In animal models, the habenula has been identified as a key structure involved in mood disorders (MDs). Thanks to recent technological advancements, a burgeoning body of work has also investigated the habenula in the context of human MDs. This systematic review aims to synthesize findings from human studies concerning the habenula and its relationship with MDs. The review was conducted according to PRISMA guidelines. The literature search yielded 93 articles, of which 50 articles were included in the review. We found that the evidence for baseline habenular hyperactivity in human depression is mixed. Although the finding of baseline habenular hyperactivity is widely replicated in animal models of depression, the available evidence is not sufficient to either conclude the presence or the absence of this hyperactivity in human depression. As for findings from resting-state functional connectivity (RSFC) studies, they were mainly inconsistent across studies. Nevertheless, a notable observation is that alterations in connectivity between the habenula and regions of the default mode network (DMN) were overrepresented in the results, suggesting that connections between the habenula and DMN regions may play a role in MDs. Lastly, we found no evidence indicating that MDs are linked to changes in habenular volume.
Fortin et al. (2025) studied this question.