Investigational drugs in recent clinical trials for treatment-resistant depression

Abstract

Introduction The authors describe the medications for treatment-resistant depression (TRD) in phase II/III of clinical development in the EU and USA and provide an opinion on how current treatment can be improved in the near future. Areas covered Sixty-two trials were identified in US and EU clinical trial registries that included six investigational compounds in recent phase III development and 12 others in recent phase II clinical trials. Glutamatergic agents have been the focus of many studies. A single intravenous dose of the glutamatergic modulator ketamine produces a robust and rapid antidepressant effect in persons with TRD; this effect continues to remain significant for 1 week. This observation was a turning point that opened the way for other, more selective glutamatergic modulators (intranasal esketamine, AVP-786, AVP-923, AV-101, and rapastinel). Of the remaining compounds, monoclonal antibodies open highly innovative therapeutic options, based on new pathophysiological approaches to depression. Expert commentary Promising new agents are emerging for TRD treatment. Glutamatergic modulators likely represent a very promising alternative to monoaminergic antidepressant monotherapy. We could see the arrival of the first robust and rapid acting antidepressant drug in the near future, which would strongly facilitate the ultimate goal of recovery in persons with TRD.

Novel Treatment Options in Depression and Psychosis

“…14,15 The observation that a single intravenous dose of glutamatergic modulator ketamine produces a robust and rapid AD effect was a turning point that opened the way for other, more selective glutamatergic modulators (intranasal esketamine, rapastinel). 16 …”

The development of glutamate-based antidepressants is taking longer than expected

“…In 2000, a pilot study reported that intravenous infusion of a subanesthetic dose (0.5 mg/kg) of the NMDAR antagonist ketamine (0.5 mg/kg) produced a rapid and robust antidepressant effect in patients with depression [2]. These observations raised the possibility of an alternative to available biogenic amine-based antide pressants that often take weeks to months to produce a clinically meaningful therapeutic effect, leaving patients at increased risk of suicide [1,3,4]. …”

“…Between 15% and 30% of patients who have a major depressive disorder (MDD) do not respond satisfactorily to two successive courses of antidepressant treatment (‘treatment-resistant depression’;TRD) [1,3,4]. In 2006, a randomized controlled trial (RCT) conducted by the National Institute of Health (NIH) [5] clearly demonstrated a rapid and robust effect of subanesthetic ketamine in TRD.…”

“…In 2006, a randomized controlled trial (RCT) conducted by the National Institute of Health (NIH) [5] clearly demonstrated a rapid and robust effect of subanesthetic ketamine in TRD. This study was a milestone because of the profound impact of TRD on public health: patients with TRD experience a reduced quality of life, severe impairment in social functioning and workplace performance, and are at increased risk of suicide, all contributing to a significant healthcare burden [1,3,4]. Although growing in popularity, the use of intravenous subanesthetic ketamine in TRD remains off-label, limited to a medical setting, and is burdened by other significant challenges [3].…”

Vaccinating against depression or anxiety: is it plausible?

“…Even though it did not capture clinical interest, the hypothesis of Rook et al [1] deserves to be revisited because relapse is common in MDD and at least 15%-30% of patients with MDD are resistant to treatment, resulting in considerable morbidity and increased risk of suicidal behavior [3]. A vaccine can prevent episodes of MDD, as well as being safe and well tolerated in the long term.…”