Melanopsin-Driven Pupil Response and Light Exposure in Non-seasonal Major Depressive Disorder

The discovery of projections of melanopsin-expressing intrinsically photosensitive Retinal Ganglion Cells (ipRGCs) to brain mood centers (1) has redefined understanding of light-mediated mood regulation (2, 3). These inner retinal cells have major roles in non-image-forming functions including entrainment of the body clock to a ~24 h day-night circadian rhythm (4), regulating the pupil light response (5, 6) as well as in image forming brightness perception, temporal, and color processing in humans (7–9). The post-illumination pupil response (PIPR) (6) is the sustained pupil constriction to high irradiance, short wavelength light that is controlled by the intrinsic melanopsin response from ~1.8 s onwards after light offset (10). During light stimulation, outer retinal inputs to ipRGCs can be assessed with the transient pupil light response (transient PLR) and peak constriction amplitude, with melanopsin contributing to the maintenance of pupil constriction (11, 12).

In seasonal affective disorder (SAD), the melanopsin-mediated PIPR is attenuated (2) whereas daily light exposure and time spent under bright illumination (>1,000 lux) is not different to healthy individuals (13), indicating that impaired light signaling due to ipRGC dysfunction can influence mood in SAD. In contrast, the PIPR amplitudes were normal in a combined cohort of patients with major depressive disorder (MDD) with SAD (n = 7) and non-seasonal depressive disorder (n = 12) (14). These non-significant differences may reflect the mixed cohort of patients (with and without seasonal depression) and the high variability in the data in the MDD group (14). In MDD patients and healthy controls in the northern hemisphere, the PIPR amplitude is less pronounced in winter compared to the summer months with longer daylight hours (14) and irrespective of season, the transient pupil response to dim light is impaired in MDD, which may reflect dysfunctional outer retinal inputs to ipRGCs (14). The link between light exposure and melanopsin function in patients with MDD, and in particular in non-seasonal depression, has not been examined. This study therefore objectively determined the mean daylight and daily hourly light exposure and duration of exposure to illumination levels recommended for light therapy in depression (15) in a group of patients with non-seasonal depression and healthy participants, and quantified melanopsin function with an optimized pupillometric paradigm that is robust to the presence of subtle melanopsin defects at early stages of retinal disease (16, 17).

Given the known effects of Selective Serotonin Reuptake Inhibitors (SNRIs) on the baseline pupil diameter, pupil constriction amplitude and the PIPR (28), a separate analysis excluding the patients taking SNRIs showed no significant group difference in the baseline pupil diameter (U = 33.5, p = 0.6), and peak PLR (blue, U = 34, p = 0.7; red, U = 36, p = 0.8) and PIPR amplitudes (blue, U = 37, p = 0.9; red, U = 26, p = 0.3). There are contentious reports of the effects of Selective Serotonin Reuptake Inhibitors (SSRI), with either no effect (28) or increasing pupil diameter (29); in this study, four patients were taking the drug but there were no significant difference in resting baseline pupil diameter compared to the control group. Similarly, other less commonly used psychotropic drugs did not have a significant effect on PIPR amplitudes (antimanic drug, Mann-Whitney U = 38, p = 0.9; agomelatine, U = 43, p = 0.9; MAOI (monoamine oxidase inhibitor), U = 38, p = 0.6).

There was no significant difference between the groups for age (U = 31.5, p = 0.1), the global solar exposure (GSE) (U = 33, p = 0.2) and the photoperiods [t₍₁₉₎ = 2.0, p = 0.06]. The mean (± SD) BDI-II scores for MDD and control groups were 25.8 ± 5.7 and 0.5 ± 0.9, respectively (U = 0, p < 0.0001). The sleep length (U = 44, p = 0.6) and mid-sleep times [t₍₁₉₎ = 0.1, p = 0.9] were not significantly different between the groups indicating the groups were comparable on circadian phase and chronotype.

The average light exposure at every clock hour over the 2 week recording period using a 24 h period were not significantly different between the MDD group and healthy controls [F_{(23, 408)} = 0.4, p = 0.9] (Figures 1A,B). The mean daylight exposure in the MDD group was also not significantly different from controls [t₍₁₉₎ = 0.9, p = 0.3] (Figure 1B). During the day (8:00–16:00 clock hours), both groups were exposed for at least 8 h after wake time to photopic illumination equivalent to that on an overcast day (~1,000 lux) (Figure 1B). During the evening (16:00–18:00 clock hours), both groups experienced light levels equivalent to an office light exposure (250–500 lux) (Figure 1B). During the night hours, both groups were exposed to illumination level common to the mesopic range and the scotopic ranges (30) and the median nightlight exposure was not significantly different between groups (Mann-Whitney U = 50, p = 0.9) (Figure 1B).

The light exposure levels were not significantly different between season (summer or winter) or time of day for the two groups [F_{(23, 408)} = 0.9, p = 0.6]. The duration (mins) of light exposure under illuminations commonly recommended for depression light therapy (≥ 10,000 lux) (15) did not differ between groups (Mann-Whitney U = 43, p = 0.5), ≥ 5000 lux [t₍₁₉₎ = 0.5, p = 0.6] and ≥ 2500 lux [t₍₁₉₎ = 0.8, p = 0.43] (Figure 1C).

Each participant underwent four pupil measurements (2 blue and 2 red) resulting in a total of 84 pupil recordings. Table 1 outlines the mean pupil light reflex data for both groups. Figure 1D shows the mean pupil response (± 95% confidence intervals) to 1 s short wavelength (blue) and long wavelength (red) light stimuli. The baseline pupil diameter was not significantly different between the groups [t₍₁₉₎ = 0.7, p = 0.5]. The PIPR amplitudes were also not significantly different between groups [t₍₁₉₎ = 0.02, p = 0.9] (Figure 1E). There was no difference in PIPR amplitudes for participants recruited during the summer and winter dominating months [t₍₂₉₎ = 1.4, p = 0.2]. Peak constriction and transient PLR amplitudes (Figures 1F,G) were not different between the groups for blue [peak, t₍₁₉₎ = 0.9, p = 0.4; transient PLR, t₍₁₉₎ = 0.4, p = 0.7] or red stimuli [peak PLR, Mann-Whitney U = 37, p = 0.3; transient PLR, t₍₁₉₎ = 0.3, p = 0.7]. There was no linear relationship between light exposure and PIPR amplitude in the MDD [F_{(1, 6)} = 0.6, R² = 0.1, p = 0.5] or control group [F_{(1, 11)} = 2.1, R² = 0.2, p = 0.2].

This study provides the initial evidence that there are no significant differences between patients with mainly moderate and mild non-seasonal MDD and healthy controls in either daily and hourly light exposure or the duration spent under bright illuminations commonly recommended for light therapy in MDD. The findings of normal PIPR amplitudes and transient PLR to stimuli with high melanopsin excitation are consistent with a recent study based in the northern hemisphere that investigated 12 MDD patients with non-seasonal depressive disorder (14). That study however, did not record detailed light exposure data in their control group. That a previous study in 15 patients with SAD detected a significant reduction in the melanopsin-mediated PIPR amplitude (2), may indicate different pathomechanisms are involved in SAD, and/or that different ipRGCs subtypes, including those that do not primarily signal to the OPN to regulate the pupil, are differentially affected in the two conditions. M1 ipRGC subtypes have more projections to the SCN than other brain areas (31) which implies that they may have a more prominent role in photoentrainment than in other behavioral functions such as mood. Within M1 subtypes, there is evidence from mouse models that Brn3b-positive M1 ipRGCs project to the OPN shell to control the pupil light reflex and to many other brain areas, whereas Brn3b-negative M1 cells only project to the SCN to drive circadian photoentrainment (32). Based on this, it could be postulated that Brn3b-positive M1 subtypes might be spared in non-seasonal depression, but further evidence is needed in human studies to directly examine this.

We did not find a positive correlation between the PIPR and longer day light hours as previously observed in a study performed in MDD and healthy controls (14). These contrasting findings may be due to the higher light exposure in this geographical area in the southern hemisphere. Importantly, with the melanopsin threshold at ~11.0 quanta.cm⁻².s⁻¹ (33), in our sample light exposure levels were above this threshold throughout their entire wake time in both the summer and winter seasons. Therefore a correlation between the PIPR amplitude and season is not to be expected in study locations closer to the equator.

The small sample of patients with non-seasonal depression is a limitation, and similarly sized to a study evaluating the relationship between non-seasonal MDD and the PIPR in the northern hemisphere (14). We augment existing studies in MDD by providing well defined melanopsin driven pupil responses and initial data on light exposure in a cohort of patients with mainly mild/moderate non-seasonal depression residing in the southern hemisphere. These data can provide a starting point for large-scale, controlled, multi-center studies evaluating the role of the melanopsin pathway in MDD that may lead to targeted, irradiance and wavelength dependent light treatment in MDD in the future.

The study followed the Declaration of Helsinki and was approved by the Queensland University of Technology Human research Ethics Committee (Approval Number: 1500000597). Informed written consent was obtained and each participant was offered a $30 gift voucher to compensate for their participation in the study.

BF and AJZ conceptualized the experiment. BF, AJZ, GO, and LH are responsible for research design, data acquisition, data analysis and interpretation, and manuscript preparation. All authors reviewed the manuscript.