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Abstract There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder (BD) with oftentimes, an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in BD. We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association in a subset of BD-type I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic depressed cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement from response to emergent mania.

Abstract Background Factors associated with suicide attempts during the antecedent illness trajectory of bipolar disorder (BD) and schizophrenia (SZ) are poorly understood. Methods Utilizing the Rochester Epidemiology Project, individuals born after 1985 in Olmsted County, MN, presented with first episode mania (FEM) or psychosis (FEP), subsequently diagnosed with BD or SZ were identified. Patient demographics, suicidal ideation with plan, self-harm, suicide attempts, psychiatric hospitalizations, substance use, and childhood adversities were quantified using the electronic health record. Analyses pooled BD and SZ groups with a transdiagnostic approach given the two diseases were not yet differentiated. Factors associated with suicide attempts were examined using bivariate methods and multivariable logistic regression modeling. Results A total of 205 individuals with FEM or FEP (BD = 74, SZ = 131) were included. Suicide attempts were identified in 39 (19%) patients. Those with suicide attempts during antecedent illness trajectory were more likely to be female, victims of domestic violence or bullying behavior, and have higher rates of psychiatric hospitalizations, suicidal ideation with plan and/or self-harm, as well as alcohol, drug, and nicotine use before FEM/FEP onset. Based on multivariable logistic regression, three factors remained independently associated with suicidal attempts: psychiatric hospitalization (OR = 5.84, 95% CI 2.09–16.33, p

The aim of this narrative review is to consolidate knowledge on the role of the hypothalamic-pituitary-adrenal (HPA) axis in depression pathophysiology at different reproductive stages across the female lifespan. Despite growing evidence about the impact of gonadal hormones on mood disorders, no previous review has examined the interaction between such hormonal changes and the HPA axis within the context of depressive disorders in women. We will focus on HPA axis function in depressive disorders at different reproductive stages including the menstrual cycle (e.g., premenstrual dysphoric disorder [PMDD]), perinatally (e.g., postpartum depression), and in perimenopausal depression. Each of these reproductive stages is characterized by vast physiological changes and presents major neuroendocrine reorganization. The HPA axis is one of the main targets of such functional alterations, and with its key role in stress response, it is an etiological factor in vulnerable windows for depression across the female lifespan. We begin with an overview of the HPA axis and a brief summary of techniques for measuring HPA axis parameters. We then describe the hormonal milieu of each of these key reproductive stages, and integrate information about HPA axis function in depression across these reproductive stages, describing similarities and differences. The role of a history of stress and trauma exposure as a contributor to female depression in the context of HPA axis involvement across the reproductive stages is also presented. This review advances the pursuit of understanding common biological mechanisms across depressive disorders among women. Our overarching goal is to identify unmet needs in characterizing stress-related markers of depression in women in the context of hormonal changes across the lifespan, and to support future research in women’s mental health as it pertains to pathophysiology, early diagnosis, and treatment targets.

BackgroundThere is evidence suggesting racial disparities in diagnosis and treatment in bipolar disorder (BD) and schizophrenia (SZ). The purpose of this study is to compare psychiatric diagnoses and psychotropic use preceding a first episode of mania (FEM) or psychosis (FEP) in racially diverse patients.MethodsUsing a comprehensive medical records linkage system (Rochester Epidemiology Project, REP), we retrospectively identified individuals diagnosed with BD or SZ and a documented first episode of mania or psychosis. Illness trajectory before FEP/FEM were characterized as the time from first visit for a mental health complaint to incident case. Pathways to care and clinical events preceding FEP/FEM were compared based on subsequent incident case diagnosis (BD or SZ) and self-reported race (White vs. non-White).ResultsA total of 205 (FEM = 74; FEP = 131) incident cases were identified in the REP. Duration of psychiatric antecedents was significantly shorter in non-White patients, compared to White patients (2.2 ± 4.3 vs. 7.4 ± 6.6 years; p

Background:Bipolar disorder (BD) with co-occurring attention deficit-hyperactivity disorder (ADHD) is associated with an unfavorable course of illness. We aimed to identify potential clinical and genetic correlates of BD with and without ADHD.MethodsAmong patients with BD (N = 2,198) enrolled in the Mayo Clinic Bipolar Biobank we identified those with ADHD diagnosed in childhood (BD+cADHD; N = 350), those with adult-onset attention deficit symptoms (BD+aAD; N = 254), and those without ADHD (N = 1,594). We compared the groups using linear or logistic regression adjusting for age, sex, and recruitment site. For genotyped patients (N = 1,443), logistic regression was used to compare ADHD and BD polygenic risk scores (PRSs) between the BD groups, as well as to non-BD controls (N = 777).ResultsCompared to the non-ADHD BD group, BD+cADHD patients were younger, more often men and had a greater number of co-occurring anxiety and substance use disorders (all p < 0.001). Additionally, BD+cADHD patients had poorer responses to lithium and lamotrigine (p = 0.005 and p = 0.007, respectively). In PRS analyses, all BD patient subsets had greater genetic risk for BD and ADHD when compared to non-BD controls (p < 0.001 in all comparisons). BD+cADHD patients had a higher ADHD-PRS than non-ADHD BD patients (p = 0.012). However, BD+aAD patients showed no evidence of higher ADHD-PRS than non-ADHD BD patients (p = 0.38).ConclusionsBD+cADHD was associated with a greater number of comorbidities and reduced response to mood stabilizing treatments. The higher ADHD PRS for the BD+cADHD group may reflect a greater influence of genetic factors on early presentation of ADHD symptoms.

Lithium has been a cornerstone treatment for bipolar disorder (BD). Despite descriptions in the literature regarding associations between long-term lithium therapy (LTLT) and development of a thyroid disorder (overt/subclinical hypo/hyperthyroidism, thyroid nodule, and goiter) in BD, factors such as time to onset of thyroid abnormalities and impact on clinical outcomes in the course of illness have not been fully characterized. In this study we aimed to compare clinical characteristics of adult BD patients with and without thyroid disorders who were on LTLT. We aimed to identify the incidence of thyroid disorders in patients with BD on LTLT and response to lithium between patients with and without thyroid disorders in BD. The Cox proportional model was used to find the median time to the development of a thyroid disorder. Our results showed that up to 32% of patients with BD on LTLT developed a thyroid disorder, of which 79% developed hypothyroidism, which was corrected with thyroid hormone replacement. We did not find significant differences in lithium response between patients with or without thyroid disorders in BD. Findings from this study suggest that patients with BD and comorbid thyroid disorders when adequately treated have a response to lithium similar to patients with BD and no thyroid disorders.

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. Keywords: Bipolar disorder type I, First-degree relative, Cortical thickness, Endophenotype, Surface area

Abstract Previous evidence suggests elevated levels of oxidatively-induced DNA damage, particularly 8-hydroxy-2’-deoxyguanosine (8-OH-dG), and abnormalities in the repair of 8-OH-dG by the base excision repair (BER) in bipolar disorder (BD). However, the genetic disposition of these abnormalities remains unknown. In this study, we aimed to investigate the levels of oxidatively-induced DNA damage and BER mechanisms in individuals with BD and their siblings, as compared to healthy controls (HCs). 46 individuals with BD, 41 siblings of individuals with BD, and 51 HCs were included in the study. Liquid chromatography-tandem mass spectrometry was employed to evaluate the levels of 8-OH-dG in urine, which were then normalized based on urine creatinine levels. The real-time-polymerase chain reaction was used to measure the expression levels of 8-oxoguanine DNA glycosylase 1 (OGG1), apurinic/apyrimidinic endonuclease 1 (APE1), poly ADP-ribose polymerase 1 (PARP1), and DNA polymerase beta (POLβ). The levels of 8-OH-dG were found to be elevated in both individuals with BD and their siblings when compared to the HCs. The OGG1 and APE1 expressions were downregulated, while POLβ expressions were upregulated in both the patient and sibling groups compared to the HCs. Age, smoking status, and the number of depressive episodes had an impact on APE1 expression levels in the patient group while body mass index, smoking status, and past psychiatric history had an impact on 8-OH-dG levels in siblings. Both individuals with BD and unaffected siblings presented similar abnormalities regarding oxidatively-induced DNA damage and BER, suggesting a link between abnormalities in DNA damage/BER mechanisms and familial susceptibility to BD. Our findings suggest that targeting the oxidatively-induced DNA damage and BER pathway could offer promising therapeutic strategies for reducing the risk of age-related diseases and comorbidities in individuals with a genetic predisposition to BD.

OBJECTIVE: The aim of this study was to examine the relationship between executive functions and suicidality in terms of impulsivity and depression severity. METHODS: Depressed adolescents who have made a suicide attempt in the last year (n = 32), depressed adolescents without a suicide attempt (n = 30), and healthy controls (n = 30) participated in the study in Dokuz Eylul University Faculty of Medicine, Department of Child and Adolescent Psychiatry. Clinical diagnoses were made according to the DSM-IV by applying Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL). Data were collected by using a sociodemographic data form, the Beck Depression Inventory (BDI), Barratt Impulsiveness Scale, and the Children’s Depression Rating Scale – Revised (CDRS-R). To evaluate all participants’ intelligence scores, the Wechsler Intelligence Scale for Children (WISC-R) was applied for adolescents aged under 16 years, and the Wechsler Adult Intelligence Scale (WAIS) was applied to adolescents aged 16–18 years. To determine the performance-based executive functions, Wisconsin Card Sorting Test and Stroop Test were applied to all participants. RESULTS: In this study, the participants who had made a suicide attempt displayed lower performance in the Stroop Test, especially in part 1 and part 4 compared with the controls (p = .04 and p = .011). Depressive patients also exhibited lower performance in the Stroop Test in part 3 compared with the controls (p = .049). Impulsivity was found more severe in depressive patients compared with controls (p