Yoshiro Okubo

Objectives: The present study is the first large-scale, multicenter survey on modified electroconvulsive therapy (ECT) in Japan. We aimed to comprehend the current implementation status of ECT based on the annual reports of 2016 from 21 facilities that were certified by the Japanese Society of General Hospital Psychiatry as ECT certified facilities and participated in this multicenter observational study. Methods: We investigated the distributions of diagnosis, gender, and age of patients receiving acute-phase ECT, and the efficacy, safety, and adverse events. Results: The number of patients receiving acute-phase ECT was 524. According to International Classification of Diseases, 10th Revision, 344 patients (65.6%) were diagnosed with mood disorders (F3), 156 patients (29.8%) were diagnosed with schizophrenia and with schizotypal and delusional disorders (F2), and 151 subjects were male and 334 subjects were female. The mean age of patients was 60.4 years (SD 15.9), and patients 60 years or older accounted for 57.9%. Efficacy did not significantly differ between diagnoses, nor between genders. However, the efficacy rate was significantly higher in elderly patients. In acute-phase ECT, 4 severe adverse events occurred. Conclusions: Our multicenter study confirmed that F3 (mood disorders) was the most common indication for ECT at 66%, followed by F2 (schizophrenia, schizotypal, and delusional disorders) at 30%, with no difference in efficacy, indicating that ECT is still performed as 1 of the treatment options for schizophrenia in Japan. The present results suggested that accumulation of annual data from multiple centers can be useful for more effective and safer ECT practices.

Identification of neurobiological mechanisms underlying development of alcohol use disorder is critical to ensuring the appropriate early-phase treatment and prevention of the disorder. To this aim, we tried to elucidate the disturbance of neural functions in heavy drinking, which can lead to alcohol use disorder. Because response inhibition is affected by alcohol use disorder, we examined neural activation and task performance for response inhibition using the Go/No-Go task in an fMRI paradigm in adult non-dependent heavy and light drinkers. We examined the neural activation for error processing and inhibitory control, components of response inhibition. We then investigated the mediating effect of the relevant neural substrate on the relationship between the level of alcohol drinking and task performance using mediation analysis. We found that heavy drinking significantly decreased activation in the left insula during error processing and increased the mean commission error rate for No-Go trials compared with light drinking. Mediation analysis demonstrated full mediation of the left insula activation during error processing for the relationship between drinking level and commission error rate. Our results suggested that left insula activation may be a neural marker pivotal for potential conversion to alcohol use disorder in individuals with high clinical risk such as heavy drinking.

Background/Purpose: 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. Methods: The relationship between D₂ occupancy and plasma blonanserin concentration was analyzed using an E _max model based on data from positron emission tomography study with oral and transdermal blonanserin. D₂ occupancy was simulated using E _max models based on the observed plasma concentrations and the simulated plasma concentrations obtained from population PK model. Results: 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. Conclusions: 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.

Background: Modafinil is effective for improving wakefulness and attention, is used to treat patients with narcolepsy as an approved drug in Japan, and has been reported to be effective in attention-deficit hyperactivity disorder. On the other hand, modafinil has been reported to induce emotional instability including mania, depression, and suicidal ideation. Such side effects may be related to changes in cognitive behavior by the influence of modafinil on cerebral function of emotional recognition. However, the effect of modafinil on the neural basis of emotional processing has not been fully verified. We aimed to clarify the effects of modafinil on the neural basis of auditory emotional processing by functional magnetic resonance imaging.Methods: This study adopted a placebo-controlled within-subject cross-over design. The data of 14 subjects were finally analyzed. The effect of modafinil on cerebral activation and task performance during an emotional judgement task was analyzed.Results: Accuracy of the task decreased significantly and response time of emotional judgement was significantly delayed by modafinil compared with placebo. Right thalamic activation in auditory emotional processing was significantly less in the modafinil group than the placebo group. In addition, reduction of right thalamic activation by modafinil was positively correlated with the decrease in accuracy of emotional judgement.Conclusions: Our findings suggest that modafinil could act on the right thalamus, changing the behavior and brain function associated with auditory emotional processing. These results indicate that modafinil could change emotional recognition by reducing emotional activation related to social communication.

Aim: Anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) is known as a useful application 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 the 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 (i) performance and accuracy of implicit/explicit motor learning task (serial reaction time task/sequential finger‐tapping task), and (ii) cerebral activation while the subjects were performing the VFT by using a functional MRI protocol of a randomized sham‐controlled, within‐subjects crossover design.Results: Reaction times of the implicit motor learning task were significantly faster with tDCS in comparison with the sham. Further, language‐related left prefrontal‐parahippocampal‐parietal activation was significantly less with tDCS compared with the sham. Significant correlation was observed between shortened response time in serial reaction time task and decreased cerebral activation during VFT with 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.

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 (BP_ND) 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 BP_ND 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 BP_ND of olanzapine condition as baseline. Conclusions: Our study confirmed that blonanserin occupied both D₂ and D₃ receptors in patients with schizophrenia.

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 [¹⁸F]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 [¹⁸F]FE‐PE2I.Methods: Eleven geriatric patients with severe MDD and 27 healthy controls underwent PET with [¹⁸F]FE‐PE2I, which has high affinity and selectivity for DAT. Binding potentials (BP_ND) in the striatum (caudate and putamen), nucleus accumbens (NAc), and substantia nigra were calculated. BP_ND values were compared between MDD patients and healthy controls.Results: MDD patients showed significantly lower DAT BP_ND in the NAc (P = 0.009), and there was a trend of lower BP_ND 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.

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. 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. 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). 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.