The main aim of the current study was to investigate the effects of a single dose of lamotrigine on subjective mood and neural measures of emotional processing in healthy volunteers. Participants in the lamotrigine group were more accurate at identifying the gender of fearful faces compared to the placebo group. In addition to this behavioural effect, we saw a reduction in BOLD activity in the lamotrigine group relative to placebo in response to fearful, happy, and angry faces (versus baseline) in a network of regions associated with emotional processing, including the amygdala, insula and ACC. Lamotrigine therefore had valence-independent rather than emotion-specific effects on neural measures of emotional processing. There were no effects of lamotrigine in response to visual stimulation, supporting the conclusion that the effects on emotional processing were not driven by global drug-related modulation of the BOLD signal. Undesired side effects related to lamotrigine included reduced alertness and increased drowsiness. However, neural results were not affected by adding subjective ratings as nuisance regressors. Together these findings indicate that lamotrigine has broad ranging effects on neural response to emotional stimuli. This would suggest an effect of lamotrigine that is not specific to negative emotional stimuli, at least at a neural level, which may be relevant for models of mood stabilising action to consider.
The amygdala and ACC play an important role in emotional processing, and are postulated as a key site of traditional antidepressant action [19]. Specifically, acute doses of conventional antidepressants have been shown to reproducibly and significantly reduce amygdala response to fearful faces and/ or increase activation to happy faces in this region [20, 26, 39] perhaps reflecting early normalisation of negative affective bias in depression. These changes in emotional processing have been associated with later improvements in mood, suggesting that they represent a critical pathway through which antidepressants exert their effects [23, 25]. In our current study lamotrigine reduced BOLD activity in the amygdala and ACC in response to both positive and negative faces. The amygdala plays a key role in detecting salient information in the environment [40, 41]. It is therefore possible that this effect of reducing activity in the amygdala in response to both positive and negative valences could contribute to the mood-stabilising effect of lamotrigine, given that patients with BD suffer from mood instability and their interpretation of positive and negative events can oscillate greatly between mood episodes. This hypothesis remains speculative however and further research is needed to further explore this.
Moreover, group differences between lamotrigine and placebo were also seen in other areas, including areas related to motor control and movement, attention, and cognition. In addition, activity in areas related to emotional processing and attention other than the amygdala and ACC, such as insula, anterior PFC, PCC, precuneous, supramarginal gyrus and paracingulate gyrus, was also significantly reduced in the lamotrigine group. These findings indicate that lamotrigine may reduce brain activity in several areas related to emotional processing in a different way than other studies using SSRI antidepressants have reported. As lamotrigine regulates glutaminergic release by inhibiting voltage-gated channels associated with glutamate, it is perhaps not surprising that widespread changes in activation patterns are seen. Interestingly the areas identified overlap with regions that form the default mode network (DMN), the salience network (SAN) and the affective network (AN). These resting state networks integrate cognitive control, affective and reward-systems of the brain and have been implied in the pathophysiology of bipolar disorder [42–44]. The glutamatergic system also plays an important role in regulating these networks [45–49]. For example, it has been shown that high glutamate concentration in the PCC and precuneous area is associated with reduced deactivation of the DMN [50].
Behaviourally lamotrigine improved the performance on a simple gender discrimination task for fearful faces only. Typically healthy volunteers are less accurate and slower at identifying the gender of fearful faces than that of happy faces in this task (e.g., [38]), suggested to reflect a distraction effect from the threat relevant content of the fearful faces interfering with the unrelated decision regarding facial gender. The improved accuracy in classifying the fearful faces in those receiving lamotrigine could represent reduced threat distraction by the fearful face content, even in the absence of differences in neural response to fear vs happy faces. Difficulties in reducing activation within the DMN has been linked to increased rumination and impaired control of action [44, 51, 52]. Thus, the pattern of decreased activation of DMN activation and reduced fear distraction following lamotrigine appears consistent and highlights a potential mechanism of action. Future resting state studies may clarify our findings further.
To our knowledge this is the first study that has investigated the neural effects of lamotrigine in healthy volunteers. The effect of lamotrigine on brain activity has been somewhat more widely explored in the context of emotional and cognitive tasks in patients with bipolar disorder. In terms of resting state functional connectivity (rsFC) a recent study by [53] suggested that preserved rsFC between the frontoparietal network (FPN) and the dorsal attention network (DAN) (the networks involved in cognitive control), and the hub of the posterior DMN (the precuneus), was critical for good response to lamotrigine as an add-on treatment in patients with bipolar depression. With regards to task-based fMRI, some studies have suggested a link between symptomatic improvement and normalization and therefore increased BOLD activity in a number of brain regions, including the PFC and ACC. However, sample sizes were small and most of these studies included children and adolescents [54–56]. Turning to other pharmacological agents that influence downstream levels of glutamate, results have been mixed. For example, ebselen is a bioavailable antioxidant shown to lower glutamate levels in the ACC in healthy volunteers [57, 58]. Ebselen has been found to differentially influence the recognition of positive vs. negative facial expressions in the FERT task, a behavioural measure of emotional processing in one study [59], but not in another [60]. Experimental medicine studies with neural outcome measures of emotional processing are currently underway [58]. Ketamine on the other hand is a non-competitive NMDA receptor antagonist causing increased presynaptic glutamate release and extracellular glutamate concentrations. Similar to the results from the current study, ketamine has been shown to reduce neural reactivity in the amygdala after emotional stimulation with both positive and negative pictures [61, 62]. However, ketamine and lamotrigine would be expected to have a different profile of effect on the glutamate system suggesting that the relationship between emotional processing and glutamate is likely to be complex.
Several factors that may have influenced the current study must be taken into consideration when interpreting results. This includes significant differences between groups in self-report clinical data, as well as significant differences in behavioural task performance between groups, and unsuccessful participant and researcher blinding. The lamotrigine and placebo groups in our study differed significantly in several important assessments, including subjective state anxiety and undesired side-effects experienced. This may have served as a confounding factor that interacted with emotional processing and neural response. We tried to account for this by adding these subjective measures as nuisance regressors. Still, it is not feasible to attribute neural group differences to solely the effect of lamotrigine. It could be hypothesized that the lamotrigine group’s significantly reduced neural response to emotional stimuli resulted from the participants not processing the stimuli as much. This could be due to the lamotrigine group being significantly more anxious than the placebo group over all time points, or the lamotrigine group experiencing significantly greater negative side effects, including greater drowsiness and reduced alertness. It would be possible that lamotrigine group’s anxiety and reduced arousal caused them to avoid the emotional stimuli compared to the placebo group and therefore explain the lamotrigine group’s reduced neural response to presented emotional faces compared to baseline. However, the lamotrigine group was significantly better at identifying gender of fearful faces which doesn’t fit with this suggestion. Finally, the relatively small sample size (n = 31) may have impacted the power of the study to detect broader effects of lamotrigine on emotional pressing, in addition to type 2 errors. The generalisability of the current results to clinical populations is limited. Using healthy participants for early mechanistic work in humans has a number of advantages; in particular, it allows the characterisation of neurocognitive effects without confounding due to symptom change. However, prospective conclusions about the potential effect of lamotrigine on emotional processing and their relevance for the treatment of bipolar disorder remain to be validated in future work that uses a well-matched, high-powered sample of patients.