Immune targets for therapeutic development in depression: towards precision medicine

Drevets, Wayne C.; Wittenberg, Gayle M.; Bullmore, Edward T.; Manji, Husseini K.

doi:10.1038/s41573-021-00368-1

Cited by 145 publications

(97 citation statements)

References 194 publications

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“…Author details 1 Department of Chemical and Pharmaceutical Engineering, College of Chemical Engineering, Huaqiao University, Xiamen 361021, Fujian province, People's Republic of China. 2 Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, Jiangxi province, People's Republic of China. 3 Xiamen Hospital of Traditional Chinese Medicine, Xiamen 361009, Fujian province, People's Republic of China.…”

Section: Abbreviationsmentioning

confidence: 99%

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IL-1R/C3aR signaling regulates synaptic pruning in the prefrontal cortex of depression

Zhang

Guo

Zhang³

et al. 2022

Cell Biosci

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Background Major depressive disorder is characterized by not only monoamine neurotransmitters deficiencies but also persistent neuroinflammation. The complement system is an attractive therapeutic target for various inflammation-related diseases due to its early activation in inflammatory processes. Results In the present study, the dynamic alteration of complement C3 and its receptor C3aR during the occurrence of depression and the mechanism of astrocyte-microglia IL-1R/C3/C3aR on synaptic pruning were investigated. The proteomic analysis firstly showed that chronic stress caused an elevation of C3. GO analysis indicated that complement system-mediated synaptic pruning signaling was involved in depression. The dynamic observation indicated that C3/C3aR was activated in the early onset and throughout the course of depression induced by lipopolysaccharide (LPS) and chronic stress. In contrast, C3aR blockade inhibited the hyperactivation of microglial APT2/DHHC7 palmitoylation cycle, which mediated the translocation of STAT3 and the expression of proinflammatory cytokines. Meanwhile, C3aR blockade also attenuated the synaptic pruning and enhanced the synaptogenesis in the prefrontal cortex of mice. Moreover, the blockade of IL-1R/NF-κB signaling pathway reduced the release of C3 from astrocyte. Conclusions The current study demonstrates that astrocyte-microglia IL-1R/C3/C3aR activation causes the abnormal synaptic pruning in depression, and suggests that the activation of complement C3/C3aR may be particularly helpful in predicting the onset stage of depression.

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Section: Abbreviationsmentioning

confidence: 99%

“…Recently, increasing evidence has shown that neuroimmune is a key factor that correlates with major depression [2]. Complement system participates in both innate immunity and adaptive immunity.…”

Section: Introductionmentioning

confidence: 99%

IL-1R/C3aR signaling regulates synaptic pruning in the prefrontal cortex of depression

Zhang

Guo

Zhang³

et al. 2022

Cell Biosci

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“…Anti-cytokine therapies have been recently cornered as potential strategies for decreasing MDD symptoms severity, although they have been mostly investigated in patients with severe, chronic organic diseases, where the mood manifestations were not the center of clinical attention, but associated features ( Drevets et al, 2022 ). There is overwhelming evidence that immune dysregulation is frequently associated with depression, and MDD has been associated with elevated levels of pro-inflammatory cytokines and acute-phase proteins both in the central nervous system and in the blood, but also with decreased adaptive immune response, a bias toward autoimmunity, and other immune changes ( Drevets et al, 2022 ). The effects of anti-cytokine therapies as adjunctive agents in patients with treatment-resistant MDD or bipolar depression have been investigated in clinical trials, with mixed results ( Drevets et al, 2022 ).…”

Section: Anti-inflammatory Therapies As Potential Treatments For Depr...mentioning

confidence: 99%

“…There is overwhelming evidence that immune dysregulation is frequently associated with depression, and MDD has been associated with elevated levels of pro-inflammatory cytokines and acute-phase proteins both in the central nervous system and in the blood, but also with decreased adaptive immune response, a bias toward autoimmunity, and other immune changes ( Drevets et al, 2022 ). The effects of anti-cytokine therapies as adjunctive agents in patients with treatment-resistant MDD or bipolar depression have been investigated in clinical trials, with mixed results ( Drevets et al, 2022 ).…”

Section: Anti-inflammatory Therapies As Potential Treatments For Depr...mentioning

confidence: 99%

Investigational Drugs for the Treatment of Depression (Part 1): Monoaminergic, Orexinergic, GABA-Ergic, and Anti-Inflammatory Agents

Vasiliu¹

2022

Front. Pharmacol.

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Therapeutic management of depression has currently important limitations, and its low efficacy is reflected in high rates of non-response even after multiple trials of antidepressants. Almost two-thirds of the patients diagnosed with major depression who received a 4–6 weeks trial of antidepressant could not reach remission, and more than 30% of these patients are considered treatment-resistant. In bipolar depression, the situation is also discouraging if we analyze the high suicide rate, the risk for the treatment-emergent affective switch when antidepressants are added, the high rate of treatment resistance (up to 25%), and the severe functional impairments associated with these episodes. Therefore, new therapeutic agents are needed, as well as new pathogenetic models for depression. The vast majority of the currently approved antidepressants are based on the monoamine hypothesis, although new drugs exploiting different neurotransmitter pathways have been recently approved by FDA. Brexanolone, an allopregnanolone analog, is an example of such new antidepressants, and its approval for post-partum depression inspired the search for a new generation of neurosteroids and GABA-ergic modulators, with an easier way of administration and superior tolerability profile. Orexin receptors antagonists are also extensively studied for different psychiatric disorders, depression included, in phase II trials. Antiinflammatory drugs, both cyclo-oxygenase 2 inhibitors and biological therapy, are investigated in patients with depressive disorders based on the proven correlation between inflammation and mood disorders in preclinical and clinical studies. Also, a new generation of monoamine-based investigational drugs is explored, ranging from triple reuptake inhibitors to atypical antipsychotics, in patients with major depression. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost seven decades, that new pathogenetic pathways should be targeted to increase these patients’ response rate.

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“…This evidence includes: (1) Depression is often accompanied by increased neuroinflammation ( 68 ). In the CNS, increased pro-inflammatory cytokines, which may come from the periphery or be produced from cells within the CNS, and activation of microglia as the resident immune cells of the brain are observed in MDD by imaging and post-mortem studies ( 69 – 73 ). (2) The central administration of exogenous inflammatory irritants can induce depressive symptoms ( 74 , 75 ).…”

Section: Possible Anti-depressant Mechanisms Of Action Of Omega-3 Pufasmentioning

confidence: 99%

Possible antidepressant mechanisms of omega-3 polyunsaturated fatty acids acting on the central nervous system

et al. 2022

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Omega-3 polyunsaturated fatty acids (PUFAs) can play important roles in maintaining mental health and resistance to stress, and omega-3 PUFAs supplementation can display beneficial effects on both the prevention and treatment of depressive disorders. Although the underlying mechanisms are still unclear, accumulated evidence indicates that omega-3 PUFAs can exhibit pleiotropic effects on the neural structure and function. Thus, they play fundamental roles in brain activities involved in the mood regulation. Since depressive symptoms have been assumed to be of central origin, this review aims to summarize the recently published studies to identify the potential neurobiological mechanisms underlying the anti-depressant effects of omega-3 PUFAs. These include that of (1) anti-neuroinflammatory; (2) hypothalamus-pituitary-adrenal (HPA) axis; (3) anti-oxidative stress; (4) anti-neurodegeneration; (5) neuroplasticity and synaptic plasticity; and (6) modulation of neurotransmitter systems. Despite many lines of evidence have hinted that these mechanisms may co-exist and work in concert to produce anti-depressive effects, the potentially multiple sites of action of omega-3 PUFAs need to be fully established. We also discussed the limitations of current studies and suggest future directions for preclinical and translational research in this field.

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Immune targets for therapeutic development in depression: towards precision medicine

Cited by 145 publications

References 194 publications

IL-1R/C3aR signaling regulates synaptic pruning in the prefrontal cortex of depression

IL-1R/C3aR signaling regulates synaptic pruning in the prefrontal cortex of depression

Investigational Drugs for the Treatment of Depression (Part 1): Monoaminergic, Orexinergic, GABA-Ergic, and Anti-Inflammatory Agents

Possible antidepressant mechanisms of omega-3 polyunsaturated fatty acids acting on the central nervous system

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