New Antipsychotic Reduces Negative Symptoms of Schizophrenia

Although currently available antipsychotics are effective in decreasing positive symptoms (hallucinations and delusions) of schizophrenia, the medications tend to do very little to address the negative symptoms associated with lack of motivation, diminished quality of life, and functional impairment. Recent findings published last month in the journal Biological Psychiatry suggests that a novel antipsychotic in the pipeline may address these unmet needs in addition to causing fewer adverse events in patients taking the drug.

Jeffrey Lieberman, M.D., chair of the Department of Psychiatry at the Columbia University College of Physicians and Surgeons and New York Presbyterian Hospital and the study’s lead investigator, told Psychiatric News during an interview, “ITI-007 is a new antipsychotic with a novel mechanism of action that is currently in phase 3 of development for approval by the Food and Drug Administration.”

Lieberman, who is a former APA president, described the pharmacology and putative mechanism of action of this novel antipsychotic. ITI-007 is a new molecular entity with a first-in-class pharmacological profile that combines dose-related monoamine modulation with phosphorylation of intracellular signaling proteins, and while it interacts with targets of existing antipsychotics drugs, its full actions are complex and unique.

ITI-007 is a high-affinity serotonin 5-HT2A receptor antagonist with lower affinity for other neurobiological targets, including D2 receptors. While 5-HT2A receptor antagonism in addition to D2 receptor antagonism has been the hallmark of atypical antipsychotic drugs, ITI-007 has a wider separation (60-fold) between its affinity for 5-HT2A receptors and D2 receptors than other antipsychotic drugs. Moreover, unlike most other antipsychotics that are antagonists at D2 receptors both pre- and post-synaptically, and unlike aripriprazole and related compounds that are partial agonists at D2 receptors both pre- and post-synaptically, ITI-007 interacts with dopamine receptors in a unique way. At D2 receptors, ITI-007 is a pre-synaptic partial agonist and post-synaptic antagonist with selective mesolimbic/mesocortical selectivity.

Beyond 5-HT2A and D2 receptor interactions, ITI-007 increases phosphorylation of mesolimbic GluN2B subunits of N-methyl-D-aspartate (NMDA) receptors. An increase in GluN2B increases synaptic NMDA activity via subcellular trafficking to plasma membranes. To the extent that a deficit in NMDA-mediated glutamatergic neurotransmission contributes to schizophrenia symptoms, indirect enhancement of NMDA function is predicted to reduce psychosis and improve cognitive function and negative symptoms. ITI-007 also blocks the serotonin transporter, an effect widely associated with many antidepressant drugs. ITI-007 also lacks significant activity at many receptors (for example, H1, muscarinic, 5-HT2C) that are associated with deleterious side effects. Thus, by acting through serotonergic, dopaminergic, and glutamatergic signaling systems in a neuroanatomically selective manner, ITI-007 represents a mechanistically novel approach to the treatment of schizophrenia and other neuropsychiatric disorders.

In the recently published multisite phase 2 study showing the effectiveness of ITI-007, Lieberman and colleagues randomized 335 adults, aged 18 to 55 years, with schizophrenia to receive ITI-007 (60 mg, 120 mg), placebo, or risperidone (2 mg, 4 mg) monotherapy for four weeks. Patients were eligible for the study if they had experienced an acute exacerbation of psychosis within a month prior to study initiation. The primary outcome measure was a reduction in psychotic symptoms assessed by the Positive and Negative Symptom Scale total score. The secondary analysis measured improvements in negative and depressive symptoms as indicators of social function, assessed by the Negative Symptoms Subscale and Calgary Depression Scale for Schizophrenia, respectively.

“We found that 60 mg of ITI-007 was significantly superior to placebo in alleviating psychotic symptoms,” said Lieberman. “The drug [at 60mg] also was effective in improving negative symptoms and depressive symptoms in patients in a way that appeared greater than risperidone.

In addition, both doses of ITI-007 were well tolerated by participants and were associated with a less risky metabolic profile than risperidone, as evident by significantly lower levels of prolactin, fasting glucose, total cholesterol and triglycerides among the ITI-007 cohorts. The most reported side effect was sedation.

“These results indicate significant a therapeutic effect and favorable side-effect profile of ITI-007, in contrast to other drugs in which the antipsychotic efficacy and side effects risks seem correlated (that is, clozapine, olanzapine, risperidone),” the authors noted.

Lieberman told Psychiatric News that since the introduction of the drug clozapine as a novel antipsychotic in 1989, psychiatrists have been waiting for another breakthrough or a major advance in antipsychotic pharmacotherapy. “We have had a number antipsychotics since then to be approved, but those antipsychotics have, for the most part, been ‘me too drugs,’ ” said Lieberman.

“The hopeful expectation for ITI-007 is that it will prove to be a safer drug than current antipsychotics, while being a drug that has superior and broader therapeutic properties that other antipsychotic treatments are lacking,” Lieberman explained. “If this proves to be the case, then this will be a significant milestone in antipsychotic psychopharmacotherapy.”

Lieberman said that phase 3 studies for ITI-007 are expected to be available within a matter of weeks.

ITI-007 is manufactured by Intra-Cellular Therapies Inc. Lieberman has no financial ties in terms of stock and advisory fees to the company. ■