Inflammation in Depression

Jason Compton, MD
November 1, 2020
jcompton@health.ucsd.edu
Pathogen host defense hypothesis
The evolution and persistence of depression risk alleles and depressive symptoms
in human populations are based on their relevance to “pathogen host defense.”
• Until recently, up to 50% of humans died from infectious causes before adulthood
-> strong selective pressure for microbial interactions.
• Patterns of inflammatory activation in depression promote survival in highly
pathogenic environments (not the developed world).
• Risk alleles for depression have pro-inflammatory and/or anti-pathogen effects,
and support social behaviors that reduce pathogen exposure
• Risk factors for depression are pro-inflammatory.
• Pro-inflammatory cytokines produce a “sickness syndrome” with symptoms that
overlap with depression and can be ameliorated by antidepressants.
Stress-induced Inflammation
Peripherally (physiologic stress):
• DAMPs and PAMPs -> PRRs -> activation of
transcription factors for pro-inflammatory
cytokines in monocytes
• B and T cell activation
• Cox-1, Cox-2 -> PG synthesis
Centrally (psychologic stress):
• Catecholamines
• Increases DAMPs and production of myeloid cells
• Facilitates entry of peripheral immune cells into the
CNS
• Chronically elevated cortisol
• Glucocorticoid resistance -> inflammation
Communication of inflammation to the CNS
Humoral pathway
• Cytokine passage through leaky regions of BBB
Neural pathway
• Binding of cytokines to afferent fibers (Vagus)
-> catecholamine release in the CNS and
production of cytokines in the brain
Cellular pathway
• Catecholamines in the CNS and TNF in the
periphery -> activation of microglia into M1
microglia -> CCL2 -> infiltration of monocytes
into the brain and attraction of immune cells to
regions a/w threat detection (e.g., amygdala)
Kynurenine pathway
TNF alpha, IL-6, CRP, IL-1
-> indoleamine 2,3
dioxygenase in activated M1
microglia
IDO converts tryptophan into
Kynurenine
-> shunting Trp away from the
pathway of monoamine
production (5HT, DA, and NE)
• Anhedonia, PM
-> Increased Glu
• Neurotoxicity, decreased BDNF
-> Quinolinic acid
• Oxidative stress
Pathophysiology
Inflammatory cytokines IL-1, IL-6, TNFa
induce symptoms of depression
• Anhedonia
• Decreased 5HT, DA, and NE production and
release in basal ganglia and upregulation of
SERT, DAT, and NET
• Decreased motivation, decreased response to
positive reward, reduced responsiveness to
novelty, increased sensitivity to adverse stimuli
• Anxiety
• Increased glutamatergic transmission in
dACC, amygdala, and insula
• Activation of threat perception neurocircuitry
• Microglial-mediated neurotoxicity, decreased
hippocampal volume
Chronic inflammation -> Neurodegeneration
• Chronic inflammation
• Microglial activation
• Neurotoxicity
• NMDAR over-activity
• Oxidative stress
• Decreased BDNF
• Decreased neurogenesis
• Apoptosis
• Early neurocognitive
impairment
• Hippocampal volume loss
Gut-Brain Axis
Inflammatory sub-type of depression
Associated with higher BMI, increased waist
circumference, higher TG, lower HDL
Increased serum CRP, TNF alpha, IL-6, IL-1beta
• Lower CRP = quicker response to AD
• CRP, IL-6, and TNF alpha higher in females vs
males
• IL-6 levels decrease with treatment of
depression
• Persistently elevated TNF alpha in TRD
Predicts response to TCAs, ketamine, ECT
• Ketamine Tx a/w correction of inflammatory
markers
• Inflammation-induced low levels of BDNF
increases with ECT
Inflammation, cytokines, and biomarkers
• Patients with TRD have higher levels of IL-6 and
TNFa CRP
• Elevated CRP and IL-6 following a psychosocial
stressor indicate an increased risk of developing
depression TNFa
• Limitations
• Using immunological biomarkers in clinical decision IL-6
making limited to availability of lab testing
• Elevated inflammatory cytokines =/= depression
• Many confounding factors influence levels of IL-1
peripherally circulating inflammatory cytokines
Inflammation, cytokines, and biomarkers
Guiding treatment with inflammatory markers
• CRP <1 = escitalopram more effective than CRP
nortriptyline, the reverse is true for CRP >1
• Lower levels of TNFa predict response to escitalopram
• Citalopram -> incr. TNFa, sertraline* -> incr. IL-6
TNFa
• Increase in inflammatory cytokines mitigated by NSAIDs
• Elevated IL-6 predicts resistance to SSRIs and SNRIs, IL-6
response to ketamine and ECT esp. in female patients
• SSRI’s* decrease IL-6, TCA’s do not
• Neither has had a consistently demonstrated effect on IL-1
IL-1
References
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Augmenting treatment w/ NSAIDs
1. Muller 2006
• Reboxetine (NRI) + placebo vs reboxetine + celecoxib 400mg; 6 weeks, n40
• NRI + COX inh. > NRI alone in decreasing depressive symptoms
2. Akhondzadeh 2009
• Fluoxetine + placebo vs fluoxetine + celecoxib 400mg; 6 weeks, n40
• +celecoxib > +placebo in decreasing depressive symptoms
3. Majd 2015
• Fluoxetine + placebo vs fluoxetine + celecoxib 200mg; 8 weeks, n30
• Initial superiority of NSAID + SSRI dissipated after 4 weeks
• Did not use standard dose of celecoxib, other studies showed increased efficacy >4 weeks
Ketamine
• Not just an NMDA R antagonist
• Decreases IDO and KYN:TRP ratio -> increased monoamine synthesis
• Potentiation of BDNF -> synaptogenesis
• Modulation of AMPA and stimulates mTOR -> neuroplasticity
• Improves symptoms in TRD, elevated inflammatory cytokines predict
response of TRD to ketamine treatment
• Patients with a robust response to ketamine may represent a more inflammatory
depression subtype
• Typically given IV 0.5 mg/kg over 40 minutes
• >70% response rate with sustained sx relief for up to 1 week
• rapid effects, anti-suicidal effects within 1-4 hours
• Recently the intranasal spray Esketamine (Spravato) was approved by FDA
Minocycline Augmentation Therapy
Minocycline augmentation may be effective in decreasing depressive symptoms in patients with
otherwise TRD, but available data is limited and conflicting.
1. Miyaoka 2016
• Minocyline 150mg + fluvoxamine, paroxetine, or sertraline; no placebo; 6w
• Decreased depressive and psychotic symptoms in patients with unipolar depression with
psychotic features
2. Dean 2017
• TAU + minocycline 200mg vs TAU + placebo; 12w
• No significant decrease in depressive symptoms measured by MADRS but did result in
increased QoL and social functioning
3. Husain 2017
• Minocycline + TAU (AD, MS, or AP) vs placebo + TAU; 12w
• Robust decrease in depressive sx in patient with TRD (decrease of 18 pt on HAMD, effect size
1.21)