Efficacy of selective serotonin reuptake inhibitors in the absence of side effects: a mega-analysis of citalopram and paroxetine in adult depression

Abstract

It has been suggested that the superiority of antidepressants over placebo in controlled trials is merely a consequence of side effects enhancing the expectation of improvement by making the patient realize that he/she is not on placebo. We explored this hypothesis in a patient-level post hoc-analysis including all industry-sponsored, Food and Drug Administration-registered placebocontrolled trials of citalopram or paroxetine in adult major depression that used the Hamilton Depression Rating Scale (HDRS) and included a week 6 symptom assessment (n = 15). The primary analyses, which compared completers on active treatment without early adverse events to completers on placebo (with or without adverse events) with respect to reduction in the HDRS depressed mood item showed larger symptom reduction in patients given active treatment, the effect sizes being 0.48 for citalopram and 0.33 for paroxetine. In actively treated subjects reporting early adverse events, who also outperformed those given placebo, the severity of the adverse events did not predict response. Several sensitivity analyses, for example, including (i) those using change of the sum of all HDRS-17 items as effect parameter, (ii) those excluding all subjects with adverse events (that is, also those on placebo) and (iii) those based on the intention-to-treat population, were all in line with the primary analyses. The finding that both paroxetine and citalopram are clearly superior to placebo also when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects.

Serotonin Reuptake Inhibitors and Their Role in Chronic Pain Management

“…Even though widely prescribed, the mechanism of action of SSRIs is not yet fully understood. The traditional theories claim the fact that antidepressant drugs act by influencing certain brain neurotransmitters [15]. Serotonin (5-HT) is one of the neurotransmitters which carry signals between neurons.…”

Efficacy of antidepressants: Ten years of meta-analysis Kirša and associate

“…Deo diskusije posvećuje se činjenici da je u studiji dobijeno da je razlika u poboljšanju između leka i placeba 2.5, znači manje od 3, odnosno to je razlika koju kliničari na CGI skali procenjuju kao "bez promene"! U poslednje dve godine grupa oko Hieronimusa [15,17,20] izašla je u prvi plan u debati objavljujući čak tri meta analize za manje od dve godine. Svaki od ovih radova imao je originalan pristup problemu i ispitivao je pojedina, specifična neodgovorena pitanja koja su postojala.…”

“…Tako blagi, prolazni neželjeni efekti mogu kratkoročno da budu neprijatni za pacijenta, ali dugoročno mu otkrivaju da je dobio aktivnu supstancu i čine ga optimističnijim da će ona delovati na simptome zbog kojih se javio. Upravo s ovim na umu, uradili su mega-analizu koja je uradila post hok analizu upoređujući efikasnost antidepresiva kod pacijenata koji su imali neželjene efekte, kod pacijenata koji ih nisu imali, i kod placeba [20]. Ova analiza nije potvrdila da neželjeni efekti stvaraju bolji odgovor na lek, odnosno pokazala je da je efikasnost leka u RKS nezavisna od pojave neželjenih efekata.…”

SSRIs modulate asymmetric learning from reward and punishment

“…In this study, we tested a hypothesis of an asymmetric effect of serotonergic antidepressants on reinforcement learning that can account for a positive impact on mood. We used computational modelling to assess learning from reward and punishment in a sample of healthy volunteers exposed to week-long treatment with selective serotonin reuptake inhibitors (SSRIs), a first-line antidepressant intervention (Hieronymus et al, 2018). Specifically, we conjectured SSRIs would selectively impact on learning asymmetries, reducing learning from reward, and enhancing learning from punishment, in a manner that results in an accumulation of more positive and less negative surprise, respectively.…”