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.     

Polarity of the First Episode and Time to Diagnosis of Bipolar I Disorder

Objective

The current study explored the relationship between the polarity of the first episode and the timing of eventual diagnosis of bipolar I disorder, and associated clinical implications.

Methods

Twelve years of clinical data from the medical records of 258 inpatients meeting DSM-III-R or DSM-IV criteria for bipolar I disorder were analyzed. Subjects were divided into two groups according to the polarity of the first episode: those with depressive polarity (FE-D), and those with manic polarity (FE-M). Comparisons were made between the two groups on variables associated with the timing of diagnosis and related outcomes.

Results

In population with bipolar I disorder, a significant longer time lapse from the first major mood episode to the confirmed diagnosis was associated with the FE-D group compared to the FE-M group [5.6 (±6.1) vs. 2.5 (±5.5) years, p<0.001]. FE-D subjects tended to have prior diagnoses of schizophrenia and major depressive disorder while FE-M subjects tended to have prior diagnoses of bipolar disorder and schizophrenia. A significantly higher rate of suicide attempts was associated with the FE-D group compared to the FE-M group (12.7 vs. 1.7%, p<0.001).

Conclusion

The results of this study indicate that first-episode depressive polarity is likely to be followed by a considerable delay until an eventual confirmed diagnosis of bipolar I disorder. Given that first-episode depressive patients are particularly vulnerable to unfavorable clinical outcomes such as suicide attempts, a more systematic approach is needed to differentiate bipolar disorder among depressed patients in their early stages.     

Catatonic Schizophrenia: A Cohort Prospective Study

Background:

In the 20th century, catatonia was usually deemed a subtype of schizophrenia. Recently, the nature and classification of catatonia are being reconsidered. This study is the first to describe catatonia using prospectively collected data and to examine how catatonic schizophrenia differs from, or resembles, other types of schizophrenia.

Methods:

Data were analyzed in a cohort of 90 079 offspring followed from birth till ages 29–41 years. Proportional hazards models were used, calculating time to first psychiatric hospital admission, to compare risk factors for catatonic schizophrenia vs “other schizophrenia.”

Results:

Of 568 cases of schizophrenia, 43 (7.6%) had catatonic schizophrenia. The sexes were equally at risk for catatonic schizophrenia in contrast to other schizophrenia, for which the incidence was higher in males (1.70, 1.42–2.03, P < .0001). Advancing paternal age had no influence on the risk of catatonic schizophrenia in contrast to other schizophrenia, in which the risk to offspring of fathers age 35+ was 1.27 (1.03–1.57, P = .03) compared with those of younger fathers. Those with catatonic schizophrenia were somewhat more likely to have older mothers (aged 35+) (relative risk = 2.14, 0.85–5.54) while maternal age was not related to other schizophrenia. Both were equally affected by parental history of schizophrenia. Patients with catatonia were significantly more likely to attempt suicide (P = .006).

Conclusion:

Patients with catatonic schizophrenia show a somewhat different profile of risk factors from those with other types of schizophrenia in this cohort and are more likely to attempt suicide. This lends some support to the hypothesis that catatonic schizophrenia may have a distinct etiology.     

Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder

Background

Patients with schizophrenia show elevated brain levels of the neuroactive tryptophan metabolite kynurenic acid (KYNA). This astrocyte-derived mediator acts as a neuroprotectant and modulates sensory gating and cognitive function. We measured the levels of KYNA in the cerebrospinal fluid (CSF) of patients with bipolar disorder and healthy volunteers to investigate the putative involvement of KYNA in bipolar disorder.

Methods

We obtained CSF by lumbar puncture from 23 healthy men and 31 euthymic men with bipolar disorder. We analyzed the samples using high-performance liquid chromatography.

Results

Patients with bipolar disorder had increased levels of KYNA in their CSF compared with healthy volunteers (1.71 nM, standard error of the mean [SEM] 0.13 v. 1.13 nM, SEM 0.09; p = 0.002. The levels of KYNA were positively correlated with age among bipolar patients but not healthy volunteers.

Limitations

The influence of ongoing drug treatment among patients cannot be ruled out. We conducted our study during the euthymic phase of the disease.

Conclusion

Brain KYNA levels are increased in euthymic men with bipolar disorder. In addition, KYNA levels increased with age in these patients. These findings indicate shared mechanisms between bipolar disorder and schizophrenia. Elevated levels of brain KYNA may provide further insight to the pathophysiology and progression of bipolar disorder.     

Osteoprotegerin levels in patients with severe mental disorders

Background

Severe mental disorders are associated with elevated levels of inflammatory markers. In the present study, we investigated whether osteoprotegerin (OPG), a member of the tumour necrosis factor receptor family involved in calcification and inflammation, is elevated in patients with severe mental disorders.

Methods

We measured the plasma levels of OPG in patients with severe mental disorders (n = 312; 125 with bipolar disorder and 187 with schizophrenia) and healthy volunteers (n = 239).

Results

The mean plasma levels of OPG were significantly higher in patients than in controls (t₅₃₁ = 2.6, p = 0.01), with the same pattern in bipolar disorder and schizophrenia. The increase was significant after adjustment for possible confounding variables, including age, sex, ethnic background, alcohol consumption, liver and kidney function, diabetes, cardiovascular disease, autoimmune diseases and levels of cholesterol, glucose and C-reactive protein.

Limitations

Owing to the cross-sectional design, it is difficult to determine causality.

Conclusion

Our results indicate that elevated OPG levels are associated with severe mental disorders and suggest that mechanisms related to calcification and inflammation may play a role in disease development.     

Characterizing Suicide in Toronto: An Observational Study and Cluster Analysis

Objective:

To determine whether people who have died from suicide in a large epidemiologic sample form clusters based on demographic, clinical, and psychosocial factors.

Method:

We conducted a coroner’s chart review for 2886 people who died in Toronto, Ontario, from 1998 to 2010, and whose death was ruled as suicide by the Office of the Chief Coroner of Ontario. A cluster analysis using known suicide risk factors was performed to determine whether suicide deaths separate into distinct groups. Clusters were compared according to person- and suicide-specific factors.

Results:

Five clusters emerged. Cluster 1 had the highest proportion of females and nonviolent methods, and all had depression and a past suicide attempt. Cluster 2 had the highest proportion of people with a recent stressor and violent suicide methods, and all were married. Cluster 3 had mostly males between the ages of 20 and 64, and all had either experienced recent stressors, suffered from mental illness, or had a history of substance abuse. Cluster 4 had the youngest people and the highest proportion of deaths by jumping from height, few were married, and nearly one-half had bipolar disorder or schizophrenia. Cluster 5 had all unmarried people with no prior suicide attempts, and were the least likely to have an identified mental illness and most likely to leave a suicide note.

Conclusions:

People who die from suicide assort into different patterns of demographic, clinical, and death-specific characteristics. Identifying and studying subgroups of suicides may advance our understanding of the heterogeneous nature of suicide and help to inform development of more targeted suicide prevention strategies.     

Visual sensory processing deficits in patients with bipolar disorder revealed through high-density electrical mapping

Background

Etiological commonalities are apparent between bipolar disorder and schizophrenia. For example, it is becoming clear that both populations show similar electrophysiological deficits in the auditory domain. Recent studies have also shown robust visual sensory processing deficits in patients with schizophrenia using the event-related potential technique, but this has not been formally tested in those with bipolar disorder. Our goal here was to assess whether early visual sensory processing in patients with bipolar disorder, as indexed by decreased amplitude of the P1 component of the visual evoked potential (VEP), would show a similar deficit to that seen in those with schizophrenia. Since the P1 deficit has already been established as an endophenotype in schizophrenia, a finding of commonality between disorders would raise the possibility that it represents a measure of common genetic liability.

Methods

We visually presented isolated-check stimuli to euthymic patients with a diagnosis of bipolar disorder and age-matched healthy controls within a simple go/no-go task and recorded VEPs using high-density (72-channel) electroencephalography.

Results

The P1 VEP amplitude was substantially reduced in patients with bipolar disorder, with an effect size of f = 0.56 (large according to Cohen’s criteria).

Limitations

Our sample size was relatively small and as such, did not allow for an examination of potential relations between the physiologic measures and clinical measures.

Conclusion

This reduction in P1 amplitude among patients with bipolar disorder represents a dysfunction in early visual processing that is highly similar to that found repeatedly in patients with schizophrenia and their healthy first-degree relatives. Since the P1 deficit has been related to susceptibility genes for schizophrenia, our results raise the possibility that the deficit may in fact be more broadly related to the development of psychosis and that it merits further investigation as a candidate endophenotype for bipolar disorder.     

Genetic Association Study of the Alpha 7 Nicotinic Receptor (CHRNA7) with the Development of Schizophrenia and Bipolar Disorder in Korean Population

Objective

CHRNA7 has been shown to be a strong candidate gene for schizophrenia and bipolar disorder. It is located on chromosome 15q13-q14, which is one of the replicated linkage spots for schizophrenia and bipolar disorder.

Methods

We conducted an association study to determine whether previous positive association is replicable in the Korean population. We included 254 patients with schizophrenia, 193 patients with bipolar disorder type I, 38 patients with bipolar disorder type II, 64 schizoaffective disorder patients, and 349 controls. All subjects were ethnically Korean. A total of 898 subjects were included, and genotyping was done for three single nucleotide polymorphisms (SNPs) of CHRNA7. These three intronic SNPs were rs2337506 (A/G), rs6494223 (C/T), and rs12916879 (A/G).

Results

There was only one marginally significant association; this association was between rs12916879 and bipolar disorder type I in the male subgroup. In both the allele and genotype distributions, we found a weak signal (Chi-squared=3.57, df=1, p=0.06 for allele, Chi-squared=7.50, df=2, p=0.02 for genotype) only. Unphased haplotype analysis could not provide additional support for this finding. No SNP was associated with schizophrenia or any other affected groups in this Korean sample. The associative finding is marginal and inconclusive.

Conclusion

We could not replicate positive association in other ethnic groups previously studied. This suggests possible heterogeneity in the genes associated with schizophrenia and bipolar disorders. Because of structural complexity of the CHRNA7 gene and the limited statistical power of this study, further genetic studies with more SNPs and larger samples covering various populations, along with more fine molecular exploration of the CHRNA7 gene structure, are required.     

Neuroprotective Effects by Nimodipine Treatment in the Experimental Global Ischemic Rat Model : Real Time Estimation of Glutamate

Objective

Glutamate is a key excitatory neurotransmitter in the brain, and its excessive release plays a key role in the development of neuronal injury. In order to define the effect of nimodipine on glutamate release, we monitored extracellular glutamate release in real-time in a global ischemia rat model with eleven vessel occlusion.

Methods

Twelve rats were randomly divided into two groups: the ischemia group and the nimodipine treatment group. The changes of extracellular glutamate level were measured using microdialysis amperometric biosensor, in coincident with cerebral blood flow (CBF) and electroencephalogram. Nimodipine (0.025 µg/100 gm/min) was infused into lateral to the CBF probe, during the ischemic period. Also, we performed Nissl staining method to assess the neuroprotective effect of nimodipine.

Results

During the ischemic period, the mean maximum change in glutamate concentration was 133.22±2.57 µM in the ischemia group and 75.42±4.22 µM (p<0.001) in the group treated with nimodipine. The total amount of glutamate released was significantly different (p<0.001) between groups during the ischemic period. The %cell viability in hippocampus was 47.50±5.64 (p<0.005) in ischemia group, compared with sham group. But, the %cell viability in nimodipine treatment group was 95.46±6.60 in hippocampus (p<0.005).

Conclusion

From the real-time monitoring and Nissl staining results, we suggest that the nimodipine treatment is responsible for the protection of the neuronal cell death through the suppression of extracellular glutamate release in the 11-VO global ischemia model of rat.     

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.     

Evidence for morphological alterations in prefrontal white matter glia in schizophrenia and bipolar disorder

Background

Brain imaging studies suggest that volume reductions and compromised white matter integrity occur in schizophrenia and bipolar disorder (BD). However, the cellular correlates have not yet been identified. To address this issue we assessed oligodendrocyte, astrocyte and microglial populations in postmortem white matter from schizophrenia, BD and nonpsychiatric control samples.

Methods

The density, areal fraction and spatial distribution of glial fibrillary acidic protein (GFAP)-expressing astrocytes and ionized calcium-binding adaptor molecule-1 (IBA-1)-expressing microglia as well as the density, nuclear size and spatial distribution of Nissl-stained oligodendrocytes were quantified in postmortem white matter adjacent to the dorsolateral prefrontal cortex (Brodmann area 9) in schizophrenia, BD and control samples (n = 20). In addition, the oligodendrocyte-associated proteins myelin basic protein and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) were quantified in the same samples by enzyme-linked immunosorbent assay and immunoblotting.

Results

Oligodendrocyte density (p = 0.012) and CNPase protein levels (p = 0.038) differed between groups, being increased in BD compared with control samples. The GFAP area fraction (p = 0.05) and astrocyte spatial distribution (p = 0.040) also differed between groups, reflecting decreased area fraction and increased cell clustering in both schizophrenia and BD samples.

Limitations

Oligodendrocytes were identified using morphological criteria.

Conclusion

This study provides evidence for glial pathology in prefrontal white matter in schizophrenia and BD. Changes in oligodendrocyte and astrocyte populations in white matter in the major psychiatric disorders may reflect disruptions in structural or metabolic support of axons.     

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.     

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.     

Serotonergic Dysfunction in Patients with Bipolar Disorder Assessed by the Loudness Dependence of the Auditory Evoked Potential

Objective

The loudness dependence of the auditory evoked potential (LDAEP) is suggested to be a marker of serotonin system function. This study explored the LDAEP of multiple mood statuses (depression, mania, and euthymia) and its clinical implication in bipolar disorder patients.

Methods

A total of 89 subjects, comprising 35 patients with bipolar disorder, 32 patients with schizophrenia, and 22 healthy controls were evaluated. The bipolar disorder cases comprised 10 depressed patients, 15 patients with mania, and 10 euthymic patients. The N1/P2 peak-to-peak amplitudes were measured at 5 stimulus intensities, and the LDAEP was calculated as the slope of the linear regression. Both cortical and source LDAEP values were calculated.

Results

LDAEP varied according to mood statuses, and was significantly stronger in cases of euthymia, depression, and mania. Cortical LDAEP was significantly stronger in patients with bipolar euthymia compared with schizophrenia, stronger in bipolar depression than in schizophrenia, stronger in healthy controls than in schizophrenia patients, and stronger in healthy controls than in patients with bipolar mania. Source LDAEP was significantly stronger in patients with bipolar euthymia, bipolar depression, and bipolar mania compared with schizophrenia, stronger in bipolar euthymia than in bipolar mania. Psychotic features weakened the source LDAEP relative to nonpsychotic features. The severity of the depressive symptom was negatively correlated with source LDAEP.

Conclusion

These findings suggest that the serotonin activity of patients with bipolar disorder may vary according to mood status. A longitudinal follow-up study should be pursued using drug-naive subjects.     

Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression,bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics

Background

Metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5) are novel therapeutic targets for major depression (MD), bipolar disorder (BD) and schizophrenia. We aimed to determine whether mGluR2/3 and mGluR5 binding in the anterior cingulate cortex (ACC), a brain region essential for the regulation of mood, cognition and emotion, were differentially altered in these pathologies.

Methods

Using postmortem human brains derived from 2 cohorts, [³H]{"type":"entrez-nucleotide","attrs":{"text":"LY341495","term_id":"1257705759","term_text":"LY341495"}}LY341495 binding to mGluR2/3 and [³H]MPEP binding to mGluR5 were measured by receptor autoradiography in the ACC. The first cohort comprised samples from individuals who had MD with psychosis (MDP), MD without psychosis (MDNP) and matched controls (n = 11–12 per group). The second cohort comprised samples from individuals who had MDNP, BD, schizophrenia and matched controls (n = 15 per group).

Results

No differences in mGluR2/3 or mGluR5 binding were observed in the MDP, MDNP, BD or schizophrenia groups compared with the control group (all p > 0.05). Importantly, there were also no differences in binding densities between the psychiatric disorders (p > 0.05). We did, however, observe age-related effects, with consistent negative associations between mGluR2/3 and age in the control group (r < −0.575, p < 0.025) and the psychotic disorder groups (MDP and schizophrenia: r = −0.765 to −0.515, p < 0.05), but not in the mood disorder groups (MDNP, BD).

Limitations

Replication in larger independent cohorts and medication-naive individuals would strengthen these findings.

Conclusion

Our findings suggest that mGluRs are unaltered in the ACC; however, the presence of altered receptor function cannot be discounted and requires further investigation. Taken together with previous studies, which report differential changes in mGluR2, 3 and 5 across these disorders, we suggest mGluRs may be affected in a brain region–specific manner.     

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.     

BDNF protein levels are decreased in transformed lymphoblasts from lithium-responsive patients with bipolar disorder

Objective

Brain-derived neurotrophic factor (BDNF) is a key factor in neuroplasticity and has been implicated in the affective disorders; studies have demonstrated elevated BDNF in patients taking lithium and other mood stabilizers. The objective of our study was to analyze BDNF in lithium-responsive patients with bipolar disorder (BD) to further understand the role of BDNF in the pathophysiology of BD.

Methods

Using enzyme-linked immunosorbent assay, we measured transformed B lymphocytes for BDNF protein.

Results

BDNF levels were 36% lower in lymphoblasts from patients with BD (n = 12), compared with matched control participants (n = 13), and 55% lower when compared with their unaffected relatives (n = 14). Lithium significantly decreased BDNF levels in patients with BD and healthy control participants, although BDNF levels remained lower (33%) in the BD group posttreatment.

Conclusion

Decreased BDNF may constitute part of the pathophysiologic process of BD in a lithium-responsive subgroup of individuals with this disease. A compensatory mechanism protecting the genetically predisposed unaffected relatives from phenotypic expression of BD is suggested.Medical subject headings: bipolar disorder, brain-derived neurotrophic factor, enzyme-linked immunosorbent assay, lithium     

Large positive effect of lithium on prefrontal cortex N-acetylaspartate in patients with bipolar disorder: 2-centre study

Background

Neuroprotective effects of lithium (Li) have been well documented in tissue cultures and animal models, whereas human data continue to be limited. Previous studies investigating the association between Li treatment and brain N-acetylaspartate (NAA), a putative neuronal marker, showed mixed results because of methodological heterogeneity.

Methods

To investigate the effects of Li on prefrontal cortex NAA levels, we compared patients with bipolar disorder from specialized Li clinics in Berlin and Halifax with at least 2 years of ongoing Li treatment (Li group), patients with lifetime Li exposure of less than 3 months more than 2 years ago (non-Li group) and healthy controls. Participants in both patient groups had at least 10 years of illness and 5 episodes. We measured left prefrontal NAA levels using 1.5-T magnetic resonance spectroscopy.

Results

We enrolled 27 participants in the Li, 16 in the non-Li and 21 in the healthy control groups. The non-Li group had lower prefrontal NAA levels than the Li group (t₄₁ = −3.44, corrected p < 0.01) or control participants (t₃₅ = −2.91, corrected p < 0.05), who did not differ from the Li group (t₄₆ = −0.14, p = 0.89). The same pattern of prefrontal NAA differences was replicated in both sites. In addition, there was a negative correlation between prefrontal NAA and duration of illness in the non-Li group (r = −0.60, p = 0.019) but not in the Li group (r = 0.07, p = 0.74).

Limitations

Study limitations include the cross-sectional design and exposure to other medications.

Conclusion

Whereas patients with bipolar disorder, substantial illness burden and limited lifetime Li exposure had significantly lower prefrontal NAA levels than controls, Li-treated patients with similar illness burden showed prefrontal NAA levels comparable to those of healthy controls. These findings provide indirect support for neuroprotective effects of Li and for negative effects of illness burden on prefrontal NAA levels in patients with bipolar disorder.     

Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders

Background

Brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor (trkB-TK+) and glutamic acid decarboxylase (GAD₆₇) mRNA levels have previously been found to be reduced in the prefrontal cortex of patients with schizophrenia. To determine whether this reduction extends to other brain regions, we measured the expression levels of BDNF, trkB-TK+ and GAD₆₇ mRNA in regions of the hippocampus, including the dentate gyrus (DG), cornu ammonis subfields (CA1–4), subiculum and entorhinal cortex (EC) of individuals with schizophrenia, bipolar disorder, major depression and unaffected controls.

Methods

In situ hybridization was performed on postmortem brain tissue obtained from the Stanley Foundation Consortium and analyzed using film-based quantification.

Results

Analyses of covariance comparing the expression of mRNA among all groups revealed a significant decrease in BDNF mRNA in CA4 in the bipolar disorder group compared with controls (33%). We found trkB-TK+ mRNA levels to be significantly reduced in CA4 in the schizophrenia group (36%) and in layer II of the EC in the bipolar disorder and major depression groups (28%, 21%, respectively) compared with controls. In addition, GAD₆₇ mRNA levels were reduced in patients with schizophrenia in both the DG (23%) and CA4 (60%) compared with controls. Individuals with major depression also expressed significantly less GAD₆₇ mRNA (44%) compared with controls in CA4 of the hippocampus.

Limitations

It is necessary to account for factors that influence the molecular preservation in postmortem brain tissue, including pH, postmortem interval and tissue storage time. Moreover, there are limitations to the sensitivity of the film-based method of quantification.

Conclusion

Our findings show abnormal BDNF, trkB-TK+ and GAD₆₇ mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders, indicating that fundamental properties of hippocampal signalling transmission, plasticity and circuitry may be affected in individuals with these major mental illnesses.