjunctive therapy as demonstrated in this short-term study for patients who are nonresponsive to standard ADT.

Background: Methods used to evaluate subjective effects of electroconvulsive therapy (ECT) have relied on self-report about discrete aspects of memory. Although objective deficits are demonstrable, patients generally report improved memory after ECT. Patients have not been asked to evaluate the global impact of ECT on mood or memory. This study was undertaken to compare patients' evaluations of ECT outcomes using direct questioning about global impact compared with standard methods., Methods: A prospective, naturalistic study was conducted in seven hospitals. Patients completed clinical and neurocognitive assessments before ECT, including the Cognitive Failures Questionnaire (CFQ), the Autobiographical Memory Interview-Short Form, and a novel interview assessing expectations about the impact of ECT on mood and memory (Global Self-Evaluation-Mood [GSE-Md], GSE-memory [GSE-My]). Follow-ups were conducted one and 24 weeks after ECT, and the GSE-Md and GSE-My evaluated perceived global impact at these time points., Results: Patients reported marked improvement after ECT on the CFQ, a traditional instrument assessing specific cognitive complaints. CFQ and depression severity scores were strongly correlated. On the GSE-My, patients reported a deleterious memory effect both one and 24 weeks after ECT. GSE-My, but not CFQ, scores were associated with treatment technique and long-term retrograde amnesia., Conclusions: Characterization of patients' experience of cognitive side effects after ECT differs markedly depending on assessment method. Direct questioning about global impact revealed more negative views and associations with objective indices of cognitive impairment. This represents the first report of concordance between subjective and objective measures of the effects of ECT on memory.

Background: Patients with major depressive disorder (MDD) who fail to achieve complete remission with antidepressant therapy may benefit from augmentation therapy with an atypical antipsychotic., Method: A pooled analysis was performed on 2 identical 14-week studies (8-week prospective antidepressant therapy treatment phase followed by 6-week randomized double-blind phase) evaluating the efficacy of adjunctive aripiprazole (2-20 mg/day) in DSM-IV-TR-defined MDD patients with an inadequate response to antidepressant therapy. Primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of the prospective phase (week 8) to end of randomized phase (week 14, last observation carried forward). Subgroup analyses were performed. The key secondary endpoint was mean change in Sheehan Disability Scale (SDS) mean score., Results: At endpoint, mean change in MADRS total score was significantly greater with adjunctive aripiprazole (-8.7) than with adjunctive placebo (-5.7; p < .001). Except for a differential treatment-by-sex interaction, change in MADRS total scores were consistently greater with adjunctive aripiprazole than with adjunctive placebo, regardless of race, age, episode duration, prior antidepressant therapy response, number of historical treatment failures, severity of depressive symptoms, and antidepressant. At endpoint, MADRS remission rates were significantly greater with adjunctive aripiprazole than with placebo (25.7% vs. 15.4%; p < .001). Adjunctive aripiprazole also demonstrated significantly greater improvements in mean change from baseline in SDS total score than adjunctive placebo (-1.2 vs. -0.6; p = .001)., Conclusion: Augmentation of antidepressant therapy with the atypical antipsychotic aripiprazole resulted in significant efficacy benefits across a range of subgroups of patients with MDD. Further study of a treatment-by-sex interaction is needed., Trial Registration: www.clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.

Objective: To assess the efficacy and safety of aripiprazole versus placebo as adjunctive treatment to standard antidepressant therapy (ADT) in patients with major depressive disorder (MDD) who showed an incomplete response to 1 prospective and 1 to 3 historical courses of ADT within the current episode., Method: The study comprised a 7- to 28-day screening phase, an 8-week prospective treatment phase, and a 6-week double-blind treatment phase. Patients with DSM-IV-TR-defined MDD were enrolled between June 16, 2004, and April 27, 2006. During prospective treatment, patients received ADT: escitalopram, fluoxetine, paroxetine controlled-release, sertraline, or venlafaxine extended-release, each with single-blind, adjunctive placebo. Incomplete responders continued ADT and were randomly assigned to double-blind, adjunctive placebo or adjunctive aripiprazole (2-15 mg/day with fluoxetine or paroxetine; 2-20 mg/day with all others). The primary efficacy endpoint was the mean change from end of prospective treatment to end of double-blind treatment (week 14, last observation carried forward) in Montgomery-Asberg Depression Rating Scale (MADRS) total score (analysis of covariance)., Results: A total of 178 patients were randomly assigned to adjunctive placebo and 184 to adjunctive aripiprazole. Baseline demographics were similar between groups (mean MADRS total score of 26.0). Mean change in MADRS total score was significantly greater with adjunctive aripiprazole (-8.8) than adjunctive placebo (-5.8; p < .001). Adverse events (AEs) that occurred in > or = 10% of patients with adjunctive placebo or adjunctive aripiprazole were akathisia (4.5% vs. 23.1%), headache (10.8% vs. 6.0%), and restlessness (3.4% vs. 14.3%). Discontinuations due to AEs were low with adjunctive placebo (1.7%) and adjunctive aripiprazole (2.2%); only 1 adjunctive aripiprazole-treated patient discontinued due to akathisia., Conclusions: In patients with MDD who showed an incomplete response to ADT, adjunctive aripiprazole was efficacious and well tolerated., Clinical Trials Registration: ClinicalTrials.gov identifier NCT00095823.

Background: Despite widespread policies of deinstitutionalization, a substantial number of patients with schizophrenia require continuous custodial care. The hospital records of such patients provide contemporaneous documentation of symptoms throughout the illness, permitting a longitudinal study of the course of symptoms. We sought to describe this course, and to determine the influences of sex, age of onset, and treatment on its evolution., Methods: Using the modified Diagnostic Evaluation After Death, we performed standardized chart reviews of 99 chronic inpatients who remained in state institutions through the 1960's and 1970's and subsequently died in those institutions. Data were available from the onset of illness until death., Results: We found significant decreases in positive symptoms and increases in negative symptoms over the course of the illness. Symptom patterns were analyzed by repeated measures ANOVA. Onset before age 25 was associated with greater numbers of negative symptoms at a given age (p = 0.05). Female sex was associated with greater numbers of positive symptoms (p=0.04). The widespread introduction of neuroleptic drugs in the mid-1950's did not affect the trends in symptom patterns., Conclusions: The lifetime course of schizophrenia in chronically institutionalized individuals is characterized by a decrease in positive symptoms and an increase in negative symptoms. Schizophrenia with earlier onset is associated with greater numbers of negative symptoms throughout life. In this sample of patients, chronically hospitalized until death, neuroleptic drugs failed to effect a persistent decrease in positive symptoms., (Copyright (c) 2007 S. Karger AG, Basel)

Psychosis affects at least 5% to 8% of medication-treated patients with idiopathic Parkinson's disease (PD). Treatment options include reducing medications used for the treatment of PD-related motor symptoms or introducing an atypical antipsychotic drug. Only clozapine has been demonstrated to be efficacious and tolerated in double-blind controlled trials. This study evaluated the effect of aripiprazole, an atypical antipsychotic, on psychosis in PD in an open-label pilot study. Fourteen patients meeting entry criteria were started on aripiprazole 1 mg/day and titrated up to a maximum dose of 5 mg as needed. Subjects were evaluated on the Unified Parkinson's Disease Rating Scale (UPDRS) part III for motor function, the Neuropsychiatric Inventory (NPI), and the Brief Psychiatric Rating Scale (BPRS) for psychiatric response. Statistically significant improvement in mean BPRS and positive BPRS subscales occurred with open-label aripiprazole, but eight subjects discontinued the study due to worsened Parkinsonism (three), worsened psychosis (two), worsening of both (two), and lack of efficacy (one). While some patients had a favorable response, aripiprazole was associated with an exacerbation of motor symptoms. In this small study on psychosis in PD, aripiprazole did not appear promising., (Copyright 2006 Movement Disorder Society.)

Introduction: Cerebrovascular reactivity (CVR) reflects the compensatory dilatory capacity of cerebral arterioles to a dilatory stimulus and is important for maintaining constant cerebral blood flow. A reduced CVR increases the risk of stroke. We recently found that CVR was reduced in patients with depression. This might contribute to the higher risk of stroke that has been found in subjects suffering from depression. The characterization of pathophysiological conditions in the cerebral circulation requires the knowledge of influencing factors on CVR. We therefore investigated the influence that antidepressant administration might have on CVR in humans., Methods: We investigated CVR in 48 healthy men before and after a 10-day application of either mirtazapine or placebo. CVR was determined by calculating the increase in cerebral blood flow velocity after stimulation with acetazolamide. Blood flow velocities were measured by transcranial Doppler ultrasound., Results: There was no significant group-difference of CVR after the treatment trial compared to baseline., Discussion: Mirtazapine does not seem to have an influence on CVR, or any impact on CVR might have been quickly limited by a cerebral autoregulatory response.