Published in Research

Identifying the link between pupil response and depression

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Findings from a recent study published in Scientific Reports assessed the pupil response of individuals who anticipate a reward after completing a task in patients diagnosed with major depressive disorder (MDD) in order to understand the physiological mechanisms behind MDD.

Let’s break this down.

The locus coeruleus (LC) is the primary source of noradrenergic (NA) neurons in the brain; NA neurons, in turn, respond to norepinephrine—a neurotransmitter that is crucial to stress responses and upregulation of arousal.

Per the American Psychological Association, arousal refers to “a state of physiological activation or cortical responsiveness associated with sensory stimulation.”

Now, bring in pupillometry.

Pupillometry—the measurement of pupil size and reactivity—is an accessible marker for LC activity.

Thus, because the LC-NA system is affected by antidepressants, such as venlafaxine and duloxetine, pupillometry potentially has clinical utility in measuring hypo-arousal (a person’s “freeze response”) in MDD patients.

Further, in patients with MDD, the pupillary light reflex is altered, namely with diminished constriction velocity and lower constriction change of the pupil.

Is this the first study on depression and pupil dilation?

This study builds on findings from previous work by the research team and relies on the same task and analytical approach from that first study in an independent consecutive subsample recruited from the same population.

Of note, the initial study demonstrated a negative correlation (i.e., inverse relationship) between pupil dilation and symptom load in depressed patients during reward anticipation.

This means that patients with more severe MDD symptoms had a correspondingly diminished pupillary response.

Now talk about this study.

Investigators evaluated a sample of 40 unmedicated patients diagnosed with depression and 30 health control participants who performed a reward anticipation task (i.e., a task that causes an increase in arousal).

These results were combined with findings from a sample of 136 participants:

  • 81 unmedicated MDD participants
  • 55 healthy control participants

Using the combined original and replication samples, investigators assessed symptoms related to anhedonia (i.e., listlessness or the inability to experience pleasure from reward), fixation, and reward consumption.

How did they measure physiological differences in MDD patients?

The reward anticipation task was performed by all participants.

Investigators measured both pupil responses and performed functional magnetic resonance imaging (fMRI) to understand physiological differences in MDD participants compared to controls.


This study replicated the findings from the original study (i.e., reduced pupillary response in MDD patients during reward anticipation); however, it demonstrated a lower effect size—a measure of the strength of the relationship between two variables.

Additionally, diminished pupil dilation in anticipation of reward was inversely associated with anhedonia (listlessness) items from the Beck Depression Inventory, a self-reporting inventory that measures characteristic attitudes and symptoms of depression.

Tell me more.

Further, fMRI revealed that the right anterior insula, which regulates sympathetic activity (i.e., stress responses), was negatively correlated with depressive symptom load and anhedonia.

No correlations were found between depressive symptom load and pupil dilation during other tasks, such as fixation or reward consumption.

Expert opinion?

According to research group leader Victor Spoormaker, these findings “help us to better understand the physiological mechanisms behind listlessness (i.e., anhedonia).”

“The reduced pupillary response in patients with more listlessness indicates that the lacking activation of the LC is an important physiological process that underlies the feeling of listlessness,” he explained.

Take home.

These findings demonstrate the clinical utility of pupillometry to assess NA-mediated hypo-arousal during reward anticipation in patients with MDD, which is a physiological process that appears to impact anhedonia.

Next steps?

In the future, pupillometry could be employed as an adjunctive tool for MDD diagnosis and contribute to the development of individualized treatment protocols.

This would mean patients with significantly diminished pupil responses could benefit from antidepressants that focus on the NA system, and medication doses could be optimized based on observed pupillary reactions.