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We demonstrate a novel process for building a Resistive RAM (ReRAM) stack which reduces the forming voltage ( $\text{V}_{\textit {form}}$ ) and increases the switching resistance, both characteristics that are important ingredients for the use of ReRAM in scalable analog compute for AI. Utilizing this process, we explore analog switching characteristics above 100k $\Omega $ and demonstrate 4-bit programming at Rmax $=1\text{M}\Omega $ . Utilizing the same writing characteristics, CIFAR-10 inference simulation shows 90% accuracy, comparable to the full precision model accuracy.

In this work, we presented the Hf-Zr system as a case study of materials that were evaluated in the past and are now receiving renewed interest due to its potential use in artificial intelligence (AI). A historical overview of Hf-Zr research and its promising new applications for emerging memories will be shared.

Neuromorphic computing represents a potential paradigm shift from conventional von Neumann computing architecture and shows promise for achieving massive parallelism and power efficiency for such data-centric tasks as image recognition and language processing. Based on the concept of synaptic plasticity, human-like machine learning can be potentially realized by use of arrays of electronic synapses that function in an analogous manner to biological neurons. One of the key features of this type of computing is the ability to control synaptic weights in an analog-like fashion for use in both inference and training applications. A number of existing device technologies in non-volatile memory systems exhibit attractive characteristics for such synaptic devices.[1,2] In particular, resistive switching devices (resistive random-access memory or ReRAM) can change and store their conductance value (G) in response to electrical stimuli making them potentially enabling for deep learning applications involving synaptic weights. For ReRAM devices, HfO2-based thin films can be utilized for filamentary oxide ReRAM and are an attractive option due to their fab-friendly processing and current implementation in high-volume manufacturing. In this study, we evaluated atomic layer deposition (ALD) for the growth of HfO2 for integration in both front-end-of-line (FEOL) and back-end-of-line (BEOL) compatible test structures on 300 mm wafers in order to optimize electrical performance for use as synaptic device elements in neuromorphic architectures. The effect of oxidant in the ALD process was evaluated and it was shown that H2O outperformed O3 in terms of better uniformity and lower forming voltage. By utilizing a hydrogen-based plasma either after the deposition or inserted as an intermediate step during deposition we were able to further decrease forming voltage for a fixed dielectric thickness. Reducing deposition temperature to 200°C in conjunction with the hydrogen-based plasma treatment offered an additional tuning knob to further reduce forming voltage. Stable high-resistance switching (> 100 kΩ) with analog behavior in scaled BEOL devices was also obtained using this optimized HfO2-based ReRAM. Additionally, a tight distribution of forming voltage was obtained ensuring that 99.9999% devices in a 14 nm ReRAM module can be formed below the targeted voltage. References Kuzum et al., Nanotechnology, 24, 382001 (2013) W. Burr et al., Advanced in Physics:X, 2, 89 (2016)

Miniaturization in Integrated Circuit fabrication has scaled to atomic dimensions in recent times. With critical device dimensions moving into the range of ~10nm, atomic layer processing control is becoming essential. Atomic Layer Deposition (ALD) uses separated film components at (or near) self-limiting conditions for atomic level uniformity and thickness control. The unique nature of ALD processing has opened the opportunity for a deposition technique that presents deposition components in a spatially separated method compared to sequential component exposure of traditional systems. Spatial ALD has differentiating characteristics that can benefit IC Fabrication at current fabrication dimensions. Historically, deposition systems for IC fabrication use batch furnace or single wafer configurations. The economic benefit of batch furnace processing has been challenged by the enhanced capabilities of single wafer processing as IC scaling emphasized critical film properties and uniformity. ALD processing has rejuvenated batch furnace benefits since separate exposures of deposition components provides excellent uniformity from self-limiting deposition layers, and lower particle defectivity since the components don’t mix. However, the sequential processing of individual components has strained the efficiencies of batch furnace and single wafer ALD processing. Spatial ALD moves substrates (wafers) through each deposition component separately in space, compared to the time sequential processing of batch furnaces and single wafer processing. There are several advantages to Spatial ALD processing, and several unique capabilities that can apply to IC fabrication. By depositing through movement, the deposition components can be maintained through a steady state, which is advantageous for plasma processing and for limiting peripheral equipment film accumulation. By its nature, the deposition rate of Spatial ALD is controlled by the speed of substrates passing through the deposition zones, which can provide unique controls for deposition. Deposition chemistry and process conditions can be designed to take advantage of Spatial ALD properties for unique benefits in IC fabrication. The presentation will explore some fundamental aspects of Spatial ALD processing, the dependency and opportunities of relevant chemistries, and potential applications for the unique capabilities of Spatial ALD, including unsaturated process conditions.

Objectives: To determine whether serum levels of brain-derived neurotrophic factor (BDNF) are associated with response to electroconvulsive therapy (ECT) in treatment-resistant depressed patients with a relatively lon‐ ger period of measurement. Methods: This study included 30 Japanese unipolar depressed patients with current major depressive episode. Montgomery-Asberg Depression Rating Scale (MADRS) score was ≥21 in all subjects. ECT was performed twice a week for a total of 4–10 sessions. Serum BDNF levels were measured before ECT (T0), the day after the last ECT session (T1), and 1 month after the last ECT session (T2). Patient response to treatment was de‐ 昀ned as a ≥50% decrease compared with the pretreatment total MADRS score. Results: Serum BDNF levels showed no signi 昀cant variation among the patients during the entire study period. In responders, serum BDNF levels showed a progressive increase, and the differences between T0 and T1 and between T0 and T2 were signi 昀cant (p=0.022 and p=0.007, respectively). In non-responders, serum BDNF lev‐ els showed a progressive decrease, and the difference between T0 and T2 was signi 昀cant (p=0.012). No signi 昀† cant association was identi 昀ed between change in serum BDNF level and change in total MADRS score in any of the patients following ECT. Conclusions: The present results showed that serum BDNF levels after ECT increased progressively in res‐ ponders, but not in non-responders. Our results provide important information for understanding the exact role of BDNF in the antidepressive effects of ECT.

Background: Polymorphisms in the glucocorticoid receptors (GRs) have been widely studied with rather less emphasis on relating their differences with possible pharmacological treatment outcomes. The purpose of this study was to investigate whether Bcl1 polymorphisms of GRs are associated with the antidepressant effect of milnacipran, a serotonin noradrenaline reuptake inhibitor (SNRI), and fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), in Japanese patients with depression. Methods: Patients were prescribed either milnacipran (n = 98) or fluvoxamine (n = 95). The severity of depression was assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) at 0, 1, 2, 4 and 6 weeks of treatment. Results: Both agents were similarly effective in reducing MADRS scores in 6 weeks. In all subjects receiving milnacipran or fluvoxamine, our data showed no significant interaction between Bcl1 polymorphisms and therapeutic effects. However, when milnacipran- and fluvoxamine-treated subjects were analyzed independently, patients with G allele in Bcl1 polymorphism had a significantly better response to fluvoxamine than those with C/C genotype. On the other hand, no significant relationship was found between treatment response to milnacipran and Bcl1 polymorphism. Conclusion: Bcl1 polymorphism may be one of the genetic factors in predicting treatment response to SSRI but not SNRI in Japanese patients with depression.

Reactions for dissociative ionization and neutral dissociation collisions between an electron and a tetraethoxysilane [Si(OC2H5)4, TEOS] molecule are reported, and neutral dissociation cross sections are calculated by applying the classical Rice–Ramsperger–Kassel theory. Detailed electron collision cross section set of TEOS vapor, including 18 neutral dissociation cross sections and 20 ionization cross sections, is constructed. Electron transport coefficients, such as the mean-arrival-time drift velocity, bulk drift velocity, longitudinal bulk diffusion coefficient, and ionization coefficient, and rate coefficients for both elastic and inelastic collisions in TEOS vapor are calculated from the present cross section set using a Monte Carlo method. The validity of the present cross section set is demonstrated by comparing the calculated electron transport coefficients with measured data. Furthermore, fragmentation of TEOS molecules by electron impact is simulated, and then the number of fragments produced in the simulation is compared with the measured mass spectra.

Plasma enhanced chemical vapor deposition (PECVD) of silicon oxide (SiO2) using tetraethoxysilane (TEOS) was investigated theoretically by developing an unprecedented plasma chemistry model in TEOS/O2/Ar/He gas mixture. In the gas phase reactions, a TEOS molecule is decomposed by the electron impact reaction and/or chemically oxidative reaction, forming intermediate TEOS fragments, i.e., silicon complexes. In this study, we assume that SiO is the main precursor that contributes to SiO2 film growth under a particular process or simulation condition. The surface reaction was also investigated using quantum mechanical simulations with density functional theory. Based on the gas and surface reaction models, we constructed a computational plasma model for SiO2 film deposition in a PECVD process. The simulation results using CHEMKIN pro and CFD-ACE + have shown that the neutral atomic O and SiO as well as the charged O2 + are the dominant species to obtain a high deposition rate and uniformity. The spatial distributions of various species in the TEOS/O2/Ar/He gas mixture plasma were shown in the study. The uniformity of deposited film due to the change in the plasma bulk property was also discussed.

In this paper, novel approaches to the study of the relationship between the chemical structures and the wear properties of lubricants on an ophthalmic lens by various analytical methods are described. The X-ray damage of lubricants by X-ray photoelectron spectroscopy (XPS) depends upon the lubricant structure. Further, the lubricant structure influences the wear properties. In particular, the experimentally observed X-ray damage and wear properties indicate that the straight linear chain structure with no side chain structure ((-CF2-CF2-O-)m-(CF2-O-)n) is stronger than that with the side chain structure ((-CF (CF3)-CF2-O-)m). This result suggests that the investigation of X-ray damage by XPS is equivalent to an examination of the strength of the wear characteristic. The abovementioned methods are suitable for studying the durability of lubricants on ophthalmic lenses.

Objective: Electroconvulsive therapy (ECT) is one of the most effective treatments for refractory major depressive disorder (MDD). Although studies have examined different predictors of a positive response to ECT, predictors based on symptoms listed on a depression rating scale have not been studied. Methods: This study included 24 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for MDD or bipolar disorder with current major depressive episode. All subjects had a score of 21 or higher on the Montgomery and Asberg Depression Rating Scale (MADRS). The 3-factor model of MADRS was used for analysis: factor 1 (dysphoria) was defined by 3 items, factor 2 (retardation) was defined by 4 items, and factor 3 (vegetative symptoms) was defined by 3 items. Electroconvulsive therapy was performed 2 times a week for a total of 6 sessions using the Thymatron System IV device (Somatics, Inc., Lake Bluff, Ill) with the brief-pulse technique. A clinical response was defined as a 50% or greater decrease on the pretreatment total MADRS score. Results: The mean factor 1 score of responders (n = 17) at pretreatment was significantly higher than that of the nonresponders (n = 7). Furthermore, a significant difference in mean factor 3 scores between responders and nonresponders was observed 1 week after the 6 ECT sessions were complete, indicating a lag in response time. No significant differences were observed in age, number of previous episodes, and duration of current episodes between the responders and nonresponders. Conclusions: This study suggests that a high factor 1 MADRS score at pretreatment was a good predictor of response to ECT in patients with treatment-resistant MDD.

Eleven outpatients with chronic pain syndromes other than fibromyalgia were treated for 12 weeks with milnacipran, a novel serotonin noradrenaline reuptake inhibitor. The agent was administered at 50-150 mg/day, and the mean ± SD dose at 12 weeks or at the time drug treatment was stopped was 84.1 ± 32.2 mg/day. None of the patients met the DSM-IV criteria for a major depressive disorder. Abdominal, chest, back, arm, leg or glossal pain, or headache was involved. Pain was assessed clinically by means of a visual analog scale (VAS) before and 12 weeks after the start of milnacipran treatment, or at the time drug treatment was stopped. The mean ± SD decrease in VAS scores was 42.3 ± 31.6 (50.8 ± 49.2%). One patient discontinued treatment after 4 weeks because of nausea, whereas others tolerated the agent well. These results suggest that the use of milnacipran in patients with a variety of chronic pain syndromes is beneficial.

Furunori (aged wheat starch paste) is a traditional adhesive used to bond layers of paper and/or silk in the mounting of Japanese scrolls. It differs from fresh wheat starch paste in texture, consistency, tack and ageing characteristics. Furunori is produced in traditional Japanese mounting studios using the same general process: paste is cooked as for fresh wheat starch paste, placed in large storage jars, covered with a layer of water and stored in a cool environment. For a number of years, conservators in the East Asian Paintings Conservation Studio (EAPCS) at the Freer Gallery of Art, USA, have been trying to make furunori with limited success. This article addresses various adaptations of the process of making furunori in a non‐traditional setting. The authors take a brief look at the starting material, wheat starch, and its manufacture in Japan as well as the chemistry of the process by which fresh wheat starch paste is transformed into furunori with long‐term storage. A thorough description of the ...

Objective Genetic polymorphisms of the noradrenergic pathway can be factors to predict the effect of antidepressants when their pharmacological mechanisms of action include the noradrenergic system. The purpose of the present study was to determine whether the tyrosine hydroxylase (TH) val81met and catechol-O-methyltransferase (COMT) val158met polymorphisms are associated with the antidepressant effect of milnacipran, a serotonin/noradrenaline reuptake inhibitor. Method Eighty-one Japanese patients with major depressive disorder were treated with milnacipran for 6 weeks. Severity of depression was assessed with the Montgomery and Asberg Depression Rating Scale (MADRS). Assessments were carried out at baseline and at 1, 2, 4 and 6 weeks of treatment. The method of polymerase chain reaction was used to determine allelic variants. Results The met/met genotype of the COMT val158met polymorphism was associated with a significantly faster therapeutic effect of milnacipran in the MADRS score during this study. No influence of the TH val81met polymorphism on the antidepressant effect of milnacipran was detected. Conclusion These results suggest that the COMT val158met polymorphism in part determines the antidepressant effect of milnacipran. Copyright © 2007 John Wiley & Sons, Ltd.

Prediction of the response to different classes of antidepressants has been an important matter of concern in the field of psychopharmacology. The purpose of the present study was to investigate whether the G196A polymorphism of the brain-derived neurotrophic factor (BDNF) gene is associated with the antidepressant effect of milnacipran, a serotonin norepinephrine reuptake inhibitor, and fluvoxamine, a selective serotonin reuptake inhibitor. The subjects of our previous study of milnacipran ( n = 80) and fluvoxamine ( n = 54) were included in the present study. Severity of depression was assessed with the Montgomery Åsberg depression rating scale (MADRS). Assessments were carried out at baseline and at 1, 2, 4 and 6 weeks of treatment. Polymerase chain reaction was used to determine allelic variants. In all subjects receiving milnacipran or fluvoxamine, the G/A genotype of the BDNF G196A polymorphism was associated with a significantly better therapeutic effect in the MADRS scores during this study. When milnacipran and fluvoxamine-treated subjects were analysed independently, the G/A genotype group showed greater reduction of MADRS scores than other genotype groups, irrespective of which antidepressant was administered. These results suggest that the BDNF G196A polymorphism in part determines the antidepressant effect of both milnacipran and fluvoxamine.

Background: The efficacy and safety of switching to olanzapine were investigated in patients with first-episode schizophrenia who failed to attain an adequate clinical response to an initial therapeutic trial of risperidone (2-6 mg/day for 12 weeks). Method: A total of 58 first-episode patients with DSM-IV schizophrenia who had residual symptoms following treatment with risperidone were enrolled in an open-label, 12-week study of olanzapine. Dosing was determined by clinical judgment. The main efficacy measure was the Brief Psychiatric Rating Scale (BPRS). Patients with a 20% or greater decrease in BPRS total score plus a final Clinical Global Impressions-Severity of Illness scale score of ≤ 3 (mildly ill) were considered responders. The study was conducted from April 2001 to March 2005. Results: Fifty-one patients completed the study, and 7 discontinued due to side effects and medication noncompliance. The mean dosage of olanzapine was 15.3 (SD 4.2) mg/day at study endpoint. Total BPRS scores significantly decreased (12.3%) during olanzapine treatment (p

The purpose of this study was to assess the effect of switching to risperidone in the treatment of first-episode schizophrenia who had failed to respond to an initial-prescribed antipsychotic, olanzapine. Fifty-one patients with first-episode schizophrenia after unsuccessful treatment of olanzapine (the mean (S.D.) dosage: 16.4 (4.4) mg/day) were included in this switching study. Of the 51 patients, 43 (84.3%) completed the full 12-week trial and 8 (15.7%) dropped out. The mean dosage of risperidone at the endpoint (last observation) was 3.1 (2.0) mg/day. The total scores of Brief Psychiatric Rating Scales (BPRS) were significantly reduced from baseline to endpoint, especially in the positive and excitement factors (p

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

With a multitude of antidepressants available, predictors of response to different classes of antidepressants are of considerable interest. The purpose of the present study was to determine whether norepinephrine transporter gene (NET) and serotonin transporter gene (5-HTT) polymorphisms are associated with the antidepressant response to milnacipran, a dual serotonin/norepinephrine reuptake inhibitor.Ninety-six Japanese patients with major depressive disorder were treated with milnacipran, 50-100 mg/day, for 6 weeks. Severity of depression was assessed with the Montgomery-Asberg Depression Rating Scale. Assessments were carried out at baseline and at 1, 2, 4, and 6 weeks of treatment. The method of polymerase chain reaction was used to determine allelic variants.Eighty patients completed the study. The presence of the T allele of the NET T-182C polymorphism was associated with a superior antidepressant response, whereas the A/A genotype of the NET G1287A polymorphism was associated with a slower onset of therapeutic response. In contrast, no influence of 5-HTT polymorphisms on the antidepressant response to milnacipran was detected.The results suggest that NET but not 5-HTT polymorphisms in part determine the antidepressant response to milnacipran.

The effects of the cytochrome P450 (CYP) 2D6 genotype and cigarette smoking on the steady-state plasma concentrations (C(ss)) of fluvoxamine (FLV) and its demethylated metabolite fluvoxamino acid (FLA) were studied in 49 Japanese depressed patients receiving FLV 200 mg/d. The C(ss) of FLV and FLA were measured by HPLC, and the wild-type allele (*1) and two mutated alleles causing absent (*5) or decreased (*10) CYP 2D6 activity were identified by PCR methods. The patients were divided into three genotype groups by the number of mutated alleles: 12 cases with no (*1/*1), 27 cases with one (*1/*5 and *1/*10), and 10 cases with two (*5/*10 and *10/*10) mutated alleles. The means +/- SD of the C(ss) of FLV and FLA and the FLA/FLV ratio of all patients were 169.1 +/- 147.5 ng/mL, 83.9 +/- 52.7 ng/mL, and 0.71 +/- 0.50, respectively. The C(ss) of FLV and FLA were not significantly different among the three genotype groups. However, the FLA/FLV ratio was significantly lower in the patients with one (P < 0.05) and two (P < 0.01) mutated alleles than in those with no mutated allele. There was no significant difference between nonsmokers (n = 34) and smokers (n = 15) in these values. In the stepwise multiple regression, the C(ss) of FLA (P < 0.05) and FLA/FLV ratio (P < 0.001) showed significant negative correlations with the number of mutated alleles, and the FLA/FLV ratio was significantly (P < 0.05) lower in women than in men. The present study suggests that the CYP 2D6 genotype and cigarette smoking have no major impact on the C(ss) of FLV and FLA, though CYP 2D6 is involved in the demethylation of FLV.

A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of fluvoxamine and its major metabolite fluvoxamino acid in plasma. Fluvoxamine and fluvoxamino acid in plasma were extracted using a C18 bonded-solid phase cartridge, followed by C4 reversed-phase HPLC separation. Fluvoxamine, fluvoxamino acid and moperone as an internal standard were detected by ultraviolet absorbance at 254 nm. It was possible to determine both fluvoxamine and fluvoxamino acid in the concentration range of 25.0 - 200.0 ng/mL, respectively. The detection limits of both fluvoxamine and fluvoxamino acid were 10.0 ng/mL, respectively. The mean recoveries of fluvoxamine and fluvoxamino acid added to plasma were more than 94.0% and 96.5%, with a coefficient of variation of less than 7.6% and 8.2%, respectively. This method has been used for the simultaneous determination of steady-state plasma concentration (Css) of fluvoxamine and fluvoxamino acid in depressive patients treated with 200 mg of oral fluvoxamine dosed as 100 mg twice-daily. The Css values of fluvoxamine and fluvoxamino acid in twelve Japanese patients were showed individual variations, which wree in the range of 48.3 - 532.9 ng/ml and 35.6 - 307.1 ng/ml, respectively.

Selective serotonin reuptake inhibitors cause a side effect of nausea with high frequency, but there have been no accurate methods to predict its incidence. The authors first investigated whether a functional polymorphism in the monoamine oxidase A (MAOA-VNTR) and a –1438G/A polymorphism in the promoter region of the 5-HT2A gene were associated with the incidence of nausea induced by fluvoxamine. Fluvoxamine was administered for 6 weeks with a specific dosage plan (50–200 mg/day) in 66 Japanese major depressive patients. The frequency of MAOA-VNTR allele 1 was significantly higher in the patients without nausea than in ones with nausea in the statistical analysis including the patients whose plasma levels were below the average and who were considered to be pharmacodynamically more sensitive to nausea. This study showed that the genetic polymorphism of MAOA-VNTR might affect the incidence of nausea induced by SSRIs. If this finding is replicated in other studies with more subjects, MAOA-VNTR polymorphism would be of great clinical use to predict the incidence of nausea induced by SSRIs.

The presence of the long (l) variant of the serotonin (5-hydroxytryptamine: 5-HT) transporter gene-linked polymorphic region (5-HTTLPR) is reported to be associated with a more favorable and faster antidepressant effect of selective serotonin reuptake inhibitors in Caucasians. The frequency of the l allele is lower in Japanese than in Caucasians; therefore, the antidepressant effect of fluvoxamine can be not as good in Japanese as in Caucasians. The authors investigated whether 5-HTTLPR was associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder in a protocolized-dosing 6-week study. The short (s) allele frequency was significantly higher in the responsive individuals than in the nonresponsive ones ( P =.010). The present study suggests that fluvoxamine is not less effective in depressive patients carrying the s allele than in the ones carrying the l allele and it is not less effective in Japanese than in Caucasians.

Genetic polymorphism of the serotonin 5-HT2A receptor seems to be associated with therapeutic response to selective serotonin reuptake inhibitors (SSRIs). The present study investigated whether a novel –1438G/A polymorphism in the promoter region of the 5-HT2A receptor gene is associated with therapeutic response to fluvoxamine (an SSRI) in 66 Japanese patients with major depressive disorder. Fluvoxamine (50 to 200 mg) was administered twice daily for 6 weeks. Fifty-four patients completed this study. The genotype distribution and the allele frequencies showed no significant difference between responders and non-responders. The time-course of the Montgomery-Åsberg Depression Rating Scale scores showed no significant difference among –1438G/G, –1438G/A, and –1438A/A genotype groups. The results demonstrated that the –1438G/A promoter polymorphism in the 5-HT2A receptor gene was unlikely to have a major role in therapeutic response to fluvoxamine in Japanese patients with major depressive disorder.

The effect of a single intracerebroventricular (i.c.v.) injection of α-IFN on levels of central monoamines and their metabolites in six brain regions (frontal cortex, striatum, hypothalamus, hippocampus, mid brain and medulla) of the rat was investigated. Wistar rats (n=10) were decapitated 2 h after i.c.v. injection of α-IFN. The brain tissues were homogenized, and monoamine concentrations were measured by high-performance liquid chromatography with an electrochemical detector. The levels of 5-hydroxytryptamine (5-HT) were significantly reduced in the frontal cortex in a dose-dependent manner, and the levels of both 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were reduced in the mid brain and the striatum. The levels of noradrenaline (NA) were also significantly reduced in a dose-dependent manner in the frontal cortex. Some neurophysiological changes that affect activity of the noradrenergic or/and the serotonergic neuron system may occur during IFN therapy.

We examined the effects of an L-type Ca2+ channel blocker, nilvadipine (0.5 and 2.0 mg/kg), and that of a T-type Ca2+ channel blocker, flunarizine (10.0 and 40.0 mg/kg), on the hypnotic potency of both a benzodiazepine (BZ)-hypnotic, triazolam (1.0 mg/kg), and a non-BZ hypnotic, zolpidem (20.0 mg/kg), in rats. The polysomnogram was recorded for 6 h after administration of the vehicle solution alone, or after one of the Ca2+ channel blockers, with or without one of the hypnotics. Both Ca2+ channel blockers prolonged the increased total time of non-rapid eye movement (non-REM) sleep induced by either hypnotic. In the case of triazolam, however, the non-REM sleep-enhancing effect induced by nilvadipine was greater than that induced by flunarizine. These findings indicate that the hypnotic action of triazolam is potentiated more strongly by an L-type Ca2+ channel blocker than by a T-type Ca2+ channel blocker.

In order to investigate the relative efficacy and safety of zopiclone and zolpidem, we compared the effects of higher doses of zopiclone and zolpidem on the frequency of hippocampal theta activity and sleep structure with that of triazolam. Rats were divided into triazolam treatment group (1 mg/kg, 5 mg/kg), zopiclone treatment group (20 mg/kg, 100 mg/kg) and zolpidem treatment group (20 mg/kg, 100 mg/kg). Rats were injected intraperitoneally with these drugs or their vehicle. Polygraphic sleep recording and visual frequency analysis of the hippocampal EEG activity in REM sleep were carried out for 6 h after each injection. Zolpidem, unlike triazolam and zopiclone, had a much milder reducing-effect on the frequency of hippocampal theta activity and suppressing-effect on REM sleep. These results suggest that zolpidem may prove to be a safer hypnotic drug which has fewer or milder side effects than are benzodiazepine and cyclopyrrolone hypnotics.

1. 1. The effect of electroconvulsive shock (ECS) on the extracellular concentration of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) was examined in the frontal cortex of rats with the use of in vivo microdialysis. 2. 2. The extracellular concentration of DOPAC, HVA and 5-HIAA was largely increased after the first ECS treatment. The increase after the eighth ECS treatment tended to be attenuated or was significantly attenuated as compared to that after the first ECS treatment. The baseline concentration of DOPAC and 5-HIAA was significantly increased after repeated ECS, though that of DA and HVA did not show any significant change after repeated ECS. 3. 3. These results suggest that the activating effect of repeated ECT on 5-hydroxytryptaminergic (5-HT) and DA neurotransmission, (especially on 5-HT neurotransmission), is significant in improving depression both in patients with Parkinson's disease (PD) and in those who do not suffer from PD.

Keiichiro Tominaga¹, Mioto Okazaki¹, Hisashi Higuchi¹, Itaru Utagawa¹, Etsuko Nakamura², Noboru Yamaguchi¹¹Department of Neuropsychiatry, St Marianna University School of Medicine, Miyamae-ku, Kawasaki City, Kanagawa, ²Tsurukawa Sanatorium Hospital, Machida City, Tokyo, JapanBackground: Electroconvulsive therapy (ECT) has been used for treatment-resistant depression. However, predictors of response to ECT have not been adequately studied using the Montgomery and Åsberg Depression Rating Scale, especially in older patients with treatment-resistant depression.Methods: This study included 18 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision criteria for a diagnosis of major depressive disorder or bipolar disorder with a current major depressive episode, and met the definition of treatment-resistant depression outlined by Thase and Rush, scoring ≥21 on the Montgomery and Åsberg Depression Rating Scale. The three-factor model of the Montgomery and Åsberg Depression Rating Scale was used for analysis. Factor 1 was defined by three items, factor 2 by four items, and factor 3 by three items, representing dysphoria, retardation, and vegetative symptoms, respectively. ECT was performed twice a week for a total of six sessions using a Thymatron System IV device with the brief pulse technique. Clinical responses were defined on the basis of a ≥50% decrease in total pretreatment Montgomery and Åsberg Depression Rating Scale scores.Results: The mean pretreatment factor 2 score for responders (n = 7) was significantly lower than that for nonresponders (n = 11). Furthermore, a significant difference in mean factor 3 score between responders and nonresponders was observed one week after six sessions of ECT, indicating a time lag of response. No significant differences were observed for age, number of previous episodes, and duration of the current episode between responders and nonresponders.Conclusion: This study suggests that a low pretreatment factor 2 score is a good predictor of response to ECT in older patients with major depression.Keywords: factor analysis, electroconvulsive therapy, refractory depression, Montgomery and Åsberg Depression Rating Scale, predictors of response

Background It has been suggested that the symptoms of major depressive disorder (MDD) are composed of some clusters, which are linked to distinct genetic mechanisms. The purpose of this study was to examine the associations of genetic polymorphisms in the serotonergic system with three factors of the Montgomery-Asberg Depression Rating Scale (MADRS), i.e., dysphoria, retardation, and vegetative symptoms. Methods The subjects were 132 Japanese patients of MDD. The genotypes of tryptophan hydroxylase 218A/C, serotonin transporter gene-linked polymorphic region (5HTTLPR), and 5HT2A receptor -1438 G/A polymorphisms were determined by PCR methods. Statistical analyses were performed by the multiple regression analysis. Results The A allele of 5HT2A polymorphism was associated with higher vegetative scores (p = 0.001) and total MADRS scores (p = 0.005), while the S allele of 5HTTLPR was related to higher dysphoric scores (p = 0.012). The tryptophan hydroxylase genotype was not related to any factor scores or total MADRS scores. Limitations The sample size was relatively small, and the subjects were composed of Japanese only. Conclusion This study suggests that the genetic polymorphisms in 5HT2A receptor and serotonin transporter are linked to discrete symptom clusters of MDD.

The prolactin response to an antipsychotic drug zotepine, which has both antidopaminergic and antiserotonergic effects, was studied in 24 inpatients suffering from schizophrenia. The daily dose was 100 mg in the first week, and 200 mg for the next three weeks. The mean serum concentrations of prolactin at the daily dose of 200 mg, but not 100 mg, were significantly higher than that before treatment. The δ prolactin (the change from the pretreatment concentration) was significantly correlated with zotepine concentrations at each week. At low zotepine concentrations, patients with high pre-treatment prolactin concentrations showed negative δ prolactin. The present study thus suggests that at high concentrations zotepine shows predominantly antidopaminergic effects, while at low concentrations its antiserotonergic effects are predominant and/or it acts as a dopamine agonist.

We report here the development of parkinsonian symptoms after carbamazepine discontinuation in two patients concurrently treated with risperidone. They had been receiving combined treatment of carbamazepine and risperidone for the control of aggressive behavior and psychotic symptoms. The parkinsonian symptoms had not occurred before carbamazepine discontinuation, and have achieved complete remission after the dose reduction of risperidone. These findings suggest that the development of parkinsonian symptoms may be associated with pharmacokinetic interaction between carbamazepine and risperidone.

In a milnacipran study, ninety-six patients with major depressive disorder were treated with milnacipran, 50-100 mg/day, for 6 weeks. Severity of depression was assessed with the Montgomery and Asberg Depression Rating Scale. The purpose of this study was to determine whether norepinephrine transporter (NET) gene and serotonin transporter (5-HTT) gene polymorphisms are associated with the antidepressant response to milnacipran, a serotonin and norepinephrine reuptake inhibitor. Eighty patients completed the study. The presence of the T allele of the NET T-182C polymorphism was associated with a superior antidepressant response. In contrast, no influence of 5-HTTLPR (5-HTT linked polymorphic region) on the antidepressant response to milnacipran was detected. The results suggest that NET but not 5-HTT polymorphisms in part determine the antidepressant response to milnacipran. In a fluvoxamine study, sixty-six patients with major depressive disorder were treated with fluvoxamine, 100-200 mg/day, for 6 weeks. The authors investigated whether 5-HTTLPR was associated with the antidepressant response to fluvoxamine, a selective serotonin reuptake inhibitor. Fifty-seven patients completed the study. The short (s) allele frequency was significantly higher in the responsive individuals than in the nonresponsive ones. The results suggest that fluvoxamine is not less effective in depressive patients carrying the s allele than in those carrying the long (1) allele and it is not less effective in Japanese than in Caucasians.

Hisashi Higuchi1, Kazuhiro Sato2, Shingo Naito3, Keizo Yoshida4, Hitoshi Takahashi5, et al1Department of Neuropsychiatry, St Marianna University School of Medicine, 2-16-1 Sugou, Miyamae-ku, Kawasaki City, Kanagawa 216-8511, Japan; 2Department of Psychiatry, Akita Kaiseikai Hospital, 1-7-5 Ushijima-nishi, Akita City, Akita 010-0063, Japan; 3Department of Neuropsychiatry, Akita City Hospital, 4-30 Kawamotomatsuoka-machi, Akita City, Akita 010-0933, Japan; 4Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya City, Aichi 466-8550, Japan; 5Department of Psychiatry, Tokyo Women’s Medical University School of Medicine, Kawada-cho, Shinjyukuku, Tokyo, 162-8666, Japan, et alAbstract: The effects of gender differences and age on the treatment response to fluvoxamine were investigated in major depressive Japanese patients. A total of 100 Japanese patients participated in this study. The daily dose of fluvoxamine was fixed to 100, 150 or 200 mg in the fourth week. This fixed dose was maintained until the end of the 6-week study. The patients were divided into 3 groups: younger females, older females, and males. Depressive symptoms were evaluated using the Montgomery and Åsberg Depression Rating Scale (MADRS) at pretreatment and at 1, 2, 4, and 6 weeks after the commencement of the study. Seven of the 100 patients were excluded, and the remaining 93 patients constituted the subjects (50 females, 43 males). The number of intent-to-treat responders and non-responders was 55 and 38, respectively. There was a significant difference in the changes in the time course of the MADRS score and changes in the MADRS scores at each evaluation point between the younger and older females. Younger females demonstrated a significantly better response than older females. The results suggest that fluvoxamine is more effective in younger female patients than in older female patients. Keywords: major depressive disorder, fluvoxamine, antidepressant response, menopausal status

Aims: Fluvoxamine, a selective serotonin reuptake inhibitor, is widely used to treat major depression. However, the symptomatological predictors of the response to fluvoxamine have not been studied. Methods: This study included 100 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery and Asberg Depression Rating Scale (MADRS) was 21 or higher. Eighty-one patients were included. Patients with a pretreatment MADRS score of ≥31 were defined as ‘severe’ (n = 32) and the rest were defined as ‘non-severe’ (n = 49). The three-factor model of MADRS was used for analysis: the first factor was defined by three items, the second factor was defined by four items, and the third factor was defined by three items representing dysphoria, retardation, and vegetative symptoms, respectively. Fluvoxamine (100–200 mg/day) was administered twice daily for 6 weeks. Results: In the non-severe patients, the mean factor 3 score of the non-responders at pretreatment was significantly higher than that of the responders. However, a significant difference was observed in the mean factor 3 scores from 1 week onwards between the non-severe responders and non-responders. Furthermore, the fluvoxamine response rate in the severe patients was 75% and higher than that of the non-severe patients (65.3%). Conclusions: This study suggested that a low factor 3 score at pretreatment was a good predictor of the response to fluvoxamine in non-severe patients. The marked efficacy of fluvoxamine in the treatment of severe patients was also confirmed.

Aims: Milnacipran, a new specific serotonin and norepinephrine re-uptake inhibitor, is as effective as tricyclic antidepressants. Symptomatological predictors of antidepressant response to milnacipran have not been studied until now. Methods: This study included 101 Japanese patients who fulfilled the DSM-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery and Asberg Depression Rating Scale (MADRS) was ≥21. Eighty-three patients were finally included. Patients with a pretreatment MADRS score ≥31 points were defined as severe (n = 28), and the rest as non-severe (n = 55). The three-factor model of MADRS was used for analysis; the first factor was defined by three items, the second factor was defined by four items and the third factor was defined by three items representing dysphoria, retardation, and vegetative symptoms, respectively. Milnacipran was administered twice daily for 6 weeks. The initial dose was 50 mg/day; after a week it was increased to 100 mg/day. Results: No significant difference was observed in the mean score of first factor, second factor and third factor at pretreatment time between responders and non-responders in both severe and non-severe patients. Conclusions: No predictor of antidepressant response to milnacipran was obtained using the three-factor structures of the MADRS in Japanese patients with major depressive disorders.

Using an 8-week, open label study design, we report the effect of augmentation strategy with olanzapine in hospitalized depressive patients with melancholic features who had insufficient response to a tricyclic antidepressant (TCA), amitriptyline. Subjects were hospitalized patients meeting the criteria of DSM-IV major depressive disorder with melancholic features who had been suffering from residual symptoms after treatment of amitriptyline. After study entry, olanzapine was added to amitriptyline and the dose was adjusted according to patients' clinical condition. Data were analyzed using an intent-to-treat methodology, with last observation carried forward. Paired t-test was adopted to assess the data from baseline to endpoint. Of 26 patients who enrolled in this study, 23 patients completed the trial and 3 patients dropped out. The mean dose of olanzapine was 6.5 (SD = 2.4) mg/day. The mean score of Montgomery-Asberg Depression Rating Scale (MADRS) was significantly decreased from 33.6 (SD = 3.5) to 20.8 (SD = 9.1) during this study (37.9% from baseline) (p < 0.001). Ten patients (38.5%) were considered as responders (50% or greater reduction in MADRS scores from baseline). These results suggest that augmentation with olanzapine in TCAs-resistant melancholia may be effective and well tolerated. We cannot draw any conclusion with certainty from the open-label, uncontrolled clinical trial. Double blind, controlled trial is needed to confirm this preliminary finding.

Milnacipran--a new specific serotonin and noradrenaline reuptake inhibitor--is as effective as tricyclic antidepressants and exhibits a higher remission rate for major depressive patients than selective serotonin reuptake inhibitors. However, the effectiveness of milnacipran for severe major depressive patients had not been studied adequately. The study included 96 Japanese patients who fulfilled the DSM-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery-Asberg Depression Rating Scale (MADRS) was 21 or higher. Of these, 16 patients were excluded because 10 did not complete the study, and 6 showed poor compliance. Finally, 80 patients were included. We defined patients with a baseline MADRS score of > or = 31 points as "severe" (n = 25). The remaining patients were classified as "moderate" (31 > MADRS score > or = 25, n = 30) and "mild" (MADRS score < 25, n = 25) using the median score of those patients as the cutoff. Milnacipran was administered twice daily for 6 weeks. The initial total dose was 50 mg/d; after a week it was increased to 100 mg/d. The response rates were 72%, 70%, and 44% in the "severe," "moderate," and "mild," respectively. No significant differences were found between "severe" and the "moderate"; however, significant differences were observed between "severe" and "mild" and "moderate" and "mild." These results demonstrated that milnacipran is almost equally effective in "severe" and "moderate." This study suggested that milnacipran has a reliable antidepressant effect in treating severe and moderate major depressive patients.

Major Depressive Disorder (MDD) may be composed of some symptom clusters with distinct neurochemical disturbances, suggesting the importance of the factor analysis of depressive symptoms; however, the results of previous studies using the Montgomery-Asberg Depression Rating Scale (MADRS) have been inconsistent. In the present study, factor analysis of the MADRS was performed in 132 Japanese patients (range 23–74 years, mean 47.6 years) with MDD without any psychiatric comorbidity. The principal component analysis with Varimax rotation identified three factors, accounting for 61% of the total variance: The first factor, labeled dysphoria, included pessimistic thoughts, suicidal thoughts, and reported sadness; the second factor, labeled retardation, included lassitude, inability to feel, apparent sadness, and concentration difficulties; and the third factor, labeled vegetative symptoms, included reduced sleep, reduced appetite, and inner tension. The score of the vegetative factor showed a significant positive correlation with age and was significantly higher in females than in males. This study suggests that the symptoms of MDD, as assessed by the MADRS, cluster into three factors (dysphoria, retardation, and vegetative symptoms). Depression and Anxiety 21:95–97, 2005. © 2005 Wiley-Liss, Inc.

Milnacipran is a novel serotonin noradrenaline reuptake inhibitor. The authors describe the use of milnacipran for the treatment of chronic pain in a series of patients. There were 5 outpatients who suffered chronic pain for at least 3 months. None of these patients met the DSM-IV criteria for a major depressive disorder. Chronic pain was assessed clinically by means of a visual analog scale (VAS) before and 12 weeks after the start of the milnacipran treatment or at the time the drug was stopped. The duration of pain was 17.8 +/- 9.3 months (mean +/- SD), and the baseline VAS score was 88.2 +/- 6.3 points. Milnacipran was administered at 50 to 150 mg/day, and the dose at 12 weeks or at the time the drug was stopped was 85.0 +/- 31.3 mg/day. The mean +/- SD decrease in VAS at this time was 61.2 +/- 15.5%. Three patients showed marked improvement (decrease in VAS, >75%). Their decreases in VAS scores were 86.5%, 85.7%, and 77.6%. One patient showed mild improvement (42.0% decrease in VAS). These 4 patients tolerated the drug well. The fifth patient experienced nausea and discontinued treatment after 4 weeks. The VAS decrease for this patient was 14.3%. Results of this study show milnacipran to be beneficial in patients with chronic pain. This drug should be studied further for its effectiveness in the treatment of chronic pain.

The authors present here two cases of Parkinson's disease with depression refractory to SSRIs treatment, who experienced a complete remission after replacing the ongoing SSRIs with a serotonin-noradrenalin reuptake inhibitor (SNRI), milnacipran. The case reports suggest that milnacipran may be one of the treatment options for depression in patients with Parkinson's disease who had inadequate response to SSRIs. Further studies are warranted to confirm this observation.

We illustrate 2 patients with depression who attained dramatic improvement of energy loss and fatigue when treated with cabergoline, a dopamine agonist, and milnacipran, a serotonin-noradrenalin reuptake inhibitor. Although the biologic basis of energy, motivation, and fatigue in association with depression remains unknown, some reports suggest that the decrease of noradrenalin and dopamine in the brain are particularly related to these symptoms. Therefore, treatment strategy that enhances these two monoamine neurotransmissions may be appropriate for getting a boost in energy and eliminating fatigue in patients with depression. These cases suggest that further studies are warranted to confirm the potential benefit of this strategy in the treatment of patients with depression who failed to attain complete remission due to residual symptoms including energy loss and fatigue refractory to previous treatments.

This study investigated the effectiveness and tolerability of a switching strategy using quetiapine in 16 women with schizophrenia who were suffering from haloperidol- or risperidone-induced amenorrhea. Findings revealed that 10 patients (71.6%) resumed menstruation, without worsening of psychotic symptoms.

Selective serotonin reuptake inhibitors cause a side effect of nausea with high frequency, but there have been no accurate methods to predict its incidence. The authors first investigated whether a functional polymorphism in the monoamine oxidase A (MAOA-VNTR) and a -1438G/A polymorphism in the promoter region of the 5-HT(2A) gene were associated with the incidence of nausea induced by fluvoxamine. Fluvoxamine was administered for 6 weeks with a specific dosage plan (50-200 mg/day) in 66 Japanese major depressive patients. The frequency of MAOA-VNTR allele 1 was significantly higher in the patients without nausea than in ones with nausea in the statistical analysis including the patients whose plasma levels were below the average and who were considered to be pharmacodynamically more sensitive to nausea. This study showed that the genetic polymorphism of MAOA-VNTR might affect the incidence of nausea induced by SSRIs. If this finding is replicated in other studies with more subjects, MAOA-VNTR polymorphism would be of great clinical use to predict the incidence of nausea induced by SSRIs.