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• W2938498614 abstract "A meta-analysis by Köhler-Forsberg et al. 1 involving nearly 10 000 patients, published in the current issue of Acta Psychiatrica Scandinavica, shows that anti-inflammatory treatment can reduce depressive symptoms, as well as increase remission and response rates in patients with depression. The observed effect sizes were large for three classes of anti-inflammatory medications: NSAIDs, corticosteroids, and cytokine inhibitors, with a near-doubling of effect size resulting from the add-on, and there was minimal heterogeneity in the results for these medications. In fact, the added effect size resulting from the anti-inflammatory agents added to antidepressants was larger than that reported in studies of the effects of antidepressants alone 2. Is there any reason to be surprised by these results? Perhaps not, if we keep in mind that meta-analyses have previously established that patients with depression indeed have increased levels of inflammation in the blood 3, 4. There are also several well-established biological mechanisms by which peripheral inflammation can reach the brain, induce neuroinflammation, and alter neurotransmission, thereby generating depressive symptoms 5, 6. Some of the first observations indicating that inflammation can cause depressive symptoms came from clinical studies in patients who received interferon (IFN)-based immunotherapies to treat conditions such as cancer and hepatitis. The patients developed depressive symptoms and sometimes active suicidal behaviour at an increased rate 7. In fact, at least 25% of patients receiving IFN treatment will develop depression after starting the treatment 8. In a person who is experiencing peripheral inflammation, cytokines and other inflammatory factors can reach the brain by passive diffusion across areas with high blood–brain barrier (BBB) permeability, such as the median eminence of the hypothalamus. Cytokine receptors in this region initiate some of the first responses to sickness/inflammation, including fever, malaise, appetite changes, and fatigue, often referred to as neurovegetative symptoms 9. Moreover, inflammatory factors can actively be transported across the BBB to reach other brain regions, and inflammation can also spread throughout the brain parenchyma. The resident macrophages of the brain, microglial cells, become activated upon cytokine stimulation and start secreting their own arsenal of proinflammatory molecules. Some of these neurochemicals will not only exacerbate inflammation, but also bind directly to microglial and neuronal cytokine receptors and alter neurotransmission 10. Inflammation also induces downstream metabolic pathways in the brain. For example, the kynurenine pathway breaks down tryptophan into metabolites with effects on glutamate neurotransmission. When this pathway is overactivated by inflammation, serotonin levels are reduced, as a consequence of shunting the breakdown of tryptophan down the kynurenine pathway, limiting serotonin production 11, 12. The metabolism of several other neurotransmitters, including dopamine, is also greatly impacted by neuroinflammation 13. Additional supportive evidence for a role of inflammation in depression comes from epidemiological studies showing an increased risk of depression in groups of patients that suffer from somatic inflammatory disorders, such as rheumatoid arthritis, cardiovascular disease, and diabetes, and the benefits of anti-inflammatory treatments on their mood symptoms 14, 15. Thus, there is now a large body of scientific evidence implicating inflammation in depression, including causative mechanistic studies, epidemiological and associative studies, and, as in the current meta-analysis by Köhler-Forsberg 1, positive effects from clinical trials using anti-inflammatory therapies to treat depression. Currently, the critical questions are as follows: What more is needed before there can be consensus as to whether depression is an inflammatory disorder, and before the clinical guidelines to treat depressive patients will include anti-inflammatory agents? Before a novel treatment can be approved for clinical use, rigorous preclinical and clinical trials are required. For many anti-inflammatory treatments, including the NSAIDs and corticosteroids, these requirements have already been fulfilled, as they have been tested and approved for safety and efficacy in humans to treat a wide variety of somatic inflammatory conditions. For several of these medications, the safety profiles are very well established after decades of use in humans, and many can be purchased over the counter without any need for a prescription. In order to be approved for clinical use for a new indication, the treatments also need to show efficacy in clinical trials targeting the particular condition, in this case, depression. The anti-inflammatory treatments, shown to be effective in treating depression in the studies described in the meta-analysis by Köhler-Forsberg, et al., should then be tested in large-scale, multicenter, randomized, and placebo-controlled trials (RCTs) involving several hundreds to thousands of participants. After testing whether anti-inflammatory agents are effective in treating depression in well-controlled studies at such a large-scale, governmental agencies in the respective countries could move forward to approve the anti-inflammatory drugs in question for the new indication, depression. This path might seem both straight forward and warranted at this point in time, considering the wealth of experimental data supporting the use of anti-inflammatory agents in depression. However, phase III trials are expensive, in the range of 20–30 million dollars or more, each, to conduct 16. Only drugs with a high likelihood of generating future profit are put through phase III trials. In the case of the traditionally used, safe and tolerable anti-inflammatory agents that are already on the market, there is no financial incentive for the pharmaceutical industry to conduct these costly, large-scale RCTs. Rather, they are more likely to fund newly discovered immunotherapies with a poorly characterized safety profile, as such novel immunomodulatory treatments can be patented and monetized. Therefore, putting the well-established OTC anti-inflammatory treatments through phase III clinical trials for use in depression is something that will likely need to be funded by governmental authorities. An important question brought up in the meta-analysis by Köhler-Forsberg et al. 1 is whether all patients with depression suffer from inflammation and therefore would benefit from anti-inflammatory treatment as a general recommendation, or whether the inflammation extends only to certain population groups. Some studies indeed indicate that subgroups of depressive patients, including patients with postpartum depression or suicidal depression, may exhibit particularly high levels of inflammation 17, 18. If preselection of patients based on increased peripheral inflammation would be implemented for subsequent anti-inflammatory treatment, several candidate peripheral markers could be employed based on current evidence, including cytokines IL-6 and TNF-alpha, and acute phase proteins CRP and SAA 19-21. However, it is not yet well established whether the degree of inflammation that can be measured in blood matches ongoing inflammation in the central nervous system (CNS). Thus, it could be that inflammatory mechanisms are activated in the brains of all patients with depression, even if the markers only are elevated in the periphery of some patients. It is also possible that while inflammatory markers are elevated in many patients, only those with a genetic susceptibility to inflammation and depression go on to develop a depressed phenotype. Interestingly, the meta-analysis by Köhler-Forsberg 1 indicates that depressive patients in general would benefit from the anti-inflammatory treatment, without any preselection of specific subgroups. Thus, the meta-analysis did not attempt to divide the studies based on subgroups or indications of ongoing inflammation and still detected effect sizes that were larger than those observed for the conventional antidepressive treatments. The meta-analysis by Köhler-Forsberg et al. 1 comes with some limitations. One of the most important is the likelihood of bias in the studies. The studies were all small to medium in size, and the anti-inflammatory agents tested were of several different classes, making the studies heterogeneous. In addition, duration of treatment was also variable. For example, the two corticosteroid treatment studies were ultra-short, only 2 and 4 days, while all other studies were longer than 6 weeks. However, the most commonly used treatment was the use of NSAIDs as an add-on (all studies but one used celecoxib), with 13 studies and over 4000 participants included, making the results regarding this anti-inflammatory agent particularly robust, with an effect size of −0.40. In summary, current experimental evidence points to a causative role for inflammatory mechanisms in depression. The meta-analysis by Köhler-Forsberg et al. 1 shows that anti-inflammatory treatment, both as monotherapy and as an add-on to antidepressants, has a strong beneficial effect. There is a clear incentive for future large RCTs in order to test the use of anti-inflammatory drugs for treating depression. However, the responsibility to fund these RCTs will likely fall on federal or foundation sources of funding. In 2017, the World Health Organization announced that depression was the leading cause of suffering and disability worldwide which means novel treatments are needed now more than ever 22. Perhaps finally the time has come for large-scale trials of anti-inflammatories in depression? Dr. Achtyes has received research support from Alkermes, AssurEx, Astellas, Avanir, Biogen, Boehringer Ingelheim, Janssen, Network180, Neurocrine Biosciences, Novartis, Otsuka, Pfizer, Priority Health, Takeda, and Vanguard Research Group and has served on advisory boards for Alkermes, Indivior, Janssen, Neurocrine Biosciences, Roche, and the Vanguard Research Group. Dr Brundin has received funding from the National Institutes of Health and the Michael J Fox Foundation for research projects studying the role of inflammation in neuropsychiatric disorders." @default.
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• W2938498614 title "Has the time come to treat depression with anti‐inflammatory medication?" @default.
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