Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

Background

Dysfunction of glutamate neurotransmission has been implicated in the pathology of schizophrenia and bipolar disorder, and one mechanism by which glutamate signalling can be altered is through RNA editing of ionotropic glutamate receptors (iGluRs). The objectives of the present study were to evaluate the editing status of iGluRs in the human prefrontal cortex, determine whether iGluR editing is associated with psychiatric disease or suicide and evaluate a potential association between editing and alternative splicing in the α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) iGluR subunits’ pre-mRNA.

Methods

We studied specimens derived from patients with antemortem diagnoses of bipolar disorder (n = 31) or schizophrenia (n = 34) who died by suicide or other causes, and from psychiatrically healthy controls (n = 34) who died from causes other than suicide. The RNA editing at all 8 editing sites within AMPA (GluA2–4 subunits) and kainate (GluK1–2 subunits) iGluRs was analyzed using a novel real-time quantitative polymerase chain reaction assay.

Results

No differences in editing were detected among schizophrenia, bipolar or control groups or between suicide completers and patients who died from causes other than suicide. The editing efficiency was significantly higher in the flop than in the flip splicoforms of GluA3-4 AMPA subunits (all p < 0.001).

Limitations

The study is limited by the near absence of specimens from medication-naive psychiatric patients and considerable variation in medication regimens among individuals, both of which introduce considerable uncertainty into the analysis of potential medication effects.

Conclusion

We found that iGluR RNA editing status was not associated with bipolar disorder, schizophrenia or suicide. Differences in editing between flip and flop splicoforms suggest that glutamate sensitivity of receptors containing GluA3 and/or GluA4 flop subunits is moderated as a result of increased editing.     

Dysregulation of the sympathetic nervous system,hypothalamic–pituitary–adrenal axis and executive function in individuals at risk for suicide

Background

Suicidal behaviour aggregates in families, and the hypothalamic–pituitary–adrenal (HPA) axis and noradrenergic dysregulation may play a role in suicide risk. It is unclear whether stress dysregulation is a heritable trait of suicide or how it might increase risk. We investigated stress reactivity of the autonomic nervous system and the HPA axis in suicide predisposition and characterized the effect of this dysregulation on neuropsychologic function.

Methods

In this family-based study of first-degree relatives (n = 14) of suicide completers and matched controls with no family or personal history of suicidal behaviour (n = 14), participants underwent the Trier Social Stress Test (TSST). We used salivary α-amylase and cortisol levels to characterize stress reactivity and diurnal variation. We administered a series of neuropsychologic and executive function tests before and after the TSST.

Results

Despite normal diurnal variation, relatives of suicide completers exhibited blunted cortisol and α-amylase TSST reactivity. Although there were no baseline differences in conceptual reasoning, sustained attention or executive function, the relatives of suicide completers did not improve on measures of inhibition upon repeated testing after TSST. Secondary analyses suggested that these effects were related to suicide vulnerability independent of major depression.

Limitations

The sample size was small, and the design prevents us from disentangling our findings from the possible traumatic consequences of losing a relative by suicide.

Conclusions

Blunted stress response may be a trait of suicide risk, and impairment of stress-induced executive function may contribute to suicide vulnerability.     

Differential brain glucose metabolic patterns in antipsychotic-naïve first-episode schizophrenia with and without auditory verbal hallucinations

Background

Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia. Previous reports on neural activity patterns associated with AVHs are inconsistent, arguably owing to the lack of an adequate control group (i.e., patients with similar characteristics but without AVHs) and neglect of the potential confounding effects of medication.

Methods

The current study was conducted in a homogeneous group of patients with schizophrenia to assess whether the presence or absence of AVHs was associated with differential regional cerebral glucose metabolic patterns. We investigated differences between patients with commenting AVHs and patients without AVHs among a group of dextral antipsychotic-naive inpatients with acute first-episode schizophrenia examined with [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) at rest. Univariate and multivariate approaches were used to establish between-group differences.

Results

We included 9 patients with AVHs and 7 patients without AVHs in this study. Patients experiencing AVHs during FDG uptake had significantly higher metabolic rates in the left superior and middle temporal cortices, bilateral superior medial frontal cortex and left caudate nucleus (cluster level p < 0.005, family wise error–corrected, and bootstrap ratio > 3.3, respectively). Additionally, the multivariate method identified hippocampal–parahippocampal, cerebellar and parietal relative hypoactivity during AVHs in both hemispheres (bootstrap ratio < −3.3).

Limitations

The FDG-PET imaging technique does not provide information regarding the temporal course of neural activity. The limited sample size may have increased the risk of false-negative findings.

Conclusion

Our results indicate that AVHs in patients with schizophrenia may be mediated by an alteration of neural pathways responsible for normal language function. Our findings also point to the potential role of the dominant caudate nucleus and the parahippocampal gyri in the pathophysiology of AVHs. We discuss the relevance of phenomenology-based grouping in the study of AVHs.     

Neural synchrony in patients with a first episode of schizophrenia: tracking relations with grey matter and symptom profile

Background

Although schizophrenia has been characterized by disruptions to neural synchrony, it remains unknown whether these disturbances are related to symptoms and loss of grey matter. We examined relations between 40 Hz Gamma band synchrony and grey matter in patients with schizophrenia at first episode and after 2.5 years.

Methods

From an initial recruitment of 35 medicated patients with a first episode of schizophrenia, 25 patients completed clinical and oddball task-elicited Gamma synchrony within 3 months of health service contact and again after 2.5 years, 23 completed magnetic resonance imaging (MRI) at these time points, and 13 completed all sessions. We compared patients with 35 matched healthy controls. We identified early (0–150 ms) and late (250–500 ms) peaks in Gamma synchrony locked to oddball targets, and we analyzed MRI data using voxel-based morphometry. We evaluated group and test–retest differences using repeated-measures analyses of variance.

Results

Compared with controls, at first contact, patients with a first episode of schizophrenia showed a disruption to the laterality of early Gamma synchrony and global reduction in late Gamma synchrony, with a corresponding loss of fronto–temporal–parietal grey matter. Gamma synchrony was increased at follow-up among patients with a first episode of schizophrenia. It related negatively to further loss of grey matter, but positively to improvement in reality distortion symptoms. These relations could not be explained by medication dose.

Limitations

Our study did not include unmedicated patients or normative follow-up testing.

Conclusion

Gamma synchrony may track the progression of schizophrenia from first episode. An increase in Gamma synchrony over time might reflect an attempt to adapt to a progressive loss of cortical grey matter and associated changes in cognitive and emotional function.     

Perception of smoking risks and motivation to quit among nontreatment-seeking smokers with and without schizophrenia

Objective:

We examined perceived consequences/benefits of cigarette smoking and motivation for quitting in nontreatment-seeking smokers who had schizophrenia or schizoaffective disorder (N = 100) or had no Axis I psychiatric disorder (normals, N = 100).

Methods:

Participants completed questionnaires and provided a breath carbon monoxide (CO) sample 10–15 minutes after smoking 1 preferred-brand cigarette. Primary assessments included the Smoking Consequences Questionnaire-Adult, the Reasons for Quitting Scale, and the Stages of Change.

Results:

There were no differences between the schizophrenia and control group in mean age of smoking onset (16.2 ± 5.4 vs 15.6 ± 5.5 y, P = .44), number of cigarettes daily (17.9 ± 11.6 vs 17.0 ± 7.9, P = 0.51), or in breath CO (28.0 ± 14.5 vs 22.9 ± 8.0 ppm, P = .61). Compared with normals, people with schizophrenia report greater stimulation/state enhancement (P < .0001) and social facilitation (P < .004) from smoking. People with schizophrenia had less appreciation of health risks associated with smoking than normal controls (P < .0001) and were less motivated to quit smoking than normal controls (P = .002), even though they were as likely to be in the preparation stage of change. Immediate reinforcement (P = .04) and health concerns (P = .002) were rated lower as motivators for considering quitting smoking in schizophrenia than normals. People with schizophrenia reported greater motivation to stop smoking due to social pressure/rewards than normals (P = .047).

Conclusions:

This study underscores the degree to which people with schizophrenia perceive the state-enhancing effects of smoking and their lower appreciation for health risks of smoking compared with normal controls.     

Predictors of Suicidal Ideation in People with Epilepsy Living in Korea

Background and Purpose

The risk of suicide or suicide attempts is reported higher in people with epilepsy (PWE) than in the general population. Although epileptic, psychiatric, and psychosocial factors are known risk factors for suicide or suicide attempt, no studies have evaluated the predictors of the severity of suicidal ideation-which is a warning sign for suicide attempts-in PWE. Therefore, we measured the severity of suicidal ideation and its risk factors.

Methods

Consecutive PWE who were medicated with antiepileptic drugs (AEDs) and attended epilepsy clinic were included in the study. The subjects completed self-reported questionnaires, which included the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Symptom Checklist-90-Revised (SCL-90-R), and Scale for Suicide Ideation-Beck (SSI-Beck). We compared the patients'' demographic and clinical variables, and BDI, BAI, and SCL-90-R scores with their SSI-Beck score, and used our findings to determine the predictors for suicidal ideation.

Results

In total, 257 PWE were enrolled in the study. SSI-Beck scores correlated strongly with several seizure-related variables, duration of education, IQ, BDI and BAI scores, and nine domains of the SCL-90-R questionnaire. However, the strongest predictor for suicidal ideation was BDI score (β=0.41, p<0.001), followed by several SCL-90-R domains, such as obsessive-compulsive (β=-0.39, p<0.001), depression (β=0.38, p<0.001), hostility (β=0.22, p=0.002), paranoid ideation (β=0.17, p=0.01), and IQ (β=-0.10, p=0.017). These variables explained 59% of the variance in the SSI-Beck score. The seizure-related variables that influenced the BDI score were seizure frequency, duration of education, MRI abnormality, and number of AEDs. However, these variables explained only 18% of the variance in the BDI score.

Conclusions

Major risk factors for suicidal ideation in PWE were depressive and psychiatric symptoms rather than seizure-related variables. Therefore, clinicians should focus on screening for depression and other psychiatric problems and treat them appropriately in order to reduce suicidal behavior in PWE. Since seizure-related variables also exhibited a minor role in determining depressive symptoms, stronger seizure-related risk factors for depression should be sought, such as seizure severity or psychosocial factors, to minimize suicidal behavior.     

Acute Risk of Suicide and Suicide Attempts Associated With Recent Diagnosis of Mental Disorders: A Population-Based,Propensity Score–Matched Analysis

Objective:

To determine the degree of risk during the first year after diagnosis with a mental illness.

Methods:

We used propensity scoring to create a matched sample for all identified suicide attempts and suicide deaths in the province of Manitoba from 1996 to 2009. This study identified 2100 suicide deaths and 8641 attempted suicides. Three control subjects were identified for every case and matched on age, sex, income decile, region of residence, and marital status. Five categories of physician-diagnosed mental disorders were tested: schizophrenia, anxiety, depression, dementia, and substance abuse. Logistic regression was used to determine the risk for suicide attempts and suicide deaths overall, and within 3 time periods since initial diagnosis: 1 to 90 days, 91 to 364 days, and 365 or more days.

Results:

All disorders, except dementia, were independently related to death. All disorders were related to suicide attempts. The risk of dying by suicide was particularly high within the first 90 days after initial diagnosis for many disorders, including depression (adjusted odds ratio [AOR] 7.33; 95% CI 4.76 to 11.3), substance use disorders (AOR 4.07; 95% CI 2.43 to 6.82), and schizophrenia (AOR 20.91; 95% CI 2.55 to 172). Depression and anxiety disorders had elevated risk in the first year for suicide attempts.

Conclusions:

These data suggest that several mental disorders independently increase the risk of suicide attempts and death by suicide after controlling for all mental disorders and demographic risk factors. Clinicians should be aware of the heightened risk of suicide and suicidal behaviour within the first 3 months after initial diagnosis.     

Clinical Characteristics and Precipitating Factors of Adolescent Suicide Attempters Admitted for Psychiatric Inpatient Care in South Korea

Objective

We aimed to examine the rates, correlates, methods, and precipitating factors of suicide attempts among adolescent patients admitted for psychiatric inpatient care from 1999 to 2010 in a university hospital in Korea.

Methods

The subjects consisted of 728 patients who were admitted for psychiatric inpatient care in a university hospital over a 12-year period and who were aged 10-19 years at the time of admission. We retrospectively investigated the information on suicidal behaviors and other clinical information by reviewing the subjects'' electronic medical records. Whether these patients had completed their suicide on 31 December 2010 was determined by a link to the database of the National Statistical Office.

Results

Among 728 subjects, 21.7% had suicidal ideation at admission, and 10.7% admitted for suicidal attempts. Female gender, divorced/widowed parents, and the presence of mood disorders were associated with a significantly increased likelihood of suicide attempts. Most common method of suicide attempts was cutting, and most common reason for suicide attempts was relationship problems within the primary support group. A diagnosis of schizophrenia was associated with increased risk of death by suicide after discharge.

Conclusion

These results highlight the role of specific psychosocial factor (e.g., relational problems) and psychiatric disorders (e.g., mood disorders) in the suicide attempts of Korean adolescents, and the need for effective prevention strategies for adolescents at risk for suicide.     

Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility

Background:

Our genome-wide association study of schizophrenia found association signals at the Kalirin gene (KALRN) and EPH receptor B1 gene (EPHB1) in a Japanese population. The importance of these synaptogenic pathway genes in schizophrenia is gaining independent supports. Although there has been growing interest in rare (<1%) missense mutations as potential contributors to the unexplained heritability of schizophrenia, there are no population-based studies targeting rare (<1%) coding mutations with a larger effect size (eg, OR >1.5) in KALRN or EPHB1.

Methods and Results:

The present study design consisted of 3 phases. At the discovery phase, we conducted resequencing analyses for all exon regions of KALRN and EPHB1 using a DNA microarray–based method. Seventeen rare (<1%) missense mutations were discovered in the first sample set (320 schizophrenic patients). After the prioritization phase based on frequencies in the second sample set (729 cases and 562 controls), we performed association analyses for each selected mutation using the third sample set (1511 cases and 1517 controls), along with a combined association analysis across all selected mutations. In KALRN, we detected a significant association between schizophrenia and P2255T (OR = 2.09, corrected P = .048, 1 tailed); this was supported in the combined association analysis (OR = 2.07, corrected P = .006, 1 tailed). We found no evidence of association of EPHB1 with schizophrenia. In silico analysis indicated the functional relevance of these rare missense mutations.

Conclusion:

We provide evidence that multiple rare (<1%) missense mutations in KALRN may be genetic risk factors for schizophrenia.     

Cognitive impairment in elderly women: the relative importance of selected genes, lifestyle factors, and comorbidities

Background

A variety of factors contribute to the development of cognitive impairment in elderly people. Previous studies have focused upon a single or a few risk factors. In this study we assessed and compared the significance of a wide variety of potential risk factors for cognitive impairment in postmenopausal women.

Methods

A total of 208 pairs of elderly women (mean age = 73.2 years) were examined in a cross-sectional case-control study. Each pair consisted of a case (with impaired cognition) and a control subject matched by age and educational status. Cognitive functions were determined using a modified version of the Blessed test. Participants were also subjected to a general clinical examination and they were interviewed to collect information on lifestyle practices and comorbid disorders. Genotypes for the apolipoprotein E (APOE) epsilon4, catechol-O-methyltransferase (COMT) Val/Met, and brain-derived neurotropic growth factor (BDNF) Val/Met polymorphisms were determined. Data were analyzed by conditional logistic regression.

Results

We identified a set of risk factors for age-related cognitive impairment. A statistical model for assessment of the importance of these factors was constructed. The factors in this model were physical exercise (odds ratio [OR] = 0.50, 95% confidence interval [CI] = 0.32–0.78), regular alcohol consumption (OR = 0.49, 95% CI = 0.29–0.83), metabolic syndrome (OR = 2.83, 95% CI = 1.26–6.39), depression (OR = 3.24, 95% CI = 1.28–8.22), and the APOE epsilon4 allele (OR = 1.76, 95% CI = 1.09–2.83). Also COMT genotype was present as a risk factor in the statistical model (p = 0.08).

Conclusions

Lifestyle risk factors, comorbid disorders, and genetic factors contribute to development of age-related cognitive impairment. The two former groups of risk factors appear to be particular important in this respect.     

Association between the NMDA glutamate receptor GRIN2B gene and obsessive-compulsive disorder

Background

Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neurotransmission in the pathogenesis of obsessive–compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-d-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes.

Methods

Between 2003 and 2008, we performed a case–control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′ UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions.

Results

We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37–4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22–3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions.

Limitations

Study limitations included the risk of population stratification associated with the case–control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3′ UTR and exon 13 of GRIN2B.

Conclusion

Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder.     

Phenotypically continuous with clinical psychosis, discontinuous in need for care: evidence for an extended psychosis phenotype

Background:

Rates of self-reported psychotic experiences (SRPEs) in general population samples are high; however the reliability against interview-based assessments and the clinical significance of false-positive (FP) ratings remain unclear. Design: The second Netherlands Mental Health Survey and Incidence Study-2, a general population study.

Methods:

Trained lay interviewers administered a structured interview assessing psychopathology and psychosocial characteristics in 6646 participants. Participants with at least one SRPE (N = 1084) were reassessed by clinical telephone interview.

Results:

Thirty-six percent of participants with SRPEs were confirmed by clinical interview as true positive (TP). SPREs not confirmed by clinical interview (FP group) generated less help-seeking behavior and occurred less frequently compared with TP experiences (TP group). However, compared with controls without psychotic experiences, the FP group more often displayed mood disorder (relative risk [RR] 1.7, 1.4–2.2), substance use disorder (RR 2.0, 1.6–2.6), cannabis use (RR 1.5, 1.2–1.9), higher levels of neuroticism (RR 1.8, 1.5–2.2), affective dysregulation, and social dysfunction. The FP group also experienced more sexual (RR 2.0, 1.5–2.8) and psychological childhood trauma (RR 2.1, 1.7–2.6) as well as peer victimization (RR 1.5, 1.2–2.0) and recent life events (RR 2.0, 1.6–2.4) than controls without psychotic experiences. Differences between the FP group and the TP group across these domains were much smaller and less conclusive.

Discussion:

SRPEs not confirmed by clinical interview may epresent the softest expression of an extended psychosis phenotype that is phenotypically continuous with clinical psychosis but discontinuous in need for care.     

Alterations in White Matter Evident Before the Onset of Psychosis

Background

Psychotic disorders are associated with widespread reductions in white matter (WM) integrity. However, the stage at which these abnormalities first appear and whether they are correlates of psychotic illness, as opposed to an increased vulnerability to psychosis, is unclear. We addressed these issues by using diffusion tensor imaging (DTI) to study subjects at ultra high risk (UHR) of psychosis before and after the onset of illness.

Methods

Thirty-two individuals at UHR for psychosis, 32 controls, and 15 patients with first-episode schizophrenia were studied using DTI. The UHR subjects and controls were re-scanned after 28 months. During this period, 8 UHR subjects had developed schizophrenia. Between-group differences in fractional anisotropy (FA) and diffusivity were evaluated cross sectionally and longitudinally using a nonparametric voxel-based analysis.

Results

At baseline, WM DTI properties were significantly different between the 3 groups (P < .001). Relative to controls, first-episode patients showed widespread reductions in FA and increases in diffusivity. DTI indices in the UHR group were intermediate relative to those in the other 2 groups. Longitudinal analysis revealed a significant group by time interaction in the left frontal WM (P < .001). In this region, there was a progressive reduction in FA in UHR subjects who developed psychosis that was not evident in UHR subjects who did not make a transition.

Conclusions

People at UHR for psychosis show alterations in WM qualitatively similar to, but less severe than, those in patients with schizophrenia. The onset of schizophrenia may be associated with a progressive reduction in the integrity of the frontal WM.     

Repetitive transcranial magnetic stimulation for hallucination in schizophrenia spectrum disorders A meta-analysis

OBJECTIVE:This study assessed the efficacy and tolerability of repetitive transcranial magnetic stimulation for treatment of auditory hallucination of patients with schizophrenia spectrum disorders.DATA SOURCES:Online literature retrieval was conducted using PubMed,ISI Web of Science,EMBASE,Medline and Cochrane Central Register of Controlled Trials databases from January1985 to May 2012.Key words were"transcranial magnetic stimulation","TMS","repetitive transcranial magnetic stimulation",and"hallucination".STUDY SELECTION:Selected studies were randomized controlled trials assessing therapeutic efficacy of repetitive transcranial magnetic stimulation for hallucination in patients with schizophrenia spectrum disorders.Experimental intervention was low-frequency repetitive transcranial magnetic stimulation in left temporoparietal cortex for treatment of auditory hallucination in schizophrenia spectrum disorders.Control groups received sham stimulation.MAIN OUTCOME MEASURES:The primary outcome was total scores of Auditory Hallucinations Rating Scale,Auditory Hallucination Subscale of Psychotic Symptom Rating Scale,Positive and Negative Symptom Scale-Auditory Hallucination item,and Hallucination Change Scale.Secondary outcomes included response rate,global mental state,adverse effects and cognitive function.RESULTS:Seventeen studies addressing repetitive transcranial magnetic stimulation for treatment of schizophrenia spectrum disorders were screened,with controls receiving sham stimulation.All data were completely effective,involving 398 patients.Overall mean weighted effect size for repetitive transcranial magnetic stimulation versus sham stimulation was statistically significant(MD=–0.42,95%CI:–0.64 to–0.20,P=0.000 2).Patients receiving repetitive transcranial magnetic stimulation responded more frequently than sham stimulation(OR=2.94,95%CI:1.39 to 6.24,P=0.005).No significant differences were found between active repetitive transcranial magnetic stimulation and sham stimulation for positive or negative symptoms.Compared with sham stimulation,active repetitive transcranial magnetic stimulation had equivocal outcome in cognitive function and commonly caused headache and facial muscle twitching.CONCLUSION:Repetitive transcranial magnetic stimulation is a safe and effective treatment for auditory hallucination in schizophrenia spectrum disorders.     

Clinical significance of detection of antibodies to fetal and adult acetylcholine receptors in myasthenia gravis

Objective To evaluate the frequency, distribution and clinical significance of the antibodies to the fetal and/or adult acetylcholine receptor (AChR) in patients with myasthenia gravis (MG). Methods AChR antibodies were detected by cell-based assay in the serum of ocular MG (OMG) (n = 90) and generalized MG (GMG) patients (n = 110). The fetal-type (2α: β: γ: δ) and adult-type (2α: β: ε: δ) AChR were used as antigens, and their relevance to disease presentation was assessed. Results The overall frequencies of anti-adult and anti-fetal AChR antibodies were similar in all 200 patients examined, with 14 having serum specific to the AChR-γ subunit, and 22 to the AChR-ε subunit. The overall sensitivity when using the fetal and adult AChR antibodies was higher than that when using the fetal AChR antibody only (P = 0.015). Compared with OMG patients, the mean age at disease onset and the positive ratio of antibodies to both isoforms of the AChR were significantly higher in patients who subsequently progressed to GMG. Older patients and patients with both anti-fetal and anti-adult AChR antibodies had a greater risk for developing generalized disease [odds ratio (OR), 1.03; 95% confidence interval (CI), 1.01-1.06 and OR, 5.09; 95% CI, 2.23-11.62]. Conclusion Using both fetal-and adult-type AChRs as the antigens may be more sensitive than using either subtype. Patients with serum specific to both isoforms are at a greater risk of progressing to GMG. Patients with disease onset at an advanced age appear to have a higher frequency of GMG conversion.     

Topiramate diminishes fear memory consolidation and extinguishes conditioned fear in rats

Background

Topiramate has been recognized as a drug that can induce memory and cognitive impairment. Using the one-trial inhibitory avoidance task, we sought to verify the effect of topiramate on consolidation and extinction of aversive memory. Our hypothesis was that topiramate inhibits the consolidation and enhances the extinction of this fear memory.

Methods

In experiment 1, which occured immediately or 3 hours after training, topiramate was administered to rats, and consolidation of memory was verified 18 days after the conditioning session. In experiment 2, which occured 18–22 days after the training session, rats were submitted to the extinction protocol. Rats received topiramate 14 days before or during the extinction protocol.

Results

Topiramate blocked fear memory retention (p < 0.01) and enhanced fear memory extinction (p < 0.001) only when administered during the extinction protocol.

Limitations

This experimental design did not allow us to determine whether topiramate also blocked the reconsolidation of fear memory.

Conclusion

Topiramate diminishes fear memory consolidation and promotes extinction of inhibitory avoidance memory.     

Neurocognitive Vulnerability: Suicidal and Homicidal Behaviours in Patients With Schizophrenia

Objective

Schizophrenia is associated with an increase in the risk of both homicide and suicide. The objectives of this study were to systematically review all published articles that examined the relation between neurocognitive deficits and suicidal or homicidal behaviours in schizophrenia, and to identify vulnerabilities in suicidal and homicidal behaviour that may share a common pathway in schizophrenia.

Methods:

A systematic review of the literature was performed using MEDLINE to include all studies published up to August 31, 2012.

Results:

Among the 1760 studies, 7 neuropsychological and 12 brain imaging studies met the selection criteria and were included in the final analysis. The neuropsychological and functional neuroimaging studies were inconclusive. The structural imaging studies reported various alterations in patients with schizophrenia and a history of homicidal behaviour, including: reduced inferior frontal and temporal cortices, increased mediodorsal white matter, and increased amygdala volumes. Patients with a history of suicidal acts showed volumetric reductions in left orbitofrontal and superior temporal cortices, while right amygdala volume was increased, though, these findings have rarely been replicated. Finally, no study has directly compared neurocognitive markers of suicidal and homicidal risk.

Conclusion:

These results suggest that brain alterations, in addition to those associated with schizophrenia, may predispose some patients to a higher risk of homicide or suicide in particular circumstances. Moreover, some of these alterations may be shared between homicidal and suicidal patients. However, owing to several limitations, including the small number of available studies, no firm conclusions can be drawn and further investigations are necessary.     

ApoE and cholesterol in schizophrenia and bipolar disorder: comparison of grey and white matter and relation with APOE genotype

Background

Apolipoprotein E (apoE) and cholesterol play a critical role in synapse and myelin maintenance and integrity and are thus appealing candidates in the pathogenesis of schizophrenia and bipolar disorder. To explore the role of these 2 molecules, we quantified cholesterol and apoE levels in prefrontal grey and white matter in patients with schizophrenia, bipolar disorder and healthy controls. Furthermore, we investigated the relations between apoE and cholesterol levels and the APOE genotype.

Methods

We obtained dorsolateral prefrontal grey and white matter from the Stanley Medical Research Institute Brain Collection (schizophrenia n = 35, bipolar disorder n = 35 and controls n = 35). Cholesterol levels were quantified using high-pressure liquid chromatography, whereas apoE was measured by enzyme-linked immunosorbent assay.

Results

We found no significant differences in cholesterol or apoE levels among the groups. ApoE levels were higher in grey matter than in white matter in all groups; conversely, levels of cholesterol were higher in white matter than in grey matter. We observed a significant inverse correlation between apoE and cholesterol levels in both grey and white matter. Furthermore, in grey matter, apoE levels were significantly higher in APOE ɛ2 carriers compared with APOE ɛ3 or APOE ɛ4 carriers, with cholesterol levels following the opposite trend.

Limitations

Limitations of our study include our inability to control for potential confounding variables and the small numbers of APOE ɛ2 and ɛ4 carriers in each group.

Conclusion

Although large amounts of cholesterol are present in white matter, apoE expression is limited. The APOE genotype may play a role in the regulation of both cholesterol and apoE levels in grey matter. The impact of APOE polymorphisms on lipid homeostasis in people with psychiatric disorders warrants further investigation.     

Suicide Risk Assessments: Which Suicide Risk Factors Psychiatric Residents Consider Significant?

Objective

Patients visiting the emergency department (ED) after a suicide attempt are generally assessed for suicide risk by psychiatric residents. Psychiatric residents'' competence in evaluating the risk posed by the patients who attempted suicide is critical to preventing suicide.

Methods

We investigated factors considered important by psychiatric residents when evaluating suicide risk. This study included 140 patients admitted to the ED after attempting suicide. Psychiatric residents rated patients'' severity of current and future suicide risk as low/moderate/high using the Brief Emergency Room Suicide Risk Assessment (BESRA). The association between each BESRA variable and level of suicide risk was analyzed.

Results

Many factors were commonly considered important in evaluating the severity of current and future suicide risk. However, the following factors were only associated with future suicide risk: female gender, having no religion, family psychiatric history, history of axis I disorders, having a will, harboring no regrets, and social isolation.

Conclusion

Psychiatric residents use diverse factors when assessing suicide risk. Psychiatric residents might put more emphasis on non-modifiable demographic and clinical factors, concrete evidence showing suicide determination, and social isolation to assess the risk of future suicide.     

Psychosocial Factors Contributing to Suicidal Ideation in Hospitalized Schizophrenia Patients in Korea

Objective

This study aimed to comprehensively evaluate psychosocial risk factors associated with suicidality in patients with schizophrenia in Korea.

Methods

The study sample consisted of 84 hospitalized patients with schizophrenia. Suicidal thoughts and a clear desire to be dead within 2 weeks were defined as a current suicidal ideation. Socio-demographic and clinical variables, including family history of completed suicides and psychiatric illnesses, were collected, and the Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Beck Depression Inventory (BDI), Simpson-Angus Scale (SAS), Scale to assess Unawareness of Mental Disorder (SUMD), and Alcohol Use Disorders Identification Test (AUDIT) were administered to identify factors associated with a current suicidal ideation.

Results

Forty-three subjects (51.2%) reported clear suicidal ideation. Multivariate analysis revealed that later age of illness onset, previous suicide attempt, family history of completed suicide, depression, or substance abuse, fewer than one family visitation to the hospital per month, and score on the CDSS were independently related to current suicidal ideation in these subjects. Age, education level, and scores on the SUMD were not significantly associated with current suicidal ideation in the multivariate analysis, but were associated with suicidal ideation in a univariate analysis on the level of p<0.1.

Conclusion

The above clinical factors should be evaluated to predict and prevent suicidal risk in patients with schizophrenia. In particular, modifiable factors such as depression should be managed to reduce suicidality of hospitalized patients with schizophrenia.