Abstract: "Accumulating data indicate that inflammation may play a role in a host of psychiatric illnesses.1 These data reveal reliable associations of inflammatory markers with psychiatric disorders, the induction of psychiatric symptoms following administration of inflammatory stimuli, the association of inflammation-related genes with psychiatric disease, and the elucidation of neurobiological and immunological mechanisms by which inflammation targets neurotransmitters and neurocircuits to change behavior. Nevertheless, whether therapeutic strategies that inhibit inflammation will be effective in treating psychiatric illnesses remains unclear. This question is not trivial given the pressing need for novel therapeutics based on the high rates of treatment resistance across disorders and on our relatively limited psychopharmacologic repertoire.
As reflected in recent reviews of the efficacy of anti-inflammatory drugs in treating depression and schizophrenia, including a recent meta-analysis on depression published in JAMA Psychiatry,2 the experimental strategies used to date are the ones that have failed to yield new drugs for psychiatric disorders. Clinical trials using anti-inflammatory agents with multiple off-target effects on nonselected populations of patients, using nonspecific measures of outcome without evidence of target engagement, provide limited information and run the risk of repeating an approach that, although familiar, is no longer viable. It is this very approach that has led the National Institute of Mental Health to demand more rigorous standards regarding clinical trials, including an “experimental medicine” approach to avoid the mistakes of the past.3 In the case of inflammation, these mistakes are being repeated despite the existence of a treasure trove of data that can inform future studies and ultimately determine whether inhibiting inflammation holds therapeutic promise. A brief evaluation of what we know and how it can guide future study design is a necessary first step toward making this determination. The following tenets are proffered as initial guideposts to address the challenge."