Antiepileptic drug treatment of generalized tonic-clonic seizures: An evaluation of regulatory data and five criteria for drug selection.

BACKGROUND: A generalized tonic-clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper. METHODS: Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs). RESULTS: (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs. CONCLUSION: Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices.

Alpha 2B adrenoceptor genotype moderates effect of reboxetine on negative emotional memory bias in healthy volunteers.

Evidence suggests that emotional memory plays a role in the pathophysiology of depression/anxiety disorders. Noradrenaline crucially modulates emotional memory. Genetic variants involved in noradrenergic signaling contribute to individual differences in emotional memory and vulnerability to psychopathology. A functional deletion polymorphism in the α-2B adrenoceptor gene (ADRA2B) has been linked to emotional memory and post-traumatic stress disorder. The noradrenaline reuptake inhibitor reboxetine attenuates enhanced memory for negative stimuli in healthy and depressed individuals. We examined whether the effect of reboxetine on emotional memory in healthy individuals would be moderated by ADRA2B genotype. ADRA2B deletion carriers demonstrated enhanced emotional memory for negative stimuli compared with deletion noncarriers, consistent with prior studies. Reboxetine attenuated enhanced memory for negative stimuli in deletion noncarriers but had no significant effect in deletion carriers. This is the first demonstration of genetic variation influencing antidepressant drug effects on emotional processing in healthy humans.

Catechol-O-methyltransferase val158met genotype determines effect of reboxetine on emotional memory in healthy male volunteers.

BACKGROUND: Catechol-O-methyltransferase (COMT) metabolizes catecholamines in the prefrontal cortex (PFC). A common polymorphism in the COMT gene (COMT val158met) has pleiotropic effects on cognitive and emotional processing. The met allele has been associated with enhanced cognitive processing but impaired emotional processing relative to the val allele. METHODS: We genotyped healthy, white men in relation to the COMT val158met polymorphism. They were given a single 4 mg dose of the selective noradrenaline reuptake inhibitor (NRI) reboxetine or placebo in a randomized, double-blind between-subjects model and then completed an emotional memory task 2 hours later. RESULTS: We included 75 men in the study; 41 received reboxetine and 34 received placebo. In the placebo group, met/met carriers did not demonstrate the usual memory advantage for emotional stimuli that was observed in val carriers. Reboxetine restored this emotional enhancement of memory in met/met carriers, but had no significant effect in val carriers. LIMITATIONS: We studied only men, thus limiting the generalizability of our findings. We also relied on self-reported responses to screening questions to establish healthy volunteer status, and in spite of the double-blind design, participants were significantly better than chance at identifying their intervention allocation. CONCLUSION: Emotional memory is impaired in healthy met homozygotes and selectively improved in this group by reboxetine. This has potential translational implications for the use of reboxetine, which is currently licensed as an antidepressant in several countries, and edivoxetine, a new selective NRI currently in development.

Epistasis between 5-HTTLPR and ADRA2B polymorphisms influences attentional bias for emotional information in healthy volunteers.

Individual differences in emotional processing are likely to contribute to vulnerability and resilience to emotional disorders such as depression and anxiety. Genetic variation is known to contribute to these differences but they remain incompletely understood. The serotonin transporter (5-HTTLPR) and α2B-adrenergic autoreceptor (ADRA2B) insertion/deletion polymorphisms impact on two separate but interacting monaminergic signalling mechanisms that have been implicated in both emotional processing and emotional disorders. Recent studies suggest that the 5-HTTLPR s allele is associated with a negative attentional bias and an increased risk of emotional disorders. However, such complex behavioural traits are likely to exhibit polygenicity, including epistasis. This study examined the contribution of the 5-HTTLPR and ADRA2B insertion/deletion polymorphisms to attentional biases for aversive information in 94 healthy male volunteers and found evidence of a significant epistatic effect (p<0.001). Specifically, in the presence of the 5-HTTLPR s allele, the attentional bias for aversive information was attenuated by possession of the ADRA2B deletion variant whereas in the absence of the s allele, the bias was enhanced. These data identify a cognitive mechanism linking genotype-dependent serotonergic and noradrenergic signalling that is likely to have implications for the development of cognitive markers for depression/anxiety as well as therapeutic drug effects and personalized approaches to treatment.

Sexually dimorphic changes in the amygdala in relation to delusional beliefs in first episode psychosis.

BACKGROUND: Few attempts have been made to examine the relationship between amygdala abnormalities and specific symptoms in psychosis. The present study explored the relationship between amygdala morphology and mood congruent and mood incongruent delusional beliefs. METHODS: Amygdala volumes were measured in 43 patients presenting with delusional beliefs in the context of their first episode of psychosis and 43 healthy volunteers matched for age and gender. RESULTS: Left-greater-than-right-asymmetry of the amygdala varied as a function of gender and mood congruence of delusional beliefs, due to asymmetrical enlargement of the left amygdala in women presenting with predominantly mood incongruent delusions. However, there was no difference in amygdala volumes across groups. CONCLUSIONS: Amygdala abnormalities in women may be associated with aberrant emotional processing that could contribute to the development of mood incongruent delusional beliefs. Sexually dimorphic changes in the amygdala may contribute to differential phenotypic illness expression in men and women.

The role of dopamine in attentional and memory biases for emotional information.

OBJECTIVE: Cognitive models suggest that biased processing of emotional information may play a role in the genesis and maintenance of psychotic symptoms. The role of dopamine and dopamine antagonists in the processing of such information remains unclear. The authors investigated the effect of a dopamine antagonist on perception of, and memory for, emotional information in healthy volunteers. METHOD: Thirty-three healthy male volunteers were randomly assigned to a single-blind intervention of either a single dose of the dopamine D(2)/D(3) antagonist amisulpride or placebo. An attentional blink task and an emotional memory task were then administered to assess the affective modulation of attention and memory, respectively. RESULTS: A significant interaction was observed between stimulus valence and drug on recognition memory accuracy; further contrasts revealed enhanced memory for aversive-arousing compared with neutral stimuli in the placebo but not the amisulpride group. No effect of amisulpride was observed on the perception of emotional stimuli. CONCLUSIONS: Amisulpride abolished the enhanced memory for emotionally arousing stimuli seen in the placebo group but had no effect on the perception of such stimuli. These results suggests that dopamine plays a significant role in biasing memory toward emotionally salient information and that dopamine antagonists may act by attenuating this bias.

Deletion variant of alpha2b-adrenergic receptor gene moderates the effect of COMT val(158)met polymorphism on episodic memory performance.

The COMT val(158) variant has been associated with impaired cognitive function compared to the met(158) variant yet gene-gene interactions are not well described. In this study we demonstrate an interaction between this COMT polymorphism and a deletion variant of ADRA2B, the gene encoding the alpha2b-adrenergic receptor on episodic memory performance. Specifically, carriage of the ADRA2B deletion abolished the relative memory impairment in homozygous COMT val(158) carriers compared to met(158) carriers.

Delusion formation and insight in the context of affective disturbance.

OBJECTIVE: Delusions and lack of insight have traditionally been viewed as the defining characteristics of insanity and in modern psychiatry continue to be central to the diagnosis of psychosis. Little is known about the mechanisms of delusion formation and much of the research into delusions and lack of insight has been focussed on schizophrenia, in spite of the fact that these symptoms are also prominent in other disorders e.g., affective psychosis. The objective of this paper is to review the literature on existing theories of delusions and insight with reference to the effects of affective disturbance on memory processes. METHOD: Narrative review supplemented by literature searches using Medline, PsycINFO and EMBASE databases for the period 1980 to present using terms "delusion", and "insight" and "affect". RESULTS: The role of affect on memory in normal psychology and delusions in psychopathology is being increasingly recognised. We sketch out a theory which gives weight to locating the formation and maintenance of mood congruent and mood incongruent delusional beliefs (and insight into such beliefs) within a model of normal memory processes. CONCLUSION: We conclude that delusional beliefs may represent false or biased memories of internal or external events modified and strengthened of by affective states. We propose that insight rests on an ability to identify these memories as internally generated or biased. In view of the growing body of knowledge accumulating from the study of memory, emotion and their neuropsychological correlates we would suggest using this as an evidence base for the further neuropsychiatric investigation of delusional beliefs.