Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression.

Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood-brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction.

MEG activity of the dorsolateral prefrontal cortex during optic flow stimulations detects mild cognitive impairment due to Alzheimer's disease.

Dorsal stream, which has a neuronal connection with dorsolateral prefrontal cortex (DLPFC), is known to be responsible for detection of motion including optic flow perception. Using magnetoencephalography (MEG), this study aimed to examine neural responses to optic flow stimuli with looming motion in the DLPFC in patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) compared with cognitively unimpaired participants (CU). We analyzed the neural responses by evaluating maximum source-localized power for the AD-MCI group (n = 11) and CU (n = 20), focusing on six regions of interest (ROIs) that form the DLPFC: right and left dorsal Brodmann area 9/46 (A9/46d), Brodmann area 46 (A46) and ventral Brodmann area 9/46 (A9/46v). We found significant differences in the maximum power between the groups in the left A46 and A9/46v. Moreover, in the left A9/46v, the maximum power significantly correlated with the Wechsler Memory Scale-Revised general memory score and delayed recall score. The maximum power in the left A9/46v also revealed high performance in AD-MCI versus CU classification with the area under the ROC curve of 0.90. This study demonstrated that MEG during the optic flow task can be useful in discriminating AD-MCI from CU.

Sirtuin 6 is a regulator of dendrite morphogenesis in rat hippocampal neurons.

Sirtuin 6 (SIRT6), a member of the Sirtuin family, acts as nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, mono-adenosine diphosphate (ADP)-ribosyltransferase, and fatty acid deacylase, and plays critical roles in inflammation, aging, glycolysis, and DNA repair. Accumulating evidence has suggested that SIRT6 is involved in brain functions such as neuronal differentiation, neurogenesis, and learning and memory. However, the precise molecular roles of SIRT6 during neuronal circuit formation are not yet well understood. In this study, we tried to elucidate molecular roles of SIRT6 on neurite development by using primary-cultured hippocampal neurons. We observed that SIRT6 was abundantly localized in the nucleus, and its expression was markedly increased during neurite outgrowth and synaptogenesis. By using shRNA-mediated SIRT6-knockdown, we show that both dendritic length and the number of dendrite branches were significantly reduced in the SIRT6-knockdown neurons. Microarray and subsequent gene ontology analysis revealed that reducing SIRT6 caused the downregulation of immediate early genes (IEGs) and alteration of several biological processes including MAPK (ERK1/2) signaling. We found that nuclear accumulation of phosphorylated ERK1/2 was significantly reduced in SIRT6-knockdown neurons. Overexpression of SIRT6 promoted dendritic length and branching, but the mutants lacking deacetylase activity had no significant effect on the dendritic morphology. Collectively, the presented findings reveal a role of SIRT6 in dendrite morphogenesis, and suggest that SIRT6 may act as an important regulator of ERK1/2 signaling pathway that mediates IEG expression, which leads to dendritic development.

CYP2D6*10 polymorphism and the enantioselective O-desmethylation of S-(+)- and R-(-)-venlafaxine in Japanese psychiatric patients.

According to previous studies, R-(-)-venlafaxine (VEN) has higher enantioselectivity than S-(+)-VEN, and the plasma concentration of R-(-)-VEN varies depending on CYP2D6 activity. Therefore, we examined the pharmacokinetic effects of CYP2D6*10 genotypes on the steady-state concentrations of the enantiomers of VEN. The individuals were 71 Japanese depressed patients treated with racemic VEN. The concentrations of the enantiomers of VEN and O-desmethylvenlafaxine (ODV) were measured. Polymerase chain reaction (PCR) was used to determine the CYP2D6*10 genotypes. The plasma concentrations of S-(+)-VEN were approximately 1.9-fold higher than those of R-(-)-VEN. The plasma concentrations of S-(+)-VEN and R-(-)-VEN seemed to be higher in individuals with two mutant alleles of CYP2D6*10, although no significant differences were found in the plasma levels of S-(+)-VEN and R-(-)-VEN between CYP2D6*10 genotypes. The number of mutant alleles of CYP2D6*10 was a significant factor associated with the R-(-)-ODV/R-(-)-VEN ratio (P = .004) in multiple regression analysis. This suggests that CYP2D6*10 mutations affect the metabolism of R-(-)-VEN and S-(+)-VEN. Further studies are needed to examine how these findings affect clinical practice.

Effects of CYP2D6 Genotypes on Venlafaxine Metabolism in Japanese Psychiatric Patients With Depression.

BACKGROUND: Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV) pharmacokinetics in Whites, limited data are available regarding the effects of the Asian-specific CYP2D6 genotype on VEN metabolism. This study evaluated the effects of the CYP2D6*10 and CYP2D6*5 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients. METHODS: This study included 75 Japanese patients with depression who were treated with VEN. Steady-state plasma concentrations of VEN and ODV were measured using liquid chromatography. Polymerase chain reaction was used to determine CYP2D6 genotypes. A stepwise multiple regression analysis was performed to analyze the relationship between independent variables (sex, age, smoking habit, and number of mutated alleles, CYP2D6*10 and CYP2D6*5), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio. RESULTS: Significant correlations were observed between the daily dose of VEN (corrected for body weight) and plasma concentrations of VEN (r = 0.498, P < 0.001) and ODV (r = 0.380, P = 0.001); ODV plasma concentrations were approximately 3.2 times higher than VEN plasma concentrations (VEN versus ODV = 18.60 ng/mL versus 59.10 ng/mL). VEN plasma concentrations (corrected for dose and body weight) did not differ with differing numbers of CYP2D6-mutated alleles. However, the ODV/VEN ratio decreased as the number of mutated CYP2D6 alleles increased (P = 0.001). CONCLUSIONS: This is the first study to examine the effects of CYP2D6*10 in a clinical setting. Although no effects on the plasma concentrations of VEN or ODV were observed, CYP2D6 polymorphism affects the ODV/VEN ratio. Further studies are needed to confirm the clinical relevance of these findings.

Comparison of physiological and behavioral responses to chronic restraint stress between C57BL/6J and BALB/c mice.

Rodent models of chronic restraint stress (CRS) are often used as simple models of depressive disorder. However, these models of stress have been mainly developed in rats, and the behavioral phenotypes of CRS models are still controversial. In this study, we compared the physiological and behavioral responses of C57BL/6J (B6) and BALB/c mice, which are commonly used in genetic and behavioral studies, to CRS. In addition to measuring physiological parameters and the levels of corticosterone (a stress hormone) in response to stress, we also examined changes in the levels of testosterone (an anti-stress hormone), which have rarely been studied in stressed mice. The mice were exposed to CRS for 6 h a day for 21 days. In both B6 and BALB/c mice, CRS elicited several physiological stress responses, including decreased body weight gain and changes in the tissue weights of stress-related organs. Accumulated corticosterone in the hair was measured, and BALB/c mice had significantly greater levels than control mice and B6 mice after CRS. On the other hand, in the case of accumulated testosterone in the hair, both B6 mice and BALB/c mice showed significantly higher concentrations than control mice, but the degree of change was not different between the two strains. In the sucrose preference test, BALB/c mice, but not B6 mice, showed anhedonia-like behavior after CRS. However, neither strain showed depressive-like behavior in the forced swim or tail suspension test. Our results show that the physiological and behavioral stress responses of BALB/c mice are greater than those of B6 mice, although anti-stress responses to CRS are similar in both strains. This suggests that BALB/c mice are likely to be advantageous for use as a CRS-induced depression model.

Reduced plasma orexin-A levels in patients with bipolar disorder.

PURPOSE: Orexins are hypothalamic neuropeptides involved in the regulation of sleep, appetite and arousal. An altered orexin system has been implicated in the pathophysiology of psychiatric disorders. This study aimed to examine whether plasma orexin-A levels differ in patients with schizophrenia, major depressive disorder (MDD), or bipolar disorder (BD) compared to in healthy controls. We also examined the possible correlations between plasma orexin-A levels and clinical variables. PATIENTS AND METHODS: All participants were Japanese. The sample consisted of 80 patients with schizophrenia (42 women, 52.5%; mean age 36.8 years), 80 patients with MDD (43 women, 53.8%; 43.7 years), and 40 patients with BD (24 women, 60%; 41.1 years), as well as 80 healthy controls (48 women, 60%; 47.0 years). Plasma orexin-A levels were quantified by an enzyme-linked immunosorbent assay. RESULTS: Mean orexin-A levels were significantly different across the four diagnostic groups (F=4.09; df=3; p=0.007, η2 =0.06). In particular, the patients with BD showed significantly lower orexin-A levels than did the controls. When the median value of the control group (109.8 pg/ml) was set as a cut-off value, subjects whose orexin-A levels were below the cut-off were more common in all psychiatric groups (schizophrenia: 73.8%, x2 =9.56, df=1, p=0.003, OR=2.81, 95% CI: 1.45 to 5.45, d=0.57; MDD: 78.5%, x2 =14.02, df=1, p<0.001, OR=3.65, 95% CI: 1.82 to 7.29, d=0.72; BD: 87.5%, x2 =16.0, df=1, p<0.001, OR=7.00, 95% CI: 2.49 to 19.70, d=1.07). We found no association between plasma orexin-A levels and any clinical symptoms, depression severity, or medication doses. CONCLUSION: Our results suggest that plasma orexin-A levels are reduced in patients with BD.

8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine.

INTRODUCTION: To investigate the metabolism of mirtazapine (MIR) in Japanese psychiatric patients, we determined the plasma levels of MIR, N-desmethylmirtazapine (DMIR), 8-hydroxy-mirtazapine (8-OH-MIR), mirtazapine glucuronide (MIR-G), and 8-hydroxy-mirtazapine glucuronide (8-OH-MIR-G). METHODS: Seventy-nine Japanese psychiatric patients were treated with MIR for 1-8 weeks to achieve a steady-state concentration. Plasma levels of MIR, DMIR, and 8-OH-MIR were determined using high-performance liquid chromatography. Plasma concentrations of MIR-G and 8-OH-MIR-G were determined by total MIR and total 8-OH-MIR (i. e., concentrations after hydrolysis) minus unconjugated MIR and unconjugated 8-OH-MIR, respectively. Polymerase chain reaction was used to determine CYP2D6 genotypes. RESULTS: Plasma levels of 8-OH-MIR were lower than those of MIR and DMIR (median 1.42 nmol/L vs. 92.71 nmol/L and 44.96 nmol/L, respectively). The plasma levels (median) of MIR-G and 8-OH-MIR-G were 75.00 nmol/L and 111.60 nmol/L, giving MIR-G/MIR and 8-OH-MIR-G/8-OH-MIR ratios of 0.92 and 59.50, respectively. Multiple regression analysis revealed that smoking was correlated with the plasma MIR concentration (dose- and body weight-corrected, p=0.040) and that age (years) was significantly correlated with the plasma DMIR concentration (dose- and body weight-corrected, p=0.018). The steady-state plasma concentrations of MIR and its metabolites were unaffected by the number of CYP2D6*5 and CYP2D6*10 alleles. DISCUSSION: The plasma concentration of 8-OH-MIR was as low as 1.42 nmol/L, whereas 8-OH-MIR-G had an approximate 59.50 times higher concentration than 8-OH-MIR, suggesting a significant role for hydroxylation of MIR and its glucuronidation in the Japanese population.

Construction of the common cortical space by spontaneous activity and its application in the mouse cortex.

Wide-field optical imaging of the animal brain is a useful technique for measuring brain dynamics, including spatial structure. However, quantitative inter-animal comparison is difficult due to lack of the common cortical space that can normalize individually imaged brains as done in human functional MRI studies. Here, by using wide-field functional Ca2+ imaging on anesthetized transgenic mice expressing G-CaMP7 in astrocytes and excitatory neutrons, we attempted to establish the common cortical space in mice, which can be useful as a standard of functional brain map. We initially reconstructed cortical areas embedded within spontaneous activity as the functional connectivity maps for the individual mice, then matched them in size, shape, and location across mice by geometric transformation. Finally, we assigned all the recorded signals into the transformed space, to make spatially normalized signals in the common cortical space. Using this method, we managed to extract activity patterns commonly observed across mice. These results suggest that the presented method is available to facilitate inter-animal comparison of brain dynamics, and has the potential to identify common brain activity across animals.

Effects of personality on the association between paroxetine plasma concentration and response.

BACKGROUND: We studied the differences between groups that were divided according to personality characteristics with respect to the relationship between drug concentration and symptom improvement. METHODS: A total of 120 patients with major depressive disorder were treated with paroxetine for 6 weeks, and 89 patients completed the protocol. The Montgomery-Åsberg Depression Rating Scale (MADRS) was used to evaluate the patients. Patients' paroxetine plasma concentrations at week 6 were measured. Their personalities were evaluated by the Temperament and Character Inventory (TCI) at the first visit. We divided the patients into two groups according to the median of each TCI dimension. We compared the responder rate between "high" and "low" groups in each TCI dimension and analyzed Pearson's correlation coefficients of paroxetine plasma concentration and MADRS-improvement rate. RESULTS: A total of 62 patients completed the TCI. Low-novelty-seeking, high-harm-avoidance, low-reward-dependence, and low-self-directedness groups exhibited significant negative correlations between paroxetine plasma concentration and MADRS improvement. Among the groups with combined personality traits, the high-harm-avoidance and low-self-directedness groups showed a markedly significant negative correlation. CONCLUSION: Patients with depression exhibiting specific personality traits, especially those with high harm-avoidance and low self-directedness scores, exhibited a significant negative association between paroxetine plasma concentration and MADRS-improvement rate. Therefore, a lower dose might be suitable for patients with specific personality traits.

Cerebrospinal fluid monoamine metabolite concentrations in depressive disorder: A meta-analysis of historic evidence.

Altered monoaminergic functions have been implicated in the pathophysiology of depressive disorder. However, previously reported cerebrospinal fluid (CSF) monoamine metabolite concentrations in major depression have been inconsistent. We performed a meta-analysis of historic evidence to determine whether CSF monoamine metabolite levels were different between patients with depression and normal controls, and could be used as depression biomarkers. Relevant studies that investigated CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with depression and normal controls were identified in PubMed, Web of Science, PsycINFO, and Embase databases through September 5, 2017, using a synonymous search for depression, CSF, normal, control, and each monoamine metabolite name, and in the reference lists of the acquired articles. Obtained records were individually scrutinized for eligibility. Our search strategy identified 26 studies, including our own. We employed random effects modeling and adopted "Hedges's g" as an index of effect size. In the meta-analyses, no significant difference was observed in CSF 5-HIAA or MHPG levels between patients with depressive disorder and controls. In contrast, CSF HVA was significantly decreased in patients with depression (Hedges's g = -0.30, P = 0.0000025), and these results remained significant after patients with bipolar disorder were excluded (Hedges's g = -0.37, P = 0.000061). In the meta-regression, sex was significantly associated with the Hedges's g of CSF HVA (Q = 4.41, P = 0.036). This meta-analysis revealed that only CSF HVA, and not 5-HIAA or MHPG, levels were decreased in depressive disorder. The reduction in the CSF HVA concentration in patients with depression may guide future studies on depression and serve as a useful biomarker of depressive disorder.

Effects of Cytochrome P450 (CYP) 2C19 Genotypes on Steady-State Plasma Concentrations of Escitalopram and its Desmethyl Metabolite in Japanese Patients With Depression.

BACKGROUND: Plasma concentrations of the S-enantiomer of citalopram were different between extensive and poor CYP2C19 metabolizers in healthy subjects and depressed patients. However, most studies applied dose-corrected concentrations. Thus, we studied the effects of polymorphisms of the CYP2C19 gene on raw plasma drug concentrations in Japanese patients with depression. METHODS: Subjects in this study consisted of 412 depressed patients receiving 5, 10, 15, or 20 mg of escitalopram once a day. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using HPLC. CYP2C19 genotypes were identified using polymerase chain reaction methods. RESULTS: There were no differences in the steady-state plasma concentrations of escitalopram or desmethylescitalopram in each dose group (5, 10, 15, or 20 mg of escitalopram) among CYP2C19 genotype groups. However, 1-way analysis of variance showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram but not in the dose-adjusted plasma concentration of desmethylescitalopram. Analysis of covariance including age, sex, and body weight showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram and the ratio of desmethylescitalopram to escitalopram. CONCLUSIONS: These findings suggest that the CYP2C19 variants are associated with steady-state plasma concentrations of escitalopram to some extent but are not associated with desmethylescitalopram.

Attitudes toward placebo-controlled clinical trials among depressed patients in Japan.

BACKGROUND: Placebo-controlled clinical trials are the standard in the design of clinical studies for the licensing of new drugs. Medical and ethical concerns regarding placebo use still exist in clinical trials of depressed patients. The aim of this study was to investigate the attitudes toward placebo-controlled clinical trials and to assess factors related to the willingness to participate in such trials among depressed patients in Japan. METHODS: A total of 206 depressed patients aged 49.5 ± 15.7 years (mean ± SD) who were admitted to three psychiatric hospitals were recruited for a cross-sectional study from June 2015 to March 2016. After a thorough explanation of the placebo, the study participants completed a brief 14-item questionnaire developed to evaluate patients' attitudes regarding possible participation in placebo-controlled clinical trials. The Quick Inventory of Depressive Symptomatology was also administered to assess depressive symptoms. RESULTS: The results indicated that 47% of the patients would be willing to participate in a placebo-controlled clinical trial. Expectations for the improvement of disease, desire to receive more medical care, encouragement by family or friends, and desire to support the development of new drugs were associated with the willingness to participate in such trials, whereas a belief that additional time would be required for medical examinations and fear of exacerbation of symptoms due to placebo use were associated with non-participation. LIMITATIONS: Patients were asked about possible participation in placebo-controlled clinical trials. CONCLUSIONS: Less than half of the respondents were willing to participate in placebo-controlled clinical trials. Attitudes toward participation in a placebo-controlled clinical trial need to be considered when deciding whether to conduct such a trial.

Serum x03C9;-3 and x03C9;-6 Fatty Acids Are Not Associated with Personality Traits in Healthy Japanese Young People.

BACKGROUND: Recent studies have reported that polyunsaturated fatty acids (PUFAs) are associated with mood and behaviors including depression and suicide risk. The aim of this study was to examine the relationship between PUFAs and personality traits in healthy subjects. METHODS: A total of 279 subjects completed the Temperament and Character Inventory and Beck Depression Inventory. Serum levels of the PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), the x03C9;-6 fatty acid arachidonic acid (AA), and dihomo-x03B3;-linolenic acid were measured. RESULTS: Pearson's correlation analysis showed a positive correlation between DHA and cooperativeness scores. In the multiple regression analysis, harm avoidance scores were positively associated with AA, and a negative association was found between the EPA/AA ratio and reward dependence scores. However, these associations were nonsignificant after a Bonferroni correction. CONCLUSION: The results of the present study suggest that the blood levels of PUFAs are not likely to be associated with personality traits.

Influence of the cytochrome P450 2D6 *10/*10 genotype on the pharmacokinetics of paroxetine in Japanese patients with major depressive disorder: a population pharmacokinetic analysis.

OBJECTIVE: Although the reduced function of the cytochrome P450 2D6*10 (CYP2D6*10) allele is common among Asian populations, existing evidence does not support paroxetine therapy adjustments for patients who have the CYP2D6*10 allele. In this study, we attempted to evaluate the degree of the impact of different CYP2D6 genotypes on the pharmacokinetic (PK) variability of paroxetine in a Japanese population using a population PK approach. METHODS: This retrospective study included 179 Japanese patients with major depressive disorder who were being treated with paroxetine. CYP2D6*1, *2, *5, *10, and *41 polymorphisms were observed. A total of 306 steady-state concentrations for paroxetine were collected from the patients. A nonlinear mixed-effects model identified the apparent Michaelis-Menten constant (Km) and the maximum velocity (Vmax) of paroxetine; the covariates included CYP2D6 genotypes, patient age, body weight, sex, and daily paroxetine dose. RESULTS: The allele frequencies of CYP2D6*1, *2, *5, *10, and *41 were 39.4, 14.5, 4.5, 41.1, and 0.6%, respectively. There was no poor metabolizer who had two nonfunctional CYP2D6*5 alleles. A one-compartment model showed that the apparent Km value was decreased by 20.6% in patients with the CYP2D6*10/*10 genotype in comparison with the other CYP2D6 genotypes. Female sex also influenced the apparent Km values. No PK parameters were affected by the presence of one CYP2D6*5 allele. CONCLUSION: Unexpectedly, elimination was accelerated in individuals with the CYP2D6*10/*10 genotype. Our results show that the presence of one CYP2D6*5 allele or that of any CYP2D6*10 allele may have no major effect on paroxetine PKs in the steady state.

Items of the Montgomery-Åsberg Depression Rating Scale Associated With Response to Paroxetine Treatment in Patients With Major Depressive Disorder.

OBJECTIVES: In the present study, we investigated the association between the severity of each symptom evaluated by the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline and responsiveness to treatment in patients with major depressive disorder (MDD) to identify the items that predict treatment response. METHODS: The patients received a diagnosis of MDD if they had a score greater than 20 points on the MADRS. Following admission, 120 patients were enrolled in the study, and 89 patients completed the study. For the first week, a 20-mg/d dose of paroxetine was administered; thereafter, the dose was increased to 40 mg/d. The MADRS was applied at baseline and after 1, 2, 4, and 6 weeks. We defined responders as patients with improvements in their MADRS scores of more than 50% after 6 weeks of treatment. A multiple regression analysis of MADRS scores at 6 weeks was performed to identify patients who responded to treatment. RESULTS: There was a significant difference between responders and nonresponders in the reported sadness (RS) score for all MADRS items. In the multiple logistic regression analysis, only the RS and concentration difficulties (C) scores showed a significant association with treatment response. Based on the results of χ tests, RS score cutoff values of 2/3 and 3/4 revealed significant differences in the responder rate. None of the cutoff values for the C score revealed significant differences. CONCLUSIONS: The RS score was significantly associated with responsiveness to paroxetine treatment for MDD, with higher RS scores predicting poor responses to treatment.

Characteristics of Escitalopram Discontinuation Syndrome: A Preliminary Study.

BACKGROUND: Antidepressant discontinuation syndrome (ADS) frequently occurs in patients who undergo an abrupt discontinuation of their antidepressant medication. METHODS: We evaluated 25 consecutive outpatients with depression who discontinued their use of escitalopram. The presence of ADS was evaluated according to the Antidepressants Discontinuation Syndrome checklist. RESULTS: Antidepressant discontinuation syndrome was observed in 14 of 25 patients. Frequent symptoms were dizziness (44%), muscle tension (44%), chills (44%), confusion or trouble concentrating (40%), amnesia (28%), and crying (28%). The treatment doses and plasma concentrations of escitalopram were significantly higher in patients with ADS than in patients without ADS. No group differences were observed regarding age, sex, or duration of escitalopram treatment before the discontinuation. CONCLUSIONS: These findings suggest that a higher dose and lower clearance of escitalopram lead to a higher risk of ADS. Very slow tapering is recommended for all patients.

Glutathione S-transferase K1 genotype and overweight status in schizophrenia patients: A pilot study.

Elevated oxidative stress in mitochondria and mitochondrial dysfunction are associated with weight gain in schizophrenia (SCZ) patients. Glutathione S-transferase kappa 1 (GSTK1) protects cells against exogenous and endogenous oxidative stress in the mitochondria. This exploratory study investigated the possible effects of a common GSTK1 polymorphism (rs1917760, G-1308T) on the risk for overweight status among 329 SCZ patients and 305 age- and gender-matched controls and on the GSTK1 mRNA level in peripheral blood mononuclear cells among 14 SCZ patients. The GSTK1 T/T genotype was associated with having a higher BMI value among SCZ male patients, whereas this genotype tended to be associated with a lower BMI value among female patients. Conversely, these associations were not observed among the controls. The GSTK1 T/T genotype was associated with decreased GSTK1 mRNA level among SCZ patients. The GSTK1 T/T genotype may be a novel risk factor for the prediction of overweight status in SCZ male patients, although the results of this pilot study should be verified by a larger study.

The Effects of Fluvoxamine on the Steady-State Plasma Concentrations of Escitalopram and Desmethylescitalopram in Depressed Japanese Patients.

BACKGROUND: The aim of this study was to determine the impact of fluvoxamine, an inhibitor of Cytochrome P450 (CYP) 2C19 (CYP2C19), on the pharmacokinetics of escitalopram, a substrate of CYP2C19. METHODS: Thirteen depressed patients initially received a 20-mg/d dose of escitalopram alone. Subsequently, a 50-mg/d dose of fluvoxamine was administered because of the insufficient efficacy of escitalopram. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using high-performance liquid chromatography before and after fluvoxamine coadministration. The QT and corrected QT (QTc) intervals were measured before and after fluvoxamine coadministration. RESULTS: Fluvoxamine significantly increased the plasma concentrations of escitalopram (72.3 ± 36.9 ng/mL versus 135.2 ± 79.7 ng/mL, P < 0.01) but not those of desmethylescitalopram (21.5 ± 7.0 ng/mL versus 24.9 ± 12.0 ng/mL, no significance [ns]). The ratios of desmethylescitalopram to escitalopram were significantly decreased during fluvoxamine coadministration (0.37 ± 0.21 versus 0.21 ± 0.10, P < 0.01). The CYP2C19 genotype did not fully explain the degree of the change. Fluvoxamine coadministration did not change the QT or QTc intervals. CONCLUSIONS: The results of this study suggest that adjunctive treatment with fluvoxamine increases the concentration of escitalopram. The QTc interval did not change in this condition.