| 1. |
- Hagsäter, S Melker, et al.
(author)
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A Complex Impact of Systemically Administered 5-HT2A Receptor Ligands on Conditioned Fear
- 2021
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In: International Journal of Neuropsychopharmacology. - : Oxford University Press (OUP). - 1461-1457 .- 1469-5111. ; 24:9, s. 749-757
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Journal article (peer-reviewed)abstract
- Background: Though drugs binding to serotonergic 5-HT2A receptors have long been claimed to influence human anxiety, it remains unclear if this receptor subtype is best described as anxiety promoting or anxiety dampening. Whereas conditioned fear expressed as freezing in rats is modified by application of 5-HT2A-acting drugs locally into different brain regions, reports on the effect of systemic administration of 5-HT2A receptor agonists and 5-HT2A antagonists or inverse agonists on this behavior remain sparse. Methods: We assessed the possible impact of systemic administration of 5-HT2A receptor agonists, 5-HT2A receptor inverse agonists, and a selective serotonin reuptake inhibitor (SSRI)-per se or in combination-on the freezing displayed by male rats when re-exposed to a conditioning chamber in which they received foot shocks 7 days earlier. Results: The 5-HT2A receptor agonists psilocybin and 25CN-NBOH induced a reduction in conditioned fear that was countered by pretreatment with 5-HT2A receptor inverse agonist MDL 100907. While both MDL 100907 and another 5-HT2A receptor inverse agonist, pimavanserin, failed to impact freezing per se, both compounds unmasked a robust fear-reducing effect of an SSRI, escitalopram, which by itself exerted no such effect. Conclusions: The results indicate that 5-HT2A receptor activation is not a prerequisite for normal conditioned freezing in rats but that this receptor subtype, when selectively over-activated prior to expression, exerts a marked fear-reducing influence. However, in the presence of an SSRI, the 5-HT2A receptor, on the contrary, appears to counter an anti-freezing effect of the enhanced extracellular serotonin levels following reuptake inhibition.
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| 2. |
- Hieronymus, F., et al.
(author)
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Determining maximal achievable effect sizes of antidepressant therapies in placebo-controlled trials
- 2021
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In: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 144:3, s. 300-309
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Journal article (peer-reviewed)abstract
- Objective Antidepressants outperform placebo with an effect size of around 0.30. It has been suggested that effect sizes as high as 0.875 are necessary for a minimal clinically important difference. Whether such effect sizes are achievable in placebo-controlled trials is unknown. Therefore, we aimed to assess what effect sizes are theoretically achievable in placebo-controlled trials of antidepressants. Methods Patient-level analyses comparing Hamilton Depression Rating Scale (HDRS-17) outcomes for simulated antidepressant therapies to placebo-treated participants (n = 2201) from clinical trials of selective serotonin reuptake inhibitors. Results An optimally effective antidepressant, where all treated participants achieve HDRS-17 scores comparable to those displayed by healthy volunteers (remission-type model), had a maximum effect size of 1.75, with a mean difference of 11.6 points on the HDRS-17. In simulations where patients received an additional 50% symptom reduction over that obtained with placebo (improvement-type model), the maximum effect size was 1.08 with a mean HDRS-17 difference of 7.2. When adjusting for normal rates of treatment discontinuation, maximum effect sizes were 1.10 (remission-type model) and 0.76 (improvement-type model) with HDRS-17 mean differences of 8.8 and 5.6, respectively. Conclusions Three methodological issues (i) a large and variable placebo response, (ii) a high rate of dropout and (iii) HDRS-17-ratings significantly larger than zero in healthy volunteers, reduce the degree of treatment-placebo separation achievable in depression trials. Assuming that those who discontinue treatment have only partial response, even a highly effective antidepressant would have difficulties surpassing such effect size cut-offs as have been suggested to signify a minimal clinically important difference.
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| 3. |
- Hieronymus, Fredrik, 1986, et al.
(author)
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GOOD NEWS REGARDING SSRI SAFETY IN DANISH META-ANALYSIS.
- 2020
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In: Acta neuropsychiatrica. - : Cambridge University Press (CUP). - 1601-5215 .- 0924-2708. ; 32:1, s. 54-56
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Journal article (peer-reviewed)abstract
- In two previous letters on an SSRI meta-analysis conducted by the Copenhagen Trial Unit at Copenhagen University Hospital, we have commented on a large number of errors, almost all of which have tilted the results in an anti-drug direction, that unfortunately mar this publication. While the authors have acknowledged many of these mishaps, and may now be expected to submit an extensive errata list to the journal where their paper was once published, we regretfully note that also their latest contribution to this exchange is surprisingly inaccurate. However, its many shortcomings notwithstanding, their meta-analysis does add to the current literature by confirming that SSRIs do not seem to enhance the risk for suicide or death, and also that these drugs seem to enhance the risk of side effects categorized as serious only in the elderly.
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| 4. |
- Lisinski, Alexander, 1989, et al.
(author)
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Item-based analysis of the effects of duloxetine in depression: a patient-level post hoc study
- 2020
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In: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X .- 0893-133X. ; 45:3, s. 553-560
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Journal article (peer-reviewed)abstract
- Oft-cited trial-level meta-analyses casting doubt on the usefulness of antidepressants have been based on re-analyses of to what extent the active drug has outperformed placebo in reducing the sum score of the Hamilton Depression Rating Scale (HDRS-17-sum) in clinical trials. Recent studies, however, suggest patient-level analyses of individual HDRS items to be more informative when assessing the efficacy of an antidepressant. To shed further light on both symptom-reducing and symptom-aggravating effects of a serotonin and noradrenaline reuptake inhibitor, duloxetine, when used for major depression in adults, we hence applied this approach to re-analyse data from 13 placebo-controlled trials. In addition, using patient-level data from 28 placebo-controlled trials of selective serotonin reuptake inhibitors (SSRIs), the response profile of duloxetine was compared to that of these drugs. Duloxetine induced a robust reduction in depressed mood that was not dependent on baseline severity and not caused by side-effects breaking the blind. A beneficial effect on depressed mood was at hand already after one week; when outcome was assessed using HDRS-17-sum as effect parameter, this early response was however masked by a concomitant deterioration with respect to adverse event-related items. No support for a suicide-provoking effect of duloxetine was obtained. The response profile of duloxetine was strikingly similar to that of the SSRIs. We conclude that the use of HDRS-17-sum as effect parameter underestimates the true efficacy and masks an early effect of duloxetine on core symptoms of depression. No support for major differences between duloxetine and SSRIs in clinical profile were obtained.
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| 5. |
- Näslund, Jakob, et al.
(author)
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Expression of 22 serotonin-related genes in rat brain after sub-acute serotonin depletion or reuptake inhibition
- 2020
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In: Acta Neuropsychiatrica. - : Cambridge University Press (CUP). - 0924-2708 .- 1601-5215. ; 32:3, s. 159-165
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Journal article (peer-reviewed)abstract
- Objective: Although the assessment of expression of serotonin-related genes in experimental animals has become a common strategy to shed light on variations in brain serotonergic function, it remains largely unknown to what extent the manipulation of serotonin levels causes detectable changes in gene expression. We therefore chose to investigate how sub-acute depletion or elevation of brain serotonin influences the expression of a number of serotonin-related genes in six brain areas. Methods: Male Wistar rats were administered a serotonin synthesis inhibitor, para-chlorophenylalanine (p-CPA), or a serotonin reuptake inhibitor, paroxetine, for 3 days and then sacrificed. The expression of a number of serotonin-related genes in the raphe nuclei, hypothalamus, amygdala, striatum, hippocampus and prefrontal cortex was investigated using real-time quantitative PCR (rt-qPCR). Results: While most of the studied genes were uninfluenced by paroxetine treatment, we could observe a robust downregulation of tryptophan hydroxylase-2 in the brain region where the serotonergic cell bodies reside, that is, the raphe nuclei. p-CPA induced a significant increase in the expression of Htr1b and Htr2a in amygdala and of Htr2c in the striatum and a marked reduction in the expression of Htr6 in prefrontal cortex; it also enhanced the expression of the brain-derived neurotrophic factor (Bdnf) in raphe and hippocampus. Conclusion: With some notable exceptions, the expression of most of the studied genes is left unchanged by short-term modulation of extracellular levels of serotonin.
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