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CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus.

Epilepsy syndromes have been recognized for >50 years, as distinct electroclinical phenotypes with therapeutic and prognostic implications. Nonetheless, no formally accepted International League Against Epilepsy (ILAE) classification of epilepsy syndromes has existed. The ILAE Task Force on Nosology and Definitions was established to reach consensus regarding which entities fulfilled criteria for an epilepsy syndrome and to provide definitions for each syndrome. We defined an epilepsy syndrome as “a characteristic cluster of clinical and electroencephalographic features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious).” The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age‐dependent presentations and a range of specific comorbidities. This paper describes the guiding principles and process for syndrome identification in both children and adults, and the template of clinical data included for each syndrome. We divided syndromes into typical age at onset, and further characterized them based on seizure and epilepsy types and association with developmental and/or epileptic encephalopathy or progressive neurological deterioration. Definitions for each specific syndrome are contained within the corresponding position papers.

This post hoc analysis assessed the long-term safety, tolerability, and efficacy of perampanel in Asian patients with refractory focal seizures; an additional analysis assessed the effect of perampanel on focal impaired awareness seizures (FIAS) with focal to bilateral tonic-clonic (FBTC) seizures. In this subanalysis, data from Asian patients ≥12 years of age who had focal seizures with FBTC seizures despite taking one to 3 concomitant antiepileptic drugs at baseline, and who had entered either the long-term extension phase of 3 phase-3 perampanel trials (study 307) or the 10-week extension phase of study 335, were analyzed for the effect of perampanel on duration of exposure, safety, and seizure outcomes. Of 874 Asian patients included in the analysis, 205 had previously received placebo during the double-blind phase-3 trials and 669 had previously received perampanel 2-12 mg/day; 313 had FIAS with FBTC seizures at core study baseline. The median duration of exposure to perampanel was 385.0 days, and the retention rate at one year was 62.6%. Overall, during the first 52 weeks of perampanel treatment, 777 patients (88.9%) had treatment-emergent adverse events (TEAEs), most of which were mild to moderate in severity. The most frequent TEAEs were dizziness (47.1%), somnolence (22.3%), and nasopharyngitis (17.4%). During the first 52 weeks of perampanel treatment, median percent change in seizure frequency per 28 days from pre-perampanel baseline for all focal seizures was -28.1%, and -51.7% for FIAS with FBTC seizures. The 50% responder rate relative to pre-perampanel baseline for all focal seizures was 33.8%, and 51.1% for FIAS with FBTC seizures. Long-term treatment with perampanel in Asian patients had safety, tolerability, and efficacy similar to that of the global population in the phase-3 trials and extension study 307. The safety profile and response rate suggest benefit for an Asian population of patients with refractory epilepsy.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.

Objective This post hoc analysis evaluated long‐term efficacy and safety in patients with focal to bilateral tonic‐clonic seizures (FBTCS) or generalized tonic‐clonic seizures (GTCS) who entered open‐label extension (OLEx) studies to receive long‐term adjunctive perampanel. Methods Patients aged 12 years and older who completed phase II or III randomized, double‐blind, placebo‐controlled studies could enter an OLEx study, each comprising a blinded conversion period followed by an open‐label maintenance period (32‐424 weeks; maximum perampanel dose = 12 mg/d). Exposure, seizure outcomes, and treatment‐emergent adverse events (TEAEs) were analyzed. Results Baseline characteristics were generally balanced between patients with FBTCS (n = 720) and GTCS (n = 138). Mean (standard deviation) cumulative duration of perampanel exposure was 102.3 (70.3) weeks (FBTCS) and 83.9 (38.4) weeks (GTCS). Retention rates were 50.0% for up to 4 years (FBTCS) and 49.2% for up to 2 years (GTCS). Across OLEx treatment durations, median reductions in seizure frequency per 28 days were 66.7% (FBTCS) and 80.6% (GTCS). Fifty percent and 75% responder and seizure‐freedom rates were 59.5%, 45.3%, and 18.4%, respectively (FBTCS), and 72.5%, 51.5%, and 16.7%, respectively (GTCS). Efficacy was sustained for up to 4 years (FBTCS) and up to 3 years (GTCS), even when accounting for early dropouts. TEAE incidence was highest during Year 1 (FBTCS, 85.3%; GTCS, 86.2%); most common were dizziness and somnolence. During Year 1, serious TEAEs were reported in 81 (11.3%; FBTCS) and 10 (7.2%; GTCS) patients. TEAEs were consistent with the known safety profile of perampanel; no new safety signals were identified with long‐term treatment. Significance This post hoc analysis suggests long‐term (up to 4 years) adjunctive perampanel (up to 12 mg/d) is efficacious and well tolerated in patients (aged 12 years and older) with FBTCS or GTCS.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.

AIM To unravel relationships between gastrointestinal (GI) symptoms impairing quality of life (QOL) and clinical profiles of diabetes mellitus (DM) patients. METHODS We enrolled 134 outpatients with type 2 DM. Mean age was 64.7 years, mean body mass index was 24.7 kg/m2, mean glycated hemoglobin was 7.1%, and mean DM duration was 13.7 years. GI symptom-related QOL was determined using the Izumo scale, based on five factors, i.e., heartburn, gastralgia, postprandial fullness, constipation and diarrhea. The sum of scores obtained for the three questions in each domain was calculated, and subjects with a score of 5 or higher were considered to be symptomatic with impaired QOL. JMP Clinical version 5.0 was used for all statistical analyses. RESULTS Lower abdominal symptoms were found to be more frequent than those affecting the upper abdomen. Diabetic duration and medications showed associations with GI symptoms. We identified differences in peak prevalences of the five symptoms. Gastralgia (P = 0.02 vs 10-14 years) and total GI symptoms (P = 0.01 and P = 0.02 vs 5-9 years and 10-14 years, respectively) peaked at a diabetes duration of 15-19 years. Heartburn (P = 0.004) and postprandial fullness (P = 0.03) tended to increase with disease duration. Constipation and diarrhea showed bimodal peaks, with the first early and the second late (e.g., P = 0.03 at 15-19 years vs 10-14 years for diarrhea) in the disease course. Finally, GI symptoms showed clustering that reflected the region of the GI tract affected, i.e., constipation and diarrhea had similar frequencies (P < 0.0001). CONCLUSION Our study highlights the importance of questioning patients about QOL impairment due to abdominal symptoms, especially in the early and the late periods of diabetes.

Objective Evaluation of the efficacy of antiepileptic drugs (AEDs) used in the treatment of Dravet syndrome (DS) with different genotypes. Methods Patients with DS were recruited from different tertiary hospitals. Using a direct sequencing method and Multiplex Ligation-Dependent Probe Amplification (MLPA), genetic abnormalities were assessed within the exons and flanking introns of SCN1A gene, which encodes the α1 subunit of neuronal sodium channels. Patients were divided into SCN1A -positive and SCN1A -negative groups according to the results of genetic tests. Medical records, including detailed treatment information, were surveyed to compare the effect of different AEDs on clonic or tonic–clonic seizures (GTCS). Efficacy variable was responder rate with regard to seizure reduction. Results One hundred and sixty of 276 (57.97%) patients had mutation in SCN1A gene (only 128 of them had provided detailed medical records). Among the 116 patients without SCN1A mutations, 87 had provided detailed medical records. Both older AEDs (valproate, phenobarbital, bromide, carbamazepine, clonazepam, and clobazam) and newer AEDs such as zonisamide were used in these patients. Valproate was the most frequently used AED (86.72% in the SCN1A -positive group, 78.16% in the SCN1A -negative group), with 52.25% and 41.18% responder rates in SCN1A -positive and SCN1A -negative patients, respectively ( P = 0.15). Bromide was used in 40.63% of the SCN1A -positive patients and 20.69% of the SCN1A -negative patients, and its responder rates were 71.15% and 94.44% in SCN1A -positive and SCN1A -negative patients, respectively ( P = 0.05). Efficacy rates of clonazepam, clobazam, phenobarbital, and zonisamide ranged from 30% to 50%, and these rates were not correlated with different genotypes ( P > 0.05). Carbamazepine had either no effect or aggravated seizures in all SCN1A -positive patients. Significance Bromide is most effective and is a well-tolerated drug among DS patients, especially among SCN1A -negative patients. Carbamazepine should be avoided in patients with SCN1A mutations.

We generated a transgenic rat strain with a missense mutation in V286L (V286L-TG), in the gene encoding the neuronal nicotinic acetylcholine receptor β2 subunit (CHRNB2) found in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To confirm that V286L-TG rats exhibit seizures similar to those observed in humans, gene expression patterns and behavioral phenotypes were analyzed. In situ hybridization using a V286L Chrnb2-selective probe indicated that the transgene was expressed at higher levels in the cortex, hippocampus, and cerebellum of V286L-TG than wild-type littermates (non-TG). Spontaneous epileptic seizures with ictal discharges in electroencephalograms were detected in 45% of V286L-TG rats and the frequency of seizures was 0.73 times a week. This seizure type is similar to "paroxysmal arousals" that are observed in human ADNFLE. V286L-TG rats displayed nicotine-induced abnormal motor activity including seizures in comparison to non-TGs. Response time following nicotine administration occurred faster in V286L-TG than in non-TG rats. V286L-TG rats demonstrated spontaneous epileptic seizures, which are similar to human ADNFLE, and also showed a higher sensitivity to nicotine administration. Thus, the V286L-TG rat model could be a valuable tool for developing novel mechanism-driven treatment strategies for epilepsy and provide a better understanding of ADNFLE.

Body weight (BW) gain may be induced by perampanel (PER) administration, similar to the well-known adverse effects of valproic acid and gabapentin. Intellectual disability (ID) and serum PER concentration may be risk factors of BW gain.This study investigated how ID and serum PER concentration are associated with PER-induced BW gain.Subjects were 76 patients with epilepsy (41 men, aged 16-70 years). All patients were divided by intelligence quotient (IQ) into no ID (IQ ≥ 70, n = 24), mild to moderate ID (70 IQ ≥35, n = 31), and severe to profound ID (IQ 35, n = 21) groups. BW was measured before and 2, 4, 6, and 12 months after initiation of PER treatment, and serum PER concentration at 12 months.BW gains in the mild to moderate ID group at 4, 6, and 12 months were significantly (p 0.05) higher than in the no ID and in the severe to profound ID groups. At 12 months, BW gain was associated with serum PER concentrations in the no ID (p = 0.034) and the mild to moderate ID (p = 0.001) groups but not in the severe to profound ID group. Multiple linear regression analysis found BW gain at 12 months was positively correlated with the mild to moderate ID group (β = 0.373, p = 0.002) and serum PER concentration (β = 0.241, p = 0.047).The mild to moderate ID group gained more BW than the no ID group, suggesting that PER-induced food intake was greater due to weaker behavioral control in the mild to moderate ID group. The present study suggests a linear correlation between serum PER concentration and BW change.

Psychiatric comorbidities, including mood, anxiety, psychotic disorders, and autism spectrum disorder are common in patients with epilepsy (PWE), often occurring at rates 2-3-fold or higher than in the general population without epilepsy. Furthermore, an attention should be paid to psychiatric symptoms together with those caused by antiepileptic drug therapy, epilepsy surgery, and vagus nerve stimulation because these therapies sometimes induce psychiatric comorbidities. It is important to differentiate psychogenic non epileptic seizures (PNES) from epilepsy, and to provide patients with psychiatric treatment. We focused on the process and certainty of diagnosis and the managements of PNES. An accurate, undistorted understanding of the relationship between mental status and epilepsy is essential to ensure appropriate therapy and avoid misconceptions and unnecessary treatment. Psychiatric and psychological states should be evaluated at the time of the first visit in every PWE and patients should be provided adequate psychiatric therapy if necessary within the overall therapeutic plan.

Purpose To evaluate long-term tolerability, safety and efficacy of adjunctive perampanel in a Phase II, multicentre, open-label, dose-ascending Study 231 (NCT00849212) and its extension (Study 233; NCT00903786) in Japanese patients with refractory partial-onset seizures (POS), with/without secondarily generalised seizures. Methods In Study 231, patients received adjunctive perampanel ≤12 mg/day during a 10-week treatment period. Patients completing Study 231 could enter Study 233 (≤316-week treatment period). Assessments included monitoring of treatment-related treatment-emergent adverse events (TEAEs), median percent change in seizure frequency per 28 days, 50% responder and seizure-freedom rates. During Study 231, a pharmacokinetic analysis assessed the effects of enzyme-inducing antiepileptic drugs. Results Overall, 23/30 (76.7%) patients completed Study 231; 21/30 (70.0%) received perampanel ≥8 mg/day and 10/30 (33.3%) achieved a maximum tolerated dose of 12 mg/day. Median percent change in seizure frequency per 28 days was –35.0%. 50% responder rate was 37.0%; 4 (13.3%) patients achieved seizure freedom. Twenty-one patients entered Study 233. Mean duration of exposure was 195 weeks; 9 (42.9%) patients received perampanel for ≤208 weeks. Seizure control was sustained for 316 weeks in 3/21 (14.3%) patients; 2 achieved seizure freedom. Treatment-related TEAEs were tolerable; the most common was dizziness (Study 231, 53.3%; Study 233, 14.3%). Mean perampanel plasma concentrations were lower with concomitant carbamazepine vs non-inducers (152.7 ng/mL vs 389.4 ng/mL across perampanel groups); small patient numbers for non-inducers (n = 2) should be considered when interpreting these data. Conclusion Adjunctive perampanel demonstrated a favourable safety profile and long-term tolerability in Japanese patients with refractory POS for ≤316 weeks.

In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis.Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick.A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia.Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.).

Sex hormone-binding globulin (SHBG) is a serum protein released mainly by the liver, and a low serum level correlates with a risk for metabolic syndrome including diabetes, obesity, and cardiovascular events. However, the underlying molecular mechanism(s) linking SHBG and metabolic syndrome remains unknown. In this study, using adipocytes and macrophages, we focused on thein vitroeffects of SHBG on inflammation as well as lipid metabolism. Incubation with 20 nM SHBG markedly suppressed lipopolysaccharide- (LPS-) induced inflammatory cytokines, such as MCP-1, TNFα, and IL-6 in adipocytes and macrophages, along with phosphorylations of JNK and ERK. Anti-inflammatory effects were also observed in 3T3-L1 adipocytes cocultured with LPS-stimulated macrophages. In addition, SHBG treatment for 18 hrs or longer significantly induced the lipid degradation of differentiated 3T3-L1 cells, with alterations in its corresponding gene and protein levels. Notably, these effects of SHBG were not altered by coaddition of large amounts of testosterone or estradiol. In conclusion, SHBG suppresses inflammation and lipid accumulation in macrophages and adipocytes, which might be among the mechanisms underlying the protective effect of SHBG, that is, its actions which reduce the incidence of metabolic syndrome.

Objective Intellectual disability (ID) is associated with weight gain caused by antiepileptic drugs such as valproic acid. The present study analyzed the relationship between ID and weight loss caused by topiramate (TPM). Methods Seventy-eight patients with epilepsy (35 women, aged 18 to 70 years) were enrolled in this prospective study. Body weight was measured before and 1, 6, 12, and 18 months after initiation of TPM treatment. Both patients and caregivers were provided information about TPM-related weight loss. The patients were divided into the group with no or mild ID (intelligence quotient > 50) and the group with moderate to profound ID (intelligence quotient ≤ 50). Results Body weight of both groups significantly decreased until 6 months but stabilized after 12 months. Weight loss at 6, 12, and 18 months was significantly greater in the group with no or mild ID than in the group with moderate to profound ID. Body weight change at 18 months was correlated with intellectual levels (β = 0.274, p = 0.011) and baseline body mass index (β = − 0.322, p = 0.002) by multiple linear regression analysis. Conclusions The present study suggests that the pattern of weight loss during TPM administration differs according to intellectual levels. Patients with ID maintained their body weight. Weight loss due to TPM might be weakened by caregiver control of food intake or inactivity.

Previous studies have reported changes in the dimensions of the Temperament and Character Inventory (TCI) after patients with major depressive disorder are treated. We aimed to investigate the changes in the TCI dimensions after paroxetine treatment in patients with major depressive disorder. Forty-eight patients were enrolled in this study and were treated with 10–40 mg/day of paroxetine for 6 weeks. The TCI was completed twice, at weeks 0 and 6. We used the Montgomery–Asberg Depression Rating Scale (MADRS) to evaluate patients. The participants were divided into three groups (responders, non-responders, and early responders) based on treatment response. The scores of each dimension of the TCI were compared before and after treatment using repeated-measures two-way analyses of variance. In the responders group (n = 24), no TCI dimension scores changed significantly during treatment, but the interaction between sex and MADRS score change was significantly associated with the results. In the non-responders group (n = 15), the self-directedness score increased significantly during the treatment period (p = 0.000), and the change in MADRS score significantly affected the results. In the early responders group (n = 9), no TCI dimension scores changed significantly during treatment. The results of the present study may reveal a possible correlation between paroxetine treatment and changes in personality traits. Copyright © 2015 John Wiley & Sons, Ltd.

We investigated the effects of age on the association between early and eventual responses to paroxetine treatment in patients with major depressive disorder (MDD).Eighty-nine patients with MDD were administered paroxetine and completed the 6-week protocol. On the basis of our previous study, we defined early responders as those patients with the Montgomery-Asberg Depression Rating Scale (MADRS) improvements higher than 35% at 2 weeks and responders as those patients with MADRS improvements higher than 50% at 6 weeks. The participants were divided into 4 groups in accordance with their responses: early response responders, early response nonresponders, nonearly response responders (NER-Rs), and nonearly response nonresponders (NER-NRs). Demographic data and the MADRS scores between the early response responders and the early response nonresponders and between the NER-Rs and the NER-NRs were compared. We used a receiver operating characteristic (ROC) curve to analyze age to determine the cutoff points for distinguishing responders and nonresponders in early and nonearly responders.There was a significant difference in age between the NER-Rs and the NER-NRs, with the NER-Rs being younger than the NER-NRs. The threshold for the response in the early responders was 42 years old. The area under the curve of the ROC curve of the early responders was 0.548. The threshold for the response of the nonearly responders was 55 years old. The area under the curve of the ROC curve of the early responders was 0.733.The effects of age on the association between the responsiveness in the early phase of antidepressant treatment and the eventual response were identified in patients with MDD.

Vagus nerve stimulation (VNS) is an established option of adjunctive treatment for patients with drug-resistant epilepsy, however, evidence for long-term efficacy is still limited. Studies on clinical outcomes of VNS in Asia are also limited. We report the overall outcome of a national, prospective registry that included all patients implanted in Japan. The registry included patients of all ages with all seizure types who underwent VNS implantation for drug-resistant epilepsy in the first three years after approval of VNS in 2010. The registry excluded patients who were expected to benefit from resective surgery. Efficacy analysis was assessed based on the change in frequency of all seizure types and the rate of responders. Changes in cognitive, behavioural and social status, quality of life (QOL), antiepileptic drug (AED) use, and overall AED burden were analysed as other efficacy indices. A total of 385 patients were initially registered. Efficacy analyses included data from 362 patients. Age range at the time of VNS implantation was 12 months to 72 years; 21.5% of patients were under 12 years of age and 49.7% had prior epilepsy surgery. Follow-up rate was >90%, even at 36 months. Seizure control improved over time with median seizure reduction of 25.0%, 40.9%, 53.3%, 60.0%, and 66.2%, and responder rates of 38.9%, 46.8%, 55.8%, 57.7%, and 58.8% at three, six, 12, 24, and 36 months of VNS therapy, respectively. There were no substantial changes in other indices throughout the three years of the study, except for self/family-accessed QOL which improved over time. No new safety issues were identified. Although this was not a controlled comparative study, this prospective national registry of Japanese patients with drug-resistant epilepsy, with >90% follow-up rate, indicates long-term efficacy of VNS therapy which increased over time, over a period of up to three years. The limits of such trials, in terms of AED modifications and during follow-up and difficulties in seizure counting are also discussed.

BACKGROUND We investigated the relationship between plasma concentrations of paroxetine and the therapeutic effect of the drug, and we evaluated the therapeutic reference range for plasma concentration of paroxetine in patients with major depressive disorders (MDD). METHODS In this study, 120 patients with MDD were treated with 10-40 mg/d of paroxetine for 6 weeks, and 89 patients completed the protocol. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate the patients at 0, 1, 2, 4, and 6 weeks. At the 6-week treatment time point, the patients were divided into 7 groups according to their paroxetine plasma concentrations in increments of 20 ng/mL. We used an analysis of variance and a χ test to define the therapeutic reference range for plasma paroxetine concentrations. RESULTS We used 50% as the cutoff values for the percentage of MADRS improvement to determine the responder rates, and we defined remitters as patients with MADRS scores

Clobazam (CLB) is a 1,5-benzodiazepine with antiepileptic properties. More than 70% of administered CLB is dealkylated to yield N-desmethylclobazam (N-CLB), a pharmacologically active metabolite, by cytochrome P450 (CYP) 3A4 and CYP2C19. The subsequent inactivation of N-CLB is primarily catalyzed by CYP2C19. Meanwhile, P450 oxidoreductase (POR) is the obligatory electron donor to all microsomal CYP enzymes. The aim of this study was to evaluate the impact of the CYP2C19 and POR genotypes on the pharmacokinetic parameters of CLB and N-CLB.This retrospective study included 85 Japanese patients with epilepsy who were treated with CLB. CYP2C19*2, *3, and P450 oxidoreductase (POR) *28 (rs1057868CT) polymorphisms were evaluated. A total of 128 steady-state concentrations for both CLB and N-CLB were collected from the patients. A nonlinear mixed-effects model identified the pharmacokinetics of CLB and N-CLB; the covariates included CYP2C19 and POR genotypes, weight, gender, daily CLB dose, and coadministered antiepileptic drugs.Among the 85 patients, the allele frequencies of CYP2C19*2, CYP2C19*3, and POR*28 were 27.6%, 12.9%, and 41.2%, respectively. A one-compartment model with first-order absorption and/or elimination showed that the clearance of CLB and N-CLB was significantly lower by 18.1% and 84.9%, respectively, in the CYP2C19 poor metabolizers compared with the homozygous extensive metabolizers. The CLB clearance was 44% higher in subjects homozygous for the POR*28 T allele than in those homozygous for the POR*28 C allele, although the genotypes did not affect the N-CLB clearance. The concomitant use of phenobarbital, phenytoin, and zonisamide significantly affected the CLB clearance, whereas that of carbamazepine, phenytoin, and valproic acid affected the N-CLB clearance. The weight also significantly influenced the CLB clearance and volume of distribution of both CLB and N-CLB.Our results showed that the CYP2C19 and/or POR genotypes have an impact on the CLB and/or N-CLB clearance. These results suggest that determining the CYP2C19 and/or POR genotypes is helpful for obtaining appropriate serum CLB and N-CLB concentrations and preventing an overdose when starting CLB therapy.

Mutations in GABRG2, which encodes the γ2 subunit of GABAA receptors, can cause both genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. Most GABRG2 truncating mutations associated with Dravet syndrome result in premature termination codons (PTCs) and are stably translated into mutant proteins with potential dominant-negative effects. This study involved search for mutations in candidate genes for Dravet syndrome, namely SCN1A, 2A, 1B, 2B, GABRA1, B2, and G2. A heterozygous nonsense mutation (c.118C>T, p.Q40X) in GABRG2 was identified in dizygotic twin girls with Dravet syndrome and their apparently healthy father. Electrophysiological studies with the reconstituted GABAA receptors in HEK cells showed reduced GABA-induced currents when mutated γ2 DNA was cotransfected with wild-type α1 and β2 subunits. In this case, immunohistochemistry using antibodies to the α1 and γ2 subunits of GABAA receptor showed granular staining in the soma. In addition, microinjection of mutated γ2 subunit cDNA into HEK cells severely inhibited intracellular trafficking of GABAA receptor subunits α1 and β2, and retention of these proteins in the endoplasmic reticulum. The mutated γ2 subunit-expressing neurons also showed impaired axonal transport of the α1 and β2 subunits. Our findings suggested that different phenotypes of epilepsy, e.g., GEFS+ and Dravet syndrome (which share similar abnormalities in causative genes) are likely due to impaired axonal transport associated with the dominant-negative effects of GABRG2.

OBJECTIVE We attempted to clarify the influence of polymorphisms of nuclear receptors on carbamazepine therapy. PARTICIPANTS AND METHODS The common polymorphisms of nuclear receptors--a tentative pregnane X receptor (PXR)*1B, hepatocyte nuclear factor 4α (HNF4α) rs2071197 (c.115+308G>A), and cytochrome P450 3A5*3 polymorphisms--were genotyped in 168 Japanese patients with epilepsy. The associations of these polymorphisms with the disposition, clinical efficacy, and incidence of adverse effects of carbamazepine treatment were retrospectively investigated in 104 patients treated with carbamazepine alone. The associations with disposition were also assessed in 64 patients treated with carbamazepine and other antiepileptic drugs, which constituted the internal replication group, and in the combined 168 patients. RESULTS Neither polymorphism alone affected the carbamazepine disposition, but a significant interactive effect of PXR*1B and HNF4α rs2071197 polymorphisms on the concentration-to-dose (C/D) ratios was observed (P=0.027). The C/D ratios among patients with the HNF4α G/G genotype were higher in PXR*1B carriers than in PXR*1B noncarriers, which was confirmed in the internal replication and combined groups. In patients with the HNF4α G/G genotype, the rate of freedom from seizures until 3 months after starting carbamazepine therapy was significantly greater and the time required to reach the dose required for seizure freedom was shorter in PXR*1B carriers than in PXR*1B noncarriers. CONCLUSION These results suggest that PXR*1B, in combination with HNF4α rs2071197, might be associated with the C/D ratios and the duration to reach the maintenance dose of carbamazepine therapy, thus indicating an influence upon the autoinduction of the carbamazepine metabolism.

Controversy exists regarding the similarity between depression as seen in patients with epilepsy and in those with idiopathic major depression. The objective of this study was to examine whether anger is a distinctive feature of depression in epilepsy. Participants included 487 adult patients with epilepsy (study group) and 85 patients with idiopathic major depression according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria, and without other neurological complications (control group). All participants completed the Inventory of Depressive Symptomatology Self-Report (IDS-SR) and the Buss-Perry Aggression Questionnaire (BAQ). The IDS-SR is a self-report questionnaire that measures depression severity and assesses all symptoms of depression as defined by the DSM-IV. The BAQ is a self-rating scale designed for assessing aggression. After examining potential confounding factors (i.e., demographic and clinical variables) using a multivariate linear regression model, BAQ scores were compared between the study (n = 85) and control groups (n = 54) for patients with moderate or severe depression using established cut-off points (IDS-SR score > 25). BAQ scores were significantly higher in the study group (P = 0.009). Among the BAQ subscales, only anger showed a statistically significant difference (P = 0.013). Although a significant correlation was revealed between the IDS-SR and BAQ scores in the study group, no such correlation was found in the control group. Thus, anger might be a constituent component of depression among epilepsy patients, but not among idiopathic major depression patients.

Background and Aim: Personality traits and vascular endothelial growth factor (VEGF) levels are both independently correlated with major depressive disorder and depressive mood. However, no studies have reported associations between personality traits and VEGF levels. Thus, we hypothesized that there is a correlation between the results of the Temperament and Character Inventory (TCI) and VEGF levels. Methods: We investigated 179 healthy participants who completed the TCI. We collected a serum sample from each subject and measured each participant's VEGF level by an enzyme-linked immunosorbent assay (ELISA). Simple and multiple regression analyses were performed to examine the correlations between the scores on the seven TCI dimensions and several other factors, including gender, age and VEGF level. Results: A total of 150 subjects completed the examination. Among the dimensions of the TCI, the harm avoidance (HA) scores were negatively correlated with VEGF levels, but there were no significant correlations between the scores for any other dimensions and VEGF levels. The HA score was significantly correlated with sex, age and VEGF level, and single and multiple regression analyses yielded the same results. Conclusion: VEGF may be associated with certain personality factors. This study is the first to demonstrate a direct association between VEGF levels and a dimension of the TCI in healthy subjects.

Although depression has been associated with decreased brain-derived neurotrophic factor (BDNF) levels for specific personality traits, there is a little information regarding the association between peripheral BDNF levels and such traits. The sample consisted of 178 healthy Japanese subjects (age range, 37.4±11.5 years). All subjects filled out the Temperament and Character Inventory (TCI). Plasma BDNF levels were measured using the enzyme-linked immunosorbent assay. A simple regression analysis revealed that plasma BDNF levels were significantly correlated with harm avoidance ( r =−0.177, p =0.018) and self-directedness scores ( r =0.165, p =0.028). Our findings suggest that plasma BDNF levels are associated with depression-related personality traits.

Aim The aim of this study was to investigate the association between subjective memory complaints (SMC) and sex. Methods We researched the prevalence of SMC in a sample of 394 participants who were at least 60 years of age (138 male and 256 female). We also administered the Mini-Mental State Examination (MMSE) and the Center for Epidemiologic Studies for Depression (CES-D) scale. A multiple logistic regression analysis, which included SMC in association with the MMSE or CES-D scores and other confounding factors, was performed to determine the influence of sex on SMC. A P-value

Introduction. Very few epilepsy phenotypes have been associated with causative genes; nevertheless, it is becoming possible, for some epilepsy phenotypes, to predict the most efficacious anti-epileptic drugs for patients based on their genetic makeup. The development of individualized medicine based on genetic information and the genetic diagnosis of epilepsy are expected to greatly improve the diagnosis and treatment of epilepsy. Here, we developed a DNA array (resequencing array) for the genetic diagnosis of epilepsies in which 14 epilepsy – related genes (SCN1A, SCN1B, CHRNA4, CHRNA7, CHRNB2, GABRA1, GABRD, GABRG2, CACNB4, CLCN2, KCNQ2, KCNQ3, CACNA1A, and CACNA1H) have been mounted. Aim. The aim of the present study is to evaluate the performance of our custom array in detecting the SCN1A mutations in patients with severe myoclonic epilepsy in infancy. Material and methods. We compared mutation data generated by DNA array sequencing of DNA samples from patients with severe myoclonic epilepsy in infancy to the data generated by capillary sequencing. Results. Heterozygosity was detected in 44 of 48 patients (92%). We successfully identified epilepsy mutations, and the results of DNA array analyses were largely consistent with the results of capillary sequencing analysis. Conclusion. These findings indicate that this DNA array is likely to be a useful tool in clinical settings.

Background: The Circadian Locomotor Output Cycles Kaput (CLOCK) T3111C polymorphism has been associated with several psychiatric disorders, including mood disorders and schizophrenia, which are linked to specific personality traits. We investigated the relationship between the personality traits measured by the Temperament and Character Inventory (TCI) and the C3111T polymorphism of the CLOCK gene in healthy Japanese subjects. Methods: The sample population contained 1,092 healthy subjects (age = 27.4 ± 8.7 years) who completed the TCI. Genomic DNA was isolated from whole blood and genotyped using the TaqMan allele-specific assay method. The associations between the gene polymorphisms and TCI scores were evaluated by one-way analysis of variance and multiple regression analysis. We also compared the TCI scores between the C allele carrier (C/T and C/C genotypes) and non-carrier (T/T genotype) groups using Student’s t test. Males and females were analyzed separately. Results: There was no significant association between the C3111T genotype and any TCI score, but multiple regression analyses revealed significant but opposite associations between reward dependence and the C3111T polymorphism in males and females (p = 0.032, β = 0.087 and p = 0.05, β = –0.087, respectively). Similarly, when we compared the TCI scores of CLOCK C3111T C carrier and non-carrier subjects, we found that male C allele carriers had significantly higher reward dependence scores than non-carriers (p = 0.02). Conclusion: Our findings suggest that the CLOCK C3111T polymorphism may affect personality traits in healthy Japanese subjects.

Summary Mutations of the gene encoding the α1 subunit of neuronal sodium channel, SCN1A , are reported to cause Dravet syndrome (DS). The prevalence of mutations reported in such studies (mainly in clinically confirmed DS) seems high enough to make genetic diagnosis feasible. In fact, commercially operating genetic diagnostic laboratories offering genetic analyses of SCN1A are available. Still, the exact prevalence of mutations of SCN1A remains elusive. Fukuoka University has been serving as a genetic diagnostic laboratory for DS for the last 10 years. In this study, we determined the prevalence of SCN1A mutations ( SCN1A , SCN2A , SCN1B and SCN2B ) in 448 patients with suspected DS and intractable childhood epilepsy. A total of 192 SCN1A mutations were identified in 188 of 448 patients (42.0%). The frequencies of SCN1A mutations in suspected severe myoclonic epilepsy of infancy (SMEI), its borderline phenotype (SMEB) and intractable epilepsy were 56.2%, 41.9% and 28.9% respectively. In addition, four SCN2A mutations were identified in 4 of 325 patients. No mutations of SCN1B and SCN2B were identified. These results are potentially helpful for the diagnosis of DS at early stage.

The molecular pathogenesis of benign childhood epilepsy with centrotemporal spikes (BECTS) remains unclear whereas mutations of the KCNQ2 and KCNQ3 genes have been identified as causes of benign familial neonatal convulsions. We report here a girl with benign neonatal convulsions followed by BECTS, for whom a mutation of KCNQ2 was identified. This case may provide the clue to the understanding of the molecular pathogenesis of BECTS.

Objectives In the present study, we investigated the association between the severity of each symptom evaluated by the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline and responsiveness to treatment in patients with major depressive disorder (MDD) to identify the items that predict treatment response. Methods The patients received a diagnosis of MDD if they had a score greater than 20 points on the MADRS. Following admission, 120 patients were enrolled in the study, and 89 patients completed the study. For the first week, a 20-mg/d dose of paroxetine was administered; thereafter, the dose was increased to 40 mg/d. The MADRS was applied at baseline and after 1, 2, 4, and 6 weeks. We defined responders as patients with improvements in their MADRS scores of more than 50% after 6 weeks of treatment. A multiple regression analysis of MADRS scores at 6 weeks was performed to identify patients who responded to treatment. Results There was a significant difference between responders and nonresponders in the reported sadness (RS) score for all MADRS items. In the multiple logistic regression analysis, only the RS and concentration difficulties (C) scores showed a significant association with treatment response. Based on the results of χ tests, RS score cutoff values of 2/3 and 3/4 revealed significant differences in the responder rate. None of the cutoff values for the C score revealed significant differences. Conclusions The RS score was significantly associated with responsiveness to paroxetine treatment for MDD, with higher RS scores predicting poor responses to treatment.

We report a case of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) with several characteristics distinct from previously reported cases, in which genetic studies identified mutations in two different genes. This case differed from typical ADNFLE with respect to the following: (1) slightly younger onset and refractory to antiepileptic drugs and (2) borderline intellectual functioning and coexistence of pervasive developmental disorder from infancy. Genetic testing revealed a novel mutation and a silent substitution in SCN1A (c.4285G>T, A1429S and c.4371G>C, silent) in addition to a known mutation in CHRNB2 (c.1200C>G, I312M). SCN1A is a gene that codes for the voltage-dependent sodium channel α1 subunit and has been implicated in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy in infancy. However, the relation between SCN1A and ADNFLE is unknown. We report the clinical course and symptomatic characteristics of this case although the relationship between ADNFLE mutation and SCN1A mutation remains to be elucidated.

This study examined the internal consistency and structural/construct validity of the Liebowitz Social Anxiety Scale (LSAS) for community-dwelling subjects in Japan. A cross-sectional study that included 929 participants was conducted. Structural/construct validity was assessed on confirmatory factor analysis. The internal consistency reliability was good for the overall LSAS scale (α = 0.97) and for its original four factors (α = 0.92-0.89). The original four-factor model fit the observed data relatively better than alternative models. These findings indicate that the LSAS is a valid and reliable measure of anxiety symptoms for this community-dwelling population in Japan.

Although the interaction between selective serotonin reuptake inhibitors (SSRIs) and other drugs is important in the treatment of depression, there have been few studies of SSRIs concerning transporter-mediated interactions in humans. The objective of this study was to evaluate the in vivo effects of commonly used SSRIs on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate.Twelve healthy volunteers (3 females and 9 males) were enrolled in this study. Each subject received a 60-mg dose of fexofenadine orally at baseline. Afterward, they were randomly assigned to receive 3 treatments with a 60-mg dose of fexofenadine after a 7-day treatment with fluvoxamine (50 mg/d), paroxetine (20 mg/d), or sertraline (50 mg/d), with 2-week intervals between the agents.Fluvoxamine pretreatment significantly increased the maximum plasma concentration, the area under the concentration time curves, and the 24-hour urinary fexofenadine excretion by 66% (P = 0.004), 78% (P = 0.029), and 78% (P0.001), respectively, without prolonging its elimination half-life. Paroxetine extended the elimination half-life of fexofenadine by 45% (P = 0.042), and it increased the 24-hour urinary fexofenadine excretion by 55% (P = 0.002). Sertraline did not alter any of the pharmacokinetic parameters of fexofenadine.This is the first report of the different effects of 3 commonly used SSRIs on fexofenadine pharmacokinetics in humans. Our 7-day, repeated-dose clinical study in healthy volunteers indicates that fluvoxamine and paroxetine, but not sertraline, may impact the patient exposure to fexofenadine, which is likely the result of P-glycoprotein inhibition in the small intestine and/or the liver.

The association between the superoxide dismutase 2 (SOD2) Val16Ala polymorphism and the serum aminotransferase levels was retrospectively investigated in 207 valproic acid-treated patients with epilepsy. The Val/Val genotype tended to show elevated alanine aminotransferase levels (odds ratio=3.5; P=0.056). In addition, an elevated γ-glutamyltransferase level was associated with the Val/Val genotype (odds ratio=3.1; P=0.022). The SOD2 Val/Val genotype may therefore contribute to a valproic acid-induced elevation in the serum aminotransferase levels.

Background The rate of suicides markedly increased in 1998 and leveled off at approximately 30,000 per year thereafter. The aim of the current study was to evaluate the link between the different dimensions of depressive symptoms and suicidal ideation among the middle-aged population in Japan. Method A sample of 6848 middle-aged (40–60 years of age) working individuals completed the Center for Epidemiological Studies Depression Scale (CES-D) and a questionnaire measuring suicidal ideation. The responses on the four dimensions of depressive symptoms on the CES-D (depressed affect, lack of positive affect, somatic symptoms, and interpersonal problems) were entered into regression analyses that predicted the presence of suicidal ideation among the participants with probable depression (n = 1704). Results The factor score of depressed affect was significantly higher in females than in males, whereas that of interpersonal problems was significantly higher in males than in females. Among both males and females, depressed affect was a significant predictor of suicidal ideation. Among males, interpersonal problems also significantly predicted suicidal ideation. Contrary to the results of a previous study among adolescents, we did not find a relationship between lack of positive affect and suicidal ideation. Conclusions These findings indicate that the dimensions of depressive symptoms measured with the CES-D make different contributions to suicidal ideation. Although our results could not be generalizable to a clinical setting due to lacking clinical samples, the depressed affect dimension of CES-D might be useful for screening of suicide risk among community population. Furthermore, gender differences in the relationships between the dimensions of depressive symptoms in a middle-aged population were identified. Additional studies are needed to examine gender-specific relationships between the dimensions of depressive symptoms and suicidal ideation.