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RAADs Call into Question the Utility of Existing Depression Scales. Now What?

For decades, antidepressant treatments primarily targeted biogenic amines (e.g., serotonin, norepinephrine, and dopamine). While many people with depression benefited, many others didn’t respond. Then, just a few years ago, all that changed.

In 2019 the U.S. Federal Drug Administration (FDA) approved esketamine for treatment-resistant depression and brexanolone for postpartum depression. By targeting new synaptic sites, these rapid-acting antidepressants (RAADs) challenge our previous understandings of how antidepressants work. Yet, for the most part, depression rating scales haven’t kept pace. Clinicians and researchers continue to use instruments designed for a different era; these include the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Åsberg Depression Rating Scale (MADRS).

The Assessment Methods and Endpoints for Rapid-Acting Antidepressants-RAADs Working Group of the International Society for CNS Clinical Trials and Methodology addressed this issue, documented their findings in a review recently published in Frontiers in Psychiatry.[1] This paper focuses on the emerging field of RAADs and the challenges in effectively evaluating their effects due to the use of older rating instruments designed for traditional antidepressants.

RAAD: Defying Measurement, Defying Definition

Recent developments in antidepressant treatments include drugs that act on new molecular targets, resulting in faster responses (hours or days compared to weeks or months). These targets include the N-methyl-D-glutamate receptor antagonist ketamine (and its enantiomers and derivatives) and allosteric modulators of GABA receptors. The authors also note the renewed interest in psychedelic compounds that affect various receptor sites, including D1, 5-HT7, KOR, 5-HT5A, Sigma-1, NMDA, and BDNF.

These treatments have faster onset of action compared to conventional antidepressants, and they also have the potential to resolve symptoms more quickly. They also have different symptom response patterns, potentially including effects on language use and feelings of “calm alertness.” Conventional scales may not adequately capture the experience of patients using these treatments. Scales measuring subjective experience may offer additional insight into the treatment effect, although they are typically secondary outcomes in clinical trials.

The working group recognized the need for shorter measurement intervals and real-time evaluations, as well as the need to address unresolved questions regarding what constitutes a clinically meaningful response. Discussions within the working group highlighted the need for precision in defining the concept of response as it applies to RAADs, taking into consideration factors such as the duration of symptom resolution, the number of symptoms that need to resolve, and the heterogeneity of symptom resolution.

They explored the adaptation of existing scales, the development of new ones, and the use of digital measurements to supplement existing scales.

Modification of Existing Scales

As noted, current rating scales, including HDRS and MADRS, were developed for older generations of antidepressants and typically evaluate symptoms over a 7-day period. With certain adaptations, some of them can capture certain symptomatic changes in the RAAD timeframe. Overall, however, “they remain inherently limited by their structure (items such as sleep and appetite), timeframe of retrospective review of symptoms (usually 7 days) and conceptual biases.” Thus, the working group concluded, “it is likely that these measures fail to capture some aspects of the patient experience following treatment with RAADs.”

Development of New Scales

Novel scales, such as the Symptoms of Major Depressive Disorder Scale (SMDDS) and the McIntyre And Rosenblat Rapid Response Scale (MARRRS), have been developed specifically to measure the effects of RAADs. In particular, MARRRS — a 14-item self-report scale designed to measure rapid treatment response — has shown promising psychometric characteristics, including high internal consistency and significant convergent validity. It will be used in an upcoming Phase II clinical trial.

The authors also discussed the potential of digital measurements, such as ecological momentary assessments (EMA), sleep and activity trackers, and applications using facial and vocal metrics. While these methods are not ready to replace traditional scales, they can provide valuable supplementary data and real-time assessments.

Moving Forward: Radical Change Required

Although existing rating instruments can be adapted to measure RAADs, their usefulness is limited. Newly developed scales — SMDDS and MARRRS in particular– have significant potential to address these limitations. Digital technologies could initially supplement and cross-validate items in existing or new scales.

Much more work is needed, the authors concluded.

“Further development of new measures that meaningfully evaluate the novel effects of RAADs will require new approaches, as radical as the departure was from the older generations of drugs to the newer ones, they write. “To ensure we are fully and objectively measuring what matters most to patients, clinicians and other stakeholders, our rating instruments and perhaps even our most basic assumptions about what they are and how they work may also have to adapt to keep up with the remarkable pace of change in the field of RAADs.”

The full article can be accessed here.

[1] Yavorsky C, Ballard E, Opler M, et al. Recommendations for selection and adaptation of rating scales for clinical studies of rapid-acting antidepressants. Frontiers in Psychiatry. 2023;14:1135828. doi: