Naohisa Tsujino

Abnormality of circadian rhythm accompanied by an increase in frontal cortex serotonin in animal model of autism.

Several clinical reports have indicated that autistic patients often show disturbance of the circadian rhythm, which may be related to dysfunction of the serotonergic system in the brain. Using rats exposed prenatally to valproic acid (VPA) as an animal model of autism, we examined locomotor activity and feeding under a reversed 12-h light/dark cycle, and found disturbance of the circadian rhythm characterized by frequent arousal during the light/sleep phase. In addition, measurement of brain serotonin (5-HT) level using in vivo microdialysis showed that the brain 5-HT level in VPA-exposed rats was significantly higher than that in control rats. These results suggest that a higher brain 5-HT level might be responsible for the irregular sleep/awake rhythm in autism.

Augmented brain 5-HT crosses the blood–brain barrier through the 5-HT transporter in rat

The present study re‐evaluated an existing notion that serotonin (5‐hydroxytryptamine; 5‐HT) could not cross the brain to the circulating blood via the blood–brain barrier (BBB). To elevate brain 5‐HT alone, 5‐hydroxytryptophan (5‐HTP; 30–75 mg/kg) was administrated intravenously to anaesthetized rats that had undergone gastrointestinal and kidney resections along with liver inactivation (organs contributing to increasing blood 5‐HT after 5‐HTP administration). A microdialysis method and HPLC system were used to determine the brain 5‐HT levels in samples collected from the frontal cortex. Blood 5‐HT levels were determined from whole blood, not platelet‐poor plasma, collected from the central vein. We found that blood 5‐HT levels showed a significant augmentation whenever brain 5‐HT levels were significantly elevated after the administration of 5‐HTP in those rats with the abdominal surgical procedures. This elevation was abolished after pretreatment with a selective serotonin reuptake inhibitor (fluoxetine; 10 mg/kg i.v.), although brain 5‐HT levels remained augmented. These results indicate that augmented brain 5‐HT can cross the BBB through the 5‐HT transporter from the brain to the circulating blood.

Swim stress exaggerates the hyperactive mesocortical dopamine system in a rodent model of autism.

Several clinical reports have suggested that there is a hyperactivation of the dopaminergic system in people with autism. Using rats exposed prenatally to valproic acid (VPA) as an animal model of autism, we measured dopamine (DA) levels in samples collected from the frontal cortex (FC) using in vivo microdialysis and HPLC. The basal DA level in FC was significantly higher in VPA-exposed rats relative to controls. Since the mesocortical DA system is known to be sensitive to physical and psychological stressors, we measured DA levels in FC before, during, and after a 60-min forced swim test (FST). There were further gradual increases in FC DA levels during the FST in the VPA-exposed rats, but not in the control rats. Behavioral analysis during the last 10 min of the FST revealed a significant decrease in active, escape-oriented behavior and an increase in immobility, which is thought to reflect the development of depressive behavior that disengages the animal from active forms of coping with stressful stimuli. These results suggest that this rodent model of autism exhibits a hyperactive mesocortical DA system, which is exaggerated by swim stress. This abnormality may be responsible for depressive and withdrawal behavior observed in autism.

Differential impacts of duration of untreated psychosis (DUP) on cognitive function in first-episode schizophrenia according to mode of onset

BACKGROUND The mode of onset and the course of schizophrenia illness exhibit substantial individual variations. Previous studies have pointed out that the mode of onset affects the duration of untreated psychosis (DUP) and clinical outcomes, such as cognitive and social functioning. This study attempted to clarify the association between the DUP and clinical features, taking the different modes of onset into consideration, in a prospective longitudinal study examining patients with first-episode schizophrenia. METHODS This study was conducted in six areas of Japan. Patients with first-episode schizophrenia were followed for over 18 months. Cognitive function, psychopathology, and social functioning were assessed at baseline and at 6, 12, and 18-month follow-up points. RESULTS We identified 168 patients and sufficient information was available to determine the DUP and the mode of onset for 156 patients (92.9%): 79 had an acute onset, and 77 had an insidious onset. The DUP was significantly associated with quality of life (QOL), social functioning, and cognitive function at most of the follow-up points in the insidious-onset group. The DUP and negative symptoms at baseline were significant predictors of cognitive function at the 18-month follow-up in the insidious-onset group. CONCLUSIONS The present results further support the hypothesis that the DUP affects QOL, social functioning, and cognitive function over the course of illness, especially in patients with an insidious onset. Effective strategies for detecting and caring for individuals with insidious onset early during the course of schizophrenia will be essential for achieving a full patient recovery.

Cerebral blood flow changes in very-late-onset schizophrenia-like psychosis with catatonia before and after successful treatment.

The purpose of the present study was to investigate regional cerebral blood flow (rCBF) changes in a patient with very‐late‐onset schizophrenia‐like psychosis (VLOS) with catatonia. A 64‐year‐old woman developed catatonia after experiencing persecutory delusions. The patients rCBF was examined using single photon emission computed tomography (SPECT) with easy Z‐score imaging system. Before treatment, hypoperfusion was observed in the striatum and the thalamus, whereas hyperperfusion was observed in the left lateral frontal cortex and the left temporal cortex. After treatment, the disproportions in rCBF disappeared, and hyperperfusion was observed in the motor cortex. Sequential SPECT findings suggest that rCBF abnormalities may be correlated with the symptomatology of catatonia in patients with VLOS.

Poor outcome associated with symptomatic deterioration among help-seeking individuals at risk for psychosis: a naturalistic follow-up study

It remains debatable whether early intervention for psychosis is capable of meeting the needs of at‐risk subjects. The aims of this study were to describe the actual impact of interventions on subjective difficulties and to explore the factors that may be associated with a poor outcome.

Characteristics of motivation and their impacts on the functional outcomes in patients with schizophrenia

BACKGROUND Deficits of motivation have been considered to be a core feature of schizophrenia, and recent studies have begun to reveal the biological and psychological characteristics and mechanisms underlying the deficits in motivation in schizophrenia patients. The aims of the present study were to investigate the characteristics of motivation in schizophrenia patients using the General Causality Orientations Scale (GCOS), and the impacts of motivational orientations on the functional outcomes in schizophrenia patients. METHODS A total of 53 outpatients with schizophrenia and 38 healthy controls were recruited for this study. The GCOS was used to assess individual tendencies in respect of three different motivational orientations: the autonomy, controlled, and impersonal orientations, corresponding to intrinsic motivation, extrinsic motivation, and amotivation, respectively. The cognitive functioning, psychiatric symptoms, social functioning, and quality of life of the subjects were also assessed. RESULTS The score for autonomy orientation was significantly lower in the patient group than that in the control group, while no significant differences were found between the two groups in respect of the scores for the other two orientations. The autonomy orientation was associated with various clinical variables, and regression analysis identified as one of the variables with the highest predictive accuracy for social functioning. CONCLUSIONS Intrinsic motivation measured by the GCOS in schizophrenia patients was significantly lower than that in healthy controls. The deficits of intrinsic motivation were broadly associated with the clinical features and were a determinant of social functioning. Development of treatments for enhancing intrinsic motivation would be essential for functional recovery in schizophrenia patients.

Cognitive and Behavioral Skills Exercises Completed by Patients with Major Depression During Smartphone Cognitive Behavioral Therapy: Secondary Analysis of a Randomized Controlled Trial

Background A strong and growing body of evidence has demonstrated the effectiveness of cognitive behavioral therapy (CBT), either face-to-face, in person, or as self-help via the Internet, for depression. However, CBT is a complex intervention consisting of several putatively effective components, and how each component may or may not contribute to the overall effectiveness of CBT is poorly understood. Objective The aim of this study was to investigate how the users of smartphone CBT use and benefit from various components of the program. Methods This is a secondary analysis from a 9-week, single-blind, randomized controlled trial that has demonstrated the effectiveness of adjunctive use of smartphone CBT (Kokoro-App) over antidepressant pharmacotherapy alone among patients with drug-resistant major depressive disorder (total n=164, standardized mean difference in depression severity at week 9=0.40, J Med Internet Res). Kokoro-App consists of three cognitive behavioral skills of self-monitoring, behavioral activation, and cognitive restructuring, with corresponding worksheets to fill in. All activities of the participants learning each session of the program and completing each worksheet were uploaded onto Kokoro-Web, which each patient could use for self-check. We examined what use characteristics differentiated the more successful users of the CBT app from the less successful ones, split at the median of change in depression severity. Results A total of 81 patients with major depression were allocated to the smartphone CBT. On average, they completed 7.0 (standard deviation [SD] 1.4) out of 8 sessions of the program; it took them 10.8 (SD 4.2) days to complete one session, during which they spent 62 min (SD 96) on the app. There were no statistically significant differences in the number of sessions completed, time spent for the program, or the number of completed self-monitoring worksheets between the beneficiaries and the nonbeneficiaries. However, the former completed more behavioral activation tasks, engaged in different types of activities, and also filled in more cognitive restructuring worksheets than the latter. Activities such as “test-drive a new car,” “go to a coffee shop after lunch,” or “call up an old friend” were found to be particularly rewarding. All cognitive restructuring strategies were found to significantly decrease the distress level, with “What would be your advice to a friend who has a similar problem?” found more helpful than some other strategies. Conclusions The CBT program offered via smartphone and connected to the remote server is not only effective in alleviating depression but also opens a new avenue in gathering information of what and how each participant may utilize the program. The activities and strategies found useful in this analysis will provide valuable information in brush-ups of the program itself and of mobile health (mHealth) in general. Trial Registration Japanese Clinical Trials Registry UMIN CTR 000013693; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ ctr_view.cgi?recptno=R000015984 (Archived by WebCite at http://www.webcitation.org/6u6pxVwik)

Longitudinal study examining abnormal white matter integrity using a tract-specific analysis in individuals with a high risk for psychosis

Although volume reductions in the grey matter have been previously observed in individuals with an at‐risk mental state (ARMS) for psychosis, the features of white matter integrity and their correlation with psychiatric symptoms remain unclear.

School mental healthcare services using internet‐based cognitive behaviour therapy for young male athletes in Japan

Preventive intervention and treatment using internet‐based cognitive behaviour therapy (iCBT) can be easily administered to school students, as they are quite familiar with internet tools. This study aims to investigate the effectiveness and contribution of iCBT to mental healthcare in a school setting.