Serotonin and Epilepsy: The Story Continues

The 5-HT_1A receptor and 5-HT transporter in temporal lobe epilepsy

Martinez A, Finegersh A, Cannon DM, Dustin I, Nugent A, Herscovitch P, Theodore WH. Neurology 2013;80:1465–1471.

OBJECTION: To study 5-HT transport and 5-HT_1A receptors in temporal lobe epilepsy (TLE) and depression. METHODS: Thirteen patients had PET with [¹¹C]DASB for 5-HTT and [¹⁸F]FCWAY for 5-HT_1A receptor binding, MRI, and psychiatric assessment. Sixteen healthy volunteers had [¹¹C]DASB, 19 had [¹⁸F]FCWAY, and 6 had both PET studies. We used a reference tissue model to estimate [¹¹C]DASB binding. [¹⁸F]FCWAY volume of distribution was corrected for plasma-free fraction. Images were normalized to common space. The main outcome was the regional asymmetry index. Positive asymmetry indicates relative reduced binding (reflecting transporter activity) ipsilateral to epileptic foci. RESULTS: Mean regional [¹¹C]DASB binding and asymmetry did not differ between patients and controls. [¹⁸F]FCWAY asymmetry was significantly greater for patients than controls in hippocampus, amygdala, and fusiform gyrus. On analysis of variance with region as a repeated measure, depression diagnosis had a significant effect on [¹¹C]DASB asymmetry, with significantly higher [¹¹C]DASB asymmetry in insular cortex (trend for fusiform gyrus). In insular cortex, patients had a significant correlation between [¹⁸F]FCWAY asymmetry and [¹¹C]DASB asymmetry. CONCLUSIONS: Our study showed increased [¹¹C]DASB asymmetry in insula and fusiform gyrus, and relatively reduced transporter activity, in subjects with both TLE and depression, as compared to subjects with TLE alone, implying reduced reuptake and thus increased synaptic 5-HT availability. This finding may represent a compensatory mechanism for 5-HT_1A receptor loss. Altered serotonergic mechanisms have an important role in TLE and concomitant depression.

Commentary

The observation that mood disorders and epilepsy often go hand in hand is certainly not new. Indeed, the reported prevalence of depression in patients with epilepsy has been reported to range between 12 and 40 percent in various patient populations and settings. One recent meta-analysis suggested and overall prevalence of active depression of about 24% (1). Left inadequately treated, depression may not only contribute to decreased quality of life but may also contribute to increased healthcare costs and decreased economic productivity (2). In patients with temporal lobe epilepsy (TLE) who have pharmacologically refractory seizures, depression may be even more common and severe. Despite common misperceptions, this apparent relationship is likely bidirectional. Not only are patients with epilepsy at increased risk of developing depression, but patients with psychiatric comorbidities are at substantially greater risk of developing epilepsy (3). Given this relationship, is it truly appropriate to consider mood and seizure disorders as simply comorbidities? The answer to that question will require an understanding of the neurobiological associations between the two disorders.

While much progress has been made in both highlighting the importance and clinical identification of this common, debilitating comorbidity in our patients, our understanding of its neurobiological underpinnings is still rather unclear. While the biochemical causes of depression in patients with epilepsy are most certainly multifactorial (4, 5), the role of serotonin dysregulation and epilepsy has become an increasingly interesting story. Serotonin neurotransmission is important in modulating cortical excitatory and inhibitory balance in the brain. Both animal models and limited clinical experience suggest that reduced serotonergic tone is associated with seizure genesis and exacerbation (6) and that enhanced serotonergic activity may have anticonvulsant effects (7, 8).

Previous work using PET has demonstrated reductions in binding of serotonin (5-HT_1A) in mesial temporal structures in patients with TLE (9), and that patients with TLE with major depression may show greater reductions in 5HT_1A binding than patients with TLE who are not depressed (10, 11). Taken together, experimental data and studies in patients clearly demonstrate impaired 5-HT binding in patients with epilepsy. Alterations in 5-HT_1A receptor density is only one part of the story. The serotonin transporter (5-HTT) is the key regulator in serotonergic transmission and is primarily responsible for 5-HT inactivation via selective reuptake. Studies have suggested a possible role for genetic polymorphisms of this transporter in patients with TLE (12), with some data hinting that greater 5-HTT activity, leading to reduced synaptic 5-HT, might be associated with poorer response to antiepileptic drugs in patients with TLE (13).

Now, in a report by Martinez and colleagues, 13 patients with TLE were compared with 29 healthy volunteers who had never met criteria for a major psychiatric disorder. Of the patients, four had a history of major depression, with two of these individuals reporting symptoms of depression at the time of study. Using PET, 5-HTT and 5-HT_1A binding was assessed in the insula, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and cingulate cortex. In agreement with previous studies, the investigators found that 5-HT_1A binding was reduced in the limbic areas on the ipsilateral side in patients with TLE, and that 5-HT_1A-binding asymmetry was greater for patients as compared with healthy controls. Overall, 5-HTT-binding differences in patients with TLE, however, were not apparent. Neither sex, nor AED use, nor side of epilepsy focus appeared to affect 5-HTT binding. Of interest, differences in 5-HTT binding were noted in patients with TLE and a history of major depression. In these patients, greater asymmetry in transporter activity was seen in the insular cortex (likely an important neural structure in major depression) (14) and in the fusiform gyrus on the ipsilateral side. Correlations between 5-HT_1A and 5-HTT asymmetry in the insular cortex were also seen in TLE patients but not healthy controls. These observations suggest several things. First, patients with TLE appear to have subtle alterations in 5-HT neurotransmission as compared with healthy individuals. Those patients with clinical expressions of depression may have a somewhat different neurochemical marker. In the patient with TLE and depression, a compensatory mechanism may exist. Perhaps, in response to markedly reduced 5-HT_1A-receptor density, uptake, the primary mechanism terminating serotonin activity, is also reduced, allowing for increased synaptic serotonin concentrations.

Clearly, one must be cautious not to overinterpret these findings. Subtle differences in clinical expression of TLE and depressive symptoms may have been obscured by the relatively small sample size. These findings do raise interesting questions. Could it be that in patients with TLE and depression, there is an endogenous mechanism in place to try and increase synaptic serotonin concentrations? If so, clearly this compensatory mechanism is not entirely sufficient in all patients. Of note, in this report, there was a trend (albeit not statistically significant) toward a correlation between higher Beck Depression scores and increased insular 5-HTT asymmetry. Perhaps these neurochemical markers are indicative of either severity of the mood disorder or of differing clinical syndromes in patients with TLE. It is possible therefore that neuroimaging might lend insight as to potential patient subtypes that might benefit from treatment with selective serotonin reuptake inhibitors (SSRIs).

Finally, the observations of Martinez and colleagues also prompts one to ask whether it is entirely appropriate to consider depression simply a comorbid finding in patients with epilepsy. As it is commonly defined, comorbidity refers to the presence of more than one diagnosis occurring at the same time in a given patient. This implies a distinct clinical disorder occurring during the course of the “index” disease. This might be imprecise, if not frankly inaccurate, in this patient population. Given the observed bidirectionality of epilepsy and depression, common neurochemical markers, and perhaps compensatory neurotransmitter adaptations, it is perhaps more correct to view epilepsy and depression as different expressions of a single disorder. Clearly, TLE is a heterogeneous disorder. Perhaps patients with TLE and significant mood disturbance represent a subgroup of patients with a unique neurochemical signature. These observations take us one step closer to understanding the mechanistic underpinnings of this common debilitating “comorbidity” and, perhaps, to designing personalized screening and treatment approaches.