Antipsychotic medications and severe sepsis in schizophrenia: A nested case-control study.

BACKGROUND: Sepsis constitutes a condition that involves life-threatening organ dysfunction induced by severe infection. This nested case-control study investigated risk factors for severe sepsis and whether antipsychotic use is associated with severe sepsis risk in patients with schizophrenia, a topic that has not been comprehensively explored in previous studies. METHODS: We selected 39,432 patients with schizophrenia aged between 15 and 65 years from Taiwan's Psychiatric Inpatient Medical Claims database for the period 2000-2012. The case group comprised patients with severe sepsis after their first psychiatric admission (n = 1382). The case and control groups were randomly matched (1:4) by age, sex and first psychiatric admission (year) and finally comprised 1382 and 5528 individuals, respectively. We employed multivariable conditional logistic regression to identify (1) risk factors (physical illnesses and nonpsychiatric medications) and (2) antipsychotic-severe sepsis associations. RESULTS: Higher numbers of psychiatric admissions and physical illnesses such as delirium, cerebrovascular disease and cancer were significantly associated with a higher risk of severe sepsis. Furthermore, severe sepsis was associated with the use of antithrombotic agents, systemic corticosteroids and agents targeting the renin-angiotensin system. Clozapine (adjusted risk ratio = 1.65) and quetiapine (adjusted risk ratio = 1.59) use were associated with an increased risk of severe sepsis. The use of more than one antipsychotic drug could further increase this risk. CONCLUSION: Several physical illnesses and nonpsychiatric medications increase the risk of severe sepsis in patients with schizophrenia. Specifically, clozapine or quetiapine use significantly increased the risk of severe sepsis in these patients.

Cluster analysis dissecting cognitive deficits in older adults with major depressive disorder and the association with neurofilament light chain.

BACKGROUND: Cognitive impairment is a growing problem with increasing burden in global aging. Older adults with major depressive disorder (MDD) have higher risk of dementia. Neurofilament light chain (NfL) has been proven as a potential biomarker in neurodegenerative disease, including dementia. We aimed to investigate the association between cognitive deficits and NfL levels in older adults with MDD. METHODS: In this cross-sectional study, we enrolled 39 MDD patients and 15 individuals with mild neurocognitive disorder or major neurocognitive disorder, Alzheimer's type, as controls, from a tertiary psychiatric hospital. Both groups were over age 65 and with matched Mini-Mental State Examination (MMSE) score. Demographic data, clinical variables, and plasma NfL levels were obtained. We used cluster analysis according to their cognitive profile and estimated the correlation between plasma NfL levels and each cognitive domain. RESULTS: In the MDD group, participants had higher rate of family psychiatry history and current alcohol use habit compared with controls. Control group of neurocognitive disorders showed significantly lower score in total MMSE and higher plasma NfL levels. Part of the MDD patients presented cognitive deficits clustered with that of neurocognitive disorders (cluster A). In cluster A, the total MMSE score (r=-0.58277, p=0.0287) and the comprehension domain (r=-0.71717, p=0.0039) were negatively correlated to NfL levels after adjusting for age, while the associations had not been observed in the other cluster. CONCLUSIONS: We noted the negative correlation between NfL levels and cognition in MDD patients clustered with neurodegenerative disorder, Alzheimer's type. NfL could be a promising candidate as a biomarker to predict subtype of patients in MDD to develop cognitive decline. Further longitudinal studies and within MDD cluster analysis are required to validate our findings for clinical implications.

Cluster analysis exploring the impact of childhood neglect on cognitive function in patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a severe mental disorder related to neurocognitive deficits. Exposure to childhood trauma is associated with worse cognitive performance. Different compositions of childhood trauma in BD and their impacts on cognition are rarely reported. METHODS: We used the Brief Assessment of Cognition in Affective Disorders (BAC-A) to assess cognitive performance and the Chinese version of the Short Form of the Childhood Trauma Questionnaire (C-CTQ-SF) to assess childhood trauma experience among 55 euthymic BD patients. Cluster analysis was applied to dissect their childhood trauma experiences, which revealed three distinct clusters: a low trauma group, neglect-focus group, and multiple-trauma-experience group. We compared the cognitive function between the three clusters and used a generalized linear model to evaluate the impact of childhood neglect on cognitive domains. RESULTS: The neglect-focus cluster showed prominent exposures to physical and emotional neglect (41.8%). BD patients in this cluster performed worse in BAC-A compared with patients in the multiple trauma cluster, especially in working memory and processing speed. The neglect-focus group revealed a significant negative effect on the composite score (ß = -0.904, p = 0.025) and working memory (ß = -1.150, p = 0.002) after adjusting sex, age, education year, BMI and total psychotropic defined daily dose. CONCLUSIONS: Distinct patterns of childhood trauma experience are seen in BD patients and are related with different cognitive profiles. Early exposure of neglect-focus trauma was associated with the worst cognitive performance in current study. Further studies investigating the intensity of the neglect, as well as individual resilience and coping mechanisms in BD, are warranted.

Efficacy of neuromodulation on the treatment of fibromyalgia: A network meta-analysis.

OBJECTIVE: Several types of neuromodulation have been investigated for the treatment of fibromyalgia, but they show varied efficacy on pain, functioning, comorbid depression and comorbid anxiety. Whether some types of neuromodulation or some factors are associated with a better response also awaits clarification. METHODS: We conducted a systematic review and network meta-analysis of randomized controlled trials to evaluate the efficacy of neuromodulation in patients with fibromyalgia. We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and PsycINFO before March 2022. We employed a frequentist random-effects network meta-analysis. RESULTS: Forty trials involving 1541 participants were included. Compared with sham control interventions, several types of transcranial direct current stimulation (tDCS), transcranial random noise stimulation (tRNS), and high-frequency repetitive transcranial magnetic stimulation (rTMS) were associated with significant reduction of pain, depression, anxiety, and improvement in functioning. Many significantly effective treatment options involve stimulation of the primary motor cortex or dorsolateral prefrontal cortex. CONCLUSION: We concluded that several types of rTMS, tDCS and tRNS may have the potential to be applied for clinical purposes.

Incidence and Risk Profiles for Suicide Mortality in Patients With Schizophrenia Receiving Homecare Case Management in Taiwan.

Case management (CM)-based community therapy for patients with schizophrenia had little effect on reducing suicide mortality. We investigate the long-term suicide mortality outcome and associated risk factors in patients with schizophrenia receiving homecare (CM) in Taiwan. We enrolled a nationwide cohort of patients with schizophrenia who newly received homecare CM intervention (n = 13 317) between January 1, 2001, and December 31, 2015; their data were derived from Taiwan's National Health Insurance Research Database. We calculated the incidence rate of suicide methods. We examined the demographic and medical utilization profile for suicide and then performed a nested case-control study and multivariate regression to identify independent risk factors for suicide mortality. Among the 13 317 patients who received homecare CM intervention, 1766 died during the study period, of whom 213 died by suicide, which is the leading cause of unnatural death. Jumping from a high place, self-poisoning, and hanging were the top 3 suicide methods. Increased medical utilization was noted for both psychiatric and non-psychiatric services within 3 months of suicide mortality. Comorbidities of depressive disorder, nonspecific heart diseases, pneumonia, and gastrointestinal ulcers were identified as independent risk factors for suicide mortality. Suicide was the leading cause of unnatural mortality in patients with schizophrenia receiving homecare CM intervention in Taiwan. We noted the preferred suicide methods, high medical utilization, and comorbidities before suicide. Thus, we suggest that the CM team should assess lethal methods for suicide and ensure that patients adhere to psychiatry treatment for improving the current care model for this specified population.

Unfavorable cancer mortality-to-incidence ratios in patients with schizophrenia: A nationwide cohort study in Taiwan, 2000-2019.

OBJECTIVES: Studies on cancer incidence and mortality in patients with schizophrenia have reported inconsistent findings. In this study, we simultaneously investigated cancer incidence and mortality in patients with schizophrenia and evaluated the cancer mortality-to-incidence ratio (MIR), which is rare in the literature. METHODS: From the Taiwan National Health Insurance Database, we collected the data of 107,489 patients who received a diagnosis of schizophrenia between 2000 and 2019. Data regarding cancer incidence and mortality were obtained from the Taiwan Cancer Registry and National Mortality Database, respectively. In total, 3881 incident cancer cases and 2288 cancer mortality cases were identified. Standardized incidence ratios (SIRs), mortality rate ratios (MRRs), and MIRs were compared between patients with schizophrenia and the general population. RESULTS: The overall rate of cancer incidence was slightly lower (SIR: 0.95; 95% confidence interval [CI]: 0.92-0.98; p < 0.001) and that of cancer mortality was higher (MRR: 1.29; 95% CI: 1.23-1.3; p < 0.001) in patients with schizophrenia than in the general population. The MIR for overall cancer was significantly higher in the patients with schizophrenia. The relative MIR (MIR of patients with schizophrenia divided by that of the general population) was 1.36 (95% CI: 1.30-1.42). CONCLUSION: The MIR was significantly higher in the patients with schizophrenia than in the general population, indicating the possible presence of healthcare disparities. Additional studies are required to investigate the potential association between the significantly higher MIR in patients with schizophrenia and healthcare disparities.

Clozapine and its protective effect on all-cause, natural, and suicide mortality in patients with schizophrenia: A nationwide cohort study in Taiwan.

AIM: Clozapine is indicated as the last-line agent for the treatment of refractory schizophrenia due to its side effects. This study included an Asian schizophrenia population and investigated the effect of clozapine on the risks of all-cause, natural, and suicide mortality. METHODS: This study included a large-scale schizophrenia inpatient cohort derived from the National Health Insurance Research Database from January 1, 2001, to December 31, 2019 (n = 43,025). Of them, we selected those who received clozapine (clozapine cohort, n = 5800). From those who never used clozapine, we selected two individuals for each patient in the clozapine cohort by matching by age, sex, and the year of the index date (ratio: 1:2, control cohort, n = 11,583). The clozapine and nonclozapine control cohorts together were defined as the study cohort (n = 17,383). Multivariate Cox proportional-hazards regression with a time-dependent model was performed to investigate the effect of individual antipsychotic agents on mortality. RESULTS: All individual first-generation antipsychotics were not associated with mortality risk. However, most individual second-generation antipsychotics exerted protective effects against all-cause and natural mortality. Furthermore, only clozapine and risperidone were significantly associated with a low risk of suicide mortality. Only clozapine exhibited a dose-dependent relationship with all-cause, natural, and suicide mortality. CONCLUSIONS: This study provides robust evidence supporting the strong protective effect of clozapine on all-cause, suicide, and natural mortality risks in an Asian population. Under close monitoring, clozapine use can be advantageous in patients with schizophrenia who are at a high risk of suicide.

Effects of Vitamin D Supplementation on Cognitive Outcomes: A Systematic Review and Meta-Analysis.

Clinical studies examining the effects of vitamin D on cognition have reported inconsistent results. To date, no comprehensive study has examined this effect on the basis of sample characteristics or intervention model-related factors. This systematic review and meta-analysis of randomized controlled trials investigated the effects of vitamin D supplementation on global cognitive function and specific cognitive domains. This review was preregistered in the PROSPERO database (CRD42021249908) and comprised 24 trials enrolling 7557 participants (mean age: 65.21 years; 78.54% women). The meta-analysis revealed that vitamin D significantly influenced global cognition (Hedges' g = 0.128, p = .008) but not specific cognitive domains. A subgroup analysis indicated that the effect size of vitamin D was stronger for vulnerable populations (Hedges' g = 0.414) and those with baseline vitamin D deficiency (Hedges' g = 0.480). On the basis of subgroup analyses in studies without biological flaws (Hedges' g = 0.549), we suggest that an intervention model should correct baseline vitamin D deficiency. Our results indicate that vitamin D supplementation has a small but significant positive effect on cognition in adults.

Effects of early aquatic exercise intervention on trunk strength and functional recovery of patients with lumbar fusion: a randomized controlled trial.

This study investigated the effectiveness of an early aquatic exercise program on trunk muscle function and functional recovery of patients with lumbar fusion. Twenty-eight subjects were divided into two equal groups. Patients in the aquatic group performed two 60-min aquatic exercise sessions and three 60-min home exercise sessions per week for 6 weeks, whereas those in the control group performed five sessions of 60-min home exercises per week for 6 weeks. The primary outcomes were the Numerical Pain Rating Scale (NPRS) and Oswestry Disability Index (ODI), and the secondary outcomes were Timed Up and Go Test (TUGT), trunk flexor and extensor muscle strength, lumbopelvic stability, and lumbar multifidus muscle thickness measured pre- and post-intervention. Compared with participants in the control group, those in the experimental group showed significant improvement in NPRS, ODI, trunk extensor strength, lumbopelvic control, lumbar multifidus muscle thickness, and relative change in multifidus muscle thickness (significant time by group interactions, P < 0.05). Participants in both groups showed significant time effects (P < 0.001) for TUGT and trunk flexor strength outcome. Aquatic exercise combined with home exercise was superior to home exercise alone in reducing pain, disability and improving muscle strength, lumbopelvic stability, and lumbar multifidus muscle thickness.

Neuroprotective Effects of a Multi-Herbal Extract on Axonal and Synaptic Disruption in Vitro and Cognitive Impairment in Vivo.

Background: Alzheimer's disease (AD) is a multifactorial disorder characterized by cognitive decline. Current available therapeutics for AD have limited clinical benefit. Therefore, preventive therapies for interrupting the development of AD are critically needed. Molecules targeting multifunction to interact with various pathlogical components have been considered to improve the therapeutic efficiency of AD. In particular, herbal medicines with multiplicity of actions produce cognitive benefits on AD. Bugu-M is a multi-herbal extract composed of Ganoderma lucidum (Antler form), Nelumbo nucifera Gaertn., Ziziphus jujuba Mill., and Dimocarpus longan, with the ability of its various components to confer resilience to cognitive deficits. Objective: To evaluate the potential of Bugu-M on amyloid-ß (Aß) toxicity and its in vitro mechanisms and on in vivo cognitive function. Methods: We illustrated the effect of Bugu-M on Aß25-35-evoked toxicity as well as its possible mechanisms to diminish the pathogenesis of AD in rat cortical neurons. For cognitive function studies, 2-month-old female 3×Tg-AD mice were administered 400 mg/kg Bugu-M for 30 days. Behavioral tests were performed to assess the efficacy of Bugu-M on cognitive impairment. Results: In primary cortical neuronal cultures, Bugu-M mitigated Aß-evoked toxicity by reducing cytoskeletal aberrations and axonal disruption, restoring presynaptic and postsynaptic protein expression, suppressing mitochondrial damage and apoptotic signaling, and reserving neurogenic and neurotrophic factors. Importantly, 30-day administration of Bugu-M effectively prevented development of cognitive impairment in 3-month-old female 3×Tg-AD mice. Conclusion: Bugu-M might be beneficial in delaying the progression of AD, and thus warrants consideration for its preventive potential for AD.

The interactions between vitamin D and neurofilament light chain levels on cognitive domains in bipolar disorder.

BACKGROUND: Bipolar disorder is a chronic mental disorder related to cognitive deficits. Low serum vitamin D levels are significantly associated with compromised cognition in neuropsychiatric disorders. Although patients with bipolar disorder frequently exhibit hypovitaminosis D, the association between vitamin D and cognition in bipolar disorder, and their neuroaxonal integrity, is unclear. AIMS: To investigate the interaction effects between vitamin D and neurofilament light chain (NfL) levels on cognitive domains in bipolar disorder. METHOD: Serum vitamin D and NfL levels were determined in 100 euthymic patients with bipolar disorder in a cross-sectional study. Cognitive function was measured with the Brief Assessment of Cognition in Affective Disorders. We stratified by age groups and used general linear models to identify associations between vitamin D and NfL levels and their interaction effects on cognitive domains. RESULTS: The mean vitamin D and NfL levels were 16.46 ng/nL and 11.10 pg/mL, respectively; 72% of patients were vitamin D deficient. In the older group, more frequent hospital admissions and lower physical activity were identified in the group with versus without vitamin D deficiency. The age-modified interaction effect of vitamin D and NfL was associated with composite neurocognitive scores and verbal fluency in both age groups, and with processing speed domain in the younger group. CONCLUSIONS: We observed a high vitamin D deficiency prevalence in bipolar disorder. We identified the interaction of vitamin D and NfL on cognitive domains, and the effect was modified by age. Longitudinal or randomised controlled studies enrolling patients with various illness durations and mood statuses are required to validate our findings.

The association of personality polygenic risk score, psychosocial protective factors and suicide attempt in mood disorder.

Some personality traits, especially neuroticism, has been found to be associated with suicide attempt (SA) in mood disorder patients. The present study explored the association between personality traits and SA using polygenic risk scores (PRS) for personality among patients with mood disorders. We also investigated the effects of a variety of psychosocial variables on SA. Patients with bipolar disorder (BPD, N = 841) and major depressive disorder (MDD, N = 710) were recruited from hospitals in Taiwan. Lifetime SA and information on psychosocial factors was collected. We calculated the PRS of neuroticism and extraversion. A trend test for SA was performed across quartiles of the PRS for neuroticism and extraversion, and logistic regression analyses were performed to examine the associations between psychosocial factors and SA, accounting for the PRS of personality traits. The prevalence of SA was higher in MDD than in BPD patients. The risk of SA was elevated in MDD patients with a higher quintile of PRS in neuroticism and a lower quintile of PRS in extraversion. The multiple regression analysis results demonstrated that later age of onset, higher family support and resilience, and lower overall social support were protective factors against SA. From the perspective of suicide prevention efforts, strengthening family support and conducting resilience training for patients with mood disorders may be beneficial interventions in clinical settings.

Risk Factors for the Development of Colistin Resistance during Colistin Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections.

Colistin is one of the last-resort options for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections if novel antibiotics are unavailable, where the development of colistin resistance during treatment represents a major challenge for clinicians. We aimed to investigate the risk factors associated with the development of colistin resistance in patients with CRKP infections following colistin treatment. We conducted a retrospective case-control study of patients with CRKP strains available before and after colistin treatment at a medical center in Taiwan, between October 2016 and November 2020. Cases (n = 35) included patients with an initial colistin-susceptible CRKP (ColS-CRKP) strain and a subsequent colistin-resistant CRKP (ColR-CRKP) strain. Controls (n = 18) included patients with ColS-CRKP as both the initial and subsequent strains. The 30-day mortality rate after the subsequent CRKP isolation was not different between cases and controls (12/35 [34%] versus 5/18 [28%] [P = 0.631]). blaKPC (n = 38) and blaOXA-48 (n = 11) accounted for the major mechanisms of carbapenem resistance. Alterations in mgrB were found in 18/35 (51%) ColR-CRKP strains, and mcr-1 was not detected in any of the strains. More patients received combination therapy in the control group than in the case group (17/18 versus 21/35 [P = 0.008]). The logistic regression model indicated that combination therapy with tigecycline was protective against the acquisition of colistin resistance (odds ratio, 0.17; 95% confidence interval, 0.05 to 0.62 [P = 0.008]). We observed that the inclusion of tigecycline in colistin treatment mitigated the risk of acquiring colistin resistance. These results offer insight into using the combination of tigecycline and colistin for the treatment of CRKP infections in antimicrobial stewardship. IMPORTANCE Treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is challenging due to the limited options of antibiotics. Colistin is one of the last-resort antibiotics if novel antimicrobial agents are not available. It is crucial to identify modifiable clinical factors associated with the emergence of resistance during colistin treatment. Here, we found that the addition of tigecycline to colistin treatment prevented the acquisition of colistin resistance. Colistin-tigecycline combination therapy is therefore considered a hopeful option in antimicrobial stewardship to treat CRKP infections.

Increased antibiotic exposure in early life is associated with adverse outcomes in very low birth weight infants.

BACKGROUND: The use of antibiotics in the early lives of premature infants may alter the microbiota and influence their clinical outcomes. However, whether the administration of probiotics can influence these outcomes remains unknown. In our study, probiotics were routinely administered unless contraindicated. We explored whether increased antibiotic exposure with the routine use of probiotics was associated with necrotizing enterocolitis (NEC) or bronchopulmonary dysplasia (BPD). METHODS: A retrospective cohort study was conducted, enrolling very low birth weight (VLBW) infants admitted between January 1, 2016, and March 31, 2020, to a medical center. Days of antibiotic exposure in the first 14 days of life were recorded. The primary outcomes were NEC and BPD. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated using multivariable regression analyses to assess risk factors. RESULTS: Of 185 VLBW infants admitted to the medical center, 132 met the inclusion criteria. Each additional day of antibiotic treatment was associated with increased odds of NEC (aOR, 1.278; 95% CI, 1.025-1.593) and BPD (aOR, 1.630; 95% CI, 1.233-2.156). The association remained in the NEC analysis after adjustment for probiotic use. CONCLUSION: Increased antibiotic exposure in the early lives of VLBW infants was associated with increased risks of NEC and BPD. The probiotics did not influence the outcomes. Our findings suggest that clinicians should be alerted to the adverse outcomes of antibiotic use in infants with VLBWs.

Therapeutic Drug Monitoring of Paliperidone in Patients With Schizophrenia in Taiwan.

BACKGROUND: The blood level of antipsychotics affects clinical responses to the drug; it can be influenced by race and several individual factors. This study analyzed the therapeutic plasma concentrations (Cps) of paliperidone for both oral and long-acting injectable (LAI) formulations in clinical samples from Taiwanese patients. METHODS: Patients diagnosed with schizophrenia and treated with either oral paliperidone for at least 4 weeks or LAI paliperidone for at least 6 months were enrolled. Blood samples were taken before the morning dose of oral paliperidone or the injection of LAI paliperidone to obtain the trough Cps. RESULTS: Among the patients in this study, 51 were taking oral paliperidone, and 26 were receiving LAI paliperidone. In the oral group, the mean Cps were 40.2 ± 19.8 ng/mL in patients taking 9 mg/d and 44.2 ± 15.9 ng/mL in those taking 12 mg/d. In the LAI group, the mean Cps were 32.9 ± 12.7 ng/mL in patients receiving 100 mg per 28 days and 49.9 ± 25.9 ng/mL in those receiving 150 mg per 28 days. The mean Cps per daily dose (Cps/DD) were 4.11 ± 1.99 ng/mL/mg in the oral group and 9.24 ± 3.78 ng/mL/mg in the LAI group. CONCLUSIONS: Under the suggested DD for oral and LAI paliperidone treatment, most Taiwanese patients with schizophrenia can reach the suggested therapeutic Cps range. Wide interindividual differences were observed in the Cps/DD for both the oral (7-fold) and LAI paliperidone (4-fold) groups. Compared with Western reports, no difference was observed in the body weight-adjusted Cps/DD.

Altered corticospinal excitability of scapular muscles in individuals with shoulder impingement syndrome.

The purpose of this study is to assess and compare corticospinal excitability in the upper and lower trapezius and serratus anterior muscles in participants with and without shoulder impingement syndrome (SIS). Fourteen participants with SIS, and 14 without SIS were recruited through convenient sampling in this study. Transcranial magnetic stimulation assessment of the scapular muscles was performed while the participants were holding their arm at 90 degrees scaption. The motor-evoked potential (MEP), active motor threshold (AMT), latency of MEP, cortical silent period (CSP), activated area and center of gravity (COG) of cortical mapping were compared between groups using the Mann-Whitney U tests. The SIS group demonstrated following significances, higher AMTs of the lower trapezius (SIS: 0.60 ± 0.06; Comparison: 0.54 ± 0.07, p = 0.028) and the serratus anterior (SIS: 0.59 ± 0.04; Comparison: 0.54 ± 0.06, p = 0.022), longer CSP of the lower trapezius (SIS: 62.23 ± 22.87 ms; Comparison: 45.22 ± 14.64 ms, p = 0.019), and posteriorly shifted COG in the upper trapezius (SIS: 1.88 ± 1.06; Comparison: 2.76 ± 1.55, p = 0.048) and the serratus anterior (SIS: 2.13 ± 1.02; Comparison: 3.12 ± 1.88, p = 0.043), than the control group. In conclusion, participants with SIS demonstrated different organization of the corticospinal system, including decreased excitability, increased inhibition, and shift in motor representation of the scapular muscles.

Effect of Pharmacological and Neurostimulation Interventions for Cognitive Domains in Patients with Bipolar Disorder: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The priority of interventions to alleviate cognitive deficits in patients with bipolar disorder (BD) is inconclusive. We systematically evaluate the efficacy of pharmacological or neurostimulation interventions for cognitive function in BD through a network meta-analysis. METHODS: The PubMed, PsycINFO, Embase, and Cochrane Library databases were searched from database inception to September 30, 2021. Following PRISMA guidelines, all eligible studies were randomized controlled trials of adult bipolar patients that provided detailed cognitive outcomes. Studies were excluded if participants limited to comorbid substance use disorder or the intervention was a psychotherapy. Network meta-analysis comparing different interventions was conducted for 8 cognitive domains. Partially ordered set with Hasse diagram was used to resolve conflicting rankings between outcomes. The study was preregistered on PROSPERO database (CRD42020152044). RESULTS: Total 21 RCTs including 42 tests for assessing intervention effects on cognition were retrieved. Adjunctive erythropoietin (SMD = 0.61, 95% CI = 0.00-1.23), Withania somnifera (SMD = 0.58, 95% CI = 0.03-1.13), and galantamine (SMD = 1.22, 95% CI = 0.10-2.35) was more beneficial for attention, working memory, and verbal learning in euthymic BD patients than treatment as usual, respectively. Hasse diagram suggested ranking of choice when multiple domains were combined. CONCLUSION: Considerable variability in measurements of cognitive domains in BD was observed, and no intervention resulted in superior benefits across all domains. We suggested interventions priority can be tailored according to individual patients' cognitive deficits. As current findings from relatively small and heterogeneous dataset, future trials with consensus should be applied for building further evidence.

The Heterogeneity of Longitudinal Cognitive Decline in Euthymic Bipolar I Disorder With Clinical Characteristics and Functional Outcomes.

We characterized the heterogeneity and risk factors of cognitive decline in euthymic bipolar disorder (BD), and their magnitude of associations with subjective daily functions. In this retrospective cohort, BD type I patients (N = 128) were followed for an average of 6.5 years. Intelligence quotient (IQ) at index date was recorded, and premorbid IQ was estimated. We used Brief Assessment of Cognition in Affective Disorders (BAC-A) to assess cognition at follow-up. We evaluated current functions with World Health Organization Disability Assessment Schedule 2.0. Clinical and sociodemographic factors were examined for their independent effects on longitudinal cognitive decline. In addition, we employed multivariate adaptive regression spline to detect inflection points for the nature of slope changes in cognitive decline among BD patients. During follow-up years, 21 BD patients (16.4%) showed longitudinal cognitive decline. In cognitive decline group, all cognitive domains of BAC-A were significantly worsened. We found that density of episodes with psychotic features was an independent risk factor for cognitive decline after adjusted for age, gender and dose of mood stabilizer. After the age of 42 years, a steeper cognitive change was observed in the cognitive decline group. The correlation pattern between cognitive domains and functional outcomes differed between patients with and without cognitive decline. The present study characterized cognitive heterogeneity longitudinally in BD patients. As density of episodes play roles for cognitive decline, our results emphasize the importance of relapse prevention. Our findings provide hints for future personalized interventions and facilitating genetic and biological studies for dissecting the heterogeneity of bipolar illness.