Modifiers in Effects of Combined Pharmacotherapy and Psychotherapy versus Pharmacotherapy Alone for Adult Depression: An Individual Participant Data Meta-Analysis

Introduction: It is not clear which individual-patient- and study-level variables modify the effects in the comparison of combined treatment versus pharmacotherapy alone for adult depression. Methods: Randomized trials comparing combined treatment with pharmacotherapy alone were identified on September 1, 2024, and individual participant data (IPD) requested from the authors. One-stage IPD meta-analyses were conducted to estimate effects on depressive symptoms at posttreatment and follow-up, response, remission, and reliable improvement and to assess effect modifiers. Results: Of 75 eligible studies, 31 (41.33%) provided their IPD (3,703 participants). Combined treatment was more effective in reducing depressive symptoms at posttreatment (SMD = 0.45, 95% confidence interval [95% CI]: 0.27-0.64), 6- (SMD = 0.55, 95% CI: 0.25-0.85) and 12-month follow-up (SMD = 0.22, 95% CI: 0.02-0.43). The effect size was smaller in studies that provided IPD than in those that did not. No patient-level effect modifiers were identified. No difference between the two arms was found in studies using SSRIs (as opposed to other antidepressants) and recruiting specific target groups (versus unselected adult populations), and the difference between combined treatment and pharmacotherapy alone was larger if pharmacotherapy was not administered adequately, but these findings were not confirmed in sensitivity analyses. Several patient-level characteristics predicted higher depressive symptoms at posttreatment, regardless of treatment condition. Conclusion: Combined treatment outperforms pharmacotherapy alone regardless of individual characteristics. Thus, its delivery does not have to be limited to specific patient subgroups. However, IPD were available for only 41% of eligible studies, thus limiting this sample's representativeness. Plain Language Summary Providing combined treatments to adults with depression who will likely benefit from them may increase effectiveness, but we also need to prevent wasting resources if patients do not need intensive treatments to get better. To understand which treatment works better for whom, we need to know baseline socio-demographic or clinical characteristics which make patients more likely to benefit from one treatment or another, so-called effect modifiers. However, effect modifiers are not known for the comparison between combined psychotherapy and pharmacotherapy, and pharmacotherapy alone. Therefore, we conducted an individual participant data meta-analysis, meaning statistical integration of data of specific participants, coming from 31 previous studies, to identify these effect modifiers. Combined treatment was more effective than pharmacotherapy alone, and this was regardless of any socio-demographic or clinical characteristics, such as gender, age, education, ethnicity, severity, or comorbidity. The only lack of difference was found in studies which used selective serotonin reuptake inhibitors as their antidepressant medication, or those which were conducted in specific subgroups, such as patients with comorbidities. If pharmacotherapy was delivered according to treatment guidelines, the difference between pharmacotherapy alone and combined treatment was smaller. Yet, these findings were not confirmed in subsequent analyses. In addition, several characteristics related to severity and comorbidity, and unemployment, were associated with higher depressive symptoms after treatment, no matter which treatment the participant received. Combined treatment is the best treatment option for depression.Adequately taken pharmacotherapy might decrease the need of additional psychotherapy if psychotherapy is unavailable or not according to patient's wishes.