Edronax (reboxetine) is another crappy antidepressant

Bad news for Pfizer:

Inclusion of previously unpublished data demonstrated that reboxetine (a norepinephrine reuptake inhibitor) is an ineffective and potentially harmful antidepressant. The efficacy of reboxetine was inferior to SSRIs (fluoxetine, paroxetine, and citalopram), and its response rate was not significantly different from placebo.



Eyding D, Lelgemann M, Grouven U, Härter M, Kromp M, Kaiser T, Kerekes MF, Gerken M, Wieseler B. (2010). Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ Oct 12.

Objectives To assess the benefits and harms of reboxetine versus placebo or selective serotonin reuptake inhibitors (SSRIs) in the acute treatment of depression, and to measure the impact of potential publication bias in trials of reboxetine.

Design Systematic review and meta-analysis including unpublished data.

Data sources Bibliographic databases (Medline, Embase, PsycINFO, BIOSIS, and Cochrane Library), clinical trial registries, trial results databases, and regulatory authority websites up until February 2009, as well as unpublished data from the manufacturer of reboxetine (Pfizer, Berlin).

Eligibility criteria Double blind, randomised, controlled trials of acute treatment (six weeks or more) with reboxetine versus placebo or SSRIs in adults with major depression.

Outcome measures Remission and response rates (benefit outcomes), as well as rates of patients with at least one adverse event and withdrawals owing to adverse events (harm outcomes).

Data extraction and data synthesis The procedures for data extraction and assessment of risk of bias were always conducted by one person and checked by another. If feasible, data were pooled by meta-analyses (random effects model). Publication bias was measured by comparing results of published and unpublished trials.

Results We analysed 13 acute treatment trials that were placebo controlled, SSRI controlled, or both, which included 4098 patients. Data on 74% (3033/4098) of these patients were unpublished. In the reboxetine versus placebo comparison, no significant differences in remission rates were shown (odds ratio 1.17, 95% confidence interval 0.91 to 1.51; P=0.216). Substantial heterogeneity (I2=67.3%) was shown in the meta-analysis of the eight trials that investigated response rates for reboxetine versus placebo. A sensitivity analysis that excluded a small inpatient trial showed no significant difference in response rates between patients receiving reboxetine and those receiving placebo (OR 1.24, 95% CI 0.98 to 1.56; P=0.071; I2=42.1%). Reboxetine was inferior to SSRIs (fluoxetine, paroxetine, and citalopram) for remission rates (OR 0.80, 95% CI 0.67 to 0.96; P=0.015) and response rates (OR 0.80, 95% CI 0.67 to 0.95; P=0.01). Reboxetine was inferior to placebo for both harm outcomes (P<0.001 for both), and to fluoxetine for withdrawals owing to adverse events (OR 1.79, 95% CI 1.06 to 3.05; P=0.031). Published data overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm.

Conclusions Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.

New Marc Hauser Paper on Antidepressants and Moral Judgments

Serotonin selectively influences moral judgment and behavior through effects on harm aversion

General Procedure. Participants attended three sessions at Addenbrooke’s Hospital in Cambridge, UK (at least 1 wk apart) and received single doses of atomoxetine (60 mg), citalopram (30 mg), and placebo in a double-blind fully counterbalanced design.

Hauser is 3rd of 4 authors on a new paper in PNAS that administered acute doses of two antidepressants (a norepinephrine reuptake inhibitor and a selective serotonin reuptake inhibitor, respectively) to healthy control participants, then tested them in the Trolley Problem paradigm.


Aversive emotional reactions to real or imagined social harms infuse moral judgment and motivate prosocial behavior. Here, we show that the neurotransmitter serotonin directly alters both moral judgment and behavior through increasing subjects’ aversion to personally harming others. We enhanced serotonin in healthy volunteers with citalopram (a selective serotonin reuptake inhibitor) and contrasted its effects with both a pharmacological control treatment and a placebo on tests of moral judgment and behavior. We measured the drugs’ effects on moral judgment in a set of moral ‘dilemmas’ pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person). Enhancing serotonin made subjects more likely to judge harmful actions as forbidden, but only in cases where harms were emotionally salient. This harm-avoidant bias after citalopram was also evident in behavior during the ultimatum game, in which subjects decide to accept or reject fair or unfair monetary offers from another player. Rejecting unfair offers enforces a fairness norm but also harms the other player financially. Enhancing serotonin made subjects less likely to reject unfair offers. Furthermore, the prosocial effects of citalopram varied as a function of trait empathy. Individuals high in trait empathy showed stronger effects of citalopram on moral judgment and behavior than individuals low in trait empathy. Together, these findings provide unique evidence that serotonin could promote prosocial behavior by enhancing harm aversion, a prosocial sentiment that directly affects both moral judgment and moral behavior.


Molly J. Crockett, Luke Clark, Marc D. Hauser, Trevor W. Robbins (2010). Serotonin selectively influences moral judgment and behavior through effects on harm aversion. Proceedings of the National Academy of Sciences. Published online before print September 27, 2010.

Cymbalta (duloxetine) is a crappy antidepressant

Bad news for Lilly:

Duloxetine offers no advantages in efficacy and is less well-tolerated than SSRIs, TCAs, and even venlafaxine (Effexor), another SNRI.



Schueler Y-B, Koesters M, Wieseler B, Grouven U, Kromp M, Kerekes MF, Kreis J, Kaiser T, Becker T, Weinmann S. (2010). A systematic review of duloxetine and venlafaxine in major depression, including unpublished data. Acta Psychiatrica Scandinavica. DOI: 10.1111/j.1600-0447.2010.01599.x

Objective:  To determine the short-term antidepressant efficacy and tolerability of duloxetine and venlafaxine vs. each other, placebo, selective serotonin reuptake inhibitors (SSRIs), and tri- and tetracyclic antidepressants (TCAs) in adults with major depression.

Method:  Meta-analysis of randomised controlled trials identified through bibliographical databases and other sources, including unpublished manufacturer reports.

Results:  Fifty-four studies including venlafaxine arms (n = 12 816), 14 including duloxetine arms (n = 4528), and two direct comparisons (n = 836) were analysed. Twenty-three studies were previously unpublished. In the meta-analysis, both duloxetine and venlafaxine showed superior efficacy (higher remission and response rates) and inferior tolerability (higher discontinuation rates due to adverse events) to placebo. Venlafaxine had superior efficacy in response rates but inferior tolerability to SSRIs (OR = 1.20, 95% CI 1.07–1.35 and 1.38, 95% CI 1.15–1.66, respectively), and no differences in efficacy and tolerability to TCAs. Duloxetine did not show any advantages over other antidepressants and was less well tolerated than SSRIs and venlafaxine (OR = 1.53, 95% CI 1.10–2.13 and OR 1.79, 95% CI 1.16–2.78, respectively).

Conclusion:  Rather than being a first-line option, venlafaxine appears to be a valid alternative in patients who do not tolerate or respond to SSRIs or TCAs. Duloxetine does not seem to be indicated as a first-line treatment.