Not All Controls of Psychotherapeutic Interventions for Depression Are Equal

This study compared the control conditions of no psychological treatment, waiting list, psychological placebo, and pill placebo.

According to results of a systematic review and meta-analysis of control conditions implemented in studies of psychotherapeutic interventions, control groups were not equivalent between studies. These findings were published in the Journal of Clinical Epidemiology.

Publication databases were searched through January 1, 2019, for studies of cognitive behavioral interventions, including a control group, for the treatment of depression. A total of 123 studies comprising 12,596 participants were included in this analysis. The control conditions of no psychological treatment (NT), waiting list (WL), psychological placebo (psych-placebo), and pill placebo (pill-placebo) were compared.

Of these studies published between 1977 and 2018, 25.2% had a low risk, 39.8% had a moderate risk, and 35.0% had a high-risk of bias.

Participants had a mean age of 45.4 (range, 18.2-81.9) years, 30.9% were diagnosed with major depression, 21.9% with major and minor depression, 4.9% with subclinical depression, and 0.8% with chronic depression. Interventions included individual (42.3%) or group (41.5%) therapy with cognitive behavioral therapy (36.1%), behavioral activation therapy (7.3%), problem-solving therapy (6.2%), and third wave cognitive behavioral therapies (6.5%).

Control methods included WL (21.9%), NT (12.3%), psych-placebo (6.5%), and pill-placebo (3.1%).

No significant difference was observed among the active interventions.

Compared with WL, pill-placebo (odds ratio [OR], 2.66; 95% CI, 1.45-4.89), psych-placebo (OR, 2.03; 95% CI, 1.21-3.39), and NT (OR, 1.93; 95% CI, 1.30-2.86) were significantly superior.

Although moderate heterogeneity was observed among all studies (I2, 55.9%; 95% CI, 45.9%-64.0%), little heterogeneity was observed among nonpharmacologic interventions (t2, 0.35; 95% CI, 0.005-3.33).

This study may have been limited by publication bias because “negative” results are less likely to be published. The study also could have been limited by the limitations of the original studies.

These data indicated the choice of control condition when designing a study may produce different effect sizes for randomized clinical trials of psychotherapy interventions for depression, in which all controls had higher response compared with WL. The study authors asserted that stronger controls should be used in later phases of clinical trials and that future meta-analyses should not pool all control groups into a single category.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Michopoulos I, Furukawa TA, Noma H, et al. Different control conditions can produce different effect estimates in psychotherapy trials for depression. J Clin Epidemiol. 2020;132:59-70. doi:10.1016/j.jclinepi.2020.12.012