Author: Mark Agius
Position: Associate Specialist
Institution: Bedford Hospital
E-mail: ma393@cam.ac.uk
Submitted Date: March 18, 2008
Published Date: March 25, 2008
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

Kirsch et al reported that their metanalysis suggests that drug–placebo differences in antidepressant efficacy are relatively small even for severely depressed patients..
They have based their arguments on their recovery from the FDA of studies which not previously reported. It is right that all studies used by regulatory authorities should be published, but many of the studies quoted are only of three months duration.
The FDA’s purpose in establishing safety and some efficacy may well be served by three month studies. However such studies are inappropriate for the establishment of the efficacy of a treatment of depression. It is known that, an appropriate duration of treatment for patients with depression is considered to be at least six months.
Kirsch has quoted the NICE as requiring a three point improvement in antidepressant efficacy in order to prove appropriate efficacy of antidepressants. He has criticised the FDA for only accepting a one point improvement, but this may be appropriate for the purposes of the FDA.
Furthermore, Kirsch has chosen to study four different antidepressants, belonging to three separate groups, which are known to have different modes of action and potency.
These drugs are fluoxetine, venlafaxine, nefazodone, paroxetine. Sertraline, and citalopram were excluded from the study. This means that two of the most commonly used SSRIs have been excluded from the study. Whether the present study can as a consequence be extrapolated to these drugs or to SSRIs as a class must remain a matter of discussion.
Nefazodone and Venlafaxine belong to two classes of anti- depressants both different from SSRIs. Thus it is questionable whether these four drugs can be seen as representing either SSRIs as a whole or all antidepressants as a class.
It is worth considering that in the NICE assessment of the antidepressant efficacy of SSRIs as opposed to Placebo , sixteen of the studies considered by NICE were of a duration of between 8 and 24 weeks.
While NICE is unable to prove that SSRIs are better than placebo in achieving remission of depression , NICE can show that a 50% reduction in depression symptoms within the limits of the trials which they studied.
It is worth remembering that we now have a clear knowledge of how SSRIs work, both at the level of inhibition of the Serotonin Reuptake Transporter and at the level of supporting Hippocampal Neogenesis.
We are also aware of the fact that the halting of the prescription of SSRIs to adolescents has led to an increase in the incidence of suicide in this age group. It thus seems that SSRIs do have an effect on depression and suicidality at least at a population level.
Under these circumstances, we suggest that while the metanalysis by Kirsch is insufficient evidence in itself to warrant a change in our present policies and guidelines for the treatment of depression.
References
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, etal. (2008) Initial severity and antidepressant benefits: A metaanalysis of data submitted to the Food and Drug Administration. PLoS Med 5(2): e45. doi:10.1371/journal.pmed.0050045

Depression:Management of depression in primary and secondary care [2004]
National Clinical Practice Guideline Number 23 NICE

Gibbons RD et al Early evidenceon the effects of regulators’ suicidalitywarnings on SSRI prescriptionsand suicide in children and adolescents. Am J Psychiatry2007;164;1356-63.