Rather than conceptualize anti-inflammatory agents as mechanistically identical, it would be more accurate to evaluate these agents separately according to their postulated mechanism of action, as not all agents can be expected to be helpful, and some may even engender psychopathology. For example, corticosteroid therapy prescribed to individuals with established or latent mood disorders unequivocally exacerbate risk and severity of mood disturbance in select cases. Moreover, available evidence indicates that NSAIDs may interfere with optimal antidepressant efficacy. It is conjectured that deleterious effects of corticosteroids on cognitive emotional processing are in part due to “off-target” effects of these agents (ie, suppressing endogenous anti-inflammatory effects and amplifying proinflammatory balance), while for NSAIDs they may alter critical molecular targets relevant to SSRI efficacy.
It may be that the beneficial effects of anti-inflammatory interventions are elevated in discrete subpopulations with mood disorders with perhaps less meaningful effects in other subpopulations. For example, infliximab, FDA-approved for several inflammatory related conditions, significantly mitigates depressive symptom severity in individuals with elevated pre-treatment CRP levels, but not in depressed individuals with lower CRP levels. Furthermore, a proinflammatory balance observed in pretreatment may also identify a subgroup of individuals more likely to benefit from other approaches that engage inflammatory systems (eg, omega-3 fatty acids, ketamine, L-methylfolate, aerobic exercise).5–7 Nonpharmacological approaches (eg, electroconvulsive therapy, mindfulness-based therapy, aerobic therapy), are all “anti-inflammatory,” indicating that the inflammatory system is a convergent target across multiple treatment modalities.8,9
Other anti-inflammatory approaches that appear promising include the use of minocycline 60 to 200 mg daily, which has demonstrated beneficial effects on negative and cognitive symptoms of schizophrenia, as well as depressive symptoms of bipolar disorder.10,11 The antidiabetic agent liraglutide, which also targets the inflammatory system, is FDA-approved for not only type 2 diabetes but also weight loss.12 Preliminary proof-of-concept data indicate that liraglutide may improve depressive and cognitive symptoms in adults with bipolar disorder. A randomized placebo controlled double blind proof-of-concept study is evaluating infliximab for adults with bipolar disorder, who have pretreatment elevated CRP levels; results are expected in July of 2018. Finally, renewed interest in the gut microbiome/microbiota provides convergent evidence indicating that for some individuals with mood disorders, disturbances in the inflammatory system may be partially mediated by gut dysbiosis. It is not known, however, whether dietary manipulation, as a single modality intervention, is sufficient to correct gut dysbiosis and normalize a proinflammatory balance with associated improvement in psychopathology.
For some individuals with mood disorders, disturbances in the inflammatory system are directly causative of select symptom/domain of psychopathology (eg, fatigue, anhedonia, cognitive impairment). The pivotal role played by inflammatory systems suggests that engaging with this target could modify illness trajectory in mood disorders.
In the short term, what type of “anti-inflammatory” approaches should clinicians consider for their patients? Sleep hygiene, normalization of sleep behavior, and resetting chronobiology are all potently anti-inflammatory. Education and lifestyle modifications, including detailed information related to appropriate diet and exercise, are not only part of good lifestyle choices, but may in fact have direct effects on inflammatory systems relevant to psychopathology in select individuals.
Dr. McIntyre reports that he is on the Speakers Bureau for AstraZeneca, Bristol-Myers Squibb, Janssen-Ortho, Eli Lilly, Lundbeck, Pfizer, Shire, Otsuka, Purdue, Takeda, and Allergan; he has received research support/grants from Stanley Medical Research Institute, National Alliance for Research on Schizophrenia and Depression (NARSAD), and National Institutes of Mental Health. Dr. Rong reports no conflicts of interest concerning the subject matter of this article.
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