The macrophage–T-cell theory of depression^1,2 postulates an activated inflammatory response system in mood disorders and considers this activated inflammatory response system to be a driving force behind the illness, because proinflammatory cytokines are capable of destabilizing brain function. This makes the brain vulnerable to stress and unknown endogenous factors such that major mood disturbances are the consequence. In animal models, the behavioral changes induced by proinflammatory cytokines (sickness behavior) are comparable to the symptoms of depression as seen in humans.³Also in humans, low intravenous doses of endotoxin increase the level of these cytokines and induce depressive symptoms.^4,5 Furthermore, depressive symptoms and mania can be precipitated by interferon alpha treatment,⁶ whereas anti–tumor necrosis factor (TNF) therapy given for psoriasis resulted in a markedly improved mood.⁷ Last, in patients with mood disorders, increased serum, saliva, and cerebral spinal fluid levels of several proinflammatory compounds have been found, such as interleukin 6 (IL-6), IL-1β, TNF-α, prostaglandin E₂ (PGE₂), and chemokine ligand 2 (CCL2),^5,8-11 although other studies have reported negative findings.¹² In addition, there have been reports on high serum levels of positive acute-phase proteins (eg, haptoglobin, α₁-antitrypsin, ceruloplasmin, and C-reactive protein) and low levels of negative acute-phase proteins (eg, albumin and retinal-binding protein) in patients with mood disorders, indicating that mood disorders are accompanied by an acute-phase response.^13-15

Low-grade inflammation plays a role not only in the pathogenesis of major depressive disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications that anti-inflammatory agents improve the outcomes of antidepressants. Aim: To study whether the presence of low-grade inflammation predicts the outcome of antidepressants, anti-inflammatory agents, or combinations thereof. Methods: We carried out a systematic review of the literature on the prediction capability of the serum levels of inflammatory compounds and/or the inflammatory state of circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in MDD. We compared outcomes of the review with original data (collected in two limited trials carried out in the EU project MOODINFLAME) on the prediction capability of the inflammatory state of monocytes (as measured by inflammatory gene expression) for the outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without celecoxib added. Results: Collectively, the literature and original data showed that: 1) raised serum levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents, but a better responsiveness to antidepressant regimens with a) (add-on) noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory agents such as infliximab, minocycline, or eicosapentaenoic acid, showing—next to anti-inflammatory—dopaminergic or lipid corrective action; 2) these successful anti-inflammatory (add-on) agents, when used in patients with low serum levels of CRP/IL-6, decreased response rates in comparison to placebo. Add-on aspirin, in contrast, improved responsiveness in such “non-inflammatory” patients; 3) patients with increased inflammatory gene expression in circulating leukocytes had a poor responsiveness to serotonergic/noradrenergic agents. Conclusions: The presence of inflammation in patients with MDD heralds a poor outcome of first-line antidepressant therapies. Immediate step-ups to dopaminergic or glutamatergic regimens or to (add-on) anti-inflammatory agents are most likely indicated. However, at present, insufficient data exist to design protocols with reliable inflammation parameter cutoff points to guide such therapies, the more since detrimental outcomes are possible of anti-inflammatory agents in “non-inflamed” patients.

There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer's disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory 'braking signals', including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor-α and interleukin (IL)--6, but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.

Context: Thyroid function has been related to Alzheimer disease (AD), but it remains unclear whether thyroid dysfunction results from or contributes to developing AD. Objective: The objective of the study was to determine the association between thyroid function and both medial temporal lobe atrophy on brain magnetic resonance imaging (MRI) as putative early sign of AD and risk of dementia. Design and Participants: This was a population-based cohort study among 1077 elderly subjects aged 60–90 yr and dementia free at baseline (1995–1996). Main Outcome Measures: Nonfasting serum levels of TSH, free T₄ (fT₄), T₃, and rT₃ were available in 1025 subjects followed up for incident dementia until 2005. In a subset of 489 nondemented elderly, we assessed volumes of the hippocampus and amygdala on brain MRI. Subjects using thyroid medication were excluded. Results: During 5657 person-years of follow-up (mean 5.5 yr), 63 subjects were diagnosed with dementia (46 with AD). TSH and thyroid hormones were not associated with risk of dementia or AD. TSH and T₃ were also not related to brain atrophy, whereas nondemented subjects with higher fT₄ levels had more hippocampal and amygdalar atrophy on MRI. Similar associations were found for rT₃. Excluding subjects with thyroid disorders or incipient AD did not change the results. Conclusion: In our study, TSH was related neither to risk of AD nor with early MRI markers thereof, arguing against an important role of thyroid function in the development of AD. Whether the association of higher fT₄ and rT₃ levels with brain atrophy on MRI has functional significance remains to be elucidated.

OBJECTIVE—There is evidence that monocytes of patients with type 1 diabetes show proinflammatory activation and disturbed migration/adhesion, but the evidence is inconsistent. Our hypothesis is that monocytes are distinctly activated/disturbed in different subforms of autoimmune diabetes.RESEARCH DESIGN AND METHODS—We studied patterns of inflammatory gene expression in monocytes of patients with type 1 diabetes (juvenile onset, n = 30; adult onset, n = 30) and latent autoimmune diabetes of the adult (LADA) (n = 30) (controls subjects, n = 49; type 2 diabetic patients, n = 30) using quantitative PCR. We tested 25 selected genes: 12 genes detected in a prestudy via whole-genome analyses plus an additional 13 genes identified as part of a monocyte inflammatory signature previously reported.RESULTS—We identified two distinct monocyte gene expression clusters in autoimmune diabetes. One cluster (comprising 12 proinflammatory cytokine/compound genes with a putative key gene PDE4B) was detected in 60% of LADA and 28% of adult-onset type 1 diabetic patients but in only 10% of juvenile-onset type 1 diabetic patients. A second cluster (comprising 10 chemotaxis, adhesion, motility, and metabolism genes) was detected in 43% of juvenile-onset type 1 diabetic and 33% of LADA patients but in only 9% of adult-onset type 1 diabetic patients.CONCLUSIONS—Subgroups of type 1 diabetic patients show an abnormal monocyte gene expression with two profiles, supporting a concept of heterogeneity in the pathogenesis of autoimmune diabetes only partly overlapping with the presently known diagnostic categories.