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.

Association between the Arylalkylamine N-Acetyltransferase (AANAT) Gene and Seasonality in Patients with Bipolar Disorder.

OBJECTIVE: Bipolar disorder (BD) is complex genetic disorder. Therefore, approaches using clinical phenotypes such as biological rhythm disruption could be an alternative. In this study, we explored the relationship between melatonin pathway genes with circadian and seasonal rhythms of BD. METHODS: We recruited clinically stable patients with BD (n=324). We measured the seasonal variation of mood and behavior (seasonality), and circadian preference, on a lifetime basis. We analyzed 34 variants in four genes (MTNR1a, MTNR1b, AANAT, ASMT) involved in the melatonin pathway. RESULTS: Four variants were nominally associated with seasonality and circadian preference. After multiple test corrections, the rs116879618 in AANAT remained significantly associated with seasonality (corrected p=0.0151). When analyzing additional variants of AANAT through imputation, the rs117849139, rs77121614 and rs28936679 (corrected p=0.0086, 0.0154, and 0.0092) also showed a significant association with seasonality. CONCLUSION: This is the first study reporting the relationship between variants of AANAT and seasonality in patients with BD. Since AANAT controls the level of melatonin production in accordance with light and darkness, this study suggests that melatonin may be involved in the pathogenesis of BD, which frequently shows a seasonality of behaviors and symptom manifestations.

Defining phenotypes of long-term lithium and valproate response, including combination therapy: a modified application of the Alda scale in patients with bipolar disorders.

BACKGROUND: When evaluating the long-term treatment response to mood stabilizers using the Alda scale, mood stabilizer combination therapy is typically considered a confounding factor, and patients receiving combination therapy are excluded from the analysis. However, this may result in bias if those under combination therapy are worse treatment responders. This study aims to explore whether the Alda scale is applicable to patients taking lithium and valproate combination therapy. We compared long-term treatment response in patients receiving monotherapy and combination therapy of the two drugs, and investigated clinical correlates of the responses to each drug. METHODS: The study subjects consisted of 102 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder who had been undergoing maintenance treatment with lithium and/or valproate for more than 2 years at a single specialized bipolar disorder clinic. Long-term treatment response was measured using the Alda scale and compared among the lithium monotherapy group, the valproate monotherapy group, and the mood stabilizer combination group. Clinical correlates of long-term treatment response were evaluated in lithium users and valproate users separately. RESULTS: There were no significant differences in terms of baseline illness characteristics among groups. The combination group showed the worst treatment response for all the response measurements applied. This group also had the higher rate of 'poor responder' with a statistically significant difference compared to valproate group. Older age at onset and (hypo)manic episode at onset showed significant positive associations with total Alda score in lithium users, while comorbid anxiety disorders, obsessive-compulsive disorder and mixed episode showed significant negative associations in valproate users. CONCLUSIONS: The combination group had poorer long-term treatment response but did not show distinct clinical characteristics compared to the monotherapy groups. When exploring the long-term effects of mood stabilizers, excluding patients undergoing combination treatment could result in bias because they may represent a poor response group. The long-term treatment responses of lithium and valproate had different clinical correlates.

Lifetime psychopathological characteristics associated with comorbid obsessive-compulsive disorder in clinically stable patients with chronic schizophrenia.

Obsessive-compulsive symptoms (OCS) commonly occur in the course of schizophrenia. The aim of this study was to investigate the rate of obsessive-compulsive disorder (OCD) in patients with chronic schizophrenia and evaluate lifetime correlates of the comorbidity. Subjects were clinically stable patients with chronic schizophrenia (n = 320). Patients having comorbid OCD and those without OCD were compared in terms of symptoms dimensions and cognitive function. OCD was found in 20.6 % of subjects. Earlier age at onset, male gender, higher level of education, comorbid panic disorder, and specific phobia were associated with comorbid OCD. In terms of lifetime symptoms, depression (p = 0.001) and anxiety (p = 0.014) showed significant association with the comorbidity, which corroborates with our previous study findings regarding OCD in bipolar disorder. In addition, decreased emotional response (p = 0.016), less formal thought disorder (p = 0.007), and less prodromal impairment (p = 0.005) were independently associated with the comorbidity. The OCD group showed better performance in working memory domain (p = 0.027) while other cognitive domains did not show any significant difference between the two groups. Association of OCSs with depressive symptoms and other comorbid anxiety disorders seems to be a common finding across schizophrenia and bipolar disorder. This study also suggests that comorbidity of OCD in schizophrenia is associated with less impairment of thought process and cognitive function throughout the disease course.

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.

Exploration of comorbid obsessive-compulsive disorder in patients with bipolar disorder: The clinic-based prevalence rate, symptoms nature and clinical correlates.

BACKGROUND: Comorbidity of bipolar disorder (BD) and obsessive-compulsive disorder (OCD) has received clinical attention. However, the detailed nature and nolosogic validity of the comorbidity have not been fully explored. This study investigated the comorbidity rate, clinical nature, and correlates of OCD in patients with BD. METHODS: Patients (n = 314) with BD were recruited and lifetime clinical characteristics were evaluated comprehensively. The comorbid OCD ('OCD-BD') group and the 'non-OC BD' group were compared in terms of the clinical variables of BD. RESULTS: OCD was found in 15.9% of patients. Earlier age at onset, more frequent pharmacological (hypo)manic switch and a higher rate of comorbid panic disorder were associated with comorbid OCD. In two-thirds (65.4%) of the OCD-BD subjects, obsessive-compulsive symptoms worsened or were confined to depressive episodes. Contamination obsession and checking compulsion were the most common types of obsessive-compulsive symptoms. Drug-induced (hypo)manic switch was observed in more than 60% of the OCD-BD subjects who were previously exposed to antidepressants. None of the OCD-BD subjects were taking antidepressants for OCD in the current specialty clinics. LIMITATIONS: Subject recruitment from specialty clinics, retrospective and cross-sectional evaluation, and difficulties in clarifying the causal relationships. CONCLUSIONS: The comorbidity rate of OCD in Korean BD patients was comparable to that of Caucasian patients. Even though OCD seems to be more often linked to depressive episodes, a heterogeneous nosologic relationship including a possibility of drug-mediated induction is suggested.

Effects of genetic variants of ST8SIA2 and NCAM1 genes on seasonal mood changes and circadian preference in the general population.

ST8SIA2 and NCAM1 are functionally related genes forming polysialic acid (PSA) - neural cell adhesion molecule (NCAM) complex in suprachiasmatic nucleus (SCN), the regulating site of circadian biological rhythm. In this study, the relationship of ST8SIA2 and NCAM1 with circadian and seasonal rhythms of human behavior was explored. Subjects were 261 healthy Korean adults who were free of any history of clinically significant psychiatric symptoms. The phenotypes were circadian preference and seasonal change of mood and behavior (seasonality) measured by the Composite Scale of Morningness and the Seasonal Pattern Assessment Questionnaire, respectively. Thirty-four single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and 15 SNPs of NCAM1 were analyzed. A nominally significant association with seasonality and circadian preference was observed in 21 variants of both genes. After corrections for multiple testing, associations of 8 SNPs of ST8SIA2 and 2 SNPs of NCAM1 with seasonality remained significant. Some of these SNPs were also associated with psychiatric disorders in previous studies. This study demonstrated a meaningful and/or suggestive evidence of association between behavioral phenotypes reflecting human biological rhythm and two interplaying genes involved in the plasticity of SCN's neuronal network.

Long-term response to mood stabilizer treatment and its clinical correlates in patients with bipolar disorders: a retrospective observational study.

BACKGROUND: The efficacy and utility of long-term prophylactic treatment in patients with bipolar disorders (BDs) have not been fully explored. This study aims to estimate the long-term clinical response of patients with BDs to mood stabilizer treatment and to identify the clinical factors associated with that response. METHODS: The study subjects consisted of 80 patients with bipolar I or bipolar II disorder who had been receiving treatment with lithium and/or valproate for more than 2 years at a single bipolar disorder clinic. The long-term response to the best treatment option based on treatment algorithms was evaluated using the Alda scale. Clinical characteristics were evaluated on a lifetime basis. Patients were classified into two response groups based on frequentist mixture analysis using the total Alda scale score. RESULTS: Thirty-four percent of the patients were good responders, with a total Alda score of 5 or higher. The treatment response rate did not differ between the lithium and valproate groups, but lithium and valproate combination therapy was associated with poorer response. The number of previous mixed episodes was associated with a worse response (p = 0.026). Of individual symptoms, delusions during manic episodes (p = 0.008) and increased appetite (p = 0.035) during depressive episodes were more common in moderate/poor responders than in good responders. Co-morbid anxiety disorders were more frequently observed in the moderate/poor response group (p = 0.008). CONCLUSIONS: Psychotic, mixed, and atypical features of BDs were found to be correlated with long-term treatment outcomes. Lithium and valproate showed similar efficacy but moderate/poor responders preferred to use polypharmacy.

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.

Association between ST8SIA2 and the Risk of Schizophrenia and Bipolar I Disorder across Diagnostic Boundaries.

BACKGROUND: Findings from family studies and recent genome-wide association studies have indicated overlap in the risk genes between schizophrenia and bipolar disorder (BD). After finding a linkage between the ST8SIA2 (ST8 alpha-N-acetyl-neuraminide alpha-2, 8-sicalyltransferase 2 gene) locus (15q26) and mixed families with schizophrenia and BD, several studies have reported a significant association between this gene and schizophrenia or BD. We investigated the genetic association between ST8SIA2 and both schizophrenia and BD in the Korean population. METHODS: A total of 582 patients with schizophrenia, 339 patients with BD, and 502 healthy controls were included. Thirty-one tag single nucleotide polymorphisms (SNPs) across the ST8SIA2 region and three other SNPs showing significant associations in previous studies were genotyped. The associations were evaluated by logistic regression analysis using additive, dominant, and recessive genetic models. RESULTS: Fourteen of 34 SNPs showed a nominally significant association (p < 0.05) with at least one diagnostic group. These association trends were strongest for the schizophrenia and combined schizophrenia and bipolar I disorder (BD-I) groups. The strongest association was observed in rs11637898 for schizophrenia (p = 0.0033) and BD-I (p = 0.0050) under the dominant model. The association between rs11637898 and the combined schizophrenia and BD-I group (p = 0.0006, under the dominant model) remained significant after correcting for multiple testing. DISCUSSION: We identified a possible role of ST8SIA2 in the common susceptibility of schizophrenia and BD-I. However, no association trend was observed for bipolar II disorder. Further efforts are needed to identify a specific phenotype associated with this gene crossing the current diagnostic categories.