Recommendations for selection and adaptation of rating scales for clinical studies of rapid-acting antidepressants

Abstract

The novel mechanisms of action (MOA) derived from some recently introduced molecular targets have led to regulatory approvals for rapid acting antidepressants (RAADs) that can generate responses within hours or days, rather than weeks or months. These novel targets include the N-methyl-D-glutamate receptor antagonist ketamine, along with its enantiomers and various derivatives, and the allosteric modulators of gamma-aminobutyric acid (GABA) receptors. There has also been a strong resurgence in interest in psychedelic compounds that impact a range of receptor sites including D1, 5-HT7, KOR, 5-HT5A, Sigma-1, NMDA, and BDNF. The RAADs developed from these novel targets have enabled successful treatment for difficult to treat depressed individuals and has generated a new wave of innovation in research and treatment. Despite the advances in the neurobiology and clinical treatment of mood disorders, we are still using rating instruments that were created decades ago for drugs from a different era (e.g., The Hamilton and Montgomery-Åsberg depression rating scales, HDRS, and MADRS) continue to be used. These rating instruments were designed to assess mood symptoms over a 7-day time frame. Consequently, the use of these rating instruments often requires modifications to address items that cannot be assessed in short time frames, such as the sleep and appetite items. This review describes the adaptative approaches that have been made with the existing scales to meet this need and examines additional domains such as daily activities, side effects, suicidal ideation and behavior, and role functioning. Recommendations for future studies are described, including the challenges related to implementation of these adapted measures and approaches to mitigation.

A qualitative investigation of the Montgomery–Åsberg depression rating scale: discrepancies in rater perceptions and data trends in remote assessments of rapid-acting antidepressants in treatment resistant depression

“…Certainly, not all depressed individuals have the same depressive symptoms at baseline and the dynamic nature of a therapeutic response to RAADs could potentially result in a rapid alleviation of certain symptoms, e.g. improvements in subjective mood, while leaving some other functional aspects less improved, resulting in a heterogeneity of symptom resolution and a sense of uncertainty in raters ( 36 ).…”

“…provide an excellent summary on adaptations to the standard rating instruments allowing to reflect short-term changes in which RAADs act, as well as implementing novel rating measures. Critically, they also discuss limitations and challenges to the currently used rating measures including any conceptual biases of raters ( 36 ).…”

Ketamine for treatment-resistant major depressive disorder: Double-blind active-controlled crossover study

“…The MADRS and Hamilton Depression Scales are the most commonly used instruments to evaluate mood responses to ketamine in patients with TRD ( Yavorsky et al, 2023 ). The HADS is another validated scale ( Bjelland et al, 2002 ), and although it has been used to evaluate the antidepressant effects of ketamine ( Irwin et al, 2013 ; Jafarinia et al, 2016 ; Moitra et al, 2016 ; Voute et al, 2023 ; Zhou et al, 2021 ), this has been mainly in patients with medical or surgical comorbidities.…”