Estimating the smallest worthwhile difference of antidepressants: a cross-sectional survey.

BACKGROUND: Approximately 30% of patients experience substantial improvement in depression after 2 months without treatment, and 45% with antidepressants. The smallest worthwhile difference (SWD) refers to an intervention's smallest beneficial effect over a comparison patients deem worthwhile given treatment burdens (harms, expenses and inconveniences), but is undetermined for antidepressants. OBJECTIVE: Estimating the SWD of commonly prescribed antidepressants for depression compared to no treatment. METHODS: The SWD was estimated as a patient-required difference in response rates between antidepressants and no treatment after 2 months. An online cross-sectional survey using Prolific, MQ Mental Health and Amazon Mechanical Turk crowdsourcing services in the UK and USA between October 2022 and January 2023 garnered participants (N=935) that were a mean age of 44.1 (SD=13.9) and 66% women (n=617). FINDINGS: Of 935 participants, 124 reported moderate-to-severe depressive symptoms but were not in treatment, 390 were in treatment and 495 reported absent-to-mild symptoms with or without treatment experiences. The median SWD was a 20% (IQR=10-30%) difference in response rates for people with moderate-to-severe depressive symptoms, not in treatment, and willing to consider antidepressants, and 25% (IQR=10-35%) for the full sample. CONCLUSIONS: Our observed SWDs mean that the current 15% antidepressant benefit over no treatment was sufficient for one in three people to accept antidepressants given the burdens, but two in three expected greater treatment benefits. IMPLICATIONS: While a minority may be satisfied with the best currently available antidepressants, more effective and/or less burdensome medications are needed, with more attention given to patient perspectives.

A phytoceramide analog stimulates the production of chemokines through CREB activation in human endothelial cells.

Innate immunity is the front-line of self-defense against microbial infection. In mammals, innate immunity interacts with adaptive immunity and has a key role in the regulated immune response. From a pharmaceutical point of view, innate immunity is an ideal target for the development of immunoregulators. Therefore, we aimed to isolate and characterize a novel mammalian immunoregulator isolated from the thermophilic cellulotic fungus Talaromyces sp. 2'-(R)-hydroxy-C(24) phytoceramide (C(24)(2'OH)Phy) was isolated from Talaromyces sp. using a Drosophila ex vivo culture system. C(24)(2'OH)Phy suppressed the immune deficiency (IMD) pathway-dependent expression of antibacterial peptides in Drosophila, whereas it stimulated the production of chemokines in human cells. Structure activity relationship studies of C(24)(2'OH)Phy analogs revealed that both the 2'-(R)-hydroxylignoceroyl group and phytoceramide backbone are essential for the biologic activity of C(24)(2'OH)Phy. Microarray analysis revealed that C(24)(2'OH)Phy selectively activates the transcription of inflammatory response genes, including chemokines. Furthermore, a reporter gene assay and small interfering RNA analysis demonstrated that C(24)(2'OH)Phy stimulates chemokine production through cAMP response element-binding protein activation in human cells. C(24)(2'OH)Phy may be a lead immunostimulating compound in humans.

Synthesis and innate immunosuppressive effect of 1,2-cyclopentanediol derivatives.

Innate immunity is the front line of self-defense against infectious microorganisms. In mammals, innate immunity interacts with adaptive immunity and plays a key role in regulating the immune response. Therefore, innate immunity is a good pharmaceutical target for the development of immune regulators. After searching for natural substances that regulate innate immunity using an ex vivo Drosophila culture system, we identified a cyclopentanediol-type compound 1 as an immunosuppressor. In this study, we synthesized and evaluated 1 and its derivatives. Several methylamide- or phenylamide-containing derivatives showed effects that were 20-25 times more potent than those of 1.

A cyclopentanediol analogue selectively suppresses the conserved innate immunity pathways, Drosophila IMD and TNF-alpha pathways.

Innate immunity comprises evolutionarily conserved self-defense mechanisms against microbial infections. In mammals, innate immunity interacts with adaptive immunity and has a key role in the regulated immune response. Therefore, innate immunity is a pharmaceutical target for the development of immune regulators. Using Drosophila ex vivo culture systems, we isolated a cyclopentanediol analogue from Aspergillus sp. as an immunosuppressive substance. This compound selectively suppressed activation of the IMD pathway in Drosophila in vivo and the target molecules of the compound lie between the Imd adaptor protein and dTAK1 kinase in the IMD pathway. In human cells, the compound suppressed TNF-alpha, but not IL-1beta, stimulation-induced activation of NF-kappaB, suggesting that its target molecules are upstream of TAK1 in mammalian innate immunity.