The aim of this study was to investigate whether subchronic (21 days of) escitalopram treatment would attenuate emotion processing related activation in limbic and paralimbic structures. Escitalopram did not affect behavior on this task nor did it change levels of anxiety in these healthy volunteers. The escitalopram treatment phase (compared to the placebo treatment phase) was not associated with an altered BOLD response to the task when including all subjects in the analysis. However, when urinary concentrations of escitalopram (which had been collected primarily as an indicator of SSRI adherence) were considered, strong concentration-dependent relationships between amygdala and insular activity were observed. An additional set of analyses including only the 10 of 13 subjects with concentrations of escitalopram in urine that were well above the assay detection threshold (which we interpreted as indicative of good compliance with the escitalopram administration) revealed a significant attenuation for fearful faces as well as a marginal attenuation for angry but not for happy faces. Taken together, these observations suggest that there was an attenuation of BOLD activity in the bilateral insula and amygdala (but not in the fusiform gyrus) directly related to bioavailability of escitalopram, and a direct attenuation for negative faces in those who most likely complied with chronic administration of escitalopram. Because we had not measured plasma concentrations of escitalopram (and metabolites) at various phases of the study, there is some uncertainty as to whether blood (and, by inference, brain) concentrations of escitalopram do, indeed, correlate with the observed BOLD fMRI responses. Thus, future work will be required, using pharmacodynamic modeling, to confirm these suspected effects.
In line with a recent fMRI study by Harmer and colleagues (2006)
, our results suggested that subchronic SSRI administration attenuates amygdala activation (when compared against placebo) to negatively but not positively valenced emotional faces.. Similarities with the current study include same population type (i.e., healthy volunteers) and sub-chronic SSRI treatment. Nevertheless, some important differences should be noted. Regarding the behavioral paradigm, the current participants were presented with unmasked (versus masked in the Harmet et al. 2006
study) presentations of facial expressions which also differed in the emotion depicted (anger, fear and happiness as opposed to threat and happiness). Additionally, the fMRI task used by the Harmer et al group did not include a sensorimotor condition and subjects were asked to judge the gender of the face versus matching its affect. Duration of treatment is three times longer in the current study (21 versus 7 day administration). Finally, and perhaps most importantly, the current study is a double-blind placebo-control crossover versus a double-blind between groups design in which treatment compliance was not reported.
An unexpected opposite effect (greater activation with escitalopram) was revealed in the insula. However, several aspects may account for this result. First, this effect was restricted to the emotion of anger (as opposed to the amygdala attenuation that was valence dependent). Second, the task effect for angry was not as robust as for the fear contrast, suggesting that it may be the result of lack of power due to the reduced number of subjects (n=10). Furthermore, results from the regression analysis suggested that escitalopram attenuates activation in the insular cortex on a urine concentration-dependent basis. A recent review paper published by our group postulates that individuals prone to anxiety disorders present an altered interoceptive predictive signal (Paulus and Stein 2006
). Interoception involves the self-perception of bodily signals that are important for internal body integrity and the connections that are crucial for allocating attention, contextual evaluation, and action planning. The insula is the structure tasked with evaluating the impact that certain stimuli may have in the body state. Insula activation correlates with anxiety indices during a risk-taking task (Paulus, Rogalsky et al. 2003
), is heightened in subjects with specific phobia when viewing fearful faces (Wright, Martis et al. 2003
), and in subjects with high trait anxiety (Simmons, Strigo et al. 2006
;Stein, Simmons et al. 2006
;Stein, Simmons et al. 2007
). Because activation in the insular cortex has been associated with the processing of affective modulation, cognitive processing during learning, and interoception of aversive stimuli, the insula emerges as a structure that links emotion, cognition and behavior. In summary, the link between altered insular function and several anxiety disorders (Hoehn-Saric, Schlund et al. 2004
;Lorberbaum, Kose et al. 2004
;Malizia, Cunningham et al. 1998
;Mataix-Cols, Rauch et al. 1999
;Rauch, Savage et al. 1997
;Wright, Martis et al. 2003
) suggests a common denominator that could be used as a biomarker for their treatment.
SSRIs were developed to regulate serotonin levels within the central serotonin 5-HT2 receptor in order to treat affective disorders (Mendlewicz 1999
). Rodent studies have suggested that escitalopram may be effective in reducing aggressive behavior (Sanchez, Bergqvist et al. 2003
), panic-like anxiety (Hogg, Michan et al. 2006
) as well as reverse conditioned fear-related behaviors (Sanchez, Gruca et al. 2003
). The current findings of reduced limbic and paralimbic activity following escitalopram treatment contribute to our understanding of how SSRIs can be effective therapeutic agents in the treatment of a broad array of disorders such as anxiety and depression. That is, the selective attenuation of emotion processing structures, as opposed to overall brain activation changes (i.e., lack of attenuation in motor or fusiform cortex), provides evidence for the specificity of SSRIs in targeting relevant processes in the pathophysiology of anxiety and mood disorders. Studies with depressive as well as anxious individuals should be conducted to explore whether the current findings can be translated from healthy volunteers to clinical populations.
This study has a number of limitations. Foremost among these is the lack of escitalopram blood levels. Thus, while we found a robust relationship between escitalopram urine levels and activation in emotion-processing brain areas, we cannot be certain that higher urine levels can be considered to reflect higher blood (and brain) levels. The relationship between urine and plasma levels can be supported by a pharmacokinetic report that suggested consistency between both t1/2
of urine and plasma (Sogaard, Mengel et al. 2005
). We have also used urine levels to make inferences about compliance with escitalopram administration. This resulted in us excluding subjects with non-detectable or very low urine escitalopram levels, under the assumption that such subjects were non-compliant with the protocol. The limited sensitivity of the urine analysis test (5 to 2000 Ng/ml) may have caused a possible range restriction effect given that 5 out of 13 individuals presented scores within the upper limit of the detection range. However, if anything, this would have reduced the power to detect correlations. Nevertheless, we have performed non-parametric tests to minimize the influence of this effect. Future pharmaco-imaging studies may incorporate urine and blood assays with greater assiduity to monitor compliance and determine the relationship between plasma levels and brain effects. Another consideration for future studies is that highly arousing and graphic images may be able to more effectively probe the therapeutic effects of pharmacological agents by assuring greater pretreatment levels of limbic and paralimbic hyperactivity which can be reduced after treatment.
In summary, the current investigation provides additional neuroimaging evidence of a change in brain regions critical for the mediation of anxiety and depression induced by a well-established pharmacological agent, an SSRI. This study offers further support for the use of BOLD-fMRI in combination with pharmacological probes to assess neurophysiological models proposed for anxiety and depression, and highlights the a role for fMRI in the evaluation of novel pharmacological treatments.