New Antidepressants only better than Placebo in Severe Depression

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients.

This is the conclusion of a meta-analysis of all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. These antidepressants are: include fluoxetine, venlafaxine, nefazodone, paroxetine. The article is published in PloS Medicine and free to read. They specifically tested the influence of depression severity and outcome of these newer antidepressants compared to placebo.

The overall result of the meta-analysis comparing these new antidepressants with placebo confirmed earlier analyzes. Weighted mean improvement was 9.60 points on the HRSD in the drug groups and 7.80 in the placebo groups, yielding a mean drug–placebo difference of 1.80 on HRSD improvement scores. Although the difference between these means easily attained statistical significance it does not meet the three-point drug–placebo criterion for clinical significance used by NICE.

They also found that efficacy reaches clinical significance only in trials involving the most extremely depressed patients, and that this pattern is due to a decrease in the response to placebo rather than an increase in the response to medication.

Now I am not a great fan of these newer antidepressants especially with severe depression. In the past Anderson and others have shown a couple of times in reviews and randomized controlled trials that TCA are significantly better for depressed inpatients.
These inpatients with depression are more likely to be suicidal, psychotically depressed (30%) and suffer from psychiatric and somatic co morbidity. In the review by Anderson the Tricyclic Antidepressants were used in a low average dosage and mostly not plasma controlled. Patients can benefit from plasma level controlled dosing of tricyclic antidepressants. Therapeutic dosage is reached faster, and side-effects due to a high dosage is prevented.

This outcome of this meta-analysis seems to bold to be true, might be the selection of trials?
Kirsch, I., Deacon, B.J., Huedo-Medina, T.B., Scoboria, A., Moore, T.J., Johnson, B.T. (2008). Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Medicine, 5(2), e45. DOI: 10.1371/journal.pmed.0050045
Anderson, I. (2000). Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. Journal of Affective Disorders, 58(1), 19-36. DOI: 10.1016/S0165-0327(99)00092-0
Broek, W., Birkenh�ger, T., Mulder, P., Bruijn, J., Moleman, P. (2004). A double-blind randomized study comparing imipramine with fluvoxamine in depressed inpatients. Psychopharmacology DOI: 10.1007/s00213-004-1853-3
Bruijn, J.A., Moleman, P., Mulder, P.G., van den Broek, W.W., van Hulst, A.M., van der Mast, R.C., van de Wetering, B.J. (1996). A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients. Psychopharmacology, 127(3), 231-237. DOI: 10.1007/s002130050081