Synergistic Effects of Pharmacological, Environmental, and Transcranial Direct Current Stimulation Interventions on Depression-Like Behaviours in Rats Under Social and Movement Restriction

Abstract

Major depressive disorder (MDD), one of the most prevalent and debilitating mental health conditions, is found to have the highest rates of treatment resistance and recurrence. The current therapeutic approach is primarily based on pharmacological and psychotherapeutic interventions, which fail to achieve complete remission for a significant part of the patients. New interest is emerging in combining pharmacological treatments with neuromodulation and environmental improvements to enhance therapeutic outcomes in this context. This one-year longitudinal study investigated the individual and combined effects of social isolation, chronic restraint stress, sertraline administration, transcranial direct current stimulation (tDCS), and social rehabilitation on depression-like behaviours in male Sprague Dawley rats. Behavioural outcomes were assessed using the Open Field Test, Sucrose Preference Test, Elevated Plus Maze, and Novel Object Recognition Test across ten experimental phases. Social isolation and chronic restraint effectively induced depression-like behaviours, as indicated by reduced exploration and sucrose preference. Sertraline treatment yielded partial improvements in affective and motivational behaviour, though inter-individual variability was notable. The addition of tDCS produced more consistent behavioural benefits and appeared to stabilise recovery trajectories. Social rehabilitation also contributed to behavioural improvement but was influenced by prior treatment history. Depression treatment usually has a high risk of relapse, so continuous interventions and individualised strategies are needed to increase the chance of effective treatment. Our findings support a multimodal approach to depression treatment, where combining pharmacological, neuromodulatory, and environmental interventions offers more significant potential for recovery than single treatments alone. These results underscore the complexity of depressive disorders and the need for long-term, personalised therapeutic strategies.