Neurobiology of depression: an integrated view of key findings

Abstract

Aims: The objectives of the present review were to summarise the key findings from the clinical literature regarding the neurobiology of major depressive disorder (MDD) and their implications for maximising treatment outcomes. Several neuroanatomical structures in the prefrontal and limbic areas of the brain are involved in affective regulation. In patients with MDD, alterations in the dynamic patterns of activity among these structures have profound implications for the pathogenesis of this illness.

Discussion: The present work reviews the evidence for the progressive nature of MDD along with associated changes in neuroanatomical structure and function, especially for the hippocampus. The role of glucocorticoids, inflammatory cytokines and brain-derived growth factors are discussed as mediators of these pathological alterations. From this integrated model, the role of antidepressant therapy in restoring normative processes is examined along with additional treatment guidelines.

Conclusion: Major depressive disorder is an illness with significant neurobiological consequences involving structural, functional and molecular alterations in several areas of the brain. Antidepressant pharmacotherapy is associated with restoration of the underlying physiology. Clinicians are advised to intervene with MDD using an early, comprehensive treatment approach that has remission as the goal.

Figure 1

Major depression as a progressive illness. As the number of major depressive episodes increase, the risk for subsequent episodes is predicted more from the number of prior episodes and less from the occurrence of a recent life stress. Figure adapted from ref. no. (14)

Figure 2

Major depressive disorder affects the dynamic connectivity among neuroanatomical structures involved in regulation of mood and stress response. Limbic structures (amygdala, hippocampus and nucleus accumbens) have reciprocal connections with ‘para-limbic’ cortical areas, subgenual anterior cingluate and ventromedial prefrontal cortex (VMPFC). Hypothetically, disrupted ‘connectivity’ between limbic/para-limbic areas and rostral integrative prefrontal formations, results in compromised feedback regulation of limbic activity. Consequently, dorsal cognitive/executive network is hypoactive while overly active limbic areas continue to stimulate the hypothalamus leading to neuroendocrine dysregulation and sympathetic hyperactivity

Figure 3

Molecular processes are impacted by stress and depression. Stress results in release of glucocorticoids and corticotrophin releasing hormones (CRH) and pro-inflammatory cytokines (TNF, IL-1, IL-6). In depression, disruption of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) transmission impair the regulatory feedback loops that ‘turn off’ the stress response. Sympathetic overactivity contributes to immune activation and release of inflammatory cytokines. Inflammatory cytokines further interfere with monoaminergic and neurotrophic signalling. They may also diminish central corticosteroid receptor sensitivity, leading to disruption of feedback control. Figure adapted from ref. no. (46)

Figure 4

Antidepressant therapy is associated with restoring normative processes. Treatment with various selective serotonin antidepressant treatments and serotonergic noradrenergic reuptake inhibitors resulted in increases in serum brain-derived neurotrophic factor (BDNF) for patients with MDD to levels comparable that were observed with healthy controls. Reprinted with copyright permission from ref. no. (66)