“…When interpreting the present data, it should be considered that an association between SEs and corresponding HDRS-17 items may not only reflect actual SEs impacting the rating, but could also be caused by symptoms of depression being erroneously reported as SEs. As the included SEs are more common on active treatment, and since most of them can be elicited, at similar frequency, also in non-depressed subjects exposed to molecules inhibiting serotonin reuptake 26 , it however seems likely that the covariation to a considerable extent be indeed due to SEs influencing the HDRS-17. The possibility that certain symptoms, and/or patients with certain symptom constellations, are less likely to improve, or more likely to deteriorate, with antidepressant treatment, can however not be excluded.…”
Section: Discussionmentioning
confidence: 99%
“…Relatedly, since the HDRS-17 separates between loss of appetite (HDRS-17 item 12) and weight loss (HDRS-17 item 16), we originally intended to include weight loss as a separate SE category, but opted not to do so after noting that SEs coded as ‘weight loss’ had low prevalence at endpoint (1.2%). Given the well-known short-term weight decreasing properties of drugs inhibiting serotonin reuptake 26 , the low prevalence of weight loss-related SEs may reflect underreporting. Third, the association between adverse events and treatment response may also have been attenuated by the fact that both response and side effects should be influenced in the same direction by factors for which we did not control, such as inter-individual differences in dose, compliance, and drug metabolism.…”
The Hamilton Depression Rating Scale (HDRS-17) measures symptoms that may overlap with common antidepressant side effects (e.g., sexual dysfunction), thus making it possible that side effects of antidepressant treatment are erroneously rated as symptoms of depression, and vice versa. This study uses patient-level data from previously conducted antidepressant treatment trials to assess whether side effect ratings co-vary with HDRS-17 ratings. Data from all HDRS-17-rated, industry-sponsored pre- and post-marketing trials (n = 4647) comparing the serotonin and noradrenaline reuptake inhibitor, duloxetine, to placebo and/or to a selective serotonin reuptake inhibitor were pooled; three studies, which utilised sub-therapeutic doses, did not have symptom-level ratings available and could not be included. Severity was assessed for side effects related to sleep, somatic anxiety, gastrointestinal function, and sexual dysfunction. Analysis of covariance was used to assess the relation between these side effects and ratings of relevant HDRS-17-derived outcome parameters. Side effects related to sleep, somatic anxiety and sexual dysfunction significantly and exclusively associated with higher scores on HDRS-17 items measuring the corresponding domains. Side effects related to gastrointestinal function associated with higher HDRS-17 item scores on all assessed domains. Treatment outcome was significantly related to side effect severity when assessed using HDRS-17-sum (beta 0.32 (0.074), p < 0.001), but not when the HDRS-6-sum-score (beta 0.035 (0.043), p = 0.415) or the depressed mood item (beta 0.007 (0.012), p = .527) were used as effect parameters. That some HDRS-17 items co-vary with common antidepressant side effects suggests some of these adverse events are counted twice, potentially leading to an underestimation of antidepressant efficacy.
“…When interpreting the present data, it should be considered that an association between SEs and corresponding HDRS-17 items may not only reflect actual SEs impacting the rating, but could also be caused by symptoms of depression being erroneously reported as SEs. As the included SEs are more common on active treatment, and since most of them can be elicited, at similar frequency, also in non-depressed subjects exposed to molecules inhibiting serotonin reuptake 26 , it however seems likely that the covariation to a considerable extent be indeed due to SEs influencing the HDRS-17. The possibility that certain symptoms, and/or patients with certain symptom constellations, are less likely to improve, or more likely to deteriorate, with antidepressant treatment, can however not be excluded.…”
Section: Discussionmentioning
confidence: 99%
“…Relatedly, since the HDRS-17 separates between loss of appetite (HDRS-17 item 12) and weight loss (HDRS-17 item 16), we originally intended to include weight loss as a separate SE category, but opted not to do so after noting that SEs coded as ‘weight loss’ had low prevalence at endpoint (1.2%). Given the well-known short-term weight decreasing properties of drugs inhibiting serotonin reuptake 26 , the low prevalence of weight loss-related SEs may reflect underreporting. Third, the association between adverse events and treatment response may also have been attenuated by the fact that both response and side effects should be influenced in the same direction by factors for which we did not control, such as inter-individual differences in dose, compliance, and drug metabolism.…”
The Hamilton Depression Rating Scale (HDRS-17) measures symptoms that may overlap with common antidepressant side effects (e.g., sexual dysfunction), thus making it possible that side effects of antidepressant treatment are erroneously rated as symptoms of depression, and vice versa. This study uses patient-level data from previously conducted antidepressant treatment trials to assess whether side effect ratings co-vary with HDRS-17 ratings. Data from all HDRS-17-rated, industry-sponsored pre- and post-marketing trials (n = 4647) comparing the serotonin and noradrenaline reuptake inhibitor, duloxetine, to placebo and/or to a selective serotonin reuptake inhibitor were pooled; three studies, which utilised sub-therapeutic doses, did not have symptom-level ratings available and could not be included. Severity was assessed for side effects related to sleep, somatic anxiety, gastrointestinal function, and sexual dysfunction. Analysis of covariance was used to assess the relation between these side effects and ratings of relevant HDRS-17-derived outcome parameters. Side effects related to sleep, somatic anxiety and sexual dysfunction significantly and exclusively associated with higher scores on HDRS-17 items measuring the corresponding domains. Side effects related to gastrointestinal function associated with higher HDRS-17 item scores on all assessed domains. Treatment outcome was significantly related to side effect severity when assessed using HDRS-17-sum (beta 0.32 (0.074), p < 0.001), but not when the HDRS-6-sum-score (beta 0.035 (0.043), p = 0.415) or the depressed mood item (beta 0.007 (0.012), p = .527) were used as effect parameters. That some HDRS-17 items co-vary with common antidepressant side effects suggests some of these adverse events are counted twice, potentially leading to an underestimation of antidepressant efficacy.
“…Thus, it is possible that mice are more sensitive to the anergic effects of fluoxetine (Table 2), and much less to its appetite suppressant effects. Moreover, although previous clinical studies have shown how this SERT blocker decreases appetite (Silverstone, 1992;Michelson et al, 1999), a recent metanalysis study (Serralde-Zúñiga et al, 2019) comparing different categories of anti-obesity drugs indicates that, unlike other drugs, fluoxetine treatment does not conclusively decrease weight, but there is a clear increase in the risk for drowsiness and fatigue. In addition, unlike TBZ alone, mice treated with 20.0 mg/kg of fluoxetine showed avoidance for the RW in general; not only they spent significantly less time running, in addition, they also reduced the total number of entries into the RW compartment, an effect that was not observed for the other compartments.…”
Impaired behavioral activation and effort-related motivational dysfunctions like fatigue and anergia are debilitating treatment-resistant symptoms of depression. Depressed people show a bias towards the selection of low effort activities. To determine if the broadly used antidepressant fluoxetine can improve behavioral activation and reverse dopamine (DA) depletion-induced anergia, male CD1 mice were evaluated for vigorous escape behaviors in an aversive context (forced swim test, FST), and also with an exercise preference choice task [running wheel (RW)-T-maze choice task]. In the FST, fluoxetine increased active behaviors (swimming, climbing) while reducing passive ones (immobility). However, fluoxetine was not effective at reducing anergia induced by the DA-depleting agent tetrabenazine, further decreasing vigorous climbing and increasing immobility. In the T-maze, fluoxetine alone produced the same pattern of effects as tetrabenazine. Moreover, fluoxetine did not reverse tetrabenazine-induced suppression of RW time but it reduced sucrose intake duration. This pattern of effects produced by fluoxetine in DA-depleted mice was dissimilar from devaluing food reinforcement by pre-feeding or making the food bitter since in both cases sucrose intake time was reduced but animals compensated by increasing time in the RW. Thus, fluoxetine improved escape in an aversive context but decreased relative preference for active reinforcement. Moreover, fluoxetine did not reverse the anergic effects of DA depletion. These results have implications for the use of fluoxetine for treating motivational symptoms such as anergia in depressed patients.
“…The response to the three compounds suggests that the C. elegans Nile red assay has a certain degree of translatability to mammals as all three tested pharmacological agents are known to modulate mammalian fat similar, i.e. olanzapine is known to exacerbate hyperlipidemia and type-2 diabetes and induce fat accumulation in humans 61 – 63 ; the serotonin reuptake inhibitor fluoxetine is known to lead to weight reduction in obese patients 64 and the investigational drug and AMPK activator AICAR blocked high-fat diet induced body weight gain in mice 65 . Figure 4 Effects of drugs on Nile red fluorescence of SS104 C. elegans .…”
In this study a robust, whole organism screening based on Caenorhabditis elegans is presented for the discovery of natural products (NP) with beneficial effects against obesity and age-related diseases. Several parameters of the elaborated workflow were optimized to be adapted for probing multicomponent mixtures combining knowledge from traditional medicine and np chemistry by generating optimized small-scale extracts considering scarcity of the natural source, solubility issues, and potential assay interferences. The established miniaturized assay protocol allows for in vivo probing of small amounts of even complex samples (~ 1 mg) to test their ability to increase the nematodes' survival time and the suppression of fat accumulation assessed by nile red staining as hall marks of "healthy aging". The workflow was applied on 24 herbal and fungal materials traditionally used against symptoms of the metabolic syndrome and revealed promising results for the extracts of Gardenia jasminoides fruits and the sclerotia from Inonotus obliquus. Tested at 100 µg/mL they were able to significantly reduce the Nile red fluorescence and extend the 50% survival rate (DT 50) compared to the control groups. This phenotype-directed in vivo approach opens up new horizons for the selection of natural starting materials and the investigation of their active principles as fast drug discovery tool with predictive value for human diseases. Caenorhabditis elegans (Maupas, 1900), a 1 mm sized roundworm, is a popular model organism in almost all areas of modern biology. It can be maintained at low cost, has a short reproductive cycle of three days with a large brood size of 300 progenies per hermaphrodite worm and a transparent body comprising exactly 959 somatic cells 1. In recent years it has been increasingly used as a model organism for drug screenings 2-7. The fundamental idea behind is that basic molecular processes which are causal for the development of diseases including aging processes are conserved in the animal kingdom. Indeed C. elegans shares many similarities with humans such as autophagy, mitochondrial regulation, apoptosis, proteostasis, energy control, fat-storage, stress response systems and neuronal regeneration 8-16. A recent meta-analysis estimated that 41.7% of the protein-coding genes in C. elegans have orthologs in humans 17. In this light, screening for substances beneficial to a disease phenotype in C. elegans can have important predictive value also for human diseases 18, 19. The simplicity and tractability of the worm compared to classical mammal models represents a large advantage. Its small size makes it amenable to whole organism screening in microtiter plates for medium/high-throughput screening with little consumption of materials and sample 20. This possibility is particularly helpful for drug discovery from natural sources, which is often impeded by scarcity of natural starting materials, and even more relevant for their isolates which require tedious isolation or synthesizing efforts 21-24. There is an in...
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