Previous studies of anxiety disorder emphasized the role of the limbic brain and the cerebral cortex regions.19-22
In line with our results, Boshuisen et al.23
reported PD patients had hypoactivity in the precentral gyrus, the inferior frontal gyrus, and the anterior insula, both during anticipatory anxiety and at rest after pentagastrin challenge. Unfortunately, our study did not include a control group, and we did not know which brain structures of the patients were abnormal compared with those of normal subjects. However, our results suggest a link between cerebral cortex regions and SSRI treatment in terms of brain glucose metabolism. Similar to previous studies, we could detect the functional changes after treatment in the hippocampal and parahippocampal areas or the amygdala in patients with PD. Functional or structural abnormalities of the hippocampus, parahippocampus, and amygdala are often reported in PD.6
Our findings suggest that cerebral cortex regions, as well as limbic brain areas including the amygdala, hippocampus, and parahippocampal gyrus, may play a more important role in PD treatment. This study is the first to examine the effect of a single SSRI on brain metabolism in PD patients and suggests that paroxetine treatment may work its therapeutic action by increasing the activities of not only the limbic brain but also cerebral cortex regions, including the prefrontal cortex.
Gorman et al.6
suggested a possible mechanism for the two different main treatment modalities, SSRIs and cognitive behavior therapy (CBT), in PD patients. The hypothesis is that medications, particularly those that influence the serotonin system, desensitize the fear network, from the level of the amygdala through its projections into the hypothalamus and the brainstem.24
Effective psychosocial treatments may also reduce contextual fear and cognitive misattributions at the level of the prefrontal cortex and hippocampus.25
Prasko et al.26
examined the effects of SSRIs, as well as CBT, on PD patients in terms of basal glucose metabolism, using [18
F]FDG-PET. They reported SSRIs cause metabolic changes at the cortical level, such as decreases in the inferior temporal gyrus and the right hemisphere's superior and inferior frontal gyri, increases in the inferior frontal gyrus and middle temporal gyrus, and (increases in) insulin in the left hemisphere. They did not detect changes in [18
F]FDG uptake in the limbic regions (hippocampus, parahippocampal gyrus, and amygdala). However, their study had some limitations, such as using a priori hypothesized ROIs and using different medications on each patient.
Icreased metabolism in the right amygdala and left parahippocampal gyrus after paroxetine treatment seems paradoxical, because the amygdala and parahippocampal gyrus important structures in fear acquisition and consolidation. Many studies have shown that acutely increasing 5-HT levels, either globally or regionally, in the brain of an experimental animal increases fear and avoidance.27
In some studies, long-term administration of 5-HT precursors or agonists appear to maintain this fear increase,28
although some contradictory data exist. This stimulating effect of serotonin seems to be related to increased metabolism in the amygdala and the parahippocampal gyrus.29
However, the stimulating effect of serotonin in PD patients is usually temporary, and SSRIs are effective in reducing panic symptoms. Thus, in PD, paroxetine's effect may result from increased frontal cortex activity, whereas the paroxetine's role in the amygdala and the parahippocampal gyrus is still in debate.
Our study had several limitations. First, as this was a pilot study, our sample size was too small. Examining the exact pathophysiology of PD woud require a larger patient sample size, with a control group. Second, this study's design was semi-naturalistic, and the medication dosages were flexible, according to the physician's decisions. Finally, the relatively short pharmacotherapy duration may be a potential limitation in assessing our results.
In conclusion, PD patients' cerebral cortex and limbic brain functions changed after short-term treatment with paroxetine. Paroxetine's therapeutic action may be related to altered glucose metabolism in both the cerebral cortex and limbic brain areas.