The introduction of ketamine/esketamine and the neurosteroid brexanolone represents remarkable advances in drug discovery and development in psychiatry [Citation1]. Rather than serendipity being the guiding principle in their development, the development of these foregoing treatments were informed by a conceptual framework implicating disturbances in both glutamate and GABAergic functions, respectively. These agents are also associated with significant symptomatic relief within 1–2 days of treatment administration. Moreover, benefits in treatment-resistant depression and depression with imminent risk of suicidal behavior, along with efficacy in postpartum depression, are significant public health priorities and unmet needs.
The ability of ketamine/esketamine and brexanolone represents the first of what is expected to be a new time in psychiatry wherein persons who live with depression can expect antidepressant treatments to offer immediate symptomatic relief. Promising agents include, but are not limited to, other GABAergic agents (e.g. zuranolone), orexin antagonists (e.g. seltorexant), trace-amine-associated receptors, opioid antagonists (e.g. aticaprant), combination treatments (e.g. bupropion-dextromethorphan), derivatives/isomers of ketamine, as well as psychedelics (e.g. psilocybin) [Citation2–8].
With respect to psychedelic treatment, there has been enormous media, public, academic, clinical, and advocacy interests in this particular category of agents that far outpaces the extant science. Many unanswered questions, however, remain with respect to efficacy, safety, implementation, and best practices. It is concerning to me that the development of psychedelics, specifically psilocybin and related 5HT2 agonists, has been associated with a notion that investigators/therapists/clinicians should also self-administered these agents. The rationale proffered for this behavior is to facilitate empathy with the identified patient/subject. In addition to lacking any empirical evidence that healthcare providers self-administering psychedelic agents have any relationship to patient-reported outcomes, it introduces serious questions about safety, ethics, and professional standards of conduct.
A related issue is that persons who are evaluating the safety and efficacy profile of psychedelics should have competencies in clinical trial design and methodology in persons with mood and other mental disorders, as evidenced by their objective track record in this space. The importance of the foregoing can never be over emphasized insofar as I have seen first-hand pharmacologic agents with tremendous potential across psychiatric disorders that did not demonstrate significant drug–placebo differences largely due to deficits in the quality of the development process.
This special issue of Expert Opinion is intended to synthesize extant literature in the broad encompassing area of ‘rapid-acting antidepressants’ (RAADs) with a co-primary focus on efficacy and safety considerations. The RAAD moniker does invite the need for a definition, as no consensus definition currently exists. My personal bias is that RAADs should be those treatments that offer PRO improvement in 1–4 days, recognizing that the FDA may conceptualize rapid-acting being within 1 week. Certainly, treatments that demonstrate drug–placebo differences in a week or less would also be a remarkable advance.
Many academic and clinical questions remain as to how to sustain the benefit of RAADs and whether the future of psychiatry will be ‘intermittent’ or ‘episodic’ dosing, rather than the familiar recommendation to take medications daily. This special issue also attempts to bring together the important safety information that investigators, academics, and clinicians should be considering as they adjudicate the benefit and risk of RAADs. As with all benefit–risk analyses, the risks and human capital loss of depression and its association with suicide need to be strongly considered against the background of theoretical and real safety concerns with recently introduced RAADs.
As advocates and scientists, we need to provide for persons who live with depression innovation, hope, safe and highly effective treatments that can preserve and restore their human capital, well-being, quality of life, and sense of purpose. As the field pivots toward RAADs in research and development, the availability of large databases capturing real-world outcomes will be essential to inform best practices. It is an exciting time that the field has pivoted toward, but it needs to be done thoughtfully, scientifically, with measure and regard for the seriousness of human suffering and always mindful of the safety of the treatment that we are suggesting to our patients.
Disclosure statement
Dr Roger McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC); speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, AbbVie, and Atai Life Sciences. Dr Roger McIntyre is a CEO of Braxia Scientific Corp.
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.
References
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