Mounting evidence supports the concept of a microbiota-gut-brain axis and suggests that this axis is perturbed in neuropsychiatric disorders. The gut microbiota regulates host exposure to its products by modulating gut epithelial and blood-brain permeability, 1,2 both of which are altered in patients with major depressive disorder. [3][4][5][6] In addition, patients with major depressive dis order have shown substantial shifts in both the relative abun dance of taxa and the neuroactive metabolic potential of the gut microbiota, compared with healthy controls. [7][8][9][10][11][12] Because of this compelling preclinical data, 1-12 interven tions affecting the microbiota-gut-brain axis are a poten tial treatment modality for depressive symptoms. Multiple systematic reviews have been conducted to assess the effect of microbiotatargeting interventions on depressive symp toms, but they include diverse populations and different study designs, include different subsets of the interventions targeting the gut microbiota and, not surprisingly, report conflicting findings. [13][14][15] The objective of this study is to summarize the effect of microbiometargeting interven tions on depressive symptoms.
Methods
DesignWe conducted a systematic review and metaanalysis, following Cochrane recommendations for best practice, and the Pre ferred Reporting Items for Systematic Review and Meta Analysis (PRISMA) for reporting. 16,17 We registered the proto col with PROSPERO (ID: 143178). As domain know ledge was refined, so too was the protocol and analysis strategy, in con sultation with domain experts; deviations from the registered protocol are outlined in Appendix 1, Section 1, available at www.cmajopen.ca/content/9/4/E1195/suppl/DC1. Briefly, we decided to focus on depressive symptoms, rather than all men tal health outcomes, to enhance interpretability.
Background: Subcutaneous trastuzumab (T-SC) administration does not allow the historical target concentration of 20 µg/mL for efficacy to be reached, from the start of treatment in patients with a body mass index (BMI) >30 kg/m2. Objectives: To analyze the influence of the strategy of dosification (fixed vs adjusted patient’s body weight dose) on the initial minimum plasma concentration ( Cmin) of trastuzumab in obese patients. Methods: This was an observational, prospective study, which included patients with HER2-positive nonmetastatic breast cancer treated with trastuzumab. The determination of the Cmin of trastuzumab was performed on day +21 of the first cycle using the ELISA technique. Patients were stratified according to the strategy of dosification and BMI. Results: A total of 50 patients were included; 16 patients received the drug intravenously and 34 in a fixed dosage subcutaneous (T-SC) regimen. The proportion of patients who achieved an adequate plasma concentration since the beginning of treatment was significantly higher when the drug was administered intravenously (93.8% vs 67.6%, P = 0.042). These differences are especially greater in T-SC patients with BMI >30 kg/m2, with only 20% of patients exceeding the pharmacokinetic target. Conclusion and Relevance: Our study suggests that trastuzumab SC fixed dose of 600 mg is not equivalent to IV administration, especially in obese patients. An adequate trastuzumab exposure in this population needs patient weight–adjusted IV dosage in the first administration. The clinical relevance of these findings remains to be elucidated, and further research, including larger controlled trials, is warranted.
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