Exploring intra-diagnosis heterogeneity and inter-diagnosis commonality in genetic architectures of bipolar disorders: association of polygenic risks of major psychiatric illnesses and lifetime phenotype dimensions.

BACKGROUND: Bipolar disorder (BD) shows heterogeneous illness presentation both cross-sectionally and longitudinally. This phenotypic heterogeneity might reflect underlying genetic heterogeneity. At the same time, overlapping characteristics between BD and other psychiatric illnesses are observed at clinical and biomarker levels, which implies a shared biological mechanism between them. Incorporating these two issues in a single study design, this study investigated whether phenotypically heterogeneous subtypes of BD have a distinct polygenic basis shared with other psychiatric illnesses. METHODS: Six lifetime phenotype dimensions of BD identified in our previous study were used as target phenotypes. Associations between these phenotype dimensions and polygenic risk scores (PRSs) of major psychiatric illnesses from East Asian (EA) and other available populations were analyzed. RESULTS: Each phenotype dimension showed a different association pattern with PRSs of mental illnesses. PRS for EA schizophrenia showed a significant negative association with the cyclicity dimension (p = 0.044) but a significant positive association with the psychotic/irritable mania dimension (p = 0.001). PRS of EA major depressive disorder demonstrated a significant negative association with the elation dimension (p = 0.003) but a significant positive association with the comorbidity dimension (p = 0.028). CONCLUSION: This study demonstrates that well-defined phenotype dimensions of lifetime-basis in BD have distinct genetic risks shared with other major mental illnesses. This finding supports genetic heterogeneity in BD and suggests a pleiotropy among BD subtypes and other psychiatric disorders beyond BD. Further genomic analyses adopting deep phenotyping across mental illnesses in ancestrally diverse populations are warranted to clarify intra-diagnosis heterogeneity and inter-diagnoses commonality issues in psychiatry.

Heterogeneous early illness courses of Korean patients with bipolar disorders: replication of the staging model.

BACKGROUND: Clinical staging of bipolar disorder (BD) requires application of real-world data, as the next step in hypothesis. This study used the staging model to analyze the long-term course of BD in Korean patients based on clinical features and treatment responses to map the progression of bipolar illness from its early phase after the onset of illness. METHODS: A total of 136 patients diagnosed with BD-I (n = 62) or BD-II (n = 74) were recruited. Their progressive stages were retrospectively evaluated. A multi-state model was used to calculate the probability of progression to each stage. Hazard ratios of covariates expected to influence different courses of BD were calculated. Using the Alda score, long-term responses to mood stabilizers depending on the current stage were compared. RESULTS: Several sub-populations showed varied courses during the first five years after the onset of illness, with 41.5% remaining in stage 2 and 53% progressing to higher stages with shortened time for transition. Profiles of patients with BD-I and BD-II were different, suggesting biologically distinct groups. Comorbid psychiatric disorders, such as obsessive-compulsive disorder (OCD) and bulimia nervosa (BN) were associated with a recurrent course (stage 3a or 3b) or a malignant course (stage 3c or 4). Early age of onset, shorter duration of illness, older age at the start of medication, and poor response to lithium affected the illness progression. CONCLUSION: We were able to apply the stage model based on episode recurrence patterns in early illness courses of Korean patients with BD. The stage progression pattern differed from the early phase in BD-I and BD-II patients. Psychotic comorbidity, age at onset, age at starting psychiatric treatment showed associations with the illness progression.

Psychopathologic structure of bipolar disorders: exploring dimensional phenotypes, their relationships, and their associations with bipolar I and II disorders.

BACKGROUND: Given its diverse disease courses and symptom presentations, multiple phenotype dimensions with different biological underpinnings are expected with bipolar disorders (BPs). In this study, we aimed to identify lifetime BP psychopathology dimensions. We also explored the differing associations with bipolar I (BP-I) and bipolar II (BP-II) disorders. METHODS: We included a total of 307 subjects with BPs in the analysis. For the factor analysis, we chose six variables related to clinical courses, 29 indicators covering lifetime symptoms of mood episodes, and 6 specific comorbid conditions. To determine the relationships among the identified phenotypic dimensions and their effects on differentiating BP subtypes, we applied structural equation modeling. RESULTS: We selected a six-factor solution through scree plot, Velicer's minimum average partial test, and face validity evaluations; the six factors were cyclicity, depression, atypical vegetative symptoms, elation, psychotic/irritable mania, and comorbidity. In the path analysis, five factors excluding atypical vegetative symptoms were associated with one another. Cyclicity, depression, and comorbidity had positive associations, and they correlated negatively with psychotic/irritable mania; elation showed positive correlations with cyclicity and psychotic/irritable mania. Depression, cyclicity, and comorbidity were stronger in BP-II than in BP-I, and they contributed significantly to the distinction between the two disorders. CONCLUSIONS: We identified six phenotype dimensions; in addition to symptom features of manic and depressive episodes, various comorbidities and high cyclicity constructed separate dimensions. Except for atypical vegetative symptoms, all factors showed a complex interdependency and played roles in discriminating BP-II from BP-I.

Long-Term Response to Clozapine and Its Clinical Correlates in the Treatment of Tardive Movement Syndromes: A Naturalistic Observational Study in Patients With Psychotic Disorders.

PURPOSE: Given that switching to clozapine is an important treatment option for tardive movement syndrome (TMS), its effect and clinical correlates have not been fully explored yet. This study investigated the improvement of TMS after switching to clozapine and factors associated with the response in a naturalistic outpatient setting. METHODS: Subjects were 35 patients with schizophrenia or bipolar disorder receiving only clozapine as an antipsychotic drug for more than 12 months. Their prior antipsychotics were switched to clozapine after the onset of tardive dyskinesia and/or tardive dystonia. Tardive movement syndrome and clinical characteristics were assessed through direct examination and review of hospital records. FINDINGS: Offending antipsychotics administered at the time of TMS onset were second-generation antipsychotics in 88.6% of patients. Tardive movement syndrome symptoms were remitted in 65.7% of patients after switching to clozapine. Younger age, younger age at onset of TMS, and lower baseline Abnormal Involuntary Movement Scale score were significantly associated with remission of TMS. Female sex and good antipsychotic effects of clozapine showed a trend of association with better response. IMPLICATIONS: Clozapine seems to be an excellent treatment option for TMS in the era of second-generation antipsychotics, especially for younger patients with mild tardive dyskinesia. Clinical trials comparing the effect of switching antipsychotics to clozapine with add-on therapy of new drugs targeting TMS are difficult to design in ordinary clinical settings. Therefore, more naturalistic observational studies are warranted to identify predictors of TMS response to clozapine.

Exploring the Prevalence of Clozapine Phenotypic Poor Metabolizers in 4 Asian Samples: They Ranged Between 2% and 13.

PURPOSE/BACKGROUND: Clozapine clearance is influenced by sex, smoking status, ethnicity, coprescription of inducers or inhibitors, obesity, and inflammation. In 126 Beijing inpatients, we measured repeated trough steady-state serum concentrations and identified 4% (5/126) who were phenotypical poor metabolizers (PMs); none were ultrarapid metabolizers (UMs). They were defined as being 2 SDs beyond the means of total clozapine concentration/dose ratios stratified by sex and smoking. Using this definition, this study explores the prevalence of PMs and UMs using data from 4 already published Asian samples. Three samples were East Asian (Beijing 2, Taipei, and Seoul); one was from South India (Vellore). FINDINGS/RESULTS: The prevalence of phenotypical PMs ranged from 2% to 13%, but inflammation was not excluded. The prevalence was 7% (14/191) for Beijing 2, 11% (8/70) for Taipei, 13% (9/67) for Seoul, and 2% (2/101) for the Vellore sample. Five phenotypic PMs appeared to be associated with extreme obesity. Phenotypic UM prevalence ranged from 0% to 1.6% but may be partly explained by lack of adherence. A Vellore phenotypic UM appeared to be associated with induction through high coffee intake. IMPLICATIONS/CONCLUSIONS: Approximately 10% of Asians may be clozapine PMs and may need only 50 to 150 mg/d to get therapeutic concentrations. Future studies combining gene sequencing for new alleles with repeated concentrations and careful control of confounders including inhibitors, inflammation, and obesity should provide better estimations of the prevalence of phenotypic clozapine PMs across races. Clozapine UM studies require excluding potent inducers, careful supervision of compliance in inpatient settings, and multiple serum concentrations.

Association between the zinc finger protein 804A (ZNF804A) gene and the risk of schizophrenia and bipolar I disorder across diagnostic boundaries.

OBJECTIVES: In this study, we aimed to determine the role of genetic variations within the zinc finger protein 804A (ZNF804A) gene, a candidate for a psychosis risk-conferring gene, in the development of schizophrenia (SZ) and bipolar disorder (BP) in the Korean population. METHODS: A total of 921 patients with SZ, bipolar I (BP-I) and II (BP-II) disorder, and 502 control subjects participated in the study. Twenty-one tag single nucleotide polymorphisms (SNPs) across the genomic region of ZNF804A and seven reference SNPs based on previous reports were genotyped. We applied logistic regression analyses under additive, dominant and recessive models. RESULTS: Fifteen of the 28 SNPs showed a nominally significant association with at least one diagnostic group. However, none of these associations remained significant after false discovery rate (FDR) correction. As the trend of association was observed mostly in SZ and BP-I with similar patterns, we performed a post hoc analysis for the combined SZ and BP-I group. Five SNPs (rs2369595, rs6755404, rs10931156, rs12476147 and rs1366842) showed a significant association with an FDR-corrected P of <.05. CONCLUSIONS: This study supports a possible role of ZNF804A in the common susceptibility of major psychoses, and identified additional candidate variants of the gene in the Korean population.

Investigation of the clinical utility of the hypomania checklist 32 (HCL-32) for the screening of bipolar disorders in the non-clinical adult population.

BACKGROUND: The hypomania checklist-32 (HCL-32) is a widely used questionnaire developed for identifying hypomanic components in patients with a depressive episode. Measuring and screening previous hypomanic symptoms in individuals without any definite history of depressive episode would also be needed for early detection of bipolar disorders (BDs). This study aimed at testing the clinical utility of the HCL-32 for screening of BDs in the non-clinical population. METHODS: Lifetime history of hypomanic symptoms was evaluated by using the HCL-32 in 220 patients with BDs and 313 non-clinical individuals. Sensitivity, specificity, and the area under the curve (AUC) of the Receiver Operating Characteristic (ROC) were evaluated for assessing the discriminatory power of the scale and its two sub-domains in screening BDs. RESULTS: The mean HCL-32 total score was significantly higher in the Bipolar II disorder group compared to the non-clinical group (P < 0.001). Most of the items (10/12) of the irritable/risk-taking factor showed higher positive responses in patient groups. Items of active/elated factor showed mixed results. The HCL-32 total score and the active/elated factor score were not adequate for both BDs and its subgroups with AUC values of less than 0.7. The irritable/risk-taking factor score showed higher discrimination power, i.e. AUC for BDs, Bipolar I disorder, and Bipolar II disorder was 0.71, 0.67, and 0.75, respectively. CONCLUSIONS: The HCL-32 could not adequately distinguish BD patients from the non-clinical adult population. However, the current study identified items of irritable/risk-taking factor of the scale that could be useful in screening BDs in the general population.

Lifetime Characteristics of Evening-Preference and Irregular Bed-Rise Time Are Associated With Lifetime Seasonal Variation of Mood and Behavior: Comparison Between Individuals With Bipolar Disorder and Healthy Controls.

Sleep-wake cycle disruption and seasonal variation in mood and behavior have been associated with mood disorders. This study aimed to investigate the lifetime characteristics of the sleep-wake cycle and its association with the lifetime characteristics of seasonality in individuals with bipolar disorder. Circadian preference, regularity of bed-rise time, and seasonality were evaluated on a lifetime basis using the Composite Scale of Morningness, the Sleep Timing Questionnaire, and the Seasonal Pattern Assessment Questionnaire in clinically stable individuals with bipolar I/II disorders (n = 103/97) and healthy controls (n = 270). Bipolar groups were more likely to have evening preference and irregular bed-rise time. These characteristics were interrelated and, particularly, more prevalent in bipolar II disorder. Seasonality, which was also more prevalent in the bipolar groups, was associated with evening preference and irregularity of the weekday bed-rise time.

Tardive dyskinesia and tardive dystonia with second-generation antipsychotics in non-elderly schizophrenic patients unexposed to first-generation antipsychotics: a cross-sectional and retrospective study.

This study investigates the clinical nature, prevalence rates, and associated factors of second-generation antipsychotic (SGA)-related tardive dyskinesia and tardive dystonia. To date, these subjects have not been thoroughly investigated.The subjects were 80 non-elderly schizophrenic patients who received SGAs for more than 1 year without any previous exposure to first-generation antipsychotics. Multiple (≥2) direct assessments of movement symptoms were performed. Hospital records longer than 1 recent year describing any observed tardive movement symptoms were reviewed.A current or history of tardive dyskinesia and/or tardive dystonia associated with SGA was identified in 28 (35%) subjects. These patients were being treated with risperidone (n = 15), amisulpride, olanzapine, aripiprazole, ziprasidone, or clozapine at the time of the onset of the movement symptoms. Tardive dyskinesia was mostly in the orolingual area, and the most frequently observed tardive dystonia was torticollis. The median interval between the first exposure to the SGA and the movement syndrome onset was 15 months for tardive dyskinesia and 43 months for tardive dystonia. A history of acute dystonia was significantly associated with tardive dystonia, and comorbid obsessive-compulsive syndrome was related to both tardive movement syndromes.This study indicates that more clinical attention and research efforts are needed regarding SGA-associated tardive movement syndromes, including a larger-scale prevalence assessment. This study is the first to indicate that a comorbid obsessive-compulsive syndrome might be an associated factor of tardive movement syndrome. The association warrants further investigation.

Prevalence, behavioral manifestations and associated individual and climatic factors of seasonality in the Korean general population.

BACKGROUNDS: Seasonality, an individual trait of seasonal variations in mood and behavior, has received clinical attention for its association with mood disorders. This study aimed to explore the prevalence, specific manifestation, and associated individual and climatic factors of seasonality in the non-elderly adult population. METHODS: Five hundred fifty-two participants [male n=220; female n=332; mean age 34.92years, standard deviation (SD) 10.18] with no psychiatric history were recruited from the Seoul metropolitan area (37°33'58.87″N 126°58'40.63″E). Seasonality was evaluated using the Seasonal Pattern Assessment Questionnaire. Climatic variables used in analyses were averaged over recent 5years (from 2008 to 2013) on a monthly basis. RESULTS: The mean global seasonality score (GSS) was 5.53 (SD 3.91), and 16.2% (n=89) of participants had seasonal affective disorder (SAD) or sub-SAD. The "feeling worst" month in most of the participants with significant seasonality were winter (41.6%) or summer (38.2%). Socio-demographic factors including age and sex were not related to the seasonality. Decreased sunlight amount and diurnal temperature range in a given and previous month, and increased humidity in a previous month showed significant associations with the percentage of participants with the worst mood. The most frequently reported symptom related to seasonality was 'changes in energy level'. Specific manifestations were not significantly different between the winter type and the summer type. CONCLUSION: The summer and winter type seasonality in the non-clinical adult population did not differ in terms of behavioral manifestations. Decreased sunlight amount, diurnal temperature range, and increased humidity appeared to be major climatic factors associated with seasonality.

Pattern of pharmacotherapy by episode types for patients with bipolar disorders and its concordance with treatment guidelines.

This study aimed to investigate the overall prescription pattern for patients with bipolar disorders in Korea and its relevance to the practice guidelines. Prescription records from all patients with bipolar I and II disorders who have been admitted or who started the outpatient treatment during the year of 2009 in 10 academic setting hospitals were reviewed. A total of 1447 patients with bipolar I and II disorders were included in this study. Longitudinal prescription patterns of inpatients and outpatients were analyzed by episode types and compared with the clinical practice guideline algorithms. In all phases, polypharmacy was chosen as an initial treatment strategy (>80%). The combination of mood stabilizer and atypical antipsychotics was the most favored. Antipsychotics were prescribed in more than 80% of subjects across all phases. The rate of antidepressant use ranged from 15% to 40%, and it was more frequently used in acute treatment and bipolar II subjects. The concordance rate of prescriptions for manic inpatients to the guidelines was higher and relatively more consistent (43.8%-48.7%) compared with that for depressive inpatients (18.6%-46.9%). Polypharmacy was the most common reason for nonconcordance. In Korean psychiatric academic setting, polypharmacy and atypical antipsychotics were prominently favored in the treatment of bipolar disorder, even with the lack of evidence of its superiority. More evidence is needed to establish suitable treatment strategies. In particular, the treatment strategy for acute bipolar depression awaits more consensuses.

Lifetime experiences of hypomanic symptoms are associated with delayed and irregular sleep-wake cycle and seasonality in non-clinical adult samples.

OBJECTIVES: Disturbances of the sleep-wake cycle and seasonality have been reported in patients with bipolar disorder (BD). Considering that BD seems to be a spectrum condition in terms of clinical and biological characteristics, circadian and seasonal rhythm related to BD could be detected in non-clinical individuals with subthreshold bipolarity. The aim of this study was to screen past hypomanic symptoms in non-clinical samples and investigate their association with deviated sleep-wake cycle and seasonality. METHODS: Lifetime history of hypomanic symptoms was assessed with the Hypomania Checklist-32 (HCL-32). Circadian preference, variability of sleep-wake time and seasonal changes in mood and behavior were evaluated on a lifetime-basis in non-clinical adult samples (n=313), using the Composite Scale of Morningness (CSM), the Sleep Timing Questionnaire (STQ), and the Seasonal Pattern Assessment Questionnaire (SPAQ). RESULTS: Two subdomains of hypomanic symptoms were identified through factor analysis of HCL-32, i.e., "active/elated" factor and "irritable/risk-taking" factor. The HCL-32 total score (p<0.001) and the "active/elated" factor score (p=0.028) were weakly correlated only with seasonality, whereas the "irritable/risk-taking" factor score was associated not only with seasonality (p<0.001), but also with evening preference (p<0.001) and irregularity of sleep-wake times (p=0.001~0.011). CONCLUSION: Circadian and seasonal characteristics related to BD are also associated with a past history of hypomanic symptoms in non-clinical samples, especially "irritable/risk-taking" symptoms, suggesting the existence of subclinical presentation of BD and their biological traits.

Integrated proteomic and genomic analysis to identify predictive biomarkers for valproate response in bipolar disorder: a 6-month follow-up study.

BACKGROUND: Several genetic studies have been undertaken to elucidate the intricate interplay between genetics and drug responses in bipolar disorder (BD). However, there has been notably limited research on biomarkers specifically linked to valproate, with only a few studies investigating integrated proteomic and genomic factors in response to valproate treatment. Therefore, this study aimed to identify biological markers for the therapeutic response to valproate treatment in BD. Patients with BD in remission were assessed only at baseline, whereas those experiencing acute mood episodes were evaluated at three points (baseline, 8 ± 2 weeks, and 6 ± 1 months). The response to valproate treatment was measured using the Alda scale, with individuals scoring an Alda A score ≥ 5 categorized into the acute-valproate responder (acute-VPAR) group. We analyzed 158 peptides (92 proteins) from peripheral blood samples using multiple reaction monitoring mass spectrometry, and proteomic result-guided candidate gene association analyses, with 1,627 single nucleotide variants (SNVs), were performed using the Korean chip. RESULTS: The markers of 37 peptides (27 protein) showed temporal upregulation, indicating possible association with response to valproate treatment. A total of 58 SNVs in 22 genes and 37 SNVs in 16 genes showed nominally significant associations with the Alda A continuous score and the acute-VPAR group, respectively. No SNVs reached the genome-wide significance threshold; however, three SNVs (rs115788299, rs11563197, and rs117669164) in the secreted phosphoprotein 2 gene reached a gene-based false discovery rate-corrected significance threshold with response to valproate treatment. Significant markers were associated with the pathophysiological processes of bipolar disorders, including the immune response, acute phase reaction, and coagulation cascade. These results suggest that valproate effectively suppresses mechanisms associated with disease progression. CONCLUSIONS: The markers identified in this study could be valuable indicators of the underlying mechanisms associated with response to valproate treatment.

Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response.

OBJECTIVE: Pharmacogenetic studies on clozapine (CLZ) have provided meaningful insights but have shown redundancies owing to wide interindividual variability and insufficient replication. The present study was designed to validate hitherto suggested candidate genes on CLZ pharmacokinetics and pharmacodynamics and explore new markers through an integrative study. METHODS: Based on a literature review, a total of 127 variations in 27 candidate genes were selected and analyzed. Ninety-six schizophrenic patients of Korean ethnicity with constant CLZ dosing were recruited, and information on body weight and smoking habits was gathered, as well as plasma drug levels and treatment responses. RESULTS: Among the pharmacokinetic-related single nucleotide polymorphisms, rs2069521 and rs2069522 in CYP1A2 for CLZ/(dose/weight) and norclozapine/(dose/weight) and rs1135840 in CYP2D6 for norclozapine/CLZ showed borderline associations that were insignificant after correction for multiple testing. Regarding treatment response, significant associations were exhibited in rs7787082 and rs10248420 of ABCB1 (P = 0.0005 and P = 0.0013, respectively) even after correction, and the rs7787082 G and rs10248420 A alleles in ABCB1 were more frequently observed in nonresponders. We also observed a trend in the associations of rs13064530 in HRH1 and rs4938013 in DRD2/ANKK1 with treatment response. CONCLUSIONS: We could not convincingly replicate most of the previous studies, a result that is possibly due to modest association between the suggested genes. Rather, we found a new candidate gene, ABCB1, for treatment response, which may provide a hypothesis on the relationship between the blood-brain distribution of CLZ and its clinical efficacy.

Clinical and neurocognitive profiles of subjects at high risk for psychosis with and without obsessive-compulsive symptoms.

OBJECTIVE: Obsessive-compulsive symptoms (OCS), which are common in psychotic-spectrum illnesses, are of clinical interest because of their association with poor prognosis or cognitive dysfunction. However, few studies on the clinical and neurocognitive implications of OCS in individuals at ultra-high risk for psychosis (UHR) have been conducted. METHOD: Sixty-five UHR subjects [24 with OCS (UHR+OCS), 41 without OCS (UHR-OCS)], and 40 healthy controls were assessed using clinical scales and neurocognitive tests. RESULTS: Those with UHR+OCS showed more severe clinical symptoms and poorer global functioning as compared to both healthy controls and the UHR-OCS group, according to the results of the Global Assessment of Functioning, the Comprehensive Assessment of At-Risk Mental States, and the Positive and Negative Syndrome Scale (total, negative, and general scores). In the neurocognitive domain, those in the UHR-OCS group showed notably greater latency in the Stroop task and more confabulation errors in immediate recall in the Rey-Osterrieth Complex Figure Test compared with those in UHR+OCS group, whose performance levels were similar to those of the healthy control group. CONCLUSIONS: The OCS manifested in UHR individuals was associated with a more severe clinical symptomatic presentation, including lower global functioning and more psychotic symptoms. On the other hand, those with UHR-OCS performed more poorly on some cognitive tests. The features that distinguish the groups can be used for developing prognoses and intervention strategies for the heterogeneous UHR group.

Association of genetic variations in DTNBP1 with cognitive function in schizophrenia patients and healthy subjects.

The dystrobrevin-binding protein 1 gene (DTNBP1) has been regarded as a susceptibility gene for schizophrenia. Recent studies have investigated its role on cognitive function that is frequently impaired in schizophrenia patients, and generated inconsistent results. The present study was performed to elucidate effects of genetic variations in DTNBP1 on various cognitive domains in both schizophrenia patients and healthy subjects. Comprehensive neuropsychological tests were administered to 122 clinically stable schizophrenia patients and 119 healthy subjects. Based on positive findings reported in previous association studies, six SNPs were selected and genotyped. Compared to healthy subjects, schizophrenia patients showed expected lower performance for all of the cognitive domains. After adjusting for age, gender, and educational level, four SNPs showed a nominally significant association with cognitive domains. The association of rs760761 and rs1018381 with the attention and vigilance domain remained significant after applying the correction for multiple testing (P < 0.001). Similar association patterns were observed both, in patients and healthy subjects. The observed results suggest the involvement of DTNBP1 not only in the development of attention deficit of schizophrenia, but also in the inter-individual variability of this cognitive domain within the normal functional range.

Estimated glomerular filtration rate in Korean patients exposed to long-term lithium maintenance therapy.

BACKGROUND: Lithium-induced nephrotoxicity has long been debated. However, it has been rarely explored in Asian populations. The aim of the present study was to assess the effect of lithium maintenance therapy on estimated glomerular filtration rate (eGFR) in Korean patients diagnosed with a psychiatric illness. METHODS: This was a single-centered, retrospective study that included patients treated with lithium or comparator drug (valproate) in Samsung Seoul Medical Center between November 1994 and July 2020. Patients diagnosed with ICD codes F20-33 who had ≥ 6 months of exposure to lithium or valproate were included. Patients had to have ≥ 1 baseline and ≥ 2 post-baseline eGFR data with post-baseline data having an interval of at least 30 days. Chronic kidney disease (CKD) was defined as CKD stage 3 (eGFR < 60 mL/min/1.732). To be considered as CKD, the threshold had to be met at two consecutive post-baseline measurements. Those treated with both lithium and valproate, diagnosed with CKD stages 3-5, diagnosed with a renal disease, or received kidney transplantation were excluded. RESULTS: A total of 766 patients were included (242 treated with lithium and 524 with valproate). Two (0.8%) in the lithium group and 8 (1.5%) in the valproate group developed CKD stage 3. None developed CKD stages 4-5. Median yearly eGFR change was - 1.3 mL/min/1.732 (IQR: - 6.8, 1.7) for the lithium group and - 1.1 mL/min/1.732 (IQR: - 4.5, 1.5) for the valproate group, showing no significant difference between the two groups (p = 0.389). The rate of decline was more rapid for those with CKD in both groups. eGFR values of lithium and valproate groups did not show significant differences during a follow-up duration of 15 years or more. A significant negative correlation between baseline eGFR and yearly eGFR change was identified in a linear regression analysis. CONCLUSIONS: In Korean patients, treatment with lithium did not increase the risk of developing CKD compared to treatment with valproate. Prevalence of CKD was lower than those previously reported in western populations. Low baseline eGFR showed significant correlation with changes in renal function.

Comparison of Patterns of Non-suicidal Self-Injury and Emotion Dysregulation Across Mood Disorder Subtypes.

Introduction: Non-suicidal self-injury (NSSI) is frequently encountered in patients with mood disorders. Emotion dysregulation (ED), frequently observed in mood disorders, could be a major mediating factor in NSSI. The aim of this study was to explore differences in NSSI behavior and ED across mood disorder subtypes. The relationships between childhood trauma and NSSI and ED were also explored. Methods: A total of 191 patients with mood disorders were included in this study. The patterns of NSSI behavior and ED across patients with bipolar I disorder (BD-I), bipolar II disorder (BD-II), and major depressive disorder (MDD) were compared. Results: More than half (54%) of the subjects experienced NSSI. Patients with BD-II and MDD engaged in NSSI behavior more frequently than those diagnosed with BD-I. NSSI behaviors in patients with BD-II most commonly included cutting, whereas hitting behaviors were most common among other groups. Patients with BD-II and MDD reported more severe ED than those with BD-I. In the case of childhood trauma, those with BD-II and MDD reported greater emotional neglect than those with BD-I. Structural equation modeling revealed that ED mediated the association between childhood trauma and NSSI. Conclusion: BD-I was associated with less frequent NSSI behavior and less severe ED than BD-II and MDD. ED mediated the association between childhood trauma and NSSI. Promoting emotion regulation strategies could prevent NSSI behavior in patients with mood disorders.

Dissecting the genetic architecture of suicide attempt and repeated attempts in Korean patients with bipolar disorder using polygenic risk scores.

BACKGROUND: Bipolar disorder (BD) has the greatest suicide risk among mental and physical disorders. A recent genome-wide association study (GWAS) of European ancestry (EUR) samples revealed that the genetic etiology of suicide attempt (SA) was not only polygenic but also, in part, diagnosis-specific. The authors aimed to examine whether the polygenic risk score (PRS) for SA derived from that study is associated with SA or repeated attempts in Korean patients with BD. This study also investigated the shared heritability of SA and mental disorders which showed an increased risk of SA and a high genetic correlation with BD. METHODS: The study participants were 383 patients with BD. The history of SA was assessed on a lifetime basis. PRSs for reference disorders were calculated using the aforementioned GWAS data for SA and the Psychiatric Genomics Consortium data of BD, schizophrenia, major depressive disorder (MDD), and obsessive-compulsive disorder (OCD). RESULTS: The PRS for SA was significantly associated with lifetime SA in the current subjects (Nagelkerke's R2 = 2.73%, odds ratio [OR] = 1.36, p = 0.007). Among other PRSs, only the PRS for OCD was significantly associated with lifetime SA (Nagelkerke's R2 = 2.72%, OR = 1.36, p = 0.007). The PRS for OCD was higher in multiple attempters than in single attempters (Nagelkerke's R2 = 4.91%, OR = 1.53, p = 0.043). CONCLUSION: The PRS for SA derived from EUR data was generalized to SA in Korean patients with BD. The PRS for OCD seemed to affect repeated attempts. Genetic studies on suicide could benefit from focusing on specific psychiatric diagnoses and refined sub-phenotypes, as well as from utilizing multiple PRSs for related disorders.