Five promising approaches to expand the depression armory.
The lack of candidates in the pipeline for the treatment of depression has been causing concern for some time. However, recent Datamonitor Healthcare analysis has identified five approaches to treating depression, all still at a relatively early stage of investigation, that could revitalize the field in coming years:
NMDA receptor antagonist and partial agonists
Glutamate is known to be important in regulating a variety of mood disorders, and there is growing clinical evidence, led by ketamine studies in treatment-resistant depression, that modulating glutamatergic signaling can produce a large and rapid antidepressant effect.
Datamonitor believes that glutamate receptor modulators have significant potential, highlighted by the clinical rationale provided by ketamine, the number of candidates in clinical development, and the involvement of a big player such as J&J. Given these drugs’ non-serotonergic mode of action, it is possible that they will fare better than a new serotonin reuptake inhibitor in patients that respond poorly to current treatments. The commercial potential of this mechanism of action is also increased by the fact that all the candidates in development are pursuing indications for treatment-resistant depression.
Metabotropic glutamate receptor antagonists
Metabotropic glutamate receptor modulation is currently an area of high interest in drug development for CNS disorders, attracting interest from some of the biggest pharma companies, including J&J, Eli Lilly, Pfizer, Merck & Co, Novartis and Roche. Clinical trials are underway across a range of neurological and psychiatric indications, although Roche remains the only company investigating the pathway in the development of novel antidepressants.
It has two antagonists in its clinical pipeline: basimglurant is an antagonist at mGluR5 receptors, while decoglurant antagonizes the mGluR2 and mGluR3 subtypes. Both programs are targeting treatment-resistant depression. Datamonitor Healthcare believes that these drugs will likely possess a therapeutic role as later-line antidepressants, either as an adjunct or monotherapy. As first-in-class antidepressants, they would enjoy significant novelty and may possess synergistic effects with antidepressants targeted to the monoamine neurotransmitter modulation.
The most advanced opioid receptor-targeting drug for use as an antidepressant is Alkermes’ ALKS 5461, which contains the broad-spectrum opioid buprenorphine, and samidorphan, a selective mu-opioid receptor antagonist. After positive Phase II results, Alkermes has initiated a large Phase III program of ALKS 5461 in patients with treatment-resistant major depression.
Nociceptin/orphanin FQ peptide receptor antagonists
Preclinical studies involving knockout rats for the NOP receptor gene have shown that nociceptin/orphanin FQ (N/OFQ) signaling plays an important role in regulating anxiety- and mood-related behaviors.
The lead company is Lilly, whose NOP receptor antagonist, LY2940094, is in Phase II as a once-daily oral drug for MDD.
Datamonitor Healthcare expects that the effect of these drugs will be complementary to that of common antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). In this way, LY2940094 may be used as an adjunctive to generic SSRIs. However, with Lilly conducting its first Phase II trial of LY2940094 as a monotherapy, Datamonitor Healthcare assumes that the company will seek to position the drug as a possible first-line treatment choice, in direct competition with established SSRI antidepressants.
Mu-opioid receptor partial agonists
e-Therapeutics is investigating ETS6103, which contains a low dose of the commonly used analgesic tramadol, as a potential new antidepressant. Tramadol has a mixed pharmacological profile, targeting both mu-opioid receptors as a partial agonist, as well as being an SSRI, which is an extremely common antidepressant mechanism.
It is not known how much of ETS6103’s potential antidepressant effect derives from tramadol’s SSRI and opioid activities, although if successful it would represent a new drug class for the treatment of depression. Tramadol is generally seen as a weaker opioid than other mu-opioid receptor full agonists such as morphine or oxycodone, and it has a lower potential for abuse and addiction.
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Posted in Central Nervous System.