Volume enlargement of the choroid plexus and brain ventricles in drug-naïve, first-episode major depressive disorder.

BACKGROUND: We investigated volumetric alterations in the bilateral choroid plexus (ChP) and brain ventricles of patients during their first episode of major depressive disorder (MDD) prior to antidepressant treatment. METHODS: Seventy-one first-episode drug-naïve patients with MDD and seventy-four healthy control (HC) subjects were recruited. MRI data were obtained, and bilateral ChP and brain ventricle volumes were evaluated using segmentation, based on the adaptive multiscale and expectation maximization method. One-way multivariate analysis of covariance was used to calculate volumetric differences in the bilateral ChP and brain ventricles between the groups, and partial Pearson correlation analyses were used to investigate the relationship between the volumes of the bilateral ChP and brain ventricles. RESULTS: First-episode drug-naïve patients with MDD showed enlarged volumes of the bilateral ChP, bilateral lateral ventricle (LV), and third ventricle compared with HCs. The ChP volume positively correlated with the LV and third ventricle, but not with the fourth ventricle in patients with MDD, whereas it correlated with all four brain ventricles in HCs. We did not observe significant correlations between bilateral ChP volume and brain ventricles, HAMD scores, or symptom severity. LIMITATIONS: Our study populations differed in age and sex and we did not extensively measure the amount of neuroinflammation in the brain or blood, include a functional assessment, nor evaluate other neural comorbidities or neuropsychiatric conditions. CONCLUSIONS: Our study extends the existing research to suggest that illness-related alterations in ChP volume enlargement in first-episode antidepressant-naïve patients with MDD may serve as a trait measure.

Triple network connectivity changes in patients with major depressive disorder versus healthy controls via structural network imaging after electroconvulsive therapy treatment.

OBJECTIVE: To investigate the effect of electroconvulsive treatment (ECT) on dynamic structural network connectivity in major depressive disorder (MDD), based on the triple-network model. METHODS: Twenty-one first-episode, drug-naïve patients with MDD and 21 age- and sex-matched healthy subjects were recruited. Bilateral electrical stimulation was performed thrice a week for a total of 4-5 weeks in the MDD group. MRI data were obtained, and triple-network structural connectivity was evaluated using source-based morphometry (SBM) analysis. A paired t-test was used to analyze structural connectivity differences between pre- and post-ECT MDD groups, one-way analysis was used to calculate three intrinsic network differences between HCs, pre- and post-ECT groups, and partial least squares structural equation modelling was used to investigate dynamic structural network connectivity (dSNC) across groups. RESULTS: Pre-ECT patients with MDD exhibited significantly lower salience network (SN) structural connectivity (p = 0.010) than the healthy control (HC) group and after ECT therapy SN structural connectivity was significantly elevated (p = 0.002) in post-ECT group compared with pre-ECT. PLS-SEM analysis conducted on inter-network connectivity in the triple-network model indicated a significant difference between SN and central executive network (CEN) in all three groups. The HC and post-ECT MDD groups showed notable direct connectivity between the SN and default mode network (DMN), while the pre-ECT MDD group showed consequential pathological connectivity between the CEN and DMN. A mediation analysis revealed a significant indirect effect of the SN on the DMN through the CEN (ß = 0.363, p = 0.008) only in the pre-ECT MDD group. CONCLUSIONS: ECT may be an effective and minimally invasive treatment for addressing structural changes in the SN and direct communication abnormalities between the three core brain networks in patients with MDD, with possible beneficial correction of indirect connections.

Acute pancreatitis during valproic acid administration in a patient with vascular dementia, epileptic seizures, and psychiatric symptoms: a case report.

BACKGROUND: Valproic acid (VPA) is a relatively safe drug widely used for the treatment of epileptic seizures and mania in bipolar disorder, as well as the prevention of migraine headaches. Here, we present a case of VPA-induced pancreatitis in a patient with vascular dementia, epileptic seizures, and psychiatric symptoms. He had no distinctive abdominal symptoms. CASE PRESENTATION: A 66-year-old Japanese man was treated with VPA for agitation and violent behavior due to vascular dementia, epileptic seizures, and psychiatric symptoms. During admission, he experienced a sudden decrease in consciousness and blood pressure. Abdominal findings were unremarkable; however, blood tests showed an inflammatory response and elevated amylase levels. Contrast-enhanced abdominal computed tomography showed diffuse pancreatic enlargement and inflammation extending to the subrenal pole. VPA-induced acute pancreatitis was diagnosed, VPA was discontinued, and high-dose infusions were administered. Acute pancreatitis resolved after treatment initiation. CONCLUSIONS: Clinicians should be aware of this relatively rare side effect of VPA. Diagnosis may be challenging in elderly people and patients with dementia as they may present with non-specific symptoms. Clinicians should consider the risk of acute pancreatitis when using VPA in patients who cannot report spontaneous symptoms. Blood amylase and other parameters should be measured accordingly.

Infrared spectroscopy and theoretical structure analyses of protonated fluoroalcohol clusters: the impact of fluorination on the hydrogen bond networks.

To explore the impact of fluorination on the hydrogen bond networks of protonated alkylalcohols, infrared spectroscopy and theoretical computations of protonated 2,2,2-trifluoroethanol clusters, H+(TFE)n, (n = 4-7), were performed. It has been demonstrated that the development of the hydrogen bond networks from a linear type to cyclic types occurs in this size region for the protonated alkylalcohol clusters. In contrast, infrared spectroscopy of H+(TFE)n in the OH/CH stretch region clearly indicated that the linear type structures are held in the whole size range, irrespective of temperature of the clusters. The extensive stable isomer structure search of H+(TFE)n based on our latest sampling approach supported the strong preference of the linear type hydrogen bond networks. Detailed analyses of the free OH stretching vibrational bands evidenced the intra- and intermolecular OH⋯FC interactions in the clusters. In addition, infrared spectra of protonated clusters of 2,2-difluoroethanol, 2,2-difluoropropanol, and 3,3,3-trifluoropropanol were measured for n = 4 and 5, and their spectra also indicated the effective inhibition of the cyclic hydrogen bond network formation by the fluorination.

Brain structural network alterations related to serum cortisol levels in drug-naïve, first-episode major depressive disorder patients: a source-based morphometric study.

Higher cortisol levels due to a hyperactive hypothalamic-pituitary-adrenal axis have been reported in patients with major depressive disorder (MDD). Increased cortisol levels change both the brain morphology and function in MDD patients. The multivariate source-based morphometry (SBM) technique has been applied to investigate neuroanatomical changes in some neuropsychiatric diseases, but not MDD. We aimed to examine the alterations in gray matter (GM) networks and their relationship with serum cortisol levels in first-episode, drug-naïve MDD patients using SBM. Forty-two patients with MDD and 39 controls were recruited via interviews. Morning serum cortisol levels were measured, and high-resolution T1-weighted imaging followed by SBM analysis was performed in all participants. The patients had significantly higher serum cortisol levels than the controls. We found two GM sources, which were significantly different between patients with MDD and controls (prefrontal network, p < .01; insula-temporal network, p < .01). Serum cortisol levels showed a statistically significant negative correlation with the loading coefficients of the prefrontal network (r = - 0.354, p = 0.02). In conclusion, increased serum cortisol levels were associated with reductions in the prefrontal network in the early stage of MDD, and SBM may be a useful approach for analyzing structural MRI data.

Effects of mixing between short-chain and branched-chain alcohols in protonated clusters.

The previous analysis of the neat protonated branched-chain alcohol clusters revealed the impact of steric repulsion and dispersion of the bulky alkyl group on the hydrogen-bonded (H-bonded) structures and their temperature-dependence. To further understand the influence of the alkyl groups in H-bonded clusters, we studied the mixing of the two extremes of alcohols, methanol (MeOH) and tert-butyl alcohol (t-BuOH), with an excess proton. Infrared spectroscopy and a structural search of first principles calculations on the size-selected clusters H+(MeOH)m(t-BuOH)t (m + t = 4 and 5) were conducted. Temperature-dependence of the dominant H-bonded structures was explored by the Ar-tagging technique and quantum harmonic superposition approach. By introducing the dispersion-corrected density functional theory methods, it was shown that the effects of dispersion due to the bulky alkyl groups in the mixed clusters cannot be ignored for t≥ 2. The computational results qualitatively depicted the characteristics of the observed IR spectra, but overestimation of the temperature-dependence with dispersion correction was clearly seen due to the unbalanced correction between linear H-bonded structures and compact cyclic ones. These results demonstrate the importance of extensive investigation and benchmarks on different levels of theory, and that a properly sampled structure database is crucial to evaluate theoretical models.

Hemifield Crossings during Multiple Object Tracking Affect Task Performance and Steady-State Visual Evoked Potentials.

The ability to track multiple objects is important for daily life activities such as driving, but it is subject to some restrictions. One limitation concerns the hemifields in which objects move. A previous study showed that when subjects were restricted to the use of one hemifield, both the maximum number of tracked objects and the tracking accuracy were lower than when they were permitted to use both hemifields. However, daily life involves many tracked objects moving between hemifields. In this study, we investigated the effects of such hemifield crossings on behavioral performance (Behavioral experiment) and on the amplitudes and phase synchronization of steady-state visual evoked potentials (SSVEPs) (SSVEP experiment) by comparing the Within condition, in which tracked objects moved within their respective hemifields, and the Crossover condition, in which tracked objects moved between hemifields. In the Behavioral experiment, tracking performance was worse under the Crossover condition than under the Within condition. In the SSVEP experiment, SSVEP amplitudes for target and distractor frequencies differed under the Within condition but did not differ under the Crossover condition. However, phase synchronization between the left and right hemifields exhibited the opposite trend. This study provides evidence that attention to objects moving between hemifields is suppressed relative to attention to objects moving within hemifields and that Crossover tracking diminishes attentional modulation at an early sensory processing level while modulating interhemispheric functional connectivity.

Attention-deficit/hyperactivity disorder symptoms and suicidal behavior in adult psychiatric outpatients.

AIM: We aimed to examine the association between attention-deficit/hyperactivity disorder (ADHD) symptoms and suicidal behavior in psychiatric outpatients and whether this association differs among patients with different psychiatric disorders. METHODS: Cross-sectional data came from the Japan Prevalence Study of Adult ADHD at Psychiatric Outpatient Care, which included psychiatric outpatients aged 18-65 years recruited from one university hospital and three general psychiatric outpatient clinics in Kitakyushu City, Fukuoka, Japan from April 2014 to January 2015 (N = 864). The Adult ADHD Self-Report Scale (ASRS) Screener was used to collect information on ADHD symptoms. Reports of current and lifetime suicidal behavior were also obtained. A multivariable Poisson regression analysis was used to examine the association between ADHD symptoms and suicidal behavior. RESULTS: After adjusting for covariates there was a strong association between possible ADHD (ASRS ≥14) and suicidal behavior with prevalence ratios ranging from 1.17 (lifetime suicidal ideation) to 1.59 (lifetime suicide attempt) and 2.36 (current suicidal ideation). When ASRS strata were used, there was a dose-response association between increasing ADHD symptoms and suicidal ideation and suicide attempts. Analyses of individual ICD-10 psychiatric disorders showed that associations varied across disorders and that for anxiety disorder, ADHD symptoms were significantly linked to all forms of suicidal behavior. CONCLUSION: ADHD symptom severity is associated with an increased risk for suicidal behavior in general psychiatric outpatients. As ADHD symptoms are common among adult psychiatric outpatients, detecting and treating ADHD in this population may be important for preventing suicidal behavior.

[Examination of factors for promoting cooperation using documents between occupational health physicians and psychiatrists].

OBJECTIVES: There is little specific information concerning the method and the efficacy of sharing information between occupational health physicians and psychiatrists regarding the employment status and medical history of their patients with mental illnesses. To promote cooperation between occupational health physicians and psychiatrists, we examined the points necessary to be included on medical information request forms exchanged between them. METHODS: We conducted focused group discussion (FGD) to identify the points that need to be described on the request form and the concerns in cooperation between occupational health physicians and psychiatrists. We conducted FGDs twice, with two different groups of nine psychiatrists participating in each round. We extracted and organized FGD results and determined the necessary request form points. Next, we assumed two different cases of workers with mental illnesses and created three request form templates with differing item descriptions and lengths. We also conducted a questionnaire survey among clinical psychiatrists to determine their impression of the templates. We performed logistic regression analysis on the obtained results. RESULTS: On the basis of the FGD results we extracted the situation in the workplace, clarification of points to be confirmed, representation of the occupational health physician's position, and handling of information provided by the doctor as points required for the request form. On the basis of these results and the opinions of occupational health specialists, we created a new request form using these points. Additionally, the results from the questionnaire survey about the prescribed items revealed the proportion of favorable answers regarding sufficient information written on the request form and a feeling of security for information provision increased (p < 0.01). Conversely, the proportion of favorable responses for readability decreased. CONCLUSIONS: Psychiatrists are concerned about the possibility that their patient may be at a disadvantageous situation by providing their personal medical information and believe the clinical information required by the occupational health physicians is unclear. This suggests that there are factors impeding the cooperation between the occupational health physicians and psychiatrists. When an occupational health physician writes a request form, cooperation with psychiatrists may be promoted by enriching the request form contents and by including the representation of the occupational health physician's position and the intended purpose of the provided information by paying attention to the volume of sentences.

[Nicotine dependence].

Smoking is the most widespread addictive behavior in the world, and it causes physical and psychological dependence on nicotine. As for physical nicotine dependence, nicotine produces rewarding effects by interacting with nicotinic acetylcholine receptors on neurons in the brain's reward system. Psychological dependence on nicotine comes with a complex psychological procedure that is based on distorted cognition which justifies their smoking behavior. Clinicians should support smokers with willingness to quit smoking comprehensively with this knowledge, although the success rate of smoking cessation is no ideal in general.

Effect of COMT Val108/158Met genotype on risk for polydipsia in chronic patients with schizophrenia.

Polydipsia is a serious condition often seen among patients with schizophrenia (SCZ). The cause of polydipsia is unknown; hence, it is hard to treat or manage. Animal studies showed that the drinking behavior is regulated by central dopaminergic neurotransmission at the hypothalamus. Meanwhile, the existence of a genetic predisposition to polydipsia in patients with SCZ has been suggested. The purpose of this study was to assess whether a functional polymorphism, Val(108/158)Met in the gene for catechol-O-methyltransferase (COMT), is associated with susceptibility to polydipsia using a Japanese sample of SCZ. Our sample includes 330 chronic patients with SCZ (83 polydipsic patients and 247 non-polydipsic controls). The common COMT Val(108/158)Met polymorphism was genotyped, and the differences in genotype distribution and allele frequency between cases and controls were evaluated using the χ(2) test. A significant association between the COMT Val(108/158)Met polymorphism and polydipsia was found (genotype distribution: χ(2) = 13.0, df = 2, p = 0.001; allele frequency: χ(2) = 7.50, df = 1, p = 0.006). The high-COMT activity group (Val/Val) was more frequent among patients with polydipsia compared with the low-COMT activity group (Val/Met + Met/Met) [odds ratio (OR) = 2.46]. The association survived after controlling for other possible confounding factors, including gender, age, age of onset, current antipsychotic dose, and smoking status. Our results suggest that the COMT Val(108/158)Met genotype may confer susceptibility to polydipsia in SCZ. To our knowledge, this is the first association study between the COMT gene and polydipsia in SCZ. Further studies with larger sample sizes are warranted to confirm present findings.

Follow-up Study on Electroconvulsive Therapy in Treatment-resistant Depressed Patients after Remission: A Chart Review.

OBJECTIVE: Electroconvulsive therapy (ECT) has proven to be effective in treatment-resistant depression (TRD). In recent reports, 70% to 90% of patients with TRD responded to ECT. However, post-ECT relapse is a significant problem. There are no studies investigating risk factors associated with reintroducing ECT in depressive patients after remission previously achieved with former ECT. The aim of the present study is to examine such risk factors using a sample of TRD patients. METHODS: We conducted a chart review to examine patient outcomes and adverse events over short- and long-term periods. Forty-two patients met the criteria for major depressive disorder. RESULTS: The response rate was 85.7% (36/42). There were no significant differences in the baseline characteristics of patients exhibiting remission, response or non-response. The rate of adverse events was 21.4% (9/42). Among 34 patients who were available for follow-up, 18 patients relapsed (relapse rate, 52.9%), and 6 patients were reintroduced to ECT. The patients' age and age of onset were significantly higher in the re-ECT group than non re-ECT group. CONCLUSION: Our results suggest that older age and older age of onset might be considered for requirement of re-ECT after remission previously achieved with former ECT.

Finite mixture regression model analysis on antipsychotics induced weight gain: investigation of the role of the serotonergic genes.

Antipsychotics-induced weight gain is a complex phenomenon with a relevant underlying genetic basis. Polymorphisms of serotonin receptors and related proteins were genotyped in 139 schizophrenia patients and incorporated as covariates in a mixture regression model of weight gain in combination with clinical covariates. The HTR1D rs6300 polymorphism was showing a slight significance conferring risk for obesity (heavy weight gain group) under additive model. After correcting for multiple testing all the genetic predictors were non-significant, however the clinical predictors were associated with the risk of heavy weight gain. These findings suggest a role of ethnicity and olanzapine in increasing the risk for obesity in the heavy weight gain group and haloperidol protecting against heavy weight gain. The mixture regression model appears to be a useful strategy to highlight different weight gain subgroups that are affected differently by clinical and genetic predictors.

Analysis of treatment-resistant schizophrenia and 384 markers from candidate genes.

The treatment of patients with schizophrenia who fail to respond to antipsychotics is a major challenge and the proportion of treatment-resistant patients is estimated to be 20 to 40%. There are few genetic association studies that have compared resistant versus non-resistant schizophrenic patients; however, many genetic association studies focusing on antipsychotic response have been published. This contribution investigates the genetics of treatment-resistant schizophrenia, testing 384 candidate gene loci related to the neurobiology of the disease. First, we identified a subgroup of treatment-resistant patients in a sample of 240 schizophrenia patients using the American Psychiatric Association criteria and then we genotyped all patients using a custom Illumina Bead Chip comprising of 384 single nucleotide polymorphisms. We screened all markers for nominal significance and for statistical significance after multiple-testing correction. The most significant single nucleotide polymorphism was the rs2152324 marker in the NALCN gene (P=0.004); however, after the FDR correction, the P-value was not significant. Our analysis of 384 markers across candidate genes did not indicate any robust association with treatment-resistant schizophrenia. However, this phenotype can be assessed retrospectively in cross-sectional studies and these preliminary results point out the importance of choosing alternative phenotypes in psychiatric pharmacogenetics.

[Antidepressants: clinical guidance of treatment for people with depression and physical health problems].

Current management in primary care of depression with comorbid physical illness is considered suboptimal. Detection and management of depression is somewhat complex. In particular, primary care clinicians need guidance to address the social needs of depressed patients. This review for clinical physicians provides guidance how to treat those patients with depression in particular at primary care settings. The viewpoints of clinical use of newer antidepressants including SSRIs and SNRIs are described. Given that depression would affect the outcome of physical illness, managing depressed people with comorbid physical illness is very important and understanding relevant drug treatment for depression is essential for primary care physicians.

Genetic association between the dopamine D3 receptor gene polymorphism (Ser9Gly) and tardive dyskinesia in patients with schizophrenia: a reevaluation in East Asian populations.

The dopamine D3 receptor gene (DRD3) is considered being one of the candidate genes contributing to the development of tardive dyskinesia (TD). In a recent meta-analysis with mixed ethnicities, only a barely positive association was found between the functional DRD3 Ser9Gly polymorphism and TD in patients with schizophrenia (OR=1.17; 95% CI: 1.01-1.37; p=0.041). To further evaluate the controversial association between the polymorphism and TD using only Japanese subjects, we tested the association in a case-control design. We also conducted a meta-analysis including 8 studies with 3 East Asian populations (Japanese, Chinese, and Korean). In our Japanese case-control sample (43 with TD/157 without TD), we found no association between the DRD3 Ser9Gly polymorphism in schizophrenia and TD (genotype: p=0.92; allele: p=1.00). Furthermore, no significant difference in the mean AIMS score among the three genotypic groups was observed in our sample. The meta-analysis comprising 1291 East Asian subjects also showed no association between the polymorphism and TD; the Mantel-Haenszel pooled OR for TD among carriers of the DRD3 Ser9Gly of the eight Asian studies was 0.94 (95% CI: 0.78-1.12). Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to TD in East Asian populations. Given that the Ser9Gly variant may play a putative role in the DRD3 function, further studies on the DRD3 are warranted.

Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia.

OBJECTIVE: The D-amino acid oxidase activator (DAOA, or G72) is involved in the oxidation of D-serine, an endogenous modulator of N-methyl-D-aspartate receptors and thus represents an important candidate in psychotic disorders. Several studies reported the DAOA/G72 gene to be associated with schizophrenia (SZ) and bipolar disorder (BD); however, the associated polymorphisms varied between SZ and BD. This study attempts to replicate the DAOA/G72 findings in BD and to conduct subgroup analyses based on the presence or absence of psychotic symptoms. METHODS: Five polymorphisms of the DAOA/G72 gene (rs1341402, rs1935062, rs2391191, rs947267, and rs778294) were analysed for association with BD in a family-based study design (303 core families including 916 individuals). We also conducted a meta-analysis of DAOA/G72 polymorphisms in BD and SZ. RESULTS: Marker rs1935062 was significantly associated with BD diagnosis in our sample (Z-score for C-allele= -2.33, p=0.02, uncorrected for genome-wide multiple comparisons). When we examined the subset of BD patients with psychotic symptoms (157 families), no significant results were obtained. Our meta-analysis yielded negative findings for DAOA/G72 markers in BD and positive findings for marker rs2391191 in SZ in East Asians. However, significant heterogeneity across studies limits interpretation. CONCLUSIONS: Our results provide evidence that suggests a possible role of the DAOA/G72 gene in BD and SZ. Marker rs1935062 may be specifically associated with BD, while marker rs2391191 may be associated with SZ but not with BD. Together with previous studies, these findings suggest that the DAOA/G72 gene confers susceptibility to both BD and SZ, but that different polymorphisms may potentially differentiate between these two disorders.

The catechol-O-methyl-transferase gene in tardive dyskinesia.

UNLABELLED: Tardive dyskinesia (TD) is a severe and potentially irreversible motor side effect linked to long-term antipsychotic exposure. Changes in dopamine neurotransmission have been implicated in the etiology of TD, and catechol-O-methyl-transferase (COMT) is an enzyme that metabolizes dopamine. OBJECTIVES: We investigated five single-nucleotide polymorphisms in addition to the functional Val158Met variant spanning the COMT gene for association with TD. METHODS: We analyzed the six COMT single-nucleotide polymorphisms in a sample of schizophrenia/schizoaffective disorder patients (n=226; 196 Caucasians and 30 African Americans). RESULTS: We found a significant association between the marker rs165599 in the 3' untranslated region of COMT and TD (AA versus G-carrier: OR(AA)=2.22, 95% CI:1.23-4.03; P=0.007). The association appeared to be originating from males. We did not find a significant association of the other five tested polymorphisms with TD in our samples. We performed a sex-stratified meta-analysis across all of the published studies (n=6 plus our own data) of COMT and TD, and found an association between ValVal genotype and TD in females (OR(ValVal)=1.63, 95% CI: 1.09-2.45; P=0.019) but not in males. CONCLUSIONS: Overall, our results suggest that the COMT gene may have a minor but consistent role in TD, although sex-stratified studies with additional markers in larger clinical samples should be performed.