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The number of suicides in Japan decreased during the period from 2012 through 2019. Because data on factors associated with this decline are limited, we conducted a retrospective longitudinal study of psychiatric diagnoses of serious suicide attempters before 2012 and after 2019.Serious suicide attempters admitted to the critical care medicine (CCM) department of Nippon Medical School Hospital between 2006 and 2017 were included and classified as those before and after the suicide decline in 2012. Chi-square test and residual analysis were used to analyze changes in the proportion of suicide attempters among all patients admitted to CCM and to examine differences in the proportion of psychiatric diagnoses.The proportion of suicide attempters among CCM hospitalized patients decreased overall (χThe decrease in the proportion of attempted suicides among patients admitted to CCM was consistent with the decline in suicides in Japan. Analysis by psychiatric diagnosis confirmed a significant decrease in the proportion of suicide attempts associated with depressive disorders, schizophrenia, and reaction to stress disorders, which were the most common disorders associated with attempted suicide. Depressive disorders made the greatest contribution to the reduction in suicide attempts.

Background Electroconvulsive therapy (ECT) is an effective treatment for depressive disorders, although its molecular mechanism of action is unknown. The serotonin 1B (5-HT1B) receptor is a potential target for treatment of depression and low 5-HT1B receptor binding in limbic regions has been reported in previous positron emission tomography (PET) studies of depression. Methods The objective of this longitudinal PET study was to examine the effect of ECT for depression on 5-HT1B receptor binding. Fifteen hospitalized patients with major depressive episodes were examined with PET and the 5-HT1B receptor selective radioligand [11C]AZ10419369, before and after ECT. Fifteen controls matched for age and sex were examined. Limbic regions with previously reported low 5-HT1B receptor binding in depression and a dorsal brain stem region were selected. Results Thirteen patients completed the study according to protocol. Eleven out of thirteen patients responded to ECT. 5-HT1B receptor binding in hippocampus increased with 30 % after ECT (p=0.021). Using linear mixed effects modelling, we observed increases in 5-HT1B receptor binding following ECT with a moderate to large effect size, which did not differ significantly between regions. In an exploratory analysis, strong correlations between changes in 5-HT1B receptor binding and agitation scores on the Hamilton Depression Rating Scale after ECT were observed. Limitations Albeit representative of a PET study, the sample size is still small and there are potential confounding effects of medication. Conclusions Increased 5-HT1B receptor binding was observed following ECT for depression, corresponding to previous findings of increased 5-HT1B receptor binding in hippocampus after rapid acting ketamine for treatment resistant depression.

Blonanserin is an atypical antipsychotic, a potent selective antagonist of dopamine D2 receptor (D2), prescribed as oral formulations in patients with schizophrenia. Blonanserin transdermal patch was developed to provide a new treatment option, but the corresponding dose to oral blonanserin was not clear. The aims of this study were to clarify the pharmacokinetic (PK)-pharmacodynamic characteristics of blonanserin after transdermal patch application and to evaluate the corresponding dose to oral formulation based on striatal D2 occupancy.The relationship between D2 occupancy and plasma blonanserin concentration was analyzed using an Emax model based on data from positron emission tomography study with oral and transdermal blonanserin. D2 occupancy was simulated using Emax models based on the observed plasma concentrations and the simulated plasma concentrations obtained from population PK model.Plasma blonanserin concentration levels after repeated patch applications were nearly stable throughout the day and no effect of sex, advanced age, or application site was detected. The concentration at half maximal D2 occupancy during transdermal patch applications, 0.857 ng/mL, was higher than that after oral doses, 0.112 ng/mL, suggesting metabolite contribution after oral doses. The median predicted D2 occupancy during blonanserin patch applications at doses of 40 and 80 mg/d was 48.7% and 62.5%, respectively, and the distribution of D2 occupancy at these doses could cover most of that at oral doses of 8 to 24 mg/d.Predicted D2 occupancy suggested that a 40- to 80-mg/d blonanserin transdermal patch dose corresponds to an 8- to 24-mg/d oral dose for the treatment of schizophrenia.

Rationale Unlike other antipsychotics, our previous positron emission tomography (PET) study demonstrated that a single dose of blonanserin occupied dopamine D3 as well as dopamine D2 receptors in healthy subjects. However, there has been no study concerning the continued use of blonanserin. Objectives We examined D2 and D3 receptor occupancies in patients with schizophrenia who had been treated with blonanserin. Methods Thirteen patients with schizophrenia participated. PET examinations were performed on patients treated with clinical dosage of blonanserin or olanzapine alone. A crossover design was used in which seven patients switched drugs after the first scan, and PET examinations were conducted again. D2 and D3 receptor occupancies were evaluated by [11C]-(+)-PHNO. We used nondisplaceable binding potential (BPND) of 6 healthy subjects which we previously reported as baseline. To consider the effect of upregulation of D3 receptor by continued use of antipsychotics, D3 receptor occupancy by blonanserin in seven subjects who completed 2 PET scans were re-analyzed by using BPND of olanzapine condition as baseline. Results Average occupancy by olanzapine (10.8 ± 6.0 mg/day) was as follows: caudate 32.8 ± 18.3%, putamen 26.3 ± 18.2%, globus pallidus − 33.7 ± 34.9%, substantia nigra − 112.8 ± 90.7%. Average occupancy by blonanserin (12.8 ± 5.6 mg/day) was as follows: caudate 61.0 ± 8.3%, putamen 55.5 ± 9.5%, globus pallidus 48.9 ± 12.4%, substantia nigra 34.0 ± 20.6%. EC50 was 0.30 ng/mL for D2 receptor for caudate and putamen (df = 19, p < 0.0001) and 0.70 ng/mL for D3 receptor for globus pallidus and substantia nigra (df = 19, p < 0.0001). EC50 for D3 receptor of blonanserin changed to 0.22 ng/mL (df = 13, p = 0.0041) when we used BPND of olanzapine condition as baseline. Conclusions Our study confirmed that blonanserin occupied both D2 and D3 receptors in patients with schizophrenia.

Background Transdermal antipsychotic patch formulations offer potential benefits, including improved adherence. This study investigated the striatal dopamine D2 receptor occupancy with daily blonanserin transdermal patch application. Methods This open-label, phase II study enrolled 18 Japanese outpatients (20 to Results Of 18 patients who started the blonanserin tablet treatment period, 14 patients completed treatment. Mean D2 receptor occupancy for blonanserin tablets 8 mg/d (59.2%, n = 5) and 16 mg/d (66.3%, n = 9) was within the values for blonanserin patches: 10 mg/d (33.3%, n = 3), 20 mg/d (29.9%, n = 2), 40 mg/d (61.2%, n = 3), 60 mg/d (59.0%, n = 3), and 80 mg/d (69.9%, n = 3). Occupancy generally increased with increasing blonanserin dose for both formulations with the half maximal receptor occupancy for tablets and patches associated with doses of 6.9 mg/d and 31.9 mg/d, respectively. Diurnal variability in occupancy was lower during transdermal patch treatment than during tablet treatment. Blonanserin transdermal patches were well tolerated with no major safety concerns. Conclusions Blonanserin patches (40/80 mg/d) have lower diurnal variability in occupancy than blonanserin tablets (8/16 mg/d), and patches at doses of 40 mg/d and 80 mg/d appear to be a suitable alternative for blonanserin tablets at doses of 8 mg/d and 16 mg/d, respectively. Blonanserin patches represent a potential new treatment option for patients with schizophrenia. Trial registry JAPIC Clinical Trials Information registry (www.clinicaltrials.jp; JapicCTI-No: JapicCTI-121914).

The rising older population in Japan is associated with a rise in cases of dementia. Support for the increased number of family caregivers of people living with dementia is crucial, as caring may negatively affect a family caregiver’s health. This study seeks to evaluate the feasibility and applicability of a recently developed Japanese version of START (STrAtegies for RelaTives). START is a psychosocial coping intervention program developed in the United Kingdom that has been shown to improve caregivers’ mood and quality of life in a randomized controlled trial. We made changes to START (e.g., idioms, linguistic nuance, and providing care insurance information suited for Japan) to make it culturally appropriate. Fourteen Japanese female family caregivers of relatives with mild dementia (n = 10) or mild cognitive impairment (n = 4) were referred to the study, but six were excluded owing to illness and busyness. This single-arm study had a before–after trial evaluating psychological outcomes including depression, anxiety, quality of life, and subjective care burden. The acceptance retention and satisfaction rate suggest the feasibility and acceptability of the START program; 8/14 (>55%) eligible, prospective participants consented and were included in this study, all (8/8) of whom completed all START sessions. The mean program satisfaction score was 30.25 (standard deviation = 2.25) out of a potential 32. The results suggest that it is feasible and acceptable to deliver START in Japanese and based on the results of analysis using a linear mixed model, there is initial indication that the intervention improved family caregivers’ quality of life, depressive symptoms, and care burden.

Background Connecting individuals in need of psychiatric treatment with adequate medical services has been a major strategy for suicide prevention in Japan. By investigating serious suicide attempters admitted to our Critical Care Medical Center (CCM), we aimed to examine longitudinal changes in the psychiatric treatment status of high-risk suicidal individuals, and to explore the association between any improvement in psychiatric treatment status and suicide decline. Methods Subjects from two periods, 2006–2011 and 2012–2017, were enrolled. We collected the data of 32,252 suicides in Tokyo from police reports and the data of 942 suicide attempters admitted to CCM from medical records. Data were annually collected by both age and gender for the number of suicide completers, the number of suicide attempters, and the psychiatric treatment rates, respectively. ANOVA and t-test were used to examine whether there were differences in the number of suicides and attempers between the two periods. The difference in psychiatric treatment rate between the two periods was examined by chi-square test. Additionally, we used Pearson’s correlation coefficient to analyze any correlation between annual treatment rate and the number of suicide completers in subgroups with altered psychiatric treatment rates. Results The number of suicide attempters in the 20–39-year age group of decreased together with the number of suicides. Psychiatric treatment rates of male attempters aged 20–59 years improved significantly from 48.7 to 70.6% and this improvement correlated with a decrease in suicides. However, psychiatric treatment rates in the elderly, which have the highest number of suicides in both genders, did not improve and remain low. Conclusions The number of suicide attempters, as well as that of suicides, decreased in Tokyo. Improvement of psychiatric treatment status in high-risk suicidal male adults may have contributed to the reduction of suicides in Tokyo. However, the continuing low rate of psychiatric treatment in the elderly is a pressing issue for future suicide prevention.

Studies have shown that cognitive behavioural therapy (CBT) for older people with cognitive decline and depression/anxiety improves negative moods. However, CBT research focusing on this population in Japan is limited. This study aimed to evaluate the feasibility of a cognitive behavioural program for people with cognitive decline. Sixteen Japanese patients with mild dementia (n = 3) and mild cognitive impairment (MCI, n = 13) participated in the study. A single-arm, pre–post study was implemented in two hospitals in Japan. The CBT program included eight bi-weekly sessions. The feasibility outcomes (satisfaction, understanding and usefulness) were measured immediately after completing the sessions, and depression, anxiety, quality of life (QOL), neuropsychiatric symptoms, and caregiver burden were measured at three time points (i.e. before, immediately after, and 3-month follow-up). Ten MCI participants attended all sessions and the mean patient satisfaction scores using the Client Satisfaction Questionnaire were 31.0±10.05 out of 32. Linear mixed model analyses demonstrated that the time effect was significant for depression (d = 1.62), anxiety (d = 1.39), and QOL (d = 1.00) for the patients, and significant for anxiety (d = 1.08) for their caregivers. The study found that this CBT program is feasible and acceptable for older Japanese people with cognitive decline. The program also improved patients’ QOL, anxiety and depressive symptoms, and decreased caregivers’ anxiety. Key learning aims (1) Recently, studies have shown that CBT for older people living with dementia has been effective in treating their depression and anxiety. However, evidence for the efficacy of CBT and other curative or care options for people living with dementia is limited in Japan. (2) We studied a short-period CBT program and found that it was likely to be feasible and acceptable for use among older Japanese people with mild cognitive impairment, that it may improve negative mood among this group, and that it may lessen the care burden for caregivers. (3) Furthermore, we found that caregiver involvement in the implementation of CBT for older people may be effective in improving the mood of family members.

This study investigated the feasibility of a cognitive behavioral therapy (CBT) program for improving mood and quality of life in an older woman with mild cognitive impairment (MCI), depression, and anxiety. The program comprised eight 30-minute weekly sessions; interventions included behavioral activation, relaxation, and cognitive reconstruction, in which the patient's caregiver also participated. The patient's condition was assessed before and immediately after the intervention. After 3 and 12 months, the caregiver reported the patient's behavioral and psychological symptoms by using self-reported psychological scales for depression, anxiety, and quality of life. Although CBT helped to improve mood and quality of life in the short term (3 months), the results were not sustained over the long term (12 months). Even though improvement in psychological symptoms did not persist and only one patient with MCI was evaluated, these results suggest that CBT is a feasible nonpharmacological treatment option and provide preliminary support for wider use of CBT in Japan. CBT programs should be tailored to the needs of patients with MCI and dementia, and regular follow-up sessions should be used to evaluate program feasibility and improvement in patient mental health.

Since ephedrine has a dopamine transporter (DAT) inhibitory effect similar to amphetamine, dl-methylephedrine, a derivative of ephedrine, is considered to have the characteristics of a central nervous system stimulant due to the DAT inhibitory effect. For example, the World Anti-Doping Agency categorizes dl-methylephedrine as a stimulant in the prohibited list for competitions. Assuming to have the same effect as ephedrine, the urinary concentration of dl-methylephedrine is regulated below 10 μg/mL, as is ephedrine. However, the extent to which dl-methylephedrine affects brain function is not yet fully understood.The purpose of this study was to evaluate DAT occupancy by a single oral administration of a daily dose of dl-methylephedrine using positron emission tomography (PET) with [Nine healthy male volunteers were enrolled in the study. The experiments were designed as a placebo-controlled randomized double-blind crossover comparative study. After the first PET scan in a drug-free state, the second and third PET scans were performed with randomized dosing at 60 mg of dl-methylephedrine or placebo. The plasma and urine concentrations of dl-methylephedrine were measured just before and after the PET scans, respectively.Mean urine and plasma concentrations of dl-methylephedrine were 13.9 μg/mL and 215.2 ng/mL, respectively. Mean DAT occupancy in the caudate was 4.4% for dl-methylephedrine and 1.2% for placebo. Mean DAT occupancy in the putamen was 3.6% for dl-methylephedrine and 0.5% for placebo. There was no significant difference of DAT occupancies between the groups.In this study, the urinary concentration of dl-methylephedrine (13.9 μg/mL) was higher than the prohibited reference value (10.0 μg/mL), and there was no significant difference in DAT occupancy between dl-methylephedrine and placebo. These findings suggest that a clinical daily dose of dl-methylephedrine may exceed the doping regulation value according to urine concentration; however, it was considered that at least the central excitatory effect mediated by DAT inhibition was not observed at the daily dose of dl-methylephedrine.

Purpose The sound of dental treatments can evoke anxiety in some dental patients. While women have shown greater dental anxiety than men, little is known about the gender differences in the perception of dental sounds. The purpose of this preliminary study was to evaluate differences in the perception of dental sounds according to the level of dental fear and gender. Patients and methods Based on the level of dental fear, 69 adults (39 women, 30 men; average age, 28.1±8.1 years) were categorized into four groups. Three types of sounds were presented to participants: two sounds associated with dental treatment and a neutral sound. All participants rated their emotional reaction to each sound on a visual analog scale. Results Significant differences were observed for ratings of valence and disgust for a dental drilling sound among the four groups (p=0.007 and 0.004, respectively). Female participants in the dental fear group rated the dental drilling sound as more negative and disgusting than did female participants in the control group (p=0.002 for both ratings). However, no significant differences were found in ratings between males in the dental fear and control groups. Conclusion Perception of dental sounds appears to differ by level of dental fear and by gender. Considering these differences may contribute to reducing fear in dental patients.

Aims: This study aimed to analyze the performance of multi-atlas MRI-based parcellation for 123I-FP-CIT SPECT (DAT-SPECT) in healthy volunteers. The proposed method was compared with the SPECT-atlas-based and Bolt methods. 18F-FE-PE2I-PET (DAT-PET) was used as a reference.Methods: Thirty healthy subjects underwent DAT-SPECT, DAT-PET, and 3D-T1WI-MRI. We calculated the striatum uptake ratio (SUR/SBR), caudate uptake ratio (CUR), and putamen uptake ratio (PUR) for DAT-SPECT using the multi-atlas MRI-based method, SPECT-atlas-based method, and Bolt method. In the multi-atlas MRI-based method, the cerebellum, occipital cortex, and whole-brain were used as reference regions. The correlation of age with DAT-SPECT activity and the correlations of SUR/SBR, CUR, and PUR between DAT-SPECT and DAT-PET were calculated by each of the three methods.Results: The correlation between age and SUR/SBR for DAT-SPECT based on the multi-atlas MRI-based method was comparable to that based on the SPECT-atlas-based method (r = −0.441 to −0.496 vs. −0.488). The highest correlation between DAT-SPECT and DAT-PET was observed using the multi-atlas MRI-based method with the occipital lobe defined as the reference region compared with the SPECT-atlas-based and Bolt methods (SUR, CUR, and PUR: 0.687, 0.723, and 0.676 vs. 0.698, 0.660, and 0.616 vs. 0.655).Conclusion: Multi-atlas MRI-based parcellation with the occipital lobe defined as the reference region was at least comparable to the clinical methods.

BACKGROUND This study developed a Japanese version of the Geriatric Anxiety Inventory (GAI-J) and its short form (GAI-J-SF) to evaluate anxiety in older adults in Japan and assess these measures' psychometric properties with a cross-sectional design. METHODS Participants (N = 400; mean age: 75 years) were community-dwelling older adults who answered a set of self-report questionnaires. They were recruited from a community centre for older persons in the Kanto region of Japan. Of the respondents, 100 participated in a follow-up survey to evaluate test-retest reliability. Item response theory was adopted to evaluate item parameters. RESULTS Confirmatory factor analysis with categorical data suggested that, as with the original Geriatric Anxiety Inventory, the GAI-J/GAI-J-SF had a unifactor structure. Test-retest correlation and internal consistency analyses indicated that these scales had high reliability. Item response theory results showed that both measures' item parameters were acceptable. Correlations with the Penn State Worry Questionnaire, State Trait Anxiety Inventory-State Only, Generalized Anxiety Disorder-7 and Patient Health Questionnaire-9 were mostly consistent with our hypotheses. This supports the high convergent validity of the GAI-J/GAI-J-SF. CONCLUSIONS The findings indicate that the GAI-J and the GAI-J-SF have robust psychometric properties for assessing late-life anxiety in older Japanese adults. Future GAI-J studies in clinical groups are needed.

Aim Anodal transcranial Direct Current Stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) is known as one of the useful applications for improving depressive symptoms or cognitive performance. Antidepressive effects by anodal tDCS over the left DLPFC are expected, but the neural mechanisms of these effects are still unclear. Further, in depression, reduced performance and left prefrontal hypofunction during verbal fluency task (VFT) are generally known. However, few studies have examined the effect of tDCS on the language-related cerebral network. We aimed to investigate whether anodal tDCS at the left DLPFC affects cognitive performance and the neural basis of verbal fluency. Methods Nineteen healthy volunteers participated in this study. The effects of tDCS on cognitive behavior and cerebral function were evaluated by 1) performance and accuracy of implicit/explicit motor learning task (serial reaction time task: SRTT/sequential finger-tapping task: SFTT), and 2) cerebral activation while the subjects were performing VFT by using a functional MRI protocol of a randomized sham-controlled, within-subjects cross-over design. Results Reaction times of implicit motor learning task were significantly faster by tDCS in comparison with sham. Further, language-related left prefrontal-parahippocampal-parietal activation was significantly less by tDCS compared with sham. Significant correlation was observed between shortened response time in SRTT and decreased cerebral activation during VFT by tDCS. Conclusion Anodal tDCS over the left DLPFC could improve cognitive behavior of implicit motor learning by improving brain function of the frontoparietal-parahippocampal region related to motor learning, as well as language-related regions. This article is protected by copyright. All rights reserved.

Background Cognitive-behavioral therapy (CBT) for older people with dementia and depression/anxiety alleviates negative moods. However, CBT research focusing on this population in Japan is limited. This study aimed to evaluate the feasibility and acceptability of a recently developed cognitive-behavioral program for people with dementia or mild cognitive impairment (MCI), focusing on symptom alleviation and patient satisfaction. Method Sixteen Japanese patients with mild dementia ( n =3) and MCI ( n =13) participated in the study. A single-arm, pre-post study was implemented in two medical school hospitals in Japan. The CBT program included eight bi-weekly sessions conducted by one clinical psychologist. The feasibility and acceptability outcomes (perceived satisfaction, understanding, and usefulness of the program) were measured before and immediately after completing the sessions, and the psychological outcomes (depression, anxiety, quality of life [QOL], neuropsychiatric symptoms, and caregiver burden) were measured at three periods (i.e., before, immediately after, and three months after the intervention). A linear mixed model was adopted for comparing these outcomes. Results Three candidates were excluded because of unavailability, lack of interest, and refusal to participate; therefore, 13 candidates (81%) participated in this study. However, three participants dropped out because of lack of motivation and health-related reasons during the program. Finally, ten participants (76.9%) attended all program modules. The mean patient and caregiver satisfaction scores using the Client Satisfaction Questionnaire were 31.0±10.05 and 28.0±2.83 out of 32, respectively. The linear mixed model demonstrated that the time effect was significant at a 99% level for depression ( d =1.62), anxiety ( d =1.39), and QOL ( d =1.00) for the patients, and significant at a 95% level for anxiety ( d =1.08) for their caregivers. Conclusion The study found that this CBT program is feasible and acceptable for older Japanese people with dementia and MCI. The program also improved patients’ QOL, alleviated anxiety and depressive symptoms, and decreased caregivers’ anxiety.

Aim Dysfunction of dopaminergic neurons in the central nervous system is considered to be related to major depressive disorder (MDD). Especially, MDD in geriatric patients is characterized by anhedonia, which is assumed to be associated with reduced dopamine neurotransmission in the reward system. Dopamine transporter (DAT) is considered to reflect the function of the dopamine nerve system. However, previous DAT imaging studies using single photon emission computed tomography or positron emission tomography (PET) have shown inconsistent results. The radioligand [18 F]FE-PE2I for PET enables more precise evaluation of DAT availability. Hence, we aimed to evaluate the DAT availability in geriatric patients with MDD using [18 F]FE-PE2I. Methods Eleven geriatric patients with severe MDD and 27 healthy controls underwent PET with [18 F]FE-PE2I, which has high affinity and selectivity for DAT. Binding potentials (BPND ) in the striatum (caudate and putamen), nucleus accumbens (NAc), and substantia nigra were calculated. BPND values were compared between MDD patients and healthy controls. Results MDD patients showed significantly lower DAT BPND in the NAc (P = 0.009), and there was a trend of lower BPND in the putamen (P = 0.032) compared to controls. Conclusion We found low DAT in the NAc and putamen in geriatric patients with severe MDD, which could be related to dysregulation of the reward system.

Tramadol is an analgesic with monoamine reuptake inhibition and μ-opioid receptor activation. Although tramadol has been widely used for treatment of various pain conditions, there is controversy over the risk of abuse potential. We examined the effects of tramadol on the reward system in humans using functional magnetic resonance imaging (fMRI) to assess the potential of tramadol for drug abuse or dependence. A randomized, double-blind, placebo-controlled, crossover study was conducted for 19 healthy adults under tramadol or placebo. In association with subjective mood questionnaires, monetary incentive delay (MID) task was performed to assess the neural response to reward anticipation during fMRI. Subjective mood measures and blood oxygenation level-dependent (BOLD) signal during gain and loss anticipation were compared between tramadol and placebo. Tramadol significantly reduced anxiety (Z = − 2.513, p = 0.012) and enhanced vigor (Z = − 2.725, p = 0.006) compared with placebo. By Mood Rating Scale, tramadol provoked contented (Z = − 2.316, p = 0.021), relaxed (Z = − 2.236, p = 0.025), and amicable feelings (Z = − 2.015, p = 0.044) as well as increased alertness (Z = − 1.972, p = 0.049) and contentedness domains (Z = − 2.174, p = 0.030) compared with placebo. Several brain regions including nucleus accumbens (NAc) were activated during gain anticipation in the MID task under both tramadol and placebo. Tramadol increased the %BOLD signal change in NAc at +¥500 cue significantly more than the placebo (Z = − 2.295, p = 0.022). Tramadol enhances the reward system and thereby may have abuse potential or precipitate drug abuse in human.

The aim of this multicenter trial was to generate a [123I]FP-CIT SPECT database of healthy controls from the common SPECT systems available in Japan. This study included 510 sets of SPECT data from 256 healthy controls (116 men and 140 women; age range, 30–83 years) acquired from eight different centers. Images were reconstructed without attenuation or scatter correction (NOACNOSC), with only attenuation correction using the Chang method (ChangACNOSC) or X-ray CT (CTACNOSC), and with both scatter and attenuation correction using the Chang method (ChangACSC) or X-ray CT (CTACSC). These SPECT images were analyzed using the Southampton method. The outcome measure was the specific binding ratio (SBR) in the striatum. These striatal SBRs were calibrated from prior experiments using a striatal phantom. The original SBRs gradually decreased in the order of ChangACSC, CTACSC, ChangACNOSC, CTACNOSC, and NOACNOSC. The SBRs for NOACNOSC were 46% lower than those for ChangACSC. In contrast, the calibrated SBRs were almost equal under no scatter correction (NOSC) conditions. A significant effect of age was found, with an SBR decline rate of 6.3% per decade. In the 30–39 age group, SBRs were 12.2% higher in women than in men, but this increase declined with age and was absent in the 70–79 age group. This study provided a large-scale quantitative database of [123I]FP-CIT SPECT scans from different scanners in healthy controls across a wide age range and with balanced sex representation. The phantom calibration effectively harmonizes SPECT data from different SPECT systems under NOSC conditions. The data collected in this study may serve as a reference database.

Introduction The plasma concentration of beta-amyloid (Aβ) has been considered another biomarker of Alzheimer's disease and was reportedly associated with cortical Aβ accumulation. Methods We analyzed 28 subjects with apolipoprotein E4 (ApoE4; E4 group) and 89 subjects without ApoE4 (non-E4 group) to determine the association between cortical Aβ accumulation by standard uptake value ratio with [ 18 F]florbetapir positron emission tomography and plasma Aβ 1–40 and Aβ 1–42 . Results Aβ 1–42 /Aβ 1–40 correlated significantly with mean regional [ 18 F]florbetapir standard uptake value ratio in the non-E4 group ( R 2 = 0.06, P = .02) but not in the E4 group, and receiver operating characteristic curve analysis for Aβ 1–42 /Aβ 1–40 in the non-E4 group showed sensitivity (92.9%) and specificity (45.9%) with a cutoff value of 0.150 for Aβ positivity. Discussion We verified that the correlation between Aβ 1–42 /Aβ 1–40 and Aβ accumulation differed according to ApoE phenotype. The high sensitivity of plasma Aβ 1–42 /Aβ 1–40 for Aβ positivity in non-E4 subjects indicated a possible role of plasma Aβ 1–42 /Aβ 1–40 as a screening biomarker before amyloid positron emission tomography in clinical settings.

Electroconvulsive therapy (ECT) is an effective treatment for major depression. Previous studies suggested that dopaminergic neurotransmission plays a crucial role in the mechanism of the action of ECT. Since dopamine transporters (DAT) regulate extracellular dopamine concentration, DAT represents an interesting target for the study of the mechanism of action of ECT. Eight inpatients (7 patients with major depressive disorder and 1 patient with bipolar disorder with a DSM-IV diagnosis) received a series of 7-15(11.3±5.2) bilateral ECT sessions.The severity of symptoms was assessed using the 21-item Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression-Severity (CGI-S). All patients were examined with [

Background A recent neurocognitive model of attention-deficit hyperactivity disorder (ADHD) has proposed a primary deficit in reward function as well as in executive function to account for underlying neural substrates of ADHD symptoms. Atomoxetine has been widely used as a non-stimulant medication for ADHD with little abuse liability. Although animal studies have reported that atomoxetine increases extracellular levels of both noradrenaline and dopamine in the prefrontal cortex, which receives input from a mesocorticolimbic pathway involved in reward function, there have been few studies in humans concerning the effects of atomoxetine in terms of reward function. Therefore, we investigated whether a single dose of atomoxetine (acute atomoxetine) affects reward processing in healthy adults. Methods We used functional magnetic resonance imaging and adopted the monetary incentive delay task to separately examine neural responses to monetary reward anticipation in the nucleus accumbens and outcome in the ventral medial prefrontal cortex (vmPFC). The experiment was designed as a randomized, placebo-controlled within-subjects cross-over trial. Fourteen healthy adults completed two series of studies, taking either atomoxetine or placebo. Results Atomoxetine significantly decreased vmPFC activation during gain outcome compared to placebo. In gain anticipation, however, atomoxetine did not show a significant increase in the nucleus accumbens activation compared with placebo. Conclusions These results suggest that atomoxetine affects reward value encoding through selective modulation of vmPFC activity related to reward outcome. Therefore, such modulatory action may partly contribute to a therapeutic effect of atomoxetine for a group of ADHD patients with increased activity in vmPFC.

Bupropion is used for major depressive disorder, smoking cessation aid, and obesity. It blocks reuptake of dopamine and noradrenaline and antagonizes nicotinic acetylcholine receptor. Animal studies showed that bupropion enhanced rewarding effects. In addition, bupropion has the potential to treat patients with reward processing dysfunction. However, neural substrates underlying the bupropion effects on reward function in human subjects are not fully understood. We investigated single-dose administration of bupropion on neural response of reward anticipation in healthy subjects using a monetary incentive delay (MID) task by functional magnetic resonance imaging (fMRI), especially focusing on nucleus accumbens (NAc) activity to non-drug reward stimuli under bupropion treatment. We used a randomized placebo-controlled within-subject crossover design. Fifteen healthy adults participated in two series of an fMRI study, taking either placebo or bupropion. The participants performed the MID task during the fMRI scanning. The effects of bupropion on behavioral performance and blood oxygenation level-dependent (BOLD) signal in NAc during anticipation of monetary gain were analyzed. We found that bupropion significantly increased BOLD responses in NAc during monetary reward anticipation. The increased BOLD responses in NAc were observed with both low and high reward incentive cues. There was no significant difference between placebo and bupropion in behavioral performance. Our findings provide support for the notion that bupropion enhances non-drug rewarding effects, suggesting a possible mechanism underlying therapeutic effects for patients with motivational deficit.

Introduction Bupropion is an antidepressant with less possibility to give rise to emotional blunting as side effect, and it also acts on improving negative self-recognition in a depressive state. Previous neuroimaging studies indicated a change in brain function by facial expression as an effect of antidepressants. As well as facial expression, vocal affective processing is essential for accurately recognizing another’s feelings, but to our knowledge, no study has investigated whether bupropion affects the cerebral function of recognition of auditory affective processing. In this study, we aimed to investigate the acute effect of bupropion on cerebral response to vocal affective processing. Methods Sixteen healthy volunteers (male = 8) participated in this study. With a randomized placebo-controlled within-subject trial, two series of fMRI scans, using either placebo or bupropion (150 mg), were examined. An auditory emotional valence judgement task was performed during fMRI scanning. The acute effects of bupropion on cerebral activation in the emotional circuit and behavioral performance during emotional processing were analyzed. Results Compared with placebo, bupropion caused a significantly greater activation of emotional voices in the left insula and right superior temporal gyrus, whereas the amygdala was not activated. By bupropion, a significantly greater activation of the positive emotional circuit was observed at the superior temporal gyrus and middle frontal gyrus. As for behavioral performance, no significant difference was observed between placebo and bupropion. Conclusions Our findings suggest that bupropion enhances the cerebral response to affective processing, especially positive emotional vocalizations, indicating a possible mechanism underlying the therapeutic effects for patients with depression.

Sixteen healthy volunteers were enrolled and divided into four groups according to the single administration of 10mg or 20mg escitalopram, 50mg sertraline, or 20mg paroxetine. Four positron emission tomography scans with [(11)C]DASB were performed on each subject, the first prior to taking the drug, followed by the others at 4, 24, and 48h after. Serotonin transporter occupancies of the drugs at each time point were calculated. All drugs showed maximum occupancy at 4h after dosing and then decreasing occupancies with time. Escitalopram and sertraline showed high occupancies of 69.1-77.9% at 4h, remaining at 52.8-57.8% after 48h. On the other hand, paroxetine showed relatively low occupancy of 44.6%, then decreasing to 10.3% at 48h. Escitalopram (both 10mg and 20mg) and sertraline (50mg) showed high and sustained occupancy. Paroxetine (20mg) showed relatively low and rapidly decreasing occupancy, possibly due to the low plasma concentration by single dosing schedule. Applying the reported concentration of multiple dosing, 20mg paroxetine will induce over 80% occupancy. The present study suggested that these drugs and doses would be sufficient for the treatment of depression.

Electroconvulsive therapy (ECT) is an effective treatment for major depression. Previous studies suggested that dopaminergic neurotransmission plays a crucial role in the mechanism of the action of ECT. Since dopamine transporters (DAT) regulate extracellular dopamine concentration, DAT represents an interesting target for the study of the mechanism of action of ECT. Eight inpatients (7 patients with major depressive disorder and 1 patient with bipolar disorder with a DSM-IV diagnosis) received a series of 7–15(11.3±5.2) bilateral ECT sessions.The severity of symptoms was assessed using the 21-item Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression-Severity (CGI-S). All patients were examined with [18F]FE-PE2I positron emission tomography (PET) at pre-ECT, after the 10th ECT, and at post-ECT. Striatal DAT-binding potential (BPND) of all patients was reduced, with an average change ratio of DAT-BPND of -13.1±5.6%. In the 2 cases with 15 ECT sessions, the ratio change of DAT-BPND after the 15th ECT was larger than that after the 10th ECT. Also, HDRS and CGI-S were reduced. These results indicate that the dopamine nervous system is part of themechanism of action of ECT.

BACKGROUND Histopathological studies have confirmed that soft drusen contains amyloid-β (Aβ). OBJECTIVE To examine the relationship between the area of soft drusen in the macular area and cerebral Aβ accumulation or plasma Aβ level in elderly persons without dementia. METHODS Fourteen consecutive patients (18 eyes) aged ≥50 years with macular soft drusen were studied prospectively. From color fundus photographs, the area of soft drusen (pixel) within a 6,000 μm diameter with the macula as center was measured. Standard uptake value ratio (SUVR) was obtained from positron emission tomography using florbetapir, which indicates the ratio of cerebral cortical-to-cerebellar Aβ accumulation. Ratio of plasma Aβ1-42 to Aβ1-40 level was calculated. RESULTS Mean age was 73.3±7.6 years. The soft drusen area was 4.32±2.42 mm2. The SUVR was 1.08±0.15. Plasma Aβ1-42/Aβ1-40 ratio was 0.17±0.08. When SUVR ≥1.10 was defined as positive and

The aim of this multicenter trial was to generate a [This study included 510 sets of SPECT data from 256 healthy controls (116 men and 140 women; age range, 30-83 years) acquired from eight different centers. Images were reconstructed without attenuation or scatter correction (NOACNOSC), with only attenuation correction using the Chang method (ChangACNOSC) or X-ray CT (CTACNOSC), and with both scatter and attenuation correction using the Chang method (ChangACSC) or X-ray CT (CTACSC). These SPECT images were analyzed using the Southampton method. The outcome measure was the specific binding ratio (SBR) in the striatum. These striatal SBRs were calibrated from prior experiments using a striatal phantom.The original SBRs gradually decreased in the order of ChangACSC, CTACSC, ChangACNOSC, CTACNOSC, and NOACNOSC. The SBRs for NOACNOSC were 46% lower than those for ChangACSC. In contrast, the calibrated SBRs were almost equal under no scatter correction (NOSC) conditions. A significant effect of age was found, with an SBR decline rate of 6.3% per decade. In the 30-39 age group, SBRs were 12.2% higher in women than in men, but this increase declined with age and was absent in the 70-79 age group.This study provided a large-scale quantitative database of [

Background Blockade of D3 receptor, a member of the dopamine D2-like receptor family, has been suggested as a possible medication for schizophrenia. Blonanserin has high affinity in vitro for D3 as well as D2 receptors. We investigated whether a single dose of 12 mg blonanserin, which was within the daily clinical dose range (i.e., 8–24 mg) for the treatment of schizophrenia, occupies D3 as well as D2 receptors in healthy subjects. Methods Six healthy males (mean 35.7±7.6 years) received 2 positron emission tomography scans, the first prior to taking blonanserin, and the second 2 hours after the administration of a single dose of 12 mg blonanserin. Dopamine receptor occupancies by blonanserin were evaluated by [11C]-(+)-PHNO. Results Occupancy of each region by 12 mg blonanserin was: caudate (range 64.3%–81.5%; mean±SD, 74.3±5.6%), putamen (range 60.4%–84.3%; mean±SD, 73.3%±8.2%), ventral striatum (range 40.1%–88.2%; mean±SD, 60.8%±17.1%), globus pallidus (range 65.8%–87.6%; mean±SD, 75.7%±8.6%), and substantia nigra (range 56.0%–88.7%; mean±SD, 72.4%±11.0%). Correlation analysis between plasma concentration of blonanserin and receptor occupancy in D2-rich (caudate and putamen) and D3-rich (globus pallidus and substantia nigra) regions showed that EC50 for D2-rich region was 0.39 ng/mL (r=0.43) and EC50 for D3-rich region was 0.40 ng/mL (r=0.79). Conclusions A single dose of 12 mg blonanserin occupied D3 receptor to the same degree as D2 receptor in vivo. Our results were consistent with previous studies that reported that some of the pharmacological effect of blonanserin is mediated via D3 receptor antagonism.

Modafinil is a wake-promoting agent and has been reported to be effective in improving attention in patients with attentional disturbance. However, neural substrates underlying the modafinil effects on attention are not fully understood. We employed a functional magnetic resonance imaging (fMRI) study with the attention network test (ANT) task in healthy adults and examined which networks of attention are mainly affected by modafinil and which neural substrates are responsible for the drug effects. We used a randomized placebo-controlled within-subjects cross-over design. Twenty-three healthy adults participated in two series of an fMRI study, taking either a placebo or modafinil. The participants performed the ANT task, which is designed to measure three distinct attentional networks, alerting, orienting, and executive control, during the fMRI scanning. The effects of modafinil on behavioral performance and regional brain activity were analyzed. We found that modafinil enhanced alerting performance and showed greater alerting network activity in the left middle and inferior occipital gyri as compared with the placebo. The brain activations in the occipital regions were positively correlated with alerting performance. Modafinil enhanced alerting performance and increased activation in the occipital lobe in the alerting network possibly relevant to noradrenergic activity during the ANT task. The present study may provide a rationale for the treatment of patients with distinct symptoms of impaired attention.

Objective We compared amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) in subjects clinically diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI), and older healthy controls (OHC) in order to test how these imaging biomarkers represent cognitive decline in AD. Methods Fifteen OHC, 19 patients with MCI, and 19 patients with AD were examined by [18F]florbetapir PET to quantify the standard uptake value ratio (SUVR) as the degree of amyloid accumulation, by MRI and the voxel-based specific regional analysis system for AD to calculate z-score as the degree of entorhinal cortex atrophy, and by mini-mental state examination (MMSE) and Alzheimer's Disease Assessment Scale–cognitive component—Japanese version (ADAS-Jcog) for cognitive functions. Results Both cutoff values for measuring AD-like levels of amyloid (1.099 for SUVR) and entorhinal cortex atrophy (1.60 for z-score) were well differentially diagnosed and clinically defined AD from OHC (84.2% for SUVR and 86.7% for z-score). Subgroup analysis based on beta-amyloid positivity revealed that z-score significantly correlated with MMSE (r = −0.626, p

Modafinil, a wake-promoting drug used to treat narcolepsy, is a dopamine transporter inhibitor and is said to have very low abuse liability; this, however, is still up for debate. We conducted a dopamine transporter (DAT) occupancy study with modafinil (200 or 300mg) in ten healthy volunteers using positron emission tomography (PET) with [ 18 F]FE-PE2I, a new PET radioligand with high affinity and selectivity for the dopamine transporter, to characterize its relation to abuse liability. Mean striatal DAT occupancies were 51.4% at 200 mg and 56.9% at 300 mg. There was a significant correlation between occupancy and plasma concentration, indicating dose dependency of DAT inhibition by modafinil in the striatum, and especially in the nucleus accumbens. This study showed that DAT occupancy by modafinil was close to that of methylphenidate, indicating that modafinil may be near the same level as methylphenidate in relation to abuse liability in terms of dopaminergic transmission.

Objective Dopamine transporter (DAT) density is considered as a marker of pre-synaptic function. Numerous neuroimaging studies have consistently demonstrated an age-related decrease in DAT density in normal human brain. However, the precise degree of the regional decline is not yet clear. The purpose of this study was to evaluate the effect of the normal aging process on DAT densities in human-specific brain regions including the substantia nigra and thalamus using positron emission tomography (PET) with [18F]FE-PE2I, a new PET radioligand with high affinity and selectivity for DAT.

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹⁸F]FMeNER-D₂ to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED₅₀) and concentration (EC₅₀) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

The primary brain structures of reward processing are mainly situated in the mid-brain dopamine system. The nucleus accumbens (NAc) receives dopaminergic projections from the ventral tegmental area and works as a key brain region for the positive incentive value of rewards. Because neurokinin-1 (NK1) receptor, the cognate receptor for substance P (SP), is highly expressed in the NAc, we hypothesized that the SP/NK1 receptor system might play a role in positive reward processing in the NAc in humans. Therefore, we conducted a functional MRI (fMRI) study to assess the effects of an NK1 receptor antagonist on human reward processing through a monetary incentive delay task that is known to elicit robust activation in the NAc especially during gain anticipation. Eighteen healthy adults participated in two series of an fMRI study, taking either a placebo or the NK1 receptor antagonist aprepitant. Behavioural measurements revealed that there was no significant difference in reaction time, hit rate, or self-reported effort for incentive cues between the placebo and aprepitant treatments. fMRI showed significant decrease in blood oxygenation-level-dependent signals in the NAc during gain anticipation with the aprepitant treatment compared to the placebo treatment. These results suggest that SP/NK1 receptor system is involved in processing of positive incentive anticipation and plays a role in accentuating positive valence in association with the primary dopaminergic pathways in the reward circuit.

Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [11C]DASB and (S,S)-[18F]FMeNER-D2, in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED50 was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.

Blonanserin is a novel antipsychotic with high affinities for dopamine D(2) and 5-HT(2A) receptors, and it was recently approved for the treatment of schizophrenia in Japan and Korea. Although double-blind clinical trials have demonstrated that blonanserin has equal efficacy to risperidone, and with a better profile especially with respect to prolactin elevation, its profile of in vivo receptor binding has not been investigated in patients with schizophrenia. Using positron emission tomography (PET), we measured striatal and extrastriatal dopamine D(2) receptor occupancy by blonanserin in 15 patients with schizophrenia treated with fixed doses of blonanserin (ie, 8, 16, and 24 mg/d) for at least 4 weeks before PET scans, and in 15 healthy volunteers. Two PET scans, 1 with [(11)C]raclopride for the striatum and 1 with [(11)C]FLB 457 for the temporal cortex and pituitary, were performed on the same day. Striatal dopamine D(2) receptor occupancy by blonanserin was 60.8% (3.0%) [mean (SD)] at 8 mg, 73.4% (4.9%) at 16 mg, and 79.7% (2.3%) at 24 mg. The brain/plasma concentration ratio calculated from D(2) receptor occupancy in the temporal cortex and pituitary was 3.38, indicating good blood-brain barrier permeability. This was the first study to show clinical daily dose amounts of blonanserin occupying dopamine D(2) receptors in patients with schizophrenia. The clinical implications obtained in this study were the optimal therapeutic dose range of 12.9 to 22.1 mg/d of blonanserin required for 70% to 80% dopamine D(2) receptor occupancy in the striatum, and the good blood-brain barrier permeability that suggested a relatively lower risk of hyperprolactinemia.

Aim The aim of this study was to investigate the influences of menopause on brain morphological changes in schizophrenia using magnetic resonance imaging (MRI). Methods Forty female schizophrenia patients, 20 premenopausal and 20 postmenopausal, and 50 female controls underwent cerebral MRI. Optimized voxel-based morphometry was performed with Statistical Parametric Mapping version 5. Results Compared with controls, regional gray matter reductions in schizophrenia patients were observed in the insula, superior temporal gyrus, anterior cingulate, parahippocampal gyrus, and thalamus. Direct comparison between the patient groups showed that the gray matter of postmenopausal patients was significantly smaller when compared with premenopausal patients in the left middle frontal gyrus, and no region had significantly lower gray matter volume in premenopausal patients relative to postmenopausal patients. Significant negative correlation between gray matter volume and the interval after menopause was found in the right superior frontal gyrus in the postmenopause patient group. Conclusion Differential morphological alterations between postmenopausal and premenopausal schizophrenia patients were observed, suggesting that the female hormone plays a protective role against schizophrenia.

Aim: Somatoform pain disorder is characterized by persistent and chronic pain at one or more sites without an associated general medical condition and in which psychological factors are thought to play a role. This study aimed to investigate the pathological features of somatoform pain disorder localized to the oral region by single photon emission computed tomography (SPECT). Methods: Ten patients (nine females and one male; average age 55.0 ± 14.4 years) having somatoform pain disorder with oral symptoms participated. SPECT was performed using N-isopropyl-4-[123I] iodoamphetamine intravenous injections, and regional cerebral blood flow (rCBF) was assessed by three-dimensional stereotactic surface projections. We also selected 12 healthy individuals (seven females and five males; average age 61.8 ± 13.2 years) to act as controls. Results: Both the patient and control groups showed no atrophy or infarction on CT or magnetic resonance imaging. The patient group showed higher rCBF in the subcortical area, especially in the thalamus and cingulate gyri, than the control group. In contrast, the patient group showed lower rCBF in the bilateral frontal and occipital lobes as well as in the left temporal lobe. Conclusions: These results suggest that the biological process involved in somatoform pain disorder of the oral region is characterized by changes in limbic and cortical functions. The finding that somatoform pain disorder with oral symptoms is associated with brain functional changes will help to develop treatment regimes for this disorder and clarify the underlying pathology.