Depression and brain inflammation

Evidence for the role of brain inflammation in depression is proliferating as noted in a report published recently in JAMA (Journal of the American Medical Association):

"Activation of the immune system is the body’s natural reaction to infection or tissue damage, but when this protective response is prolonged or excessive, it can play a role in many chronic illnesses, not only of the body, but also of the brain...“Psychiatric and neurodevelopmental disorders are being thought of more and more as systemic illnesses in which inflammation is involved,” noted Eric Hollander, MD, of Montefiore Medical Center and Albert Einstein College of Medicine, New York City."

Certain biomarkers including the proinflammatory cytokines interleukin-6 (IL-6) and TNF, and CRP are standing out in depression:

"...early studies showing that patients with depression, regardless of their physical health status, exhibited cardinal features of inflammation, including increases in inflammatory cytokines in the blood and cerebrospinal fluid."

 IL-6 and CRP In Neuropsychiatric Disorders

Along these lines, a study just published in JAMA Psychiatry shows that higher levels of the proinflammatory cytokine IL-6 and the inflammatory biomarker CRP (C-reactive protein) are associated with depression in childhood and psychosis in young adulthood. Noting that...

"Recent meta-analyses of cross-sectional studies have reported increased serum levels of these inflammatory markers in depression, first-episode psychosis, and acute psychotic relapse; however, the direction of the association has been unclear"...

The authors determined to...

"..test the hypothesis that higher serum levels of IL-6 and CRP in childhood would increase future risks for depression and psychosis."

To do so they measured levels of IL-6 and CRP in 4500 individuals at age 9 years, then assessed them at age 18 years for depression using the Clinical Interview Schedule–Revised (CIS-R) and Mood and Feelings Questionnaire (MFQ); and psychotic experiences (PEs) and psychotic disorder by semistructured interviews. Their data were particularly striking for IL-6 in depression and psychosis:

"After adjusting for sex, age, body mass index, ethnicity, social class, past psychological and behavioral problems, and maternal postpartum depression, participants in the top third of IL-6 values compared with the bottom third at age 9 years were more likely to be depressed (CIS-R) at age 18 years (adjusted odds ratio [OR], 1.55). Results using the MFQ were similar. Risks of PEs and of psychotic disorder at age 18 years were also increased with higher IL-6 levels at baseline (adjusted OR, 1.81). Higher IL-6 levels in childhood were associated with subsequent risks of depression and PEs in a dose-dependent manner."

IL-6 proved to be a more robust biomarker than CRP as there was no association of childhood CRP levels and psychiatric illness at age 18, while IL-6 was a good predictor. The authors conclude:

"Higher levels of the systemic inflammatory marker IL-6 in childhood are associated with an increased risk of developing depression and psychosis in young adulthood. Inflammatory pathways may provide important new intervention and prevention targets for these disorders. Inflammation might explain the high comorbidity between heart disease, diabetes mellitus, depression, and schizophrenia."

Inflammation and Antidepressants

The authors of a study recently published in the American Journal of Psychiatry report that levels of CRP predicted the response to a SSRI (escitalopram/Lexapro®) versus nortryptipline (tricyclic antidepressant that is primarily a norepinephrine reuptake inhibitor):

"Major depressive disorder has been linked with inflammatory processes, but it is unclear whether individual differences in levels of inflammatory biomarkers could help match patients to treatments that are most likely to be beneficial. The authors tested the hypothesis that C-reactive protein (CRP), a commonly available marker of systemic inflammation, predicts differential response to escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor)."

They measured CRP in 241 adult men and women with major depressive disorder who were randomly allocated to 12 weeks of treatment with Lexapro® or nortriptyline and rated their response weekly with the Montgomery-Åsberg Depression Rating Scale (MADRS). CRP levels were indeed able to predict the response:

"CRP level at baseline differentially predicted treatment outcome with the two antidepressants (CRP-drug interaction: β=3.27, 95% CI=1.65, 4.89). For patients with low levels of CRP (<1 mg/L), improvement on the MADRS score was 3 points higher with escitalopram than with nortriptyline. For patients with higher CRP levels, improvement on the MADRS score was 3 points higher with nortriptyline than with escitalopram. CRP and its interaction with medication explained more than 10% of individual-level variance in treatment outcome."

These data lead the authors to conclude:

"An easily accessible peripheral blood biomarker may contribute to improvement in outcomes of major depressive disorder by personalizing treatment choice."

So inflammation impaired the response to the SSRI Lexapro®. Patients with higher levels of inflammation did better with nortryptiline, but why?

Norepinephrine reduces  brain oinflammation

A fascinating study published in PNAS (Proceedings of the National Academy of Sciences) sheds light on this by demonstrating that norepinephrine (the levels of which are raised by nortryptiline, a norepinephrine reuptake inhibitor), acts as an antiinflammatory agent in the brain. The authors observed this in the course of investigating the role of norepinephrine in promoting brain inflammation that clears the amyloid beta (Aβ) associated with Alzheimer's disease:

"Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer's disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed Aβ-induced cytokine and chemokine production and increased microglial migration and phagocytosis of Aβ... In vivo laser microscopy confirmed a reduced recruitment of microglia to Aβ plaque sites and impaired microglial Aβ phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced Aβ clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion."

In other words, inflammation went up as norepinephrine went down. This informs us that well-regulated inflammation is an important housekeeping function of the brain's glial cells, but also reveals the link between the relief of depression due dysregulated inflammation when suppressed by norepinephrine.Clinical note: no analysis and treatment plan for depression is complete without investigating for neuroinflammation and its causes, for which there are numerous sustainable interventions.