Characteristics of Sputtered Lead Zirconate Titanate Thin Films With Different Layer Configurations and Large Thickness.

To evaluate the characteristics of Pb(Zr,Ti)O3 (PZT) thin films (about [Formula: see text] thick) with three different sputtering configurations-single-layer (SL) deposition, multilayer (ML) deposition with internal electrodes, and multistep (MS) deposition-were prepared. The SL films exhibited poorer dielectric characteristics than the ML and MS films. The reliability and piezoelectric characteristics were especially high in the MS film, with an [Formula: see text] constant of -9.5 C · m-2. To investigate the porosity of the films, reconstructed 3-D SEM technique is employed. Reconstructed 3-D SEM images revealed decreased void densities in the ML and MS films, which improved their performance. The MS configuration provided the best dielectric and piezoelectric performance of PZT films.

Long-term mood/antidepressant effects of quetiapine extended-release formulation: an open-label, non-controlled extension study in Japanese patients with bipolar depression.

BACKGROUND: In an 8-week, randomized, placebo-controlled, double-blind study, an extended-release formulation of quetiapine, quetiapine XR, demonstrated efficacy and safety in Japanese patients with bipolar depression. Bipolar disorder is a chronic disease requiring continuous treatment. METHODS: This was a long-term (52-week), open-label, non-controlled extension study to evaluate the long-term safety and efficacy of quetiapine XR in Japanese patients with bipolar depression who had previously completed the initial 8-week double-blind study. Efficacy was determined by the Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Depression Scale 17-item (HAM-D17), and Clinical Global Impressions-Bipolar scale (CGI-BP). Safety evaluations included analysis of adverse events, clinical laboratory measures, vital signs, Drug-induced Extrapyramidal Symptoms Scale, Young Mania Rating Scale, and the Columbia Suicide Severity Rating Scale. RESULTS: The mean (SD) MADRS total score decreased from 30.9 (6.9) at baseline to 16.1 (10.6) at week 8, and eventually to 9.1 (8.7) at week 52. The sustained efficacy of quetiapine XR treatment was also shown using HAM-D17 total scores, CGI-BP-Severity and Change evaluations. The most common adverse events were somnolence, nasopharyngitis, and thirst. Long-term treatment with quetiapine XR caused no substantial changes in the safety profiles, including clinical laboratory parameters, and no new safety concerns were identified. CONCLUSIONS: The efficacy of quetiapine XR was sustained long-term and no new safety concerns were identified in Japanese patients with bipolar depression. TRIAL REGISTRATION: ClinicalTrials.gov Registration: NCT01725308. Date of registration; 12th November 2012 (retrospectively registered).

Correction to: Multi-center, randomized, double-blind, placebocontrolled study of quetiapine extended-release formulation in Japanese patients with bipolar depression.

The original version of this article contained a mistake in Table 5. Correct version is presented here.

Multi-center, randomized, double-blind, placebo-controlled study of quetiapine extended-release formulation in Japanese patients with bipolar depression.

RATIONALE: Quetiapine fumarate is an atypical antipsychotic indicated for various mental disorders, but it has not been studied in Japanese patients with bipolar depression. OBJECTIVES: To evaluate the efficacy and safety of quetiapine XR (extended release) in Japanese patients with bipolar depression. METHODS: In this multi-center, randomized, double-blind, placebo-controlled, fixed-dose study of 431 Japanese adults with bipolar I or II disorder, efficacy was determined by analyzing the mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary end points included MADRS response and remission rates, Hamilton Depression Scale 17-Item (HAM-D17), and Clinical Global Impressions-Bipolar (CGI-BP) scale scores. Safety was determined by monitoring adverse events and clinical assessments. RESULTS: This study revealed a statistically significantly greater decrease in MADRS total score after 8 weeks of quetiapine XR 300 mg/day monotherapy compared with placebo (- 12.6 vs. - 10.1; p = 0.034). There were also improvements in MADRS response (44.1 vs. 35.6%) and remission (38.0 vs. 26.6%) rates as well as in HAM-D17 and CGI-BP scale scores compared with placebo. In the subgroup analysis of patients with bipolar I or II disorder, the adjusted mean changes in MADRS total score compared to placebo were - 2.3 and - 2.1, respectively. Adverse events occurred in 149 patients (83.2%) receiving quetiapine XR 300 mg/day and in 81 patients (45.8%) receiving placebo. The most common adverse events were somnolence and thirst, which is consistent with the previously reported safety profile. CONCLUSIONS: Once-daily monotherapy with quetiapine XR is an effective and well-tolerated treatment for bipolar depression in Japanese patients.

Long-term administration of escitalopram in patients with social anxiety disorder in Japan.

PURPOSE: To investigate the safety, tolerability, and effectiveness of escitalopram in patients with social anxiety disorder in Japan. METHODS: A 52-week, open-label study was conducted in Japanese patients with social anxiety disorder with a total score ≥60 on the Liebowitz Social Anxiety Scale - Japanese Version (LSAS-J) and ≥4 on the Clinical Global Impression - Severity Scale. Escitalopram 10 mg/day was administered for the first week and could be increased to 20 mg/day. RESULTS: The study included 158 patients: 81.0% (128/158) completed 52 weeks of escitalopram treatment, 68.4% (108/158) increased their dose to 20 mg/day, and 56.3% (89/158) remained on 20 mg/day. Adverse drug reactions were reported by 57.6% (91/158) of patients. The most common (incidence ≥10%) were somnolence and nausea. The incidence of adverse drug reactions was similar in extensive and poor metabolizers of cytochrome P450 2C19. No adverse drug reactions increased in incidence by >5% after week 12. The incidence of serious adverse events was 1.3% (2/158). No deaths occurred. The LSAS-J total scores improved until week 52. The LSAS-J response rate (≥30% improvement in LSAS-J) was 69.0%, the Clinical Global Impression - Improvement Scale response rate (≤2) was 73.0%, and the LSAS-J remission rate (≤30) was 27.0%. CONCLUSION: In this first 52-week clinical study of social anxiety disorder, escitalopram 10-20 mg/day was safe, well tolerated, and effective in Japanese patients.

Asenapine reduces anxiety-related behaviours in rat conditioned fear stress model.

OBJECTIVE: Asenapine is an atypical antipsychotic that is currently available for the treatment of schizophrenia and bipolar I disorder. Although the atypical antipsychotics clozapine and olanzapine are effective for depression and anxiety in schizophrenia, as demonstrated by animal model studies, this has not been clarified for asenapine. Therefore, we compared the effects of asenapine in the conditioned fear stress model with those of clozapine and olanzapine. METHOD: Rats were individually fear conditioned using electrical foot shock in a Skinner box. Approximately 24 h later, individual animals were returned to the same Skinner box (without electrical shock) and their freezing behaviour was observed for 5 min. Animals were treated with asenapine, clozapine, olanzapine, the 5-HT1A receptor partial agonist buspirone, or the 5-HT2C receptor antagonist SB242084 at 30 min before freezing behaviour assessment. The 5-HT1A receptor antagonist WAY100635 or the 5-HT2C receptor agonist Ro60-0175 was also used concomitantly with asenapine. The effects of asenapine, clozapine, and olanzapine on serotonin release in the rat hippocampus were also measured using in vivo microdialysis. RESULTS: Asenapine reduced freezing behaviour, while neither clozapine nor olanzapine reduced freezing behaviour. Buspirone and SB242084 also reduced freezing behaviour. The effect of asenapine in reducing freezing behaviour was not altered by the concomitant administration of WAY100635 or Ro60-0175. Both asenapine and clozapine, but not olanzapine, increased serotonin release in the rat hippocampus. CONCLUSION: Asenapine may have superior therapeutic effect on anxiety symptoms than other agents, although the underlying mechanism of its anxiolytic activity remains unknown.

Efficacy of escitalopram in the treatment of social anxiety disorder: A meta-analysis versus placebo.

Escitalopram is the most selective of the serotonin reuptake inhibitor (SSRI) antidepressants. We conducted a meta-analysis of placebo-controlled studies where escitalopram was used to treat patients with social anxiety disorder (SAD). Data from all randomised, double-blind placebo-controlled studies in SAD with escitalopram from both specialist settings and general practice were used. Patients met the DSM-IV criteria for SAD, were ≥18 years old, and had a Liebowitz Social Anxiety Scale (LSAS) ≥60. The primary outcome measure was the estimated treatment difference in LSAS total score at Week 12. Secondary outcome measures included the estimated treatment difference in the Clinical Global Impression-Severity (CGI-S) score at Week 12. A total of 1598 patients from 3 randomised controlled trials were included in the analyses. Escitalopram (n=1061) was superior to placebo (n=537), with an estimated treatment difference on the LSAS of -9.2 points (95%CI: [-14.4; -4.0], p<0.01) (escitalopram 5mg/day), -4.6 points (95%CI: [-8.1; -1.0], p<0.01) (escitalopram 10mg/day), -10.1 points (95%CI: [-13.7; -6.5], p<0.01) (escitalopram 20mg/day) and -7.3 points (95%CI: [-12.3; -2.2], p<0.01) (escitalopram 10-20mg/day). For the CGI-S, the corresponding values were -0.55 points (95%CI: [-0.79; -0.31], p<0.01) (escitalopram 5mg/day), -0.26 points (95%CI: [-0.42; -0.10], p<0.01) (escitalopram 10mg/day), -0.48 points (95%CI: [-0.64; -0.31], p<0.01) (escitalopram 20mg/day) and -0.29 points (95%CI: [-0.51; -0.07], p<0.05) (escitalopram 10-20mg/day). The withdrawal rate due to adverse events was 7.2% for escitalopram, compared with 4.3% for placebo (p<0.05). In this meta-analysis, all doses of escitalopram showed significant superiority in efficacy versus placebo in the treatment of patients with SAD.

A randomized, double-blind, placebo-controlled study of escitalopram in patients with social anxiety disorder in Japan.

OBJECTIVE: This randomized, double-blind placebo-controlled study compared the efficacy and tolerability of escitalopram (10 and 20 mg/day) in Japanese patients with social anxiety disorder (SAD). RESEARCH DESIGN AND METHODS: Patients aged 18-64 years with a primary diagnosis of DSM-IV-TR defined SAD, a Liebowitz Social Anxiety Scale Japanese version (LSAS-J) total score ≥60 and a Clinical Global Impression-Severity (CGI-S) score ≥4 at baseline were randomly assigned (1:1:1) to placebo, escitalopram 10 mg or escitalopram 20 mg. The primary endpoint was change from baseline to Week 12 in the LSAS-J total score for both escitalopram 10 mg and 20 mg versus placebo (ANCOVA, FAS, LOCF), using a hierarchical testing procedure. Pre-specified secondary endpoints included LSAS-J sensitivity analyses. CLINICAL TRIAL REGISTRATION: This study has the www.japic.or.jp identifier: JapicCTI-121842. RESULTS: For the primary efficacy endpoint, the difference from placebo in the LSAS-J was -3.9 (p = 0.089) for escitalopram 10 mg. Since the superiority of escitalopram 10 mg over placebo was not confirmed, an analysis without multiplicity adjustment was made, which showed a difference for escitalopram 20 mg versus placebo of -9.8 (p < 0.001). In pre-specified sensitivity analyses, the difference versus placebo was -4.9 (p = 0.035) (ANCOVA, FAS, OC) and -5.0 (p = 0.028) (MMRM, FAS) (escitalopram 10 mg) and -10.1 (p < 0.001) (ANCOVA, FAS, OC) and -10.6 (p < 0.001) (MMRM, FAS) (escitalopram 20 mg). Common adverse events (incidence ≥5% and significantly different from placebo) were somnolence, nausea and ejaculation disorder. CONCLUSION: Escitalopram was efficacious, safe and well tolerated by patients with SAD in Japan. Study limitations are discussed including patient characteristics.

Involvement of serotonin transporter gene polymorphisms (5-HTT) in impulsive behavior in the japanese population.

The serotonergic pathway has been implicated in the pathogenesis of impulsivity, and sensitivity to aversive outcomes may be linked to serotonin (5-HT) levels. Polymorphisms in the gene that encodes the serotonin transporter (5-HTT), which have differential effects on the level of serotonin transmission, display alternate responses to aversive stimuli. However, recent studies have shown that 5-HT does not affect motor function, which suggests that the functioning of the serotonin-transporter-linked polymorphic region (5-HTTLPR) does not directly affect the behavioral regulatory process itself, but instead exerts an effect via the evaluation of the potential risk associated with particular behavioral outputs. The aim of the present study was to examine the effect of specific 5-HTTLPR genotypes on the motor regulatory process, as observed during a Go/Nogo punishment feedback task. 5-HTT gene-linked promoter polymorphisms were analyzed by polymerase chain reaction, using lymphocytes from 61 healthy Japanese volunteers. Impulsivity was defined as the number of commission errors (responding when one should not) made during a Go/Nogo task. We found that the s/s genotype group made fewer impulsive responses, specifically under aversive conditions for committing such errors, compared to those in the s/l group, without affecting overall motor inhibition. These results suggest that 5-HTTLPRs do not directly affect the behavioral regulatory process itself, but may instead exert an effect on the evaluation of potential risk. The results also indicate that under such aversive conditions, decreased expression of 5-HTT may promote motor inhibitory control.

Efficacy comparison of duloxetine and SSRIs at doses approved in Japan.

BACKGROUND: Approved doses of antidepressants in Japan are usually lower than those in the USA and European Union, but to date meta-analyses comparing antidepressants have all used the higher doses approved in the USA and European Union and often have used indirect comparisons. The purpose of this study was to conduct an integrated database analysis of patient level data to compare the effects of duloxetine with those of selective serotonin reuptake inhibitors (SSRIs) at the doses approved in Japan. METHODS: Pooled data were analyzed from four randomized, double-blind, placebo-controlled studies that compared duloxetine at the dose range approved in Japan (40-60 mg/day) with other SSRIs (paroxetine 20 mg/day or escitalopram 10 mg/day) and placebo in patients with major depressive disorder. In total, 1,694 patients were included in the analysis (duloxetine, n=688; selective serotonin reuptake inhibitors, n=690; placebo, n=316). The primary outcome measure was the mean change from baseline at week 8 in 17-item Hamilton Rating Scale for Depression (HAMD17) total and subscale scores. RESULTS: Duloxetine and both selective serotonin reuptake inhibitors were superior to placebo in HAMD17 total score at week 8 in both the all-randomized group and the more severe subgroup (HAMD17 total scores ≥19). Duloxetine was superior to SSRIs in improving the HAMD17 Retardation subscale score (least squares mean difference [95% confidence interval]): all-randomized group, -0.33 [-0.60, -0.07], P=0.015; severe subgroup, -0.45 [-0.83, -0.07], P=0.020). CONCLUSION: Within the dose range approved in Japan for patients with major depressive disorder, duloxetine and selective serotonin reuptake inhibitors demonstrated comparable overall efficacy, with a possible advantage for duloxetine in improving loss of energy and interest. To the best of our knowledge, this analysis is unique not only in evaluating dosages specific to Japan, but also in using individual patient data and the same endpoint across studies to allow for strictly direct head-to-head data comparisons as opposed to pooling direct and indirect comparisons.

Long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response-a prospective open-label study.

BACKGROUND: While the frequency and importance of antipsychotic switching in patients with schizophrenia, there is insufficient evidence with regard to switching strategy. Quetiapine is one of the drugs of choice for switch because of its unique receptor profile. However, there were no data on the long-term clinical and neurocognitive effect of quetiapine in patients who had responded inadequately to prior antipsychotics. The purpose of this study is to examine the long-term efficacy and tolerability of quetiapine in patients with schizophrenia who switched from other antipsychotics because of inadequate therapeutic response. We hypothesized that quetiapine would show long-term effectiveness in broad symptom dimensions including negative and neurocognitive symptoms while having good tolerability. METHODS: Twenty-nine subjects with schizophrenia who did not respond to their current monotherapy of antipsychotic or who could not tolerate the treatment were switched to quetiapine and assessed at baseline and at 3, 6, and 12 months. The outcome measures included the brief assessment of cognition in schizophrenia (BACS), the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale (CGI), the Schizophrenia Quality of Life Scale Japanese version (JSQLS), the Athens Insomnia Scale (AIS), and the Drug Attitude Inventory with 30 items (DAI-30). The Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), HbA1c, prolactin (PRL), and body weight were also evaluated. RESULTS: Statistically significant improvements were observed in all subscores of the PANSS, the GAF, and the symptoms and side effects subscale of the JSQLS, the DIEPSS, the AIS, and the PRL level, and nearly significant improvements were observed in the DAI-30. Quetiapine monotherapy was associated with significant improvement in the verbal memory test, even after controlling for the practice effect. Although quetiapine was well tolerated, three subjects dropped out because of the worsening of the psychotic symptoms and two additional subjects dropped out because of somnolence. CONCLUSION: In this open-label, single-arm study of 29 patients, quetiapine improved both the clinical symptoms and the neurocognitive impairment in chronic schizophrenia patients who failed to respond to prior antipsychotic treatment.

Different P50 sensory gating measures reflect different cognitive dysfunctions in schizophrenia.

The P50 is an early component of auditory evoked potentials and a measure of sensory gating deficits. This evoked potential component is thought to be an important endophenotype candidate for schizophrenia. Recent research suggests that instead of the P50 ratio, S1 and S2 amplitudes should be evaluated for sensory gating. However, no studies have focused on the relationship between cognitive dysfunction and P50 sensory gating deficits using S1 and S2 amplitudes. The purpose of the present study was to investigate the association between the P50 ratio (S2/S1), S1 and S2 amplitudes, and neuropsychological cognitive domains using stepwise multiple linear regression analyses. Results demonstrated a significant relationship between executive functioning and the P50 ratio and between sustained attention and S2 amplitude, respectively. Our findings suggest that the P50 ratio and S2 amplitude reflect distinct neurophysiological substrates associated with different cognitive functions.

Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter.

BACKGROUND: Early life stress is thought to contribute to psychiatric disorders, but the precise mechanisms underlying this link are poorly understood. As neonatal stress decreases adult hippocampal neurogenesis, which, in turn, functionally contributes to many behavioral phenotypes relevant to psychiatric disorders, we examined how in vivo neonatal maternal separation (NMS) impacts the capacity of adult hippocampal neural precursor cells via epigenetic alterations in vitro. METHODS: Rat pups were separated from their dams for 3 hours daily from postnatal day (PND) 2 to PND 14 or were never separated from the dam (as control animals). We isolated adult neural precursor cells from the hippocampal dentate gyrus at PND 56 and assessed rates of proliferation, apoptosis, and differentiation in cell culture. We also evaluated the effect of DNA methylation at the retinoic acid receptor (RAR) promoter stemming from NMS on adult neural precursor cells. RESULTS: NMS attenuated neural differentiation of adult neural precursor cells but had no detectible effect on proliferation, apoptosis, or astroglial differentiation. The DNA methyltransferase (DNMT) inhibitor, 5-aza-dC, reversed a reduction by NMS of neural differentiation of adult neural precursor cells. NMS increased DNMT1 expression and decreased expression of RARα. An RARα agonist increased neural differentiation and an antagonist reduced retinoic acid-induced neural differentiation. NMS increased the methylated portion of RARα promoter, and the DNMT inhibitor reversed a reduction by NMS of RARα messenger RNA expression. CONCLUSIONS: NMS attenuates the capacity of adult hippocampal neural precursor cells to differentiate into neurons by decreasing expression of RARα through DNMT1-mediated methylation of its promoter.

Local infusion of citalopram into the basolateral amygdala decreased conditioned fear of rats through increasing extracellular serotonin levels.

Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of depressive disorders and anxiety disorders. The anxiolytic mechanism of SSRIs is currently unclear. To investigate the anxiolytic effects of SSRIs, we measured both freezing behavior and extracellular serotonin and dopamine levels in the basolateral amygdala when rats were given conditioned fear stress under local reverse-dialysis of citalopram, an SSRI, into the basolateral amygdala. Local administration of citalopram into the basolateral amygdala significantly decreased freezing behavior induced by conditioned fear stress, and serotonin levels were simultaneously found to be significantly higher. Furthermore, repeated conditioned fear stress under local infusion of citalopram into the basolateral amygdala induced further increases in extracellular dopamine levels. Further studies investigating the role of dopamine in the amygdala for conditioned fear stress will be necessary. These results suggest that the basolateral amygdala is one of the target areas of the anxiolytic effects of citalopram and the increases of extracellular serotonin levels in the basolateral amygdala may be related to the anxiolytic effects.

Maternal separation enhances conditioned fear and decreases the mRNA levels of the neurotensin receptor 1 gene with hypermethylation of this gene in the rat amygdala.

Stress during postnatal development is associated with an increased risk for depression, anxiety disorders, and substance abuse later in life, almost as if mental illness is able to be programed by early life stressors. Recent studies suggest that such "programmed" effects can be caused by epigenetic regulation. With respect to conditioned fear, previous studies have indicated that early life stress influences its development in adulthood, whereas no potential role of epigenetic regulation has been reported. Neurotensin (NTS) is an endogenous neuropeptide that has receptors densely located in the amygdala and hippocampus. Recently, NTS systems have constituted an emerging target for the treatment of anxiety. The aim of the present work is to clarify whether the NTS system is involved in the disturbance of conditioned fear in rats stressed by maternal separation (MS). The results showed that MS enhanced freezing behaviors in fear-conditioned stress and reduced the gene expression of NTS receptor (NTSR) 1 but not of NTS or NTSR2 in the amygdalas of adult rats. The microinjection of a NTSR1 antagonist into the amygdala increased the percentage of freezing in conditioned fear, whereas the microinjection of NTSR1 agonist decreased freezing. These results suggest that NTSR1 in the amygdala may play a role in the effects of MS on conditioned fear stress in adult rats. Moreover, MS increased DNA methylation in the promoter region of NTSR1 in the amygdala. Taken together, MS may leave epigenetic marks in the NTSR1 gene in the amygdala, which may enhance conditioned fear in adulthood. The MS-induced alternations of DNA methylation in the promoter region of NTSR1 in the amygdala may be associated with vulnerability to the development of anxiety disorders and depression in adulthood.

The potential of SLC6A4 gene methylation analysis for the diagnosis and treatment of major depression.

We examined the utility of DNA methylation profiles at the CpG island of SLC6A4 (DMS) as a diagnostic biomarker for major depression (MD). In addition, the relationship between DMS and the serotonin transporter gene-linked polymorphic region (5-HTTLPR) allele, the severity of symptoms, number of early adversities, and therapeutic responses to antidepressants were examined. Genomic DNA was extracted from peripheral blood of Japanese healthy controls and patients with MD before and after treatment. DMS was analyzed using a MassARRAY Compact System. The severity of depression was evaluated using the Hamilton Rating Scale for Depression, and early adversity was evaluated using the Early Trauma Inventory. We were unable to distinguish between and healthy controls, or between unmedicated patients and medicated patients using DMS. The 5-HTTLPR allele had no significant effect on DMS. The methylation rates for several CpGs differed significantly after treatment. Notably, the methylation rate of CpG 3 in patients with better therapeutic responses was significantly higher than that in patients with poorer responses. Although further studies examining the function of specific CpG units of SLC6A4 are required, these results suggest that the pre-treatment methylation rate of SLC6A4 is associated with therapeutic responses to antidepressants in unmedicated patients with MD.

Effect of the coadministration of citalopram with mirtazapine or atipamezole on rat contextual conditioned fear.

BACKGROUND: Mirtazapine, a noradrenergic and specific serotonergic antidepressant, which blocks the α2-adrenergic autoreceptors and heteroreceptors, has shown anxiolytic properties in clinical trials and preclinical animal experiments. The addition of mirtazapine to selective serotonin reuptake inhibitors (SSRIs) is clinically suggested to be more effective for anxiety disorders. In this study, we examined the combined effects of mirtazapine and citalopram, an SSRI, on the freezing behavior of rats, which was induced by contextual conditioned fear as an index of anxiety or fear. METHODS: Male Sprague Dawley rats individually received footshocks in a shock chamber, and 24 hours later, they were given citalopram and/or mirtazapine injections. One hour after citalopram and 30 minutes after mirtazapine administration, freezing behavior was analyzed in the same shock chamber without shocks. RESULTS: Mirtazapine decreased freezing in a dose-dependent manner, which is consistent with a previous report; it also enhanced an anxiolytic-like effect at a high dose (30 mg/kg) of citalopram. Because mirtazapine blocks α2-adrenoreceptors, the combined effect of atipamezole, a selective α2 receptor antagonist, with citalopram was also examined. Similar to mirtazapine, atipamezole reduced freezing dose-dependently, but the enhancement of citalopram's effects by atipamezole was not clear when compared with mirtazapine. CONCLUSION: The present findings suggest that mirtazapine has an anxiolytic-like effect and may enhance the anxiolytic-like effect of SSRIs, but this enhancement may not be explained by its anti-α2 property alone.

Post-Marketing Surveillance of Fluvoxamine Maleate Used Long-Term in Patients with Social Anxiety Disorder in Japan.

BACKGROUND: No data on the long-term 'real-world' use of fluvoxamine for the treatment of social anxiety disorder (SAD) in Japanese patients are currently available. OBJECTIVE: To evaluate the long-term safety and efficacy of fluvoxamine for SAD in the clinical setting. METHODS: Japanese patients with SAD who initiated treatment with fluvoxamine were enrolled in this 53-week post-marketing survey from 407 institutions nationwide. Data including rates of adverse drug reactions (ADRs) and efficacy were collected. Overall improvement was assessed using the Clinical Global Impression for Improvement. SAD symptoms and treatment responses were assessed with the Japanese version of the Liebowitz Social Anxiety Scale. RESULTS: From the 1,974 patients surveyed, 1,790 and 1,504 patients were eligible for analysis of safety and efficacy, respectively. ADRs were reported in 18.2 % of patients, with nausea, somnolence, and constipation the most common. Over 50 % of these ADRs developed in the first 4 weeks of treatment. Serious ADRs were reported in 0.8 % of patients and included six cases of suicide attempt and three cases of suicidal ideation. Response to fluvoxamine was reported in 78.4 % of patients. In patients comorbid with depression, improvement in SAD symptoms with fluvoxamine treatment was significantly affected by clinical improvement in the depression. CONCLUSIONS: These findings support the long-term safety and efficacy of fluvoxamine in patients with SAD. Most ADRs developed during the early treatment phase, and higher doses during the later phase were not associated with an increase in ADRs.

The effect of dopamine on adult hippocampal neurogenesis.

Cumulative studies indicated that adult hippocampal neurogenesis might be involved in the action mechanism of antidepressant drugs and/or the pathophysiology of depression. Dopamine (DA) is involved in the regulation of motivation, volition, interest/pleasure, and attention/concentration, all of which are likely to be impaired in depressed patients. Several previous reports suggest that depression may often be accompanied by a relative hypo-dopaminergic state, and some DA receptor agonists are beneficial effects in the treatment for refractory and bipolar depression. In the present study, to clarify the direct effect of DA on neural progenitor cells, we examined the effect of DA on the proliferation of adult rat dentate gyrus-derived neural precursor cells (ADPs). In addition, we examined the effect of DA receptor agonists on adult rat hippocampal neurogenesis in vivo. Results showed that DA promoted the increase of ADPs via D1-like receptor and D1-like receptor agonist promoted the survival of newborn cells in the adult hippocampus. On the contrary, D2-like receptor agonist did not affect both proliferation and survival. These results suggested that DA might play, at least in part, a role in adult hippocampal neurogenesis via D1-like receptor and the activation of D1-like receptor has a therapeutic potential for depression.

Selegiline remarkably improved stage 5 treatment-resistant major depressive disorder: a case report.

We report a case in which selegiline, an irreversible monoamine oxidase B (MAO-B) inhibitor, greatly improved depressive symptoms in an adult with stage 5 treatment-resistant major depressive disorder. Four antidepressants and four augmentation therapies had previously been ineffective or intolerable, and electroconvulsive therapy had only a temporary effect. After 20 weeks of treatment with selegiline (10 mg/day), the patient's score on the 17-item Hamilton Depression Rating Scale (HDRS) had decreased from 19 to 4 points. [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) showed increased glucose metabolism in the bilateral basal ganglia after initiating selegiline treatment; blood dopamine levels were also increased after selegiline treatment. These results raise the possibility that selegiline enhances dopamin-ergic neural transmission in treatment-resistant depression, thus leading to an improvement in depressive symptoms.