Differential power of placebo across major psychiatric disorders: a preliminary meta-analysis and machine learning study

Abstract

The placebo effect across psychiatric disorders is still not well understood. In the present study, we conducted meta-analyses including meta-regression, and machine learning analyses to investigate whether the power of placebo effect depends on the types of psychiatric disorders. We included 108 clinical trials (32,035 participants) investigating pharmacological intervention effects on major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ). We developed measures based on clinical rating scales and Clinical Global Impression scores to compare placebo effects across these disorders. We performed meta-analysis including meta-regression using sample-size weighted bootstrapping techniques, and machine learning analysis to identify the disorder type included in a trial based on the placebo response. Consistently through multiple measures and analyses, we found differential placebo effects across the three disorders, and found lower placebo effect in SCZ compared to mood disorders. The differential placebo effects could also distinguish the condition involved in each trial between SCZ and mood disorders with machine learning. Our study indicates differential placebo effect across MDD, BD, and SCZ, which is important for future neurobiological studies of placebo effects across psychiatric disorders and may lead to potential therapeutic applications of placebo on disorders more responsive to placebo compared to other conditions.

Figure 1

Searching and screening process of clinical trials. MDD major depressive disorder, BD bipolar disorder, SCZ schizophrenia.

Figure 2

Differential placebo effect for MDD, bipolar disorder-depression (BDdep), bipolar disorder-mania (BDman), and SCZ, as measured by $R_{\mathit{clinical}}$, $R_{\mathit{CGI}}$ and $R_{CGIBasline}$. The box size indicates power estimates, a larger box representing a smaller range of confidence interval.

Figure 3

Differential placebo effect for SCZ, BDman, BDdep and MDD, as confirmed by sample-size weighted bootstrapping using (a) the ratio of clinical measurement change from baseline for placebo to intervention, (b) ratio of CGI-S change from baseline for placebo to intervention, and (c) ratio of CGI-S decrease from baseline to the CGI-S value at the baseline for placebo. The placebo effect was always greater than zero, while less than one, meaning patients could not fully recover or achieve improvement comparable to intervention by just taking placebo. The placebo effect for SCZ is significantly lower than that for MDD and BD. *Denotes significant difference from other distributions at P < 0.001.

Figure 4

Confusion matrix of L1 penalized logistic regression classification model based on (a) the original data, and (b) the weighted bootstrapped data. Both results confirmed that we could identify SCZ and mood disorders at the individual-trial level based on the three measures of placebo effect. Mood Disorder consists of MDD, BDdep and BDman, while SCZ denotes Schizophrenia.

Figure 5

The additive model of placebo effect. The observed treatment effect includes the observed placebo effect, while the observed placebo effect includes independent effect (e.g., spontaneous improvement and natural course of the disease). In an additive model, the true treatment effect is the observed treatment effect subtracting the true placebo effect and the independent effect, and the true placebo effect is the observed placebo effect subtracting the independent effect.