Suicidal Ideation in Bipolar Depression: A Potential New Treatment
Jonathan C. Javitt, MD, PhD, discusses a new agent designed to treat suicidal ideation in bipolar depression.
Suicide rates are estimated to be 60 times higher in people with bipolar disorder compared with the general population. In addition, the ratio of suicide attempts to suicide is approximately 30:1 in this group vs 3:1 in the general population, which indicates greater lethality of suicidal acts in such individuals.1 These statistics underscore the urgent need for effective therapeutic approaches for this disorder — especially for bipolar depression, which has been found to be particularly treatment-resistant.2
Meanwhile, one company aims to directly address the need for suicide prevention in this population with an agent designed to treat suicidal ideation and behavior. If it receives US Food and Drug Administration (FDA) approval, it will be the first oral treatment for Acute Suicidal Ideation/Behavior (ASIB) in bipolar depression. To learn more about this drug candidate, called NRX-101 (Cyclurad™), Psychiatry Advisor spoke with Jonathan C. Javitt, MD, MPH, an adjunct professor at the Johns Hopkins School of Medicine in Baltimore, Maryland and former White House Health Advisor with 30 years of experience in drug development. He co-founded NeuroRx with Daniel C. Javitt, MD, PhD, a professor of psychiatry at Columbia University in New York who was among the first to discover the role of the N-methyl-D- aspartate (NMDA) receptor in psychiatric illness, and is the author of more than 300 frequently cited scientific papers in cognitive neuroscience.
Psychiatry Advisor: How did the idea for this treatment come about?
Dr Javitt: NeuroRx draws upon 30 years of basic and clinical science in the role of the NMDA, a receptor that regulates human thought processes, particularly depression and suicidality. The company has developed the first NMDA/ serotonin 2A receptor (5-HT2A) dual-targeted approach to the treatment of depression — a patented scientific advance that has the potential to overcome the limitations of previous generations of antidepressant drugs.
The NMDA class of drugs, including ketamine, was recognized as having the potential to treat depression decades ago, but was never developed because of its propensity to cause hallucinations and other side effects. In a similar manner, serotonin pathway antidepressants are contraindicated in suicidal patients because of their tendency to cause akathisia, a side effect known to be associated with suicidal behavior. NeuroRx scientists have demonstrated, in preclinical and early clinical studies, that combining NMDA and 5-HT2A antagonist agents in the same drug achieves an antidepressant effect that is comparable to that of leading antidepressants, while also blocking akathisia in preclinical studies and reducing suicidal ideation in clinical studies.
NeuroRx's rapid drug development platform is enhanced by the discovery that the antidepressant effect of NeuroRx compounds is closely correlated with beneficial changes in brain chemistry, which can be measured non-invasively by magnetic resonance spectroscopy.
Psychiatry Advisor: Why is there a need for a treatment designed for this specific indication?
Dr Javitt: Based on clinical data, experts now concur that acute suicidal ideation/behavior (ASIB) and depression are 2 separate entities. They are not one and the same, despite being related. Also, the FDA has agreed that ASIB is an approvable indication. Today there is no approved medicine for ASIB in bipolar depression; standard-of-care consists of hospitalized observation and, frequently, electroconvulsive therapy (ECT). This is very unfortunate because recent hospitalization for suicidal intent is one of the highest risk factors for further attempts, especially in the first months after release.3,4 Most recently, a research group from Yale [University] published data showing in magnetic resonance imaging (MRI) scans that the brains of bipolar individuals with suicidal tendencies are different.5
Glaxo, Eli Lilly, Astra-Zeneca, and other big pharmaceutical companies have abandoned the field of psychiatry, because they struggled after their billion-dollar antidepressants became generic. The science at hand also did not enable them to bring forward agents that would truly be viewed as significant improvements. Key areas of unmet need remain: faster onset of action, higher levels of efficacy or overall response, and reduction in suicidal thoughts and behavior.
Traditionally, big pharma focused on major depressive disorder and schizophrenia. The bipolar field has received little attention —virtually all treatments are merely additional indications of antipsychotics or other agent classes such as olanzapine, quetiapine, lurasidone, and valproic acid, most of which are also generic now. Even more pressing is that clinical studies of virtually all antidepressants and antipsychotics have systematically excluded patients at increased risk of suicide. Serotonergic drugs have the potential to cause akathisia, which can increase the risk of suicide. Hence, they carry a black-box warning of this increased risk.
Psychiatry Advisor: What is NRX-101?
Dr Javitt: NRX-101 is a potentially rapid-onset and sustained oral treatment regimen currently in an FDA-cleared phase 2b/3 pending clinical trial for ASIB in patients with bipolar depression.6 The treatment, which is currently investigational, is a patented, oral, fixed-dose combination of 2 FDA- approved drugs: d-cycloserine, an NMDA receptor modulator, and lurasidone, a 5-HT2a receptor antagonist. NeuroRx's investigational treatment approach begins with a single, one-time dose of ketamine for rapid stabilization, followed by approximately 6 weeks of daily oral NRX-101.
Preclinical studies have demonstrated an antidepressant effect comparable to market-leading antidepressants without the akathisia that occurs in 15% of clinical subjects given standard antidepressants. Peer-reviewed results from 2 phase 2 proof-of- concept studies showed a 50% reduction in symptoms of depression and a 75% reduction in suicidal ideation in patients with bipolar and treatment-resistant depression (TRD). Initial peer-reviewed studies measuring brain chemical changes in neurotransmitters (Glx) using MRI have demonstrated beneficial brain chemistry changes that meet or exceed changes reported with ECT, without the damaging side effects.
Psychiatry Advisor: For which types of patients will NRX-101 be best suited, and for whom might it not be indicated?
Dr Javitt: To date, NRX-101 is the only treatment in development for ASIB in bipolar patients. All other treatments are focused on TRD or suicidal ideation associated with TRD. The only drug planned to be studied as treatment in suicidal patients is esketamine. However, the study will specifically exclude bipolar patients, in whom the incidence of suicidal ideation is the highest. In considering the needs of patients and the potential competition, we think that NRX-101 will help patients leave the hospital sooner, supported by an initial response to ketamine, and treated on an outpatient basis with 1 oral agent twice a day while maintaining close contact with their outpatient healthcare provider, thereby helping patients resume their normal routine sooner. Because it is not expected to be a controlled substance, this is especially crucial in a vulnerable population.
Psychiatry Advisor: What is the current status of development for NRX-101?
Dr Javitt: NRX-101 is initiating its phase 2b/3 study this year. As we are working on the recruitment of clinical study sites, our discussions with leading investigators at these sites consistently confirm our views of the high level of unmet need in this vulnerable population.
- Baldessarini RJ, Pompili M, Tondo L. Suicide in bipolar disorder: Risks and management. CNS Spectr. 2006;11(6):465-471.
- Poon SH, Sim K, Baldessarini RJ. Pharmacological Approaches for Treatment-resistant Bipolar Disorder. Curr Neuropharmacol. 2015;13(5):592-604.
- Pompili M, Innamorati M, Michele Raja, et al. Suicide risk in depression and bipolar disorder: Do impulsiveness-aggressiveness and pharmacotherapy predict suicidal intent? Neuropsychiatr Dis Treat. 2008;4(1):247-255.
- Tidemalm D, Haglund A, Karanti A, Landén M, Runeson B. Attempted suicide in bipolar disorder: risk factors in a cohort of 6086 patients. PLoS One. 2014;9(4):e94097.
- Yale News. Brain circuits may reveal which young people are likely to commit suicide. January 17, 2017. http://news.yale.edu/2017/01/31/brain-circuits-may-reveal-which-young-people-are-likely-commit-suicide. Accessed March 29, 2017.
- Clinicaltrials.gov. STABIL-B Trial of NRX-101 for Acute Suicidal Ideation and Behavior (STABIL-B). https://clinicaltrials.gov/ct2/show/NCT02974010. Accessed March 29, 2017.