ITI-007 for the Treatment of Schizophrenia: A 4-Week Randomized, Double-Blind, Controlled Trial

Abstract

The mechanistically novel investigational drug ITI-007 was effective for the treatment of schizophrenia and comparable with placebo on safety measures in this trial. Secondary analyses indicated that ITI-007 improved negative and depression symptoms and might have expanded therapeutic efficacy in comparison with current antipsychotic drugs.

Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future

“…The combination of ITI-007's high potency blockade of 5-HT 2A receptors, efficient dopamine modulation, serotonin reuptake inhibition, and indirect enhancement of glutamatergic neurotransmission has been shown to yield antipsychotic efficacy without motor side effects or cardiometabolic safety issues. ITI-007 demonstrated a reduction of positive symptoms in patients with schizophrenia comparable to risperidone, but with significantly lower blood levels of biomarkers indicative of potential metabolic dysfunction (i.e., insulin, glucose, cholesterol and triglycerides) and prolactin [124]. ITI-007 was also associated with lower rates of motor side effects, such as akathisia, and cardiovascular side effects, such as tachycardia, than risperidone.…”

“…In addition, ITI-007 possesses minimal binding affinity for 5-HT 2C serotonin receptors (K i = 173 nM) and the H 1 histamine receptors (K i > 1000 nM) [23] implicated in both weight gain and the aberrant metabolic side effects leading to type II diabetes in patients treated with antipsychotic drugs [162, 164, 165]. Results of human clinical trials of ITI-007, to date [124, 125] have not shown significant weight gain in patients with schizophrenia, suggesting that the compound’s unique receptor binding profile is key in alleviating this side effect.…”

“…At a 40 mg dose, ITI-007 also demonstrated occupancy of serotonin transporters in healthy volunteers in a range similar to that of its D 2 receptor occupancy, consistent with its in vitro pharmacological profile and antidepressant-like effects. In a double-blind, placebo-controlled efficacy trial, a dose of 60 mg ITI-007 was evaluated in patients with acute schizophrenia and demonstrated antipsychotic efficacy with a placebo-like motor side effect profile and no hyperprolactinemia [124]. Subsequently, 60 mg ITI-007 demonstrated approximately 40% striatal D 2 receptor occupancy at plasma steady state after two weeks of administration in patients with schizophrenia who had been washed off their previous antipsychotic medications for at least two weeks prior to a within-subject baseline PET scan [125].…”

“…Patients treated with ITI-007 60 mg and 40 mg showed statistically significant improvement on the Clinical Global Impression Scale for Severity of Illness (CGI-S; p=0.003 for 60 mg, p=0.025 for 40 mg) [125]. Importantly, ITI-007 improved prosocial behavior and psychosocial function [124]. …”

Pharmacological treatment of schizophrenia - a review of progress

“…Furthermore, at therapeutic doses it increases phosphorylation of the GluN2B subunits of the NMDA receptor, indirectly leading to enhanced glutamatergic transmission in the mesolimbic pathway. 25 Although previous attempts to solely target the glutamatergic system were not as fruitful as expected, there is a wellidentified link between glutamate and dopamine neurotransmission in schizophrenia and the combination of glutamatergic together with antidopaminergic action may prove more effective in practice. A phase II 4-week randomised, double-blind, controlled trial showed both statistically and clinically significant improvement in schizophrenia symptoms compared with placebo and comparable efficacy to risperidone.…”