Influence of TPH2 variants on diagnosis and response to treatment in patients with major depression, bipolar disorder and schizophrenia

The present study is aimed at exploring whether some single nucleotide polymorphisms (SNPs) within the tryptophan hydroxylase 2 gene (TPH2) could be associated with major depression (MD), bipolar disorder (BD) and schizophrenia and whether they could predict clinical outcomes in Korean in-patients treated with antidepressants, mood stabilizers and antipsychotics, respectively. One hundred forty-five patients with MD, 132 patients with BD, 221 patients with schizophrenia and 170 psychiatrically healthy controls were genotyped for six TPH2 SNPs (rs4570625, rs10748185, rs11179027, rs1386498, rs4469933, and rs17110747). Baseline and final clinical measures, including the Montgomery-Åsberg Depression Rating Scale (MADRS), Young Mania Rating Scale and Positive and Negative Syndrome Scale, for patients with MD, BD and schizophrenia, respectively were recorded. None of the SNPs under investigation were associated with MD, BD and schizophrenia. However, in patients with MD, the rs4570625-rs10748185 G-A haplotype was significantly associated with higher endpoint MADRS severity, though not with response. Our results suggest that TPH2 variants neither have a major role in MD, BD and schizophrenia nor in response to treatments.     

Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population

The phosphodiesterase 4B (PDE4B) gene is located at 1p31, a susceptibility region for schizophrenia (SZ). Moreover, PDE4B interacts with DISC1, which is a known genetic risk factor for SZ. Recently, it was reported that the PDE4B gene is associated with SZ in Caucasian and African American populations. In this study, case-controlled association analyses were performed in the Japanese population to determine if the PDE4B gene is implicated in SZ. Thirteen single nucleotide polymorphisms (SNPs) were analyzed in 444 schizophrenic patients and 452 control subjects. Three SNPs (rs2180335, rs910694 and rs472952) were significantly associated with SZ after applying multiple test correction (p = 0.039, 0.004 and 0.028). In addition, a significant association was found between specific haplotypes (rs2180335 and rs910694) and SZ (permutation p = 0.001). Our result suggests that variations at the PDE4B locus may play a significant role in the etiology of SZ in the Japanese population.     

Expression of cellular prion protein (PrP<Superscript>c</Superscript>) in schizophrenia,bipolar disorder,and depression

Cellular prion protein (PrP(c)) is a copper-binding, membrane-attached GPI-anchored glycoprotein characterized by a high degree of amino acid sequence conservation among mammals. PrP(c) expression has been demonstrated in neurons, microglia, lymphocytes, and keratinocytes. Recently, the concept that PrP(c) may be involved in the defense against oxidative stress was advanced. In the present study, we used immunohistochemistry for PrP(c) to investigate 60 brains from the Stanley Neuropathology Consortium (15 controls, 15 patients with schizophrenia, 15 with bipolar disorder, and 15 with major depression). Rating scores as well as the numerical density of PrP(c)-positive and -negative neurons and glial cells were determined in the cingulate gyrus. All four groups showed a very high interindividual variation. PrP(c)-positive glial cells were significantly reduced in the white matter of patients with schizophrenia, bipolar disorder, and major depression. A similar result was obtained for the white matter in bipolar patients using rating scales. From the confounding variables, use of medication (i.e. antipsychotics, antidepressants, and mood stabilizers) had a significant effect on the expression of PrP(c) by neurons and glial cells. PrP(c)-immunoreactivities were significantly reduced for white matter glial cells in all examined groups. However, the results are not indicative for the occurrence of oxidative stress in the brains of schizophrenic and bipolar patients. Since the effect of antipsychotic and antidepressant medication as well as of mood stabilizers on the expression of PrP(c) was significant, it needs further clarification in experimental models.     

CTLA-4 confers a risk of recurrent schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population

Previous studies have reported that the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, which is related to immunological function such as T-cell regulation, is associated with psychiatric disorders. In this study, we studied the relationship between CTLA-4 and three major psychiatric disorders, schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population. We recruited 1140 schizophrenia patients, 1140 major depressive disorder patients, 1140 bipolar disorder patients, and 1140 normal controls to examine the risk conferred by 6 tag SNPs (rs231777, rs231775, rs231779, rs3087243, rs5742909, rs16840252) in the CTLA-4 gene. We found that rs231779 conferred a risk for schizophrenia (P_allele = 0.0003, P_genotype = 0.0016), major depressive disorder (P_allele = 0.0006, P_genotype = 0.0026) and bipolar disorder (P_allele = 0.0004, P_genotype = 0.0018). In addition, rs231777 and rs16840252 had a significant association with schizophrenia (rs231777: P_allele = 0.0201, rs16840252: P_allele = 0.0081, P_genotype = 0.0117), and rs231777 had significant association with bipolar disorder (rs231777: P_allele = 0.0199). However, after 10,000 permutations, only rs231779 remained significant (schizophrenia: P_allele = 0.0010, P_genotype = 0.0145, major depressive disorder: P_allele = 0.0010, P_genotype = 0.0201, bipolar disorder: P_allele = 0.0008, P_genotype = 0.0125). Our results suggest that shared common risk factors for schizophrenia, major depressive disorder and bipolar disorder exist in the CTLA-4 gene in the Chinese Han population.     

Case-control association study of 36 single-nucleotide polymorphisms within 10 candidate genes for major depression and bipolar disorder

In this study we investigated 36 single nucleotide polymorphisms within 10 genes previously associated with major depression and bipolar disorder, as well as with the response to their treatment (ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2). No association with mood disorders and clinical outcomes was observed.     

A comparison of neuropsychological dysfunction in first-episode psychosis patients with unipolar depression, bipolar disorder, and schizophrenia

The severity and profile of cognitive dysfunction in first episode schizophrenia and psychotic affective disorders were compared before and after antipsychotic treatment. Parallel recruitment of consecutively admitted study-eligible first-episode psychotic patients (30 schizophrenia, 22 bipolar with psychosis, and 21 psychotic depression) reduced confounds of acute and chronic disease/medication effects as well as differential treatment and course. Patient groups completed a neuropsychological battery and were demographically similar to healthy controls (n = 41) studied in parallel. Prior to treatment, schizophrenia patients displayed significant deficits in all cognitive domains. The two psychotic affective groups were also impaired overall, generally performing intermediate between the schizophrenia and healthy comparison groups. No profile differences in neuropsychological deficits were observed across patient groups. Following 6 weeks of treatment, no patient group improved more than practice effects seen in healthy individuals, and level of performance improvement was similar for affective psychosis and schizophrenia groups. Although less severe in psychotic affective disorders, similar profiles of generalized neuropsychological deficits were observed across patient groups. Recovery of cognitive function after clinical stabilization was similar in mood disorders and schizophrenia. To the extent that these findings are generalizable, neuropsychological deficits in psychotic affective disorders, like schizophrenia, may be trait-like deficits with persistent functional implications.     

Systematic review of appropriate cognitive assessment instruments used in clinical trials of schizophrenia,major depressive disorder and bipolar disorder

Cognitive dysfunction is increasingly recognized as a symptom in mental conditions including schizophrenia, major depressive disorder (MDD), and bipolar disorder (BPD). Despite the many available cognitive assessment instruments, consensus is lacking on their appropriate use in clinical trials. We conducted a systematic literature review in Embase, PubMed/Medline and PsychINFO to identify appropriate cognitive function instruments for use in clinical trials of schizophrenia, MDD, and BPD. Instruments were identified from the articles. Instruments and articles were excluded if they did not address schizophrenia, MDD, or BPD. Instrument appropriateness was further assessed by the criteria of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative: test–retest reliability, utility, relationship to functional status, potential changeability to pharmacological agents, and tolerability and practicality for clinical trials. The database search yielded 173 articles describing 150 instruments used to assess cognitive function. Seventeen additional instruments were identified through Google and clinicaltrials.gov. Among all these, only 30 (18%) were deemed appropriate for use in the diseases of interest. Of these, 27 were studied in schizophrenia, one in MDD and two in BPD. These findings suggest the need for careful selection of appropriate cognitive assessment instruments, as not all may be valid in these disorders.     

Higher risk of developing major depression and bipolar disorder in later life among adolescents with asthma: A nationwide prospective study

ObjectivePrevious studies have suggested an immunological dysfunction in mood disorders, but rarely have investigated the temporal association between allergic diseases and mood disorders. Using the Taiwan National Health Insurance Research Database, we attempted to investigate the association between asthma in early adolescence and the risk of unipolar depression and bipolar disorder in later life.MethodsIn all, 1453 adolescents with asthma aged between 10 and 15 years and 5812 age-/gender-matched controls were selected in 1998–2000. Subjects with unipolar depression and bipolar disorder that occurred up to the end of follow-up (December 31 2010) were identified.ResultsAdolescents with asthma had a higher incidence of major depression (2.8% vs. 1.1%, p < 0.001), any depressive disorder (6.1% vs. 2.6%, p < 0.001), and bipolar disorder (1.0% vs. 0.3%, p < 0.001) than the control group. Cox regression analysis showed that asthma in early adolescence was associated with an increased risk of developing major depression (hazard ratio [HR]: 1.81, 95% confidence interval [CI]: 1.14–2.89), any depressive disorder (HR: 1.74, 95% CI: 1.27–2.37), and bipolar disorder (HR: 2.27, 95% CI: 1.01–5.07), after adjusting for demographic data and comorbid allergic diseases.DiscussionAdolescents with asthma had an elevated risk of developing mood disorders in later life. Further studies would be required to investigate the underlying mechanisms for this comorbid association and elucidate whether prompt intervention for asthma would decrease the risk of developing mood disorders.     

S100B蛋白与心境障碍的相关性研究进展

心境障碍是由各种原因引起的以显著而持久的心境或情感改变为主要特征的一组疾病,包括重性抑郁障碍和双相障碍两个主要疾病亚型.随着现代生活节奏的加快,其患病率正逐年上升.世界卫生组织(WHO)有关全球疾病总负担的统计显示,1990年重性抑郁障碍和双相障碍分别排在第5位和第18位,预计到2020年,重性抑郁障碍的疾病负担将上升至第二位.目前心境障碍的病因及发病机制仍不明,近来国外学者开始提出心境障碍就是胶质细胞的功能障碍,而S100B蛋白作为一种胶质细胞源性的蛋白质,可能与心境障碍有着密切的联系[1].本文总结国内外相关研究,对S100B蛋白与心境障碍的关系作如下综述.     

Association of MIF and MBL2 gene polymorphisms with attempted suicide in patients diagnosed with schizophrenia or bipolar disorder

The aim of this study to investigate the genetic polymorphisms in macrophage inhibitory factor (MIF) and mannose-binding lectin 2 (MBL2) gene in schizophrenia (SCZ) or bipolar disorder (BD) patients with attempted suicide by comparing with a non-attempted SCZ or BD patients and healthy controls. A sample of 108 patients with SCZ, 100 patients with BD and 100 healthy volunteers were included in the study. SCID-I was used to confirm the diagnosis according to DSM-IV-TR criteria. The patients were evaluated by data forms that included sociodemographic, suicidal behavior and symptom severity information. PCR-RFLP was used to determine MIF and MBL2 gene polymorphisms from DNA material. Our results demonstrated that the distributions of MBL2 genotype (AA, AB, BB), combined genotype (AA, AB/BB) and the allele frequencies (A, B) of attempted suicide patients in SCZ were significantly different from the non-attempted SCZ patients. The distributions of the MBL2 genotype of attempted suicide patients in SCZ were significantly different from the control group. The distributions of MIF genotype (GG, GC, CC), combined genotype (GG, GC/CC) and the allele frequencies (G, C) of attempted suicide patients in BD were significantly different from the non-attempted BD patients or control group. In summary MBL2 gene polymorphism may be associated with attempted suicide in SCZ and MIF gene polymorphism might be associated with attempted suicide in BD. However, further studies with other gene variants in different ethnic populations are needed to address the exact role of these polymorphisms in SCZ or BD.     

Mitochondrial haplogroups and hypervariable region polymorphisms in schizophrenia: A case-control study

Previous studies have detected associations between mitochondrial haplogroups and schizophrenia (SZ). However, no study has examined the relationship between major mitochondrial DNA (mtDNA) haplogroups and SZ in the Chinese population. The aim of this study was to assess the association between mtDNA haplogroups and SZ genesis in the Chinese Han population. We used a case-control study and sequenced the mtDNA hypervariable regions (HVR1, HVR2, and HVR3) in the Han population. We analyzed mtDNA haplogroups and HVR polymorphisms in 298 SZ patients and 298 controls. The haplotypes were classified into 10 major haplogroups: A, B, CZ, D, F, G, M, N, N9a, and R. Statistical analysis revealed that only N9a showed a nominally significant association with protection from SZ [1.68% vs. 6.38%, p=0.004, OR=0.251 (0.092–0.680); after adjustment for age and sex: p=0.006, OR=0.246 (0.090–0.669)]. Three HVR polymorphisms were found to be nominally significantly different between subjects with SZ and controls, and all except one (m.204T>C) are linked to the N9a haplogroup. Our results indicate that mtDNA haplogroup N9a might be a protective factor for SZ.     

Abnormal fatty acid pattern in the superior temporal gyrus distinguishes bipolar disorder from major depression and schizophrenia and resembles multiple sclerosis

This study investigated the fatty acid composition of the postmortem superior temporal gyrus (STG), a cortical region implicated in emotional processing, from normal controls (n=15) and patients with bipolar disorder (BD, n=15), major depressive disorder (MDD, n=15), and schizophrenia (SZ, n=15). For comparative purposes, STG fatty acid composition was determined in a separate cohort of multiple sclerosis patients (MS, n=15) and normal controls (n=15). Compared with controls, patients with BD, but not MDD or SZ, exhibited abnormal elevations in the saturated fatty acids (SFA) palmitic acid (16:0), stearic acid (18:0), the polyunsaturated fatty acids (PUFA) linoleic acid (18:2n-6), arachidonic acid (20:4n-6), and docosahexaenoic acid (22:6n-3), and reductions in the monounsaturated fatty acid (MUFA) oleic acid (18:1n-9). The total MUFA/SFA and 18:1/18:0 ratios were lower in the STG of BD patients and were inversely correlated with total PUFA composition. MS patients exhibited a pattern of fatty acid abnormalities similar to that observed in BD patients including elevated PUFA and a lower 18:1/18:0 ratio. Collectively, these data demonstrate that BD patients exhibit a pattern of fatty acid abnormalities in the STG that is not observed in MDD and SZ patients and closely resembles MS patients.     

Metacognition in psychosis: Comparison of schizophrenia with bipolar disorder

While deficits in metacognition have been observed in schizophrenia (SZ), it is less clear whether these are specific to the disorder. Accordingly, this study compared metacognitive abilities of patients with schizophrenia and bipolar disorder (BD) and examined the degree to which neurocognition contributed to metacognitive deficits in both groups. Participants were 30 patients with SZ and 30 with BD. Metacognitive capacity was measured using the Metacognition Assessment Scale Abbreviated (MAS-A). This scale comprises four domains: self-reflectivity, understanding others? minds, decentration and mastery. Verbal memory, executive functioning and symptoms were concurrently assessed. Group comparisons revealed that SZ patients had greater deficits in metacognitive self-reflectivity, which correctly classified 85.2% of patients with SZ in a logistic regression. Self-reflectivity and understanding others? minds were related to verbal memory and executive functioning in the SZ group, but not in the BD group. Furthermore, greater positive and general psychotic symptoms were associated with poorer metacognition in SZ. Results suggest SZ involves unique deficits in the ability to self-reflect and that these deficits may be uniquely linked with neurocognition.     

Altered expression of neurotrophic factors in patients with major depression

There is an abundance of evidence suggesting the involvement of altered levels of expression of neurotrophic factors in the pathophysiology of neuropsychiatric disorders. Although postmortem brain studies have indicated the alterations in the expression levels of neurotrophic factors in mood disorder patients, it is unclear whether these changes are state- or trait-dependent. In this study, we examined the expression levels of the members of the glial cell line-derived neurotrophic factor (GDNF) family (GDNF, artemin (ARTN), neurturin, and persephin), brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 (NT-3), and neurotrophin-4 mRNAs by using quantitative real-time PCR method in peripheral blood cells of patients with major depressive and bipolar disorders in both a current depressive and a remissive states. Reduced expression levels of GDNF, ARTN, and NT-3 mRNAs were found in patients with major depressive disorder in a current depressive state, but not in a remissive state. Altered expressions of these mRNAs were not found in patients with bipolar disorder. Our results suggest that the changes in the expression levels of GDNF, ARTN, and NT-3 mRNAs might be state-dependent and associated with the pathophysiology of major depression.     

精神分裂症患者与躁狂发作患者父母教养方式对照研究

目的 探讨精神分裂症与双相情感障碍躁狂发作患者的父母教养方式特点.方法 采用父母教养方式评价量表(EMBU)对43例精神分裂症患者及38例双相情感障碍躁狂发作患者父母教养方式(研究组)进行评定,并与38例正常受试者(对照组)比较.结果 与双相情感障碍躁狂发作及正常被试比较,精神分裂症患者组在教养方式上,父母均表现为高惩罚与严厉、高过分干涉和高拒绝与否认(P＜0.05);双相情感障碍躁狂发作患者组教养方式各因子得分虽低于正常对照组,但差异无统计学意义(P＞0.05).结论 精神分裂症患者父母教养方式均存在多方面问题,可能对精神分裂症发病有一定影响.双相情感障碍躁狂发作患者的父母教养方式可能存在一定问题,需要进一步研究.     

Prevalence of liver disease in veterans with bipolar disorder or schizophrenia

Objective

To assess the prevalence of three liver diseases [hepatitis C virus (HCV), nonalcoholic fatty liver disease and alcohol-induced cirrhosis] in patients (veterans) with/without schizophrenia/schizoaffective disorder and bipolar disorder.

Methods

A retrospective electronic chart review of Veterans Integrated Services Network 20 facilities from January 1, 2001 to December 21, 2006 selected patients to one of two groups: schizophrenia/schizoaffective disorder or bipolar disorder. Patients in both groups were compared with veterans in an equal-sized random sample from the same data set of veterans without psychiatric diagnoses. Logistic regression models evaluated risk for overall liver diseases as well as HCV, nonalcoholic fatty liver disease and alcoholic-induced cirrhosis.

Results

Patients with schizophrenia (n=6521) had a higher prevalence of liver disease [22.4% versus 3.2%; odds ratio (OR)=8.73]; HCV (16.5% versus 1.9%; OR=10.21); and alcohol-related cirrhosis (1.6% versus 0.4%; OR=4.09) than matched controls. Patients with bipolar disorder (n=5319) had a higher prevalence of liver disease (21.5% versus 3.5%; OR=7.58); HCV (15.5% versus 2.1%; OR=8.60); and alcohol-related cirrhosis (1.6% versus 0.4%; OR=3.82) than matched controls. Risk factors for liver disease in patients with schizophrenia (versus matched controls) included diabetes (OR=1.29), hypertension (OR=1.27), HIV (OR=3.54), substance use disorder (SUD) (OR=2.28), alcohol use disorder (OR=3.05) and schizophrenia (OR=2.74). Risk factors for development of liver disease for patients with bipolar disorder: diabetes (OR=1.40), HIV (OR=3.66), SUD (OR=2.68), alcohol use disorder (OR=3.22) and bipolar disorder (OR=2.27).

Conclusions

This study in veterans shows that the presence of mental illness and its comorbidities represents a significant risk factor for the diagnosis of liver disease, including HCV and alcohol-related cirrhosis.     

住院双相障碍与精神分裂症患者自知力水平的保护性因素

目的 探讨住院双相障碍与精神分裂症患者自知力水平及其保护性因素。方法 在广州市4家精神科住院部连续入组符合《国际疾病分类（第10版）》（ICD-10）双相障碍或精神分裂症诊断标准的患者465例。采用自编人口学及临床特征问卷、自知力与治疗态度问卷（ITAQ）进行调查,比较不同自知力水平患者的人口学和临床特征,采用两分类Logistic回归分析探讨自知力的保护因素。结果 年龄小（OR=0.977）、男性（OR=1.705）、曾经结婚或同居（OR=1.677）、诊断为双相障碍（OR=2.185）、最近一个月有悲观厌世（OR=2.663）、每天睡眠时间≥7小时（OR=1.620）、每周运动1~2次（OR=1.770）是住院双相障碍和精神分裂症患者自知力的保护因素。结论 住院双相障碍和精神分裂症患者自知力水平与多种人口学特征及临床特征相关。     

Better understanding of mechanisms of schizophrenia and bipolar disorder: from human gene expression profiles to mouse models

The molecular mechanisms of major mental illnesses, such as schizophrenia and bipolar disorder, are unclear. To address this fundamental question, many groups have studied molecular expression profiles in postmortem brains and other tissues from patients compared with those from normal controls. Development of unbiased high-throughput approaches, such as microarray, RNA-seq, and proteomics, have supported and facilitated this endeavor. In addition to genes directly involved in neuron/glia signaling, especially those encoding for synaptic proteins, genes for metabolic cascades are differentially expressed in the brains of patients with schizophrenia and bipolar disorder, compared with those from normal controls in DNA microarray studies. Here we propose the importance and usefulness of genetic mouse models in which such differentially expressed molecules are modulated. These animal models allow us to dissect the mechanisms of how such molecular changes in patient brains may play a role in neuronal circuitries and overall behavioral phenotypes. We also point out that models in which the metabolic genes are modified are obviously untested from mental illness viewpoints, suggesting the potential to re-address these models with behavioral assays and neurochemical assessments.     

Effects of daytime naps on procedural and declarative memory in patients with schizophrenia

Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory. Straight memory deficits and sleep disturbances are well-known in patients with schizophrenia. This study tested the hypothesis that patients with schizophrenia have a deficit in procedural and declarative memory consolidation after a short midday nap when compared to healthy controls and patients with remitted to moderate major depression.Following a normal night’s sleep, 22 healthy subjects, 20 patients with major depression and 21 patients with schizophrenia were studied in a napping and wake condition in a random-order cross-over design, early in the afternoon. To test declarative memory, the Rey-Osterrieth Complex Figure Test respectively the Taylor Complex Figure Test and, for procedural learning, a mirror tracing task were performed.The present study is the first to demonstrate significant differences between individuals with schizophrenia, depression and healthy matched controls with regard to measures of sleep and memory performance after a short period of daytime sleep (napping). In particular we found that a daytime nap of only about 40 min led to improvement of declarative memory performance in all investigated groups, whereas no beneficial effect was seen on procedural performance in the group of medicated patients with schizophrenia in contrast to healthy controls and patients with remitted to moderate major depression.