What Is the Minimum Clinically Important Change in Negative Symptoms of Schizophrenia? PANSS Based Post-hoc Analyses of a Phase III Clinical Trial

Abstract

Introduction: Minimum clinically important difference (MCID) is a measure that defines the minimum amount of change in an objective score of a clinical test that must be reached for that change to be clinically noticeable. We aimed to find the MCID for patients with predominantly negative symptoms of schizophrenia at its earliest occurrence.

Methods: Data of a 26-week long, double-blind study with 454 patients [Positive and Negative Symptom Scale Negative Factor Score (PANSS-FSNS) ≥24, Positive and Negative Symptom Scale Positive Factor Score (PANSS-FSPS) ≤ 19] treated with cariprazine 4.5 mg/d or risperidone 4 mg/d were analyzed. The Clinical Global Impression-Improvement scale was used to quantify minimum improvement (CGI-I = 3) and no clinical change (CGI-I = 4) on the PANSS-FSNS, and the MCID was estimated with the following methods: as the mean PANSS-FSNS changes corresponding to the first instance of minimal improvement across all visits (MCID₁); as the difference between the PANSS-FSNS change associated with the first instance and the PANSS-FSNS changes associated with the last recorded clinically unchanged status across all visits (MCID₂); with the effect size approach (MCID₃); as the Youden Index based cut-off value between no clinical change and minimal improvement (MCID₄); as the relative likelihood of minimal improvement (MCID₅).

Results: The MCID₁ and MCID₂ resulted in, respectively, a 3.8-point (18.5%) and a 1.5-point (7.3%) decrease from baseline severity on the PANSS-FSNS. Greater values were required for the MCID at later evaluation times. The cut-off between minimum improvement and no clinical change defined by the Youden Index was a-3-point (15%) change in the PANSS-FSNS. The effect size approach indicated the 1.5-point difference between minimally improved and unchanged patients to be a medium effect (ES = 0.6).

Conclusion: Applying different methods led to different results, ranging between 7.3 and 18.5% improvement from the baseline for the MCID at its earliest occurrence in patients with predominantly negative symptoms of schizophrenia.

Keywords: MCID; cariprazine; clinical trial; minimum clinically important difference; negative symptoms; schizophrenia.

Figure 1

Change from baseline in PANSS-FSNS (Positive- and Negative Syndrome Scale—Factor Score for Negative Symptoms) as a function of minimal change vs. no change.

Figure 2

Receiver Operating Characteristic (ROC) curve: predictive accuracy of the PANSS-FSNS (Positive and Negative Syndrome Scale Factor Score for Negative Symptoms) scale for differentiating minimally improved vs. clinically unchanged status. The values on the vertical and horizontal axis, respectively, depict the sensitivity (“true positive rate”) and 1− specificity (“false positive rate”) values for the differentiation as a function of change from baseline in the PANSS-FSNS scale. The leftmost part of the ROC curve represents the highest empirically observed improvements in the sample as compared to baseline while the rightmost part represents no improvement (or even deterioration). Please note that the ROC curve for differentiating the minimally improved from the clinically unchanged status based on the PANSS-FSNS (ROC model, depicted in blue in the figure) significantly outperforms the random classification (ROC1 model, in red), with an area under the curve (AUC, labeled as “Area”) value of 0.7232 vs. 0.5000 (p < 0.0001).

Figure 3

Cut-off values (Youden's indices) for predicting improvement from no clinical change to minimal improvement. To differentiate minimal improvement from no clinical change, Youden's J indices were computed at different cut-off points based on the PANSS-FSNS change. The sensitivity (vertical axis) and 1- specificity (horizontal axis) values for the differentiation of minimal improvement from no clinical change are depicted in the figure for various values of change from baseline in the PANSS-FSNS (labeled as “Cutoff”). Please note that the Youden's J index, which shows the efficiency of differentiation based on the combination of sensitivity and specificity, first increases then decreases with increasingly greater improvements (i.e., with greater negative values) as compared to baseline. The highest value of the Youden's J Index is reached at the cut-off value of −3 (i.e., at a 3 point reduction of symptom severity from baseline in the PANSS-FSNS), which identifies the optimal change value that maximizes sensitivity and specificity simultaneously.