An increase of inflammatory markers has also been seen in patients with anxiety and personality disorders. Bipolar disorder has been associated with increased blood inflammatory markers as well as increased inflammatory cytokines, NF-κB, and markers of microglial activation in postmortem brain tissue. Patients with medical illnesses are well known to exhibit increased inflammation secondary to infection and the tissue damage and destruction that can activate the inflammatory response. The data indicate that treatment resistance may be in part a function of activation of inflammatory pathways. The clinical factors that may alert the clinician to which patients are most likely to exhibit increased inflammatory biomarkers and risk for treatment resistance include obesity, childhood maltreatment, bipolar disorder, and comorbid medical illness
Multiple lifestyle, environmental, psychiatric, and medical factors contribute to and are a function of an inflammatory milieu associated with increased inflammatory cytokines, which can reduce the availability of monoamines, inhibit neurogenesis, and increase glutamate. Conventional antidepressants act on monoamine pathways to increase monoamine availability and require neurogenesis for efficacy. Moreover, glutamate is not a primary target of conventional antidepressant therapy. Cytokine effects on these biological processes thus conspire to sabotage and circumvent the mechanism of action of conventional antidepressants, leading to treatment resistance.