# Genetic Variations Associated with Long-Term Treatment Response in Bipolar Depression
## 3 Results
### Primary Results  
Based on the premise that response to a pharmacological treatment, in terms of efficacy and/or tolerability, may be different when a medication is taken by a patient who carries a genetic polymorphism associated with efficacy, metabolism, and/or side effects, compared with a person with a wild-type genotype, multiple linear regression analysis was used to detect statistically significant associations between the clinical outcome of patients and the putatively predictive variables. Given the high number of drugs per case and the impossibility to assign a unique type of gene-drug interaction to each patient based on the PGx report, the analysis was focused on the effect of individual gene-drug pairs. Specifically, the analysis was conducted on those drugs for which, among patients taking them, there was a minimum of two cases with and without a particular pharmacogenetic variant. The primary clinical outcome (dependent variable) analyzed was the CGI-BP-M score at enrollment. The CGI-BP-M score at the IE of major depression was considered as an independent variable in the statistical models to account for the possible effect of the severity of patients at beginning of the IE. The HDRS-17 score at enrollment and the number of adverse effects were included as secondary dependent variables in this study. Basic descriptive statistics and regression coefficients are shown in Table 3. \begin{table}
\begin{tabular}{c c c c} \hline \hline  & \multicolumn{3}{c}{**Time of Assessment**} \\ \hline
**Variable** & **Onset of the Episode** & **End of the Episode** & **Enrollment Visit** \\ \hline CGI-BP-M, mean \(\pm\) SD & & & \\ Overall & 3.95 \(\pm\) 0.79 & 2.01 \(\pm\) 0.76 & 2.01 \(\pm\) 0.85 \\ Depression & 3.99 \(\pm\) 0.72 & 2.04 \(\pm\) 0.76 & 1.99 \(\pm\) 0.87 \\ Mania & 1.39 \(\pm\) 0.54 & 1.45 \(\pm\) 0.60 & 1.16 \(\pm\) 0.40 \\ HDRS-17, mean \(\pm\) SD & na & na & 7.90 \(\pm\) 6.04 \\ FAST, mean \(\pm\) SD & na & na & 26.99 \(\pm\) 19.04 \\ \hline \hline \end{tabular}  
* CGI-BP-M: Clinical Global Impression for Bipolar Disorder, Modified version; FAST: Functioning Assessment; Short Test; HDRS-17: 17-Item Hamilton Depression Rating Scale; na: Not assessed; SD: Standard Deviation.  
\end{table} 
Table 2: Clinical assessment of the study population. Figure 3: Clinical Global Impression for Bipolar Disorder modified version (CGI-BP-M) average scores (overall, depression and mania subscales) at the beginning of the index episode (IE) of major depression, end of IE, and at enrollment. Pharmacogenetic variables that significantly correlated with the scores in the CGI-BP-M scale at enrollment were a response to SNRs and reduced metabolism of quetiapine (Table 3). The genetically determined response to SNRs--based on the analysis of the _ABCB1_ gene--showed a significant negative correlation with the CGI-BP-M overall score (\(p\)-value \(<\) 0.030) and the depression subscore (\(p\)-value \(<\) 0.026) at enrollment, indicating an association with lower scores in both domains of this scale (Table 3). The response to SNRs was also correlated with lower scores in the HDRS-17 scale at the time of analysis, and with a higher number of adverse effects (\(p\)-value \(<\) 0.024) (Table 3). The variable \"reduced metabolism of quetiapine\"--determined by the presence of _CYP3A4_*22 allele--was identified as a significant predictor of lower scores in the overall CGI-BP-M (\(p\)-value \(<\) 0.038) and the depression subdomain (\(p\)-value \(<\) 0.025) at enrollment. The pharmacogenetic variable lower risk of side effects of risperidone or paliperidone--based on the analysis of an mTOR-related multigenic predictor--was negatively correlated with the number of adverse effects, when including suicidal ideation and mood switch (\(p\) = 0.013)