Well-being as a primary endpoint in clinical trials: a call for consensus

Well-being should be treated as a legitimate clinical outcome—not merely an optional secondary measure.

In this perspective/consensus paper, the central argument is that clinical research should measure whether an intervention helps people live better, not just whether it changes a disease score.

The key points are:

• Well-being should be treated as a legitimate clinical outcome—not merely an optional secondary measure.

Marseille, Kettner and colleagues argue that conventional clinical trials are heavily oriented around disease-specific outcomes: symptom reduction, biomarkers, physiological measures, relapse rates or survival. These are important, but they don't necessarily tell us whether patients actually experience an improvement in their lives.

The authors therefore call for greater recognition of well-being as an outcome in its own right, particularly for conditions where the ultimate therapeutic goal extends beyond disease control.

• "Health" is broader than absence of disease.

The argument is closely aligned with the WHO's longstanding conceptualisation of health as encompassing physical, mental and social well-being.

This is particularly relevant to mental health, where reducing a symptom score does not necessarily mean that someone has regained functioning, meaning, relationships, vitality or the ability to engage with life.

• Depression illustrates the problem particularly well.

A person can score substantially better on a depression scale while still experiencing poor quality of life, social isolation, lack of purpose, low positive affect or impaired functioning.

Conversely, improvements in well-being may occur that aren't fully captured by conventional symptom scales.

This matters considerably for psychedelic research because psychedelic-assisted therapies are frequently associated with outcomes such as meaning, connectedness, psychological flexibility, positive affect and quality of life—constructs that traditional symptom scales can miss.

• The authors call for consensus on what "well-being" actually means.

This is an important caveat. "Well-being" is not a single biological variable.

Different instruments measure different constructs—for example:

• psychological well-being

• positive affect

• life satisfaction

• functioning

• quality of life

• social connectedness

• sense of purpose/meaning

• general mental well-being.

The authors therefore argue that the field needs greater conceptual and methodological consensus about what constitutes well-being and how it should be measured in clinical trials.

• Patient-reported outcome measures become much more important.

Well-being is inherently subjective. A clinician cannot reliably determine someone's overall sense of well-being simply by measuring their blood pressure, inflammatory markers or symptom severity.

Abstract

Psychiatric trials typically define success as symptom reduction, yet patients prioritize meaning, vitality, and functioning. This imbalance undervalues experiential benefits, distorting clinical, policy, and FDA decisions. Psychedelic trials illustrate this, where robust well-being gains sometimes accompany modest symptom effects. We argue well-being should be elevated to co-primary endpoint status, propose a Delphi-developed consensus well-being instrument with rigorous validation, and outline guardrails preventing approval of therapies that worsen the underlying condition.

Marseille, E., Kettner, H., Sgambati, T.J. et al. Well-being as a primary endpoint in clinical trials: a call for consensus. npj Mental Health Res5, 39 (2026). Read Paper

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