Henry A. Nasrallah

A Randomized, Double-Blind, Placebo-Controlled Trial of Aripiprazole Lauroxil in Acute Exacerbation of Schizophrenia

OBJECTIVE This study evaluated the efficacy, safety, and tolerability of aripiprazole lauroxil, a novel long-acting injectable atypical antipsychotic, for the treatment of schizophrenia. METHOD An international multicenter, randomized, double-blind, placebo-controlled trial was conducted between December 2011 and March 2014. Patients (N = 623) aged 18 to 70 years with schizophrenia (DSM-IV-TR criteria), experiencing an acute exacerbation, were randomized in a 1:1:1 ratio to receive gluteal intramuscular injection of aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or matching placebo once monthly for 12 weeks. The primary efficacy outcome was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to day 85. The Clinical Global Impressions-Improvement scale (CGI-I) score at day 85 was the secondary efficacy outcome. Safety and tolerability were assessed. RESULTS The PANSS total score (mean ± standard error [SE]) improved significantly from baseline to day 85 in the aripiprazole lauroxil 441 mg and 882 mg groups, with placebo-adjusted differences of -10.9 ± 1.8 (P < .001) and -11.9 ± 1.8 (P < .001), respectively. Significant (P ≤ .004) improvements in both active treatment groups were demonstrated as early as day 8 and continued throughout the treatment period. The proportion of patients who were very much or much improved on the CGI-I was significantly greater with aripiprazole lauroxil 441 mg and 882 mg treatment versus placebo (P < .001). The most common treatment-emergent adverse events were insomnia, akathisia, headache, and anxiety. The incidence of injection site reactions was low, predominantly described as injection site pain, and was associated with the first injection. CONCLUSIONS Aripiprazole lauroxil demonstrated robust efficacy for treatment of patients experiencing acute exacerbation of schizophrenia. The improvement in psychotic symptoms was statistically significant and clinically meaningful. Symptom improvement occurred rapidly after initiation of aripiprazole lauroxil treatment and was maintained throughout the study. Both aripiprazole lauroxil 441 mg and 882 mg doses were well tolerated. These results support aripiprazole lauroxil as an important new treatment option for schizophrenia. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01469039; Clinicaltrialsregister.eu identifier: 2012-003445-15.

Lurasidone for the treatment of depressive symptoms in schizophrenia: analysis of 4 pooled, 6-week, placebo-controlled studies.

Objective Depressive symptoms are common in schizophrenia and can worsen outcomes and increase suicide risk. Lurasidone is an atypical antipsychotic agent indicated for the treatment of schizophrenia and for the treatment of major depressive episodes associated with bipolar I disorder. This post hoc analysis evaluated the effect of lurasidone on depressive symptoms in patients with schizophrenia. Methods Patient-level data were pooled from 4 similarly designed, double-blind, placebo-controlled, 6-week registration studies of lurasidone (40–160 mg/d) in adult patients with an acute exacerbation of schizophrenia. Changes in depressive symptoms, measured by the Montgomery–Åsberg Depression Rating Scale (MADRS), were analyzed for the overall sample and for subgroups of patients stratified by baseline MADRS scores. Results MADRS assessments at baseline and endpoint (day 42 or last observation carried forward [LOCF]) were available for 1330 patients. Patients receiving lurasidone experienced significantly greater decreases in MADRS score (–2.8, least-squares [LS] mean change, LOCF) compared with patients receiving placebo (–1.4, P < .001, effect size 0.24). Analysis of change in MADRS score (LOCF) by baseline symptom severity (MADRS score of ≥12, ≥14, ≥16, ≥18) showed significantly greater improvement for lurasidone-treated patients across all severity groups; effect sizes ranged from 0.25 to 0.34. Among patients with a baseline MADRS score of ≥12, depressive symptom remission (defined as MADRS score <10 at LOCF endpoint) was attained by 45.0% of lurasidone-treated patients and 36.3% of patients receiving placebo (P < .05). Conclusions In a pooled analysis of short-term, placebo-controlled studies, lurasidone significantly improved depressive symptoms in patients with schizophrenia.

Bitopertin in Negative Symptoms of Schizophrenia—Results From the Phase III FlashLyte and DayLyte Studies

BACKGROUND There is currently no standard of care for treatment of negative symptoms of schizophrenia, although some previous results with glutamatergic agonists have been promising. METHODS Three (SunLyte [WN25308], DayLyte [WN25309], and FlashLyte [NN25310]) phase III, multicenter, randomized, 24-week, double-blind, parallel-group, placebo-controlled studies evaluated the efficacy and safety of adjunctive bitopertin in stable patients with persistent predominant negative symptoms of schizophrenia treated with antipsychotics. SunLyte met the prespecified criteria for lack of efficacy and was declared futile. Key inclusion criteria were age ≥18 years, DSM-IV-TR diagnosis of schizophrenia, score ≥40 on the sum of the 14 Positive and Negative Syndrome Scale negative symptoms and disorganized thought factors, unaltered antipsychotic treatment, and clinical stability. Following a 4-week prospective stabilization period, patients were randomly assigned 1:1:1 to bitopertin (5 mg and 10 mg [DayLyte] and 10 mg and 20 mg [FlashLyte]) or placebo once daily for 24 weeks. The primary efficacy end point was mean change from baseline in Positive and Negative Syndrome Scale negative symptom factor score at week 24. RESULTS The intent-to-treat population in DayLyte and FlashLyte included 605 and 594 patients, respectively. At week 24, mean change from baseline showed improvement in all treatment arms but no statistically significant separation from placebo in Positive and Negative Syndrome Scale negative symptom factor score and all other end points. Bitopertin was well tolerated. CONCLUSIONS These studies provide no evidence for superior efficacy of adjunctive bitopertin in any of the doses tested over placebo in patients with persistent predominant negative symptoms of schizophrenia.

New drug developments in psychosis: Challenges, opportunities and strategies.

ABSTRACT All currently approved drugs for schizophrenia work mainly by dopaminergic antagonism. While they are efficacious for psychotic symptoms, their efficacy is limited for negative symptoms and cognitive deficits which underlie the substantive disability in this illness. Recent insights into the biological basis of schizophrenia, especially in relation to non‐dopaminergic mechanisms, have raised the efforts to find novel and effective drug targets, though with relatively little success thus far. Potential impediments to novel drug discovery include the continued use of symptom based disease definitions which leads to etiological and pathophysiological heterogeneity, lack of valid preclinical models for drug testing, and design limitations in clinical trials. These roadblocks can be addressed by (i) characterizing trans‐diagnostic, translational pathophysiological dimensions as potential treatment targets, (ii) efficiency, accountability and, transparency in approaches to the clinical trials process, and (iii) leveraging recent advances in genetics and in vitro phenotypes. Accomplishing these goals is urgent given the significant unmet needs in the pharmacological treatment of schizophrenia. As this happens, it is imperative that clinicians employ optimal dosing, measurement‐based care, and other best practices in utilizing existing treatments to optimize outcomes for their patients today.

Defining therapeutic benefit for people with schizophrenia: focus on negative symptoms.

Schizophrenia is a complex, heterogeneous, multidimensional disorder within which negative symptoms are a significant and disabling feature. Whilst there is no established treatment for these symptoms, some pharmacological and psychosocial interventions have shown promise and this is an active area of research. Despite the effort to identify effective interventions, as yet there is no broadly accepted definition of therapeutic success. This article reviews concepts of clinical relevance and reports on a consensus conference whose goal was to apply these concepts to the treatment of negative symptoms. A number of key issues were identified and discussed including: assessment of specific negative symptom domains; defining response and remission for negative symptoms; assessment of functional outcomes; measurement of outcomes within clinical trials; and the assessment of duration/persistence of a response. The group reached a definition of therapeutic success using an achieved threshold of function that persisted over time. Recommendations were agreed upon with respect to: assessment of negative symptom domains of apathy-avolition and deficit of expression symptoms; thresholds for response and remission of negative symptoms based on level of symptomatology; assessing multiple domains of function including social occupation, activities of daily living, and socialization; the need for clinical trial data to include rate of change over time and converging sources of evidence; use of clinician, patient and caregiver perspectives to assess success; and the need for establishing criteria for the persistence of therapeutic benefit. A consensus statement and associated research criteria are offered as an initial step towards developing broad agreement regarding outcomes of negative symptoms treatment.

The Management of Schizophrenia in Clinical Practice (MOSAIC) Registry: A focus on patients, caregivers, illness severity, functional status, disease burden and healthcare utilization

BACKGROUND The Management of Schizophrenia in Clinical Practice (MOSAIC), a disease-based registry of schizophrenia, was initiated in December 2012 to address important gaps in our understanding of the impact and burden of schizophrenia and to provide insight into the current status of schizophrenia care in the US. Recruitment began in December 2012 with ongoing assessment continuing through May 2014. METHODS Participants were recruited from a network of 15 centralized Patient Assessment Centers supporting proximal care sites. Broad entry criteria included patients diagnosed with schizophrenia, schizophreniform or schizoaffective disorder, presenting within the normal course of care, in usual treatment settings, aged ≥18years and able to read and speak English. RESULTS By May 2014, 550 participants (65.8% male, 59.8% White, 64.4% single, mean age 42.9years), were enrolled. The majority had a diagnosis of schizophrenia (62.0%). Mean illness duration at entry was 15.0years. Common comorbidities at entry were high lipid levels (26.9%), hypertension (23.1%) and type II diabetes (13%). Participants were categorized by baseline overall Clinical Global Impression-Schizophrenia Severity Score as minimally (9.1%), mildly (25.3%), moderately (39.9%), markedly (22.3%) and severely (3.4%) ill. Most commonly used second generation antipsychotics at entry were risperidone (17.8%), clozapine (16.5%), olanzapine (14.0%), aripiprazole (13.6%) and quetiapine (5.6%). CONCLUSIONS No large-scale patient registry has been conducted in the US to longitudinally follow patients with schizophrenia and describe symptom attributes, support network, care access and disease burden. These data provide important epidemiological, clinical and outcome insights into the burden of schizophrenia in the US.

Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial

Cariprazine, a dopamine D3/D2 receptor partial agonist with preference for D3 receptors, has demonstrated efficacy in randomized controlled trials in schizophrenia. This multinational, randomized, double-blind, placebo-controlled, parallel-group study evaluated the efficacy, safety, and tolerability of cariprazine for relapse prevention in adults with schizophrenia; total study duration was up to 97weeks. Schizophrenia symptoms were treated/stabilized with cariprazine 3-9mg/d during 20-week open-label treatment consisting of an 8-week, flexible-dose run-in phase and a 12-week fixed-dose stabilization phase. Stable patients who completed open-label treatment could be randomized to continued cariprazine (3, 6, or 9mg/d) or placebo for double-blind treatment (up to 72weeks). The primary efficacy parameter was time to relapse (worsening of symptom scores, psychiatric hospitalization, aggressive/violent behavior, or suicidal risk); clinical measures were implemented to ensure safety in case of impending relapse. A total of 264/765 patients completed open-label treatment; 200 eligible patients were randomized to double-blind placebo (n=99) or cariprazine (n=101). Time to relapse was significantly longer in cariprazine- versus placebo-treated patients (P=.0010, log-rank test). Relapse occurred in 24.8% of cariprazine- and 47.5% of placebo-treated patients (hazard ratio [95% CI]=0.45 [0.28, 0.73]). Akathisia (19.2%), insomnia (14.4%), and headache (12.0%) were reported in ≥10% of patients during open-label treatment; there were no cariprazine adverse events ≥10% during double-blind treatment. Long-term cariprazine treatment was significantly more effective than placebo for relapse prevention in patients with schizophrenia. The long-term safety profile in this study was consistent with the safety profile observed in previous cariprazine clinical trials. ClincalTrials.gov identifier: NCT01412060.

Examining the reliability and validity of the Clinical Assessment Interview for Negative Symptoms within the Management of Schizophrenia in Clinical Practice (MOSAIC) multisite national study

The current study sought to expand on prior reports of the validity and reliability of the CAINS (CAINS) by examining its performance across diverse non-academic clinical settings as employed by raters not affiliated with the scales developers and across a longer test-retest follow-up period. The properties of the CAINS were examined within the Management of Schizophrenia in Clinical Practice (MOSAIC) schizophrenia registry. A total of 501 participants with a schizophrenia spectrum diagnosis who were receiving usual care were recruited across 15 national Patient Assessment Centers and evaluated with the CAINS, other negative symptom measures, and assessments of functioning, quality of life and cognition. Temporal stability of negative symptoms was assessed across a 3-month follow-up. Results replicated the two-factor structure of the CAINS reflecting Motivation and Pleasure and expression symptoms. The CAINS scales exhibited high internal consistency and temporal stability. Convergent validity was supported by significant correlations between the CAINS subscales with other negative symptom measures. Additionally, the CAINS was significantly correlated with functioning and quality of life. Discriminant validity was demonstrated by small to moderate associations between the CAINS and positive symptoms, depression, and cognition (and these associations were comparable to those found with other negative symptom scales). Findings suggest that the CAINS is a reliable and valid tool for measuring negative symptoms in schizophrenia across diverse clinical samples and settings.

Multiple retinal anomalies in schizophrenia

INTRODUCTION In addition to being a critical component of the visual system, the retina provides the opportunity for an accessible and noninvasive probe of brain pathology in neuropsychiatric disorders. Several studies have reported various retinal abnormalities in schizophrenia, some primary and others iatrogenic. There is now increasing evidence supporting the existence of retinal anomalies in schizophrenia across structural, neurochemical and physiological parameters. Here, we review the types of retinal pathology in schizophrenia and discuss how these findings may provide novel insights for future research into the neurodevelopmental neurobiology of this syndrome, and possibly as useful biomarkers. METHODS Using the keywords schizophrenia, retina, pathology, electroretinogram (ERG), and/or optical coherence tomography (OCT) on PubMed, all studies using the English language within 30years were reviewed. Methods were examined, and common themes were identified, tabulated, and discussed. RESULTS We classified the reports of retinal pathology into primary and secondary. The major secondary retinal pathology is related to the iatrogenic effects of a once widely prescribed first generation antipsychotic (thioridazine), which was found to be associated with retinal pigment deposits, decreased visual acuity, and suppression of dark adapted ERG responses. The primary retinal findings were obtained via different measures primarily using ERG, OCT, and microvascular imaging. The most consistent findings were 1) decreased ERG wave amplitudes, 2) reduced macular volume, 3) thinning of retinal nerve fiber layer, and 4) widened venule caliber. CONCLUSION The abnormal pathobiological findings of the retina in schizophrenia may represent an important avenue for elucidating some of the neurodevelopmental aberrations in schizophrenia. The well replicated retinal anomalies could serve as biomarkers for schizophrenia and perhaps an endophenotype that may help identify at-risk individuals and to facilitate early intervention.

“Just the facts”: Meandering in schizophrenia's many forests

To paraphrase a famous American philosopher and pragmatist William James “The facts of schizophrenia are like islands in the sea or like trees in the forest which comingle their roots in the darkness underground” (Bowers and Skrupskelis, 1975). The papers in our series “Schizophrenia” Just the Facts”, (Keshavan et al., 2008; Tandon et al., 2008a, 2008b, 2009, 2010) which take stock of what we have learned about schizophrenia in the last three decades, highlight our inability to precisely define the tree-facts that constitute the forest-construct of schizophrenia or exactly delineate how their roots comingle in the underground to characterize this entity. Our conclusions suggest the need for a shift in perspective towards viewing the trees from much higher aboveordeeperunderneath tobetterdeterminewhether a forest exists and, if so, what its boundaries are. The last paper in our series (Keshavan et al., 2011) likened schizophrenia to an elephant in the dark room being groped by several blind men each of whom come up with different interpretations of the nature of this beast depending onwhich part theywere “looking at”. All the commentators to this last paper in our series have thoughtfully reflected on our central message— discarding the idea of schizophrenia as a single nosological entity and the need to envision the elephant or the forest from far above. In his engaging, yet provocative commentary, Kapur (2011)muses about the scenario of Emil Kraepelin looking at our current state of affairs and wondering why we have not moved beyond his century-old unitary construct of dementia praecox even as its definition is vastly changed. Carpenter (2011) perspicaciously discusses the contradictionbetween the need to consider schizophrenia a singular entity for thepurposeof its elucidation contrastedwith the reality that it is many. Maj (2011) is similarly skeptical of how well we really understand schizophrenia and wonders about the paradox that the more “data” that are generated about schizophrenia, the less certain and confused we are about its true nature. DeLisi (2011) perceptively points out that generating viable hypotheses and models of schizophrenia has laggedbehind theabundanceoffindingsproduced. JohnSweeney (2011), in his effort to visualize the elephant from far above, astutely points the need to think outside the nosological box, and to simultaneously examine genotype–phenotype relationships across diverse disorders in order to delineate both unique and shared aspects of phenomenologically nebulous psychiatric syndromes. In his commentary, Van Os (2011) cleverly points out that the “facts”we identify as defining schizophrenia are really non-facts, since none of them is necessary or sufficient for this