Is Really Crocus Sativus as Effective as Citalopram in the Treatment of Depression?

Sir,

Recently you published a comparison of crocus sativus vs. citalopram [1]. This paper concludes that crocus is as effective as citalopram in the treatment of mild to moderate depression. Unfortunately there is a number of important issues with this study.

First, in the title the term ‘controlled’ is used. This is misleading. The study is not controlled with anything, it is simply a head to head comparison. Then, the inclusion criteria demand a HAM-D below 19. This means that the patients were mainly mildly depressed, since the cut-off score between mild and moderate is 17 and between moderate and severe is 24 [2]. In patients with significant anxiety and that low HAM-D score, not only the severity but also the very presence of major depression is questionable, after taking into consideration the item composition of the HAM-D.

The study is probably underpowered, since the calculation it is based on a 3-point difference in HAM-D change, which is a clinically meaningful difference according to an old and abandoned NICE concept, but highly unlikely it can be found even between antidepressants vs. placebo in this kind of study sample. At this HAM-D severity level, the target difference should not had been more than 1 HAM-D point and subsequently the appropriate sample size is seven times higher (400 patients). Then there would had been a significant difference even at week 4, while with a smaller sample size of five times higher (300 patients) there would have been a difference at endpoint in favor of citalopram.

The primary outcome is very vague, not in accord with modern methodology, and what is more important is that according to the results it is negative. Then the authors start over-analyzing the data in a post hoc way and come up with misleading conclusions.

It is interesting to see the standardized mean differences (SMD) since they can give us an idea whether the outcome is in the active drug or in the placebo area [3]. For citalopram and crocus the change from baseline is 2.17±2.63 vs. 1.83±3.70, p=0.689 and SMD 0.82 and 0.49 for week 2 and for week 4 the respected values were 5.97±3.42 vs. 5.07±5.11, p=0.689 and SMD equal to 1.74 and 0.99 respectively. At week 6 the change is 11.27±3.67 vs. 10.13±5.96, p=0.380, with SMD 3.07 and 1.69. These results are clearly in the placebo area of outcomes, for the crocus at all time points and for citalopram at week 2

On the basis of the above, and especially on the basis of the negative primary outcome (no change from baseline, no difference between arms) the study should be considered to be a failed study, with problematic design and misleading conclusions. This is especially important since the overwhelming majority of studies concerning crocus comes from a single country and suggest it is efficacious in a variety of unrelated disorders, from dyspepsia and erectile dysfunction to metabolic syndrome and coagulation.

• References

• 1 Ghajar A, Neishabouri SM, Velayati N. et al. Crocus sativus L. versus Citalopram in the treatment of major depressive disorder with anxious distress: A double-blind, controlled clinical trial. Pharmacopsychiatry 2016; DOI: 10.1055/s-0042-116159.
• 2 Zimmerman M, Martinez JH, Young D. et al. Severity classification on the hamilton depression rating scale. Journal of affective disorders 2013; 150: 384-388
• 3 Fountoulakis KN, Veroniki AA, Siamouli M. et al. No role for initial severity on the efficacy of antidepressants: Results of a multi-meta-analysis. Annals of general psychiatry 2013; 12: 26