The Role of Depressive Subtypes within the Neuroinflammation Hypothesis of Major Depressive Disorder

Major depressive disorder (MDD) is a very common disease that affects more than 350 million people worldwide, representing an enormous socioeconomic burden. From a clinical perspective, MDD can be divided into different subtypes, such as melancholic or atypical MDD. Interestingly, increasing evidence points toward an involvement of the immune system in MDD pathogenesis. However, inflammation does not seem to have the same impact on every MDD type. Here, we describe how inflammation can affect monoaminergic and glutamatergic neurotransmission, which provides a possible mechanism for MDD onset. Next, we examine the regional specificity of neuroinflammation, which shows striking overlaps with neural patterns activated in atypical MDD. Furthermore, we outline how inflammation may translate to subtype-specific clinical features and we suggest how this could be used for diagnostic and treatment purposes. By providing a link back to a dysregulated immune system as a contributing factor to MDD subtypes, we explain how brain regions particularly affected by certain subtypes may regulate the cortisol circuitry.