Altered functional connectivity in fronto-limbic circuits, dysregulation of the hypothalamic–pituitary–adrenal axis (HPA), and serotonergic dysfunction in Major Depressive Disorder (MDD)

Major Depressive Disorder (MDD) is a complex neuropsychiatric condition characterized by widespread alterations in neural circuitry, neurotransmission, and neuroendocrine regulation. This review integrates findings from neuroimaging, molecular, and pharmacological studies to elucidate the neurobiological substrates of MDD, with particular emphasis on fronto-limbic network dysfunction, hypothalamic–pituitary–adrenal (HPA) axis dysregulation, and serotonergic signaling abnormalities. Convergent evidence from resting-state and task-based functional MRI indicates reduced functional connectivity within prefrontal–limbic circuits, including the medial prefrontal cortex, anterior cingulate cortex, amygdala, hippocampus, and hypothalamus, alongside impaired top-down regulation of emotional processing. At the neurochemical level, MDD is associated with serotonergic hypoactivity, altered receptor dynamics (notably 5-HT1A and 5-HT2A), and disrupted monoamine transport, as well as emerging dysregulation in glutamatergic and GABAergic systems that contribute to excitatory–inhibitory imbalance. Additionally, reduced expression of brain-derived neurotrophic factor (BDNF) and impaired synaptic plasticity are consistently observed, linking molecular deficits to circuit-level dysfunction. Hyperactivation of the HPA axis and chronic hypercortisolemia further exacerbate hippocampal and prefrontal abnormalities, reinforcing maladaptive stress responses. Collectively, these findings support a systems-level model in which MDD arises from the interaction of dysfunctional neural networks, impaired neuroplasticity, and neuroendocrine imbalance. Advancing this integrative framework is critical for the development of targeted, mechanism-based therapeutic interventions.