Fredrik Hieronymus

Consistent superiority of selective serotonin reuptake inhibitors over placebo in reducing depressed mood in patients with major depression

The recent questioning of the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) is partly based on the observation that approximately half of company-sponsored trials have failed to reveal a significant difference between active drug and placebo. Most of these have applied the Hamilton depression rating scale to assess symptom severity, the sum score for its 17 items (HDRS-17-sum) serving as effect parameter. In this study, we examined whether the negative outcomes of many SSRI trials may be partly caused by the use of this frequently questioned measure of response. We undertook patient-level post-hoc analyses of 18 industry-sponsored placebo-controlled trials regarding paroxetine, citalopram, sertraline or fluoxetine, and including in total 6669 adults with major depression, the aim being to assess what the outcome would have been if the single item depressed mood (rated 0–4) had been used as a measure of efficacy. In total, 32 drug-placebo comparisons were reassessed. While 18 out of 32 comparisons (56%) failed to separate active drug from placebo at week 6 with respect to reduction in HDRS-17-sum, only 3 out of 32 comparisons (9%) were negative when depressed mood was used as an effect parameter (P<0.001). The observation that 29 out of 32 comparisons detected an antidepressant signal from the tested SSRI suggests the effect of these drugs to be more consistent across trials than previously assumed. Further, the frequent use of the HDRS-17-sum as an effect parameter may have distorted the current view on the usefulness of SSRIs and hampered the development of novel antidepressants.

A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors.

The possible dose-dependency for the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) remains controversial. We believe we have conducted the first comprehensive patient-level mega-analysis exploring this issue, one incentive being to address the possibility that inclusion of low-dose arms in previous meta-analyses may have caused an underestimation of the efficacy of these drugs. All company-sponsored, acute-phase, placebo-controlled, fixed-dose trials using the Hamilton Depression Rating Scale (HDRS) and conducted to evaluate the effect of citalopram, paroxetine or sertraline in adult major depression were included (11 trials, n=2859 patients). The single-item depressed mood, which has proven a more sensitive measure to detect an antidepressant signal than the sum score of all HDRS items, was designated the primary effect parameter. Doses below or at the lower end of the usually recommended dose range (citalopram: 10–20 mg, paroxetine: 10 mg; sertraline: 50 mg) were superior to placebo but inferior to higher doses, hence confirming a dose-dependency to be at hand. In contrast, among doses above these, there was no indication of a dose–response relationship. The effect size (ES) after exclusion of suboptimal doses was of a more respectable magnitude (0.5) than that usually attributed to the antidepressant effect of the SSRIs. In conclusion, the observation that low doses are less effective than higher ones challenges the oft-cited view that the effect of the SSRIs is not dose-dependent and hence not caused by a specific, pharmacological antidepressant action. Moreover, we suggest that inclusion of suboptimal doses in previous meta-analyses has led to an underestimation of the efficacy of these drugs.

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

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 placebo-controlled 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.

Incidence of early anxiety aggravation in trials of selective serotonin reuptake inhibitors in depression

Selective serotonin reuptake inhibitors (SSRIs) may aggravate anxiety and agitation during the first days of treatment but the frequency of such reactions remains unknown.

The alleged ineffectiveness of SSRIs in depression is an artefact caused by the use of an inappropriate measure of efficacy

Objective: Many studies have questioned if summation of the scores of the 17 disparate items constituting the Hamilton Depression Rating Scale (HDRS-17) is a reliable index of severity in depression; yet the cur- rent questioning of the ef fi cacy of antidepressant drugs is to a large extent based on the assumption that response to treatment is reliably re fl ected by this instrument. We aimed to investigate the possibility that the shortcom- ings of the HDRS may contribute to the failure of antidepressants to out- perform placebo in many trials. Methods: We analyzed thirteen industry-sponsored trials of selective serotonin reuptake inhibitors (SSRIs) comprising twenty-four drug- placebo comparisons and including patient-level data from 5381 subjects (administered paroxetine, citalopram, fl uoxetine, or placebo), the aim being to assess what the outcome would have been if the single item de- pressed mood (rated 0 – 4) had been used as measure of ef fi cacy. Results: While 12 out of 24 comparisons (50%) revealed a signi fi cant difference between active drug and placebo at week 6 with respect to re- duction in HDRS-17-sum, 23 out of 24 comparisons (96%) showed the ac- tive drug to be superior to placebo in reducing depressed mood. Correspondingly, a pooled analysis of all cases showed the effect size when assessed using the HDRS-17-sum to be 0.30, whereas it, when mea- sured using the depressed mood item alone, was 0.42. Conclusion: While not claiming that measuring one item only is the most appropriate way of recording symptom severity in depression, we do suggest that the inclusion of a number of varying symptoms in the as- sessment, some of which may be side-effects of treatment and/or are unre- lated to the disorder, reduces the sensitivity to detect a difference between active drug and placebo. This lack of sensitivity of HDRS-17 might partly explain why a high fraction of antidepressant trials fail to reveal a signi fi - cant difference between treatment groupsAbstracts from the 29th CINP World Congress of Neuropsychopharmacology, Vancouver, Canada, 22-26 June 2014. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication Details Han, M., Huang, X. -F. & Zhang, X. Y. (2014). The differences of cognitive deficits in chronic schizophrenia on long-term treatment with typical and atypical antipsychotics. International Journal of Neuropsychopharmacology, 17 (Suppl. 1), 105-105. This journal article is available at Research Online: http://ro.uow.edu.au/smhpapers/2258 P-25-019 The differences of cognitive deficits in chronic schizophrenia on long-term treatment with typical and atypical antipsychotics M. Han, X.-F. Huang, X. Y. Zhang. University of Wollongong, Wollongong, Australia; University of Wollongong, Schizophrenia Research Institute, Wollongong, Australia; Baylor College of Medicine, Beijing HuiLongGuan Hospital, Houston, USA Objective: Cognitive deficits have been presented in the prior to the onset of other symptoms of schizophrenia and generally persisted during the course of the disease. Whether cognitive function is affects by antipsychotic treatment during the course of schizophrenia is still debated. This study aimed to examine the effect of long-term treatment of antipsychotic drugs on cognitive function in patients with chronic schizophrenia. Methods: The study assessed cognitive function in 395 healthy controls and 438 patients with chronic schizophrenia on long-term treatments with antipsychotics, including mainly monotherapy with clozapine (n=224), risperidone (n=99) and typical antipsychotics (n=115). Results: Cognitive test scores were significantly lower in all patient groups than healthy controls on all scales (all p<0.001) except for visuospitial/constructional index. Clozapine treatment had significantly lower immediate memory and delayed memory than typical antipsychotics (all p<0.01). Clozapine treatment had better language index than risperidone (p<0.01). Conclusion: Patients with chronic schizophrenia performed significant cognitive deficits than healthy controls in all examined cognitive domains except for the visuospitial/constructional index. Cognitive deficits in patients with chronic schizophrenia were significantly influenced by different type’s antipsychotics treatment. Clozapine treatment had worse immediate memory and delayed memory than typical antipsychotics, and better language performance than risperidone. Policy of full disclosure: None. 105

Effects of selective serotonin reuptake inhibitors on rating-scale-assessed suicidality in adults with depression

BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) have been claimed to elicit or aggravate suicidal ideation. Aims To explore the effect of SSRIs on the suicidality item of the Hamilton Rating Scale for Depression (HRSD). METHOD We undertook a patient-level mega-analysis of adults with depression participating in industry-sponsored studies of sertraline, paroxetine or citalopram, comparing patients on an SSRI (n = 5681) with those on placebo (n = 2581) with respect to HRSD-rated suicidality. Separate analyses were conducted for young adults (age 18-24; n = 537) and adults (age ≥25; n = 7725). RESULTS Among adults, the reduction in mean rating of suicidality was larger and the risk for aggravation of suicidality lower in patients receiving an SSRI from week 1 and onwards. In young adults, SSRI treatment neither reduced nor increased suicidality ratings relative to placebo at the end-point. CONCLUSIONS 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 speakers fees from Servier. E.E. has previously been on the advisory boards and/or received speakers honoraria and/or research grants from Eli Lilly, GlaxoSmithKline, Servier and Lundbeck.

Katakam and co-workers have not shown SSRIs to be harmful and ineffective and should stop claiming that they have

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.