Duration of Adjunctive Antidepressant Maintenance in Bipolar I Depression.

BACKGROUND: Antidepressants are used to treat acute depression in patients with bipolar I disorder, but their effect as maintenance treatment after the remission of depression has not been well studied. METHODS: We conducted a multisite, double-blind, randomized, placebo-controlled trial of maintenance of treatment with adjunctive escitalopram or bupropion XL as compared with discontinuation of antidepressant therapy in patients with bipolar I disorder who had recently had remission of a depressive episode. Patients were randomly assigned in a 1:1 ratio to continue treatment with antidepressants for 52 weeks after remission or to switch to placebo at 8 weeks. The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide. Key secondary outcomes included the time to an episode of mania or hypomania or depression. RESULTS: Of 209 patients with bipolar I disorder who participated in an open-label treatment phase, 150 who had remission of depression were enrolled in the double-blind phase in addition to 27 patients who were enrolled directly. A total of 90 patients were assigned to continue treatment with the prescribed antidepressant for 52 weeks (52-week group) and 87 were assigned to switch to placebo at 8 weeks (8-week group). The trial was stopped before full recruitment was reached owing to slow recruitment and funding limitations. At 52 weeks, 28 of the patients in the 52-week group (31%) and 40 in the 8-week group (46%) had a primary-outcome event. The hazard ratio for time to any mood episode in the 52-week group relative to the 8-week group was 0.68 (95% confidence interval [CI], 0.43 to 1.10; P = 0.12 by log-rank test). A total of 11 patients in the 52-week group (12%) as compared with 5 patients in the 8-week group (6%) had mania or hypomania (hazard ratio, 2.28; 95% CI, 0.86 to 6.08), and 15 patients (17%) as compared with 35 patients (40%) had recurrence of depression (hazard ratio, 0.43; 95% CI, 0.25 to 0.75). The incidence of adverse events was similar in the two groups. CONCLUSIONS: In a trial involving patients with bipolar I disorder and a recently remitted depressive episode, adjunctive treatment with escitalopram or bupropion XL that continued for 52 weeks did not show a significant benefit as compared with treatment for 8 weeks in preventing relapse of any mood episode. The trial was stopped early owing to slow recruitment and funding limitations. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00958633.).

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.

Quantitative Proteomic Approach for Discriminating Major Depressive Disorder and Bipolar Disorder by Multiple Reaction Monitoring-Mass Spectrometry.

Because major depressive disorder (MDD) and bipolar disorder (BD) manifest with similar symptoms, misdiagnosis is a persistent issue, necessitating their differentiation through objective methods. This study was aimed to differentiate between these disorders using a targeted proteomic approach. Multiple reaction monitoring-mass spectrometry (MRM-MS) analysis was performed to quantify protein targets regarding the two disorders in plasma samples of 270 individuals (90 MDD, 90 BD, and 90 healthy controls (HCs)). In the training set (72 MDD and 72 BD), a generalizable model comprising nine proteins was developed. The model was evaluated in the test set (18 MDD and 18 BD). The model demonstrated a good performance (area under the curve (AUC) >0.8) in discriminating MDD from BD in the training (AUC = 0.84) and test sets (AUC = 0.81) and in distinguishing MDD from BD without current hypomanic/manic/mixed symptoms (90 MDD and 75 BD) (AUC = 0.83). Subsequently, the model demonstrated excellent performance for drug-free MDD versus BD (11 MDD and 10 BD) (AUC = 0.96) and good performance for MDD versus HC (AUC = 0.87) and BD versus HC (AUC = 0.86). Furthermore, the nine proteins were associated with neuro, oxidative/nitrosative stress, and immunity/inflammation-related biological functions. This proof-of-concept study introduces a potential model for distinguishing between the two disorders.

The influence of poverty attribution on attitudes toward suicide and suicidal thought: A cross-national comparison between South Korean, Japanese, and American populations.

BACKGROUND: Previous studies report that income inequality is an important risk factor for depression and suicide, and an increasing income gap appears inevitable. However, little study to date has investigated associations between the attribution of poverty and suicide. Though we previously reported associations between socio-cultural factors, including income, and suicide, we tried to explore more focused associations between income, attribution of poverty (individualistic, societal), permissive attitude toward suicide, and suicidal thought using a structural equation model. METHODS: A total of 2213 participants from each of three nations (South Korea, Japan, and the United States) completed an online survey. Participants without a history of psychological disorders or suicide attempts completed scales measuring attributions of poverty, attitudes toward suicide, and severity of suicidal thoughts. RESULTS: We established a structural equation model, which exhibited a good fit for all nations, and compared significant path coefficients by country. South Korea had the highest severity of suicidal thought and societal attribution of poverty, followed by Japan and America. In all nations, a permissive attitude was positively related to the severity of suicidal thought and individualistic attribution of poverty was positively related to a permissive attitude toward suicide. Societal attribution of poverty was positively associated with a permissive attitude in Japan and the United States. Income was negatively associated with the severity of suicide in South Korea and the United States. CONCLUSION: Through an established structural equation model, we found the influence of poverty on suicide and identify the common and distinctive factors associated with suicide in each country.

Self-Transcendence Mediates the Relationship between Early Trauma and Fatal Methods of Suicide Attempts.

BACKGROUND: Early trauma is known to be a risk factor of suicide-related behavior. On the other hand, people who attempt suicide using a fatal method are reported to be more likely to complete suicide. In this study, we assumed that early trauma affects an individual's temperament and character and thereby increases the risk of a fatal method of suicide attempts. METHODS: We analyzed 92 people with a history of previous suicide attempts. We compared the Temperament and Character Inventory-Revised scores between the groups with and without early trauma, and between the groups with and without a history of suicide attempt using fatal methods through an analysis of covariance with age, sex, and presence of a psychiatric history as covariates. A mediation analysis was conducted of the relationship between early trauma and fatal methods of suicide attempt with self-transcendence as a mediator. RESULTS: Higher self-transcendence was reported in the fatal group (27.71 ± 13.78 vs. 20.97 ± 12.27, P = 0.010) and the early trauma group (28.05 ± 14.30 vs. 19.43 ± 10.73, P = 0.001), respectively. The mediation model showed that self-transcendence mediates the relationship between early trauma and fatal methods of suicide attempt. The 95% confidence intervals for the direct and indirect effect were (-0.559, 1.390) and (0.026, 0.947), respectively. CONCLUSION: Self-transcendence may mediate the relationship between early trauma and fatal methods of suicide attempt. Self-transcendence may be associated with unhealthy defenses and suicidal behavior for self-punishment and may constitute a marker of higher suicide risk.

Comparison of serum protein profiles between major depressive disorder and bipolar disorder.

BACKGROUND: Major depressive disorder and bipolar disorder are prevalent and debilitating psychiatric disorders that are difficult to distinguish, as their diagnosis is based on behavioural observations and subjective symptoms. Quantitative protein profile analysis might help to objectively distinguish between these disorders and increase our understanding of their pathophysiology. Thus, this study was conducted to compare the peripheral protein profiles between the two disorders. METHODS: Serum samples were collected from 18 subjects with major depressive disorder and 15 subjects with bipolar disorder. After depleting abundant proteins, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and label-free quantification were performed. Data-dependent acquisition data were statistically analysed from the samples of 15 subjects with major depressive disorder and 10 subjects with bipolar disorder who were psychotropic drug-free. Two-sided t-tests were performed for pairwise comparisons of proteomes to detect differentially-expressed proteins (DEPs). Ingenuity Pathway Analysis of canonical pathways, disease and functions, and protein networks based on these DEPs was further conducted. RESULTS: Fourteen DEPs were significant between subjects with major depressive disorder and those with bipolar disorder. Ras-related protein Rab-7a (t = 5.975, p = 4.3 × 10- 6) and Rho-associated protein kinase 2 (t = 4.782, p = 8.0 × 10- 5) were significantly overexpressed in subjects with major depressive disorder and Exportin-7 (t = -4.520, p = 1.5 × 10- 4) was significantly overexpressed in subjects with bipolar disorder after considering multiple comparisons. Bioinformatics analysis showed that cellular functions and inflammation/immune pathways were significantly different. CONCLUSIONS: Ras-related protein Rab-7a, Rho-associated protein kinase 2, and Exportin-7 were identified as potential peripheral protein candidates to distinguish major depressive disorder and bipolar disorder. Further large sample studies with longitudinal designs and validation processes are warranted.

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.

Factors Affecting Suicide Method Lethality Among Suicide Attempters in the Korea National Suicide Survey.

This is the first national survey study in South Korea investigating the relationship between suicide lethality and the clinical information of suicide attempters. An interview questionnaire was used to assess their sociodemographic factors, medical and psychiatric information, and two suicide scales, the Columbia-Suicide Severity Rating Scale and the Suicide Intent Scale. Suicide methods were categorized as low and high lethality; low lethality covered drug overdose or self-cutting behavior, and high lethality covered all other methods. High and low lethality suicide method groups were significantly different in demographic, medical, and psychiatric factors. The two scale score distributions differed significantly across two groups, and the difference was also valid for the subcategory analyses of the Suicide Intent Scale. Multiple factors such as older age, male sex, no previous psychiatric history, and previous suicide attempt, as well as high suicide intent by means of suicide scale, affect selection of suicide method of high lethality.

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.

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.

International Society for Bipolar Disorders Task Force on Suicide: meta-analyses and meta-regression of correlates of suicide attempts and suicide deaths in bipolar disorder.

OBJECTIVES: Bipolar disorder is associated with a high risk of suicide attempts and suicide death. The main objective of the present study was to identify and quantify the demographic and clinical correlates of attempted and completed suicide in people with bipolar disorder. METHODS: Within the framework of the International Society for Bipolar Disorders Task Force on Suicide, a systematic review of articles published since 1980, characterized by the key terms bipolar disorder and 'suicide attempts' or 'suicide', was conducted, and data extracted for analysis from all eligible articles. Demographic and clinical variables for which ≥ 3 studies with usable data were available were meta-analyzed using fixed or random-effects models for association with suicide attempts and suicide deaths. There was considerable heterogeneity in the methods employed by the included studies. RESULTS: Variables significantly associated with suicide attempts were: female gender, younger age at illness onset, depressive polarity of first illness episode, depressive polarity of current or most recent episode, comorbid anxiety disorder, any comorbid substance use disorder, alcohol use disorder, any illicit substance use, comorbid cluster B/borderline personality disorder, and first-degree family history of suicide. Suicide deaths were significantly associated with male gender and first-degree family history of suicide. CONCLUSIONS: This paper reports on the presence and magnitude of the correlates of suicide attempts and suicide deaths in bipolar disorder. These findings do not address causation, and the heterogeneity of data sources should limit the direct clinical ranking of correlates. Our results nonetheless support the notion of incorporating diagnosis-specific data in the development of models of understanding suicide in bipolar disorder.

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.

Manic patients exhibit more utilitarian moral judgments in comparison with euthymic bipolar and healthy persons.

Both emotional and cognitive processes are involved in moral judgments. Ventromedial prefrontal lesions are related to impaired prosocial emotions and emotional dysregulation, and patients with these lesions exhibit increased utilitarian judgments of emotionally salient personal moral dilemmas. Bipolar patients experiencing manic episode also have impaired emotional regulation and behavioral control. We investigated the characteristics of moral judgment in manic and euthymic patients with bipolar disorder using the 50 hypothetical moral dilemma task (17 non-moral, 20 personal, and 13 impersonal). Our study included 27 manic bipolar patients, 26 euthymic bipolar patients, and 42 healthy controls. Subjects were instructed to determine whether or not each dilemma was morally acceptable, and their reaction times were recorded. Manic patients showed significantly greater utilitarian judgment than euthymic patients and normal controls for personal moral dilemmas. However, there were no significant between-group differences for the non-moral and impersonal moral dilemmas. Our results suggest that increased utilitarian judgments of personal moral dilemmas may be a state-related finding observed only in manic patients. This difference in moral judgment assessments may reflect the decision-making characteristics and underlying neurobiological mechanisms of bipolar disorder, especially during the manic state.

A review of factors associated with greater likelihood of suicide attempts and suicide deaths in bipolar disorder: Part II of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder.

OBJECTIVES: Many factors influence the likelihood of suicide attempts or deaths in persons with bipolar disorder. One key aim of the International Society for Bipolar Disorders Task Force on Suicide was to summarize the available literature on the presence and magnitude of effect of these factors. METHODS: A systematic review of studies published from 1 January 1980 to 30 May 2014 identified using keywords 'bipolar disorder' and 'suicide attempts or suicide'. This specific paper examined all reports on factors putatively associated with suicide attempts or suicide deaths in bipolar disorder samples. Factors were subcategorized into: (1) sociodemographics, (2) clinical characteristics of bipolar disorder, (3) comorbidities, and (4) other clinical variables. RESULTS: We identified 141 studies that examined how 20 specific factors influenced the likelihood of suicide attempts or deaths. While the level of evidence and degree of confluence varied across factors, there was at least one study that found an effect for each of the following factors: sex, age, race, marital status, religious affiliation, age of illness onset, duration of illness, bipolar disorder subtype, polarity of first episode, polarity of current/recent episode, predominant polarity, mood episode characteristics, psychosis, psychiatric comorbidity, personality characteristics, sexual dysfunction, first-degree family history of suicide or mood disorders, past suicide attempts, early life trauma, and psychosocial precipitants. CONCLUSION: There is a wealth of data on factors that influence the likelihood of suicide attempts and suicide deaths in people with bipolar disorder. Given the heterogeneity of study samples and designs, further research is needed to replicate and determine the magnitude of effect of most of these factors. This approach can ultimately lead to enhanced risk stratification for patients with bipolar disorder.

Epidemiology, neurobiology and pharmacological interventions related to suicide deaths and suicide attempts in bipolar disorder: Part I of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder.

OBJECTIVES: Bipolar disorder is associated with elevated risk of suicide attempts and deaths. Key aims of the International Society for Bipolar Disorders Task Force on Suicide included examining the extant literature on epidemiology, neurobiology and pharmacotherapy related to suicide attempts and deaths in bipolar disorder. METHODS: Systematic review of studies from 1 January 1980 to 30 May 2014 examining suicide attempts or deaths in bipolar disorder, with a specific focus on the incidence and characterization of suicide attempts and deaths, genetic and non-genetic biological studies and pharmacotherapy studies specific to bipolar disorder. We conducted pooled, weighted analyses of suicide rates. RESULTS: The pooled suicide rate in bipolar disorder is 164 per 100,000 person-years (95% confidence interval = [5, 324]). Sex-specific data on suicide rates identified a 1.7:1 ratio in men compared to women. People with bipolar disorder account for 3.4-14% of all suicide deaths, with self-poisoning and hanging being the most common methods. Epidemiological studies report that 23-26% of people with bipolar disorder attempt suicide, with higher rates in clinical samples. There are numerous genetic associations with suicide attempts and deaths in bipolar disorder, but few replication studies. Data on treatment with lithium or anticonvulsants are strongly suggestive for prevention of suicide attempts and deaths, but additional data are required before relative anti-suicide effects can be confirmed. There were limited data on potential anti-suicide effects of treatment with antipsychotics or antidepressants. CONCLUSION: This analysis identified a lower estimated suicide rate in bipolar disorder than what was previously published. Understanding the overall risk of suicide deaths and attempts, and the most common methods, are important building blocks to greater awareness and improved interventions for suicide prevention in bipolar disorder. Replication of genetic findings and stronger prospective data on treatment options are required before more decisive conclusions can be made regarding the neurobiology and specific treatment of suicide risk in bipolar disorder.

Egr1 regulates lithium-induced transcription of the Period 2 (PER2) gene.

A growing body of evidence suggests that the circadian molecular system is involved in the pathogenic and therapeutic mechanisms underlying bipolar disorders. Lithium, a representative mood stabilizer, has been reported to induce the Period 2 (PER2) gene; however, the underlying molecular mechanisms require further study. We found that lithium upregulated PER2 expression at the transcriptional level in neuronally differentiated SH-SY5Y human neuroblastoma cells. Promoter reporter analyses using serial deletions of the PER2 promoter revealed that two early growth response 1 (Egr1)-binding sites (EBS) between positions -180 and -100 are required for maximal activation of the PER2 promoter by lithium. Ectopic expression of Egr1 enhanced lithium-induced PER2 promoter activity, while a point mutation in EBS abolished it. Electrophoretic mobility shift assays and chromatin immunoprecipitation indicated that Egr1 bound directly to the PER2 promoter. Stimulation of the extracellular-signal regulated kinase (ERK)1/2/Elk1 pathway by lithium was functionally linked to PER2 expression through Egr1 induction, and lithium-induced PER2 expression was strongly attenuated by depletion of Egr1 by siRNA. Lithium also upregulated the expression of Per2 and Egr1 in mouse frontal cortex. Induction of Per2 by lithium was attenuated in Egr1(-/-) mice. In conclusion, lithium stimulates PER2 transcription through the ERK/Elk1/Egr1 pathway in neuronal cells, indicating a connection between the ERK-Egr1 pathway and a circadian gene system in the mechanism of action of lithium.

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.

Autobiographical memory and its association with neuropsychological function in bipolar disorder.

OBJECTIVE: The aim of this study was to investigate the overgeneralization of autobiographical memory (AM) in bipolar disorder (BD) and assess its association with multiple cognitive domains. METHOD: Twenty-eight clinically stable bipolar I patients and an equal number of age- and gender-matched healthy controls (HC) were included. All participants were examined using the autobiographical memory test (AMT) and the neuropsychological battery including the general intelligence, attention, verbal memory, verbal fluency, visual memory, and executive functions domain. Demographic, clinical, and test variables were compared between BD and HC groups. Correlation analyses of AMT scores with cognitive functions were performed within each group, controlling for demographic and clinical variables. RESULTS: Total and negative scores of AMT were significantly lower in BD patients compared to HC individuals. AMT scores were significantly correlated with WAIS similarities, WCST perseverative errors, and WCST categories completed in BD, whereas AMT scores were correlated with verbal memory and verbal fluency in HC. CONCLUSION: Our findings suggest that overgeneral AM is a characteristic of BD and is related to executive function. Future studies should investigate the benefit of additional treatment focusing on overgeneral AM in BD.

Assessment of implicit self-esteem in bipolar manic and euthymic patients using the implicit association test.

OBJECTIVE: Although self-esteem is thought to be an important psychological factor in bipolar disorder, little is known about implicit and explicit self-esteem in manic patients. In this study, we investigated differences in implicit and explicit self-esteem among bipolar manic patients, bipolar euthymic patients, and healthy controls using the Implicit Association Test (IAT). METHODS: Participants included 19 manic patients, 27 euthymic patients, and 27 healthy controls. Participants completed a self-esteem scale to evaluate explicit self-esteem and performed the self-esteem IAT to evaluate implicit self-esteem. RESULTS: There were no differences among groups in explicit self-esteem. However, there were significant differences among groups in implicit self-esteem. Manic patients had higher IAT scores than euthymic patients and a trend toward higher IAT scores than healthy controls. CONCLUSIONS: Our findings suggest that, on the latent level, a manic state is not simply the opposite of a depressed state. Furthermore, there may be a discontinuity of implicit self-esteem between manic and euthymic states. These unexpected results may be due to characteristics of the study participants or the methods used to assess implicit self-esteem. Nevertheless, they provide greater insights on the psychological status of manic patients.