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. Author manuscript; available in PMC: 2021 Jul 22.
Published in final edited form as: Neuron. 2020 Jun 17;107(2):234–256. doi: 10.1016/j.neuron.2020.06.002

Table 2.

Open Research Questions

Questions
1. Does dysregulation of the immune system contribute to MDD pathology?
If so:
What are the important immune system components that contribute to MDD?
Do these act independently or in synergy to promote MDD?
Is central or peripheral immune system dysregulation mediating the effects?
What are the CNS systems that are altered by the immune system dysregulation that promote MDD?
Are there different immune system alterations that promote MDD in different individuals, or are specific changes common to many MDD patients?
2. What causes immune system dysregulation linked to MDD?
To what extent do genetic influences determine these immune system characteristics?
Does stress (and is it acute or chronic) contribute to immune dysregulation linked to MDD?
How does the environment modulate the immune system dysregulation linked to MDD?
Do repeated episodes of depression cause long-lasting changes in immune characteristics?
Does the microbiome contribute to immune system dysregulation in MDD?
3. Can treating immune system dysregulation facilitate recovery from MDD and/or promote resilience to MDD onset?
What are the immune system targets that are effective interventions for MDD?
Can controlling the stress response normalize immune system characteristics?
Is controlling peripheral immune system characteristics sufficient to counteract MDD or does the central immune system need to be targeted?
Do non-invasive interventions (therapy, nutrition, exercise) normalize immune system alterations associated with MDD?
Are microbiome interventions that alter the immune system effective in MDD?