Randomized, double-blind comparison of aripiprazole/sertraline combination and placebo/sertraline combination in patients with major depressive disorder.

AIM: This study compared the efficacy and safety of aripiprazole/sertraline combination (ASC) and placebo/sertraline combination (PSC) in patients with major depressive disorder (MDD) who showed an inadequate response to sertraline 100 mg/day. METHODS: The study comprised a screening period, an 8-week prospective treatment (single-blind sertraline 25-100 mg/day) period, and a 6-week double-blind treatment period. Patients with DSM-5-defined MDD were enrolled. Following the prospective treatment, non-responders were randomly assigned to the ASC group (aripiprazole 3-12 mg/day/sertraline 100 mg/day) or the PSC group (sertraline 100 mg/day). The primary efficacy end-point was the mean change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to 6 weeks. RESULTS: A total of 412 patients were randomly assigned to either the ASC group (n = 209) or the PSC group (n = 203). Mean change in MADRS total score was significantly greater in patients with ASC than PSC (-9.2 vs -7.2; P = 0.0070). Treatment-emergent adverse events (TEAE) that occurred in ≥10% of patients with ASC versus PSC were nasopharyngitis (13.4% vs 11.3%) and akathisia (12.9% vs 3.4%). All TEAE reported in the ASC group were mild or moderate in severity. Rates of discontinuations due to TEAE were low in both the ASC (1.9%) and PSC (1.5%) groups. There were no notable issues in safety assessments in the ASC group compared with the PSC group. CONCLUSION: In patients with MDD who showed an inadequate response to treatment with sertraline 100 mg/day, ASC was efficacious and well tolerated.

Efficacy of aripiprazole augmentation in Japanese patients with major depressive disorder: a subgroup analysis and Montgomery-Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression item analyses of the Aripiprazole Depression Multicenter Efficacy study.

AIM: Results from this randomized, placebo-controlled study of aripiprazole augmentation to antidepressant therapy (ADT) in Japanese patients with major depressive disorder (MDD) (the Aripiprazole Depression Multicenter Efficacy [ADMIRE] study) revealed that aripiprazole augmentation was superior to ADT alone and was well tolerated. In subgroup analyses, we investigated the influence of demographic- and disease-related factors on the observed responses. We also examined how individual symptom improvement was related to overall improvement in MDD. METHODS: Data from the ADMIRE study were analyzed. Subgroup analyses were performed on the primary outcome measures: the mean change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score from the end of selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI) treatment to the end of the randomized treatment. RESULTS: Changes in the MADRS total scores were consistently greater with aripiprazole than placebo in each of the subgroups. Efficacy was not related to sex, age, number of adequate ADT trials in the current episode, MDD diagnosis, number of depressive episodes, duration of the current episode, age at first depressive episode, time since the first depressive episode, type of SSRI/SNRI, or severity at the end of SSRI/SNRI treatment phase. Compared to placebo, aripiprazole resulted in significant and rapid improvement on seven of the 10 MADRS items, including sadness. CONCLUSION: These post-hoc analyses indicated that aripiprazole was effective for a variety of Japanese patients with MDD who had exhibited inadequate responses to ADT. Additionally, we suggest that aripiprazole significantly and rapidly improved the core depressive symptoms.

Analysis of depression in asthmatic patients using the Japanese version of Patient Health Questionnaire-9.

BACKGROUND: Previous studies show that depression plays an important role in asthma. However, the association between asthma control and severity, and depression is inconclusive. METHODS: To investigate the association between asthma control and severity, and depression, we assessed differences in asthma control and asthma severity between groups with various grades of depressive state as defined by the PHQ-9 score using data from the Japanese version of Patient Health Questionnaire-9 (J-PHQ-9) and a questionnaire survey including the Asthma Control Test (ACT). RESULTS: The ACT scores in the symptom-screen positive (SP) and major/other depressive disorder (MDD/ODD) group were significantly lower than those in the symptom-screen negative (SN) and non-MDD/ODD groups, respectively. The rate of step1 and of step 3 and 4 in the SP group were significantly lower and higher than those in the SN group, respectively. When the SP group was divided into three, that is minimal, mild, and more than mild (MTM) depressive state subgroups, the ACT scores in the mild and MTM depressive state subgroups were significantly lower than those in the minimal depressive state subgroup. When the MTM subgroup was divided into moderate, moderate-severe and severe depressive state groups, however, there was no significant variation in ACT score and asthma severity among these three depressive state groups. CONCLUSIONS: This study is the first, large-scale investigation of the use of the J-PHQ-9 in asthma patients. Using the J-PHQ-9 and the questionnaire, there was a clear association between asthma control and severity, and depression. As the depression became more severe, the existence of other depression-associated factors unrelated to asthma control and severity might be assumed, although further investigation will be required.

Paroxetine controlled-release formulation in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled study in Japan and Korea.

AIM: The main purpose of this study was to evaluate the efficacy of paroxetine controlled-release (CR) formulation compared to placebo. A secondary objective was to test the hypothesis that the CR decreases selective-serotonin-reuptake-inhibitors-induced nausea as its formulation allows more distal gastrointestinal absorption than the paroxetine immediate-release (IR) formulation. METHODS: We conducted this study in Japanese and Korean patients with major depressive disorder (MDD) in order to demonstrate the efficacy and safety of paroxetine CR compared with placebo. The primary efficacy end-point was the adjusted mean change from baseline in the 17-item Hamilton Rating Scale for Depression total score at Week 8. RESULTS: A total of 416 patients with MDD were randomly assigned to the CR, IR and placebo groups. The mean change from baseline in the 17-item Hamilton Rating Scale for Depression was -12.8 in the CR group, -12.5 in the IR group, and -10.4 in the placebo group, which showed a statistically significant difference compared to placebo in CR (P < 0.001) and IR (P = 0.015). The incidence of adverse events was 65% in CR, 69% in IR and 55% in placebo. The adverse events were mostly mild or moderate in severity. In the early treatment period, when initiated from 12.5 mg, the incidence of nausea in the CR group was 6%, which was comparable with that of placebo (5%). CONCLUSION: Paroxetine CR is efficacious in the acute treatment of MDD and may have the potential benefit of decreasing the incidence of nausea in the early treatment period.

Obsessive-compulsive disorder and obsessive-compulsive symptoms in Japanese inpatients with chronic schizophrenia - a possible schizophrenic subtype.

To investigate the prevalence of obsessive-compulsive disorder (OCD) and obsessive-compulsive symptoms (OCS) and their association with demographic and clinical factors, 92 inpatients with chronic schizophrenia participated in this study. Demographic factors, severity of psychiatric symptoms as determined by Brief Psychiatric Rating Scale and OCS by Yale-Brown Obsessive Compulsive Scale, general functioning, extrapyramidal symptoms, and dose of antipsychotics were compared between patients with and without OCD or OCS. The Mini-International Neuropsychiatric Interview was employed for diagnosis of OCD and OCS. OCD and OCS were observed in 14.1% and 51.1% of inpatients with schizophrenia, respectively. Schizophrenic patients with OCS exhibited significantly earlier onset of schizophrenia, lower socioeconomic status, and more severe psychiatric symptoms than those without OCS. Earlier hospitalization of schizophrenia, family history of psychosis, and more severe schizophrenic symptoms were associated with comorbidity of OCS, as determined by logistic regression analysis, and younger age was associated with more severe OCS. However, negative symptoms were associated with comorbidity of OCD in chronic schizophrenia. Our findings suggest there is a subtype of schizophrenia with OCS, which is related to earlier onset and more severe psychotic symptoms.

Tumor necrosis factor receptor-associated protein 1 regulates cell adhesion and synaptic morphology via modulation of N-cadherin expression.

An increase in serum tumor necrosis factor-alpha (TNF-alpha) levels is closely related to the pathogenesis of major depression. However, the underlying molecular mechanism between this increase and impairment of brain function remains elusive. To better understand TNF-alpha/TNF receptor 1 signaling in the brain, we analyzed the brain distribution and function of tumor necrosis factor receptor-associated protein 1 (TRAP1). Here we show that TRAP1 is broadly expressed in neurons in the mouse brain, including regions that are implicated in the pathogenesis of major depression. We demonstrate that small interfering RNA-mediated knockdown of TRAP1 in a neuronal cell line decreases tyrosine phosphorylation of STAT3, followed by a reduction of the transcription factor E2F1, resulting in a down-regulation of N-cadherin, and affects the adhesive properties of the cells. In addition, in cultured hippocampal neurons, reduced expression of N-cadherin by TRAP1 knockdown influences the morphology of dendritic spines. We also report a significant association between several single nucleotide polymorphisms in the TRAP1 gene and major depression. Our findings indicate that TRAP1 mediates TNF-alpha/TNF receptor 1 signaling to modulate N-cadherin expression and to regulate cell adhesion and synaptic morphology, which may contribute to the pathogenesis of major depression.

Thought disorder and executive dysfunction in patients with schizophrenia.

Although, impairment of executive functioning is often reported in schizophrenia, its association with thought disorder has not been fully determined. The present study examined the relationships between positive thought disorder assessed using the Harrow's Thought Disorder Scale (Harrow's scale) and executive function by Wisconsin Card Sorting Test (WCST) in 27 inpatients with schizophrenia. Age at onset exhibited a significant negative correlation with Wechsler Adult Intelligence Scale comprehension test score of Harrow's scale and a significant positive correlation with percentage of perseverative errors on the WCST. No significant correlations were found between parameters of positive thought disorder and executive function. Thought disorder and executive function may play different roles in the pathophysiology of schizophrenia.

Longitudinal neuroendocrine changes assessed by dexamethasone/CRH and growth hormone releasing hormone tests in psychotic depression.

Although psychotic depression has been reported to exhibit a greater degree of dysregulation of hypothalamic-pituitary-adrenocortical (HPA) function than non-psychotic depression, little is known concerning hypothalamic-pituitary-somatotropic (HPS) function in psychotic depression and how neuroendocrine function changes after treatment. To investigate the longitudinal changes in HPA and HPS system function in psychotic depression, we performed repeated dexamethasone/corticotropin releasing hormone (DEX/CRH) tests and growth hormone (GH) releasing hormone (GHRH) tests in inpatients with major depressive disorder. The psychotic depression group exhibited greater elevation of ACTH responses to the DEX/CRH test and stronger decreases in GH responses to the GHRH test than the non-psychotic depression group at admission. At discharge, the neuroendocrine responses to the DEX/CRH test of the psychotic depression group were still stronger than those of the non-psychotic depression group, though there were no significant differences in severity of depression between the groups. There were significant longitudinal changes in neuroendocrine responses to the DEX/CRH test between admission and discharge. The psychotic depression group exhibited increased GH responses to GHRH at discharge compared with those at admission, whereas no significant longitudinal change in GH response was found in the non-psychotic depression group. Consequently, there were no significant differences in GH responses to GHRH between the psychotic and non-psychotic depression groups at discharge. The results of GHRH test showed no significant relationships with severity of depression except psychotic features and the results of the DEX/CRH test. Our findings suggest that the HPS axis may be associated with psychotic features rather than general severity of depression. Further longitudinal studies are needed to clarify the role of HPS function in psychotic depression and whether sustained dysregulation of HPA function in psychotic depression is associated with a poor outcome after discharge.

Relationships of DEX/CRH and GHRH test results to the outcome of depression--preliminary results suggest the GHRH test may predict relapse after discharge.

To explore and compare hypothalamic-pituitary-somatotropic (HPS) axis function and hypothalamic-pituitary-adrenocortical (HPA) axis function in depression, the dexamethasone (DEX)/CRH test and growth hormone releasing hormone (GHRH) test were prospectively performed on patients with depression at the time of admission and discharge. The patients who relapsed within six months after discharge exhibited significantly lower growth hormone (GH) responses to GHRH at the time of discharge than those who did not relapse. There were no significant correlations between GH response to GHRH and the results of DEX/CRH tests after controlling for age, sex, and body mass index. The findings of this study suggest that results of the GHRH test may be a predictor of future relapse in patients with depression.

Gender differences in lateralization of mismatch negativity in dichotic listening tasks.

OBJECTIVE: With the aim of investigating gender differences in the functional lateralization subserving preattentive processing of language stimuli, we compared auditory mismatch negativities (MMNs) using dichotic listening tasks. METHODS: Forty-four healthy volunteers, including 23 males and 21 females, participated in the study. MMNs generated by pure-tone and phonetic stimuli were compared, to check for the existence of language-specific gender differences in lateralization. Both EEG amplitude and scalp current density (SCD) data were analyzed. RESULTS: With phonetic MMNs, EEG findings revealed significantly larger amplitude in females than males, especially in the right hemisphere, while SCD findings revealed left hemisphere dominance and contralateral dominance in males alone. With pure-tone MMNs, no significant gender differences in hemispheric lateralization appeared in either EEG or SCD findings. CONCLUSION: While males exhibited left-lateralized activation with phonetic MMNs, females exhibited more bilateral activity. Further, the contralateral dominance of the SCD distribution associated with the ear receiving deviant stimuli in males indicated that ipsilateral input as well as interhemispheric transfer across the corpus callosum to the ipsilateral side was more suppressed in males than in females. SIGNIFICANCE: The findings of the present study suggest that functional lateralization subserving preattentive detection of phonetic change differs between the genders. These results underscore the significance of considering the gender differences in the study of MMN, especially when phonetic stimulus is adopted. Moreover, they support the view of Voyer and Flight [Voyer, D., Flight, J., 2001. Gender differences in laterality on a dichotic task: the influence of report strategies. Cortex 37, 345-362.] in that the gender difference in hemispheric lateralization of language function is observed in a well-managed-attention condition, which fits the condition adopted in the MMN measurement; subjects are required to focus attention to a distraction task and thereby ignore the phonetic stimuli that elicit MMN.

Real-world effectiveness and safety of aripiprazole augmentation therapy in patients with major depressive disorder.

AIMS: Augmentation therapy is an option for patients with major depressive disorder who do respond sufficiently to adequate dosages of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors, but little is known about application of this strategy in everyday practice. METHODS: This prospective, multi-center, observational study investigated the effectiveness and safety of aripiprazole augmentation in Japanese patients with inadequate response to conventional antidepressant therapy in real-world clinical practice. The primary endpoint was mean change in the (Japanese version) Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to study end. Safety was assessed by monitoring adverse events. RESULTS: There were 1103 patients in the safety population and 1090 patients in the effectiveness population. Mean change in the MADRS total score at study end was -14.9 ± 12.3 (p < .001 vs baseline). The remission rate increased from 34.5% at Month 6 to 43.3% at Month 12, suggesting additional benefit with continued treatment. The type of primary antidepressant (paroxetine, fluvoxamine, sertraline, milnacipran, duloxetine, mirtazapine, or escitalopram) had no influence on the effectiveness of aripiprazole augmentation therapy. A baseline MADRS total score of <33 points and an elapsed time of <176 days from an episode of depression to the start of aripiprazole treatment increased the likelihood of achieving remission; 24.8% of patients experienced at least one adverse event, but no new safety signals were identified. CONCLUSIONS: Aripiprazole augmentation therapy appears to be effective and safe in Japanese patients with depression/depressive symptoms treated in everyday clinical practice, taking into account factors associated with achieving remission.

Performance of the Japanese version of the Patient Health Questionnaire-9 (J-PHQ-9) for depression in primary care.

OBJECTIVE: To assess the performance of the Japanese version of the Patient Health Questionnaire-9 (J-PHQ-9) for depression in primary care. METHODS: Participants in both phases completed the J-PHQ-9, while patients in the second phase also completed the SF-8 (the short form for the health-related QOL scale SF-36). Subjects (n = 284; male = 107, female = 177) had to return the questionnaires to their health care professional within 48 hours and undergo a diagnostic evaluation interview based on the Japanese version of M.I.N.I-Plus. RESULTS: 93 patients were diagnosed as having major depressive disorder (MDD). In the J-PHQ-9, the optimal cutpoint ≥ 10 had sensitivity of 90.5% and specificity of 76.6%. As for the categorical algorithms, the sensitivity was 80.6%; specificity was 89.5%, and a positive likelihood ratio of 7.7. The Stratum-specific likelihood ratios (SSLRs) of the J-PHQ-9 scores of 0-9, 10-14, 15-19, and 20-27 for major depression were 0.10 (95% CI: 0.05-0.20), 1.67 (95% CI: 1.02-2.76), 5.41 (95% CI: 2.87-10.22), and 11.98 (95% CI: 5.39-26.63), respectively. The relationship between the severity of J-PHQ-9 and the MCS of SF-8 was significant (χ 2 ＝ 85.72, df = 4, P ≤ 0.0001). CONCLUSIONS: This study has validated the J-PHQ-9 as a useful tool for the assessment of MDD in primary care in Japan.

The patient health questionnaire, Japanese version: validity according to the mini-international neuropsychiatric interview-plus.

To validate the Japanese version of the Patient Health Questionnaire against the Mini-International Neuropsychiatric Interview-Plus in Japan 131 patients in 4 primary care settings and 2 general hospital settings participated. These patients completed the Patient Health Questionnaire and returned it to their physician within 48 hr. Subsequently, the subjects underwent a diagnostic evaluation interview based on the Mini-International Neuropsychiatric Interview-Plus by an interviewer blind to the results of the Patient Health Questionnaire screening. The Patient Health Questionnaire diagnosis was characterized using kappa values between 0.70 and 1.0 for Somatoform Disorder, Major Depressive Disorder, Panic Disorder, Bulimia Nervosa, Alcohol Abuse/Dependence, and Premenstrual Disorder. Sensitivities, specificities, and negative predictive values were very good (between 0.84 and 1.0) for the first 4 diagnoses but not Alcohol Abuse/Dependence or Premenstrual Disorder, as were the Positive predictive values (between 0.78 and 1.0). Findings show very good concordance of the Japanese version of the Patient Health Questionnaire with the Japanese version of the Mini-International Neuropsychiatric Interview-Plus.

Assessment of the dexamethasone/CRH test as a state-dependent marker for hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depressive episode: a Multicenter Study.

There is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA axis abnormalities. We organized a multicenter study to assess the DEX/CRH test as a state-dependent marker for major depressive episode in the Japanese population. We conducted the DEX/CRH test in 61 inpatients with major depressive episode (Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV)) and 57 healthy subjects. In all, 35 patients were repeatedly assessed with the DEX/CRH test on admission and before discharge. The possible relationships between clinical variables and the DEX/CRH test were also examined. Significantly enhanced pituitary-adrenocortical responses to the DEX/CRH test were observed in patients on admission compared with controls. Such abnormalities in patients were significantly reduced after treatment, particularly in those who underwent electroconvulsive therapy (ECT) in addition to pharmacotherapy. Age and female gender were associated with enhanced hormonal responses to the DEX/CRH test. Severity of depression correlated with DEX/CRH test results, although this was explained, at least in part, by a positive correlation between age and severity in our patients. Medication per se was unrelated to DEX/CRH test results. These results suggest that the DEX/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities in major depressive episode during treatment. Restoration from HPA axis abnormalities occurred with clinical responses to treatment, particularly in depressed patients who underwent ECT.

A placebo-controlled, randomized withdrawal study of sertraline for major depressive disorder in Japan.

The objective of this double-blind, placebo-controlled, multicentre randomized withdrawal study was to evaluate the efficacy and tolerability of sertraline for 16 weeks in treating Japanese patients with major depressive disorder (MDD) who had achieved a response to 8 weeks of sertraline treatment. Patients (n=361) were initially treated with 8 weeks of open-label sertraline treatment followed by 16 weeks of double-blind treatment with either sertraline (50-100 mg/day) or placebo. Responders during the open-label phase were eligible to be entered into the double-blind phase. A total of 235 patients (65.1%) were entered to the double-blind phase and randomly assigned to receive sertraline (n=117) or placebo (n=118). A significantly (P=0.016) lower relapse rate was found for sertraline (8.5%) compared to placebo (19.5%) during the double-blind phase. Examination of time-to-relapse showed that the relapse free rate curve was significantly higher for sertraline (log-rank test, P=0.026) than placebo. Mean changes from beginning to end of the double-blind phase on measure of depressive symptoms, quality of life and global improvement also significantly favoured sertraline over placebo. Sertraline was well-tolerated, with similar adverse events as found in previous studies. These results confirm the efficacy of sertraline in preventing the relapse of MDD in Japanese patients.

Induction of neuroserpin expression in rat frontal cortex after chronic antidepressant treatment and electroconvulsive treatment.

Using expressed sequence tag (EST) analysis, we previously identified certain molecular machinery that mediates antidepressant effects. To date, several partial cDNA fragments, termed antidepressant-related genes (ADRGs), have been isolated as ESTs from rat brain. In the present study, we identified two of the ADRGs to be rat neuroserpin. Using real-time quantitative PCR, we demonstrated increased neuroserpin mRNA expression in rat frontal cortex after chronic treatment with several classes of antidepressants, including imipramine, fluoxetine, sertraline, and venlafaxine. Electroconvulsive treatment (ECT), another therapeutic treatment for depression, also increased neuroserpin expression in rat frontal cortex. Neuroserpin is a serine protease inhibitor that is implicated in the regulation of synaptic plasticity, neuronal migration, and axogenesis in the central nervous system. In conclusion, our results support the hypothesis that neuroserpin-mediated plastic changes in frontal cortex may underlie the therapeutic action of antidepressants and ECT.

A randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of venlafaxine extended release and a long-term extension study for patients with major depressive disorder in Japan.

The aim of this study was to assess antidepressant efficacy and safety of venlafaxine extended release in Japanese patients with major depressive disorder (MDD). We carried out a double-blinded, placebo-controlled, randomized study using fixed (75 mg/day) and flexible (75-225 mg/day, most patients attained to 225 mg/day) doses, followed by the long-term, open-labeled, extension study. Outpatients aged at least 20 years diagnosed with MDD were included. The primary efficacy measure was change from baseline in the Hamilton Rating Scale for Depression (HAM-D17) score at week 8; secondary efficacy measures included the Montgomery-Åsberg Depression Rating Scale, the Quick Inventory of Depressive Symptomatology self-report version, HAM-D6, and Clinical Global Impression scales in the double-blinded study. Overall, 538 patients were randomized; significant differences were observed in the primary efficacy variable in the fixed-dose group (-10.76; P=0.031), but not in the flexible-dose (-10.37; P=0.106) group compared with placebo (-9.25). However, the flexible-dose group showed significant efficacy in several secondary measures. Treatment-related adverse events in the treatment period were 51.7 and 67.8% in the fixed-dose and flexible-dose groups, respectively, versus 38.8% with placebo. Throughout the study period, no Japanese-specific adverse events were observed. Thus, venlafaxine extended release was efficacious and safe for MDD treatment in Japan.

The breakpoint cluster region gene on chromosome 22q11 is associated with bipolar disorder.

BACKGROUND: Although the pathogenesis of bipolar disorder remains unclear, heritable factors have been shown to be involved. The breakpoint cluster region (BCR) gene is located on chromosome 22q11, one of the most significant susceptibility loci in bipolar disorder linkage studies. The BCR gene encodes a Rho GTPase activating protein, which is known to play important roles in neurite growth and axonal guidance. METHODS: We examined patients with bipolar disorder (n = 171), major depressive disorder (n = 329) and controls (n = 351) in Japanese ethnicity for genetic association using eleven single nucleotide polymorphisms (SNPs), including a missense one (A2387G; N796S), in the genomic region of BCR. RESULTS: Significant allelic associations with bipolar disorder were observed for three SNPs, and associations with bipolar II disorder were observed in ten SNPs including N796S SNP (bipolar disorder, p = .0054; bipolar II disorder p = .0014). There was a significant association with major depression in six SNPs. S796 allele carriers were in excess in bipolar II patients (p = .0046, odds ratio = 3.1, 95% CI 1.53-8.76). Furthermore, we found a stronger evidence for association with bipolar II disorder in a multi-marker haplotype analysis (p = .0002). CONCLUSIONS: Our results suggest that genetic variations in the BCR gene could confer susceptibility to bipolar disorder and major depressive disorder.

High prevalence of Chlamydia pneumoniae antibodies and increased high-sensitive C-reactive protein in patients with vascular dementia.

OBJECTIVES: To determine the relationships between Chlamydia pneumoniae infection, carotid atherosclerosis, and dyslipidemia in patients with vascular dementia (VaD) and Alzheimer's disease (AD). DESIGN: Case control study. SETTING: Showa University Karasuyama Hospital, Tokyo, Japan. PARTICIPANTS: One hundred twenty-four elderly subjects: 31 with VaD, 61 with AD, and 32 age-matched controls without dementia. MEASUREMENTS: Presence of antibodies to C. pneumoniae (immunoglobulin G (IgG) and IgA), the serum concentrations of high-sensitive C-reactive protein (hs-CRP) and atherogenic lipoproteins, and the carotid artery intima-media thickness (IMT) and plaques were determined. RESULTS: Age; body mass index; systolic and diastolic blood pressures; and fasting plasma glucose, hemoglobin A(1c), high-density lipoprotein cholesterol, and apolipoprotein A-I, B, and E concentrations did not differ significantly between the three groups, but the mean IMT and frequency of atherosclerotic plaques in the carotid arteries, as well as the serum concentrations of low-density lipoprotein cholesterol (LDL-C), lipoprotein(a), and lipid peroxides were significantly greater in VaD patients than in AD patients or nondemented controls. Hs-CRP concentrations and prevalence of C. pneumoniae IgG and IgA antibodies also were significantly higher in VaD patients than in AD patients and nondemented controls. Multiple logistic regression analysis revealed that carotid IMT and plaques, LDL-C, lipid peroxides, hs-CRP, and IgG and IgA C. pneumoniae seropositivity were independent risk factors for VaD. CONCLUSION: These results suggest that carotid atherosclerosis, atherogenic lipoproteins, and C. pneumoniae infection (as documented by the IgG and IgA seropositivity together with increased hs-CRP) may be VaD risk factors.