The main finding of this paper was that citalopram pharmacotherapy resulted in significant deactivation within anterior and superior cingulate cortex, the left hippocampus and the right thalamus in a combined group of patients with different anxiety disorders (OCD, PTSD, and SAD). Furthermore, deactivation was significantly more apparent in responders than in non-responders to SSRI treatment within precentral, right inferior, middle frontal and left prefrontal regions. Interestingly, no pre-treatment differences in regional perfusion between subsequent treatment responders vs non-responders were found.
Although there are important differences in the symptomatology of the anxiety disorders, these conditions do share certain aspects of their phenomenology, including heightened anxiety and avoidance behaviour. Furthermore, previous functional brain imaging work has demonstrated overlapping neurocircuitry across different anxiety disorders with activation of paralimbic circuitry and right inferior frontal cortex in a combined group comprising subjects with OCD, PTSD, and specific phobia [1
]. Results in the present study now also point to an overlap in the functional neuroanatomy, primarily implicating paralimbic neurocircuitry, in treatment response to the same SSRI, citalopram, across anxiety disorders. In citalopram responders, effects across disorders were most pronounced in the mid, inferior and prefrontal cortex. In other regions, such as the striatum, data on treatment response and symptom provocation seems to indicate less overlap across anxiety disorders, which may suggest only partial and regionally specific overlap between disorders [1
Specific limbic regions are well-known to play a role in broadly mediating anxiety. Early observations of epileptogenic cingulate lesions support its role in regulating affect [27
]. Furthermore, recent work has suggested a role for the anterior cingulate in integrating cognitive and motivational processes. These include evaluating environmental cues and monitoring performance [28
] On the other hand, a central role for the hippocampus in contextual aspects of fear conditioning has been demonstrated [29
The findings here complement previous studies of OCD, PTSD, and SAD that have demonstrated a specific role for the cingulate and hippocampus in these conditions. Studies in OCD have shown increased anterior cingulate activity at baseline, or deactivation during pharmacotherapy with serotonergic agents [31
]. In PTSD, anterior cingulate activity is also increased in some, although not all, studies of PTSD [32
] Further, the anterior cingulate is deactivated during citalopram treatment of SAD patients [17
]. Dysfunction of the hippocampus, as indicated by smaller hippocampal volume and declarative memory deficits, may play an important role in PTSD [34
The medial prefrontal cortex comprises several related areas including anterior cingulate cortex. Lesions of this area are associated with suboptimal responses to stress, and the area has important inhibitory inputs to the amygdala which mediate extinction of fear conditioning [29
]. The middle and inferior frontal cortex, on the other hand, is involved in encoding and retrieval of verbal memories. Our finding that the right inferior frontal cortex was more deactivated in responders is perhaps consistent with previous findings showing increased activity pre-treatment in this region across different anxiety disorders [2
] and in some, but not all, studies of PTSD [35
Serotonergic circuits innervate the medial prefrontal cortex and other limbic structures, and chronic administration of a serotonin reuptake inhibitor may lead to an increase in their neurotransmission. It is possible that the medial prefrontal cortex deactivation during serotonergic pharmacotherapy indicates that a compensatory increase of activity in this region is no longer needed after symptom improvement. Along these lines, a number of functional and electrophysiological imaging studies of depression have found that anterior cingulate hyperactivity predicts a positive response to pharmacotherapy, a finding that has also been interpreted as indicating the baseline presence of an adaptive compensatory response [36
]. In addition changes in cognitive processing of frontal cortex may be secondary to symptom reduction caused by primary drug-induced changes within the limbic system. We have previously demonstrated similarly higher pre-treatment prefrontal perfusion in subsequent responders relative to non-responders using inositol in OCD [37
]. Interestingly, inositol responsive disorders overlap with those responsive to SSRI's which may suggest that it is serotonergic components of these disorders that account for at least some of the overlap in perfusion patterns demonstrated here.
In contrast, however, increased activity in anterior cingulate or orbitofrontal region in OCD has also been shown to predict a poorer response to pharmacotherapy [9
Perhaps increased activity in particular limbic circuits plays a different functional role in different psychiatric disorders. Only limited functional imaging studies of pharmacotherapy effects have involved provocation paradigms [38
] and such differences in design may account for certain inconsistencies across studies. Alternatively, it is feasible that different effects in different disorders may also help explain inconsistencies. In the current dataset, however, we were unable to demonstrate any associations between baseline activity and pharmacotherapy response for the combined group.
This study is limited by the slightly different inclusion criteria (inclusion of secondary depression in PTSD group) and pharmacotherapy duration for different disorders. While the absence of untreated controls may to some extent limit the conclusions we can draw, comparing non-responders to responders we believe serves as a reasonable evaluation of changes that result from treatment response. The lower spatial resolution of SPECT may be considered a limitation nevertheless this study usefully emphasizes the importance of limbic regions (amygdala, hippocampus) in mediating anxiety. Furthermore, deactivation within these regions as well as richly connected frontal regions following SSRI treatment, particularly in responders, is clearly demonstrated. Further research combining pharmacological interventions and functional methodologies, and using tracers tailored to specific neurotransmitter receptors, will undoubtedly lead to increased understanding of the pathogenesis of the anxiety disorders and the mechanisms of response to treatment in the future.