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Background Although clozapine is effective for treatment-resistant schizophrenia (TRS), the rate of clozapine prescription is still low. Whereas antipsychotic monotherapy is recommended in clinical practice guidelines, the rate of antipsychotic polypharmacy is still high. There is little evidence on whether a clozapine prescription influences changes in the rate of monotherapy and polypharmacy, including antipsychotics and other psychotropics. We therefore hypothesized that the rate of antipsychotic monotherapy in patients with TRS who were prescribed clozapine would be higher than that in patients with schizophrenia who were not prescribed clozapine. Methods We assessed 8306 patients with schizophrenia nationwide from 178 institutions in Japan from 2016 to 2019. We analyzed the psychotropic prescription data at discharge in patients diagnosed with TRS and with no description of TRS (ND-TRS) based on the diagnosis listed in the discharge summary. Results The rate of antipsychotic monotherapy in the TRS with clozapine group (91.3%) was significantly higher than that in the TRS without clozapine group (45.9%; P Conclusions Clozapine prescription could be associated with a high rate of antipsychotic monotherapy. Patients will benefit from the correct diagnosis of TRS and thus from proper clozapine prescription.

Background Polypharmacy of additional psychotropics alongside the main treatment drug (antipsychotics in schizophrenia and antidepressants in major depressive disorder) is common in Japan. Our goal is to align psychotropic prescription in Japan with international standards, while reducing the differences between facilities. To achieve this goal, we aimed to compare prescriptions at the time of hospital admission and discharge. Methods Data on prescriptions at admission and discharge from 2016 to 2020 were collected. We divided the patients into four groups: 1) mono_mono group, monotherapy of the main drug at admission and discharge; 2) mono_poly group, monotherapy at admission and polypharmacy at discharge; 3) poly_poly group, polypharmacy at admission and discharge; and 4) poly_mono group, polypharmacy at admission and monotherapy at discharge. We compared the changes in dosage and number of psychotropics among the four groups. Results For both schizophrenia and major depressive disorder, the patients who received monotherapy with the main drug at admission were likely to receive main drug monotherapy at discharge and vice versa. For schizophrenia, the polypharmacy was prescribed more often in the mono_poly group than that in the mono_mono group. The prescription was not changed at all for more than 10% of the patients. Conclusions It is critical to avoid a polypharmacy regimen to ensure that guideline-compliant treatment is provided. We expect higher rates of monotherapy with the main drug after the EGUIDE lectures. Trial registration:The study protocol was registered in the University Hospital Medical Information Network Registry(UMIN000022645).

Treatment guidelines are designed to assist patients and health care providers and are used as tools for making treatment decisions in clinical situations. The treatment guidelines of the Japanese Society of Mood Disorders establish treatment recommendations for each severity of depression. The individual fitness score (IFS) was developed as a simple and objective indicator to assess whether individual patients are practicing treatment by the recommendations of the depression treatment guidelines of the Japanese Society of Mood Disorders.The EGUIDE project members determined the IFS through the modified Delphi method. In this article, the IFS was calculated based on the treatment of depressed patients treated and discharged between 2016 and 2020 at facilities participating in the EGUIDE project. In addition, we compared scores at admission and discharge.The study included 428 depressed patients (mild n = 22, moderate/severe n = 331, psychotic n = 75) at 57 facilities. The mean IFS scores by severity were statistically significantly higher at discharge than at admission with moderate/severe depression (mild 36.1 ± 34.2 vs. 41.6 ± 36.9, p = 0.49; moderate/severe 50.2 ± 33.6 vs. 55.7 ± 32.6, p = 2.1 × 10-3; psychotic 47.4 ± 32.9 versus 52.9 ± 36.0, p = 0.23).We developed the IFS based on the depression treatment guideline, which enables us to objectively determine how close the treatment is to the guideline at the time of evaluation in individual cases. Therefore, the IFS may influence guideline-oriented treatment behavior and lead to the equalization of depression treatment in Japan, including pharmacotherapy.

Purpose: In the treatment guidelines for major depressive disorder (MDD), the recommended treatment differs based on the severity. However, the type of treatment provided based on the severity of MDD in real-world clinical practice has not been investigated. In this study, we clarified the actual situation of MDD treatment in clinical practice and compared the treatment based on the severity of MDD. Methods: We used data from 1484 patients with MDD at discharge from October 2016 to March 2020. Results: The number of psychotropic prescriptions tended to be lower in those diagnosed with MDD in the severe group compared to in the non-severe group. There were significant differences among the three groups (mild, moderate/severe, and psychotic) in the percentage of patients who were not prescribed antipsychotics (p = 1.9 ×10-6), a combination of antipsychotics and antidepressants (p = 5.0 ×10-4), and the implementation rate of modified electroconvulsive therapy (m-ECT) (p = 3.4 ×10-9). The percentage of patients with a severe diagnosis who underwent m-ECT was higher, which corresponded to the severity. Conclusion: Our findings showed that the use of psychotropics decreased when the severity of MDD was diagnosed, and the rate of a combination of antipsychotics and antidepressants and the implementation rate of m-ECT increased with the severity. However, this study suggests that there is still an evidence-practice gap in the treatment of MDD in Japan, and guidelines are only partially adhered to in the treatment of depression.

Patients with major depressive disorder (MDD) exhibit several clinical symptoms including difficulties in flexible thinking. Flexible thinking mainly relies on a cognitive ability called shifting; however, the mechanisms underlying shifting in patients with MDD have not yet been clarified. Therefore, we conducted a preliminary intervention study to clarify the association between depression and shifting ability. We examined the hemodynamic responses in the frontal regions during the shifting task using functional near-infrared spectroscopy (fNIRS) in 21 patients with MDD who were treated using high-frequency repetitive transcranial magnetic stimulation (rTMS). Behavioral performance on the shifting task did not change between pre- and posttreatments, whereas patients who responded well to rTMS treatment showed a significant decrease in hemodynamic responses posttreatment. On the other hand, the poor responders did not show significant changes in the hemodynamic responses between pre- and posttreatments. These results suggest that the good responders were successfully remedied with rTMS treatment and did not need effortful activity in frontal regions for shifting, which made their brain activity more efficient.

Aim Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the aggregation of amyloid-β and phosphorylated tau proteins. Magnetic resonance imaging (MRI) is a useful means of detecting hippocampal atrophy. However, instead of visual inspection, objective and time-saving tools for automated region of interest (ROI) analysis are needed. Advances in MRI segmentation techniques have enabled a multi-atlas approach with fewer errors than a conventional single-atlas approach. To support the clinical application of multi-atlas segmentation, an automated ROI analytic application consisting of multi-atlas segmentation with joint label fusion and corrective learning was developed: T-Proto. In the present study, we evaluated the inter-method reliability between T-Proto and a reference ROI analytic software, FreeSurfer. Methods This was a database study. MRI data from 30 patients with AD were selected, and the inter-method reliability was assessed in terms of the intra-class correlation coefficient (ICC). A post-hoc comparison according to the severity of AD was also performed. Results Almost all the regional volumes estimated with T-Proto were smaller than those estimated with FreeSurfer. The regional ICC values between the two methods showed moderate to excellent reliability. A post-hoc comparison revealed a similar t-value and effect size between both methods for the hippocampus. Conclusion In the present study, we showed that automated regional analysis using T-Proto was reliable in the hippocampus in terms of ICC, compared with FreeSurfer.

BackgroundAesthetically unappealing adverse periocular reactions to prostaglandin (PG) eye-drops are a major challenge in glaucoma treatment. This study analysed the personality traits of patients with glaucoma based on a five-factor model and examined the associations between these factors and adverse periocular reactions.MethodsOne hundred and forty-seven patients with glaucoma were surveyed anonymously regarding their personality traits and how often adverse periocular reactions were experienced.ResultsThe analysis included 117 valid responses (71 men and 46 women, age: 61.9±11.5 years). Patients who experienced hypertrichosis of the eyelashes scored significantly higher on extraversion (pConclusionThe experience of adverse reactions differed according to patient age and personality traits. Therefore, eye-drops should be chosen based on these factors.Trial registration numberUMIN000035155.

The factors associated with the clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) in patients with major depressive disorder (MDD) remain largely unexplored. Therefore, this study aimed to examine whether rTMS can change the functional laterality of the prefrontal hemodynamic response and whether baseline functional laterality can predict the clinical outcomes of rTMS using functional near-infrared spectroscopy (fNIRS). We included 19 patients with MDD who were treated with high-frequency rTMS. The verbal fluency task was used as the activation task. We calculated the laterality index (LI) based on the task-related oxygenation response in the frontal region. First, the LI was compared before and after rTMS treatment. Second, the reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS) score was compared between the rightward dominance group (pre-LI0) and the leftward dominance group (pre-LI ≥ 0). The findings showed a significant change in the LI after rTMS treatment. The rightward dominance group had a significantly greater reduction in MADRS score than the leftward dominance group. Subsequently, the laterality of the task-related hemodynamic response of the prefrontal region shifted leftward following left high-frequency rTMS treatment. Thus, the pre-LI calculated using fNIRS data is a possible predictor of rTMS outcomes in patients with MDD.

IntroductionRecent studies have shown a high frequency of abnormal electrocardiograms in patients with schizophrenia. The objective of this study was to associate schizophrenia diagnoses with early repolarization patterns in a sample of hospitalized patients from a single hospital in Japan.MethodsWe conducted a retrospective age, sex and coronary risk factors matched case-control study on 85 patients with schizophrenia and 89 controls from medical checkups. First, we compared the presence of early repolarization patterns in both groups. Secondly, we elucidated an association between the presence of an early repolarization pattern and clinical findings in the patients’ groups. We also evaluated J-point elevation patterns.ResultsAs a result, we found that both early repolarization patterns and J-point elevation patterns observed were significantly higher in the schizophrenic group than in the matched control group (early repolarization pattern 23;6 P < 0.001; J-point elevation pattern 34:12; P = 0.001). After multivariable logistic regression among the patients and controls, schizophrenia was the independent predictor for early repolarization pattern (P = 0.001) and J-point elevation (P < 0.001). Among the patients, the independent predictor for early repolarization pattern was psychiatric family history (P = 0.006), while older age (P = 0.038) and psychiatric family history (P = 0.014) were predictors for J-point elevation patterns.ConclusionThese findings suggest that an association between early repolarization pattern or J-point elevation pattern and schizophrenia in a single Japanese center.

IntroductionSchizophrenia is believed to be etiologically associated with environmental factors. Poor parental bonding, especially arising from "low care" and "overprotection," may contribute to the prognosis in patients with psychosis. In the present study, we investigated the associations between the aforementioned two different parental bonding types and the prognosis, in terms of the functional recovery, of patients with schizophrenia.MethodsA total of 89 patients with schizophrenia were recruited, and 79 patients were registered for the study. After the parental bonding types and representative childhood adverse events were assessed, specific items on the PANSS were assessed at 0 and 24 weeks of the study period to define the functional prognosis.ResultsAt the end of the 24-week follow-up period, 36% of the patients were judged as showing recovery from schizophrenia. The score for "overprotective attitude," but not that for "low care," was found to be significantly higher in the non-recovery (defined below) group. Exploratory logistic regression analysis identified only "overprotective attitude" of the parents as being predictive of non-recovery. Moreover, a significant negative correlation was found between "low care" and "overprotective attitude" only in the non-recovery group.ConclusionIn the present study, we showed that an overprotective attitude of the parents was associated with non-recovery in patients with schizophrenia.

The central dopaminergic system is of major importance in the pathophysiology of Parkinson's disease, schizophrenia, and other neuropsychiatric disorders. In the present study, the normative data of dopaminergic neurotransmission functions in the midbrain, consisting of neuromelanin, dopamine synthesis, dopamine transporters and dopamine D2 receptors, were constructed using magnetic resonance (MR) imaging and positron emission tomography (PET). PET studies with L-[β-11C]DOPA, [18F]FE-PE2I and [11C]FLB457 and MRI studies were performed on healthy young men. Neuromelanin accumulation measured by MRI was compared with dopaminergic functions, dopamine synthesis capacity, dopamine transporter binding and dopamine D2 receptor binding measured by PET in the substantia nigra. Although neuromelanin is synthesized from DOPA and dopamine in dopaminergic neurons, neuromelanin accumulation did not correlate with dopamine synthesis capacity in young healthy subjects. The role of dopamine transporters in the substantia nigra is considered to be the transport of dopamine into neurons, and therefore dopamine transporter binding might be related to neuromelanin accumulation; however, no significant correlation was observed between them. A positive correlation between dopamine D2 receptor binding and neuromelanin accumulation was observed, indicating a feedback mechanism by dopaminergic autoreceptors. Discrepancies in regional distribution between neuromelanin accumulation and dopamine synthesis capacity, dopamine transporter binding or dopamine D2 receptor binding were observed in the substantia nigra.

Introduction Neuroticism is a personality trait often described in individuals with glaucoma (GLC), but is not necessarily representative of the total population of patients. There is a population of patients with GLC who are invisible to clinical ophthalmologists; in other words, those who once have been diagnosed with GLC, but spontaneously stop visiting an ophthalmologist. Little is known about their neuroticism personality trait. In the present study, the authors compared the level of neuroticism between patients no longer visiting an ophthalmologist and those who continue visit them regularly. Methods Patients were assigned to two groups according to the duration of their last visit to an ophthalmologist: the Discontinued group included those patients who had not visited an ophthalmologist for the last 6 months, and the Regular Visitor group included those patients who continued to make regular visits to an ophthalmologist. The Japanese version of Ten Items Personality Inventory (TIPI-J), a questionnaire specifically used to assess the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness), was completed by patients through a dedicated website. Results Three-hundred and seventy-three patients with GLC were recruited. The neuroticism score from the TIPI-J in the Discontinued group was significantly lower than that in the Regular Visitor group (7.63 ± 2.23 vs. 8.23 ± 2.21, respectively; P = 0.01). No significant difference was found in the other TIPI-J sub-item scores between the Discontinued and the Regular Visitor groups. Conclusion In this study, the authors showed that neuroticism trait in patients with GLC who have discontinued visiting their ophthalmologists was lower than that in patients who regularly visited them, on the basis of the Big Five personality traits as measured by the TIPT-J. Funding Santen Pharmaceutical Co., Ltd.

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 characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The (18)F-labeled amyloid tracer, [(18)F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1,3-benzoxazol-6-yl)oxy]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [(11)C]Pittsburgh compound B (PIB) and [(18)F]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared.Two PET scans, one of each with [(11)C]PIB and [(18)F]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation.No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [(18)F]FACT studies without partial volume correction, while significant differences were observed in [(11)C]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [(18)F]FACT studies as well as [(11)C]PIB. Relatively lower uptakes of [(11)C]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [(18)F]FACT. Relatively higher uptake of [(11)C]PIB in distribution was observed in the frontal and parietal cortices.Since [(18)F]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [(11)C]PIB and [(18)F]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic and histochemical assays of postmortem AD brain sections.

Purpose [ 11 C]FLB 457, a radioligand with very high affinity and selectivity for dopamine D 2/3 receptors, is used to measure receptor binding in extrastriatal regions showing low density of the receptors. The purpose of this study was to estimate the whole-body biodistribution of radioactivity and the radiation absorbed doses to organs after intravenous injection of [ 11 C]FLB 457 in healthy human subjects. Methods Whole-body images were acquired for 2 h after an injection of [ 11 C]FLB 457 in six healthy humans. Radiation absorbed doses were estimated by the MIRD scheme implemented in OLINDA/EXM 1.1 software. Results Organs with the longest residence time were the liver, lungs, and brain. The organs with the highest radiation doses were the kidneys, liver, and pancreas. The effective dose delivered by [ 11 C]FLB 457 is 5.9 μSv/MBq, similar to those of other 11 C-labeled tracers. Conclusions This effective dose would allow multiple scans in the same individual based on prevailing maximum recommended-dose guidelines in the USA and Europe.

Experiential auditory hallucinations have been reported in patients with epilepsy. We report the case of a 46-year-old woman with a history of more than three years of experiential auditory hallucinations caused by chronic epileptic discharges, which developed after radiotherapy for an oligoastrocytoma in the left temporal lobe. Electroencephalography revealed frequent spikes in the left temporal lobe. In response to clonazepam, but not antipsychotics, her auditory hallucinations almost completely disappeared and spikes were reduced. Her auditory hallucinations exhibited the characteristics of first-rank symptoms of schizophrenia, however, the content of experiential auditory hallucinations endured by our patient suggested an epileptic origin. We believe that the persistent subictal discharges, in combination with hyperexcitability of the temporal neocortex near radiation-induced necrotic lesions, were the cause of the auditory hallucinations.

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.

Dopamine D2/3 receptors (D2/3Rs) have two affinity states for endogenous dopamine, referred to as high-affinity state (D2/3 HIGH), which has a high affinity for endogenous dopamine, and low-affinity state (D2/3 LOW). The density of D2/3 HIGH can be measured with (R)-2-11CH3O-N-n-propylnorapomorphine ([11C]MNPA), while total density of D2/3 HIGH and D2/3 LOW (D2/3Rs) can be measured with [11C]raclopride using positron emission tomography (PET). Thus, the ratio of the binding potential (BP) of [11C]MNPA to that of [11C]raclopride ([11C]MNPA/[11C]raclopride) may reflect the proportion of the density of D2/3 HIGH to that of D2/3Rs. In the caudate and putamen, [11C]MNPA/[11C]raclopride reflects the proportion of the density of D2 HIGH to that of D2Rs. To evaluate the reliability of the PET paradigm with [11C]MNPA and [11C]raclopride, we investigated the test-retest reproducibility of non-displaceable BP (BP ND) measured with [11C]MNPA and of [11C]MNPA/[11C]raclopride in healthy humans. Eleven healthy male volunteers underwent two sets of PET studies on separate days that each included [11C]MNPA and [11C]raclopride scans. BP ND values in the caudate and putamen were calculated. Test-retest reproducibility of BP ND of [11C]MNPA and [11C]MNPA/[11C]raclopride was assessed by intra-subject variability (absolute variability) and test-retest reliability (intraclass correlation coefficient: ICC). The absolute variability of [11C]MNPA BP ND was 5.30 ± 3.96 % and 12.3 ± 7.95 % and the ICC values of [11C]MNPA BP ND were 0.72 and 0.82 in the caudate and putamen, respectively. The absolute variability of [11C]MNPA/[11C]raclopride was 6.11 ± 3.68 % and 11.60 ± 5.70 % and the ICC values of [11C]MNPA/[11C]raclopride were 0.79 and 0.80 in the caudate and putamen, respectively. In the present preliminary study, the test-retest reproducibility of BP ND of [11C]MNPA and of [11C]MNPA/[11C]raclopride was reliable in the caudate and putamen.

The sunk cost effect, an interesting and well-known maladaptive behavior, is pervasive in real life, and thus has been studied in various disciplines, including economics, psychology, organizational behavior, politics, and biology. However, the neural mechanisms underlying the sunk cost effect have not been clearly established, nor have their association with differences in individual susceptibility to the effect. Using functional magnetic resonance imaging, we investigated neural responses induced by sunk costs along with measures of core human personality. We found that individuals who tend to adhere to social rules and regulations (who are high in measured agreeableness and conscientiousness) are more susceptible to the sunk cost effect. Furthermore, this behavioral observation was strongly mediated by insula activity during sunk cost decision-making. Tight coupling between the insula and lateral prefrontal cortex was also observed during decision-making under sunk costs. Our findings reveal how individual differences can affect decision-making under sunk costs, thereby contributing to a better understanding of the psychological and neural mechanisms of the sunk cost effect.

How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness.

Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D2 receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D2 receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D2 receptors have reported inconsistent results regarding regional differences of dopamine D2 receptor occupancy by aripiprazole. To test the hypothesis of preferential binding to extrastriatal dopamine D2 receptors by aripiprazole, we investigated its regional dopamine D2 receptor occupancies in healthy young subjects. Using PET and two radioligands with different affinities for dopamine D2 receptors, [11C]raclopride and [11C]FLB457, striatal and extrastriatal dopamine D2 receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects. Our data showed that dopamine D2 receptor occupancies in the striatum measured with [11C]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [11C]FLB457 ranging from 46.6% to 58.4%. In the present study, preferential extrastriatal dopamine D2 receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D2 receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole.

The central serotonergic (5-HT) system is closely involved in regulating various mental functions such as mood and emotion. In this system, the serotonin transporter (5-HTT) and the 5-HT1A receptor play important roles in the pathophysiology and treatment of mood and anxiety disorders. However, only a few integrated databases have considered the intraindividual relationship between pre- and postsynaptic serotonergic transmission. In the present study, we constructed a database of 5-HTT and 5-HT1A receptors using positron emission tomography (PET) with [11C]DASB and [11C]WAY100635, respectively. Seventeen healthy young men participated in this study. After anatomic standardization of original images, BPND was calculated on a voxel-by-voxel basis using reference tissue methods. The highest binding to 5-HTT was observed in the dorsal raphe nucleus, striatum, and thalamus; moderate binding, in the insula and cingulate cortex; and very low binding, in the cerebral neocortex. In contrast, the highest binding to 5-HT1A receptors was seen in the hippocampal regions, insula, neocortical regions, and dorsal raphe nucleus, and very low binding was found in the thalamus and basal ganglia. These distribution patterns were in agreement with those reported in human postmortem studies and previous PET investigations. In addition, exploratory analysis indicated significant negative correlations between the BPND values with both radiotracers in certain regions of the brain, such as the cingulate, insula, and frontal, temporal and parietal cortices (Pearson's correlation, P < 0.05). These databases facilitate the understanding of the regional distribution of serotonergic neurotransmission function in the living human brain and the pathophysiology of various neuropsychiatric disorders. Synapse, 2011. © 2010 Wiley-Liss, Inc.

Both presynaptic and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET). While both presynaptic and postsynaptic dopaminergic functions would be regulated by corresponding genes and related to personality traits, the relation between presynaptic and postsynaptic functions in terms of interindividual variation has hardly been investigated. In the present study, both striatal dopamine D2receptor binding and endogenous dopamine synthesis rate were measured in the same healthy subjects using PET with [11C]raclopride andl-[β-11C]DOPA, respectively, and these two parameters were compared. Two PET studies with [11C]raclopride andl-[β-11C]DOPA were performed sequentially at rest condition on 14 healthy men. For [11C]raclopride PET, the binding potential was calculated by the reference tissue model method. Forl-[β-11C]DOPA PET, the endogenous dopamine synthesis rate was estimated by graphical analysis. A significant negative correlation was observed between the binding potential of dopamine D2receptors and endogenous dopamine synthesis rate (r= −0.66,p< 0.05). Although the interindividual variation of binding potential of [11C]raclopride would be due to both the interindividual difference in the receptor density and that in the concentration of endogenous dopamine in the synaptic cleft, the negative correlation between parameters for both presynaptic and postsynaptic functions might indicate a compensative relation between the two functions.

Misestimating risk could lead to disadvantaged choices such as initiation of drug use (or gambling) and transition to regular drug use (or gambling). Although the normative theory in decision-making under risks assumes that people typically take the probability-weighted expectation over possible utilities, experimental studies of choices among risks suggest that outcome probabilities are transformed nonlinearly into subjective decision weights by a nonlinear weighting function that overweights low probabilities and underweights high probabilities. Recent studies have revealed the neurocognitive mechanism of decision-making under risk. However, the role of modulatory neurotransmission in this process remains unclear. Using positron emission tomography, we directly investigated whether dopamine D1and D2receptors in the brain are associated with transformation of probabilities into decision weights in healthy volunteers. The binding of striatal D1receptors is negatively correlated with the degree of nonlinearity of weighting function. Individuals with lower striatal D1receptor density showed more pronounced overestimation of low probabilities and underestimation of high probabilities. This finding should contribute to a better understanding of the molecular mechanism of risky choice, and extreme or impaired decision-making observed in drug and gambling addiction.

It is well known that the positron emission tomography (PET) system is subject to inter-scanner differences of regional radioactivity distribution. In the present study, the effect of inter-scanner difference of regional radioactivity on estimated binding potential (BPND) of [11C]FLB457 using the simplified reference tissue model (SRTM) was investigated. Each of the 11 subjects was given two PET scans using [11C]FLB457, one each with both SET-3000 GCT/X (Shimadzu) and with ECAT EXACT HR+ (Siemens/CTI). In order to assess regional differences between the two scanners, estimated BPND values in six volumes of interest (VOIs) by SRTM method were compared in both individual PET space and anatomical template space after anatomical normalization. Statistical voxel-by-voxel paired t test of BPND images between SET-3000 GCT/X and ECAT EXACT HR+ was also performed. Shapes of time–activity curves of the two PET scanners were slightly different in each VOI, with estimated BPND values from ECAT EXACT HR+ appearing greater in the cerebral cortical regions and thalamus than that of SET-3000 GCT/X in both individual PET space and anatomical template space after anatomical normalization. Statistical voxel-by-voxel analysis showed similar tendency to BPND value estimation, with greater BPND values from ECAT EXACT HR+ than from SET-3000 GCT/X. We demonstrated the inter-scanner differences in dopamine D2 receptor binding measured with [11C]FLB457. In particular, statistically significant differences of BPND in certain regions were observed between two PET scanners, despite the subject groups being the same. Our results suggest that we reconsider the effect of the scanner model on the measurement of receptor binding.