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

Rapid acting antidepressants (RAADs), including ketamine and its derivatives along with GABA receptor modulators, can produce mood improvements within hours or days rather than weeks. There is also renewed interest in psychedelic compounds affecting multiple receptor sites. However, the rating instruments used to measure antidepressant response, such as the Hamilton and Montgomery-Åsberg depression rating scales, were designed decades ago for older drugs and assess symptoms over a seven-day timeframe. This review describes adaptations made to these existing scales for use with RAADs, including modifications for items like sleep and appetite that cannot be assessed in short time frames, and examines additional domains such as daily activities, side effects, suicidal ideation, and role functioning. Recommendations for future studies and implementation challenges are discussed.

Study at a glance

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.