Neurobiology of Depression: An Integrated View Of Key Findings

V. Maletic; M. Robinson; T. Oakes; S. Iyengar; S. G. Ball; J. Russell


Int J Clin Pract. 2007;61(12):2030-2040. 

In This Article

Role of Neurotransmitters in Recovery From MDD

Therapeutically, selective serotonergic reuptake inhibitors (SSRIs) and NE reuptake inhibitors (NRIs) are known to increase their respective monoamine levels in the brain. Chronic treatment with monoamine reuptake inhibitors increases activation of cyclic adenosine 3-5 monophosphatase (cAMP), which in turn stimulates protein kinase A. Activation of this protein enzyme regulates target genes leading to an increase in BDNF synthesis.[52] The antidepressant-induced cAMP activity can also enhance GR sensitivity and inhibit cytokine signalling, further assisting in the restoration of the neurocircuitry feedback loops.[61]

The effect of increasing monoamine levels (dopamine, 5-HT and NE) on BDNF and growth factors may be one mechanism that produces the antidepressant response. Preclinical study of rat brain cells has demonstrated that monoamenergic activity (NE, 5-HT) upregulates BDNF synthesis in astrocytes.[62] Clinically, successful treatment with antidepressants results in normalisation of serum BDNF level, which is considered an indirect measure of cortical BDNF activity. Support for the relationship between serum and cortical BDNF levels has been derived from correlations in animal studies as well as findings that serum BDNF passes the blood-brain barrier and reflects stored and circulating BDNF in humans.[63,64] In a study of 10 patients who were treated for 12 weeks with a dual reuptake inhibitor, improvement in depressive symptoms was correlated with increases in BDNF levels, and the BDNF levels of remitted patients had normalised to the same level observed in healthy controls.[65] Response to various SSRI and 5-HT noradrenalin reuptake inhibitors (SNRI) treatments has been similarly associated with restoration of normative BDNF values.[66] Figure 4 Postmortem analysis of brain tissue has shown that subjects who had been treated with an antidepressant at time of death had greater hippocampal BDNF expression as measured by immunoreactivity than did untreated subjects with mood disorders.[67]

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]

Antidepressant therapeutic response is also associated with re-establishment of normative cortical activity. A study of 17 inpatients with MDD examined regional activity changes following 1 week and 6 week fluoxetine treatment. At 1 week, all patients showed increases in hippocampal activity and decreases in posterior cingulate and prefrontal cortex activity. After 6 weeks of treatment, patients who had responded to treatment showed a reversal of this pattern with decreased limbic activity and increased prefrontal cortical activity whereas non-responders continued to show the 1-week pattern.[68] Normalisation in the amygdala and ACC has also been associated with positive response to treatment. Using a masking paradigm for subconscious activation, patients with MDD showed a baseline hyper-reactivity of the left amygdala that attenuated following 8-week treatment with sertraline.[69]

Other lines of evidence also support the restorative nature of antidepressant therapy. Structural and functional MRI assessments of patients with MDD who were treated with fluoxetine indicated the importance of ACC grey matter volume for treatment response as there was a positive association among grey matter volume, normalisation of ACC activity, and response to treatment.[70] Conversely, in patients with MDD who failed to respond to antidepressant treatment, plasma levels of proinflammatory cytokines were elevated compared with healthy controls or euthymic patients with MDD.[71]

Symptomatically, improvements in specific MDD symptoms have been associated with regional improvements in brain metabolic activity. In 39 outpatients with MDD, improvement in cognitive symptoms was correlated with increases in DLPFC and improvements in fatigue/psychomotor retardation was associated with decreases in VMPFC activity. Interestingly, these changes were seen in responders regardless of whether treatment was pharmacological or psychological.[72] Restoration of the neurobiological regulation in MDD via neurotrophic factors and neurogenesis appears to be a common factor across various effective treatments for MDD, including pharmacological, psychological and somatic treatments, such as diet and exercise.[73]


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