INDIANAPOLIS, Ind., Sept. 7 -- The investigational schizophrenia drug LY2140023 may effectively reduce the symptoms of schizophrenia without causing any of the side effects seen with older therapies.
A phase II proof-of-concept study showed that patients who took LY2140023 or olanzapine (Zyprexa) showed greater improvements on the Positive and Negative Syndrome Scale (PANSS), compared with their counterparts who received placebo, according to results reported online in Nature Medicine.
Moreover, the experimental drug did not appear to cause the adverse effects associated with approved schizophrenia drugs including prolactin elevation, extrapyramidal symptoms, and weight gain, said the researchers, led by Sandeep T. Patil, of Eli Lilly and Company, manufacturer of the drug.
During the four-week trial, 200 patients in Russian mental institutions were randomized to receive LY2140023 (40 mg given twice a day), olanzapine (15 mg daily), or placebo. Patients in both the active treatment arms responded within one week (P<0.05)>
Patients in the active treatment arms also showed improvements in PANNS total score, compared with placebo (P<0.001>
After four weeks of treatment, the study showed that 32% of patients in the LY2140023 group and 41.2% of patients in olanzapine group responded to therapy, compared with 3.2% of those patients in the placebo arm (P<0.001>
Patients in the active arms of the study also showed improvements in the Clinical Global Impression-Severity scores and PANNS positive and negative subscores, compared with those patients randomized to receive placebo.
Additionally, a mean 0.51-kg weight reduction from baseline was noted in the LY2140023 group. A moderate but statistically significant weight gain of 0.74 kg was observed in the olanzapine group (P=0.017), compared with the placebo group, the study showed.
Patients in the placebo arm showed the highest rate of study discontinuation because they were seeing no effect. The rate of discontinuation because of adverse events was not significantly different across any of the three treatment groups (P=0.66).
Most adverse events in the LY2140023 group were mild to moderate and did not lead to discontinuation. The most common adverse events included insomnia, affect lability (P=0.038), nausea, headache, somnolence, and an increase in blood creatine phosphokinase. The adverse event profile of LY2140023 did not include prolactin increase or worsening of extrapyramidal symptoms.
The mood lability was only observed at one study site. In general, these patients were more emotional than before, according to an investigator at the site. "In future trials, we will attempt to closely follow and increase our understanding of this potentially interesting observation."
By contrast, treatment-emergent adverse events in the olanzapine group included elevation in blood triglyceride levels (P=0.005), insomnia, weight gain (P=0.034), somnolence, akathisia, agitation, and periodontitis (P=0.03).
"Our data provides strong new evidence for the role of glutamate modulation in treating psychosis, and specifically for mGlu2/3 receptor activation as a viable therapeutic approach to treat schizophrenia," the researchers concluded.
They did acknowledge, however, that "additional larger and longer-term studies are warranted to further support and optimally characterize the benefits and potential risks of this approach to treat schizophrenia."
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