Subjects reported mild or no side effects, which did not differ between drug and placebo infusions. There were no remarkable differences in amygdala activation between scans during placebo infusion. There were only two small clusters in the left amygdala that decreased early in the placebo infusion ((−30, 2, −24), cluster size = 13 voxels, T = 3.90, p = 0.004, and (−20, −6, −8), cluster size = 26 voxels, T = 3.87, p = 0.004). In contrast, mean amygdala reactivity significantly increased across successive scans during citalopram infusion. A cluster in the right amygdala exhibited increased activation early in the citalopram infusion compared to the baseline ((22, −4, −20), cluster size = 55 voxels, T = 3.01, p = 0.01). An even greater bilateral amygdala response during citalopram administration was found at the end of infusion, when drug concentrations approach their maxima, compared to baseline (; left amygdala (−24, −6, −22), cluster size = 115 voxels, T = 6.05, p < 0.001; right amygdala (22, 4, −16) cluster size = 56 voxels, T=3.39, p = 0.006).
Figure 1 (a) Amygdala clusters exhibiting greater activation as a function of acute citalopram, Left amygdala (−24, −6, −22) cluster size = 115 voxels, T = 6.05, p < 0.001; right amygdala (22, 4, −16) cluster size = 56 voxels, (more ...)
Direct comparisons in the differential activation of the amygdala between baseline and late infusion during placebo and citalopram administrations confirmed these observations. The increase in bilateral amygdala reactivity between late infusion and baseline is significantly greater during citalopram administration in comparison with placebo (left amygdala (−26, −6, −26), cluster size = 52 voxels, T = 5.75, p = 0.001 and right amygdala (16, −6, −22), cluster size = 11 voxels, T = 2.80, p = 0.01). In fact, average amygdala activation significantly increased between baseline and late infusion during citalopram treatment (mean 1.081, SD 0.658) whereas average amygdala activation decreased between baseline and late infusion during placebo (mean −0.5406, SD 1.108), ().
Change in left amygdala reactivity (−26, −6, −26) between baseline and late infusion during citalopram and placebo. Paired t-test (t = 5.35, df = 7, p = 0.001).
Finally, linear regression analysis between scan-specific plasma citalopram concentrations and amygdala activation revealed a strong concentration-dependent increase in amygdala reactivity over infusion (; r2 = 0.334, p = 0.0306). A separate linear mixed-effects model produced an identical y intercept (−0.51) and slope (0.03). The NONMEM objective function change between the initial model, which modeled BOLD as a constant with random effects (ie concentration was held constant), and the final model, which modeled both the slope (ie change in concentration) and intercept (ie baseline BOLD value) with random effects, was also significant (5.6 point decrease in objective function; p = 0.018), which confirms the SPM linear regression ().
Amygdala reactivity correlates with citalopram concentration. Scans are color coded (time 2 is shaded, time 3 is solid). Citalopram concentrations could not be estimated for one subject due to missing plasma samples (n = 7 for this analysis only).