According to a systematic review on the use of selective serotonin reuptake inhibitors (SSRIs) in adult depression that was recently published in BMC Psychiatry, the results of which have been widely disseminated in lay media, these drugs increase the risk for serious adverse events (SAEs) while exerting poor antidepressant efficacy. A cursory analysis, however, suggests the analysis of SAEs conducted by the authors to be marred by both methodological inaccuracies and blatant errors. After having corrected for these apparent mistakes, we conducted a sensitivity analysis in which we also accounted for a possible moderating effect of age; while this suggests SSRIs to be safe drugs in the non-elderly, they do confirm what is already known, that is, that they may enhance the risk for SAEs in the old. Given the loose definition of SAE, including also innocuous phenomena, the possible clinical significance of the latter observation, however, remains unclear until the nature and actual impact of the SAEs in question have been clarified. Moreover, with respect to efficacy, we find the paper in BMC Psychiatry misleading: first, the authors seem unaware of the well-established shortcomings associated with the conventional efficacy parameter on which their analysis is based, second, they have included suboptimal SSRI doses and third, they have missed some pivotal trials. Unless there are explanations for the many peculiarities in this paper that have escaped us, and which may be satisfactorily clarified by the authors, it seems important that the conclusions presented in this paper be publicly rectified.
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.
The net effect of SSRIs on suicidality appears beneficial in people above the age of 24 and neutral in those aged 18-24. Declaration of interest F.H. has received speaker's fees from Servier. E.E. has previously been on the advisory boards and/or received speaker's honoraria and/or research grants from Eli Lilly, GlaxoSmithKline, Servier and Lundbeck.
Recent discoveries indicate an important role for ghrelin in drug and alcohol reward and an ability of ghrelin to regulate mesolimbic dopamine activity. The role of dopamine in novelty seeking, and the association between this trait and drug and alcohol abuse, led us to hypothesize that ghrelin may influence novelty seeking behavior. To test this possibility we applied several complementary rodent models of novelty seeking behavior, i.e. inescapable novelty-induced locomotor activity (NILA), novelty-induced place preference and novel object exploration, in rats subjected to acute ghrelin receptor (growth hormone secretagogue receptor; GHSR) stimulation or blockade. Furthermore we assessed the possible association between polymorphisms in the genes encoding ghrelin and GHSR and novelty seeking behavior in humans. The rodent studies indicate an important role for ghrelin in a wide range of novelty seeking behaviors. Ghrelin-injected rats exhibited a higher preference for a novel environment and increased novel object exploration. Conversely, those with GHSR blockade drastically reduced their preference for a novel environment and displayed decreased NILA. Importantly, the mesolimbic ventral tegmental area selective GHSR blockade was sufficient to reduce the NILA response indicating that the mesolimbic GHSRs might play an important role in the observed novelty responses. Moreover, in untreated animals, a striking positive correlation between NILA and sucrose reward behavior was detected. Two GHSR single nucleotide polymorphisms (SNPs), rs2948694 and rs495225, were significantly associated with the personality trait novelty seeking, as assessed using the Temperament and Character Inventory (TCI), in human subjects. This study provides the first evidence for a role of ghrelin in novelty seeking behavior in animals and humans, and also points to an association between food reward and novelty seeking in rodents.
Funded by the Danish state to provide guidance in health-related matters, the Copenhagen Trial Unit (CTU) at Rigshospitalet may cause considerable societal harm if allowing their analyses to be influenced by bias and prejudice rather than rigor and impartiality. This is why we found it worthwhile to comment on a report from the CTU in which the authors invoked analyses marred by numerous errors and methodological mistakes to claim that selective serotonin reuptake inhibitors (SSRIs) are harmful and ineffective. The CTU group has now produced a response to our comment which is on par with their original contribution in terms of bias, misconceptions and mistakes. Our conclusion is that the reputation of the CTU would be best served by the authors asking for retraction of their SSRI paper.
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