The use of light to potentiate antidepressant medication: Preclinical evidence

Purpose of the study Major Depression (MD) is the most frequent psychiatric disorders. Despite the large range of available antidepressants, MD treatments remain unsatisfactory due to delayed onset of action and partial therapeutic responsiveness. Hence, more effective antidepressant treatments are urgently required. Recently, an increased awareness of light on mood has been highlighted. Light was shown to synchronize the circadian clock and modulate brain structures involved in sleep regulation, mood and cognition, via light sensitive melanopsin retinal ganglion cells (ipRGCs). Aberrant light cycles and/or disrupted circadian rhythmicity produce depressive states. Inversely, luminotherapy has been proven to be effective in seasonal depression but also in unipolar depression [1]. However, the underlying mechanisms of light are still unknown. Several studies reveal that i) ipRGCs play an important role in mood regulation induced by light [2] and ii) circadian and 5-HT systems are two important interactive regulatory brain networks that modulate mood. The purpose of this study was to decipher the neurobiological mechanisms by which light potentiates the antidepressant response. Methods An original model of treatment resistant depression [3] was used, based on a modified version of the forced swimming test. Briefly, mice were put in a tank filled with water (25°C) during 10 minutes 5 consecutive days (4 hours after lights off). Then, one group of mice were exposed to standard light (100 lux) and another group received add-on one hour of bright light (1000 lux, one hour before lights off) during 9 weeks. Weekly, during 2 months (2 hours after lights off), the immobility time was analyzed during the 4 first minutes of the swimming time. In parallel, the locomotor activity of the mice was assessed in their home-cage using the Circadian Activity Monitoring System. Drugs were injected 30 minutes prior to FST on week 8 and 9. Results In both groups of mice, the immobility time, observed in day 2 to 5, was significantly increased (+40%) and remained stable for at least 8 weeks while a single dose of the NMDA receptor antagonist ketamine (3 mg/kg, i.p) failed to reverse this pseudo-depressive behavior. Interestingly, only the combination of ketamine (3 mg/kg) and the muscarinic antagonist scopolamine (0.1 mg/kg) associated with bright light stimulation was able to decrease the immobility time. No difference was observed in locomotor activity, suggesting that the immobility evaluation corresponds to a behavioral despair. Moreover, a reduced sucrose preference was observed in stressed mice. Conclusion In this novel, validated model of depression [3], we showed that the immobility observed after 5 days of swim stress could remain stable for more than 5 weeks and this mainly because the repeated stress was performed during the dark phase [4]. Repeated bright light exposure, one hour per day during 8 weeks, potentiates the antidepressant effect of a sub-effective combination of ketamine and scopolamine [5]. Together, these results suggest, for the first time in treatment resistant mice, that light, in combination of a pharmacological treatment, can unveil an antidepressant response. Studies are currently ongoing to determine the role of ipRGCs in this surprising response.