Scientific rationale supports the approach of combining an NMDA antagonist, such as D-cycloserine, with additional therapeutic targets in the treatment of Acute Suicidal Ideation/Behavior (ASIB) in Bipolar Depression. This is crucial due to the fact that despite the substantial promise shown by D-cycloserine in the treatment of depression and schizophrenia, the treatment must be administered with an antipsychotic to counteract side effects.
5-HT2a Receptor Antagonist
One key potential combination target that has shown promise in counteracting the side effects of
D-cycloserine is the 5-HT2a receptor, a G protein-coupled receptor and a member of the serotonin family. It is known for its role in mediating certain antipsychotic drugs. Studies have demonstrated that deceased suicidal and other depressed patients have had more 5-HT2a receptors than normal patients, indicating that the increased presence of 5-HT2a receptors may play a role in depression.
Lurasidone (Latuda®), a 5-HT2a antagonist, is currently marketed as a tier three antipsychotic and is occasionally used in bipolar depression. However, in animal akathisia studies, it was discovered that lurasidone and other 5-HT2a antagonists have an unexpected synergistic effect with D-cycloserine, potentially enhancing the antidepressant effect while minimizing the potential psychomimetic side effects.
The synergistic effects of NMDA and 5-HT2a antagonists in the rat akathisia model are described in detail in several US and ex-US patent filings. The combination of lurasidone (and other 5HT2a antagonists) and D-cycloserine led to a significant reduction in akathisia compared to control and to lurasidone alone. akathisia is defined as a state of agitation, distress, and restlessness that is an occasional side-effect of antipsychotic and antidepressant drugs.
The inclusion of ketamine, an FDA-approved anesthetic, in a combination treatment for acute suicidal crisis in bipolar depression is also supported by scientific research. Like D-cycloserine, ketamine works by targeting the NMDA receptor. Clinical research has demonstrated that by blocking the NMDA channel, ketamine has a nearly immediate effect on reversing depression and suicidality in people with bipolar disorder.
Despite these promising clinical findings, ketamine is not FDA-approved for the treatment of bipolar depression. Ketamine's anti-depressant and anti-suicidal activity is short-lived. Treatment of acute suicidality in bipolar patients would therefore require repeat infusions of ketamine. However, ketamine administration is associated with hallucinations and other psychomimetic side effects, and could require 1-2 weekly visits of the patient to a treatment center.
A sequential treatment approach that can leverage the immediate anti-suicidal benefit of ketamine, while limiting the drug to a single, initial dose, has the potential to offer acutely suicidal bipolar patients a much needed therapeutic option. NeuroRx believes that an induction of ketamine, followed by a fixed-dose combination of D-cycloserine and lurasidone could offer an oral, outpatient therapy. This fixed-dose combination is the basis of our NRX-101 investigational drug, has the potential to significantly extend ketamine’s anti-suicidal / anti-depressant benefits and offer an improved side effect profile.
NeuroRx is pursuing a strategic combination treatment approach
based on scientific rationale that supports pairing an NMDA antagonist with
additional therapeutic targets in the treatment of Acute Suicidal Ideation/Behavior (ASIB) in Bipolar Depression.