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Reconsideration of bipolar disorder as a developmental disorder: Importance of the time of onset
Abstract
Bipolar disorder is a multifactorial psychiatric disorder with developmental and progressive neurophysiological alterations. This disorder is typically characterized by cyclical and recurrent episodes of mania and depression but is heterogeneous in its clinical presentation and outcome. Although the DSM-IV-TR criteria identify several features that are of phenomenological relevance, these are of less utility for defining homogeneous subgroups, for analyses of correlations with biomarkers or for directing focused medication strategies. We provide a comprehensive review of existing evidence regarding to age at onset in bipolar disorder. Eight admixture studies demonstrate three homogeneous subgroups of patients with bipolar disorder identified according to age at onset (early, intermediate and late age at onset), with two cutoff points, at 21 and 34 years. It is suggested that the early-onset subgroup has specific clinical features and outcomes different from those of the other subgroups. Early-onset subgroup may be considered a more suitable clinical phenotype for the identification of susceptibility genes with recent data demonstrating associations with genetic variants specifically in this subgroup. The use of age at onset as a specifier may also facilitate the identification of other biological markers for use in brain imaging, circadian, inflammatory and cognitive research. A key challenge is posed by the use of age at onset in treatment decision algorithms, although further research is required to increase the evidence-base. We discuss three potential benefits of specifying age at onset, namely: focused medication strategies, the targeted prevention of specific comorbid conditions and decreasing the duration of untreated illness. We argue that age at onset should be included as a specifier for bipolar disorders.
... 19 In their pooled analysis, 45% of patients had onset before 21·33 years and 81% experienced first-episode bipolar illness before 34·67 years. 21 In a retrospective study, Berk and colleagues 22 identified the median age of mania onset was 24·1 years (IQR 19-31·5), compared with the median age of bipolar disorder or schizoaffective disorder diagnosis and initiation of diagnosis-appropriate treatment at 30 years (IQR 23-37·3). 22 Participants had their first depressive episode aged 21·2 years (17-28·5), with onset of any symptoms nearly 4 years before the initial episode. ...
... The authors identified that no direct comparison between childhood onset and adult-onset illness had been done; they also noted heterogeneity among all studies. 27 Early age of onset (defined by the cutoff given by Geoffroy and colleagues) 21 is associated with more suicide attempts, rapid cycling, drug abuse, obsessive-compulsive disorder, and increased familial risk of affective disorders compared with late age illness onset. Although focused discussion on cognitive function is outside the scope of this Personal View, we note results of a longitudinal study of youths with bipolar disorder, followed up for over 2·5 years, which found no difference in measures of the Cambridge Neuro psychological Test Automated Battery compared with normative data, and allowed the identification of three subtypes, with the poorest function having more mood episodes. ...
... Pertinently, this cross over between child and adult services falls in the middle of peak age of onset. 21 Additionally, limited resources and prioritisation of more severely unwell patients can lead to early intervention being neglected. Furthermore, those with early bipolar disorder typically do not identify themselves as having an enduring or severe mental illness. ...
The care of people with first-episode mania has been overlooked in comparison with the care of patients with other non-affective psychoses, despite evidence suggesting targeted treatments might be of benefit for this patient group. In this Personal View, we outline the general epidemiology of first-episode mania in the context of bipolar disorder, the natural history of mania (with an emphasis on its recurrent nature), current evidence for pharmacological, psychological, and service-level interventions, current guidelines for the treatment of first-episode mania, and provide a patient's point of view of the care pathway (appendix). We note the paucity of high-quality evidence for interventions in first-episode mania and the lack of agreement among treatment guidelines in relation to treatment, especially maintenance treatment. We suggest that, based on high morbidity and clinical need, research evidence to inform guideline development is necessary, and in the interim, clearer guidance on treatment and diagnosis should be given; specifically, we have suggested that patients should be cared for within a first-episode psychosis service, when such a service exists.
... Two hypotheses have been put forward to explain such phenomena. First, bipolar disorder may be a developmental disorder in which brain alterations happen from the onset of the disorder (Geoffroy et al., 2013;Mann-Wrobel et al., 2011;Sani et al., 2016). From a clinical and neurobiological perspective, many studies have found a link between childhood trauma and bipolar disorder (Janiri et al., 2015(Janiri et al., , 2017. ...
... Early age of onset has also been associated with cognitive deficit and a specific neuroanatomy (Blond et al., 2012). Age at onset of the first mood episodes may determine the degree to which the brain undergoes structural changes as well as cognitive impairment (Geoffroy et al., 2013;Nieto and Castellanos, 2011), and may therefore be a crucial determinant of outcome. The risk factors of early onset bipolar disorder have best been established for genetic loading and environmental factors such as psychosocial stress in childhood (Post et al., 2016). ...
... The risk factors of early onset bipolar disorder have best been established for genetic loading and environmental factors such as psychosocial stress in childhood (Post et al., 2016). Therefore, understanding of onset and the clinical course is needed to propose personalized treatments to enhance prognoses (Geoffroy et al., 2013). ...
1.Background:
Bipolar disorder is a complicated and chronic mental disorder. This study investigated factors affecting time to remission for inpatients with bipolar mania after 4 weeks of acute treatment.
2.Methods:
This naturalistic study recruited inpatients with bipolar mania for acute treatment. Symptom severity was assessed using the Young Mania Rating Scale (YMRS) at weeks 0, 1, 2, 3, and 4. Patients were included if they had had assessments at weeks 0 and 1 Remission was defined as an YMRS score ≤ 12. The Cox regression analysis was used to analyze factors associated with time to remission after 4 weeks of acute treatment.
3.Results:
Four hundred and forty-nine patients entered the analysis. Seventy-one of the 449 subjects (15.8%) reached symptomatic remission within 4 weeks of acute treatment. Using forward multivariate Cox regression analysis, comorbid substance use disorders, earlier age at onset, and greater manic symptom severity at baseline found to be statistically significant predictors of a longer time to reach remission after 4 weeks of treatment.
4.Limitations:
As a retrospective chart review and naturalistic design, placebo effect and potentially confounding factors such as the possibility of missing records may have limited our results.
5.Conclusions:
Early identification and intervention with integrated therapy is considered to shorten time to remission for patients at high risk of poor treatment outcome. More studies are needed in other real-world settings to generalize our results.
... It has been postulated that clinical sub-phenotypes of BD may identify more etiologically homogenous subset of patients, which can be studied with increased power to detect genetic variation (Belmonte et al., 2011). Studies have considered age at onset a phenotypic specifier ( GrigoroiuSerbanescu et al., 2014) and have identified early-onset BD (EO-BD) subgroup as a clinically distinct BD subtype with specific clinical fea- tures and outcomes and conceivably distinct genetic risk factors (Bellivier et al., 2003;Geoffroy et al., 2013;Lin et al., 2006;Manchia et al., 2008;Tozzi et al., 2011). Previous studies have identified asso- ciations between EO-BD patients and high incidence of psychosis (Javaid et al., 2011), greater rates of comorbid anxiety disorder and substance abuse (Cate-Carter et al., 2003;Perlis et al., 2004), rapid cycling (Cate-Carter et al., 2003;Lin et al., 2006;Post et al., 2010), poorer lithium-response ( Leboyer et al., 2005), more suicide attempts (Cate-Carter et al., 2003;Geoffroy et al., 2013;Lin et al., 2006;Perlis et al., 2004) and worse prognosis compared to late-onset BD (LO-BD) patients. ...
... Studies have considered age at onset a phenotypic specifier ( GrigoroiuSerbanescu et al., 2014) and have identified early-onset BD (EO-BD) subgroup as a clinically distinct BD subtype with specific clinical fea- tures and outcomes and conceivably distinct genetic risk factors (Bellivier et al., 2003;Geoffroy et al., 2013;Lin et al., 2006;Manchia et al., 2008;Tozzi et al., 2011). Previous studies have identified asso- ciations between EO-BD patients and high incidence of psychosis (Javaid et al., 2011), greater rates of comorbid anxiety disorder and substance abuse (Cate-Carter et al., 2003;Perlis et al., 2004), rapid cycling (Cate-Carter et al., 2003;Lin et al., 2006;Post et al., 2010), poorer lithium-response ( Leboyer et al., 2005), more suicide attempts (Cate-Carter et al., 2003;Geoffroy et al., 2013;Lin et al., 2006;Perlis et al., 2004) and worse prognosis compared to late-onset BD (LO-BD) patients. EO-BD has also been correlated with impaired cognitive and social functioning as well as with reduced quality of life (Dell'Osso et al., 2016). ...
... EO-BD has also been correlated with impaired cognitive and social functioning as well as with reduced quality of life (Dell'Osso et al., 2016). In addition, EO-BD patients have been shown to be ge- netically more homogenous than LO-BD patients ( Leboyer et al., 2005) showing higher familial loading ( Etain et al., 2010;Geoffroy et al., 2013;Grigoroiu-Serbanescu et al., 2001;Mick and Faraone, 2009;Ortiz et al., 2011;Schürhoff et al., 2000). ...
Introduction:
The age at onset of bipolar disorder (BD) has significant implications for severity, duration of affective episodes, response to treatment, and psychiatric comorbidities. It has been suggested that early-onset BD (EO-BD) could represent a clinically distinct subtype with probable genetic risk factors different from those of late-onset BD (LO-BD). To date, several genes have been associated with BD risk but few studies have investigated the genetic differences between EO-BD and LO-BD. The aim of this study was to evaluate if variants of the gene coding for myo-inositol monophosphatase (IMPA2) are linked to age at onset of BD.
Method:
235 bipolar patients were recruited and assessed. The final sample consisting of 192 euthymic individuals, was compared according to the age at onset. Polymorphisms were genotyped in the IMPA2 gene (rs669838, rs1020294, rs1250171, and rs630110). Early-onset was defined by the appearance of a first affective episode before the age of 18.
Results:
The analyses showed that in the genotype distribution rs1020294 (p = .01) and rs1250171 (p = .01) were associated with the age at onset. The significant effect remained only in the rs1020294 SNP in which G carriers were more likely to debut later compared to patients presenting the AA genotype (p = .002; OR = 9.57, CI95%[2.37-38.64]). The results also showed that EO-BD tended to experience more alcohol misuse (p = .003; OR = .197, CI95%[.07-.58]) compared to LO-BD.
Conclusions:
Our results provide evidence for genetic differences between EO-BD and LO-BD at the IMPA2 gene as well as clinical differences between subgroups with therapeutic implications.
... This does not apply, however, to ELOBD. Concerning comorbidities, individuals with ELOBD and VELOBD more often had substance use disorders, as reported in other studies [23,24,32]. Our data concerning psychotic features differ slightly from those of other studies. ...
... In contrast, we found fewer psychotic features in VELOBD than non-VELOBD. Although it has often been reported that earlier-life onset BD is associated with a higher prevalence of psychotic symptoms, the evidence from the literature is actually heterogeneous [23,24,32,58,67]. ...
Defining homogeneous subgroups of bipolar disorder (BD) is a major goal in personalized psychiatry and research. According to the neurodevelopmental theory, age at onset may be a key variable. As potential trait markers of neurodevelopment, cognitive and functional impairment should be greater in the early form of the disease, particularly type 1 BD (BD I). The age at onset was assessed in a multicenter, observational sample of 4190 outpatients with BD. We used a battery of neuropsychological tests to assess six domains of cognition. Functioning was measured using the Functioning Assessment Short Test (FAST). We studied the potential moderation of the type of BD on the associations between the age at onset and cognitive and functioning in a subsample of 2072 euthymic participants, controlling for potential clinical and socio-demographic covariates. Multivariable analyses showed cognition to not be impaired in individuals with early (21–30 years) and very early-life (before 14 years) onset of BD. Functioning was equivalent between individuals with early and midlife-onset of BD II and NOS but better for individuals with early onset of BD I. In contrast, functioning was not worse in individuals with very early-onset BD I but worse in those with very early-onset BD II and NOS. Early-life onset BDs were not characterized by poorer cognition and functioning. Our results do not support the neurodevelopmental view that a worse cognitive prognosis characterizes early-life onset BD. This study suggests that functional remediation may be prioritized for individuals with midlife-onset BD I and very early life onset BD 2 and NOS.
... They also have motor or language development preceding the onset of BD (Arango et al., 2014;Murray et al., 2004;Sigurdsson et al., 1999). They share more comorbidities or familial aggregation (Schulze et al., 2006;Schürhoff et al., 2000) and they are associated with worse prognosis (Geoffroy et al., 2013;Levy et al., 2013;Özyıldırım et al., 2010). ...
... We chose to consider both criteria together since they have been described as major features of neurodevelopmental phenotype and frequently associated (Fu-I et al., 2019;Kloiber et al., 2020). Moreover, early age of onset was set at 21 in (Sarrazin et al., 2018) while we used a more selective threshold (i.e., age of onset <18) consistently with previous reports (Arango et al., 2014;Geoffroy et al., 2013;Perlis et al., 2004). Furthermore, gyrification index was computed at the scale of sulci in (Sarrazin et al., 2018), while we referred to a much more local measure: the sulcal pit. ...
Background:
Analyzing cortical folding may provide insight into the biological underpinnings of neurodevelopmental diseases. A neurodevelopmental subtype of bipolar disorders (BD-ND) has been characterized by the combination of early age of onset and psychotic features. We investigate potential cortical morphology differences associated with this subtype. We analyze, for the first time in bipolar disorders, the sulcal pits, the deepest points in each fold of the cerebral cortex.
Methods:
We extracted the sulcal pits from anatomical MRI among 512 participants gathered from 7 scanning sites. We compared the number of sulcal pits in each hemisphere as well as their regional occurrence and depth between the BD-ND subgroup (N = 184), a subgroup without neurodevelopmental features (BD, N = 77) and a group of healthy controls (HC, N = 251).
Results:
In whole brain analysis, BD-ND group have a higher number of sulcal pits in comparison to the BD group. The local analysis revealed, after correction for multiple testing, a higher occurrence of sulcal pits in the left premotor cortex among the BD-ND subgroup compared to the BD and the HC groups.
Conclusion:
Our findings confirm that BD-ND is associated with a specific brain morphology revealed by the analysis of sulcal pits. These markers may help to better understand neurodevelopment in mood disorder and stratify patients according to a pathophysiological hypothesis.
... Bipolar disorder (BD) is a recurrent and severe mood disorder contributing to global disability (Whiteford et al. 2013) likely due to its early onset (Geoffroy et al. 2013), relapsing and remitting course, and impacts on education, employment and cohabitation (Marwaha et al. 2013;Conus et al. 2014;Sletved et al. 2021). It has been argued that earlier use of evidence-based treatments may have a protective effect and could mitigate disability associated with the disorder (Vieta et al. 2018;. ...
... While several excellent guidelines are available for the care of persons with BD (Goodwin et al. 2016;Grunze et al. 2009Grunze et al. , 2010Grunze et al. , 2013Yatham et al. 2018;Malhi et al. 2021), these guidelines do not distinguish recommendations for those in the earlier vs. later course of illness. Interventions for children and adolescents may receive separate attention (Goodwin et al. 2016;Yatham et al. 2018;Goldstein et al. 2017) but a substantial proportion of patients with BD have an onset in adulthood (Geoffroy et al. 2013;Post et al. 2008) and a minority even in late life (Tohen et al. 1994). Thus, there is a need to examine the impact of interventions early in illness course more broadly, not just early in chronological age. ...
Background
Given the likelihood of progressive illness in bipolar disorder (BD), it is important to understand the benefits and risks of interventions administered early in illness course. We conducted a systematic review of the effectiveness of interventions in the early course of BD I or II.
Methods
We completed a systematic search on MEDLINE, PsycINFO, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL and Google Scholar from 1/1/1979 till 14/9/2022. We included controlled trials examining intervention effects on symptomatic, course, functional and tolerability outcomes of patients in the ‘early course’ of BD I or II. We classified patients to be in early course if they (a) were seeking help for the first time for a manic episode, (b) had a lifetime history of up to 3 manic episodes, or (c) had up to 6 lifetime mood episodes. Evidence quality was assessed using the GRADE approach.
Results
From 4135 unique publications we included 25 reports representing 2212 participants in 16 randomized studies, and 17,714 participants from nine non-randomized studies. Available evidence suggested that in early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers. Mood stabilizers were also associated with better global functioning, compared with the use of antipsychotics in the medium term. While summative findings regarding psychological therapies were limited by heterogeneity, family-focused and cognitive-behavioral interventions were associated with reduced recurrence risk or improved symptomatic outcomes. There was some evidence that the same pharmacological interventions were more efficacious in preventing recurrences when utilized in earlier rather than later illness course.
Conclusions and recommendations
While there are promising initial findings, there is a need for more adequately powered trials to examine the efficacy and tolerability of interventions in youth and adults in early illness course. Specifically, there is a compelling need to compare the relative benefits of lithium with other pharmacological agents in preventing recurrences. In addition to symptomatic outcomes, there should be a greater focus on functional impact and tolerability. Effective pharmacological and psychological interventions should be offered to those in early course of BD, balancing potential risks using shared decision-making approaches.
... 4 To date no research has systematically validated what the various AAO subgroups should be, and there is no concurrence across studies regarding what is meant by 'early onset'. 5,6 In recent years, it has been acknowledged that AAO in bipolar disorder is not a simple unimodal distribution, but can better be explained by a mixture of distributions. Evidence has suggested that BD aggregates either into a bimodal distribution with two subgroups (early vs. late AAO), or a trimodal distribution with three subgroups (early vs. mid vs. late AAO). ...
... 53,54 Initial evidence suggests that there is genetic homogeneity within AAO subgroups and heterogeneity between groups. [55][56][57] It is thought that early onset may be a more heritable form of BD than late onset, with studies demonstrating differences in transmission patterns and more pronounced familial aggregation in early-compared to late-onset BD. 4,6,8,54,57,58 Genetics does not explain the whole picture, however, and there are environmental and neurobiological factors that are thought to interact with various susceptibility genes to influence the AAO of BD. 59 It is thought that exposure to childhood trauma interacts with genes that are involved in pathways relating to neuroplasticity, inflammation and calcium signalling to influence AAO. [60][61][62][63] Epigenetic modifications in gene function may play an important role in the mechanism underlying the relationship between childhood trauma and a younger AAO of BD. 64 it has been suggested that immune system dysregulation, puerperal hormones and genetic factors may activate disease pathways. ...
Objective:
Bipolar disorder (BD) is a chronic mental health disorder with significant morbidity and mortality. Age at onset (AAO) may be a key variable in delineating more homogeneous subgroups of BD patients. However, no known research has systematically assessed how BD age-at-onset subgroups should be defined.
Methods:
We systematically searched the following databases: Cochrane Central Register of Controlled Trials, PsycINFO, MEDLINE, Embase, CINAHL, Scopus, Proquest Dissertations and Theses, Google Scholar and BIOSIS Previews. Original quantitative English language studies investigating AAO in BD were sought.
Results:
A total of 9454 unique publications were identified. Twenty-one of these were included in data analysis (n = 22981 BD participants). Fourteen of these studies (67%, n = 13626 participants) found a trimodal AAO distribution: early-onset (µ = 17.3, σ = 1.19, 45% of sample), mid-onset (µ = 26.0,
σ
= 1.72, 35%), and late-onset (µ = 41.9,
σ
= 6.16, 20%). Five studies (24%, n = 1422 participants) described a bimodal AAO distribution: early-onset (µ = 24.3, σ = 6.57, 66% of sample) and late-onset (µ = 46.3, σ = 14.15, 34%). Two studies investigated cohort effects on BD AAO and found that when the sample was not split by cohort, a trimodal AAO was the winning model, but when separated by cohort a bimodal distribution fit the data better.
Conclusions:
We propose that the field conceptualises bipolar disorder age-at-onset subgroups as referring broadly to life stages. Demarcating BD AAO groups can inform treatment and provide a framework for future research to continue to investigate potential mechanisms of disease onset.
... Bipolar disorder (BD) is the fourth most significant contributor to disability amongst adolescents and young adults (Gore et al., 2011) and has one of the highest rates of suicide amongst mental disorders (Chesney et al., 2014). Most adults with BD experience the onset of mood symptoms before their 20s (Geoffroy et al., 2013). While earlier diagnosis and rapid implementation of effective evidence-based treatment can improve outcomes for those with BD (Kessing et al., 2014), there is typically a significant delay of 5-10 years between symptom onset and diagnosis (Baldessarini et al., 2003;Post et al., 2010). ...
... The guidelines relating to adolescents may be relevant to those in early stage disorder, as the categories are overlapping, given that the peak age of onset of the disorder is in the late teens (Lin et al., 2006). However, as a substantial proportion of those with BD will have an onset in adulthood (Geoffroy et al., 2013), there is a need for a focus on early stage or course of the disorder rather than a focus on age of the affected individuals alone. ...
Background: Interventions early in the course of Bipolar Disorder (BD) may have the potential to limit its functional and symptomatic impact. However, the implementation of specific early interventions for BD has been limited which may at least partly be due to the lack of guidelines focused on the early illness stages. We therefore aimed to review the current recommendations for early stage BD from clinical practice guidelines.
Methods: We searched PubMED and PsychINFO for clinical guidelines for BD published in the ten years prior to 1 November 2018. Recommendations from identified guidelines that addressed early stage BD or first episode mania were consolidated and compared. We also reviewed the guidelines relating to adolescents with BD to complement the guidelines related to those in the early illness course.
Results:We identified fourteen international and national guidelines on BD or affective psychoses. Most guidelines contained a separate section on adolescents, but only a few referred specifically to early stage BD. There were no consistent recommendations for early stage disorder, except with respect to the indications for maintenance medication treatments. For adolescents, there was a consistent recommendation for the use of second generation antipsychotics for treating acute mania.
Limitation: The main limitation is that the identified guidelines did not include primary data that clearly separated illness and developmental stages.
Conclusions: There is a lack of emphasis on early BD among widely-respected current clinical guidelines, likely reflecting the dearth of primary data. Future evidence or consensus-based recommendations could significantly inform clinical practice for this population.
... Differently from what reported in the literature, our study failed to confirm in the BD1 subgroup the wellestablished association of EO BD with a higher familial load for BD and for mood disorders in general, as well as with higher rates of suicidal behaviour (Geoffroy et al. 2013). On the contrary, EO BD2 showed a higher familial load for BD (p = 0.02) compared to LO BD. ...
... Similarly, Baek et al. (2011) found higher rates of major depression, but not of BD, in BD2 patients compared to BD1, although their sample was not stratified according to AAO. Further, another recent study showed that both BD1 and BD2 presented a similar familial load for mood disorders (Dell'Osso et al. 2016) There is compelling evidence that EO BD patients appear also to be more frequently associated with rapid cycling, drug abuse, higher rates of obsessive-compulsive disorder, and possibly for psychotic features, and panic disorder (Geoffroy et al. 2013). Although our study did not test for association most of these clinical correlates, there were no statistically significant associations with EO for drug dependence. ...
BACKGROUND: Admixture analysis of age at onset (AAO) has helped delineating the clinical profile of early onset (EO) bipolar disorder (BD). However, there is scarce evidence comparing the distributional properties of AAO as well as the clinical features of EO BD type 1 (BD1) with EO BD type 2 (BD2). To this end, we studied 515 BD patients (224 BD1, 279 BD2, and 12 BD not otherwise specified [NOS]) diagnosed according to DSM-IV-TR criteria.
METHODS: AAO was defined as the first reliably diagnosed hypo/manic or depressive episode according to diagnostic criteria. We used normal distribution mixture analysis to identify subgroups of patients according to AAO. Models were chosen according to the Schwarz's Bayesian information criteria (BIC). Clinical correlates of EO were analysed using univariate tests and multivariate logistic regression models.
RESULTS: A two normal components model best fitted the observed distribution of AAO in BD1 (BIC = -1599.3), BD2 (BIC = -2158.4), and in the whole sample (BIC = -3854.9). A higher number of EO BD2 patients had a depression-(hypo)mania-free interval (DMI) course, while a higher rate of (hypo)mania-depression-free interval (MDI) course was found in EO BD1. EO BD2 had also a higher rate of comorbidity with alcohol dependence compared to EO BD1. The latter finding was confirmed by multivariate logistic regression analysis.
CONCLUSIONS: In conclusion, both BD1 and BD2 had bimodal AAO distributions, but EO subgroups had a diagnostic-specific clinical delineation.
... The aim of the current study is to determine whether differences in efficacy (defined as a difference between drug effect and placebo response), in the treatment of patients with an acute manic episode are moderated by gender and dichotomized age as a proxy for menopausal status. Our hypotheses, based on the anti-manic, anti-estrogenic effects of Tamoxifen, are that women with acute mania show lower efficacy of treatment with anti-manic medication than men (Morgan et al., 2005), that women respond slower relative to men (Arnold, 2003), that women aged 47 or under (with a relatively higher level of estrogen) with acute mania have a poorer efficacy than women older than 47 and (Geoffroy et al., 2013) that these effects are independent of baseline symptom severity. ...
... Therefore, identifying those chil dren at greater risk to develop a bipolar disorder poses unique clinical and therapeutic challenges. The presentation of a mood disorder is frequently preceded by attenuated psychopathological phenomena with childhood onset Geoffroy et al., 2013;Salvatore et al., 2014;Skjelstad et al., 2010). Early signs and symptoms pre ceding the onset of bipolar disorder can be identified in childhood and adolescence in 30% to 50% of bipolar adult patients (Egeland et al., 2000;Lish et al., 1994). ...
Objective:
To identify childhood psychopathological features that predict the onset of adolescent Bipolar (BD) versus Unipolar Major Depressive Disorder (UD) during adolescence.
Method:
We analyzed clinical data from 495 juveniles diagnosed with DSM-5 UD (n = 359), and BD (n = 136), using bivariate analysis and multivariate logistic regression model.
Results:
BD subjects exhibited earlier onset of any psychiatric feature compared to UD. Antecedents associated with later BD were: oppositional defiant > specific phobias > ADHD > obsessive compulsive (OCD). Antecedents selectively associated with later UD were: social anxiety and separation anxiety. Factors significantly and independently associated with later BD diagnosis were: [a] emotional dysregulation at onset of the mood disorder; [b] first depressive episode with mixed features; [c] antecedent ADHD; [d] antecedent OCD, and [e] antecedent oppositional-defiance.
Conclusion:
Identifying developmental differences in BD and UD symptoms can aid clinicians in early identification and treatment planning for bipolar disorder in youth.
... The primary outcome will be electrophysiological measurements with ERG flash Introduction Background Bipolar disorder (BD) is a chronic and common psychiatric pathology, which can be particularly disabling. The disease has a global prevalence rate of 1-4% (1), begins at an early age, i.e. predominantly between 15 and 25 years old and persists throughout the life of patients (2). BD is characterized by a recurrence of mood depressive episodes (pathological decrease in mood and energy), hypomanic or manic episodes (pathological increase in mood and energy), or even mixed episodes (simultaneous presence of depressive and manic symptoms). ...
Background
Bipolar disorders (BD) is a common, chronic and disabling psychiatric condition. In addition to being characterized by significant clinical heterogeneity, notable disturbances of sleep and cognitive function are frequently observed in all phases of the disease. Currently, there is no readily available biomarker in current clinical practice to help diagnose or predict the disease course. Thus, identification of biomarkers in BD is today a major challenge. In this context, the study of electrophysiological biomarkers based on electroretinogram (ERG) measurements in BD seems highly promising. The BiMAR study aims to compare electrophysiological data measured with ERG between a group of euthymic patients with BD and a group of healthy control subjects. Secondarily, we will also describe the existing potential relationship between clinical, sleep and neuropsychological phenotypes of patients and electrophysiological data.
Methods
The BiMAR study is a comparative and monocentric study carried out at the Expert Center for BD in Nancy, France. In total, 70 euthymic adult patients with BD and 70 healthy control subjects will be recruited. Electrophysiological recordings with ERG and electroencephalogram (EEG) will be performed with a virtual reality headset after a standardized clinical evaluation to all participants. Then, an actigraphic monitoring of 21 consecutive days will be carried out. At the end of this period a neuropsychological evaluation will be performed during a second visit. The primary outcome will be electrophysiological measurements with ERG flash and pattern. Secondary outcomes will be EEG data, sleep settings, clinical and neuropsychological assessments. For patients only, a complementary ancillary study, carried out at the University Hospital of Nancy, will be proposed to assess the retinal structure and microvascularization using Optical Coherence Tomography. Recruitment started in January 2022 and will continue until the end of July 2023.
Discussion
The BiMAR study will contribute to identifying candidate ERG electrophysiological markers for helping the diagnosis of BD and identify subgroups of patients with different clinical profiles. Eventually, this would allow earlier diagnosis and personalized therapeutic interventions.
Clinical trial registration
The study is registered at Clinicaltrials.gov, NCT05161546, on 17 December 2021 (https://clinicaltrials.gov/ct2/show/NCT05161546).
... The comparison of the novel c.278_2A>G variant with phenotypic features, revealed that there was an early onset of the disease in patients with the aG genotype. The early-onset BP has been generally associated with a worse prognosis than late-onset BP, including more psychotic features, substance addiction, comorbidity with panic and obsessive-compulsive disorders, a lower lithium response, and further suicide attempts (46)(47)(48). in a previous study, it has been suggested that early-onset Bd has a high degree of homogeneity and a unique genetic etiology that has not yet been established in practice (49). in a study investigating the role of age at onset and family history in the clinic for BD, a significantly higher prevalence of family history and a higher number of attacks per year were observed in the early-onset group (50). although a number of interesting preliminary studies have been conducted for the investigation of the basis of the different phenotypic characteristics of Bd disease among individuals, the results obtained in genome-wide association studies (GWaS) with large samples need to be replicated to prove their actual validity. ...
NOD‑like receptor pyrin domain‑containing 3 (NLRP3) has been considered to play a crucial role in triggering the host's immune and inflammatory responses. Genetic variants are critical determinants of interindividual variances in inflammatory responses and clinical outcomes. The role of NLRP3 gene variations in bipolar I (BPI) disorder, which is known to include genetic factors in its aetiology, has not been previously reported, at least to the best of our knowledge. The present study aimed to determine the role and frequency ofta exon 2 and exon 3 variants of NLRP3 in BPI disorder and to evaluate the association between different phenotypic traits. A case‑control study with 123 patients and 107 healthy controls was conducted to investigate the association of variants identified in the exon 2 and exon 3 regions of NLRP3, with the risk of BPI. Regions of interest were sequenced using a PCR‑based Sanger sequencing method. Three BPI‑related variants were identified. The genotype Q705K CA was detected more frequently in BPI patients, as compared to the control group [P<0.001; odds ratio (OR), 0.202; 95% confidence interval (CI), 0.080‑0.508]. In addition, two novel splice‑site variants (c.393G>A and c.278_2A>G) that, to the best of our knowledge, have not been previously reported in any database, were detected only in the BPI patient group [P<0.001; OR, 0.846; 95% CI, 0.784‑0.912; P<0.001; OR, 0.886; 95% CI, 0.832‑0.944, respectively]. There was no significant association between the Q795K variant and phenotypic traits (P>0.05). However, there was a significant association between those carrying the heterozygous c.393G>A variant and a positive family history (P=0.043). It was also observed that those with the heterozygous c.278‑2A>G variant presented with a significantly early‑onset (P=0.003). On the whole, the data of the present study suggested that NLRP3 plays a crucial role in the pathogenesis of BPI and may be a potential risk factor. However, further functional studies and repeated studies in other populations are required to properly comprehend the roles of the NLRP3 variants in the risk of developing BPI.
... 27 As suggested by prior research, the trauma of childhood abuse may expedite the AAO of bipolar disorder. 27,52 For instance, recent research (which has partial sample overlap with the current study) found that the path between childhood abuse and an earlier AAO was selectively explained by individuals' mood instability. 53 The authors suggest that mood instabilitydefined as rapid and intense fluctuations in affectmay bring forward illness onset in children who are vulnerable because of abuse, with increased mood instability developing into episodes of mania or depression. ...
Background
Bipolar disorder is a chronic and severe mental health disorder. Early stratification of individuals into subgroups based on age at onset (AAO) has the potential to inform diagnosis and early intervention. Yet, the psychosocial predictors associated with AAO are unknown.
Aims
We aim to identify psychosocial factors associated with bipolar disorder AAO.
Method
Using data from the Bipolar Disorder Research Network UK, we employed least absolute shrinkage and selection operator regression to identify psychosocial factors associated with bipolar disorder AAO. Twenty-eight factors were entered into our model, with AAO as our outcome measure.
Results
We included 1022 participants with bipolar disorder (μ = 23.0, s.d. ± 9.86) in our model. Six variables predicted an earlier AAO: childhood abuse (β = −0.2855), regular cannabis use in the year before onset (β = −0.2765), death of a close family friend or relative in the 6 months before onset (β = −0.2435), family history of suicide (β = −0.1385), schizotypal personality traits (β = −0.1055) and irritable temperament (β = −0.0685). Five predicted a later AAO: the average number of alcohol units consumed per week in the year before onset (β = 0.1385); birth of a child in the 6 months before onset (β = 0.2755); death of parent, partner, child or sibling in the 6 months before onset (β = 0.3125); seeking work without success for 1 month or more in the 6 months before onset (β = 0.3505) and a major financial crisis in the 6 months before onset (β = 0.4575).
Conclusions
The identified predictor variables have the potential to help stratify high-risk individuals into likely AAO groups, to inform treatment provision and early intervention.
... Psychiatric disorders, including ADHD, anxiety disorders, ASD, BIP, and schizophrenia, are severe neurodevelopmental disorders characterized by considerable impairments in cognitive function such as information processing [34][35][36][37][38]. The results from observational studies on this topic remains debatable, yet many studies reported a positive association [39][40][41]. ...
Background:
Extensive studies put forward the association between Alzheimer's disease (AD) and psychiatric disorders; however, it remains unclear whether these associations are causal.
Objective:
We aimed to assess the potential causal relationship between major psychiatric disorders and AD.
Methods:
A bidirectional two-sample Mendelian randomization (MR) was applied to evaluate potential causality between five psychiatric disorders and AD by selecting the single-nucleotide polymorphisms from the genome-wide association studies as instrumental variables. Inverse-variance weighted (IVW) method was used as the main analyzing approach to estimate possible causal effects, alternative methods including MR-Egger, the MR pleiotropy residual sum and outlier, and leave-one-out analysis method were implemented as sensitivity analyzing approaches to ensure the robustness of results.
Results:
All forward and reverse MR analyses consistently suggested absent causal relations between psychiatric disorders and AD risk [forward IVW: ORADHD, 1.030, 95% CI, 0.908-1.168, p = 0.674; ORanxiety disorders, 0.904, 95% CI, 0.722-1.131, p = 0.377; ORASD, 0.973, 95% CI, 0.746-1.272, p = 0.846; ORBIP, 1.033, 95% CI, 0.925-1.153, p = 0.564; and ORschizophrenia, 1.039, 95% CI, 0.986-1.095, p = 0.156; reverse IVW: ORADHD, 0.993, 95% CI, 0.954-1.034, p = 0.746; ORanxiety disorders, 1.000, 95% CI, 0.999-1.000, p = 0.898; ORASD, 1.001, 95% CI, 0.962-1.042, p = 0.949; ORBIP, 0.997, 95% CI, 0.966-1.028, p = 0.831; and ORschizophrenia, 1.013, 95% CI, 0.978-1.051, p = 0.466].
Conclusion:
There is no significant evidence supporting the causal association between the five major psychiatric disorders and AD.
... Previous studies have suggested that the age of onset may be a key risk factor for inclination toward suicidal behavior in BD patients (Hauser et al., 2013). The early age of onset may be associated with a higher suicide rate in BD patients along with the higher frequency and severity of depressive symptoms (Biffin et al., 2009;Etain et al., 2012;Geoffroy et al., 2013;Grunebaum et al., 2010). It may also indicate the importance of screening BD patients with high scores of emotional abuse, emotional neglect, and physical neglect for early diagnosis of the disease severity and minimizing the suicide risk in these patients. ...
Objective
: This study aimed to investigate the relationship between childhood trauma and clinical correlates in bipolar depression.
Methods
: A total of 61 bipolar depression patients were enrolled and assessed based on the Childhood Trauma Questionnaire-Short Form (CTQ-SF), Patient Health Questionaire-15 (PHQ-15), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7) systems.
Results
: The age of onset in bipolar depression patients with either trauma or abuse or neglect was significantly lower than in patients without these factors. There were statistically significant negative correlations between the age of onset and the number of different trauma types in bipolar depression patients. Multiple variable regression showed a significant association between the number of trauma types and the age of onset. Furthermore, there was a significant negative correlation between the age of onset with CTQ-SF total score (CTS), emotional abuse score and emotional neglect score, and physical neglect score. However, multiple variable regression analysis revealed that there was a significant association between emotional abuse score and the age of onset of bipolar depression patients.
Taken together, our results suggest that childhood trauma may be associated with physical symptoms and the age of onset in bipolar depression patients.
... Hastalık başlangıç yaşı kompleks genetik hastalıklarda hastalık genlerinin tanımlanması için gerekli fenotipik ayrımda önemli bir rol oynayabilir. Bunun için BB'nin başlangıç yaşı son zamanlarda klinik sınıflandırma için bir araç olarak önerilmiştir (12). Bipolar bozukluğun başlangıç yaşı için genel olarak bimodal dağılımdan bahsedilse de çocukluk çağında görülen BB verilerinin artmasıyla yakın zamanlı çalışmalarda trimodal dağılım öne sürülmektedir (13). ...
Amaç: Farklı klinik sunumlara rağmen, postpartum psikoz ataklarının psikolojik ve fizyolojik değişim sırasında meydana gelen bipolar bozukluğun sunumları olduğuna dair klinik ve genetik çalışmalardan gelen güçlü kanıtlar vardır. Bu çalışmada postpartum başlangıç gösteren bipolar bozukluk tanılı hastalar ile en az bir doğum yapmış ve postpartum süreçte dönem yaşamamış olan bipolar bozukluk tanılı hastaların klinik özelliklerinin karşılaştırılması amaçlanmıştır.
Gereç ve Yöntem: Çalışma Bakırköy Ruh ve Sinir Hastalıkları Hastanesi ve Selçuk Üniversitesi Tıp Fakültesi Duygudurum Merkezlerinde bipolar bozukluk tanısı ile takip edilen hastalar ile yürütülmüştür. İlk hastalık belirtileri postpartum sürecin ilk 6 haftası içinde olan hastalar veri tabanlarından kontrol edilmiş ve bu hastalardan ulaşılabilen ve çalışmayı kabul eden 30 hasta çalışmanın ilk grubunu oluşturmak için ardışık olarak alınmıştır. İkinci grubu oluşturmak için en az bir doğum yapmış ve postpartum döneminde epizodu olmayan 30 kadın hasta ilk grubun yaşı ile birebir eşleştirilerek çalışmaya alınmıştır.
Bulgular: Örneklemin ortalama yaşı 38,77±9,58 yıldı. Her iki grup arasında gebelik sayısı açısından istatiksel fark yoktu. Postpartum başlangıçlı grubunun ilk epizodunda psikotik bulguların olma oranı %33,3 (n=10) iken diğer grupta bu oran %10 (n=3) idi ve aradaki fark anlamlıydı (x2=4,812, p=0,028). Hastaların hastalık başlangıç yaşı istatiksel olarak anlamlı çıkmasa da tip-1 hata oranı eşik düzeye yakındı (p=0,074) ve hastalık başlangıç yaşı ortalaması postpartum başlangıç gösteren grupta yaklaşık 3,5 yıl daha erkendi.
Sonuç: Bu çalışma küçük örneklemine rağmen postpartum başlangıç ile bipolar bozukluğun klinik özelliklerini değerlendiren ilk çalışma olması açısından değerli bilgiler sunmaktadır. Daha büyük örneklemli araştırmalarda postpartum başlangıç öyküsünün önemine ilişkin daha güçlü sonuçlar elde edilebilir.
... The pooled lifetime prevalences of BD type 1 and type 2 were reported as 1.06% and 1.57%, respectively (Clemente et al. 2015). Patients with BD experience a chronic course of the disorder characterized by progressive cognitive impairment, residual symptoms, sleep and circadian rhythm disturbances, emotional dysregulation, and increased risk for comorbid psychiatric and medical situations in changing mood episodes (Clemente et al. 2015;Geoffroy et al. 2013). Approximately 50-67% of adults with BD report onset of their first episode before the age of 18 years and early-onset BD maybe accepted as a distinct endophenotype with greater illness severity, more switches of mood polarity, longer episodes, more comorbid diseases, genetic loading, and greater long-term morbidity when compared with late-onset BD patients (Croarkin et al. 2017;Miklowitz 2012). ...
Clock genes play significant roles in the regulation of circadian rhythms, which are thought to be involved in the pathophysiology of neurodegenerative and psychiatric diseases. We aimed to investigate the association of five gene polymorphisms (PER3 VNTR (rs57875989), PER2 rs2304672, CLOCK rs1801260, CLOCK rs10462028, CLOCK rs11932595) with PCR-based methods as potential risk factors in bipolar disorder (BD). We used a multiple testing methodology in BD patients (n = 121) and healthy control individuals (n = 121) of Turkish descent to analyze the effects of these gene variants both as risk factors for the disorder and for the evaluation of these variants in the patient group with multiple subscales. We evaluated the circadian rhythm disturbances and seasonal variations in mood and behavior in BD patients using the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) and Seasonal Pattern Assessment Questionnaire (SPAQ) to enlighten the possible links between these scores and the studied circadian gene variants. The results of our study revealed significant associations: PER3 VNTR (rs57875989) 5/5 repeat genotype displayed a protective effect against BD when compared with 4/4 repeat genotype. Moreover, patients with PER3 VNTR 5/5 repeat genotype displayed a higher ratio of hypomania. PER2 rs2304672 G allele frequency increased the risk for BD. There was no association in terms of genotype/allele frequency comparisons between patients and controls for CLOCK gene variants. However, significant associations were found in patients in terms of clinical and behavioral patterns such as mean age at disease onset and BRIAN total scores enabling some risk stratifications for patients. Our results indicate the significance of circadian gene variants in BD, which need to be confirmed in different studies with larger samples. Thus, the possible endophenotypes of BD can be enlightened and advanced chronotherapeutics approaches can be manipulated in the future for clinical benefit.
... Bipolar disorder has a lifelong impact on patients' overall health status, quality of life, and ability to function. 1 Bipolar disorder is a multifactorial psychiatric disorder with developmental and progressive neurophysiological changes typically characterised by cyclical and recurrent episodes of mania and depression but it is heterogeneous in its clinical presentation and outcome. 2 More than half of patients with bipolar disorder will experience psychotic symptoms in their lifetime; up to 68% of patients with bipolar mania may suffer from psychotic symptoms. 3 The relationship between psychiatric illness and criminal behaviour are complex; it may be direct, or indirect, through co-morbid conditions or environmental factors. ...
bipolar disorder at the time of committing murder according to iranian law
... Cross-sectional studies showed that patients with high cognitive reserve (CR), for example, displayed better cognitive performance than patients with low CR (Anaya et al., 2016;Forcada et al., 2015). Furthermore, the number of hospitalizations, number of mood episodes, and early onset of disease are also related to worse clinical, functional, and cognitive outcomes (Cardoso, Bauer, Meyer, Kapczinski, & Soares, 2015;Geoffroy et al., 2013). Although there seems to be a subset of patients with a progressive cognitive decline throughout the disease (Passos, Mwangi, Vieta, Berk, & Kapczinski, 2016), not all subjects with BD will lead to unfavorable clinical outcomes. ...
Background. Subjects with bipolar disorder (BD) show heterogeneous cognitive profile and
that not necessarily the disease will lead to unfavorable clinical outcomes. We aimed to
identify clinical markers of severity among cognitive clusters in individuals with BD through
data-driven methods.
Methods. We recruited 167 outpatients with BD and 100 unaffected volunteers from Brazil
and Spain that underwent a neuropsychological assessment. Cognitive functions assessed
were inhibitory control, processing speed, cognitive flexibility, verbal fluency, working memory,
short- and long-term verbal memory. We performed hierarchical cluster analysis and
discriminant function analysis to determine and confirm cognitive clusters, respectively.
Then, we used classification and regression tree (CART) algorithm to determine clinical
and sociodemographic variables of the previously defined cognitive clusters.
Results. We identified three neuropsychological subgroups in individuals with BD: intact
(35.3%), selectively impaired (34.7%), and severely impaired individuals (29.9%). The most
important predictors of cognitive subgroups were years of education, the number of hospitalizations,
and age, respectively. The model with CART algorithm showed sensitivity 45.8%,
specificity 78.4%, balanced accuracy 62.1%, and the area under the ROC curve was 0.61. Of
10 attributes included in the model, only three variables were able to separate cognitive
clusters in BD individuals: years of education, number of hospitalizations, and age.
Conclusion. These results corroborate with recent findings of neuropsychological heterogeneity
in BD, and suggest an overlapping between premorbid and morbid aspects that influence
distinct cognitive courses of the disease.
... The age at illness onset may play an important role in the phenotypic distinction required for the identification of genes in complex genetic diseases. Therefore, the age at onset of BD has recently been proposed as a tool for clinical classification [36]. In the study sample, the average age at illness onset was 23.86 years. ...
Background: Family history is one of the most important known risk factors for the occurrence of bipolar disorder (BD). Identifying clustering factors in BD families may facilitate the identification of the hereditary sub-phenotypes of the disorder and might reveal the underlying genetic features. This retrospective study aimed to investigate the effect of family history and gender on the clinical features of the disease in a large BD sample followed in a specialized mood center in Turkey. Methods: Research was carried out by reviewing the medical files of patients diagnosed with bipolar disorder who were followed up in the Raşit Tahsin Mood Clinic. Family histories and other demographic and clinical information of the patients were retrieved from the Mood Disorders Patient Registration Form (SKIP-TURK) completed for each patient. A patient's family history was considered positive if any diagnosis of mood disorders and/or psychotic disorders was present in their first and/or second-degree relatives. Results: Family history was positive in 64.5% (n = 474) of 735 patients whose family history was recorded. Female patients made up 59.9% of the sample. Eighty point three percent (n = 590) of the patients were diagnosed with type 1 BD, 8.4% (n = 62) with type 2 BD, 11.3% (n = 83) with bipolar disorder not otherwise specified (BD-NOS). In the sample divided into 4 groups according to gender and family history, differences in the age at onset of the illness (F = 3.662, p = .012) were found to be statistically significant. In post hoc analysis, a significant difference was obtained between female patients without a positive family history and patients with a relevant family history. Regardless of family history status, the type of first episode in male patients tended to be hypomania/mania. Regarding treatment preferences, there was no significant difference between patients with and without a positive family history. Conclusions: In the literature, some studies evaluating the familial burden only included first-degree relatives, while others considered first-and second-degree relatives, and some studies defined the family history including only relatives with mood disorders, while others would include any psychiatric disease. In the present study, family history of those diagnosed with mood disorders and/or psychotic disorders in their first-and/or second-degree relatives was considered positive. This study provides valuable information by evaluating the effect of family history and gender on the clinical features of the disease in a large BD sample in Turkey.
... There is not an agreed upon cut off age for what is considered early onset bipolar disorder. To produce a more homogeneous sample, we set the age threshold lower (≤ 19 years) than in earlier studies (Etain et al., 2010;Geoffroy et al., 2013;Jamain et al., 2014), which has correlated with biological marker in at previous study (Nassan et al., 2015). Patients with BD-Type 1 that did not meet our definition for early onset were classified as late onset. ...
Background:
The brain-derived neurotrophic factor (BDNF) rs6265 (Val66Met) Met allele is associated with early onset (≤ 19 years old) bipolar disorder (BD). Val66Met (G196A) creates a CpG site when the Val/G allele is present. We sought to study the methylation of the BDNF promoter and its interaction with Val66Met genotype in BD.
Methods:
Sex/age-matched previously genotyped DNA samples from BD-Type 1 cases [N = 166: early onset (≤ 19 years old) n = 79, late onset (> 20 years old) n = 87] and controls (N = 162) were studied. Pyrosequencing of four CpGs in Promoter-I, four CpGs in promoter-IV, and two CpGs in Promoter-IX (CpG2 includes G= Val allele) was performed. Logistic regression adjusting for batch effect was used to compare cases vs. controls. Analyses also included stratification by disease onset and adjustment for Val66Met genotype. Secondary exploratory analyses for the association of life stressors, comorbid substance abuse, and psychotropic use with methylation patterns were performed.
Results:
Comparing all BD cases vs. controls and adjusting for Val66Met genotype, BD cases had significantly higher methylation in promoter -IX/CPG-2 (p = 0.0074). This was driven by early onset cases vs. controls (p = 0.00039) and not late onset cases vs. controls (p = 0.2).
Limitation:
Relatively small sample size.
Conclusion:
Early onset BD is associated with increased methylation of CpG site created by Val=G allele of the Val66Met variance. Further studies could include larger sample size and postmortem brain samples in an attempt to replicate these findings.
... Bipolar disorder has a lifelong impact on patients' overall health status, quality of life, and ability to function. 1 Bipolar disorder is a multifactorial psychiatric disorder with developmental and progressive neurophysiological changes typically characterised by cyclical and recurrent episodes of mania and depression but it is heterogeneous in its clinical presentation and outcome. 2 More than half of patients with bipolar disorder will experience psychotic symptoms in their lifetime; up to 68% of patients with bipolar mania may suffer from psychotic symptoms. 3 The relationship between psychiatric illness and criminal behaviour are complex; it may be direct, or indirect, through co-morbid conditions or environmental factors. ...
Bipolar disorder is a chronic, relapsing illness characterised by recurrent episodes of manic or depressive symptoms, with intervening periods that are relatively (but not fully) symptom-free. Studies have found higher rates of psychiatric disorders in homicide offenders than in the general population. The insanity defence is a legal construct that, under some circumstances, excuses defendants with mental illness from legal responsibility for criminal behaviour. Here we report two cases of family murder by the mother of the family caused by bipolar disease. The role of the forensic psychiatrist in diagnosing insanity during the commission of a crime is very important as these patients should be diagnosed, treated as soon as possible, and monitored. Public education through social media should be considered to reduce crimes in societies. Diagnosing insanity during the commission of a crime is very important and requires high precision forensic psychiatry. Public education through social media should be considered to reduce crimes in societies.
... Bipolar disorder has a lifelong impact on patients' overall health status, quality of life, and ability to function. 1 Bipolar disorder is a multifactorial psychiatric disorder with developmental and progressive neurophysiological changes typically characterised by cyclical and recurrent episodes of mania and depression but it is heterogeneous in its clinical presentation and outcome. 2 More than half of patients with bipolar disorder will experience psychotic symptoms in their lifetime; up to 68% of patients with bipolar mania may suffer from psychotic symptoms. 3 The relationship between psychiatric illness and criminal behaviour are complex; it may be direct, or indirect, through co-morbid conditions or environmental factors. ...
Introduction: Selecting unusual and uncommon means for suicide may be rooted in psychiatric disorders. Case Presentation: Herein, we report a case of suicide attempt occurring with a grinding stone as an unusual tool for suicide. After surgical repair of the injury and owing to a suspicion of psychological problems, psychiatric consultation was requested to rule out the possibility of borderline personality disorder, brief psychotic disorder, and major depression with psychotic features. Conclusions: The presence of psychotic patterns and behaviors, especially auditory hallucination and depressed mood, influence suicide attempts. The selection of uncommon tools emphasizes the need for psychiatric consultants to prevent repeated suicide attempts effectively in the same conditions.
... Second, our results of FR group should be evaluated with the information that siblings, parents and offspring have different genetic risk for BD. Furthermore, it has been shown that approximately the 45% of bipolar disorder patients have their illness onset before the mean age of 21 and up to 80% before the mean age of 35 (Geoffroy et al., 2013).The mean age of our FR group was 32 and FR-SB was 34, which were very near to exceed the defined age threshold for the onset of illness. From this aspect, our relative sample could be at low risk or resilient for developing BDI which may have hindered finding any potential brain areas as a risk marker. ...
Objectives
So far, few studies have investigated cortical thickness (CT) and surface area (SA) measures in bipolar disorder type I (BDI) in comparison to a high genetic risk group such as first-degree relatives (FR). This study aimed to examine CT and SA differences between BDI, FR and healthy controls (HC).
Methods
3D T1 magnetic resonance images were acquired from 27 euthymic BDI patients, 24 unaffected FR and 29 HC. CT and SA measures were obtained with FreeSurfer version 5.3.0. Generalized estimating equations were used to compare CT and SA between groups. Group comparisons were repeated with restricting the FR group to 17 siblings (FR-SB) only.
Results
\Mean age in years was 36.3 ± 9.5 for BDI, 32.1 ± 10.9 for FR, 34.7 ± 9.8 for FR-SB and 33.1 ± 9.0 for HC group respectively. BDI patients revealed larger SA of left pars triangularis (LPT) compared to HC (p = .001). In addition, increased SA in superior temporal cortex (STC) in FR-SB group compared to HC was identified (p = .0001).
Conclusions
Our result of increased SA in LPT of BDI could be a disease marker and increased SA in STC of FR-SB could be a marker related with resilience to illness.
... In both samples, age at onset (AAO) was defined as the age at which the first mood episode (depressive, manic or hypomanic) occurred. The threshold for early-onset BD (AAO before the age of 22 years) was defined on the basis of previous admixture analyses in eight independent samples (Geoffroy et al., 2013). ...
Reports of association of genetic variants of IL6 and its receptor (IL6R) with psychiatric disorders are inconsistent, and there are few population-based studies thus far in bipolar disorder (BD). We genotyped the IL6 rs1800795 and IL6R rs2228145 polymorphisms in two independent sets of patients exposed to different environmental stimuli such as climatic conditions or specific infectious burden – a French sample and a south Indian Tamil sample of BD with quantitation of circulating plasma IL-6 levels in the latter sub-sample.
In both populations, allele and genotype frequencies did not differ significantly between cases and controls for either polymorphism. Upon stratifying based on age at onset, we found no associations with the IL6 rs1800795 variant. However, the IL6R rs2228145 C allele and CC genotype were associated with early onset of disease in the French sample when compared to late onset BD. A similar trend was observed in the Indian population where we also found that plasma IL-6 levels were significantly higher in BD and also in patients who were in residual phase or remission both as compared to controls.
Our findings are in favour of a possible trans-ethnic implication of the IL6R genetic diversity in BD and reinforce the notion that IL-6 is an important marker of the operating inflammatory processes in the disease.
... There has been a consensus that individuals with congenital developmental abnormalities are prone to develop psychiatric disorders later in life [85,86], and the prevalence of major psychiatric illnesses in children with mental retardation is significantly higher than that in general populations [87][88][89]. Indeed, the etiological contribution of developmental deficits to psychiatric and neurological disorders including SCZ [50,90], autism [91,92], MDD [93,94], and potentially BPD [95] have been recognized. A core mechanism underlying this neurodevelopmental hypothesis for psychiatric disorders is impaired brain development, which might also be manifested as a series of congenital abnormalities, such as microcephaly [96,97] and intellectual disability [98]. ...
Recent large-scale genetic approaches, such as genome-wide association studies, have identified multiple genetic variations that contribute to the risk of mental illnesses, among which single nucleotide polymorphisms (SNPs) within or near the vaccinia related kinase 2 (VRK2) gene have gained consistent support for their correlations with multiple psychiatric and neurological disorders including schizophrenia (SCZ), major depressive disorder (MDD), and genetic generalized epilepsy. For instance, the genetic variant rs1518395 in VRK2 showed genome-wide significant associations with SCZ (35,476 cases and 46,839 controls, p = 3.43 × 10–8) and MDD (130,620 cases and 347,620 controls, p = 4.32 × 10–12) in European populations. This SNP was also genome-wide significantly associated with SCZ in Han Chinese population (12,083 cases and 24,097 controls, p = 3.78 × 10–13), and all associations were in the same direction of allelic effects. These studies highlight the potential roles of VRK2 in the central nervous system, and this gene therefore might be a good candidate to investigate the shared genetic and molecular basis between SCZ and MDD, as it is one of the few genes known to show genome-wide significant associations with both illnesses. Furthermore, the VRK2 gene was found to be involved in multiple other congenital deficits related to the malfunction of neurodevelopment, adding further support for the involvement of this gene in the pathogenesis of these neurological and psychiatric illnesses. While the precise function of VRK2 in these conditions remains unclear, preliminary evidence suggests that it may affect neuronal proliferation and migration via interacting with multiple essential signaling pathways involving other susceptibility genes/proteins for psychiatric disorders. Here, we have reviewed the recent progress of genetic and molecular studies of VRK2, with an emphasis on its role in psychiatric illnesses and neurological functions. We believe that attention to this important gene is necessary, and further investigations of VRK2 may provide hints into the underlying mechanisms of SCZ and MDD.
... 12,13 Indeed, patients with psychotic BD have a younger age at onset than those with non-psychotic BD. 14 Early-onset BD share a high degree of intra-familial aggregation 15,16 and are associated with a worse prognosis. [17][18][19] Moreover, early exposure, including during fetal life, to unfavorable environmental factors may increase the risk of BD with psychosis 20 and early-onset BD. 6 Taken together, these findings suggest that psychotic and early-onset BD may be a clinical BD subgroup with a high load of neurodevelopmental insults. 21 Sulcation and gyrification are developmental processes that occur as early as the 10th gestational week and extend to the 44th week in the fetal brain. ...
Objectives
Brain sulcation is an indirect marker of neurodevelopmental processes. Studies of the cortical sulcation in bipolar disorder have yielded mixed results, probably due to high variability in clinical phenotype. We investigated whole‐brain cortical sulcation in a large sample of selected patients with high neurodevelopmental load.
Methods
A total of 263 patients with bipolar disorder I and 320 controls were included in a multicentric magnetic resonance imaging (MRI) study. All subjects underwent high‐resolution T1‐weighted brain MRI. Images were processed with an automatized pipeline to extract the global sulcal index (g‐SI) and the local sulcal indices (l‐SIs) from 12 a priori determined brain regions covering the whole brain. We compared l‐SI and g‐SI between patients with and without early‐onset bipolar disorder and between patients with and without a positive history of psychosis, adjusting for age, gender and handedness.
Results
Patients with early‐onset bipolar disorder had a higher l‐SI in the right prefrontal dorsolateral region. Patients with psychotic bipolar disorder had a decreased l‐SI in the left superior parietal cortex. No group differences in g‐SI or l‐SI were found between healthy subjects and the whole patient cohort. We could replicate the early‐onset finding in an independent cohort.
Conclusions
Our work suggests that bipolar disorder is not associated with generalized abnormalities of sulcation, but rather with localized changes of cortical folding restricted to patients with a heavy neurodevelopmental loading. These findings support the hypothesis that bipolar disorder is heterogeneous but may be disentangled using MRI, and suggest the need for investigations into neurodevelopmental deviations in the disorder.
... Age at onset (AAO) was defined as the age at which the first mood episode (depressive, manic or hypomanic) occurred. The threshold for 105 early-onset BD (AAO before the age of 22 years) was defined on the basis of previous admixture analyses in multiple independent samples (Geoffroy et al., 2013), which allows patient categorization into early onset BD (EO-BD) and late onset BD (LO-BD). All the participants provided written informed consent for participation in the study, which was reviewed and approved by the JIPMER institutional ethics committee (approval no.JIP/IEC/3/ 110 2012/12). ...
Bipolar disorder (BD) is frequently associated with immune dysfunctions. Studying the genetic diversity of the immuno-modulatory human leukocyte antigen (HLA)-G locus in a French BD cohort, we previously reported an association between a functionally relevant 14 bp Ins/Del polymorphism and BD risk. The present study investigated the genetic and expression diversities of HLA-G in a geographically distinct South Indian population-group BD patients, as well as the influence of exposure to the neurotropic Toxoplasma gondii pathogen. Three functionally relevant HLA-G polymorphisms, i.e. HLA-G 14 bp Ins/Del (rs66554220), +3142G>C (rs1063320) and +3187A>G (rs9380142) were genotyped by polymerase chain reaction (PCR) and real-time PCR. Sub-samples of BD patients and healthy controls (HC) were investigated for plasma levels of soluble HLA-G (sHLA-G) isoforms, as well as circulating stigma of T. gondii infection.
Findings indicate: (i) the frequency of the HLA-G 14 bp Del/Del genotype was higher in BD cases, as compared to HC; (ii) the HLA-G + 3142 C allele and CC genotype were more prevalent in BD patients than in HC; (iii) sHLA-G levels were significantly higher in BD cases, especially in females and in the early onset sub-group; and (iv) the InsGA haplotype was more prevalent in HC.
Our findings further support the genetic contribution of HLA-G to BD risk, as well as indicate relevant expression profiles. Such data may also indicate a potential developmental role in BD etiology, given that HLA-G is an important immune regulator from the intrauterine period and across development.
... The average age of onset can only be stated in decades of life. Accordingly, the second and third decades of life are considered typical onset times (Geoffroy et al., 2013). BD can remain undiagnosed and untreated for many years with an average eight years' delay from a patient's first recollected mood episode to receiving a diagnosis of BD (Hirschfeld and Vornik, 2004;Mantere et al., 2004). ...
To assess the occurrence and frequency of bipolar at-risk symptoms in a large sample of previously undiagnosed students using the new screening tool Bochumer Screeningbogen Bipolar (BSB). 2329 students of the Ruhr-University Bochum, Germany completed online demographic data as well as various self-rating questionnaires (BSB; Hypomania Checklist 32; Altman Self-Rating Mania Scale; Beck Depression Inventory). Within the student cohort (64.4% female, mean age 24.3 years) every fifth student currently suffered from moderate to severe depressive symptoms; every sixth student had already thought about suicide and every other student reported a history of mood swings. The most frequently reported depressive symptoms included physical exhaustion, depressed mood, and tiredness. The most frequently reported (hypo)manic symptoms included physical agitation, feeling extremely energetic, and lack of concentration. The BSB showed good convergent validity with other established questionnaires capturing depressive or (hypo)manic symptoms, as well as a stable administration of underlying constructs. The BSB correlated significantly with the already established applied questionnaires. The predictive power of the BSB regarding the development of bipolar disorder cannot be correctly quantified at present. The further purpose of this exploratory web-based study should be to examine the validity of the presented measures in a longitudinal design.
... Consecutive recruitment of patients and controls (all of French descent with at least three grandparents from the mainland of France) extended between February 2006 and January 2010. The age at onset (AAO) threshold (22 years) of BD corresponding to that at which the first mood episode (depressive, manic, hypomanic or mixed) occurred was defined as previously reported (Geoffroy et al. 2013) and were categorized into two sub-groups i.e., early and late (Oliveira et al. 2014). Rapid cycling status was defined (according to DSM-IV), as the occurrence of at least four major depressive, manic, hypomanic, or mixed episodes during the previous year and thyroid disorders were objectivized by routine standard biological testing. ...
Background:
Chronic low-grade inflammation is believed to contribute, at least in a subset of patients, to the development of bipolar disorder (BD). In this context, the most investigated biological marker is the acute phase response molecule, C-reactive protein (CRP). While the genetic diversity of CRP was amply studied in various pathological settings, little is known in BD.
Methods:
568 BD patients along with 163 healthy controls (HC) were genotyped for the following single-nucleotide polymorphisms (SNPs) on the CRP gene: intron rs1417938 (+ 29) T/A, 3'-UTR rs1130864 (+ 1444) G/A, and downstream rs1205 (+ 1846) (C/T). The statistical analysis was performed using Chi-square testing and consisted of comparisons of allele/genotype frequencies between patients and controls and within patient sub-groups according to BD clinical phenotypes and the presence of thyroid disorders.
Results:
We found that the frequencies of the studied SNPs were similar in BD and HC groups. However, the CRP rs1130864 A allele carrier state was significantly more frequent: (i) in BD patients with thyroid disorders than in those without (pc = 0.046), especially among females (pc = 0.01) and independently of lithium treatment, (ii) in BD patients with rapid cycling than in those without (pc = 0.004).
Conclusions:
Overall, our findings suggest the possibility that CRP genetic diversity may contribute to the development of auto-immune comorbid disorders and rapid cycling, both proxy of BD severity. Such findings, if replicated, may allow to predict complex clinical presentations of the disease, a possible step towards precision medicine in psychiatry.
... Mood disorders, according to contemporary diagnostic definitions, vary largely across patients with the same diagnosis in terms of symptoms manifestations, course, and treatment response [39,40]. To increase diagnostic homogeneity, Gottesman and Gould have suggested studying endophenotypes in psychiatry i.e., measureable components of the disorder, which may represent intermediate forms of expression of underlying genes, rather than the disorder as a whole [41]. ...
PurposeStudies focusing on the offspring of affected parents utilize the well-established familial aggregation of mood disorders as a powerful tool for the identification of risk factors, early clinical manifestations, and prodromes of mood disorders in these offspring. The major goals of the Lausanne–Geneva mood cohort study are to: (1) assess the familial aggregation of bipolar and unipolar mood disorders; (2) prospectively identify risk factors for mood disorders as well as their early signs and prodromes; (3) identify their endophenotypes including cognitive features, alterations in brain structure, HPA-axis dysregulation, and abnormalities of the circadian rhythm of activity. Methods
Probands with bipolar disorders, major depressive disorder, and controls with at least one child aged from 4 to 17.9 years at study intake, their offspring, as well as their spouses are invited to take part in follow-up assessments at predetermined ages of the offspring. Direct semi-structured diagnostic interviews have been used for all participants. Probands, spouses, and adult offspring also undergo neurocognitive testing, anthropomorphic measures and biochemical exams, structural Magnetic Resonance Imaging, as well as objective assessments of physical activity using accelerometers in combination with ecological momentary assessments. ResultsCurrently, our study has up to seven follow-up assessments extending over a period of 20 years. There are 214 probands and 389 offspring with one direct interview before age 18 as well as a second assessment over follow-up. Data on 236 co-parents are also available from whom 55% have been directly interviewed. First publications support the specificity of the familial aggregation of BPD and the strong influence of an early onset of the parental BPD, which amplifies the risk of developing this disorder in offspring. Conclusions
Information from clinical, biological, cognitive, and behavioral measures, based on contemporary knowledge, should further enhance our understanding of mood disorder psychopathology, its consequences, and underlying mechanisms.
... Unsurprisingly, there is now considerable interest in exploring if these concepts and strategies can be translated from psychosis to other severe mental disorders, especially bipolar disorders (BD), which also have a peak age of onset in late adolescence and early adulthood (Geoffroy et al. 2013a;Jones 2013;Merikangas et al. 2012). To improve the prospects for EI in BD, clinicians need to be able to identify individuals with the earliest manifestations of a sub-threshold presentation and/or other risk markers of BD, and to be able to predict transitions, e.g. to a first manic episode, even in cases where the course of illness may show discontinuities (e.g. ...
Background
In the last decade, an increasing number of publications have examined the precursors of bipolar disorders (BD) and attempted to clarify the early origins and illness trajectory. This is a complex task as the evolution of BD often shows greater heterogeneity than psychosis, and the first onset episode of BD may be dominated by depressive or manic features or both. To date, most of the published reviews have not clarified whether they are focused on prodromes, risk syndromes or addressing both phenomena. To assist in the interpretation of the findings from previous reviews and independent studies, this paper examines two concepts deemed critical to understanding the pre-onset phase of any mental disorder: prodromes and risk syndromes. The utility of these concepts to studies of the evolution of bipolar disorder (BD) is explored.
Findings
The term “prodrome” is commonly used to describe the symptoms and signs that precede episode onset. If strictly defined, the term should only be applied retrospectively as it refers to cohorts of cases that all progress to meet diagnostic criteria for a specific disorder and gives insights into equifinality. Whilst prodromes may reliably predict individual relapses, the findings cannot necessarily be extrapolated to identify prospectively who will develop a first episode of a specific disorder from within a given population. In contrast, ‘risk syndrome’ is a term that encompasses sub-threshold symptom clusters, but has often been extended to include other putative risk factors such as family history, or other variables expressed continuously in the population, such as personality traits. Only a minority of individuals ‘at risk’ make the transition to a specific mental disorder. By prospectively observing those cases where the risk syndrome does not progress to severe disorder or progress to a non-BD condition, we gain insights into the discriminant validity of different pre-BD characteristics, pluripotentiality of outcomes, and protective factors and resilience.
Conclusion
We emphasize the clinical and research utility of prodromes and risk syndromes, examine examples of the conflation of the concepts, and highlight the rationale for regarding them as discrete entities.
Mental health problems, behavior problems and psychiatric problems in adolescents were increased around the world, including in Thailand. A retrospective study in psychiatric patients and people with mental health problems showed mood swings as early warning signs of a mental health problem or psychiatric disorder. The objective of this article was to present the concepts and the evidence-based in the mood swings which was a characteristic in mental health problems and psychiatric patients among adolescents. Consideration of mood swings and the factors associated, it is a challenge of psychiatric nurses to prevent mental health problems among adolescents by assessing mood swings in adolescents and taking care. Advising to parents in raising their child to prevent mood swings. Based on understand the concepts of emotional development, family relationship, and management of emotion, using therapeutic communication.
Background
It is unclear whether treatment early after onset in bipolar disorder may improve the long‐term illness course. The early intervention in affective disorders (EIA) randomised controlled trial found that 2‐years treatment in a specialised mood disorder clinic combining evidence‐based pharmacological treatment with group psychoeducation improved clinical outcomes compared with standard treatment in patients with bipolar disorder discharged after their 1st, 2nd, or 3rd hospital admission. We aimed to assess the 16 years long‐term outcomes after randomisation of the participants in the EIA trial.
Methods
Data were obtained by linking nation‐wide Danish population‐based registers. All 158 participants of the EIA trial (Trial Registration Number NCT00253071) were followed from time of randomisation (2005–2009) to end of study (31 December 2021). The primary outcome was risk of psychiatric readmission. Secondary outcomes were total admissions and costs, medication use, intentional self‐harm or suicide attempt or suicide, and socio‐economic measures.
Results
The absolute mean risk of psychiatric readmission was 49.3% in the intervention group and 59.8% in the control group, with no statistically significant difference between the groups ( b = −0.10, 95% CI: −0.26 to 0.047, p = 0.18). Compared with the control group, patients in the intervention group had numerically fewer total admission days (mean (SD) 44 (77) versus 62 (109)), lower total cost of psychiatric hospital admissions and hospital‐based outpatient visits (mean (SD) 22,001 (36793) euros versus 29,822 (52671) euros) and higher use of lithium and antipsychotics, but the differences were not statistically significant. Fewer patients in the intervention group had an event of intentional self‐harm or suicide attempt or suicide during follow‐up (OR 0.25, 95% CI: 0.15–0.40, p < 0.001) compared with the control group and more patients in the intervention group used antiepileptics (OR 2.21, 95% CI: 1.08–4.60, p = 0.031).
Conclusion
Analyses of very long‐term outcomes of the EIA trial may potentially indicate a beneficial effect of the intervention at the long term but were likely underpowered to detect a more subtle effect and for most outcomes the differences between groups were not statistically significant.
The recent Draft Mental Health Bill for England and Wales proposes changes to the Mental Health Act 1983 which will include, for the first time, a legal definition of autism. This article explores the specific potential issue that the definition, owing to its breadth, potentially encompasses a number of conditions other than autism, consequently leaving the definitionally dependent concept of ‘psychiatric disorder’ significantly narrowed in scope. The potential implications of this – primarily the concern that a range of other conditions and presentations could be unintentionally excluded from the scope of the civil powers in the Mental Health Act – are discussed.
Objective:
This study used independent component analysis (ICA) to investigate the connectivity patterns of resting-state functional large-scale brain networks in patients with early-onset bipolar disorder (BD).
Methods:
ICA was used to extract brain functional network components from 43 early-onset BD patients and 21 healthy controls (HCs). Then, the functional connectivity (FC) and functional network connectivity (FNC) within and between the independent brain networks was calculated, and the correlation between the connectivity changes and neuropsychological scale was evaluated.
Results:
Compared with HCs, FC increased in the right hippocampus and inferior temporal gyrus, left triangular inferior frontal gyrus of the anterior DMN (aDMN); right median cingulate, paracingulate gyri, and inferior parietal lobule of the posterior DMN (pDMN); and right precentral and posterior gyrus of the sensorimotor network (SMN) in early-onset BD patients. However, FC decreased in the left superior frontal gyrus of the aDMN, left paracentral lobule of the SMN, and left lingual gyrus and calcarine of the visual network in early-onset BD patients. There was no significant correlation between FC values of differential brain regions within resting-state networks (RSNs) and neuropsychological scores (uncorrected p > 0.05). In addition, the FNC among the pDMN-auditory network, pDMN-visual network, left frontoparietal network (lFPN)-visual network, lFPN-aDMN and dorsal attention network-visual attention network (DAN-VAN) were increased in early-onset BD patients. The zFNC of the pDMN-visual network was positively correlated with the anxiety/somatization score (r = 0.5822, p < 0.0001) and sleep disorders (r = 0.6150, p < 0.0001). The zFNC of the lFPN-aDMN was positively correlated with despair (r = 0.4505, p = 0.004 × 10 < 0.05 after Bonferroni correction). The zFNC of the DAN-VAN was positively correlated with cognitive impairment (r = 0.4598, p = 0.0032 × 10 < 0.05 after Bonferroni correction). The zFNC of the DAN-VAN showed a positive correlation trend with the Hamilton Depression Scale (HAMD) total score (r = 0.4404, p = 0.005 × 10 = 0.05 after Bonferroni correction).
Conclusions:
Patients with early-onset BD showed changes in a wide range of neural functional networks, involving changes in executive control, attention, perceptual regulation, cognition and other neural networks, which may provide new imaging evidence for understanding the pathogenesis of BD and for therapeutic intervention targets.
Background:
Bipolar disorder (BD) is a clinical risk factor for Alzheimer's disease (AD). Apolipoprotein E ε4 (APOE ε4), a genetic risk factor for AD, has been associated with brain structure and neurocognition in healthy youth.
Aims:
We evaluated whether there was an association between APOE ε4 with neurostructure and neurocognition in youth with BD.
Methods:
Participants included 150 youth (78 BD:19 ε4-carriers, 72 controls:17 ε4-carriers). 3T-magnetic resonance imaging yielded measures of cortical thickness, surface area, and volume. Regions-of-interest (ROI) and vertex-wise analyses of the cortex were conducted. Neurocognitive tests of attention and working memory were examined.
Results:
Vertex-wise analyses revealed clusters with a diagnosis-by-APOE ε4 interaction effect for surface area (p = 0.002) and volume (p = 0.046) in pars triangularis (BD ε4-carriers > BD noncarriers), and surface area (p = 0.03) in superior frontal gyrus (controls ε4-carriers > other groups). ROI analyses were not significant. A significant interaction effect for working memory (p = 0.001) appeared to be driven by nominally poorer performance in BD ε4-carriers but not control ε4-carriers; however, post hoc contrasts were not significant.
Conclusions:
APOE ε4 was associated with larger neurostructural metrics in BD and controls, however, the regional association of APOE ε4 with neurostructure differed between groups. The role of APOE ε4 on neurodevelopmental processes is a plausible explanation for the observed differences. Future studies should evaluate the association of APOE ε4 with pars triangularis and its neurofunctional implications among youth with BD.
Objective:
The objective of this study was to determine any association of age at onset (AAO) with clinical presentation of bipolar disorder (BD) and family history of illness.
Materials and methods:
A hospital-based cross-sectional observational study was conducted including 162 patients having a diagnosis of BD current episode manic. Individuals were divided into three subgroups according to AAO, i.e., early-onset BD (EOBD) (AAO ≤21 years), intermediate-onset BD (AAO - 22-34 years), and late-onset BD (AAO ≥35 years). The subgroups were compared on clinical variables; items of the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D), and Scale for the Assessment of Positive Symptoms (SAPS); and family history of illness.
Results:
The early-onset group had significantly more episodes per year than the other groups (P < 0.001). The prevalence of family history of mood disorder was also significantly higher in the early-onset group than the other subgroups. AAO was found to be significantly associated with different items of YMRS, HAM-D, and SAPS. The early-onset group had higher rating on irritability, motor activity-energy, sexual interest, depressed mood, delusions, and thought disorders, whereas the late-onset group had higher rating on elevated mood.
Conclusion:
EOBD can be considered as a specific phenotype of BD, which is more homogenous, severe, and inheritable form of illness.
There is substantial evidence of the high prevalence of obesity (OB) and overweight (OW) and their association with increased medical and psychiatric burden among adults with bipolar disorder (BD). However, little is known regarding its prevalence among young people with BD, other than the risk from psychotropic medication, which has been the focus of research in this population. We present a systematic review and meta‐analysis of the literature on prevalence and correlates of OB and OW children and adolescents with BD using a different perspective than impact of medication. Four studies met inclusion criteria. The prevalence of OB in children and adolescents with BD was 15% (95% CI 11–20%). We observed a higher prevalence of OB in comparison to the general population. Different studies found significant associations between OB, OW, and BD in young populations including non‐Caucasian race, physical abuse, suicide attempts, self‐injurious behaviours, psychotropic medication, and psychiatric hospitalizations.
Objective
This study aimed to analyze time to rehospitalization in patients with bipolar mania discharged on long-acting injectable antipsychotics (LAIs) or oral antipsychotics (OAPs). Additionally, temporal trends in LAI prescription were investigated.
Methods
Patients with bipolar mania discharged from the study hospital on antipsychotics between 2006 and 2018 were included. Survival analysis was used to compare time to rehospitalization within one year of discharge between patients discharged on LAIs and OAPs, and between FGA-LAIs (first- generation antipsychotic) and SGA-LAIs (second-generation antipsychotic). The Cochrane-Armitage trend test was used to test whether a temporal trend existed for LAI prescription rates during the study period.
Results
The LAI group (n = 224) had a significantly lower rehospitalization rate and a significantly longer time to rehospitalization than the OAP group (n = 3836). Rehospitalization rate and time to rehospitalization were not significantly different between patients discharged on FGA-LAIs or SGA-LAIs. The LAI prescription rate grew significantly from 2.20% in 2006 to 11.58% in 2018 (Z = 5.5843, p < 0.0001). The prescription rate of SGA-LAIs also increased significantly (Z = 7.7141, p < 0.0001), but not the prescription rate of FGA-LAIs.
Limitations
The treatment allocation is not randomized in this retrospective study. Furthermore, various clinical characteristics were unavailable in our analysis, such as symptom severity, functional impairment, and others.
Conclusions
LAIs were significantly superior to OAPs in reducing rehospitalization risk. However, SGA-LAIs were comparable with FGA-LAIs in reducing rehospitalization risk. Use of LAIs increased significantly in discharged patients with bipolar disorder during the study period, especially SGA-LAIs.
Bipolar disorder (BD) is a heterogeneous disorder that contains neurodevelopmental differences. Defining homogeneous subgroups of BD patients by using age at onset (AAO) as a specifier may promote the classification of biomarkers. This study compares peripheral BDNF levels between pediatric and adult BD patients to investigate the associations between BDNF levels, AAO, and illness duration. We enrolled two groups of euthymic patients, those with pediatric BD (n = 39) and those with adult BD (n = 31), as well as a group of healthy controls (HCs) (n = 90). Participants were assessed using clinical measures and BDNF serum levels were obtained using ELISA. We observed that BDNF levels were comparable between adult BD and HCs, but were clearly lower in pediatric BD than in HCs. In adult BD with AAO ≥30 years, BDNF levels were significantly higher than in adult BD with AAO <30 years. In pediatric BD, patients with prepubertal-onset had higher BDNF levels than those with pubertal-onset. BDNF levels demonstrated the accuracy of being able to distinguish pediatric BD from healthy controls in a receiver operating characteristic (ROC) curve analysis (area under the curve [AUC] = 0.792). In adult BD, higher BDNF levels were associated with later disease onset, but this was not the case in pediatric BD. Finally, reduced BDNF levels were associated with illness duration in adult BD. The findings indicate that BDNF levels in BD patients are associated with AAO. BDNF may, therefore, potentially serve as a developmental marker in BD, when AAO is taken into account.
Pin-prick injuries which prove not to be infected may still cause fear and distress, but allow the victims, who are often young women, no opportunity for redress. These attacks are causing panic among the targeted population who fear AIDS.
Mood disorders are characterized by emotional dysregulation that can involve periods of elevated or depressed mood of varying intensity and duration. Associated changes in behavior and cognition adversely impact functioning across settings, including the classroom. Underlying weaknesses in executive functioning, mediated by the frontal-subcortical neurological networks that facilitate emotional regulation, often exist prior to the onset of a mood episode and become exacerbated during a mood episode. Accurate differential assessment of symptoms and clarification of comorbidities must be conducted in the context of developmental expectations and shared neurological weaknesses. Conceptualization of etiology often requires specialized training by a child psychologist or psychiatrist which informs psychological, pharmacological, and school-based accommodations and services. Treatment outcomes and longitudinal outcomes among youth with mood disorders are also discussed.
Background
We conducted this nationwide study to examine the prevalence and incidence of chronic obstructive pulmonary disease (COPD) among patients with bipolar disorder in Taiwan.
Methods
We used a random sample of 766,427 subjects who were aged ≥18 years in 2005. Patients with at least one primary diagnosis of bipolar disorder were identified. Study participants with one primary or secondary diagnosis of COPD for either ambulatory or inpatient care were also identified. We compared the prevalence of COPD in patients with bipolar disorder and the general population in 2005. In addition, we further investigated this cohort from 2006 to 2010 to detect incident cases of COPD in patients with bipolar disorder compared with the general population. The factors associated with COPD among patients with bipolar disorder were also analyzed.
Results
The prevalence of COPD in patients with bipolar disorder was higher than in the general population in 2005 (5.68% vs. 2.88%, odds ratio 2.03; 95% confidence interval, 1.53–2.67). The average annual incidence of COPD in patients with bipolar disorder was also higher than in the general population (2.03% vs. 1.03%, risk ratio 1.94; 95% confidence interval, 1.65–2.29) from 2006 to 2010.
Limitations
Some risk factors for COPD such as substance use, obesity, or lifestyle pattern were not available in this study.
Conclusions
Patients with bipolar disorder had a higher prevalence and incidence of COPD compared with the general population. Higher prevalence of COPD among bipolar patients was associated with increased age, males, hypertension, and second-generation antidepressant use.
Problem:
Pediatric bipolar disorder (PBD) prevalence is estimated to be 1-3%. Nationally and internationally, rates of PBD have increased by over 400%. However, in Iowa and at one psychiatric clinic in Iowa, from 2008-2013, there was a decrease in PBD diagnosis of 33 and 51.2% respectively. This study examined the diagnosing practices of PBD by local providers in one outpatient mental health center.
Method:
Parents completed a screening packet to differentiate between PBD and attention deficit hyperactivity disorder (ADHD) using three tools: Child Mania Rating Scale (CMRS), Child Behavior Checklist-Mania Scale (CBCL-MS), and the NICHQ Vanderbilt. Symptom agreement analysis between the screeners and the provider's clinical diagnoses was performed using ANOVA and Tukey HSD posthoc analysis.
Findings:
A 19.6% of the participants were positive for PBD on the CMRS and 55.9% were positive on the CBCL-MS. A total of 36.60% were positive for ADHD on the Vanderbilt. The screening data compared to the provider's clinical diagnosis showed no diagnostic agreement for PBD (p < .05). Providers' rates of diagnosing PBD did not match the rate of PBD symptoms identified by the screeners.
Conclusion:
Further evidence to determine the criteria and use of current screening measures for PBD is needed to guide practice for distinguishing PBD from related disorders.
Gene identification in common disorders such as Alzheimer disease and breast cancer has greatly profited from the use of age of onset as criterion to delineate subgroups of disease characterized by different inheritance patterns. In bipolar affective disorder, where the majority of linkage studies have produced conflicting results, studies reporting clinical characteristics and familial occurrence of disease have suggested that age of onset might serve as an indicator for identifying more homogeneous subgroups of disease. Our study was the first to examine this hypothesis by the means of segregation analysis. We investigated a sample of 177 bipolar I probands recruited from consecutive admissions and their first- and second-degree relatives (2,407 subjects). Probands were subdivided into an early-onset (n = 107) and a late-onset group (n = 70) using an age of onset of 25 as a cut-off point. This age was chosen because the observed age of onset distribution was bimodal with a cut-off of 25 years. Morbid risks for affective disorder were found significantly higher (P = 0.01) in relatives of probands with an early onset than in probands with late onset of disease. The segregation analysis showed that the disease is transmitted differently in early- and late-onset groups. In the early-onset group, a non-Mendelian major gene with a polygenic component was favored while the data in the late-onset group were compatible with a multifactorial model. This result may have important implications for future molecular studies aiming at the identification of disease-associated genes. © 2001 Wiley-Liss, Inc.
Mood symptoms in adult bipolar disorder are associated with increased proinflammatory markers and decreased brain-derived neurotrophic factor (BDNF). We examined serum interleukin-6, high-sensitivity C-reactive protein (hsCRP), and BDNF among 30 bipolar disorder adolescents. Hypomanic/manic symptoms were positively associated with hsCRP. BDNF levels were negatively associated with interleukin-6. Forty percent had cardiovascular high-risk hsCRP levels. Larger longitudinal studies are warranted.
We used genome-wide single nucleotide polymorphism (SNP) data to search for the presence of copy number variants (CNVs) in 882 patients with bipolar disorder (BD) and 872 population-based controls. A total of 291 (33%) patients had an early age-at-onset < or =21 years (AO < or =21 years). We systematically filtered for CNVs that cover at least 30 consecutive SNPs and which directly affect at least one RefSeq gene. We tested whether (a) the genome-wide burden of these filtered CNVs differed between patients and controls and whether (b) the frequency of specific CNVs differed between patients and controls. Genome-wide burden analyses revealed that the frequency and size of CNVs did not differ substantially between the total samples of BD patients and controls. However, separate analysis of patients with AO < or =21 years and AO>21 years showed that the frequency of microduplications was significantly higher (P=0.0004) and the average size of singleton microdeletions was significantly larger (P=0.0056) in patients with AO < or =21 years compared with controls. A search for specific BD-associated CNVs identified two common CNVs: (a) a 160 kb microduplication on 10q11 was overrepresented in AO < or = 21 years patients (9.62%) compared with controls (3.67%, P=0.0005) and (b) a 248 kb microduplication on 6q27 was overrepresented in the AO< or = 21 years subgroup (5.84%) compared with controls (2.52%, P=0.0039). These data suggest that CNVs have an influence on the development of early-onset, but not later-onset BD. Our study provides further support for previous hypotheses of an etiological difference between early-onset and later-onset BD.
The aim of the study was to investigate which factors are associated with age at onset in bipolar disorder with a specific focus on excessive alcohol and cannabis use, and the sequence of the onsets of excessive substance use and bipolar disorder. We investigated a naturalistic sample of 151 patients with bipolar I and II disorder receiving psychiatric treatment. Whether the presence of excessive substance use prior to bipolar disorder onset or the type of substance used (alcohol or cannabis) was associated with differences in age at onset was investigated using hierarchical and multiple linear regression analyses, adjusting for potential confounders. Patients with excessive alcohol use had a significantly later onset compared with patients with excessive cannabis use. Excessive general substance use prior to bipolar disorder onset was associated with a later onset. However, excessive cannabis use was associated with an earlier onset whether it preceded or followed bipolar disorder onset, also after adjusting for possible confounders. Excessive use of alcohol or other substances was not independently associated with age at onset in multivariate analyses. Alcohol use was associated with a later onset compared with cannabis use, suggesting different relationships to the onset of bipolar disorder. Lifetime use of cannabis predicted an earlier onset, independent of the sequence of onsets. This indicates that an early onset may increase the risk of cannabis use and that cannabis use may trigger bipolar disorder in vulnerable individuals.
High rates of misdiagnosis, delayed diagnosis, and lack of recognition and treatment of comorbid conditions often lead patients with bipolar illness to have a chronic course with high disability, unemployment rates, and mortality. Despite the recognition that long-term outcome of bipolar disorder depends on systematic assessment of both interepisodic dysfunctional domains and comorbid psychiatric and medical conditions, treatment of bipolar disorder still focuses primarily on alleviation of acute symptoms and prevention of future recurrences. We propose here to review the evidence offering a modern view of bipolar disorder defined as a chronic and progressive multisystem disorder, taking into account characteristics of each patient as well as biosignatures in order to help design personalized treatments.
We conducted a systematic PubMed search of all English-language articles, published between 2000 and 2010, focusing on the English and French literature with bipolar disorder cross-referenced with the following search terms: emotional dysregulation, sleep and circadian rhythm disturbances, cognitive impairment, age at onset, comorbid medical and psychiatric conditions, psychosocial and medical interventions, outcome, remission, and personalized medicine. The search was conducted between July 2009 and July 2010. The literature on bipolar disorder was reviewed to provide supporting evidence that the assessment of various symptom domains that are dysfunctional between episodes should all be considered as core dimensions of the disorder.
Forty-one articles were identified through the PubMed search described above and selected on the basis of addressing any combination of the search terms in conjunction with bipolar disorder.
Current guidelines advocate the use of more or less similar treatment algorithms for all patients, ignoring the clinical, pathophysiological, and lifetime heterogeneity of bipolar disorder. Systematic assessment of interepisodic dimensions, along with comorbid medical and psychiatric risk factors, should be performed along the life cycle in order to plan specific and personalized pharmacologic, medical, and psychosocial interventions tailored to the needs of each patient and ready-to-test biosignatures to serve as risk factors or diagnostic or prognostic tools.
Medical and research findings, along with health economic data, support a more modern view of bipolar disorder as a chronic, progressive, multisystem disorder. This new comprehensive framework should guide the search to identify biomarkers and etiologic factors and should help design a new policy for health care, including prevention, diagnosis, treatment, and training.
Early-onset bipolar disorder is an impairing condition that is strongly associated with genetic inheritance. Neurocognitive deficits are core traits of this disorder which seem to be present in both young and adult forms. Deficits in verbal memory and attention are persistent within euthymic phases in bipolar adults, adolescents, and children. In younger samples, including type I or II and not otherwise specified patients, executive functions are not widely impaired and the existence of visual-spatial deficits remains unclear. The main aim of this study was to compare the neurocognitive performance in young stabilized type I or II bipolar patients and healthy controls. Fifteen medicated adolescents with bipolar disorder and 15 healthy adolescents, matched in age and gender, were compared on visual-spatial skills (reasoning, memory, visual-motor accuracy) and executive functioning (attention and working memory, set-shifting, inhibition) using t-tests and MANCOVA. Correcting for verbal competence, MANCOVA showed that patients performed significantly worse than controls in letters and numbers sequencing (P = 0.003), copy (P < 0.001) and immediate recall (P = 0.007) of the Rey Complex Figure Test, interference of the Stroop Color-Word Test (P = 0.007) and non-perseverative errors on the Wisconsin Card Sorting Test (P = 0.038). Impaired cognitive performance was found in young bipolar patients in working memory, visual-motor skills, and inhibitory control.
Current psychiatric disorder classifications are based exclusively on categorical models, which were designed to increase the reliability of diagnoses. However, this system has some limitations, and various psychiatric disorders may be classified using a dimensional approach, which is more appropriate when no clear boundaries exist between entities or when examining various features on a continuum. Thus, the forthcoming DSM-5 appears to be undertaking a hybrid approach by including categorical models associated with dimensions. We aim to review examples of dimensions or symptom clusters associated with a categorical approach that could be useful in refining bipolar disorder classification. We selected predominant polarity, psychotic symptoms, inhibition/activation behavioral level, and emotional reactivity to define mood episodes, impulsivity/suicidality/substance misuse, and cognitive impairment. The selection was based on the fact that these dimensions or symptom clusters are currently being discussed to be implemented in the DSM-5 and/or may orientate toward the choice of specific treatments and represent more homogeneous and thus more appropriate subgroups for research purposes. In the future, there will be a need to identify biomarkers that can definitively validate the use of these criteria.
Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Early-onset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case-control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD.
To identify the association between medical or psychiatric comorbidities, clinical characteristics, or course of illness/recovery in pediatric bipolar disorder (BD).
Data from the South Carolina Medicaid program covering all medical services and medication prescriptions between January 1996 and December 2005 were used to analyze the temporal onset of 12 comorbid medical or psychiatric conditions for 1,841 children and adolescents diagnosed with BD using DSM-IV-TR criteria and for a random sample of 4,500 children not treated for psychiatric disorders. The primary outcome measures were diagnostic codes and regression analyses of patterns of acute and outpatient treatment services for BD over time.
Ten conditions examined were significantly more prevalent in the BD cohort: obesity, type 2 diabetes mellitus, endocrine disorders, migraine headaches, central nervous system (CNS) disorders/epilepsy, organic brain disorders/mental retardation, cardiovascular disorders, attention-deficit/hyperactivity disorder (ADHD), asthma, and substance abuse (P ≤ .01). For clinical characteristics within the BD cohort, an adolescent-onset diagnosis of BD (age ≥13 years) was significantly associated with the diagnosis of preexisting obesity, hypertension, migraine, mental retardation, endocrine disorders, and substance abuse (P ≤ .05), whereas recurrent depressive episodes were associated with preexisting endocrine disorders and substance abuse. Preexisting ADHD, substance abuse, CNS disorders/epilepsy, cardiovascular disorders, obesity, and asthma were associated with higher overall medical and psychiatric outpatient and acute service use, but none of these comorbid disorders differentially impacted the course of illness or recovery for BD.
Neuropsychiatric (ie, ADHD, substance abuse, CNS disorders/epilepsy) and medical (ie, obesity, asthma, cardiovascular disease) disorders temporally precede the diagnosis of early-onset BD in pediatric patients and are associated with discrete facets of illness presentation, but they do not substantially alter the clinical course of the BD over time.
In the ongoing quest for improved diagnostic markers of bipolar illness, the focus of research has gradually shifted to examining the onset of mood difficulties early in life and investigating the potential corollaries of such early onset such as cognitive impairment, disruption of social and emotional functioning, and constriction of quality of life. This article considers the disruptions to cognitive functioning that accompany bipolar disorder and compares adult and child profiles to ascertain the likelihood of identifying a neurocognitive biomarker of the illness.
A succinct review of the literature pertaining to cognition in both adult and childhood populations is synthesised following Medline and PsychINFO searches using key-terms including 'cognition', 'bipolar disorder', 'neurocognitive' 'child', 'adolescent' and a range of neuropsychological domain names. In addition, literature known to the authors was scrutinised and relevant references further pursued.
Findings from the literature are contextualised and key findings are summarised and provide a basis for future recommendations.
A number of deficits have been consistently identified in both adolescent and adult populations that perhaps reflect disease traits. Future research needs to focus on these and employ multimodal tests in pristine patient groups, with a view to identifying reliable biomarkers.
Bipolar disorder (BD) is a prevalent, comorbid, and impairing condition. Potential predictors of response to pharmacological treatment are object of continuous investigation in patients with BD. The present naturalistic study was aimed to assess clinical features and long-term response to mood stabilizers in a sample of bipolar subjects with different ages at onset.
The study sample included 108 euthymic patients, diagnosed as affected by BD, either type I or II, according to the DSM-IV-TR, who were started on mood stabilizer treatment. Patients were followed-up for 24 months and the occurrence of any mood episode collected. At the end of the follow-up, patients were divided in 3 subgroups according to the age at onset (early-onset </=30 years, middle-onset >30-</=45 years, and late-onset >45 years, respectively) and the long-term response to mood stabilizers was compared between them along with other clinical features.
The three subgroups showed significant differences in terms of clinical and demographic features and, with respect to long-term response to mood stabilizers, the early-onset subgroup showed a better outcome in terms of reduction of major depressive episodes during the 24-month follow-up compared to the other subgroups (one way ANOVA, F = 3.57, p = 0.032).
Even though further controlled studies are needed to clarify the relationship between age at onset and outcome in BD, the present follow-up study suggests clinical peculiarities and different patterns of response to mood stabilizers across distinct subgroups of patients with BD and different ages at onset.
Since the previous publication of Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines in 1997, there has been a substantial increase in evidence-based treatment options for bipolar disorder. The present guidelines review the new evidence and use criteria to rate strength of evidence and incorporate effectiveness, safety, and tolerability data to determine global clinical recommendations for treatment of various phases of bipolar disorder. The guidelines suggest that although pharmacotherapy forms the cornerstone of management, utilization of adjunctive psychosocial treatments and incorporation of chronic disease management model involving a healthcare team are required in providing optimal management for patients with bipolar disorder. Lithium, valproate and several atypical antipsychotics are first-line treatments for acute mania. Bipolar depression and mixed states are frequently associated with suicidal acts; therefore assessment for suicide should always be an integral part of managing any bipolar patient. Lithium, lamotrigine or various combinations of antidepressant and mood-stabilizing agents are first-line treatments for bipolar depression. First-line options in the maintenance treatment of bipolar disorder are lithium, lamotrigine, valproate and olanzapine. Historical and symptom profiles help with treatment selection. With the growing recognition of bipolar 11 disorders, it is anticipated that a larger body of evidence will become available to guide treatment of this common and disabling condition. These guidelines also discuss issues related to bipolar disorder in women and those with comorbidity and include a section on safety and monitoring.
IntroductionTo determine the influence of ethnicity on the age at onset (AAO) and further understand the significance of AAO as a clinical marker of bipolar and schizoaffective disorders.
Admixture analysis was used to identify sub-groups characterized by differences in AAO. Differences in clinical features were analyzed for these sub-groups using multivariate logistic regression. Comparisons were made with previous studies using the 2-Sample Kolmogorov-Smirnov Test.
Admixture analysis yielded a combination of 2 normal theoretical distributions with means (SD) of 16.9 (3.6) for the early-onset sub-group and 24.4 (9.2) years for the late-onset sub-group. The sub-groups were divided by a cut-off of 22 years. There were significant differences between the early and late onset bipolar patient populations regarding substance abuse comorbidity (P=.044) and psychotic features (P=.015). Ethnicity did not have a significant influence on the AAO.DiscussionThe associations between early-onset and higher incidence of psychosis and substance abuse in our sample are consistent with other studies exploring the AAO in bipolar disorder.
Our findings support the notion of AAO as a clinical marker for the underlying heterogeneity of bipolar spectrum disorders. In particular, we found a strong overlap of early AAO with clinical features associated with greater severity and poor outcome.
Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, O’Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Milev R, Bond DJ, Frey BN, Goldstein BI, Lafer B, Birmaher B, Ha K, Nolen WA, Berk M.
Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013.
Bipolar Disord 2012: 00: 000–000. © 2012 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd.
The Canadian Network for Mood and Anxiety Treatments published guidelines for the management of bipolar disorder in 2005, with updates in 2007 and 2009. This third update, in conjunction with the International Society for Bipolar Disorders, reviews new evidence and is designed to be used in conjunction with the previous publications.The recommendations for the management of acute mania remain largely unchanged. Lithium, valproate, and several atypical antipsychotic agents continue to be first‐line treatments for acute mania. Monotherapy with asenapine, paliperidone extended release (ER), and divalproex ER, as well as adjunctive asenapine, have been added as first‐line options.For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, as well as olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first‐line options. Lurasidone monotherapy and the combination of lurasidone or lamotrigine plus lithium or divalproex have been added as a second‐line options. Ziprasidone alone or as adjunctive therapy, and adjunctive levetiracetam have been added as not‐recommended options for the treatment of bipolar depression. Lithium, lamotrigine, valproate, olanzapine, quetiapine, aripiprazole, risperidone long‐acting injection, and adjunctive ziprasidone continue to be first‐line options for maintenance treatment of bipolar disorder. Asenapine alone or as adjunctive therapy have been added as third‐line options.
The literature suggests that bipolar elders with early and late onset of the disorder present with different demographic, family history, and psychosocial profiles, which are less well characterized than those for elderly unipolar patients. In this cross-sectional clinical survey, we assessed subjects (n = 74) from the NIMH Clinical Research Center for the Study of Depression in Later Life at Duke University who had a consensus diagnosis of bipolar depression; the primary assessment instrument was the Duke Depression Evaluation Schedule. We found that bipolar subjects with later age of onset reported less family history of psychiatric problems, more comorbid vascular disease, and more instrumental and subjective social support. Stressful life events were more frequent among bipolar subjects with earlier age of depressive symptom onset. This study suggests that early-onset disorder may be characterized by a psychosocial component, whereas organic factors may be particularly important to late-onset bipolar disorder. Depression and Anxiety 7:76–82, 1998. © 1998 Wiley-Liss, Inc.
Patients with bipolar disorder are known to be at high risk of premature death. Comorbid cardio-vascular diseases are a leading cause of excess mortality, well above the risk associated with suicide. In this review, we explore comorbid medical disorders, highlighting evidence that bipolar disorder can be effectively conceptualized as a multi-systemic inflammatory disease.
We conducted a systematic PubMed search of all English-language articles recently published with bipolar disorder cross-referenced with the following terms: mortality and morbidity, cardio-vascular, diabetes, obesity, metabolic syndrome, inflammation, auto-antibody, retro-virus, stress, sleep and circadian rhythm.
Evidence gathered so far suggests that the multi-system involvement is present from the early stages, and therefore requires proactive screening and diagnostic procedures, as well as comprehensive treatment to reduce progression and premature mortality. Exploring the biological pathways that could account for the observed link show that dysregulated inflammatory background could be a common factor underlying cardio-vascular and bipolar disorders. Viewing bipolar disorder as a multi-system disorder should help us to re-conceptualize disorders of the mind as "disorders of the brain and the body".
The current literature substantially lacks longitudinal and mechanistic studies, as well as comparison studies to explore the magnitude of the medical burden in bipolar disorder compared to major mood disorders as well as psychotic disorders. It is also necessary to look for subgroups of bipolar disorder based on their rates of comorbid disorders.
Comorbid medical illnesses in bipolar disorder might be viewed not only as the consequence of health behaviors and of psychotropic medications, but rather as an early manifestation of a multi-systemic disorder. Medical monitoring is thus a critical component of case assessment. Exploring common biological pathways of inflammation should help biomarkers discovery, ultimately leading to innovative diagnostic tools, new methods of prevention and personalized treatments.
Background:
Polarity is the pillar of the current categorical unipolar-bipolar division of mood disorders. However, genetic studies on these polarity-based phenotypes have been largely inconclusive. Recent clinical and epidemiological studies seem to support more of a continuum than a splitting of mood disorders. A reshaping of the classification of mood disorders thus seems required. Age-at-onset and recurrence have been suggested to be more clinically and genetically useful in the phenotyping of mood disorders.
Study aim:
To test a classification of mood disorders based on age-at-onset, and to delineate its phenotypes.
Methods:
A total of 441 consecutive bipolar II disorder (BP-II) and 289 unipolar major depressive disorder (MDD) outpatients, presenting for treatment of a major depressive episode (MDE) in a clinical and research private practice, were assessed by a mood disorder specialist psychiatrist (FB) using a Structured Clinical Interview for the DSM-IV, modified for better probing past hypomania [Benazzi, F. Bipolar disorder-focus on bipolar II disorder and mixed depression. Lancet 2007a;369: 935-945]. The sample was divided according to age-at-onset. Age-at-onset was defined by the age at onset of the first MDE. Early-age-at-onset (EO) was defined as age at onset before 21 years, late-age-at-onset (LO) as onset at or after age 21 years. The study's current goal had not been planned when data were recorded between 1999 and 2006. Variables were compared in EO versus LO mood disorders, investigating phenotype differences. The main focus was on 'classic' diagnostic validators: MDE clinical picture, gender, course, and family history. Age, gender, BP-II, and mania/hypomania family history (possible confounding) were controlled for in the analyses. Logistic regression was used.
Results:
First, EO was regressed on each variable, one at a time, to find significant associations. Second, EO was regressed on all of the variables whose odds ratio (OR) was statistically significant in the previous analyses in order to find independent predictors. Independent predictors of EO mood disorder were history of hypomania, high recurrence, atypical depression, and family history of mania/hypomania. Controlling for BP-II (in addition to age and gender) did not impact the findings. The highest OR was that between EO and high recurrence (OR=4.00). Distinguishing MDE symptoms of EO mood disorder included hypersomnia and psychomotor agitation when controlling for age and gender, and, by controlling also for BP-II, hypersomnia only.
Discussion:
A close association among EO mood disorder, high recurrence, and bipolarity (history of hypomania, family history of mania/hypomania) was found. Compared to most previous studies testing EO versus LO in bipolar (mainly BP-I) or in unipolar MDD samples, the present study tested a mixed BP-II and MDD sample and controlled for polarity, reducing, as much as possible, the impact of polarity on the findings. EO (below age 21 years) was distinguished by hypersomnic depression, high recurrence, high history of hypomania, and high history of mania/hypomania. Replications are needed, especially in mixed samples also including BP-I. Results, if replicated, could have implications not only for clinical and genetic studies, but also for treatment (e.g., mood stabilizers could have better long-term effects than antidepressants in EO mood disorders, antidepressants could have negative long-term effects on EO).
The short variant of a functional length polymorphism in the promoter region of the serotonin transporter has been associated with several behavioural and psychiatric traits, including bipolar mood disorder. The same short allele has also been implicated as a modifier of the bipolar phenotype. Here we evaluate the etiologic/modifier role of this polymorphism in a case (N=103) / control (N=112) sample for bipolar mood disorder (type I) collected from an isolated South American population. We did not detect an association between bipolar disorder and the 5-HTT promoter polymorphism in this sample. However, an excess of the short allele was seen in younger cases and in cases with psychotic symptoms. When combined with data from the literature, the increased frequency of the short allele in patients with psychotic symptoms was statistically significant.
To explore the involvement of apolipoprotein E gene (APO E) in major depression, we studied the APO E gene polymorphism in a sample of 156 unrelated bipolar patients and 91 healthy volunteers. This population was stratified for age at onset of the affective disorder (onset before 18 years, after 45 years and between 18 and 45 years). Early onset bipolar patients with psychotic symptoms exhibited a significant increase of ϵ4 allele frequency (28.9%) compared to either other bipolar patients (13.1%, χ2=6.52, df=1, P<0.02) or controls (12.1%, χ2=7.01, df=1, P<0.01). The association between ϵ4 and early onset bipolar disorder (BPD) with psychotic symptoms suggests that APO E gene is a risk factor for a subgroup of BPD, or influences the phenotypic expression (i.e. psychotic symptoms or age at onset) of manic depressive illness.
Over 60% of individuals with bipolar disorders report that they received between 1-4 prior diagnoses, with delay in diagnosis being a particular problem in females with bipolar II disorders. Clinical recognition of bipolarity may take up to 10 years, during which time individuals may have received a number of inadequate or inappropriate treatments. This paper describes the adverse clinical, functional and economic consequences of the failure to identify cases of bipolar disorder at the earliest possible time.
While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.
Objective. To test for differences in reported age at onset (AAO) of bipolar I affective disorder in clinical samples drawn from Europe and the USA. Methods. Admixture analysis was used to identify the model best fitting the observed AAO distributions of two large samples of bipolar I patients from Europe and USA (n = 3616 and n = 2275, respectively). Theoretical AAO functions were compared between the two samples. Results. The model best fitting the observed distribution of AAO in both samples was a mixture of three Gaussian distributions. The theoretical AAO functions of bipolar I disorder differed significantly between the European and USA populations, with further analyses indicating that (i) the proportion of patients belonging to the early-onset subgroup was higher in the USA sample (63 vs. 25%) and (ii) mean age at onset (±SD) in the early-onset subgroup was lower for the USA sample (14.5 ± 4.9 vs. 19 ± 2.7 years). Conclusions. The models best describing the reported AAO distributions of European and USA bipolar I patients were remarkably stable. The intermediate- and late-onset subgroups had similar characteristics in the two samples. However, the theoretical AAO function differed significantly between the USA and European samples due to the higher proportion of patients in the early-onset subgroup and the lower mean age-at-onset in the USA sample.
Bipolar is a severe psychiatric disorder which ethiopathogenesis remains unclear. Despite a clearly established heritability, genetic studies have failed to elucidate the underlying mechanism of bipolar disorder, most likely due to the contributing role of environmental factors in the genesis of the disease.. Environmental factors have been consistently described to induce immuno-inflammation dysfunction, which are also known to play a role in the pathogenesis of bipolar disorders as due to the combined actions of small effects in many different genes interacting with environmental factors). Several mechanisms might explain the pro-inflammatory processes observed in bipolar disorder. Emerging evidence support the pathophysiological role of Human Endogenous Retroviruses, which reactivation (normally silenced), can be induced by infectious agents during pregnancy, early childhood and/or adolescence. ,Neurotoxic effects and inflammatory state are induced, which might in turn and after a prodromal phase, trigger acute mood episodes,. The present paper reviews the role of the immuno-inflammatory processes as key contributors to the bipolar disorders pathophysiology , the evidence supporting immuno-genetic predisposition,background, and the the possible implications of retroviruses reactivation in the pathogenesis of bipolar disorder.
Bipolar disorder is a severe mental illness that affects nearly 4.4% of the general population when bipolar spectrum disorders are taken into account. Neurocognitive impairment is thought to be a core deficit of this illness since it is present during euthymia. In fact, 40-60% of euthymic patients present with neurocognitive disturbances. Not only the clinical factors but also disturbances in neurocognition can influence the functional outcome of BD patients. Hence, further research is needed in order to clarify the relationship between these variables. Despite the growing body of evidence that has emerged during the last decade, no unique neurocognitive profile has been proposed yet for either BD subtype. The majority of the studies recluted heterogeneous samples (including both bipolar I and II) or focused on BD-I patients only. The aim of this review is to give an overall picture of the main neurocognitive disturbances found in the bipolar spectrum and particularly in BD-II, where the findings are more ambiguous. An extensive review of all the literature has been done regarding this subtype (from 1980 until July 2009). Data available until now suggest that deficits are present across the bipolar spectrum (BD-I and BD-II), but they seem slightly more severe in BD-I. The extent to which either subtype share-or not-some similarities is still unknown. More studies are required but it would also be interesting to reach a consensus in the neuropsychological assessment of BD to facilitate comparisons between the different studies.