mHealth Intervention to Promote Physical Activity Among Employees Using a Deep Learning Model for Passive Monitoring of Depression and Anxiety: Single-Arm Feasibility Trial.

BACKGROUND: Physical activity effectively prevents depression and anxiety. Although mobile health (mHealth) technologies offer promising results in promoting physical activity and improving mental health, conflicting evidence exists on their effectiveness, and employees face barriers to using mHealth services. To address these problems, we recently developed a smartphone app named ASHARE to prevent depression and anxiety in the working population; it uses a deep learning model for passive monitoring of depression and anxiety from information about physical activity. OBJECTIVE: This study aimed to preliminarily investigate (1) the effectiveness of the developed app in improving physical activity and reducing depression and anxiety and (2) the app's implementation outcomes (ie, its acceptability, appropriateness, feasibility, satisfaction, and potential harm). METHODS: We conducted a single-arm interventional study. From March to April 2023, employees aged ≥18 years who were not absent were recruited. The participants were asked to install and use the app for 1 month. The ideal usage of the app was for the participants to take about 5 minutes every day to open the app, check the physical activity patterns and results of an estimated score of psychological distress, and increase their physical activity. Self-reported physical activity (using the Global Physical Activity Questionnaire, version 2) and psychological distress (using the 6-item Kessler Psychological Distress Scale) were measured at baseline and after 1 month. The duration of physical activity was also recorded digitally. Paired t tests (two-tailed) and chi-square tests were performed to evaluate changes in these variables. Implementation Outcome Scales for Digital Mental Health were also measured for acceptability, appropriateness, feasibility, satisfaction, and harm. These average scores were assessed by comparing them with those reported in previous studies. RESULTS: This study included 24 employees. On average, the app was used for 12.54 days (44.8% of this study's period). After using the app, no significant change was observed in physical activity (-12.59 metabolic equivalent hours per week, P=.31) or psychological distress (-0.43 metabolic equivalent hours per week, P=.93). However, the number of participants with severe psychological distress decreased significantly (P=.01). The digitally recorded duration of physical activity increased during the intervention period (+0.60 minutes per day, P=.08). The scores for acceptability, appropriateness, and satisfaction were lower than those in previous mHealth studies, whereas those for feasibility and harm were better. CONCLUSIONS: The ASHARE app was insufficient in promoting physical activity or improving psychological distress. At this stage, the app has many issues that are to be addressed in terms of both implementation and effectiveness. The main reason for this low effectiveness might be the poor evaluation of the implementation outcomes by app users. Improving acceptability, appropriateness, and satisfaction are identified as key issues to be addressed in future implementation. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000050430; https://tinyurl.com/mrx5ntcmrecptno=R000057438.

Influence of maltreatment, bullying, and neurocognitive impairment on recidivism in adolescents with conduct disorder: A 3-Year prospective study.

We sought to clarify the influence of family developmental conditions (e.g., adverse childhood experiences: ACEs), peer relationships (e.g., bullying), and neurocognitive impairment on recidivism in adolescents with conduct disorder (CD). We interviewed 290 adolescents with CD (265 males, 25 females) who had been admitted to a juvenile justice assessment center for the first time about their offense(s), onset of delinquency, ACEs, and peer relationships. The participants also completed tests of neurocognitive activities and self-report symptom measures: the Symbol Digit Modalities Test (SDMT), the Memory Updating test for the assessment of attention, the Adolescent Dissociative Experiences Scale (A-DES) for the assessment of dissociation, and the Barratt Impulsiveness Scale 11th version (BIS-11) for the assessment of impulsivity. After the family court judgement and discharge, the participants were followed for 3 years. Readmissions to the center during the follow-up period were considered cases of "recidivism." During the follow-up, 102 (35.2%) participants were readmitted to the center. A survival analysis (Cox proportional hazard model) showed that lower age, bullying (as the perpetrator), and impaired cognitive function (e.g., a lower SDMT score) significantly increased recidivism, whereas bullying (as both victim and perpetrator) decreased recidivism. ACEs showed no clear effect on recidivism. Lower age and impaired cognitive function appear to predispose adolescent first-time offenders with CD to recidivism. However, the peer bullying analysis showed that being a perpetrator positively influenced recidivism, whereas being both a victim and a perpetrator negatively influenced recidivism. Further research considering the heterogeneity and comorbidity of CD could clarify bullying's influence on recidivism.

Impaired executive function in 14- to 16-year-old boys with conduct disorder is related to recidivism: A prospective longitudinal study.

BACKGROUND: Several studies have suggested a relationship between cognitive impairment and recidivism, but most have adopted a retrospective design. AIM: The aim of this study was to test for any relationship between impaired executive function in adolescents with conduct disorder and subsequent recidivism up to 3 years later. METHOD: In this prospective cohort study, 221 male adolescents with conduct disorder, admitted to a juvenile justice assessment centre for the first time, were interviewed about their offence, age, onset of delinquency and family history. They completed the Wisconsin Card Sorting Test (Keio version) (KWCST) and the Iowa gambling task. Scores were compared between those who subsequently re-offended and those who did not. RESULTS: Seventy-six (34%) participants re-offended. There was no direct difference between groups in executive function, but there were age differences both in executive function and in recidivism. Multivariate logistic regression analysis indicated that the variables, which were independently associated with recidivism, were younger age, change in the person who brought up the child, and fewer (≤4) categories achieved on the KWCST. Recidivists were about twice as likely as single offenders to have achieved four categories or less on the KWCST (odds ratio 2.2, 95% confidence interval 1.1-4.4). CONCLUSIONS: Impaired executive function appears to predispose to recidivism among young first-time male offenders with conduct disorder. Our findings also suggest that further precise assessments of environmental stress on developing neurocognitive function could clarify the background of antisocial behaviour. © 2016 The Authors. Criminal Behaviour and Mental Health Published by John Wiley & Sons Ltd.

Long-lasting effects of inescapable-predator stress on brain tryptophan metabolism and the behavior of juvenile mice.

The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase, is the main tryptophan (TRP) metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. We investigated the influence of inescapable-predator (rat) stress on behavior and brain TRP metabolism in mice. Male ICR mice (4W) were exposed to 20-min inescapable-predator stress. Behavior on an elevated plus-maze, and TRP, KYN, and 5-HT levels in the prefrontal cortex, hippocampus, amygdala, and dorsal raphe nuclei were measured 1 and 4 weeks after stress exposure. Predator stress increased the number of open-arm entries (NOA) 4 weeks after stress exposure without altering the number of closed-arm entries (NCA). Thus, the open/closed-arm entry ratio (NOA/NCA) increased after stress exposure. Predator stress increased KYN levels in the prefrontal cortex (until 4 weeks after stress exposure) and dorsal raphe nuclei (for 1 week after stress exposure), decreased 5-HT levels in all brain regions (until 4 weeks after stress exposure). Thus, predator stress increased the KYN/5-HT ratio in all regions, in particular in the prefrontal cortex and hippocampus until 4 weeks after stress exposure. Predator stress shifted the balance between the KYN and 5-HT pathways to the KYN pathway, and induced behavioral disinhibition.

Differences in frontal lobe function between violent and nonviolent conduct disorder in male adolescents.

AIMS: The objective of the present study was to investigate the differences in frontal lobe function between violent and nonviolent male adolescents with conduct disorder. METHODS: A total of 309 male adolescents who had been admitted to the Nagoya Juvenile Classification Home participated. The participants were divided into two groups, a violent group composed of individuals who had committed violence against others, and a nonviolent group. The subjects were given the Wisconsin card sorting test (Keio version: KWCST) and the Iowa Gambling task. The presence of violent cases was analyzed in terms of age, family history (crime, drug abuse/dependence, alcohol-related disorder, and psychiatric treatment), experience of being abused by their parents or by the persons who were responsible for raising them, as well as categories achieved (CA) of KWCST (< or =4, >4) and total selection of disadvantage cards of Iowa Gambling task (> or =50, <50). RESULTS: Multivariate logistic regression analyses indicated that a family history of drug abuse/dependence (odds ratio = 0.3, 95% confidence interval = 0.1-0.9) and a CA of the KWCST (odds ratio = 1.8, 95% confidence interval = 1.0-3.1) were significantly associated with violence. CONCLUSIONS: An impaired rate of CA of the KWCST was related to violence, whereas a family history of drug abuse/dependence was related to nonviolence in male adolescents with conduct disorder.

Shifting the balance of brain tryptophan metabolism elicited by isolation housing and systemic administration of lipopolysaccharide in mice.

The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase, is a key tryptophan (TRP) metabolic pathway. It shares TRP mainly with the serotonin (5-HT) pathway. Activation of the KYN pathway by stimulation of the inflammatory response system (IRS) is known to induce depressive symptoms. Thus, we considered that shifting the balance between the KYN and 5-HT systems in the brain to the KYN pathway closely relate to the etiology of depression. In the present study, we investigated the influence of environmental risk factors for depression, such as social isolation and activation of the IRS, on brain TRP metabolism. Male ICR mice (postnatal day 21) were divided into two housing conditions, isolation and group housing, reared for 4 weeks, and then given an intraperitoneal injection of lipopolysaccharide (LPS). We measured the TRP, KYN, and 5-HT levels in the prefrontal cortex, hippocampus, amygdala, and dorsal raphe nuclei. Isolation housing decreased the KYN/5-HT ratio in the amygdala and dorsal raphe nuclei. LPS increased the KYN/5-HT ratio in all regions except the dorsal raphe nuclei. Thus, isolation housing shifted the balance between the KYN and 5-HT pathways to the 5-HT pathway, whereas systemic administration of LPS shifted it to the KYN pathway.

A link between stress and depression: shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression.

Alteration of tryptophan (TRP) metabolism elicited by proinflammatory cytokines has gained attention as a new concept to explain the etiological and pathophysiological mechanisms of major depression. The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase (IDO), is the main TRP metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. Proinflammatory cytokines induce IDO under stress, promote the KYN pathway, deprive the 5-HT pathway of TRP, and reduce 5-HT synthesis. The resultant decrease in 5-HT production may relate to the monoamine hypothesis of major depression. Furthermore, metabolites of the KYN pathway have neurotoxic/neuroprotective activities; 3-hydroxykynurenine and quinolinic acid are neurotoxic, whereas kynurenic acid is neuroprotective. The hippocampal atrophy that appears in chronic depression may be associated with imbalances in neurotoxic/neuroprotective activities. Because proinflammatory cytokines also activate the hypothalamo-pituitary-adrenal (HPA) axis, these imbalances may inhibit the hippocampal negative feedback system. Thus, changes in the TRP metabolism may also relate to the HPA axis-hyperactivity hypothesis of major depression. In this article, we review the changes in TRP metabolism by proinflammatory cytokines under stress, which is assumed to be a risk factor for major depression, and the relationship between physiological risk factors for major depression and proinflammatory cytokines.

Changes in brain tryptophan metabolism elicited by ageing, social environment, and psychological stress in mice.

The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase (IDO), is a tryptophan (TRP) metabolic pathway. It shares TRP with the serotonin (5-hydroxytryptamine, 5-HT) pathway. In major depression, activation of the KYN pathway may deplete 5-HT. In the present study we investigated the influence of various risk factors for depression, such as ageing, social isolation and psychological stress, on TRP metabolism. Male ICR mice (postnatal day, PND, 21) were divided into two housing conditions, isolation and group housing, reared for 4 weeks (young adult) or 5 months (adult) and exposed to novelty stress. We measured TRP, KYN and 5-HT contents in the prefrontal cortex, hippocampus, amygdala and dorsal raphe nuclei to investigate the balance between the KYN and 5-HT pathways. Ageing decreased TRP and KYN and increased 5-HT. Thus, ageing shifted the balance to the latter. In the younger group, social isolation decreased TRP and KYN and increased the 5-HT/TRP ratio, whereas novelty stress increased TRP and KYN and decreased the 5-HT/TRP ratio. Thus, social isolation shifted the balance to the latter, whereas novelty stress shifted it to the former. In the older group, these effects were restricted to specific brain regions. Ageing and social isolation counteracted novelty stress effects on TRP metabolism.

Association of SOX10 with schizophrenia in the Japanese population.

BACKGROUND: Microarray studies of schizophrenic brains revealed decreases in the expression of myelin and oligodendrocyte-related genes. Of these genes, sex-determining region Y-box 10 (SOX10) is a major transcription factor modulating the expression of proteins involved in neurogenesis and myelination. The SOX10 gene is located on chromosome 22q13.1, a region repeatedly reported to show positive signals in linkage studies on schizophrenia. OBJECTIVE: This study was conducted to clarify the exact role of SOX10 in the pathophysiology of schizophrenia. METHODS: We performed an association analysis of SOX10 in a Japanese population of 915 schizophrenic patients and 927 controls. Genotyping was carried out using polymerase chain reaction restriction fragment length polymorphism. MAIN RESULTS: One single nucleotide polymorphism of the SOX10 gene (rs139,887) was selected as a haplotype tag single nucleotide polymorphism using 96 controls. A significant association was observed in the genotype and allelic frequency of this single nucleotide polymorphism between schizophrenic patients and controls (P=0.025 and P=0.009, respectively). Especially, a significant association was found in male patients, but not female patients. We also performed a mutational search of the whole coding region, branch site, and promoter region of SOX10 in 96 schizophrenic patients, but no potential functional polymorphisms were detected. CONCLUSION: This study suggests that the SOX10 gene is related to the development of schizophrenia in the Japanese population.

Suppressive effect of paroxetine, a selective serotonin uptake inhibitor, on tetrahydrobiopterin levels and dopamine as well as serotonin turnover in the mesoprefrontal system of mice.

Tetrahydrobiopterin (BH(4)) is a coenzyme of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), which are rate-limiting enzymes of monoamine biosynthesis. According to the monoamine hypothesis of depression, antidepressants will restore the function of the brain monoaminergic system and the BH(4) concentration. In the present study, we investigated the effect of paroxetine, a selective serotonin reuptake inhibitor (SSRI), on the BH(4) levels and dopamine (DA) and serotonin (5-HT) turnover in the mesoprefrontal system, incorporating two risk factors of depression, social isolation and acute environmental change. Male ddY mice (8W) were divided into two housing groups, i.e., group-housing (eight animals per cage; 28 days), and isolation-housing (one per cage; 28 days), being p.o.-administered paroxetine (5 or 10 mg/kg; days 15-28), and exposed to a 20-min novelty stress (day 28). The levels of BH(4), DA, homovanilic acid (HVA), 5-HT, and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the prefrontal cortex and midbrain. In both the regions, novelty stress significantly increased BH(4) levels under the isolation-housing condition, whereas these levels were decreased under the group-housing condition. Thus, social isolation altered the neurochemical response to novelty stress. Paroxetine significantly decreased BH(4) levels under the isolation-housing condition, whereas decreased HVA/DA and 5-HIAA/5-HT ratios were observed under the group-housing condition. Thus, social isolation may have influenced the suppressive effects of paroxetine on BH(4) levels as well as exerted an influence on DA and 5-HT turnover. We replicated our recent findings that SSRI, fluvoxamine, suppressed BH(4) levels, as well as DA and 5-HT turnover in the mouse mesoprefrontal system.

Prevalence and profile of methamphetamine users in adolescents at a juvenile classification home.

The objective of the present study was to investigate the prevalence and risk factors of methamphetamine use in adolescents at a juvenile classification home. The present subjects were 1362 adolescents (1172 male and 190 female) who had been admitted to the Nagoya Juvenile Classification Home. The participants were divided into two groups, a methamphetamine user group and a control group, based on history of methamphetamine use. The presence of methamphetamine use was analyzed in terms of gender, age, number of admissions, violence (types of crime), history of psychiatric treatment, family history (crime, drug misuse and/or alcohol-related disorder), and experience of being abused by their parents or by the persons who were responsible for raising them. The prevalence of methamphetamine use was 6.8% (93/1362). Multivariate logistic regression analyses indicated that gender (female; odds ratio [OR]: 8.1; 95% confidence interval [CI]: 4.6-14.3), age (OR: 1.8, 95%CI: 1.5-2.1), number of admissions (>2, OR: 2.9, 95%CI: 1.8-4.8), violence (OR: 0.4, 95%CI: 0.2-0.7), history of psychiatric treatment (OR: 8.7, 95%CI: 4.0-19.0), and family history of drug misuse (OR: 4.0, 95%CI: 1.6-9.6) were all significantly associated with methamphetamine use. Approximately 7% of participants used methamphetamine. Female gender was a risk factor. Higher age and multiple admissions suggest the persistency and repetition of delinquency. Methamphetamine users were less violent than control subjects. Psychosocial environment (family history of drug misuse) and psychiatric problems (history of psychiatric treatment) were also related to methamphetamine use.

Association between chromogranin A gene polymorphism and schizophrenia in the Japanese population.

It has been reported that expression of the chromogranin A (CHGA) gene is reduced in the prefrontal cortex and cerebrospinal fluid of patients with schizophrenia. Single-marker and haplotype analyses of SNPs within the CHGA gene were performed in 633 subjects with schizophrenia and 589 healthy controls. A significant association with schizophrenia was observed to one SNP marker, rs9658635 (p=0.0269), and with a 2 marker haplotype (p=0.0016). Significant association of rs9658635 was then replicated in a second independent cohort (377 schizophrenia and 338 control samples) (p=0.007). These results suggest that the CHGA gene is associated with the risk of developing schizophrenia in the Japanese population.

Influence of history of head trauma and epilepsy on delinquents in a juvenile classification home.

Juvenile delinquents often show poor impulse control and cognitive abnormalities, which may be related to disturbances in brain development due to head trauma and/or epilepsy. The aim of the present study was to examine the influence of head trauma and/or epilepsy on delinquent behavior. We examined 1,336 juvenile delinquents (1,151 males and 185 females) who had been admitted to the Nagoya Juvenile Classification Home, Aichi, Japan. Among them, 52 subjects with a history of epilepsy, convulsion or loss of consciousness, head injury requiring neurological assessment and/or treatment, or neurosurgical operation (head trauma/epilepsy group), were examined by electroencephalography and compared to subjects without these histories (control group) with respect to types of crime, history of amphetamine use, psychiatric treatment, child abuse, and family history. Among the 52 subjects, 43 (82.7%) showed abnormal findings. The head trauma/epilepsy group had significantly higher rates of psychiatric treatment (P<0.0001, OR=16.852, 95% CI=8.068-35.199) and family history of drug abuse (P<0.05, OR=2.303, 95% CI=1.003-5.290). Furthermore, the percentage of members who were sent to juvenile training school by the family court was significantly higher in the head trauma/epilepsy group (72.5%) than in the control group (38.9%, P<0.0001). The juvenile delinquents who had a history of head trauma and/or epilepsy showed a high prevalence of electroencephalograph abnormality, and higher rates of psychiatric treatment and family history of drug abuse, and were more likely to be sent to juvenile training school by the family court.

Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood-brain barrier.

The serious and characteristic side effects of interferon-alpha (IFN-alpha) therapy on the central nervous system, resulting in such problems as affective disorders or parkinsonism, have led us to investigate the biochemical mechanism of the effects of IFN-alpha on the monoaminergic neurotransmitter system using an animal model (rats). We first examined the concentrations of tetrahydrobiopterin (BH(4)) and monoamines in several regions of the brain after the intramuscular injection of IFN-alpha into rats; the levels of BH(4) and dopamine significantly decreased in the amygdala and raphe areas as compared with those of the controls. Based on these results, we further examined the concentrations of BH(4) and nitrite (NO(2)(-)) plus nitrate (NO(3)(-)), metabolites of nitric oxide (NO), in the amygdala and raphe areas after the intramuscular injection of IFN-alpha; the concentrations of both BH(4) and NO(2)(-)+NO(3)(-) significantly decreased as compared with the control. Furthermore, the addition of N(G)-monomethyl L-arginine, an inhibitor of NO synthase, after the injection of IFN-alpha restored the decreased levels of both NO(2)(-)+NO(3)(-) and BH(4) to control levels. As a result, nitric oxide induced by the intramuscular injection of IFN-alpha was found to cross the blood-brain barrier and suppress both tetrahydrobiopterin biosynthesis and dopamine production in the amygdala and raphe areas.

Influence of aging and social isolation on changes in brain monoamine turnover and biosynthesis of rats elicited by novelty stress.

Aging is a risk factor of human depression. Middle-aged or older men are vulnerable to adverse life events and an absence of social contact and easily become depressed. In the present study, we investigated the influence of aging on responses to life events in socially isolated conditions. We applied isolation-rearing (4 W) to two age groups, older (18 M) and younger (11 W), of male F344 rats that had been reared in a group and then examined responses to novelty stress (20 min). Changes in brain monoamines and their metabolites such as dopamine (DA), serotonin (5-HT), dihydroxyphenylacetic acid (DOPAC), homovanilic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in six regions: the prefrontal cortex, nucleus accumbens, hippocampus, amygdala, midbrain, and raphe nuclei. MANOVA was carried out for rearing condition, age, and novelty stress. Isolation significantly changed monoamines and their metabolites, except in amygdala and raphe nuclei. Aging significantly altered them in all regions, although novelty stress did not. In the amygdala and midbrain, isolation significantly changed monoamine biosynthesis, with monoamine turnover remaining unchanged. In the prefrontal cortex and nucleus accumbens, aging significantly altered turnover, while biosynthesis remained unchanged. Novelty stress significantly varied only the turnover in the prefrontal cortex. The interaction between isolation and aging indicated that aging influences changes in turnover and biosynthesis elicited by isolation primarily at the center of the mesolymbic DA system, the midbrain, and in raphe nuclei of the 5-HT system. In peripheral regions of the mesolymbic system, aging primarily affects changes in turnover induced by isolation.

Plasma biopterin levels and depressive state in pregnancy and the early puerperal period.

Plasma total biopterin and tetrahydrobiopterin levels of 14 normal pregnant and 15 normal puerperal women (within 1 week after delivery) were measured. In the first group, total biopterin levels were already increased (average: 18.2 pmol/ml) in the second trimester and remained high until the early puerperal period. In the second trimester, the ratio of tetrahydrobiopterin to total biopterin levels decreased to 72.3% and even further to 66.1% in the third trimester. This tendency continued until the puerperal period. Compared with the control group (12 healthy nonpregnant women), total biopterin levels increased during pregnancy and the puerperal period (p < 0.001), and the ratio in the third trimester and the early puerperal period decreased (p < 0.001). The depressive state according to Zung's score appeared most markedly in the third trimester with a mean score of 48, and tended to recover to a mean score of 36.2 in the early puerperal period. In this period, a correlation was found between Zung's score and the total biopterin levels (r = 0.80), and the ratio of tetrahydrobiopterin levels to the total biopterin levels (r = -0.92). In the early puerperal period, total biopterin levels were higher in subjects with Zung's scores > or = 36 (p < 0.001); the ratios of this group were lower than those of subjects with Zung's scores <36 (p < 0.001). Plasma biopterin levels in pregnancy and the early puerperal period closely resembled those of patients with mood disorders who show depressive symptoms from a psychoneurological perspective. Therefore, it seems possible that a depressive state in pregnancy and the early puerperal period has the same pathology as depression.

Attenuating effects of the isolated rearing condition on increased brain serotonin and dopamine turnover elicited by novelty stress.

Isolation and acute environmental change are risk factors in human depression. In the present study, we investigated the differences in the brain monoamine activity of rats between two rearing conditions, isolated and group. Moreover, we examined the responses to novelty stress. Male F344 rats aged 11 weeks were divided into the above two groups. Four weeks later they were further divided into non-stress and stress groups. The latter received 20 min exposure to novelty stress. Isolation significantly changed brain monoamine levels, with the levels of dopamine (DA) in the nucleus accumbens and midbrain, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the midbrain, and 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus increasing. Serotonin (5-HT) levels also increased in all brain areas except the raphe nuclei. HVA levels in the raphe nuclei decreased. Novelty stress significantly altered brain monoamine levels. DA, DOPAC, and HVA levels in the prefrontal cortex decreased, as did those of 5-HT in the prefrontal cortex and hippocampus. DA levels in the nucleus accumbens increased. Isolation attenuated the enhanced brain monoamine turnover elicited by novelty stress. The enhanced DA turnover ratio in the prefrontal cortex of the group-reared group was attenuated in the isolated-reared group, and the unchanged DA turnover ratio in the nucleus accumbens of the group-reared group declined in the isolated-reared group. The enhanced 5-HT turnover ratio in the prefrontal cortex, nucleus accumbens, and hippocampus of the group-reared group was attenuated in the isolated-reared group. Isolation may exacerbate adaptation to stress, and be related to the etiology of human depression.