Demographic variables used as predictor variables of treatment outcome were age, education, race, age of onset and depression symptom severity on MADRS. The number, mean and standard deviation of these variables are shown in and were used as covariates in the analyses. The number and percentage of patients with early onset vs. late onset depression (≥ age 60) is also shown in . MMSE scores were included and as shown in , the mean was relatively high—27.7. In addition, the mean and SD for each of the neuropsychological factor scores, the Fazekas score and the vascular risk factor score as defined by the Framingham Study (29
) are shown in . shows the demographic data for the patients who completed at least 8 weeks of the 12 week trial (“completers”) vs. the patients who failed to complete at least 8 weeks (“drop-outs”). Comparing the groups, the variable that was different for drop-outs was final dose of sertraline, which was significantly lower.
Of subjects who completed at least 8 weeks of treatment, compares those with remission of depression vs non-remitters. As shown in , 33% of all subjects achieved remission of depression (≤ 7 on MADRS). The p-values indicate significant differences in variables between subjects who achieved remission (“remitters”) vs. those who did not (“non-remitters”). Interestingly, compared with remitters, the non-remitters had a higher final dose of sertraline, indicating that an attempt had been made to increase the dose to a level that would achieve remission and that the difference in remission was not simply a matter of under- dosing. graphically displays the MADRS scores from baseline to 12 weeks of treatment for the remitters vs non-remitters.
Comparison of Remitters vs Non-Remitters
Figure 2 The MADRS scores over the 12-week course of treatment are plotted separately for subjects who achieved remission of depression and those who did not have remission of depression. All subjects in this analysis remained in the study for at least 8 weeks (more ...)
As shown in , using a Pearson's correlation, the Framingham vascular risk factor scores were statistically significantly correlated with all of the predictor variables except for working memory. In addition, we determined correlations between the categorical Fazekas score (hi vs. low) with neuropsychological factor scores (data not shown). Fazekas scores were statistically significantly correlated with all of the baseline neuropsychological factor scores: executive function (r = -.27, p = .0005); cognitive processing (r = -.27, p = 0.0005); episodic memory (r = -.21, p = 0.004); language (r = -.15, p = 0.047); and working memory (p = 0.003).
Correlations between VRF and Predictor Variables
Next, using mixed models, we examined the effect of our predictor neuropsychological measures, Fazekas scores, VRF and last sertraline dose on the trajectory of treatment response. Of note, there were different numbers of subjects in these analyses due to the different numbers of subjects completing the separate measures. We used three different prediction models for assessing the effect of baseline variables on treatment outcome. We first used a mixed model to assess the impact of predictor variables (cognitive function, Fazekas scores, VRF and last dose of sertraline) on MADRS scores, with time, age, education, age of onset and race as covariates. The following measures produced a statistically significant effect on the MADRS scores (see model 1 in ): episodic memory (p = 0.002); language (p = 0.007); working memory (p = 0.01); processing speed (p = 0.0001); executive function (p = 0.002) and categorical Fazekas score (p = 0.049). In addition higher last dose of sertraline predicted worse outcome, indicating that non-remitters received a higher dose in an attempt to adequately treat their depression.
After controlling for baseline MADRS score (model 2), episodic memory (p = 0.0081), processing speed (p = 0.0006), executive function (p = .01) language (p = .03) scores, VRF scores (p = 0.03) and last dose of sertraline (p = 0.0001) all produced a statistically significant effect on MADRS scores, indicating that these variables predicted higher or lower levels of MADRS scores during the course of treatment. It was actually higher sertraline doses that predicted worse outcome. Fazekas scores and working memory scores did not significantly predict change in MADRS scores once baseline MADRS values were entered into the model.
The predictors reported in were analyzed in separate models (in contrast to conducting a model with all predictors entered at once). As shown in , all neuropsychological factor scores had a negative relationship with MADRS score. Episodic memory, language, working memory, and executive function had a similar relationship in magnitude and direction to MADRS. The relationship between processing speed and MADRS had a larger effect than found with the other neuropsychological predictors. As the neuropsychological factor scores increased (indicating higher function) there was a decrease in the MADRS score. The relationship between total Fazekas categorical score and MADRS was positive, indicating that those with a Fazekas value of at least 3 (more severe WMH) had a larger MADRS score than with a Fazekas value less than 3. As noted above in the statistical methods section, the magnitude for all the predictors of interest (WMH and neuropsychological covariates) did slightly decrease from the model controlling for time only (not shown in ) to the model controlling for time, age, age of onset, race, and education (model 1 in ). When further adjusting for baseline time and baseline MADRS (model 2 in ), the magnitude of the effect for all of the neuropsychological factor scores and WMH decreased even more. This finding makes intuitive sense, since it would be expected that controlling for the baseline outcome value would account for some of the variability in the regression portion of the mixed model. The effect for working memory and total Fazekas categorical score was decreased by almost half when adjusting for baseline time and baseline MADRS, however the standard error remained about the same leading to nonsignificant results.
Neither the neuropsychological factors nor Fazekas scores interacted with time to predict MADRS scores (results not shown), controlling for age, race, education, age of onset, baseline time and baseline MADRS scores. This result indicates that while many of the neuropsychological variables predicted the overall magnitude of MADRS score change, they did not predict the rate of change (slope).
Examining the probability of remission using a Cox proportional hazards model, controlling for age, age of onset, education and race, the factors that predicted the remitter survival were episodic memory (p = 0.006), cognitive processing speed (p = 0.001) executive function (p = 0.01) and language function (p < 0.05) but not working memory or Fazekas scores.