Flowchart for the entire experimental procedure.

<p>Summary figure illustrating the sequential steps of experiments and analyses applied in this study, indicating the experimental groups and group sizes for each condition. CORT, corticosterone; QC, quality control.</p

Enrichment of dexamethasone-regulated genes.

<p>Histogram of 100,000 random samples indicates that paroxetine response genes show higher overlap with dex-regulated genes than expected by chance. The overlap between differential microarray probes from paroxetine-response and dex-regulated microarrays is 134 and this threshold is indicated as a vertical red dashed line. In this simulation, on average, 115 probes do overlap by chance and in 70 samples, the random overlap is higher than the tested one. All raw data for Fig 6 are available in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2002690#pbio.2002690.s001" target="_blank">S1 Data</a>. dex, dexamethasone.</p

A 14-day paroxetine treatment significantly reduces depression-like behavior in the FST.

<p>(A) Paroxetine-treated animals showed a reduction in time floating compared to vehicle-treated animals. (B) Paroxetine significantly increased active coping strategies, i.e., time struggling, compared to vehicle-treated animals. (C) Identification of different responder groups according to their performance in the FST. Animals indicated in the red squares are referred as good and poor treatment responders. Animals that showed a very high time floating represent the poor treatment responder, whereas animals that showed a very low time floating represent the good treatment responder. Animals indicated in the dotted-line square represent internal control groups. Animals within the vehicle-treated group served as a vehicle-treated control group. * indicates significant difference between the vehicle-treated control group and the paroxetine-treated group, <i>p</i> < 0.000. All raw data for Fig 3 are available in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2002690#pbio.2002690.s002" target="_blank">S2 Data</a>. FST, forced swim test.</p

Differential gene expression in animals stratified for behavioral treatment response to chronic paroxetine treatment.

<p>(A) Volcano plot showing results from blood samples. The biological effect size (difference in expression) is plotted against statistical significance (as negative log 10 transformed values of the FDR-based <i>q</i>-value). Regarded as significantly regulated, 259 probes with <i>q</i>-values < 0.1 are colored according to their difference in expression. (B) Heat map comparing patterns of differential gene expression in blood and prefrontal cortex. Each row in the plot represents the difference in expression of 1 microarray probe between poor and good responders in both blood and prefrontal cortex. The array probes are ordered according to agglomerative hierarchical clustering, but no large common gene regulation patterns are revealed between the 2 tissues. Scale for color coding difference in expression is identical for (A) and (B). All raw data for Fig 4 are available in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2002690#pbio.2002690.s001" target="_blank">S1 Data</a>. FDR, false discovery rate.</p

Classification features selected from differential gene expression in a mouse model for antidepressant treatment response are informative for treatment response in a human gene expression data set.

<p>Histogram shows the distribution of prediction accuracy over 1,000 simulated classification models that were computed with randomly chosen gene expression probe sets from human gene expression data (median prediction accuracy = 69.77%). The red dashed line marks the observed prediction accuracy (76.74%) when using our informed feature selection to build classifiers. Because only 25 of the randomly chosen feature sets yield equal or better classification results, the predictive ability of our features selected from the presented mouse model is significantly greater than expected by chance (<i>p</i> = 0.026). All raw data for Fig 5 are available in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2002690#pbio.2002690.s001" target="_blank">S1 Data</a>.</p

Murine approach modeling heterogeneity of treatment outcome in the FST.

<p>This figure illustrates the underlying hypothesis: in a large number of animals that are treated with an antidepressant, animals are stratified into subgroups of extremes according to their time-floating behavior. To allow for the distinction of effects truly related to the phenomenon of response (and not treatment per se), a second group of animals is treated with a vehicle under identical conditions. FST, forced swim test.</p