Which Severe Mental Illnesses Most Increase the Risk of Developing Dementia? Comparing the Risk of Dementia in Patients with Schizophrenia, Major Depressive Disorder and Bipolar Disorder.

Objective: Previous studies have shown that certain severe mental illnesses (SMIs) increase the risk of dementia, but those that increase the risk to a greater degree in comparison with other SMIs are unknown. Furthermore, physical illnesses may alter the risk of developing dementia, but these cannot be well-controlled. Methods: Using the Taiwan National Health Insurance Research Database, patients with schizophrenia, bipolar disorder and major depressive disorder (MDD) were recruited. We also recruited normal healthy subjects as the control group. All subjects were aged over 60 years, and the duration of follow-up was from 2008 to 2015. Multiple confounders were adjusted, including physical illnesses and other variables. Use of medications, especially benzodiazepines, was analyzed in a sensitivity analysis. Results: 36,029 subjects (MDD: 23,371, bipolar disorder: 4,883, schizophrenia: 7,775) and 108,084 control subjects were recruited after matching according to age and sex. The results showed that bipolar disorder had the highest hazard ratio (HR) (HR: 2.14, 95% confidence interval [CI]: 1.99-2.30), followed by schizophrenia (HR: 2.06, 95% CI: 1.93-2.19) and MDD (HR: 1.60, 95% CI: 1.51-1.69). The results remained robust after adjusting for covariates, and sensitivity analysis showed similar results. Anxiolytics use did not increase the risk of dementia in any of the three groups of SMI patients. Conclusion: SMIs increase the risk of dementia, and among them, bipolar disorder confers the greatest risk of developing dementia. Anxiolytics may not increase the risk of developing dementia in patients with an SMI, but still need to be used with caution in clinical practices.

Effects of comorbid alcohol use disorder on bipolar disorder: Focusing on neurocognitive function and inflammatory markers.

BACKGROUND: Alcohol use disorder (AUD) is a highly prevalent comorbid disorder in patients with bipolar disorder (BD). Both BD and AUD were found to be associated with inflammation and cognitive deficits, but few study has been done on BD comorbid with AUD (BD+AUD). We aimed to investigate the impacts of comorbid AUD and BD on cognitive function, inflammatory and neurotrophic markers. METHOD: We recruited 641 BD patients, 150 patients with BD+AUD, and 185 healthy controls (HC). Neuropsychological tests [Wisconsin card sorting test (WCST), continuous performance test (CPT), and Wechsler memory scale - third edition (WMS-III)] and cytokine plasma levels [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-8 (IL-8), transforming growth factor-ß1 (TGF-ß1), and brain-derived neurotrophic factor (BDNF)] were assessed. RESULTS: BD+AUD patients had worse cognitive performance than those without AUD. There was a significant difference in the plasma levels of TNF-α, IL-8, and BDNF (P < 0.001, <0.001, and 0.01, respectively) between the patients and the HC groups. Post hoc analysis showed that BD+AUD patients had higher levels of TNF-α and IL-8 than BD-only patients (P < 0.001). Additionally, plasma IL-8 levels were negatively associated with number of completed categories in WCST (P = 0.02), and TNF-α levels were negatively associated with visual immediate index in WMS-III (P = 0.05). CONCLUSION: Our results suggest that comorbid AUD and BD might worsen cognitive impairments and inflammatory processes. Further longitudinal studies on BD+AUD may be needed.

Occupational evaluation of community-based psychiatric rehabilitation outcomes in individuals with severe mental illnesses: A ten-year retrospective study.

BACKGROUND: There is a lack of research on the effect of community-based psychiatric rehabilitation programs (CBPRs) in individuals with severe mental illness. This research used data from a retrospective study to examine the effect of a CBPR in a community rehabilitation center. MATERIALS AND METHODS: Clinical outcomes measures from a retrospective study were collected. Outcome measures were the Allen Cognitive Level Screen assessment, Purdue Pegboard Test, Chu's Attention Test, and Activities of Daily Living Rating Scale-III (ADLRS-III) before and immediately after 12 months of intervention. RESULTS: The 141 participants with mental illness were an average age of 35.29 years (SD = 8.75). The retrospective review of medical records showed 46 people dropped out within 12 months, and 95 people continued to participate in the rehabilitation program for 1 year. After 1 year of community rehabilitation, there was a trend for the participants who completed the intervention to improve on the ADLRS-III, Purdue Pegboard Test, and Chu's Attention Test. Participants who performed better on the occupational assessment were more likely to transit to the employment status. CONCLUSION: This study found the benefits of CBPR in work-related intervention for people with mental illness. Occupational assessments are relevant for studying changes in functional outcomes in people with mental illness receiving community-based rehabilitation.

Altered glutamate level and its association with working memory among patients with treatment-resistant schizophrenia (TRS): a proton magnetic resonance spectroscopy study.

BACKGROUND: Treatment-resistant schizophrenia (TRS) and non-TRS may be associated with different dopaminergic and glutamatergic regulations. The concept of dysregulated glutamatergic concentrations in specific brain regions remains controversial. Herein, we aimed to assess (i) the distribution of the glutamatergic concentration in the brain, (ii) the association between working memory (WM) differences in TRS and non-TRS patients, and (iii) whether an alteration in the glutamate (Glu) level is associated with WM. METHODS: The participants included 38 TRS patients, 35 non-TRS patients, and 19 healthy controls (HCs), all of whom underwent 1.5-Tesla proton magnetic resonance spectroscopy of anterior cingulate cortex (ACC) and medial prefrontal cortex (MPFC). The ratios of glutamatergic neurometabolites to N-acetylaspartate + N-acetyl aspartylglutamate (NAAx) were calculated. Cognitive function was assessed using the Wechsler Adult Intelligence Scales, 4th Edition, which included the working memory index (WMI). RESULT: The TRS patients had a higher glutamate + glutamine (Glx)/NAAx ratio compared to the non-TRS patients and HCs in the ACC, but this was not significantly different in the MPFC. WM was negatively correlated with Glx/NAAx in the ACC among the non-TRS patients, but not in the TRS patients or HCs. CONCLUSIONS: Our findings were consistent with most studies indicating that the glutamatergic concentration in the ACC plays important roles in the classification of TRS and cognition. Our results may provide potential evidence for predictors and treatment response biomarkers in TRS patients. Further research is needed to probe the value using the relationship between Glu and WM as a potential prognostic predictor of schizophrenia.

Association Between Inflammatory Cytokines, Executive Function, and Substance Use in Patients With Opioid Use Disorder and Amphetamine-Type Stimulants Use Disorder.

BACKGROUND: Long-term opioid and amphetamine-type stimulants (ATS) abuse may affect immunological function and impair executive function. We aimed to determine whether biomarkers of inflammation and executive function were associated with substance use in individuals with opioid use disorder (OUD) and ATS use disorder (ATSUD). The interactions between these biomarkers were also explored. METHODS: We assessed plasma cytokines [tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-8, IL-6, transforming growth factor (TGF)-ß1, brain-derived neurotrophic factor (BDNF), and executive function in terms of the Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT) in OUD and ATSUD patients and healthy controls (HC). OUD and ATSUD patients were followed for 12 weeks, and their urine morphine and amphetamine tests, cytokine levels, and executive function were repeatedly measured. RESULTS: We enrolled 483 patients and 145 HC. Plasma TNF-α, CRP, IL-8, IL-6, and BDNF levels and most subscale scores on the WCST and CPT significantly differed between OUD and ATSUD patients and HC. Increased TNF-α levels and more perseveration error on the WCST were significantly associated with more urine drug-positive results and less abstinence. Plasma IL-6 and CRP levels were significantly negatively correlated with WCST and CPT performance. CONCLUSION: OUD and ATSUD patients had more inflammation and worse executive function than HC. Inflammatory markers and WCST performance were associated with their urinary drug results, and higher inflammation was associated with poor executive function. Studies on regulating the inflammatory process and enhancing executive function in OUD and ATSUD are warranted.

Correlation between loneliness, personality traits, and treatment outcomes in patients with methamphetamine use disorder.

The aim of this study was to investigate whether loneliness and personality traits correlate with the treatment outcome of methamphetamine use disorder. In this 1-year longitudinal study, a total 106 participants (98 males, 8 females), with a mean age 36.3 ± 9.6 years were enrolled. We measured UCLA Loneliness Scale and Tridimensional Personality Questionnaire at baseline, while craving level at baseline, week 12, 24, 36, and 48. Urinary methamphetamine tests were given 17 times. For the evaluation of the data, multiple linear regression and generalized linear mixed models were used. The baseline results showed lower levels of the harm avoidance trait and higher levels of loneliness were significantly associated with higher craving levels (p=0.04 and 0.04). Moreover, loneliness was not only positively associated with craving levels (B=0.05, p<0.01) but with urinary methamphetamine positive results (B= 0.08, p=0.03) during one-year treatment. The findings suggested that loneliness was associated with poor methamphetamine treatment outcome (greater craving levels and higher proportion of positive methamphetamine urine tests) and lower harm avoidance traits are associated with higher craving levels.

Serotonin Modulates the Correlations between Obsessive-compulsive Trait and Heart Rate Variability in Normal Healthy Subjects: A SPECT Study with [123I]ADAM and Heart Rate Variability Measurement.

Objective: The impact of serotonergic system on obsessive-compulsive disorder (OCD) is well studied. However, the correlation between OC presentations and autonomic nervous system (ANS) is still unclear. Furthermore, whether the correlation might be modulated by serotonin is also uncertain. Methods: We recruited eighty-nine healthy subjects. Serotonin transporter (SERT) availability by [123I]ADAM and heart rate variability (HRV) tests were measured. Symptoms checklist-90 was measured for the OC presentations. The interaction between HRV and SERT availability were calculated and the correlation between HRV and OC symptoms were analyzed after stratified SERT level into two groups, split at medium. Results: The interactions were significant in the factors of low frequency (LF), high frequency (HF), and root mean square of successive differences (RMSSD). Furthermore, the significantly negative correlations between OC symptoms and the above HRV indexes existed only in subjects with higher SERT availability. Conclusion: OC symptoms might be correlated with ANS regulations in subjects with higher SERT availability.

Loneliness and isolated living status in middle-aged and older adults in Taiwan: exploration on stress-related biomarkers, depressive symptoms, and disability.

PURPOSE: Loneliness is a subjective feeling by which an individual perceives a lack of closeness in interpersonal relationships. An isolated living status is linked with higher odds of risky health behavior. The conflicting impacts of loneliness and isolated living status on stress-related biomarkers, depressive symptoms, and disability remain unexplained. METHODS: Six hundred twenty-nine participants aged 66.0 (SD=7.3) separated into four groups: "Lonely and Isolated," "Not Lonely, but Isolated," "Lonely, but Not Isolated," and "Neither Lonely, nor Isolated," were retrieved from the Social Environment and Biomarkers of Aging Study conducted in 2000. Follow-up health indicators in 2006 included three stress-related biomarkers, depressive symptoms, and two physical disability indicators. A hierarchical regression was performed for the analysis. RESULTS: Firstly, compared to the "Neither Lonely nor Isolated" group, only the "Lonely, but Not Isolated" participants at baseline retained positive associations with the stress-related biomarkers levels 6 years later (urine cortisol level (B=9.25, 95% CI=3.24-15.27), serum Interleukin-6 level (B=2.76, 95% CI=0.72-4.79) and the serum high sensitivity C-reactive protein (hsCRP) level (B=0.40, 95% CI=0.17-0.62)). However, such associations were not observed in the "Lonely and Isolated" participants. Secondly, only "Lonely and Isolated" participants at baseline were positively associated with depressive symptoms 6 years later (B=1.70, 95% CI=0.11-3.30). Finally, the associations between combinations of loneliness and isolated living status and physical disability were eliminated after adjusting the covariables. CONCLUSION: Four combinations of loneliness and isolated living status were associated with different impacts on stress-related biomarkers, depressive symptoms, and physical disability. Further dynamic investigations are warranted.

Striatal dopamine D2/3 receptors in medication-naïve schizophrenia: an [123I] IBZM SPECT study.

BACKGROUND: The hyper-function of the striatal dopamine system has been suggested to underlie key pathophysiological mechanisms in schizophrenia. Moreover, patients have been observed to present a significant elevation of dopamine receptor availability compared to healthy controls. Although it is difficult to measure dopamine levels directly in humans, neurochemical imaging techniques such as single-photon emission computed tomography (SPECT) provide indirect indices of in vivo dopamine synthesis and release, and putative synaptic levels. METHODS: We focused on the role of dopamine postsynaptic regulation using [123I] iodobenzamide (IBZM) SPECT. We compared D2/3 receptor availability between 53 healthy controls and 21 medication-naive patients with recent-onset schizophrenia. RESULT: The mean specific striatal binding showed no significant difference between patients and controls (estimated difference = 0.001; 95% CI -0.11 to 0.11; F = 0.00, df = 1, 69; p = 0.99). There was a highly significant effect of age whereby IBZM binding declined with advancing age [estimated change per decade of age = -0.01(binding ratio); 95% CI -0.01 to -0.004; F = 11.5, df = 1, 69; p = 0.001]. No significant correlations were found between the mean specific striatal binding and psychopathological or cognitive rating scores. CONCLUSIONS: Medication-naïve patients with recent-onset schizophrenia have similar D2/3 receptor availability to healthy controls. We suggest that, rather than focusing exclusively on postsynaptic receptors, future treatments should target the presynaptic control of dopamine synthesis and release.

Absence of negative associations of insular and medial frontal gray matter volume with dissociative symptoms in schizophrenia.

BACKGROUND: Dissociative symptoms have been constantly found in schizophrenia (SCZ). Traumatic experience seems to relate to dissociative symptoms and brain volume alterations in SCZ. The current study aimed to clarify the inter-relations of dissociative symptoms, traumatic experience, and brain volume in SCZ. METHODS: We employed voxel-based morphometry to compare the distributions of gray matter volumes (GMV) in 37 SCZ patients and 26 healthy volunteers (HV). All participants underwent T1-weighted images on a 1.5 T MRI system. Traumatic experience was examined by the Brief Betrayal Trauma Survey. Pathological and non-pathological dissociation were measured by the Dissociative Symptoms Scale and the Dissociative Experiences Scale, respectively. RESULTS: A GMV reduction was found in SCZ patients in the right thalamus. Importantly, a significant group by pathological dissociation interaction was observed in the medial frontal cortex (MFC), bilateral anterior insular area, and precuneus. A negative correlation between MFC/insular GMV and pathological dissociation was observed in HV; higher non-pathological dissociation and smaller volume in MFC/insula were associated with pathological dissociation. In contrast, higher traumatic experience, higher non-pathological dissociation, and larger volume in MFC/insula were associated with pathological dissociation in SCZ. CONCLUSION: The negative association between MFC/insula GMV and pathological dissociation in HV was not observed in SCZ patients. The absent negative association in SCZ suggests a unique neural underpinning in SCZ with dissociative pathology, in which medial frontal and temporal regions play crucial roles.

Association of visual motor processing and social cognition in schizophrenia.

Patients with schizophrenia have difficulties in social cognitive domains including emotion recognition and mentalization, and in sensorimotor processing and learning. The relationship between social cognitive deficits and sensorimotor function in patients with schizophrenia remains largely unexplored. With the hypothesis that impaired visual motor processing may decelerate information processing and subsequently affects various domains of social cognition, we examined the association of nonverbal emotion recognition, mentalization, and visual motor processing in schizophrenia. The study examined mentalization using the verbal subset of the Chinese version of Theory of Mind (CToM) Task, an equivalent task of the Faux Pas Test; emotion recognition using the Diagnostic Analysis of Nonverbal Accuracy 2-Taiwan version (DANVA-2-TW), and visual motor processing using a joystick tracking task controlled for basic motor function in 34 individuals with chronic schizophrenia in the community and 42 healthy controls. Patients with schizophrenia had significantly worse performance than healthy controls in social cognition, including facial, prosodic emotion recognition, and mentalization. Visual motor processing was also significantly worse in patients with schizophrenia. Only in patients with schizophrenia, both emotion recognition (mainly in prosodic modality, happy, and sad emotions) and mentalization were positively associated with their learning capacity of visual motor processing. These findings suggest a prospective role of sensorimotor function in their social cognitive deficits. Despite that the underlying neural mechanism needs further research, our findings may provide a new direction for restoration of social cognitive function in schizophrenia by enhancing visual motor processing ability.

Transcranial direct current stimulation (tDCS) may reduce the expired CO concentration among opioid users who smoke cigarettes: a randomized sham-controlled study.

Transcranial direct current stimulation (tDCS) could be a potential treatment for nicotine dependency. Little is known with regards to the efficacy of this treatment in cigarette-smoking patients with heroin dependency. In this sham-controlled study, we probed the effect of 5-day, 20-min, 2-mA-intensity tDCS treatment on the outcomes of cigarette-smoking. Our objectives are to examine the effects of tDCS on two outcomes: objective expired CO concentration and subjective self-reported number of cigarettes smoked per day. A total of 30 patients were randomized into active or sham control groups. The stimulation site was randomized to anodal stimulation of the left dorsal lateral prefrontal cortex or the orbital frontal cortex. The expired CO concentration was recorded. The patients also reported their cigarette consumption and level of craving prior to each 5-day treatment period and after 5 days of follow-up. tDCS was found to be effective in terms of reducing the expired CO concentration, and both groups demonstrated reduced numbers of cigarettes smoked. However, no significant group difference was found with regards to craving tendency. tDCS may affect objective outcomes related to cigarette-smoking among patients with heroin dependence.

Collapsin response mediator protein 5 (CRMP5) modulates susceptibility to chronic social defeat stress in mice.

Collapsin response mediator protein 5 (CRMP5), a member of the CRMP family, is expressed in the brain, particularly in the hippocampus, an area of the brain that can modulate stress responses. Social stress has a well-known detrimental effect on health and can lead to depression, but not all individuals are equally sensitive to stress. To date, researchers have not conclusively determined how social stress increases the susceptibility of the brain to depression. Here, we used the chronic social defeat stress (CSDS) model and observed higher hippocampal CRMP5 expression in stress-susceptible (SS) mice than in control and stress-resilient (RES) mice. A negative correlation was observed between the expression levels of CRMP5 and the social interaction (SI) ratio. Reduced hippocampal CRMP5 expression increased the SI ratio in SS mice, whereas CRMP5 overexpression was sufficient to induce social avoidance behaviors in control mice following exposure to subthreshold social stress induced by lentivirus-based overexpression and inducible tetracycline-on strategies to upregulate CRMP5. Interestingly, increased CRMP5 expression in SS and lenti-CRMP5-treated mice also caused serum corticosterone concentrations to increase. These findings improve our understanding of the potential mechanism by which CRMP5 triggers susceptibility to social stress, and they support the further development of therapeutic agents for the treatment of stress disorders in humans.

Positive Symptoms in Antipsychotic-naïve Schizophrenia are Associated with Increased Body Mass Index after Treatment.

OBJECTIVE: Weight gain is an important risk factor for morbidity and mortality among patients with schizophrenia. We speculated that positive symptoms, related to dopaminergic hyperactivity and altered mesolimbic function, are associated with weight gain. METHODS: Twenty-two antipsychotic-naïve, first-episode patients with schizophrenia were enrolled. The Positive and Negative Syndrome Scale was completed at enrollment and follow-up. Body mass index (BMI) was also measured. RESULTS: The increase in BMI, after 6.04 ± 2.16 years of follow-up, was associated with positive symptoms, but not negative symptoms, before treatment with antipsychotics in antipsychotic-naïve patients with schizophrenia. CONCLUSION: This finding implied that dopaminergic hyperactivity could be an important factor to predict the treatment outcome. Body weight control is important for the health management of patients with schizophrenia with more severe positive symptoms.

Add-on repetitive transcranial magnetic stimulation in patients with opioid use disorder undergoing methadone maintenance therapy.

Background: Repetitive transcranial magnetic stimulation (rTMS) shows potential therapeutic effects for individuals with addiction, but few studies have examined individuals with opioid use disorder (OUD).Objectives: We conducted an add-on double-blinded, sham-controlled rTMS feasibility pilot trial to examine OUD participants undergoing methadone maintenance therapy (MMT). The current report focused on the effects of rTMS on (1) craving and heroin use behavior and (2) depression, impulsivity, and attention.Methods: Active or sham rTMS treatment was applied to the left dorsolateral prefrontal cortex (DLPFC) over a total of 11 sessions in 4 weeks (15-Hz frequency, 4 seconds per train, intertrain interval of 26 seconds, 40 trains per session) in OUD participants (ClinicalTrials.gov registration number: NCT03229642). Craving, heroin use severity, urine morphine tests, the Hamilton Depression Rating Scale (HDRS), the Barratt Impulsiveness Scale-11 (BIS-11), and the Continuous Performance Tests (CPTs) were measured.Results: Twenty-two OUD participants were enrolled, of which eleven (8 males) were undergoing active rTMS and nine (8 males) were in the sham rTMS group. After 12 weeks of follow-up, the active rTMS group did not show significantly greater improvements than the sham group with respect to craving, heroin use, or urine morphine test results. However, HDRS scores, BIS-11 attentional subscales, and CPTs commission T-scores (C-TS) were significantly lower in the active rTMS group (P = .003, 0.04, and 0.02, respectively) than in the sham group.Conclusion: Add-on rTMS did not appear to improve heroin use behavior but may have benefitted depressive symptoms, impulse control and attention in OUD participants undergoing MMT.

A pilot study on the association between the blood oxygen level-dependent signal in the reward system and dopamine transporter availability in adults with attention deficit hyperactivity disorder.

BACKGROUND: It is well-known that attention deficit hyperactivity disorder (ADHD) is associated with changes in the dopaminergic system. However, the relationship between central dopaminergic tone and the blood oxygen level-dependent (BOLD) signal during receipt of rewards and penalties in the corticostriatal pathway in adults with ADHD is unclear. METHODS: Single-photon emission computed tomography with [99mTC]TRODAT-1 was used to assess striatal dopamine transporter (DAT) availability. Event-related functional magnetic resonance imaging was conducted on subjects performing the Iowa Gambling Test. RESULT: DAT availability was found to be associated with the BOLD response, which was a covariate of monetary loss, in the medial prefrontal cortex (r = 0.55, P = .03), right ventral striatum (r = 0.69, P = .003), and right orbital frontal cortex (r = 0.53, P = .03) in adults with ADHD. However, a similar correlation was not found in the controls. CONCLUSIONS: The results confirmed that dopaminergic tone may play a different role in the penalty-elicited response of adults with ADHD. It is plausible that a lower neuro-threshold accompanied by insensitivity to punishment could be exacerbated by the hypodopaminergic tone in ADHD.

Add-on memantine may improve cognitive functions and attenuate inflammation in middle- to old-aged bipolar II disorder patients.

OBJECTIVES: Chronic inflammation and neuroprogression underlie bipolar disorder (BP) and associated cognitive deficits. Memantine (MM) exerts neuroprotective effects by reducing neuroinflammation. Therefore, we investigated whether add-on low-dose MM (5 mg/day) in BP-II patients may improve cognition and inflammation. METHODS: We combined two 12-week randomized, double-blind, placebo-controlled studies (NCT01188148 and NCT03039842) for analysis. Each participant was allocated to the MM or placebo group. Symptom severity, neuropsychological tests, and the cytokine plasma levels [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-8 (IL-8), transforming growth factor-ß1 (TGF-ß1), and brain-derived neurotrophic factor (BDNF)] were evaluated at baseline and endpoint. A subgroup analysis of middle- to old-aged BP-II patients was also performed. RESULTS: We recruited 155 BP-II patients (23 of which were middle- to old-aged) for the MM group and 170 patients (20 of which were middle- to old-aged) for the placebo group. Add-on MM did not result in significant improvements in cognitive functions in all BP-II patients, but a group difference in TNF-α levels was found in the MM group (P=0.04). Specifically, in middle- to old-aged BP-II patients, there was a significant time and group interaction effect on omission T-scores, hit reaction time T-scores, and hit reaction time standard error T-scores on continuous performance tests (CPTs) in the MM group (P=0.007, 0.02, and 0.01, respectively), and a decrease in plasma TNF-α levels (P=0.04). LIMITATIONS: The sample size of middle- to old-aged BP-II patients were limited. CONCLUSION: Add-on MM may attenuate inflammation in BP-II and improve cognition in middle- to old-aged BP-II patients.

Heart Rate Variability with Deep Breathing in Drug-Naïve Patients with Schizophrenia.

Abnormal autonomic nervous system (ANS) function may result in poor outcomes in patients with schizophrenia. Altered cardio-respiratory coupling, which indicates suppression of vagal activity, was identified as an important trait in patients with schizophrenia and their unaffected relatives. Heart rate variability (HRV) in standardized bedside reflex tests has been studied, mostly in medicated patients with schizophrenia whose ANS function could be influenced by medication. Our study aimed to explore the autonomic function differences between drug-naïve patients with schizophrenia and healthy individuals during challenge tests combining respiration and HRV analysis. Forty-two drug-naïve patients with schizophrenia were matched with 42 healthy controls in terms of age and gender. Their beat-to-beat blood pressure and heart rate were monitored in the supine position as a survey of ANS function, and the mean heart rate range (MHRR) was measured under deep-breathing challenge. A decreased MHRR, a sensitive sign indicating an impaired parasympathetic response, during the deep-breathing challenge among the drug-naïve patients with schizophrenia was found. Drug-naïve patients with schizophrenia may have a parasympathetic dysfunction in the early stages of schizophrenia before medication is introduced, which could be considered a neurobiological marker in the pathophysiology of schizophrenia.

The integrated model of glutamate and dopamine hypothesis for schizophrenia: Prediction and personalized medicine for prevent potential treatment-resistant patients.

Treatment-resistant schizophrenia (TRS) is one of the subgroups of schizophrenia of which little is known with regard to its optimal mechanism. Treatment response, either as full remission of symptoms or prediction by biomarker, is important in psychiatry. We have proposed a model that integrates dopaminergic and glutamatergic systems with the biological interactions of TRS patients. We hypothesize that the subgroups of schizophrenia may be determined by glutamatergic and dopaminergic concentrations prior to medical treatment. This hypothesis implies that higher glutamatergic concentration in the brain with normalized or decreased dopamine synthesis capacity may explain aspects of TRS as observed in clinical medical practice, neuroimaging measurements, and brain stimulations. According to this hypothesis, the ability to prescribe a proper medication combination, to predict the outcome in first-episode psychosis, and personalized medicine for chronic schizophrenia patients can be applied into practice. This represents an initial step in explaining psychosis due to the valence of two neurotransmitters. Future studies are needed to examine the validity of this mechanism.