Psychiatric Manifestations in Early to Middle Stages of Fragile X-Associated Tremor-Ataxia Syndrome (FXTAS).

OBJECTIVE: The purpose of the present study was to assess the psychiatric manifestations of early to middle stages of fragile X-associated tremor-ataxia syndrome (FXTAS) and their relationship with executive function and FMR1 cytosine-guanine-guanine (CGG) repeat numbers across genders. METHODS: Cross-sectional data from 100 participants (62 men, 38 women; mean±SD age=67.11±7.90 years) with FXTAS stage 1, 2, or 3 were analyzed, including demographic information, cognitive measures, psychiatric assessments (Symptom Checklist-90-Revised and Behavioral Dyscontrol Scale-II [BDS-II]), and CGG repeat number. RESULTS: Participants with FXTAS stage 3 exhibited significantly worse psychiatric outcomes compared with participants with either stage 1 or 2, with distinct gender-related differences. Men showed differences in anxiety and hostility between stage 3 and combined stages 1 and 2, whereas women exhibited differences in anxiety, depression, interpersonal sensitivity, obsessive-compulsive symptoms, and somatization, as well as in the Global Severity Index, the Positive Symptom Distress Index, and the Positive Symptom Total. Among male participants, negative correlations were observed between BDS-II total scores and obsessive-compulsive symptoms, as well as between anxiety and CGG repeat number. CONCLUSIONS: These findings suggest that even at early FXTAS stages, patients have significant cognitive and other psychiatric symptoms, with notable gender-specific differences. This study underscores the clinical and prognostic relevance of comorbid psychiatric conditions in FXTAS, highlighting the need for early intervention and targeted support for individuals with relatively mild motor deficits.

Sex differences in the diagnosis of autism spectrum disorder and effects of comorbid mental retardation and attention-deficit hyperactivity disorder.

BACKGROUND/PURPOSE: The association between sex and diagnostic behavior of autism spectrum disorder (ASD), and the effects of comorbid mental retardation (MR) and attention-deficit hyperactivity disorder (ADHD), were explored. METHODS: Based on the Taiwan Longitudinal Health Insurance Database (LHID)-2000 and data from 1996 through 2008, the cumulative incidence of ASD over time was compared between the sexes (both cohorts n = 38,117) using the log-rank test. The effects of comorbid MR and ADHD on the incidence of ASD were evaluated using Cox proportional hazard regression analysis. The age at first diagnosis of ASD in the two sexes was compared using the independent-sample t-test. RESULTS: The incidence was higher in males than in females (0.0007 vs. 0.0002) across ages. Comorbid MR or ADHD increased the incidence of ASD in both sexes; comorbid MR or ADHD also decreased the male to female hazard ratio of ASD, with no significant differences in the incidence density of ASD between sexes. ADHD delayed diagnosis in both sexes (males: 6.61 vs 5.10, p < 0.0001; females: 6.83 vs 4.69, p = 0.0037). CONCLUSION: The general concept of a higher incidence of ASD among males was noted in this study of a Taiwanese population, but disappeared in those with comorbid MR or ADHD, indicating unique vulnerabilities to MR/ADHD or under-identification of high-functioning females with ASD in childhood. Increasing the diagnostic sensitivity of ASD in those with comorbid ADHD is important due to a delayed diagnostic age in this group.

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.

Association between methylphenidate and risk of myocardial infarction: A multinational self-controlled case series study.

PURPOSE: To investigate the association between use of methylphenidate and risk of myocardial infarction among Asians. METHODS: We conducted a multinational self-controlled case series study using nationwide healthcare databases of South Korea (2002-2018), Taiwan (2004-2015), and Hong Kong (2001-2016). Of patients with myocardial infarction who were also prescribed methylphenidate within the observation period, methylphenidate use was classified into four mutually exclusive periods by each person-day: exposed (exposed to methylphenidate), pre-exposure (prior to the first methylphenidate prescription), washout (after the end of methylphenidate treatment), and baseline (unexposed to methylphenidate). Risk of myocardial infarction among the three periods of methylphenidate use was compared to the baseline period using conditional Poisson regression analysis to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: We identified 2104, 484, and 30 patients from South Korea, Taiwan, and Hong Kong, respectively. Risk of myocardial infarction was the highest during the pre-exposure period in all three populations: South Korea, pre-exposure (IRR 3.17, 95% CI 3.04-3.32), exposed (1.05, 1.00-1.11), washout (1.92, 1.80-2.04); Taiwan, pre-exposure (1.97, 1.78-2.17), exposed (0.72, 0.65-0.80), washout (0.56, 0.46-0.68); Hong Kong, pre-exposure (18.09, 8.19-39.96), exposed (9.32, 3.44-25.28), washout (7.69, 1.72-34.41). Following stratification for age and sex, the trends remained analogous to the main findings across all three populations. CONCLUSIONS: Although a positive association between initiating methylphenidate and the onset of myocardial infarction was observed, the risk was the highest in the period before its initiation. Thus, this multinational study suggests there was no causal relationship between methylphenidate and myocardial infarction among Asians.

Heart Rate Variability is Associated with Memory in Females.

Research into the association between heart rate variability (HRV) and cognitive function is scarce, particularly with regard to gender differences. HRV in 182 healthy volunteers was assessed by the root mean square of the successive difference (RMSSD) and spectrum analysis, while the Wechsler Memory Scale-Revised (WMS-R) was used to determine memory function. Robust and significant associations were found to exist between HRV (RMSSD and high-frequency HRV) and domains of the WMS-R in females. Caution should therefore be taken to control for gender when conducting studies on the relationships between HRV and cognitive variables.

Availability of dopamine transporters and auditory P300 abnormalities in adults with attention-deficit hyperactivity disorder: preliminary results.

OBJECTIVE: Previous studies have indicated that there is dopamine transporter (DAT) dysregulation and P300 abnormality in adults with attention-deficit hyperactivity disorder (ADHD); however, the correlations among the three have not been fully explored. METHODS: A total of 11 adults (9 males and 2 females) with ADHD and 11 age-, sex-, and education-level-matched controls were recruited. We explored differences in DAT availability using single-photon emission computed tomography and P300 wave of event-related potentials between the two groups. The correlation between DAT availability and P300 performance was also examined. RESULTS: DAT availability in the basal ganglia, caudate nucleus, and putamen was significantly lower in the ADHD group. Adults with ADHD had lower auditory P300 amplitudes at the Pz and Cz sites, as well as longer Fz latency than controls. DAT availability was negatively correlated to P300 latency at Pz and Fz. CONCLUSIONS: Adults with ADHD had both abnormal DAT availability and P300 amplitude, suggesting that ADHD is linked to dysfunction of the central dopaminergic system and poor cognitive processes related to response selection and execution.

Unaltered Dopamine Transporter Availability in Drug-Naive Patients With Schizophrenia After 6 Months of Antipsychotics Treatment: A Naturalistic Study.

BACKGROUND: Dopaminergic dysfunction, namely, dopamine transporter (DAT) availability variations in patients with drug-naive schizophrenia after long-term treatment, is still not well understood. The aims of the study were to explore (i) whether the DAT availability in patients with drug-naive schizophrenia differed after antipsychotic treatment and (ii) whether treatment with different generations of antipsychotics influenced the DAT availability after follow-up for 6 months. METHODS: Twenty-four first-episode, drug-naive patients with schizophrenia were divided into first- and second-generation antipsychotic groups naturalistically. After 6 months of follow-up, 7 patients who received first-generation antipsychotic treatment and 17 patients who received second-generation antipsychotic treatment completed the study. The patients underwent premedication and 6-month follow-up measurements using single-photon emission computed tomography with technetium Tc 99m (Tc) TRODAT-1. Psychopathological evaluations and adverse effects were recorded using appropriate scales. RESULTS: Both of the treatment groups significantly improved according to Positive and Negative Symptoms Scale evaluation. However, no significant difference was noticed between the premedication and 6-month follow-up DAT scans. Nonsignificant differences existed even in the groups of different generations of antipsychotics. CONCLUSIONS: Improvements in psychotic symptoms in patients with schizophrenia may not be influenced by DAT availability, even under treatment with different antipsychotics for a sufficient treatment period.

Bidirectional association between autism spectrum disorder and epilepsy in child and adolescent patients: a population-based cohort study.

This study aimed to assess whether there is a bidirectional association between autism spectrum disorder (ASD) and epilepsy in child and adolescent patients. The National Health Insurance Research Database of Taiwan was used to conduct two cohort studies of patients who were under 18 years of age during the period 1997-2008. Cohort 1 comprised patients with newly diagnosed ASD but excluded those diagnosed with epilepsy prior to ASD. A non-ASD comparison group was matched to each case in terms of age and sex. Cohort 2 comprised patients with newly diagnosed epilepsy but excluded those diagnosed with ASD prior to epilepsy. A non-epilepsy comparison group was matched to each case in terms of age and sex. We calculated the incidence of epilepsy in patients with ASD and hazard ratio (HR) to estimate the risk of epilepsy in association with ASD in cohort 1, and the reverse in cohort 2. In cohort 1, the incidence of epilepsy was 13.7 in the ASD group and 1.3 in the non-ASD group (per 1000 person-years). The adjusted HR for epilepsy was 8.4 (95 % CI 5.5-12.7) in the ASD group when compared with the non-ASD group. In cohort 2, the incidence of ASD was 3.4 in the epilepsy group and 0.3 in the non-epilepsy group (per 1000 person-years). The adjusted HR for ASD was 8.4 (95 % CI 6.2-11.4) in the epilepsy group when compared with the non-epilepsy group. A bidirectional association was, therefore, found to exist between ASD and epilepsy. These findings implicate that ASD and epilepsy probably share common risk factors. However, further studies are required to reveal more detail on the mechanism of this bidirectional association.

Harm Avoidance is Correlated with the Reward System in Adult Patients with Attention Deficit Hyperactivity Disorder: A Functional Magnetic Resonance Imaging Study.

Objective: Hypoactivity in the reward system among patients with attention deficit hyperactivity disorder (ADHD) is a well-known phenomenon. Whether the activity in the reward pathway is related to harm avoidance, such as in sensitivity to punishment, is unclear. Evidence regarding the potential difference between ADHD patients and controls in terms of this association is scarce. Methods: Event-related functional magnetic resonance imaging was conducted on subjects performing the Iowa gambling test. Fourteen adults with ADHD and 14 controls were enrolled in the study. Results: Harm avoidance was found to be positively correlated with the activities of the bilateral orbitofrontal cortex and right insula in individuals with ADHD. A group difference was also confirmed. Conclusion: Understanding the roles of harm avoidance and brain activation during risk tasks is important.

Intercorrelation of Molecular Biomarkers and Clinical Phenotype Measures in Fragile X Syndrome.

This study contributes to a greater understanding of the utility of molecular biomarkers to identify clinical phenotypes of fragile X syndrome (FXS). Correlations of baseline clinical trial data (molecular measures-FMR1 mRNA, CYFIP1 mRNA, MMP9 and FMRP protein expression levels, nonverbal IQ, body mass index and weight, language level, NIH Toolbox, adaptive behavior rating, autism, and other mental health correlates) of 59 participants with FXS ages of 6-32 years are reported. FMR1 mRNA expression levels correlated positively with adaptive functioning levels, expressive language, and specific NIH Toolbox measures. The findings of a positive correlation of MMP-9 levels with obesity, CYFIP1 mRNA with mood and autistic symptoms, and FMR1 mRNA expression level with better cognitive, language, and adaptive functions indicate potential biomarkers for specific FXS phenotypes. These may be potential markers for future clinical trials for targeted treatments of FXS.

Treatment response and cognitive impairment in major depression: association with C-reactive protein.

Levels of inflammatory markers have been found to be significantly associated with major depressive disorder (MDD) and cognitive impairment. The aim of this study was to investigate whether the level of C-reactive protein (CRP) is correlated with depressive mood and cognitive impairment in MDD patients. In 149 subjects with MDD, the 21-item Hamilton Rating Scale for Depression (HAM-D), Continuous Performance Test (CPT), Finger-Tapping Test (FTT), and Wisconsin Card-Sorting Test (WCST) were administered before and after antidepressant treatment. Besides, the level of CRP was measured. After 6weeks of treatment, the total HAM-D scores decreased significantly. In addition, the subjects' performance in the masked CPT and the WCST with completed categories significantly improved (p<0.001 and p=0.027, respectively) after the reliable change indices were corrected for practice effects. The CRP levels had increased significantly after six weeks of treatment after adjustment for age and gender (p<0.001). In addition, the CRP levels remained significantly high after six weeks of treatment in patients with a higher baseline level (r=0.657, p<0.001). Although the association between baseline CRP level and HAM-D score was not significant, the baseline CRP level was significantly correlated with treatment response at week 2 (r=0.327, p=0.020). The baseline CRP level was also negatively correlated with performance in the FTT before treatment (r=-0.580, p=0.006). Moreover, the baseline CRP level was significantly correlated with performance in the FTT (r=-0.501, p=0.021) and WCST with completed categories (r=-0.521, p=0.015) at week 6. The cognitive function of patients with high baseline CRP levels might remain impaired even if their mood symptoms improve after antidepressant treatment. Whether adjunctive anti-inflammatory medication may help to preserve cognitive function merits further investigation.

Comparison of antidepressant efficacy-related SNPs among Taiwanese and four populations in the HapMap database.

The genetic influence of single nucleotide polymorphisms (SNPs) on antidepressant efficacy has been previously demonstrated. To evaluate whether there are ethnic differences, we compared the allele frequencies of antidepressant efficacy-related SNPs between the Taiwanese population and four other populations in the HapMap database. We recruited 198 Taiwanese major depression patients and 106 Taiwanese controls. A panel of possible relevant SNPs (in brain-derived neurotrophic factor, 5-hydroxytryptamine receptor 2A, interleukin 1 beta, and G-protein beta 3 subunit genes) was selected for comparisons of allele frequencies using the χ(2) test. Our results suggested no difference between Taiwanese patients and controls, but there were significant differences among Taiwanese controls and the other four ethnic groups in brain-derived neurotrophic factor, 5-hydroxytryptamine receptor 2A, interleukin 1 beta and G-protein beta 3 subunit genes. We conclude that there are ethnic differences in the allele frequencies of antidepressant efficacy-related SNPs, and that the degree of variations is consistent with geographic distances. Further investigation is required to verify the attribution of genetic differences to ethnic-specific antidepressant responses.

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.

Cardiovascular and metabolic risk of antipsychotics in children and young adults: a multinational self-controlled case series study.

AIMS: The risk of antipsychotic-associated cardiovascular and metabolic events may differ among countries, and limited real-world evidence has been available comparing the corresponding risks among children and young adults. We, therefore, evaluated the risks of cardiovascular and metabolic events in children and young adults receiving antipsychotics. METHODS: We conducted a multinational self-controlled case series (SCCS) study and included patients aged 6-30 years old who had both exposure to antipsychotics and study outcomes from four nationwide databases of Taiwan (2004-2012), Korea (2010-2016), Hong Kong (2001-2014) and the UK (1997-2016) that covers a total of approximately 100 million individuals. We investigated three antipsychotics exposure windows (i.e., 90 days pre-exposure, 1-30 days, 30-90 days and 90 + days of exposure). The outcomes were cardiovascular events (stroke, ischaemic heart disease and acute myocardial infarction), or metabolic events (hypertension, type 2 diabetes mellitus and dyslipidaemia). RESULTS: We included a total of 48 515 individuals in the SCCS analysis. We found an increased risk of metabolic events only in the risk window with more than 90-day exposure, with a pooled IRR of 1.29 (95% CI 1.20-1.38). The pooled IRR was 0.98 (0.90-1.06) for 1-30 days and 0.88 (0.76-1.02) for 31-90 days. We found no association in any exposure window for cardiovascular events. The pooled IRR was 1.86 (0.74-4.64) for 1-30 days, 1.35 (0.74-2.47) for 31-90 days and 1.29 (0.98-1.70) for 90 + days. CONCLUSIONS: Long-term exposure to antipsychotics was associated with an increased risk of metabolic events but did not trigger cardiovascular events in children and young adults.

Availability of Striatal Dopamine Transporter in Healthy Individuals With and Without a Family History of ADHD.

OBJECTIVE: ADHD is the most prevalent neurodevelopmental disorder. It is highly heritable and multifactorial, but the definitive causes remain unknown. Abnormal dopamine transporter (DAT) availability has been reported, but the data are inconsistent. The aim of this study was to examine whether DAT availability differs between healthy parents with and without ADHD offspring. METHOD: Eleven healthy parents with ADHD offspring and 11 age- and sex-matched healthy controls without ADHD offspring were recruited. The availability of DAT was approximated using single-photon emission computed tomography, with [99mTc] TRODAT-1 as the ligand. RESULTS: DAT availability in the basal ganglia, caudate nucleus, and putamen was significantly lower in the parents with ADHD offspring than in the healthy controls without ADHD offspring. CONCLUSION: The results suggest that ADHD could be heritable via abnormal DAT activities.

The OXTR Polymorphism Stratified the Correlation of Oxytocin and Glucose Homeostasis in Non-Diabetic Subjects.

OBJECTIVE: Previous animal studies have shown that the oxytocin system might affect glucose homeostasis through the hypothalamus-pituitary-adrenal (HPA) axis and peripheral organs. Moreover, whether the effect is stratified by the polymorphism of oxytocin receptor gene (OXTR) remains unclear. METHODS: In this study, we recruited 89 non-diabetic participants. Their plasma oxytocin and serum insulin profiles were obtained, and the polymorphism of OXTR rs53576 was genotyped. RESULTS: There were significant correlations between the oxytocin level and fasting glucose level (r = -0.29, P <0.01), insulin level (r = -0.26, P = 0.01), and homeostasis model assessment-estimated insulin resistance (HOMA-IR) (r = -0.25, P = 0.01), when adjusted for age, gender, and body mass index (BMI). When further considering the stratification effects of OXTR variation, we found that the oxytocin level was significantly correlated with the fasting glucose level (r = -0.25, P = 0.04), insulin level (r = -0.35, P = 0.03), and HOMA-IR (r = -0.35, P < 0.01) in subjects with the OXTR A allele (n = 75) after adjustment for age, gender, and BMI. In addition, the oxytocin level in those with the GG genotype of OXTR was significantly negatively correlated with the leptin level (n = 14, r = -0.66, P = 0.02). CONCLUSION: The results demonstrated that the polymorphism of OXTR plays an important role in individual differences in the correlation of oxytocin and glucose homeostasis in non-diabetic subjects.

The association between plasma cholesterol and the effect of tryptophan depletion on heart rate variability.

Studies on the cholesterol-serotonin hypothesis and its link to mood disorders are scarce. In addition, little is known about the association between cholesterol and the effects of tryptophan depletion (TD). The aim of the present study was to investigate the association between plasma cholesterol and changes in heart rate variability (HRV), an important marker of depression and anxiety, after TD. The plasma cholesterol levels of 28 healthy participants were noted, and their HRVs were measured by spectrum analysis. TD was carried out on testing day, and participants provided blood samples just before and 5 hours for tryptophan level after TD. HRV was measured again after TD. An association was found between plasma cholesterol levels and the change in HRV. Decreased high frequency HRV was marginally associated with lower levels of high-density lipoprotein cholesterol, while increased low frequency HRV was significantly associated with lower levels of total and low-density lipoprotein cholesterol. Our findings indicate that low cholesterol levels may play parts of role in the mechanism of the deactivation of parasympathetic, and activation of sympathetic, functions induced by altered serotonergic function.

Orbitofrontal dysfunction during the reward process in adults with ADHD: An fMRI study.

OBJECTIVE: The present study aimed to detect differences in the reward response between adults with attention deficit hyperactivity disorder (ADHD) and healthy controls (HCs) using functional magnetic resonance imaging (fMRI). METHODS: The Iowa gambling task (IGT) was designed to explore participants' reward-related decision-making in relation to selections during risky behaviors. Twenty adults with ADHD and 20 HCs were enrolled. fMRI with a modified IGT was performed. RESULTS: The adults with ADHD showed a poorer performance in terms of avoidance during risky behaviors. The fMRI results indicated that the adults with ADHD had significantly lower orbitofrontal cortex (OFC) activation. A positive correlation between performance in the IGT and brain activation in the OFC was detected. CONCLUSIONS: The results suggested that the adults with ADHD exhibited abnormal OFC responses during decision-making. SIGNIFICANCE: To the best of our knowledge, this is the first study to use fMRI to collect brain activation data while performing the IGT in adults with ADHD. Our findings suggest that deficits in reward processing in ADHD are still present during adulthood.

The Interaction of Oxytocin and Social Support, Loneliness, and Cortisol Level in Major Depression.

OBJECTIVE: Loneliness is a specific risk factor for depressive symptoms and suicidal behavior. The present study examined whether the serum oxytocin level would interact with social support and buffers loneliness and hypothalamic-pituitary-adrenal (HPA)-axis activity in drug-naïve patients with major depressive disorder (MDD). METHODS: Twenty-six patients with MDD (male:female = 3:23; mean age, 45.54 ± 12.97 years) were recruited. The 17-item Hamilton Depression Rating Scale, UCLA Loneliness Scale and self-reported Measurement of Support Function Questionnaire were administered. Serum oxytocin and cortisol levels were assessed using a commercial immunoassay kits. RESULTS: In MDD patients, a negative association was found between degrees of social support and loneliness (ß= -0.39, p = 0.04). The interaction between social support and serum oxytocin level was negatively associated with loneliness (ß= -0.50, p = 0.017) and serum cortisol level (ß= -0.55, p = 0.020) after adjusting for age. Follow-up analyses showed that the association between higher social support and lower loneliness was observed only in the higher-oxytocin group (r = -0.75, p = 0.003) but not in the lower group (r = -0.19, p = 0.53). The significance remained after further adjusting for sex and depression severity. CONCLUSION: Low oxytocin level is a vulnerability factor for the buffering effect of social support for loneliness and aberrant HPA-axis activity in MDD patients.