Claim: Roche's schizophrenia drug misses goal in two late-stage trials.
Verdict: SUPPORTS

Retrieved passages:
title: Bitopertin
text: 66% on placebo (p<0.05, per-protocol population). In January 2014, Roche reported that bitopertin failed to meet its endpoints in two phase III trials assessing its efficacy in reducing negative symptoms of schizophrenia. Subsequently, in April 2014, Roche announced that it was discontinuing all of its phase III trials of bitopertin for schizophrenia except for one. Though Roche has largely ceased its studies of bitopertin for schizophrenia, it is also investigating the drug in the treatment of obsessive-compulsive disorder (OCD), and is continuing its development for this indication. As of August 2014, bitopertin is in phase II clinical trials for OCD.

title: Tamas Bartfai
text: for 'heartburn', as a consultant to Roche, the catechol-O-methyltransferase inhibitor (Tasmar-tolcapone) used in Parkinson's Disease, the first benzodiazepine–antagonist (flunitrazepam) for treatment of benzodiazepine overdoses, and as a consultant to Novartis the sphingosine 1-phosphate agonist gilenya-fingolimod as the first oral multiple sclerosis drug. He has also worked on four current drug candidates that as of 2015, are in phase 2 and 3 clinical trials. One of the most promising ones is the amyloid Αβ antibody that the Banner Alzheimer's Institute, Roche and the U.S. government are testing in Colombia for prevention of Alzheimer's disease in a large cohort with a familial

title: LY-404,039
text: Company announced their decision to stop their ongoing clinical studies investigating LY-2140023 as a treatment for schizophrenia after their phase II study did not meet its primary endpoint. The company completed a phase II, randomized, double-blind, placebo- and active-controlled, parallel-group-assignment, dose-ranging, inpatient, multi-center clinical trial. Patients were randomized to receive 5, 20, 40, or 80 mg of LY-2140023, placebo, or olanzapine for 28 days. Results of the clinical trial indicated that neither LY-2140023 nor olanzapine were significantly more efficacious than the placebo as determined with PANSS total scores. Post hoc analyses indicated only a trend towards improvement with LY-2140023, while

title: Pembrolizumab
text: chances of proving the drug would work and would make clinical trials faster. (The trials would need fewer patients because of the likelihood of greater effect size.) Moving quickly and reducing the risk of failure was essential for catching up with Bristol-Myers Squibb, which had an approximate five year lead over Merck. The phase I study started in early 2011, and Eric Rubin, who was running the melanoma trial, argued for and was able to win expansion of the trial until it reached around 1300 people. This was the largest Phase I study ever run in oncology, with the patients

title: Mad in America
text: patients on medications. He then describes fifty years of American scientists doing experiments on schizoprenia patients: to intentionally exacerbate their symptoms and study the results. He compares the doctors' behavior, unfavorably, to 1947 after American trials of Nazi doctors ended in the Nuremberg Code for ethics in human experimentation. Part Four is Whitaker's description of drug trials for the newer atypical antipsychotics. He says that many of these trials were stacked in favor of the drug being proposed by eliminating the placebo, or by comparing multiple doses of the new drug against a single, very high dose of the old

title: Pimavanserin
text: and the results showed that pimavanserin potentiated the antipsychotic effects of subtherapeutic doses of risperidone and improved the tolerability of haloperidol treatment by reducing the incidence of extrapyramidal symptoms. The drug met expectations for a Phase III clinical trial for the treatment of Parkinson's disease psychosis, and has completed Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication. On September 2, 2014, the United States Food and Drug Administration granted Breakthrough Therapy status to Acadia's New Drug Application for pimavanserin. It was approved by the FDA to treat hallucinations and delusions associated with psychosis experienced by some

title: Antipsychotic
text: bipolar disorder instead. The goals of treatment of these patients include reducing symptoms and potentially improving long-term treatment outcomes. Randomized clinical trials have provided evidence for the efficacy of antipsychotic drugs in achieving the former goal, with first-generation and second generation antipsychotics showing about equal efficacy. Evidence that early treatment has a favorable effect on long term outcomes is equivocal. Placebo-controlled trials of both first and second generation antipsychotic drugs consistently demonstrate the superiority of active drug to placebo in suppressing psychotic symptoms. A large meta-analysis of 38 trials of antipsychotic drugs in schizophrenia acute psychotic episodes showed an effect

title: Bifeprunox
text: atypical antipsychotics will instead of antagonizing D receptors, will act as partial agonists, as well as partial agonists towards 5-HT receptors. In a multi-center, placebo-controlled study, 20 mg of bifeprunox was found to be significantly more effective than placebo at reducing symptoms of schizophrenia, with a low incidence of side effects. An NDA for Bifeprunox was filed with the U.S. Food and Drug Administration in January 2007. The FDA rejected the application in August 2007. In June 2009, Solvay and Lundbeck decided to cease development because "efficacy data did not support pursuing the existing development strategy of stabilisation of non-acute

title: Atypical antipsychotic
text: thereafter. Clozapine (Clozaril), an atypical antipsychotic, fell out of favor due to concerns over drug-induced agranulocytosis. Following research indicating its effectiveness in treatment-resistant schizophrenia and the development of an adverse event monitoring system, clozapine re-emerged as a viable antipsychotic. According to Barker (2003), the three most-accepted atypical drugs are clozapine, risperidone, and olanzapine. However, he goes on to explain that clozapine is usually the last resort when other drugs fail. Clozapine can cause agranulocytosis (a decreased number of white blood cells), requiring blood monitoring for the patient. Despite the effectiveness of clozapine for treatment-resistant schizophrenia, agents with a more favorable

title: LY-404,039
text: as an adjuvant to the antipsychotic medications already used by patients participating in the study utilized a lower dose of 20 mg BID. If treatment was well-tolerated after a week at this target dose, the dose was increased to 40 mg BID. However, if the 20 mg dose was not well-tolerated, the dose was decreased to 10 mg. In 2007, a randomized phase II clinical trial showed that LY-2140023 taken twice daily for 4 weeks improved schizophrenia symptoms as measured with the PANSS and CGI-S when compared to placebo. However, post hoc analysis did not demonstrate a statistically significant difference

title: Clozapine
text: approved its use only for treatment-resistant schizophrenia, and required Restricted Distribution, a Patient Registry and regular hematological monitoring to detect granulocytopenia, before agranulocytosis develops. In December 2002, clozapine was approved in the US for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior. In 2005 FDA approved criteria to allow reduced blood monitoring frequency. In 2015 the individual manufacturer Patient Registries were consolidated by FDA request into a single shared Patient Registry Called The Clozapine REMS Registry. Clozapine is sold under many brands worldwide including Alemoxan, Azaleptine, Azaleptol, Cloment, Clonex,

title: Atypical antipsychotic
text: with dementia, anxiety disorder, autism spectrum disorder, and obsessive-compulsive disorder (an off-label use). In dementia, they should only be considered after other treatments have failed and if the patient is a risk to themselves and/or others. The first-line psychiatric treatment for schizophrenia is antipsychotic medication, which can reduce the positive symptoms of schizophrenia in about 8–15 days. Antipsychotics only appear to improve secondary negative symptoms of schizophrenia in the short term and may worsen negative symptoms overall. Overall there is no good evidence that atypical antipsychotics have any therapeutic benefit for treating the negative symptoms of schizophrenia. There is very

title: Schizophrenia
text: stopped. The choice of which antipsychotic to use is based on benefits, risks, and costs. It is debatable whether, as a class, typical or atypical antipsychotics are better. Amisulpride, olanzapine, risperidone, and clozapine may be more effective but are associated with greater side effects. Typical antipsychotics have equal drop-out and symptom relapse rates to atypicals when used at low to moderate dosages. There is a good response in 40–50%, a partial response in 30–40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two or three different antipsychotics) in 20% of people. Clozapine is an effective

title: Alcino J. Silva
text: promising, but inconclusive, clinical trials, and to two large on going clinical studies in the USA and Europe. A team led by Dan Ehninger in the Silva lab also showed that rapamycin, an FDA approved inhibitor of mTOR, can reverse the late-LTP deficits and learning impairments they discovered in an animal model of Tuberous Sclerosis (Tsc2 heterozygous mice). TSC is highly associated with autism, but the Tsc2 heterozygous mice did not show any autism-like behavioral abnormalities, such as social interaction deficits. Artificially activating the immune system of pregnant mice, however, does reveal social interaction deficits in Tsc2 heterozygous progeny, suggesting

title: Latrepirdine
text: research in 2000. Preliminary results from human trials have also been promising. In an initial six-month phase II trial, results have shown significant improvement over placebo at 12 months. Latrepirdine showed promising results in a phase III-equivalent, double-blind trial in Russia with mild–moderate stage patients. In April 2009, Pfizer and Medivation initiated a phase III trial (CONCERT study) aiming for FDA approval. In March 2010, Pfizer announced that this clinical trial failed to show any benefit for the treatment of Alzheimer's disease patients. Numerous phase III trials for AD were recruiting in 2009. In July 2009, Pfizer and Medivation announced

title: Management of schizophrenia
text: to take around 7 to 14 days to have their main effect. However, these drugs fail to significantly ameliorate the negative symptoms and cognitive dysfunction. There is evidence of clozapine, amisulpride, olanzapine and risperidone being the most effective medications, although a high proportion of studies of risperidone were undertaken by its manufacturer, Janssen-Cilag, and should be interpreted with this in mind. In those on antipsychotics, continued use decreases the risk of relapse. There is little evidence regarding consistent benefits from their use beyond two or three years. Treatment of schizophrenia changed dramatically in the mid-1950s with the development and introduction

title: Management of schizophrenia
text: gain. Risperidone has a similar rate of extrapyramidal symptoms to haloperidol. The American Psychiatric Association generally recommends that atypicals be used as first line treatment in most patients, but further states that therapy should be individually optimized for each patient. The response of symptoms to medication is variable; "Treatment-resistant schizophrenia" is the failure to respond to two or more antipsychotic medications given in therapeutic doses for six weeks or more. Patients in this category may be prescribed clozapine, a medication that may be more effective at reducing symptoms of schizophrenia, but treatment may come with a higher risk of several

title: Pierre Deniker
text: marketing it as an anti-nausea medication. After Deniker's observations, they sought and received FDA approval in 1954 to market Thorazine for the treatment of schizophrenia. Pierre Deniker Pierre Deniker (16 February 1917 in Paris – 17 August 1998) was involved, jointly with Jean Delay and J. M. Harl, in the introduction of chlorpromazine (Thorazine), the first antipsychotic used in the treatment of schizophrenia, in the 1950s. Thorazine had been used in surgical procedures peri-operatively as an anti-nausea medication in France. Patients were noted to be less anxious and calmer. This observation eventually led Deniker to try chlorpromazine with patients who

title: Management of schizophrenia
text: the studies may have an increased risk of bias. "Note: Only adjuncts for which at least one double-blind randomized placebo-controlled trial has provided support are listed in this table." Acronyms used: DB-RPCT — Double-blind randomized placebo-controlled trial. DB-RCT — Double-blind randomized controlled trial. "Note: Global in the context of schizophrenia symptoms here refers to all four symptom clusters." † No secondary sources could be found on the utility of the drug in question, treating the symptom in question (or any symptom in the case of where † has been placed next to the drug's name). Psychotherapy is also widely recommended,

title: AstraZeneca
text: Dan Markingson committed suicide while enrolled in an industry-sponsored pharmaceutical trial comparing three FDA-approved atypical antipsychotics: Seroquel (quetiapine), Zyprexa (olanzapine), and Risperdal (risperidone). University of Minnesota Professor of Bioethics Carl Elliott noted that Markingson was enrolled in the study against the wishes of his mother, Mary Weiss, and that he was forced to choose between enrolling in the study or being involuntarily committed to a state mental institution. Further investigation revealed financial ties to AstraZeneca by Markingson's psychiatrist, Stephen C. Olson, oversights and biases in AstraZeneca's trial design, and the inadequacy of university Institutional Review Board (IRB) protections for research