Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials: a systematic review and meta-analysis.
BACKGROUND
Biases in adverse effect reporting in randomized controlled trials (RCTs) [e.g. due to investigator expectations or assessment quality] can be quantified by studying the rates of adverse events reported in the placebo arms of such trials.


OBJECTIVE
We compared the rates of adverse effects reported in the placebo arms of tricyclic antidepressant (TCA) trials and placebo arms of selective serotonin reuptake inhibitor (SSRI) trials.


METHODS
We conducted a literature search for RCTs across PUBMED, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL). Only studies allowing adverse effect analysis were included. Publication year ranged from 1981 to 2007.


RESULTS
Our systematic review and meta-analysis included 143 placebocontrolled RCTs and data from 12,742 patients. Only 21% of studies used structured and systematic adverse effect ascertainment strategies. The way in which trials recorded adverse events influenced the rate of adverse effects substantially. Systematic assessment led to higher rates than less systematic assessment. Far more adverse effects were reported in TCA-placebo groups compared with SSRI-placebo groups, e.g. dry mouth (odds ratio [OR] = 3.5; 95% CI 2.9, 4.2); drowsiness (OR = 2.7; 95%CI 2.2, 3.4); constipation (OR= 2.7; 95%CI 2.1, 3.6); sexual problems (OR =2.3; 95%CI 1.5, 3.5). Regression analyses controlling for various influencing factors confirmed the results.


CONCLUSIONS
Adverse effect profiles reported in clinical trials are strongly influenced by expectations from investigators and patients. This difference cannot be attributed to ascertainment methods. Adverse effect patterns of the drug group are closely related to adverse effects of the placebo group. These results question the validity of the assumption that adverse effects in placebo groups reflect the 'drug-unspecific effects'.
Rief
Winfried
W
Department of Clinical Psychology and Psychotherapy, Philipps University, Marburg, Germany. rief@staff.uni-marburg.de
Nestoriuc
Yvonne
Y
von Lilienfeld-Toal
Anna
A
Dogan
Imis
I
Schreiber
Franziska
F
Hofmann
Stefan G
SG
Barsky
Arthur J
AJ
Avorn
Jerry
J
D018687:Antidepressive Agents, Second-Generation / Q000009:adverse effects*; D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects*; D015982:Bias; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000592:standards; D012044:Regression Analysis; D012108:Research Personnel / Q000523:psychology; D035842:Research Subjects / Q000523:psychology; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects*
D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D017367:Selective Serotonin Reuptake Inhibitors