Network hypothesis of antidepressant action:JAMA Psy.Sept.2013.


Antidepressants were discovered  more than 50 years ago, still the exact mechanism of action is not well understood.Deficiency in monoaminergic neuromodulators has been the dominant explanation and success of SSRI put serotonin defects on the forefront. Recent research points towards neuronal plasticity, neurogenesis in the adult brain, and the ability of antidepressants to regulate the expression of genes related to plasticity and resilience as their key mechanisms of action.

Eero Castrén reviews this field in this article and elaborates on the network hypothesis.

Brain function depend heavily on wiring and activity of the neuronal networks.Plasticity mediates structural and functional changes in these net- works.Hubel and Wiesel (1960s) established that sensory experience shapes how the brain develops.Plasticity  is highest during “critical periods” though use-dependent plasticity continues to take place in adulthood. Changes in strength of existing synapses, either strengthening (long-term potentiation) or weakening (long-term depression) are influenced by  internal or external experiences.

Research show that recovery from depression reflects structural and functional changes in critical neuronal networks that allow them to better adapt to environmental conditions. Mood disorders  are thought to be resulting from an inability of the neuronal networks that guide mood-related behavior to optimally or appropriately adjust to inputs from the external world. Antidepressants initiate a process whereby neuronal networks, guided by activity, readjust their structure to better represent the external and internal milieu and this would take weeks to occur.

Can antidepressant help in rewiring?   Animal studies have shown that fluoxetine treatment in adult animals can reactivate a critical period–like ( ie childhood like) plasticity, which can facilitate the reorganization and functional recovery of a network that was mis-wired during development.The interplay between multiple neurotransmitter and modulator systems is mediating these effects on plasticity.In addition to fluoxetine, histone deacetylase inhibitors have also been shown to reactivate a critical period–like plasticity.

Human experiments: Normann et al used electroencephalography to record visually evoked potentials from the visual cortex of depressed patients, control subjects, and healthy volunteers given the antidepressant sertraline . Using the magnitude of  change in visual cortical response to a visual stimulus  as an index of neuronal plasticity, they found that depressed patients had lower levels of plasticity than controls. The healthy volunteers given sertraline had significantly elevated signs of plasticity.

Depressed patients brain show many abnormalities( white matter abnormalities, changes in gray matter volume, neuronal organization, electrophysiological activity, and receptor pharmacology) in the circuitry connecting the medial prefrontal cortex, amygdala, and hippocampus. Antidepressants enhance plasticity within key networks like this and this would help in fixing the malfunctioning networks. The chance of clinical improvement is maximized if a positive environment is present to guide the network toward optimal function. This supports the notion that medications need to be combined with proper environmental guidance to achieve maximal benefit.It also might explain why patients lacking a positive support network are at increased risk for becoming treatment resistant.

There is currently little information on whether antidepressants might influence plasticity in children while critical periods are still open.It is also not clear whether the window of plasticity remains open as long as drug treatment lasts or whether it spontaneously closes after a while even on continuous treatment.

Author bring the analogy of anabolic steroids: steroids facilitate a process where exercise increases muscle growth, but they are not expected to work alone without training. Like this,  antidepressants require necessary support/guidance/ to use experiences /reflections to help in rewiring.


Network hypothesis suggest that antidepressants reactivate / promote a juvenile-like state of brain plasticity. This  facilitates the reorganization of cortical networks to better adjust to environmental experiences. 

Summary of the article: 

Neuronal Network Plasticity and Recovery From Depression.

Castrén E. JAMA Psychiatry. 2013.Sept. Vol 70,Number 9.

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