949: BIPOLAR DISORDERS AND RESOURCE UTILIZATION IN ICU TRAUMA SURGERY: A POPULATION-BASED COHORT STUDY

Despite a marked increase in treatment for bipolar disorder among youths, little is known about their pattern of service use. This article describes mental health service use in the year before and after a new clinical diagnosis of bipolar disorder. Claims were reviewed between April 1, 2004, and March 31, 2005, for 1,274,726 privately insured youths (17 years and younger) who were eligible for services at least one year before and after a service claim; 2,907 youths had new diagnosis of bipolar disorder during this period. Diagnoses of other mental disorders and prescriptions filled for psychotropic drugs were assessed in the year before and after the initial diagnosis of bipolar disorder. The one-year rate of a new diagnosis of bipolar disorder was .23%. During the year before the new diagnosis of bipolar disorder, youths were commonly diagnosed as having depressive disorder (46.5%) or disruptive behavior disorder (36.7%) and had often filled a prescription for an antidepressant (48.5%), stimulant (33.0%), mood stabilizer (31.8%), or antipsychotic (29.1%). Most youths with a new diagnosis of bipolar disorder had only one (28.8%) or two to four (28.7%) insurance claims for bipolar disorder in the year starting with the index diagnosis. The proportion starting mood stabilizers after the index diagnosis was highest for youths with five or more insurance claims for bipolar disorder (42.1%), intermediate for those with two to four claims (24.2%), and lowest for those with one claim (13.8%). Most youths with a new diagnosis of bipolar disorder had recently received treatment for depressive or disruptive behavior disorders, and many had no claims listing a diagnosis of bipolar disorder after the initial diagnosis. The service pattern suggests that a diagnosis of bipolar disorder is often given tentatively to youths treated for mental disorders with overlapping symptom profiles and is subsequently reconsidered.

Background: Up to 60% of bipolar disorder (BD) patients develop alcohol use disorders (AUD) at some point in their lives. The causes of this highly prevalent comorbidity are unknown. High trait impulsivity characterizes both isolated BD and AUD and may be a link to explain the association between BD and AUD. In this study, our aims were to investigate whether BD patients with comorbid AUD would present higher trait impulsivity levels compared to BD patients without comorbid AUD, and whether trait impulsivity levels differ within subgroups of BD according to the subcategory of AUD (abuse vs. dependence, alcoholism alone vs. alcoholism plus drug use disorders). Sampling and Methods: Forty-seven outpatients with BD with comorbid AUD (alcoholic BD group) were compared to 66 outpatients with BD alone (nonalcoholic BD group) and to 90 healthy controls (HC). BD and AUD diagnoses were obtained using the Structured Clinical Interview for DSM-IV diagnoses. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11), a self-report instrument that measures trait impulsivity in three domains: nonplanning, attentional and motor. Results: Alcoholic BD patients scored significantly higher than nonalcoholic BD and HC on the total and on each subscale BIS scores. Within the alcoholic BD patients, alcohol abusers and alcohol dependents did not statistically differ from each other on the BIS-11 scores. BD patients with AUD plus drug use disorders presented statistically higher nonplanning impulsivity than BD patients with AUD alone. Conclusions: This was a cross-sectional study and causal inferences about the relationship between impulsivity and the comorbidity phenomenon cannot be made. Increased impulsivity may be a trait marker for the co-occurrence between BD and AUD, and mediate some severe manifestations of this comorbidity.

Dysregulation of circadian rhythms has been thought to be associated with psychiatric disorders such as bipolar disorder (BD) and depression. We aimed to evaluate the relationship between clinical specifiers of BD, mainly seasonal pattern (SP), and the variable number tandem repeat (VNTR) variant of the PERIOD3 (PER3) gene (rs57875989) in BD patients by comparing genotype distributions with healthy controls considering clinical parameters. A sample of 98 BD patients and 97 healthy volunteers were included in the study. The Clinical Interview for DSM-IV Axis-I Disorders (SCID-I) was administered to all participants. The patients were evaluated with some scales (Sociodemographic and Clinical Data Form, The Young Mania Rating Scale (YMRS), the Hamilton Depression Rating Scale (HAM-D), and The Clinical Global Impression Scale (CGI)) in terms of clinical features and symptom severity. Blood samples were obtained from participants to isolate their DNA. PCR-RFLP was used to determine the PER3 gene variant. The PER3 genotype (4/4, 4/5, 5/5) distribution of BD was found to be significantly different from the control group. There was a statistically significant difference in the PER3 genotype distribution between BD patients with SP and BD patients without SP. Again, the PER3 allele (4, 5) distributions of BD patients with the SP were statistically different from the control group. The BD patients' PER3 genotype distributions with a family history of BD were significantly different from the BD patients without family history or control group. It was found that the VNTR variant of the PER3 gene (rs57875989) may be associated with the SP and family history of BD as well as the BD itself. Further studies with the VNTR variant of the PER3 gene (rs57875989) in different ethnic populations are also required to determine these polymorphisms' exact role in BD.

Bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD) may copresent and manifest as complex clinical presentations, often accompanied by further comorbidities such as anxiety and substance use disorders. ADHD/BD comorbidity not only relies on a widely reported symptomatological and neurobiological overlap, but it also creates an intricate interplay between ADHD, affective and other psychiatric conditions, requiring a more nuanced understanding of their comorbid nature. Moreover, clinical and nosological perspectives on the nature of the ADHD/BD comorbidity may significantly vary across developmental stages, ranging from an overestimated comorbidity (possibly due to the confound role of greater symptoms' overlap in childhood, adolescence and youth cases) to a prodromal developmental pattern (i.e., from ADHD to BD) or a separate nosological entity (“ADHD-BD”).1 In younger patients, in particular, recent literature also suggests a possible specific role of emotional dysregulation, a common key feature of ADHD and bipolar spectrum disorders, acting as a confound variable that may enhance the misconception of ADHD/BD comorbidity and favor the misdiagnosis of ADHD as a BD spectrum disorder.2 Clearly, the emphasis on the need to disentangle the complex relationship between juvenile ADHD and BD highlights the challenges in delineating these disorders for better diagnostic characterization and therapeutic indications. The systematic review by Miskowiak et al.3 addresses a highly relevant clinical topic, reporting on the available evidence on the efficacy and safety of ADHD pharmacotherapies to treat cognitive impairment and ADHD symptoms in juvenile and adult BD. Shared neurobiological dysregulations, particularly involving dopamine and norepinephrine signalling pathways, may significantly contribute to the symptomatic overlap between BD and ADHD. However, pharmacological interventions targeting dopamine and noradrenaline pathways (such as stimulants and alpha-2-adrenergic agonists) long held promise to ameliorate cognitive deficits and ADHD symptoms in individuals with BD. Indeed, the evidence relative to dysfunctions of the dopamine transporter (DAT) gene and catechol-O-methyltransferase (COMT) gene variants underscores the intricate interplay between these disorders and prompts for therapeutic implications.4 Miskowiak et al.3 also report preliminary favorable evidence of efficacy of ADHD drugs in treating ADHD symptoms in BD, with a current lack of evidence for psychostimulants to trigger or exacerbate mania and insufficient evidence to conclude on their role in improving cognitive symptoms in BD. Also in our previous work,5 we underscored the potential benefits of adjunctive therapy in alleviating ADHD symptoms in BD patients. Indeed, while mood stabilization should remain the main target of BD patients (as impulsivity, hyperactivity, and inattention symptoms may recede after stabilization), the presence of “residual” (and particularly cognitive) symptoms may require specific ADHD drugs. We agree that methylphenidate and mixed amphetamine salts represent the most promising options in the treatment of BD, with robust beneficial effects observed particularly in pediatric and adolescent populations. However, the paucity of data concerning atomoxetine, viloxizine, modafinil, armodafinil, and lisdexamfetamine (that, importantly, is the only stimulant marketed for use in ADHD to be studied as an add-on strategy for treatment-resistant bipolar depression) demands for a still cautious and highly individualized approach. On the other hand, we also highlighted a favorable safety profile of ADHD medications with no increased risk of manic episodes, especially when administered alongside mood stabilizers, and this evidence should favor their use in BD. A more recent examination of comorbidities in youth with BD explored both clinical characteristics and pharmacological treatment approaches.6 This review underscores the relevance of customized interventions to effectively address the diverse needs of this patient cohort. However, it also highlights a notable gap in research concerning pharmacological interventions for BD and its concurrent conditions, particularly in the pediatric and adolescent age groups. Despite the promising efficacy and safety profile of ADHD medications, significant gaps remain in our understanding of their cognitive effects and long-term outcomes in BD patients. Future research endeavors should prioritize comprehensive cognitive assessments, individual characterization of patients and larger sample sizes to elucidate the potential cognitive benefits of these medications. Also, specific attention should be devoted to develop controlled clinical trials sensitive to emotional dysregulation along different developmental stages, in order to really improve the prognosis of these highly complex patients, that require finely characterized diagnostic processes and highly personalized therapies. Indeed, tailored interventions addressing comorbidities and developmental nuances are imperative to optimize treatment outcomes and enhance the quality of life for individuals with BD and ADHD features. In conclusion, a multifaceted approach encompassing neurobiological insights, clinical complexity, and treatment implications is essential in navigating at the intersection of ADHD medications and BD. By integrating findings from different clinical perspectives, we can advance personalized care paradigms, tailored to the unique needs of individuals within the BD spectrum. Embracing interdisciplinary collaboration and prioritizing specific research endeavors are crucial steps toward optimizing treatment outcomes and improving the quality of life for this complex patient population. The author declares no conflicts of interest. Data sharing not applicable – no new data generated.

Co-morbid obsessive-compulsive disorder and bipolar disorder in highly endogamous population: Which came first?

Immune system dysregulation plays a key role in the physiopathology of bipolar disorder (BD) and major depressive disorder (MDD). However, whether interleukins might be biomarkers to distinguish these 2 affective disorders is unclear. Here, we assessed the differences in serum levels of interleukin 6 (IL-6) and interleukin 8 (IL-8) as well as C-reactive protein (CRP) in patients with MDD and BD. In total, we enrolled 21 MDD patients, 26 BD patients, and 20 healthy controls. We collected a total of 35 samples from BD patients in 3 different phases, depression phase, manic phase, and remission stage, and 27 samples from MDD patients in acute and remission phases. Serum IL-6 and IL-8 levels were assessed with solid phase sandwich ELISA-based quantitative arrays, and CRP levels were determined with an automatic analyzer. Both serum IL-6 and IL-8 levels were elevated in BD patients but not MDD patients. Subgroup analysis indicated elevated serum IL-6 in both the depression and manic phases in BD patients. The serum CRP levels did not change in either BD or MDD patients. However, sex differences in CRP concentrations were observed in healthy controls. Furthermore, there were linear correlations between the CRP levels and Bech-Rafaelsen Mania Rating Scale (BRMS) scores in BD patients. IL-6 and IL-8 levels may serve as biomarkers to differentiate between MDD and BD patients, even when the clinical manifestations are atypical. IL-6 may be used for the differential diagnosis of MDD and depressive episodes in BD.

Neurocognitive deficits have been widely reported in euthymic Bipolar Disorder (BD) patients and contribute to functional disability. However, the longitudinal trajectory of these deficits remains a subject of debate. Although most research to this date shows that neurocognitive deficits tend to be stable among middle-age BD patients, it remains plausible that deterioration occurs at either early or late stages of this condition. We conducted a comprehensive meta-analysis of studies that reported longitudinal neurocognitive performance among individuals with BD either within the year of their diagnosis or among late-life BD patients. Pooled effects of standardized mean differences (SMDs) for changes in neuropsychological scores over follow-up were estimated using random effects model. We also examined effect moderators, such as length of follow-up, mood state, or pharmacological load. Eight studies met inclusion criteria for recent-onset and four studies for late-life BD analysis. No evidence for a deterioration in neurocognitive functioning was observed among recent-onset BD patients (8 studies, 284 patients, SMD: 0.12, 95% CI -0.06 to 0.30, mean follow-up: 17months) nor for late-life BD patients (4 studies, 153 patients, SMD: -0.35, 95% CI -0.84 to 0.15, mean follow-up: 33months). None of the moderators were shown to be significant. These results, when appraised together with the findings in middle-life BD patients and individuals at genetic risk for BD, suggest that neurodevelopmental factors might play a significant role in cognitive deficits in BD and do not support the notion of progressive cognitive decline in most patients with BD.

EPA-0988 – Cognitive and affective theory of mind in schizophrenia and euthymic bipolar disorder

Bipolar disorder (BD) is a severe mental disorder, characterized by episodes of mania and depression. The longitudinal neurobiological impact of BD episodes on brain structure remains largely unknown. In 124 age-sex-matched participants (62 BD patients; 62 healthy controls; HCs), aged 20-62 years, we investigated the longitudinal relationship between BD episodes and whole-brain gray matter volume (GMV) changes (3 Tesla MRI) during a two-year interval, using voxel-based morphometry in SPM12/CAT12. We compared GMV trajectories between BD patients with at least one depressive or manic episode during the two-year interval, BD patients without an episode, and HCs. We explored associations between GMV changes and clinical variables, like the number and duration of depressive or manic episodes both during the two-year interval and before baseline assessment. BD patients showed GMV increases in the right exterior cerebellum with an increasing number of depressive episodes during the two-year interval. BD patients without recurrence showed GMV reductions in this area, relative to BD patients with recurrence and HCs. Notably, BD patients without recurrence exhibited greater GMV reductions during the two-year interval, the longer they had spent in a manic episode before baseline. Our findings underscore the dynamic nature of brain changes in BD. GMV increases in BD patients with recurrence may be due to acute neuroinflammatory mechanisms including glial cell proliferation, whereas GMV reductions in BD patients without recurrence may result from abnormal synaptic refinement or pruning, as a consequence of past neuroinflammation during BD episodes.

Nonadherence to treatment is a serious concern that affects the successful management of bipolar disorder (BD) patients. The aim of this study was to pilot test a psychosocial intervention (previously developed by this team) intended to increase adherence to medication and health behaviors targeting cardiovascular disease (CVD) risk factors in BD patients. An open, single-group design was used to assess the feasibility and acceptability of the intervention. The participants had BD, type I/II or unspecified, and CVD risk factors. Baseline demographic measures were taken. We also obtained preliminary effect sizes related to pre-post changes on measures of self-reported adherence to psychiatric medication, depressive and manic symptoms, and pharmacy records. At baseline, 29% of the participants reported recent adherence to psychiatric medications. A total of 71% of the participants completed the intervention. Pre-post improvements by medium and large effect sizes (Cohen’s d = 0.52–0.92) were seen in medication adherence, attitudes toward medication, and mania symptoms. The participants reported high levels of satisfaction with the intervention. A culturally sensitive psychosocial intervention for Puerto Rican BD patients who are at risk of CVD was found to be feasible and acceptable. Improvements in the key outcomes were seen in this small, preliminary study. Further research is needed with a larger sample size.

The study examined 1999-2005 data on first-time nursing home admissions of individuals with mental illness, dementia, or both to identify trends and characteristics. The Minimum Data Set was used to estimate the number and percentage of persons newly admitted to nursing homes who had mental illness (schizophrenia, bipolar disorder, depression, or an anxiety disorder), dementia, or both from 1999 to 2005. Data from 2005 were used to compare demographic characteristics and comorbid conditions of the three groups and treatments received. The number of individuals admitted with mental illness increased from 168,721 in 1999 to 187,478 in 2005. The 2005 number is more than 50% higher than the number admitted with dementia only (118,290 in 2005). The increase was driven by growth in admissions of persons with depression--from 128,566 to 154,262 in 2005. Persons admitted with depression had higher rates of comorbid conditions than those admitted with dementia or with neither dementia nor mental illness. They also had high rates of antidepressant treatment and high rates of receipt of training in skills required to return to the community. Current trends show that the proportion of nursing home admissions with mental illness, in particular depression, has overtaken the proportion with dementia. These changes may be related to increased recognition of depression, availability of alternatives to nursing homes for persons with dementia, and increased specialization among nursing homes in the care of postacute, rehabilitation residents. In light of these trends, it is critical to ensure that nursing homes have resources to adequately treat residents with mental illness to facilitate community reintegration.

Introduction:Bipolar disorder (BD) is one of the most encountered disorders in psychiatric clinics. Despite extensive research and advancements in BD treatment, little is known about the disease’s primary etiopathogenesis and relationship with different pathophysiological traits. The present study is aimed to evaluate the pathophysiological role of oxidative and nitrosative stress in BD patients and identify their familial aggregation.Methods:Blood samples from healthy individuals, drug-naive symptomatic BD patients, and their first-degree relatives were obtained, and intracellular reactive oxygen/nitrogen species (ROS/RNS), total nitrites, neuronal nitric oxide synthase (nNOS) mRNA expression, myeloperoxidase (MPO) activity in polymorphonuclear neutrophils (PMNs), and serum cortisol levels were assessed.Results:ROS, MPO activity, total-nitrite content, nNOS expression in PMNs, and serum cortisol concentration were considerably more in BD patients than in healthy volunteers. All these variables showed a substantial correlation with the YMRS score for disease severity and the presence of one or more manic episodes. Additionally, a positive correlation was noted between the MPO activity and serum cortisol levels of BD patients and their first-degree relatives.Conclusions:The results of the present study advance our knowledge about the role of oxidative and nitrosative stress in BD pathophysiology and its familial aggregation. Additionally, the study demonstrates a direct correlation between the disease severity and levels of ROS/RNS, MPO, total nitrite, and nNOS transcripts in PMNs. However, future research with larger and more diverse participant populations is required to understand these pathways for use as potential biomarkers for a deeper understanding of BD pathophysiology and to improve therapeutic strategies.

Regulation of inflammatory pathways in schizophrenia: A comparative study with bipolar disorder and healthy controls

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.

White matter disruptions in patients with bipolar disorder