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Objective Suicidal behavior and different mood states of bipolar I disorder (BD) have been shown to be associated with dysregulated proinflammatory cytokines. Only a few studies have examined the association between inflammation and SB in BD, and the association between proinflammatory cytokines, SB, and cognitive deficits in patients with BD remains unclear. Methods 77 patients with BD and 61 age-/sex-matched healthy controls were recruited. Patients were divided into two groups: with suicidal ideation (SI; n = 21) and no SI (n = 56). SI was defined by a score of ≥1 in item 10 of Montgomery Asberg Depression Rating Scale. Levels of proinflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), and C-reactive protein (CRP), were measured, and cognitive function was assessed using 2-back task and Go/No-Go task. Results Patients with SI had higher levels of sTNF-αR1 than those without SI and the controls (p = .004). BD patients with or without a history of suicide attempt had higher levels of CRP than the controls. SI was associated with serum levels of sTNF-αR1 and IL-6sR, even after additionally controlling for working memory and inhibitory control (p Conclusion This study indicates that serum levels of sTNF-αR1 have distinct differences between BD patients with or without SI, and our findings strengthen the hypothesis of a link between suicidal behavior and neuro-inflammation pathophysiology in BD.

Objective: We investigated the diagnostic progression to bipolar disorder (BD) among adolescents and young adults with attention-deficit/hyperactivity disorder (ADHD). Methods: Using the Taiwan National Health Insurance Research Database, we enrolled adolescents and young adults aged 10–29 years with ADHD between January 1, 2001, and December 31, 2010, who were followed up until December 31, 2011, to determine progression to BD. Cox regression analysis was used to examine candidate risk and protective factors. Results: At the 11-year follow-up, the progression rate from ADHD to BD was 5.12%. Of the participants who progressed, 62.16% (322/518) progressed within the first 3 years. Risk factors for progression were as follows: older age (hazard ratio [HR], 1.058; 95% confidence interval [CI], 1.033–1.084), comorbidity with autistic spectrum disorder (HR, 1.839; 95% CI, 1.415–2.391), disruptive behavior disorder (HR, 1.434; 95% CI, 1.132–1.816), intelligence disability (HR, 1.744; 95% CI, 1.399–2.176), depressive disorder (HR, 1.978; 95% CI, 1.577–2.482), alcohol use disorder (HR, 1.705; 95% CI, 1.057–2.751), cluster A (HR, 2.508; 95% CI, 1.167–5.391) or B (HR, 2.718; 95% CI, 1.974–3.741) personality disorder, and a family history of BD (HR, 2.618; 95% CI, 1.823–3.758) Identified protective factors were male sex (HR, 0.771; 95% CI, 0.630–0.943) and cluster C personality disorder (HR, 0.278; 95% CI, 0.086–0.898). Conclusion: The study demonstrated the specific risk and protective factors for BD progression among adolescents and young adults with ADHD. It is important for clinician and mental health care providers to recognize identified factors to focus on early detection and prompt intervention.

This Taiwan study examined the associations of parental age and mental disorders with the offspring risks of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), major depressive disorder (MDD), and bipolar disorder (BD). Children born between January 1991 and December 2004 in Taiwan were enrolled as the birth cohort (n = 4,138,151) and followed up until December 2011. A logistic regression analysis was performed to identify the odds ratio (OR). The advanced age effects were significant in ADHD (range of OR: 1.04 to 1.49) and ASD (range of OR: 1.35 to 2.27). Teenage mothers, teenage fathers, and fathers ≥ 50 years had higher offspring risks of MDD (range of OR: 1.24 to 1.46); and teenage mothers and fathers ≥ 50 years had increased offspring risks of BD (range of OR: 1.23 to 1.87). Both paternal and maternal mental disorders were associated with higher risks of within-disorder transmission for ADHD, ASD, MDD, and BD (range of OR: 2.64 to 30.41). Besides, parents with one of these four mental disorders (ADHD, ASD, MDD, and BD) might have higher risk of cross-disorder transmission to at least one of the other three mental disorders in the offspring (range of OR: 1.35 to 7.15). Parental age and mental disorders had complex and nuanced patterns in association with offspring mental disorders.

Background Accumulating evidence suggests neurological manifestations after dengue infection. However, the relationship between dengue and long-term neurocognitive sequel remains unclear. Methods We recruited 816 patients with dengue and 8,160 controls between 1997 and 2012 using data from Taiwan National Health Insurance Research Database and followed them up until the end of 2013. Individuals who exhibited any type of dementia were identified during the follow-up period. Cox regression analyses were performed with adjustments for demographic data and medical and mental comorbidities (cerebrovascular diseases, traumatic brain injury, hypertension, dyslipidemia, diabetes mellitus, depression, alcohol use disorder, and substance use disorder). The E-value for the causality of the evidence was calculated. Sensitivity analysis was conducted to exclude patients with prodromal dementia. Results Patients with dengue were more likely to develop dementia (hazard ratio [HR]: 2.23, 95% confidence interval [CI]: 1.51–3.28), Alzheimer's disease (HR: 3.03, 95% CI: 1.08–8.45), and unspecified dementia (HR: 2.25, 95% CI: 1.43–3.53), but not vascular dementia compared to controls during the follow-up period. Sensitivity analyses after exclusion of the observation period over the first three years or first five years and after exclusion of patients’ enrollment before 2010 or 2008 showed consistent findings. The E-values for the HR (range 3.62–5.51) supported the association between dengue and subsequent dementia among the whole population, men, and women. Conclusion The risk of dementia was 2.23-fold higher in patients diagnosed with dengue during the follow-up period than in the controls. Further studies are necessary to investigate the underlying pathophysiology of dengue and dementia.

BackgroundDysregulated proinflammatory cytokines have been shown to be associated with suicidal behavior. Cognitive deficits in working memory and inhibitory control have been demonstrated in depressed patients and people with suicidal ideation (SI). However, the association between proinflammatory cytokines, SI, and cognitive deficits in patients with major depressive disorder (MDD) remains unclear.MethodsA total of 77 patients with MDD and age-/sex-matched 60 healthy individuals were recruited. MDD patients were divided into two groups: with SI (n = 36) and no SI (n = 41). SI was defined by a score of ≥2 in item 3 of the 17-item Hamilton Rating Scale for Depression. Levels of proinflammatory cytokines, including soluble interleukin-6 receptor, soluble tumor necrosis factor-α receptor type 1, and C-reactive protein (CRP), were measured, and cognitive function was assessed using 2-back task and Go/No-Go task.ResultsPatients with SI had higher levels of CRP than those without SI and controls (P = .007). CRP was positively associated with SI (β = 0.21, P = .037), independent of cognitive function and depressive symptoms. Furthermore, SI was associated with cognitive deficits in working memory and inhibitory control after adjusting for confounding factors (P ConclusionOur findings suggest that higher levels of serum CRP and deficits in working memory and inhibitory control may be associated with higher SI among patients with MDD.

Background Retrospective studies have suggested that patients with dementia have higher prevalence of atopic dermatitis (AD) than those without dementia. However, the temporal association of AD with subsequent dementia remains unknown. Objective To assess the temporal association of AD with subsequent dementia. Methods We included data of patients with AD aged 45 years and older (n = 1059) and 1:10 age, sex, residence, income, and dementia-related comorbidity–matched controls (n = 10,590) from the Taiwan National Health Insurance Research Database and reviewed their subsequent dementia development from the enrollment date to the end of 2013. Results After adjustments for dementia-related comorbidities, patients with AD were found to be more likely to develop any dementia (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.24-3.29), particularly Alzheimer's disease (HR, 3.74; 95% CI, 1.17-11.97), during the follow-up period than those in the control group. Moderate-to-severe AD was associated with a high subsequent dementia risk (HR, 4.64; 95% CI, 2.58-8.33). Sensitivity analyses with the exclusion of the first 3 (HR, 2.20; 95% CI, 1.28-3.80) or 5 (HR, 2.05; 95% CI, 1.08-3.89) years of observation revealed consistent findings. Conclusion AD may be an independent risk factor for new-onset dementia. Clinicians may monitor the trajectory of neurocognitive function among elderly patients with AD. Additional studies elucidating the pathomechanisms between AD and subsequent dementia are warranted.

Background and Purpose: Patients with obsessive-compulsive disorder (OCD) tend to be comorbid with stroke-related risk factors, including obesity, hypertension, and diabetes. However, the temporal association between OCD and subsequent stroke risk is unclear. Methods: Using data collected between 2001 and 2010 by Taiwan’s National Health Insurance Research Database, 28 064 adult patients with OCD (International Classification of Diseases, Ninth Revision, Clinical Modification [ ICD-9-CM ] code: 300.3) and 28 064 age-, sex-, and comorbidity-matched controls were included in this study. Patients who developed ischemic ( ICD-9-CM codes: 433, 434, and 435) and hemorrhagic ( ICD-9-CM codes: 430, 431, and 432) stroke during follow-up (from enrollment to end of 2011) were identified. Moreover, medications used for treating OCD were assessed. Results: Patients with OCD (hazard ratio [HR], 3.02 [95% CI, 1.91–4.77]), especially middle-aged (HR, 2.66 [95% CI, 1.34–5.29]) and elderly adults (HR, 3.46 [95% CI, 1.70–7.05]), had an elevated risk of developing ischemic stroke during the follow-up period compared with non-OCD controls. The cumulative HR of hemorrhagic stroke did not differ (HR, 0.87 [95% CI, 0.42–1.80]) between the OCD and non-OCD groups. In patients with OCD, both short- (HR, 1.69 [95% CI, 0.74–3.88]; HR, 0.31 [95% CI, 0.05–1.95]) and long-term use (HR, 1.37 [95% CI, 0.60–3.16]; HR, 0.90 [95% CI, 0.22–3.76]) of OCD medications were not correlated with ischemic and hemorrhagic stroke compared with nonuse. Conclusions: Clinicians should closely monitor cerebrovascular disease and related risks in patients with OCD. The pathomechanism of OCD with an increased risk of ischemic stroke warrants further investigation.

Background The effect of relative age on the diagnoses of attention deficit hyperactivity disorder (ADHD), disruptive behavior disorder (DD), anxiety disorder, and depressive disorder and the prescription for ADHD and antidepressant medications remains unclear. Aim To clarify the impact of relative age in a school year with the diagnoses of ADHD, DD, anxiety disorder and depressive disorder and the prescription for ADHD and antidepressant medications. Methods The annual cutoff birthdate for entry to school in Taiwan is August 31. The Taiwan National Health Insurance Research Database was used to enroll 9,548,393 children and adolescents aged 3-17 years during the study period (September 1, 2001, to August 31, 2011). The poisson regression model was performed to examine the likelihood of receiving diagnoses of ADHD, DD, anxiety disorder, and depressive disorder, as well as the prescription of ADHD and antidepressant medications among children born in August (the youngest) and September (the oldest). Results Both boys and girls born in August had a higher risk of being diagnosed as having ADHD (odds ratio [OR] = boys: 1.65, girls: 1.80), DD (1.29, 1.45), anxiety disorder (1.49, 1.33), and depressive disorder (1.10, 1.10). Furthermore, children born in August were more likely to be prescribed ADHD medication (1.71, 1.72) and antidepressants (1.18, 1.09) compared with those born in September. Discussion Relative age, as an indicator of neurocognitive maturity, is a critical factor for the likelihood of being diagnosed as having ADHD, DD, anxiety disorder, and depressive disorder among children and adolescents.

The annual cut-off birthdate for entry into school in Taiwan is August 31. Thus, children and adolescents born in August are typically the youngest in their grades. The potential effect of relative age on the diagnosis of autism spectrum disorder (ASD) remains uncertain. A total of 9,548,393 individuals aged 3–17 years during the study period (from September 1, 2001, to August 31, 2011) identified from the Taiwan National Health Insurance Research Database were enrolled into our study. Logistic regression analysis was used to examine the likelihood of receiving ASD diagnosis for those who were born in August (the youngest) compared with those who were born in September (the oldest). Both boys and girls born in August had a higher likelihood of being diagnosed with ASD (odds ratio [OR]: 1.24, 95% confidence interval [CI]: 1.16–1.32; OR: 1.23, 95% CI 1.06–1.42) than did those born in September. Sensitivity analysis conducted over different periods revealed consistent findings. Relative age, as an indicator of neurocognitive maturity, is a crucial contributor to the risk of being diagnosed with ASD among children and adolescents. Our findings highlight the importance of considering the age of a child within a grade when diagnosing ASD.

Evidence suggests that levels of treatment refractoriness and brain-derived neurotrophic factor (BDNF) rs6265 polymorphism are related to the antidepressant effects of conventional antidepressants and repetitive transcranial magnetic stimulation. However, whether these factors are associated with the antidepressant effects of low-dose ketamine remains unclear. In total, 71 patients with treatment-resistant depression (TRD) were randomized to 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and saline control infusion groups. They were further divided into three treatment refractoriness groups according to the Maudsley staging method and were genotyped for Val66Met BDNF polymorphism. Participants’ Hamilton Depression Rating Scale (HDRS) scores were assessed preinfusion, at 40, 80, 120, and 240 min postinfusion, and sequentially on days 2–7 and 14 after infusion. Patients with any Val allele exhibited an antidepressant response (p = 0.029) to 0.5 mg/kg ketamine vs. 0.2 mg/kg ketamine vs. saline control infusions. However, the trajectory of HDRS scores did not differ (p = 0.236) between the treatment groups among Met/Met carriers. In the low treatment refractoriness group, the 0.2 mg/kg ketamine infusion exhibited the optimal antidepressant effect (p = 0.002); in the moderate treatment refractoriness group, the 0.5 mg/kg ketamine infusion achieved the strongest antidepressant effect (p = 0.006); however, in the high treatment refractoriness group, the trajectory of depressive symptoms did not differ between treatments (p = 0.325). In future clinical practice, ketamine dose may be adjusted according to the level of treatment refractoriness and BDNF rs6265 polymorphism to achieve the optimal antidepressant effect for patients with TRD.

Background: Evidence suggests that clinical markers, such as comorbid anxiety, body weight, and others can assist in predicting response to low-dose ketamine infusion in treatment resistant depression patients. However, whether a composite of clinical markers may improve the predicted probability of response is uncertain. Methods: The current study investigated the results of our previous randomized placebo-controlled and open-label trials in which 73 patients with treatment-resistant depression (TRD) received a single ketamine infusion of 0.5 mg/kg. Clinical characteristics at baseline, including depression severity, duration of the current episode, obesity, comorbidity of anxiety disorder, and current suicide risk, were assessed as potential predictors in a classification and regression tree model for treatment response to ketamine infusion. Results: The predicted probability of a composite of age at disease onset, depression severity, duration of current episode, and obesity/overweight was significantly greater (area under curve = .736, p = .001) than that of any one marker (all p > .05). The most powerful predictors of treatment response to ketamine infusion were younger age at disease onset and obesity/overweight. The strongest predictors of treatment nonresponse were longer duration of the current episode and greater depression severity at baseline. Discussion: Depression severity, duration of the current episode, obesity, and age at disease onset may predict treatment response versus nonresponse to low-dose ketamine infusion. However, whether our predicted probability for a single infusion may be applied to repeated infusions would require further investigation. Clinical trial registration: UMIN Clinical Trials Registry (UMIN000023581 and UMIN000016985).

Interest and activity are part of the positive mood domain. Evidence suggests the symptom domain of interest-activity at baseline as a clinical predictor for treatment response to traditional antidepressants. However, whether this domain is related to the response to a single low-dose ketamine infusion remains unclear. Seventy-one patients with treatment-resistant depression were randomized to 3 treatment groups: a single 0.5 or 0.2 mg/kg ketamine or normal saline placebo infusion. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale before infusions and at postinfusion period (at 40 min and up to 2 weeks). Low (mild) versus medium versus high (severe) interest-activity symptom domain groups were classified on the basis of the cutoff point of ± 0.4 standard deviation. The effect of baseline interest-activity symptoms on outcomes was tested using generalized estimating equation models. The interest-activity symptom domain as a continuous variable (β = 8.413, p = .016) was related to the trajectory of depressive symptoms. Stratified by levels of the interest-activity symptom domain, in the low interest-activity, 0.2 mg/kg ketamine infusion (β = 0.013) demonstrated the greatest antidepressant effect (p

Background Studies have indicated that parental depression was slightly related to the increased risk of offspring attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the association between exposure to parental depression at different neurodevelopmental stages (i.e., perinatal or postnatal period) and subsequent ADHD and ASD development remained uncertain. Method 708,515 children born between 2001 and 2008 were screened for ADHD and ASD based on ICD-9-CM codes of 314 and 299 given by psychiatrists from their birth to the end of 2011. Paternal and maternal depression was separately assessed during five periods, namely those before pregnancy (pre-pregnancy), during pregnancy (perinatal), and 3 years after childbirth (postnatal). Cox regression analyses were performed. Results Both paternal and maternal depression occurring in the pre-pregnancy, perinatal and postnatal periods were significantly associated with subsequent ADHD and ASD in the offspring, with hazard ratios between 1.42 (95% confidence interval [CI]: 1.35–1.49) and 2.25 (2.09–2.41). The chronicity and additive effect of paternal and maternal depression were related to increased risks of offspring ADHD and ASD. The effects of maternal depression were stronger than the effects of paternal depression for offspring ADHD (HR: 1.35, 95% CI: 1.27–1.45) and ASD (HR: 1.23, 95% CI: 1.05–1.46) risks. Conclusion Both paternal depression and maternal depression in the pre-pregnancy, perinatal and postnatal periods increases offspring ADHD and ASD risks, and these risks increase further with increases in the duration of parental depression and with the additive effect of parental and maternal depression.

The association between systemic inflammation, executive dysfunction, and gray matter (GM) volume difference in first-episode affective disorders, including bipolar and major depressive disorders, is unclear.Twenty-two patients with first-episode bipolar disorder, 22 age- and sex-matched patients with first-episode major depressive disorder, and 22 matched controls were enrolled in our study; all patients underwent comprehensive assessments, including clinical assessment, executive function examination (Wisconsin card sorting test [WCST]), proinflammatory cytokine receptors (soluble interleukin-6 receptor and tumor necrosis factor-α receptor 1 [TNFR1]), and brain magnetic resonance imaging. Voxel-based morphometry was performed to analyze the GM volume difference between bipolar and major depressive disorders.Patients with bipolar disorder were more likely to exhibit higher levels of TNFR1 (P = .038), more number of deficits in WCST (P.05), and smaller GM volume in the middle frontal cortex (uncorrected voxel level P.001) compared with those with major depressive disorder and healthy controls. Positive associations were observed between the middle frontal cortex volume, executive function, and the TNFR1 level.GM volume reduction in the middle frontal cortex, a greater level of systemic inflammation, and executive dysfunction were observed in first-episode affective disorders, especially bipolar disorder. A positive correlation between middle frontal cortex volume, executive function, and the TNFR1 level may indicate a divergent effect of brain and systemic inflammation functioning in the early phase (first episode) of affective disorder.

Background Frontostriatal disconnectivity plays a crucial role in the pathophysiology of major depressive disorder. However, whether the baseline functional connectivity of the frontostriatal network could predict the treatment outcome of low-dose ketamine infusion remains unknown. Methods In total, 48 patients with treatment-resistant depression were randomly divided into 3 treatment groups (a single-dose 40-minute i.v. infusion) as follows: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and saline placebo infusion. Patients were subsequently followed-up for 2 weeks. Resting-state functional magnetic resonance imaging was performed for each patient before infusion administration. In addition, the baseline frontostriatal functional connectivity of patients with treatment-resistant depression was also compared with that of healthy controls. Results Compared with the healthy controls, patients with treatment-resistant depression had a decreased functional connectivity in the frontostriatal circuits, especially between the right superior frontal cortex and executive region of the striatum and between the right paracingulate cortex and rostral-motor region of the striatum. The baseline hypoconnectivity of the bilateral superior frontal cortex to the executive region of the striatum was associated with a greater reduction of depression symptoms after a single 0.2-mg/kg ketamine infusion. Conclusion Reduced connectivity of the superior frontal cortex to the striatum predicted the response to ketamine infusion among patients with treatment-resistant depression.

Studies have demonstrated that conduct disorder is related to risky sexual behaviors, the dominant risk factor for contracting a sexually transmitted infection (STI). However, the association between conduct disorder and STIs remains unclear. Using the Taiwan National Health Insurance Research Database, 5733 adolescents with conduct disorder and 22,932 age- and sex-matched controls without conduct disorder were enrolled from 2001 to 2009 and were subject to follow-up until the end of 2011. Participants who contracted any STI during the follow-up period were identified. Cox regression analysis was performed to examine the likelihood of subsequently contracting an STI for patients and controls. Patients with conduct disorder were more likely than controls to develop any STI (HR 3.95, 95% CI 2.97–5.26) after adjusting for demographic data, psychiatric comorbidities, and use of medications. Long-term use of second-generation antipsychotics (SGAs) was related to a reduced risk (HR 0.36, 95% CI 0.14–0.91) of developing an STI among patients with conduct disorder. Adolescents with conduct disorder had an increased risk of developing any STI later in life compared with those without conduct disorder. Long-term use of SGAs was associated with a lower risk of subsequent STI.

ObjectiveIncreasing evidence supports reciprocal communication between the enteric and the central nervous system in disease, termed the ‘gut–brain axis’. Recent findings suggest a connection between IBD and development of Parkinson’s disease. The role of IBD in dementia, another insidious neurodegenerative disorder, has not been explored.DesignUsing the Taiwanese National Health Insurance Research Database, we performed comparative analysis of 1742 patients with IBD ≥45 years old against 17 420 controls to assess dementia risk following IBD diagnosis. Controls were matched on bases of sex, access to healthcare, income and dementia-related comorbidities. All individuals were followed for dementia diagnosis for up to 16 years. Subanalyses included the relationship between sex, ulcerative colitis (UC) and Crohn’s disease (CD), and dementia risk.ResultsOverall incidence of dementia among patients with IBD was significantly elevated (5.5% vs 1.4% among controls). Patients with IBD were diagnosed with dementia at 76.24 years old on average, compared with 83.45 among controls. The HR of developing dementia among patients with IBD was 2.54 (95% CI 1.91 to 3.37). Among dementia types, the risk of developing Alzheimer’s dementia demonstrated the greatest increase. Dementia risk did not differ between sex differences nor UC versus CD.ConclusionThis population-based cohort study demonstrates significant association between IBD and subsequent development of dementia. Dementia was diagnosed at an earlier age among patients with IBD, and disease risk appeared to increase with IBD chronicity. These findings highlight the need for future research to elucidate the relationship between IBD and dementia.

BackgroundThe antidepressant effect of low-dose ketamine infusion on Taiwanese patients with anxious vs nonanxious treatment-resistant depression (ANX-TRD vs NANX-TRD) has remained unknown.MethodsIn total, 71 patients with TRD were randomized to three groups. Each group had participants who received saline infusions mixed with 0 (a normal saline infusion), 0.2, and 0.5 mg/kg of ketamine. Participants were followed up for 2 weeks. Anxious depression was defined as major depressive disorder with a total score of 7 or more on the 17-item Hamilton Depression Rating Scale Anxiety-Somatization factor. Generalized estimating equation models were used to investigate the effects of treatment (ketamine vs placebo) and depression type (ANX-TRD vs NANX-TRD) in the reduction of depressive symptoms during the follow-up period.ResultsPatients with ANX-TRD were less likely to respond to a single low-dose ketamine infusion than those with NANX-TRD. Among patients with NANX-TRD, low-dose ketamine infusion was significantly superior to placebo for reducing depressive symptoms. However, among patients with ANX-TRD, ketamine was not superior to placebo; nonetheless, approximately 30% of the patients responded to ketamine infusion compared to 13% who responded to the placebo.ConclusionsLow-dose ketamine infusion was effective for Taiwanese patients with NANX-TRD but not so effective for those with ANX-TRD. A higher level of anxiety severity accompanying depression was related to greater depression severity. This may confound and reduce the antidepressant effect of ketamine infusion.

Prolonged intermittent theta burst stimulation (piTBS) with triple doses of the standard protocol is an updated form of repetitive transcranial magnetic stimulation, and it is an effective add-on intervention for major depressive disorder. In the present study, our objective was to investigate the antidepressant efficacy of piTBS monotherapy. Efficacy between the standard 5-cm method and magnetic resonance imaging (MRI)-guided coil positioning to the left dorsolateral prefrontal cortex method was also compared.In the present double-blind, randomized, sham-controlled trial, 105 patients with recurrent depression who exhibited no responses to at least one adequate antidepressant treatment for the prevailing episode were assigned randomly to one of three groups: piTBS monotherapy (n = 35), repetitive transcranial magnetic stimulation monotherapy (n = 35), or sham stimulation (n = 35). The acute treatment period was 2 weeks. Half of the patients were randomized to MRI navigation in each group.No serious adverse events were observed. The piTBS group exhibited significantly greater decreases in depression scores than the sham group at week 2 (-40.0% vs. -13.9%; p.001 after correcting for multiple comparisons by Bonferroni [effect size (Cohen's d) = 1.12]), and the odds ratio for responses was high. The MRI navigation method (-32.4%) did not yield better antidepressant effects than the standard method (-40.6%). Brain stimulation and 17-item Hamilton Depression Rating Scale changes in the first week were the most important variables for predicting antidepressant responses.Left prefrontal piTBS monotherapy is effective for the treatment of recurrent depression, and the MRI-guided method of coil targeting is not better than the standard method.

Background Studies have suggested that psychiatric comorbidities have major effects on antidepressant resistance in adult patients with major depressive disorder (MDD). However, the association between psychiatric comorbidities and antidepressant resistance remains unclear in adolescents with MDD. Methods A total of 10,624 adolescents with MDD were selected from the Taiwan National Health Insurance Research Database between 2001 and 2010 and followed for one year. Treatment-resistant depression (TRD) was defined as unresponsiveness to at least two antidepressants, and treatment resistant tendency was defined as unresponsiveness to the first antidepressant. Psychiatric comorbidities, such as anxiety disorders, substance use disorders, and attention deficit hyperactivity disorder (ADHD), were assessed as confounding factors. Results In our study, only 1.7% (n = 184) of adolescents with MDD met the TRD criteria but 23.3% (n = 2480) were classified as exhibiting treatment resistant tendency. Anxiety disorders (OR: 2.34, 95% CI: 1.73–3.16) and substance use disorders (OR: 2.41, 95% CI: 1.28–4.54) exhibited a correlation with TRD, and ADHD (OR: 1.34, 95% CI: 1.08–1.66) was associated with treatment resistant tendency. Conclusions Approximately one-fourth of adolescents with MDD respond poorly to the first antidepressant treatment. The psychiatric comorbidities of anxiety disorders, substance use disorders, and ADHD may increase the risk of treatment resistance in adolescents with MDD.

Background: Increasing evidence suggests a potential relationship between viral infection and Parkinson’s disease (PD). Objective: Herein, we explore the association between infection by dengue virus and PD. Methods: Between 1997 and 2012, we recruited 1,422 patients with dengue fever and 14,220 matched controls (age, sex, time of enrollment, and medical and mental comorbidities) from the Taiwan National Health Insurance Research Database. We identified new onset of PD to the end of 2013. The Kaplan-Meier method was used to estimate the incidence rate of PD. Cox-regression analysis was applied to calculate the hazard ratios (HRs) with 95% confidence intervals (CIs) after adjustment for confounders. Results: During the follow up period, the dengue group had higher incidence of PD than the control group (1.2% vs. 0.4% , p = 0.001). Patients with dengue fever had a significantly higher risk of developing PD [HR, 2.59; 95% CI, 1.51–4.44] compared with the controls, after adjustments for demographic data, PD-related comorbidities, and all-cause clinical visits. The subgroup analysis, stratified by age and sex, found that higher risk for PD was statistically significant for male (HR, 3.51; 95% CI, 1.76–7.00) and patients aged >60 years (HR, 2.96; 95% CI, 1.62–5.41). Conclusion: The risk of PD was 2.59-fold higher in patients with dengue fever than in non-infected controls during the follow-up period. Clinicians need to monitor signs of PD during patient recovery from dengue fever. Additional studies are needed to confirm our results and investigate the mechanisms linking PD and dengue virus infection.

Background: Alopecia areata (AA) is associated with multiple comorbidities and shares a similar inflammatory signature with dementia. The great negative psychosocial impact of AA may result in poor social engagement, a typical risk factor for dementia. However, little is known about the association between AA and dementia.Methods: Via the Taiwan National Health Insurance Research Database, 2,534 patients with AA (International Classification of Diseases, 9th Revision, Clinical Modification code: 704.01) aged ≥ 45 years and 25,340 controls matched for age, sex, residence, income, dementia-related comorbidities, systemic steroid use, and annual outpatient visit were included between 1998 and 2011 for investigation of subsequent dementia from enrollment to the end of 2013. After controlling for potential confounders, stratified Cox regression analysis on each matched pair was applied to assess the dementia risk between the AA and control groups.Results: Patients with AA were more likely to develop any dementia (adjusted hazard ratio [aHR] = 3.24; 95% CI, 2.14-4.90), Alzheimer's disease (aHR = 4.34; 95% CI, 1.45-12.97), and unspecified dementia (aHR = 3.36; 95% CI, 2.06-5.48) than the control cohort. Stratification analysis by age and sex revealed increased risks of any dementia and unspecified dementia in both age groups (ie, < 65 and ≥ 65 years) and both sex groups and increased risks of AD in male patients and in those with age at dementia onset ≥ 65 years. Sensitivity analyses after exclusion of the first year or first 3 years of observation showed consistent findings.Conclusions: Patients with AA had a higher risk of developing dementia. Further studies are needed to elucidate the underlying pathophysiology between AA and dementia risk.

BackgroundFew studies have explored the complex relationship of pro- and anti-inflammatory cytokines with cognitive function in adolescents with first-episode schizophrenia, bipolar disorder, or major depressive disorder.MethodsIn total, 26, 35, and 29 adolescents with first-episode schizophrenia, bipolar disorder, and major depressive disorder, respectively, and 22 age- and sex-matched controls were included in the current study. Cytokines, namely interleukin (IL)-2, IL-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP), were assessed. The Wisconsin Card Sorting Test (WCST) and the working memory task were administered to assess cognitive function.ResultsUsing generalized linear models with adjustment for demographic data and clinical symptoms, patients with bipolar disorder were found to exhibit the highest levels of CRP (P = .023), IL-6 (P = .022), and TNF-α (P = .011), and had the lowest IL-2 levels (P = .034) among the four groups. According to the results of the WCST and working memory task, adolescents with schizophrenia exhibited the lowest performance in cognitive function. In addition, among the assessed cytokines, only CRP levels (P = .027) were negatively associated with WCST scores.DiscussionDysregulated pro- and anti-inflammatory cytokines and impaired cognitive functioning were observed in first-episode adolescent-onset schizophrenia, bipolar disorder, and major depressive disorder. The altered cytokine profiles may play important roles in the pathophysiology of schizophrenia, bipolar disorder, and major depressive disorder.

The association of major depressive disorder (MDD) with cardiovascular diseases (CVDs) through endothelial dysfunction is bidirectional. Circulating endothelial progenitor cells (cEPCs), essential for endothelial repair and function, are associated with risks of various CVDs. Here, the relationship of cEPC counts with MDD and the related clinical presentations were investigated in 50 patients with MDD and 46 healthy controls. In patients with MDD, a battery of clinical domains was analysed: depressed mood with Hamilton Depression Rating Scale (HAMD) and Montgomery–Åsberg Depression Rating Scale (MADRS), anxiety with Hamilton Anxiety Rating Scale (HAMA), cognitive dysfunction and deficit with Digit Symbol Substitution Test (DSST) and Perceived Deficits Questionnaire-Depression (PDQ-D), somatic symptoms with Depressive and Somatic Symptom Scale (DSSS), quality of life with 12-Item Short Form Health Survey (SF-12) and functional disability with Sheehan Disability Scale (SDS). Immature and mature cEPC counts were measured through flow cytometry. Increased mature and immature cEPC counts were significantly associated with higher anxiety after controlling the confounding effect of systolic blood pressure, and potentially associated with more severe depressive symptoms, worse cognitive performance and increased cognitive deficit, higher social disability, and worse mental health outcomes. Thus, cEPCs might have pleiotropic effects on MDD-associated symptoms and psychosocial outcomes.

Background: Etiologic differences between bipolar I disorder (BD-I) and bipolar II disorder (BD-II) have been challenged recently, and family epidemiologic studies may elucidate the matter. Nevertheless, it remains unclear whether BD-I and BD-II display different familial aggregation patterns within each bipolar disorder subtype and coaggregation with other psychiatric disorders. Method: Per the Taiwan National Health Insurance Research Database (N = 23,258,175), patients with bipolar disorder were classified as having BD-I or BD-II based on the history of psychiatric hospitalization for a manic episode. During the study period (2001-2011), 184,958 first-degree relatives (FDRs) of patients with BD-I and BD-II were identified. By comparing patients with 1:4 age-, sex-, and kinship-matched samples without BD-I/BD-II probands, the relative risks (RRs) of major psychiatric disorders were estimated. Results: FDRs of BD-I probands had a significantly higher risk of BD-I than those of BD-II probands (BD-I proband: RR = 15.80 vs BD-II proband: RR = 5.68, P

BACKGROUND Whether a single low-dose ketamine infusion may have rapid antidepressant and antisuicidal effects in patients with treatment-resistant double depression remains unclear. METHODS This study enrolled 35 patients with treatment-resistant double depression, 12 of whom received 0.5 mg/kg ketamine, 11 received 0.2 mg/kg ketamine, and 12 received normal saline as a placebo. The patients were assessed using the 17-item Hamilton Rating Scale for Depression (HDRS) prior to the initiation of infusions, at 40 and 240 min post-infusion, and sequentially on Days 2-7 and on Day 14 after ketamine or placebo infusions. RESULTS A single 0.5 mg/kg ketamine infusion had rapid antidepressant (p = 0.031, measured by the HDRS) and antisuicidal (p = 0.033, measured by the HDRS item 3 scores) effects in patients with treatment-resistant double depression. However, 0.2 mg/kg ketamine was insufficient to exert rapid antidepressant and antisuicidal effects in this patient population with severe and chronic illness. DISCUSSION In this patient population, the commonly used dose of 0.5 mg/kg was sufficient. Additional studies are required to investigate whether repeated infusions of low-dose ketamine may also maintain antidepressant and antisuicidal effects in patients with treatment-resistant double depression.

The ability to classify patients with bipolar disorder (BD) is restricted by their heterogeneity, which limits the understanding of their neuropathology. Therefore, we aimed to investigate clinically discernible and neurobiologically distinguishable BD subtypes. T1-weighted and resting-state functional magnetic resonance images of 112 patients with BD were obtained, and patients were segregated according to diagnostic subtype (i.e., types I and II) and clinical patterns, including the number of episodes and hospitalizations and history of suicide and psychosis. For each clinical pattern, fewer and more occurrences subgroups and types I and II were classified through nested cross-validation for robust performance, with minimum redundancy and maximum relevance, in feature selection. To assess the proportion of variance in cognitive performance explained by the neurobiological markers, multiple linear regression between verbal memory and the selected features was conducted. Satisfactory performance (mean accuracy, 73.60%) in classifying patients with a high or low number of episodes was attained through functional connectivity, mostly from default-mode and motor networks. Moreover, these neurobiological markers explained 62% of the variance in verbal memory. The number of episodes is a potentially critical aspect of the neuropathology of BD. Neurobiological markers can help identify BD neuroprogression.

BackgroundWhether the first-degree relatives (FDRs) of patients with obsessive-compulsive disorder (OCD) have an increased risk of the major psychiatric disorders, namely schizophrenia, bipolar disorder, OCD, major depressive disorder (MDD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD), remains unclear.MethodsUsing the Taiwan National Health Insurance Research Database with the whole population sample size (n = 23 258 175), 89 500 FDRs, including parents, offspring, siblings, and twins, of patients with OCD were identified in our study. The relative risks (RRs) of major psychiatric disorders were assessed among FDRs of patients with OCD.ResultsFDRs of patients with OCD had higher RRs of major psychiatric disorders, namely OCD (RR 8.11, 95% confidence interval (CI) 7.68–8.57), bipolar disorder (RR 2.85, 95% CI 2.68–3.04), MDD (RR 2.67, 95% CI 2.58–2.76), ASD (RR 2.38, 95% CI 2.10–2.71), ADHD (RR 2.19, 95% CI 2.07–2.32), and schizophrenia (RR 1.97, 95% CI 1.86–2.09), compared with the total population. Different familial kinships of FDRs, such as parents, offspring, siblings, and twins consistently had increased risks for these disorders. In addition, a dose-dependent relationship was found between the numbers of OCD probands and the risk of each major psychiatric disorder.ConclusionsThe FDRs, including parents, offspring, siblings, and twins, of patients with OCD have a higher risk of OCD, schizophrenia, bipolar disorder, MDD, ADHD, and ASD. The familial co-aggregation of OCD with OCD and other major psychiatric disorders was existent in a dose-dependent manner. Given the increased risks of psychiatric disorders, medical practitioners should closely monitor the mental health of the FDRs of patients with OCD.

Objectives: Patients with social anxiety disorder (SAD) often have a fear of seeking professional help. In this study, we intended to validate the Taiwanese version of the Inventory of Depressive Symptomatology, Self-report (IDS-SR), and to investigate whether severity of depression and/or social anxiety is associated with professional help-seeking among Internet users with SAD. Methods: In the study part I, we recruited volunteers through the internet, assessed their social anxiety and depression, and examined the Taiwanese version of the IDS-SR. In study Part II, we again recruited volunteers from the Internet and outpatient clinic, and did the telephone or face-to-face interview to establish the validity of the IDS-SR. Finally, the results of both parts were integrated to analyze help-seeking behaviors. Results: We included 2,079 participants in study part I, which showed that the IDS-SR was reliable. In the Part II study, the IDS-SR was found to be valid from 104 participants. Among the study Part I participants who reached the threshold of SAD, a high prevalence (52.9%) of major depressive disorder was found. Multiple logistic regression analysis of scores of the participants who met the threshold of SAD (n = 1,483) revealed that the IDS-SR total score was significantly associated with professional help-seeking (p < 0.001), whereas the severity of social anxiety was not. Conclusion: The Taiwanese version of IDS-SR was valid and reliable. The severity of depression, rather than that of social anxiety, was associated with professional help-seeking behaviors among Internet users with SAD. Screening depression in people with SAD has the potential in identifying those who may seek professional help.

Background Cardiometabolic diseases are suggested to be associated with bipolar disorder. However, the risk of metabolic disorders in unaffected siblings of patients with bipolar disorder remains unclear. Methods From the Taiwan National Health Insurance Research Database, 7,225 unaffected siblings of bipolar probands and 28,900 age-/sex-/income-/residence-matched control individuals were included and followed until the end of 2011. Individuals who developed metabolic disorders during the follow-up period were identified. Results The unaffected siblings of bipolar probands had a higher prevalence of dyslipidemia (5.4% vs. 4.5%, p = 0.001), younger age at diagnosis of type 2 diabetes mellitus (34.81 vs. 37.22, p = 0.024), and higher prevalence of any stroke (1.5% vs. 1.1%, p = 0.007) than the controls. Moreover, only male siblings of bipolar probands had an increased risk of dyslipidemia (odds ratio [OR]: 1.28, 95% confidence interval [CI]: 1.10–1.48) and higher rates of any stroke (OR: 1.38, 95% CI: 1.02–1.85) and ischemic stroke (OR: 2.43, 95% CI: 1.60–3.70) during the follow-up compared with the controls. Discussion Unaffected siblings of bipolar patients, particularly brothers, had a higher prevalence of dyslipidemia and ischemic stroke compared with the controls. The result suggests the familial association between cardiometabolic diseases and bipolar disorder. Further research may be necessary to identify this shared etiology between the disorders.

Background Gray matter volume reduction in specific brain regions, such as the prefrontal cortex, was found in patients with bipolar disorder and those with unipolar depression. However, few studies have directly compared gray matter volumes between bipolar disorder and unipolar depression. In addition, it is unknown whether proinflammatory cytokines play a role in the gray matter volume difference between bipolar disorder and unipolar depression. Methods Twenty-three patients with bipolar disorder and 23 with unipolar depression in a mildly ill state (Clinical Global Impression-Severity ≤ 3) were enrolled in our study. Each participant underwent structural magnetic resonance imaging and proinflammatory cytokines examination. Voxel-based morphometry was performed to investigate the gray matter volume difference between bipolar disorder and unipolar depression. Correlations of the proinflammatory cytokines and the gray matter volume difference were analyzed. Results Several brain regions, including the orbitofrontal cortex, lingual gyrus, inferior frontal cortex, middle frontal cortex, and planum polare, were significantly smaller in patients with bipolar disorder than in those with unipolar depression. These gray matter volume differences between bipolar disorder and unipolar depression were negatively correlated with soluble IL-6 receptor levels. Discussion Proinflammatory cytokines, especially IL-6, were associated with the gray matter volumes in bipolar disorder and unipolar depression. However, the complicated associations between proinflammatory cytokines, neurocognitive function, and gray matter volumes require further investigation.

Background: The association between postpartum depression and postpartum psychosis and subsequent maternal and offspring mental disorders in Western countries has been established; however, whether the relationship can be generalized to the Asian population is unknown. Methods: Using the Taiwan National Health Insurance Research Database, this study enrolled 933,745 mother-infant pairs who delivered their first child and had no history of severe mental illness before childbirth from 2001 to 2010. Postpartum depression and postpartum psychosis were assessed in 3 periods between childbirth and 3, 6, or 12 months after childbirth. Subsequent maternal schizophrenia (ICD-9-CM code: 295), bipolar disorder (ICD-9-CM code: 296 except 296.2x, 296.3x, 296.9x, and 296.82), and depressive disorder (ICD-9-CM codes: 296.2x, 296.3x, 300.4, and 311) and offspring autism spectrum disorder (ASD; ICD-9-CM code: 299) and attention-deficit/hyperactivity disorder (ADHD; ICD-9-CM code: 314) were identified during the follow-up period to the end of 2011. Results: Both postpartum depression and postpartum psychosis were found to be related to increased risks of schizophrenia, bipolar disorder, and depressive disorder in mothers, with hazard ratios (HRs) ranging between 8.80 (95% CI, 7.95-9.74) and 63.96 (95% CI, 50.39-81.18). Children exposed to maternal postpartum depression and psychosis were more likely to develop ADHD. Only postpartum depression was related to the likelihood of offspring ASD. Conclusions: Per these findings, we clinicians and health care providers should closely monitor the mental health condition of postpartum women and their children.

Background Evidence suggests that major depressive disorder is related to neuroaxonal injury and that neurofilament light chain (NfL) is a biomarker of neuroaxonal injury. In addition, proinflammatory cytokines have been reported to be associated with major depression and neuroaxonal injury. Methods Forty patients with major depression and 40 age- and sex-matched healthy control participants were enrolled for the measurement of NfL and proinflammatory cytokines and assessment of executive function. General linear models were used to examine the association between NfL levels, proinflammatory cytokine levels, and executive function. Results Patients with major depressive disorder exhibited significantly higher NfL levels (P = .007) than the control participants. NfL levels were positively related to log-transformed levels of tumor necrosis factor-α (P = .004). Higher levels of NfL (P = .002) and tumor necrosis factor-α (P = .013) were associated with greater deficits in executive function. Discussion NfL was a novel biomarker for major depressive disorder and related executive dysfunction. Further studies are necessary to elucidate the role of NfL in the pathophysiology of major depression and related cognitive impairment.

Background Several case reports have suggested an association between obsessive-compulsive disorder (OCD) and dementia. However, the exact relationship remains unclear. Methods Using the Taiwan National Health Insurance Research Database, 1,347 patients with OCD (ICD-9-CM code 300.3) aged ≥ 45 years and 13,470 controls matched for age, sex, residence, income, and dementia-related comorbidities were included between 1996 and 2013 for investigation of subsequent dementia from enrollment to the end of 2013. Stratified Cox regression analysis on each matched pair was applied to assess the dementia risk between the OCD and control groups. The analysis for the current study was performed in 2018. Results Patients with OCD had increased risk of developing any dementia (hazard ratio [HR] = 4.28; 95% confidence interval [CI], 2.96-6.21), Alzheimer's disease (HR = 4.04; 95% CI, 1.55-10.54), and vascular dementia (HR = 3.95; 95% CI, 1.70-9.18) compared with controls. Discussion Future research on the pathogenic mechanisms and molecular underpinnings of the relationship between OCD and dementia may lead to the development of novel therapeutics.

Irritable bowel syndrome (IBS) is a functional bowel disorder that is highly comorbid with mental disorders. However, few studies have examined the risk of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), and schizophrenia in the offspring of parents with IBS. We used nationally representative cross-sectional survey data to analyze cross-generational transmission patterns of both IBS and major mental disorders. Odds ratio (OR) was calculated by using logistic regression models with adjustment for potential confounding factors. Offspring of parents with IBS were more likely to develop IBS themselves (OR = 2.41, 95% confidence interval (CI), 2.09–2.78), ADHD (OR = 1.33, 95% CI, 1.08–1.62), and MDD (OR = 1.32, 95% CI, 1.04–1.68) than the controls. Data stratification by parental sex revealed that paternal IBS increased risk of ADHD (OR = 1.34, 95% CI, 1.01–1.77) in the offspring, while maternal IBS increased the risk of MDD (OR = 1.51, 95% CI, 1.11–2.06). This is the first study to reveal parental IBS is associated with IBS, ADHD, and MDD among offspring, suggesting the necessity for early implementation of prevention strategies for at-risk children.

Background Prolonged intermittent theta-burst stimulation (piTBS) and repetitive transcranial magnetic stimulation (rTMS) are effective antidepressant interventions for major depressive disorder (MDD). Cognition-modulated frontal theta (frontalθ) activity had been identified to predict the antidepressant response to 10-Hz left prefrontal rTMS. However, whether this marker also predicts that of piTBS needs further investigation. Methods The present double-blind randomized trial recruited 105 patients with MDD who showed no response to at least one adequate antidepressant treatment in the current episode. The recruited patients were randomly assigned to one of three groups: group A received piTBS monotherapy; group B received rTMS monotherapy; and group C received sham stimulation. Before a 2-week acute treatment period, electroencephalopgraphy (EEG) and cognition-modulated frontal theta changes (Δfrontalθ) were measured. Depression scores were evaluated at baseline, 1 week, and 2 weeks after the initiation of treatment. Results The Δfrontalθ at baseline was significantly correlated with depression score changes at week 1 (r = −0.383, p = 0.025) and at week 2 for rTMS group (r = −0.419, p = 0.014), but not for the piTBS and sham groups. The area under the receiver operating characteristic curve for Δfrontalθ was 0.800 for the rTMS group (p = 0.003) and was 0.549 for the piTBS group (p = 0.619). Conclusion The predictive value of higher baseline Δfrontalθ for antidepressant efficacy for rTMS not only replicates previous results but also implies that the antidepressant responses to rTMS could be predicted reliably at baseline and both piTBS and rTMS could be effective through different neurobiological mechanisms.

Background: Proton pump inhibitors (PPIs) are among the most widely used drugs. Little is known about the association between PPI use and risk of psoriasis. Objective: To investigate the association between PPI use and subsequent psoriasis risk. Methods: We included participants from the Taiwan National Health Insurance Research Database. Patients with PPI use and an incidence of psoriasis (n = 5,756) were assigned to the case cohort and 1:1 matched to controls. PPI use was defined as >30 cumulative defined daily doses (cDDDs); PPI nonuse was defined as ≤30 cDDDs. Logistic regression was used for the analyses. Results: There was a significant association between PPI use and psoriasis risk. The confounder-adjusted odd ratios (95% confidence interval [CI]) were 1.52 (1.31–1.76) and 1.54 (1.22–1.93) for patients with 120–365 cDDDs and >365 cDDDs, respectively, compared with PPI nonusers. Stratified analyses based on PPI type showed that exposure to lansoprazole (OR, 1.25; 95% CI, 1.11–1.41) was associated with subsequent psoriasis risk. Conclusions: PPI use might be associated with an increased risk of developing psoriasis or as an epiphenomenon. Further prospective studies are needed to elucidate the association and underlying mechanisms.

Objective Previous epidemiologic studies have suggested an association between appendectomy and Parkinson's disease. The aim of the current study was to examine the risk of Alzheimer's disease (AD) and other types of dementia following appendicitis or appendectomy for appendicitis. Design Population-based cohort study. Setting and participants We used claims data from the Taiwan National Health Insurance Research Database. Participants aged ≥45 years with acute appendicitis or who received appendectomy for appendicitis were enrolled and followed up for more than 15 years. Cases and controls underwent 1:1 matching by age, sex, index date, and dementia-related comorbidities. Methods The primary outcome was AD, and secondary outcomes included other dementia types. Adjusted hazard ratios (aHRs) were calculated, and a competing risk regression model was created. The E value for causality of evidence was calculated. Results Patients developing appendicitis (0.6% vs 0.1%, P = .005) and those receiving appendectomy for appendicitis (0.4% vs 0.1%, P = .003) had higher incidences of AD than the controls during the follow-up period. A Cox regression analysis with adjustment for potential confounders showed that patients with appendicitis [aHR 6.68, 95% confidence interval (CI) 1.84-24.48] and those receiving appendectomy for appendicitis (aHR 5.01, 95% CI 1.33-18.85) were more likely to develop AD than the controls. These 2 groups also had higher risks for unspecified dementia and all types of dementia but not for vascular dementia than the controls. The age at dementia diagnosis was 88.51 years in the controls; however, among people who developed dementia following appendicitis, the mean age at diagnosis was 70.18 years, and dementia occurred 5.84 years after appendicitis. The competing risk regression models and the E values support the study findings. Conclusions and implications After recovery from appendicitis, these patients should be followed up for signs of AD.

Background Altered immunity and metabolic profiles have been compared between bipolar depression (BD) and major depressive disorder (MDD). This study aimed at developing a composite predictor of appetite hormones and proinflammatory cytokines to differentiate BD from MDD. Methods This cross-sectional study enrolled patients with BD and those with MDD aged 20 to 59 years and displaying depressive episodes. Clinical characteristics (age, sex, body mass index, and depression severity), cytokines (C-reactive protein, interleukin [IL]-2, IL-6, tumor necrosis factor [TNF]-α, P-selectin, and monocyte chemoattractant protein), and appetite hormones (leptin, adiponectin, ghrelin, and insulin) were assessed as potential predictors using a classification and regression tree (CRT) model for differentiating BD from MDD. Results The predicted probability of a composite predictor of ghrelin and TNF-α was significantly greater (for BD: area under curve = 0.877; for MDD: area under curve = 0.914) than that of any one marker (all P > .05) to distinguish BD from MDD. The most powerful predictors for diagnosing BD were high ghrelin and TNF-α levels, whereas those for MDD were low ghrelin and TNF-α levels. Conclusion A composite predictor of ghrelin and TNF-α driven by CRT could assist in the differential diagnosis of BD from MDD with high specificity. Further clinical studies are warranted to validate our results and to explore underlying mechanisms.

Background Women with bipolar disorder (BD) may continue psychotropics during pregnancy. The association of exposure to antidepressant, antipsychotics, and mood stabilizers with offspring risks of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) remains unexplored in mothers with BD. Methods A total of 5669 pregnant women with BD and 5669 psychiatrically healthy controls were identified between 2002 and 2011 from the Taiwan Longitudinal Health Insurance Database. We analyzed the odds ratios (ORs) of psychotropic types and exposure periods (3 months before pregnancy [3MbPreg] and first, second, and third trimesters [T1, T2, T3, respectively]) on the risk of ADHD and ASD by using adjusted logistic regression analyses. Results Antidepressant exposure during 3MbPreg (OR=2.15, 95% CI=1.45–3.20), T1 (OR=2.62, 95% CI=1.68–4.09), T2 (OR=2.33, 95% CI=1.18–4.63), and T3 (OR=2.33, 95% CI=1.67–6.61) was associated with increased offspring risk of ADHD, particularly for selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor. Mood stabilizer exposure during 3MbPreg increased the risks of ADHD (OR=2.39, 95% CI=1.45–3.95) and ASD (OR=3.89, 95% CI=1.30–11.65); a higher ADHD risk was associated with valproic acid (OR=2.43, 95% CI=1.32–4.47) and lamotrigine exposure (OR=8.24, 95% CI = 1.49–45.67); ASD risk was higher for lithium exposure (OR=6.75, 95% CI=1.41–32.28). Limitation In claims-data analyses, several clinical parameters or potential confounders may be incompletely captured. Conclusions Antidepressants were associated with higher offspring risk of ADHD over all gestation periods among mothers with BD than psychiatrically healthy controls, while mood stabilizers were associated with higher risk of ADHD and ASD during 3MbPreg.

Background Acetaminophen (APAP) has been associated with the development of atopic diseases. However, little is known about the relationship between prenatal APAP exposure and atopic dermatitis (AD) in offspring. Objective To investigate the association between prenatal APAP exposure and AD risk in offspring. Methods In this study, 2029 study pairs (AD-affected children and their mothers) and 5,058 control pairs were identified between 1998 and 2008 from the Taiwan Longitudinal Health Insurance Database. Maternal APAP exposure during pregnancy was assessed. Results After adjustment for potential confounders, there was a significant association between risk of offspring AD and exposure to acetaminophen in the first trimester (OR 1.16; 95% CI 1.05-1.28), the second trimester (OR 1.14; 95% CI 1.03-1.27), both first and second trimesters (OR 1.30; 95% CI 1.13-1.51), both first and third trimester (OR 1.20; 95% CI 1.04-1.39), any trimester (OR 1.12; 95% CI 1.00-1.26), and all three trimesters (OR 1.32; 95% CI 1.08-1.62) in a dose-response manner. Conclusions Prenatal exposure to acetaminophen was associated with an increased incidence of offspring AD.

Background Recent imaging studies of large datasets suggested that psychiatric disorders have common biological substrates. This study aimed to identify all the common neural substrates with connectomic abnormalities across four major psychiatric disorders by using the data-driven connectome-wide association method of multivariate distance matrix regression (MDMR). Methods This study analyzed a resting functional magnetic resonance imaging dataset of 100 patients with schizophrenia, 100 patients with bipolar I disorder, 100 patients with bipolar II disorder, 100 patients with major depressive disorder, and 100 healthy controls (HCs). We calculated a voxel-wise 4,330 × 4,330 matrix of whole-brain functional connectivity (FC) with 8-mm isotropic resolution for each participant and then performed MDMR to identify structures where the overall multivariate pattern of FC was significantly different between each patient group and the HC group. A conjunction analysis was performed to identify common neural regions with FC abnormalities across these four psychiatric disorders. Results The conjunction of the MDMR maps revealed that the four groups of patients shared connectomic abnormalities in distributed cortical and subcortical structures, which included bilateral thalamus, cerebellum, frontal pole, supramarginal gyrus, postcentral gyrus, lingual gyrus, lateral occipital cortex, and parahippocampus. The follow-up analysis based on pair-wise FC of these regions demonstrated that these psychiatric disorders also shared similar patterns of FC abnormalities characterized by sensory/subcortical hyperconnectivity, association/subcortical hypoconnectivity, and sensory/association hyperconnectivity. Conclusions These findings suggest that major psychiatric disorders share common connectomic abnormalities in distributed cortical and subcortical regions and provide crucial support for the common network hypothesis of major psychiatric disorders.

Backgrounds Evidence suggested the crucial roles of brain-derived neurotrophic factor (BDNF) and glutamate system functioning in the antidepressant mechanisms of low-dose ketamine infusion in treatment-resistant depression (TRD). Methods 65 patients with TRD were genotyped for 684,616 single nucleotide polymorphisms (SNPs). Twelve ketamine-related genes were selected for the gene-based genome-wide association study on the antidepressant effect of ketamine infusion and the resulting serum ketamine and norketamine levels. Results Specific SNPs and whole genes involved in BDNF–TrkB signaling (i.e., rs2049048 in BDNF and rs10217777 in NTRK2) and the glutamatergic and GABAergic systems (i.e., rs16966731 in GRIN2A) were associated with the rapid (within 240 min) and persistent (up to 2 weeks) antidepressant effect of low-dose ketamine infusion and with serum ketamine and norketamine levels. Discussion Our findings confirmed the predictive roles of BDNF–TrkB signaling and glutamatergic and GABAergic systems in the underlying mechanisms of low-dose ketamine infusion for TRD treatment.

Background Individuals with major depressive disorder (MDD) have a higher risk of developing Parkinson disease (PD). This study investigated whether response to treatment with antidepressants for MDD can determine patients at risk of developing PD later in life. Methods We enrolled 3303 patients with newly-diagnosed MDD and 13,212 controls between 2002 and 2004 using Taiwan's Nationwide Health Insurance Research Database. We stratified patients with MDD according to the number of antidepressant regimens prescribed to them and the age at MDD onset and followed all participants until the end of 2013. During follow-up, we evaluated patients for the possibility of developing PD. Results Patients with MDD had a greater likelihood of developing PD than controls. Patients with difficult-to-treat (DTT) MDD had a higher risk of developing PD than the other MDD subgroups (hazard ratio [HR] = 3.44, 95% confidence interval [95% CI]: = 1.99–5.95). When stratified by age ( 65 years), DTT patients with middle-age or late-onset MDD exhibited elevated risks of developing PD (50–65 years: HR: 7.03, 95% CI: 2.95–16.76; >65 years: HR: 2.89, 95% CI: 1.26–6.65). Discussion Patients with MDD and an onset age of >50 years who responded poorly to antidepressant treatment have an associated higher risk of subsequently developing PD. Therefore, when treating patients with MDD, clinicians should provide intensive antidepressant treatment and evaluations for PD so that risk-prevention measures can be implemented upon MDD diagnosis.

Background A number of mental illness is often re-diagnosed to be bipolar disorder (BD). Furthermore, the prefronto-limbic-striatal regions seem to be associated with the main dysconnectivity of BD. Functional connectivity is potentially an appropriate objective neurobiological marker that can assist with BD diagnosis. Methods Health controls (HC; n = 173) and patients with BD who had been diagnosed by experienced physicians (n = 192) were separated into 10-folds, namely, a ninefold training set and a onefold testing set. The classification involved feature selection of the training set using minimum redundancy/maximum relevance. Support vector machine was used for training. The classification was repeated 10 times until each fold had been used as the testing set. Results The mean accuracy of the 10 testing sets was 76.25%, and the area under the curve was 0.840. The selected functional within-network/between-network connectivity was mainly in the subcortical/cerebellar regions and the frontoparietal network. Furthermore, similarity within the BD patients, calculated by the cosine distance between two functional connectivity matrices, was smaller than between groups before feature selection and greater than between groups after the feature selection. Limitations The major limitations were that all the BD patients were receiving medication and that no independent dataset was included. Conclusion Our approach effectively separates a relatively large group of BD patients from HCs. This was done by selecting functional connectivity, which was more similar within BD patients, and also seems to be related to the neuropathological factors associated with BD.

Studies have suggested an association between metabolic and cerebrocardiovascular diseases and major depressive disorder (MDD). However, the risk of metabolic and cerebrocardiovascular diseases in the unaffected siblings of patients with MDD remains uncertain. Using the Taiwan National Health Insurance Research Database, 22,438 unaffected siblings of patients with MDD and 89,752 age-/sex-matched controls were selected and followed up from 1996 to the end of 2011. Individuals who developed metabolic and cerebrocardiovascular diseases during the follow-up period were identified. Compared with the controls, the unaffected siblings of patients with MDD had a higher prevalence of metabolic diseases, such as hypertension (5.0% vs. 4.5%, p = 0.007), dyslipidemia (5.6% vs. 4.8%, p < 0.001), and obesity (1.7% vs. 1.5%, p = 0.028), and cerebrocardiovascular diseases, such as ischemic stroke (0.6% vs. 0.4%, p < 0.005) and ischemic heart disease (2.1% vs. 1.7%, p < 0.001). Logistic regression analyses revealed that the unaffected siblings of patients with MDD were more likely to develop hypertension, dyslipidemia, ischemic stroke, and ischemic heart diseases during the follow-up period than the controls. Our study revealed a familial coaggregation between MDD and metabolic and cerebrocardiovascular diseases. Additional studies are required to investigate the shared pathophysiology of MDD and metabolic and cerebrocardiovascular diseases.

BackgroundFamily coaggregation of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD) and schizophrenia have been presented in previous studies. The shared genetic and environmental factors among psychiatric disorders remain elusive.MethodsThis nationwide population-based study examined familial coaggregation of major psychiatric disorders in first-degree relatives (FDRs) of individuals with ASD. Taiwan's National Health Insurance Research Database was used to identify 26 667 individuals with ASD and 67 998 FDRs of individuals with ASD. The cohort was matched in 1:4 ratio to 271 992 controls. The relative risks (RRs) and 95% confidence intervals (CI) of ADHD, ASD, BD, MDD and schizophrenia were assessed among FDRs of individuals with ASD and ASD with intellectual disability (ASD-ID).ResultsFDRs of individuals with ASD have higher RRs of major psychiatric disorders compared with controls: ASD 17.46 (CI 15.50–19.67), ADHD 3.94 (CI 3.72–4.17), schizophrenia 3.05 (CI 2.74–3.40), BD 2.22 (CI 1.98–2.48) and MDD 1.88 (CI 1.76–2.00). Higher RRs of schizophrenia (4.47, CI 3.95–5.06) and ASD (18.54, CI 16.18–21.23) were observed in FDRs of individuals with both ASD-ID, compared with ASD only.ConclusionsThe risk for major psychiatric disorders was consistently elevated across all types of FDRs of individuals with ASD. FDRs of individuals with ASD-ID are at further higher risk for ASD and schizophrenia. Our results provide leads for future investigation of shared etiologic pathways of ASD, ID and major psychiatric disorders and highlight the importance of mental health care delivered to at-risk families for early diagnoses and interventions.

The association of appetite hormones with cognitive function in patients with affective disorders remains unknown.All total, 58 adult patients with bipolar I disorder, 36 with bipolar II disorder, 40 with major depressive disorder were enrolled and age and sex-matched with 40 controls. The levels of appetite hormones leptin, ghrelin, insulin and adiponectin were assessed. Wisconsin Card Sorting Test was used to assess executive function.A general linear model, adjusted for demographic data and clinical symptoms, demonstrated the ghrelin levels were higher in patients with bipolar I or II disorder than in those with major depressive disorder and controls (Patients with bipolar I or II disorder were more likely to have high levels of ghrelin than patients with major depressive disorder and controls, which may have a positive correlation on the cognitive function of patients with bipolar I or II disorder.

Background: Evidence suggests a bidirectional association between migraine and depression in individuals and in twins. However, whether a bidirectional association between migraine and depression also occurs among siblings (probands and unaffected nontwin siblings) remains unknown. Methods: Using the Taiwan National Health Insurance Research Database, we examined the data of 1504 probands with migraine, 1595 unaffected siblings, and 6380 nonmigrainous controls born before 2000 to identify new-onset depression for the period between 1996 and 2011. Conversely, 31824 probands with depression, 34325 unaffected siblings, and 137300 nondepressive controls were examined for the identification of new-onset migraine. Results: Logistic regression analyses demonstrated that compared with the controls, patients with migraine (odds ratio [OR]: 4.09; 95% confidence interval [CI]: 3.75–4.46) and unaffected siblings (OR: 1.40; 95% CI: 1.24–1.58) were more likely to develop depression during the follow-up period. Moreover, patients with depression and unaffected siblings had a 4.13-fold (95% CI: 3.18–5.36) and 1.45-fold (95% CI: 1.03–2.05) increased risk of migraine. Discussion: The bidirectional association between migraine and depression among probands and unaffected siblings suggests a familial coaggregation of these two conditions. Additional studies are required to investigate the genetic and environmental etiologies for this coaggregation.

BackgroundStudies have suggested the detrimental effects of obesity and systemic inflammation on the cognitive function of patients with bipolar or major depressive disorder. However, the complex associations between affective disorder, obesity, systemic inflammation, and cognitive dysfunction remain unclear.MethodsOverall, 110 patients with affective disorder (59 with bipolar I disorder and 51 with major depressive disorder) who scored ≥61 on the Global Assessment of Functioning and 51 age- and sex-matched controls were enrolled. Body mass index ≥25 kg/m2 was defined as obesity or overweight. Levels of proinflammatory cytokines—including interleukin-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP)—were measured, and cognitive function was assessed using various methods, including the Wisconsin Card Sorting Test (WCST) and go/no-go task.ResultsPatients with bipolar I disorder or major depressive disorder were more likely to be obese or overweight, had higher CRP and TNF-α levels, and had greater executive dysfunction in the WCST than the controls. TNF-α level (P ConclusionsOur findings may indicate that proinflammatory cytokines, but not obesity or overweight, have crucial effects on cognitive function in patients with bipolar I disorder or major depressive disorder, although proinflammatory cytokines and obesity or overweight were found to be strongly associated. The complex relationships between affective disorder diagnosis, proinflammatory cytokine levels, obesity or overweight, and cognitive function require further investigation.