Disappointing outcome of bitopertin treatment for negative symptoms in schizophrenia

June 14, 2017
Functional magnetic resonance imaging (fMRI) and other brain imaging technologies allow for the study of differences in brain activity in people diagnosed with schizophrenia. The image shows two levels of the brain, with areas that were more active in healthy controls than in schizophrenia patients shown in orange, during an fMRI study of working memory. Credit: Kim J, Matthews NL, Park S./PLoS One.

Two new phase III clinical trials investigating the efficacy and safety of bitopertin, a glycine uptake inhibitor considered to be a promising new add-on therapy for treating negative symptoms in schizophrenia, failed to show a benefit of the drug over placebo. The findings throw a wrench in the hopeful efforts to find a treatment for negative symptoms of schizophrenia, which account for some of the most debilitating aspects of the disorder and are associated with poorer outcomes in patients.

The outcomes of the trials were published in a paper in Biological Psychiatry by Dr. Dragana Bugarski-Kirola of Roche Pharmaceuticals in Basal, Switzerland. The randomized, double-blind, parallel-group, placebo-controlled studies were a collaboration between Roche and several research institutions around the world.

"We are back to the drawing board," said Dr. John Krystal, Editor of Biological Psychiatry.

Previous attempts to treat negative symptoms have employed drugs, hormones, and brain stimulation, but none have provided the desired clinical benefit. Research fingering glutamate signaling in negative symptoms has spurred the idea of targeting glutamate receptors, but this approach has failed in large trials. Glycine reuptake inhibitors have been considered a promising alterative to enhance glutamatergic signaling, and a small proof-of-concept study showed that bitopertin, which selectively inhibits glycine transporter type 1 (GlyT-1), reduced negative symptoms in stable patients with .

"GlyT-1 inhibition was one of the most promising approaches to the treatment of schizophrenia," said Krystal. "While it still may be possible to optimize GlyT-1 inhibition as a treatment, these negative results suggest GlyT-1 inhibition is not a broadly effective or optimal therapeutic strategy to enhance NMDA glutamate receptor function in schizophrenia."

The trials were carried out over 201 sites, with each trial including about 600 patients with persistent, predominant negative symptoms of schizophrenia. Patients treated with antipsychotics were administered placebo or bitopertin (5, 10, or 20 mg) for 24 weeks. The doses were chosen to test the minimal effective dose (5 mg) and the dose with a predicted maximal effect (20 mg).

All participants showed some improvement in the negative symptom factor score, but there were no differences between placebo or bitopertin treatment at 24 weeks. No differences were observed in other symptom domains of schizophrenia either. All three doses of bitopertin were well-tolerated and generally safe over the course of the study.

According to Bugarski-Kirola, tackling complex clinical, regulatory and commercial development processes, reliability and quality control was a daunting task when dealing with over 200 study sites across different cultures. "We demonstrated that quality can be accomplished across the sites, but consider a different approach to the design," she said, explaining that rather than treating negative symptom patients as one homogenous target, priority should be given to exploring the usefulness of novel mechanisms in separate negative symptom domains to better define the target population and maximize the chance of success before launching large phase III trials.

Explore further: Disproving hypothesis clears path for research for new treatment options for schizophrenia

More information: Dragana Bugarski-Kirola et al. Bitopertin in Negative Symptoms of Schizophrenia?Results From the Phase III FlashLyte and DayLyte Studies, Biological Psychiatry (2017). DOI: 10.1016/j.biopsych.2016.11.014

Related Stories

Disproving hypothesis clears path for research for new treatment options for schizophrenia

March 10, 2016
Researchers reported results from the first repeated-dose study of a dopamine-1 receptor (D1R) agonist for treating the cognitive and negative symptoms of schizophrenia today in the Journal of Psychopharmacology.

Clinical trial: First treatment for 'emotional flatness' associated with schizophrenia

August 30, 2015
Results of a clinical trial seem to show the first effective treatment for the negative symptoms - withdrawal, lack of emotion, and apathy - associated with schizophrenia. This work is presented at the European College of ...

Study suggests valproate may be effective in patients with variant of COMT gene

September 14, 2016
A drug prescribed to many patients with schizophrenia or bipolar disorder may decrease negative symptoms for people with a certain variant of the COMT gene, suggests a new study from researchers at Columbia University Medical ...

A comparison between quetiapine and aripiprazole for treatment of schizophrenia

July 13, 2016
Schizophrenia is a common cause of incapacity and is ranked as the third-most-disabling illness subsequent to dementia and quadriplegia. Nearly, 75% of persons with schizophrenia have continuing problems with recurrent psychotic ...

New schizophrenia treatments may be effective for subgroup of patients

December 8, 2015
Mounting evidence indicates that disturbances in the brain's glutamate pathway contribute to symptoms of schizophrenia. Thus, the glutamate pathway has become the target of a number of new drug therapies. Findings published ...

New medication significantly decreases involuntary movement

April 7, 2017
Antipsychotic treatment can cause involuntary movements such as lip smacking, tongue protrusions and excessive eye blinking. These movements typically occur after more than 3 months of treatment and are called tardive dyskinesia.

Recommended for you

Researchers find common psychological traits in group of Italians aged 90 to 101

December 12, 2017
In remote Italian villages nestled between the Mediterranean Sea and mountains lives a group of several hundred citizens over the age of 90. Researchers at the University of Rome La Sapienza and University of California San ...

Your mood depends on the food you eat, and what you should eat changes as you get older

December 11, 2017
Diet and dietary practices differentially affect mental health in young adults versus older adults, according to new research from Binghamton University, State University of New York.

New therapy can help schizophrenia sufferers re-engage socially

December 11, 2017
A new therapy aimed at helping young people suffering from schizophrenia to reconnect and engage with the world around them has had promising results, according to a new University of Sussex-led study.

Twitter can reveal our shared mood

December 11, 2017
In the largest study of its kind, researchers from the University of Bristol have analysed mood indicators in text from 800 million anonymous messages posted on Twitter. These tweets were found to reflect strong patterns ...

Certain books can increase infant learning during shared reading, study shows

December 11, 2017
Parents and pediatricians know that reading to infants is a good thing, but new research shows reading books that clearly name and label people and objects is even better.

Many different types of anxiety and depression exist, new study finds

December 8, 2017
Five new categories of mental illness that cut across the current more broad diagnoses of anxiety and depression have been identified by researchers in a Stanford-led study.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.