Index depressive episode and antidepressant exposure were associated with illness characteristics of pediatric bipolar disorder.

OBJECTIVE: Pediatric bipolar disorder (PBD) is a serious, recurrent disorder leading to severe functional impairment. As a first mood episode, index episode could affect the long-term course of the illness. This study aimed to investigate the clinical characteristics of youth with PBD from our multicenter, nationwide, naturalistic follow-up samples and to identify (i) the effects of index mood episode and (ii) the effect of previous antidepressant treatments on the age at mania onset of PBD. METHOD: The study sample consisted of 271 youth with BD-I followed by the child and adolescent psychiatry clinics of seven different university hospitals and three research state hospitals, representing six geographic regions across Turkey. All diagnoses were made according to structured interviews, and all data were retrospectively obtained from clinical records by the clinicians. RESULTS: When patients with index depressive/mixed episodes (IDE, n=129) and patients with index (hypo)manic episodes (IME, n=142) were compared, the total number of mood episodes and rapid cycling feature were significantly higher in the IDE group than in the IME group. The Cox regression analysis adjusted for sociodemographic and illness characteristics revealed female adolescents in the IDE group treated with antidepressants were more likely to have an earlier onset of mania (hazard ratio=2.03, 95% confidence interval=1.31-3.12, p=0.001). CONCLUSION: This is the first large-scale nationwide follow-up study in Turkey that indicated prior antidepressant treatments were associated with an earlier onset of mania in youth, particularly in adolescent females. Larger prospective studies are needed to identify neurodevelopmental processes underlying PBD and initiate prevention approaches.

Elevated hepatocyte growth factor expression as an autocrine c-Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related deaths worldwide. Limitations in HCC treatment result due to poor prognosis and resistance against traditional radiotherapy and chemotherapies. The multikinase inhibitor sorafenib is the only FDA approved drug available for advanced HCC patients, and development of second-line treatment options for patients who cannot tolerate or develop resistance to sorafenib is an urgent medical need. In this study, we established sorafenib-resistant cells from Huh7 and Mahlavu cell lines by long-term sorafenib exposure. Sorafenib-resistant HCC cells acquired spindle-shape morphology, upregulated mesenchymal markers, and showed significant increase in both migration and invasion abilities compared to their parental counterparts. Moreover, after long-term sorafenib treatment, HCC cells showed induction of hepatocyte growth factor (HGF) synthesis and secretion along with increased levels of c-Met kinase and its active phosphorylated form, indicating autocrine activation of HGF/c-Met signaling. Importantly, the combined treatment of the resistant cells with c-Met kinase inhibitor SU11274 and HGF neutralizing antibody significantly reversed the increased invasion ability of the cells. The combined treatment also significantly augmented sorafenib-induced apoptosis, suggesting restoration of sorafenib sensitivity. These results describe, for the first time, compensatory upregulation of HGF synthesis leading to autocrine activation of HGF/c-Met signaling as a novel cellular strategy in the acquisition of sorafenib resistance. Therefore, we suggest that combinatorial therapeutic strategies with HGF and c-Met inhibitors comprise promising candidates for overcoming sorafenib resistance.

Effect of adipocyte-secreted factors on EpCAM+/CD133+ hepatic stem cell population.

Recent epidemiological studies have associated obesity with a variety of cancer types including HCC. However, the tumor initiating role of obesity in hepatocarcinogenesis is still unknown. The objective of this paper is to investigate the effect of adipocyte-secreted factors on EpCAM+/CD133+ cancer stem cells and to identify which factors play a role in modulating hepatic cancer stem cell behavior. Our results demonstrated that adipocyte-secreted factors affect motility and drug resistance of EpCAM+/CD133+ cells. When incubated with adipocyte conditioned media, EpCAM+/CD133+ cells exhibited augmented motility and reduced sorafenib-induced apoptosis. Using array-based system, we identified secretion of several cytokines such as IL6, IL8 and MCP1 by cultured adipocytes and activation of c-Met, STAT3 and ERK1/2 signaling pathways in EpCAM+/CD133+ cells incubated with adipocyte conditioned media. Treating EpCAM+/CD133+ cancer stem cells with IL6 receptor blocking antibody or c-Met inhibitor SU11274 both reduced the increase in motility; however SU11274 had greater effect on relieving protection from sorafenib-induced apoptosis. These results indicate that adipocyte-secreted factors might regulate cancer stem cell behavior through several signaling molecules including c-Met, STAT3 and ERK1/2 and inhibition of these signaling pathways offer novel strategies in targeting the effect of adipose-derived cytokines in cancer.

Intrauterine Exposure to Antidepressants or Maternal Depressive Symptoms and Offspring Brain White Matter Trajectories From Late Childhood to Adolescence.

BACKGROUND: During pregnancy, both selective serotonin reuptake inhibitor (SSRI) exposure and maternal depression have been associated with poor offspring neurodevelopmental outcomes. In a population-based cohort, we investigated the association between intrauterine exposure to SSRIs and depressive symptoms and offspring white matter development from childhood to adolescence. METHODS: Self-reported SSRI use was verified by pharmacy records. In midpregnancy, women reported on depressive symptoms using the Brief Symptom Inventory. Using diffusion tensor imaging, offspring white matter microstructure, including whole-brain and tract-specific fractional anisotropy (FA) and mean diffusivity, was measured at 3 assessments between ages 7 to 15 years. The participants were divided into 4 groups: prenatal SSRI exposure (n = 37 with 60 scans), prenatal depression exposure (n = 229 with 367 scans), SSRI use before pregnancy (n = 72 with 95 scans), and reference (n = 2640 with 4030 scans). RESULTS: Intrauterine exposure to SSRIs and depressive symptoms were associated with lower FA in the whole-brain and the forceps minor at 7 years. Exposure to higher prenatal depressive symptom scores was associated with lower FA in the uncinate fasciculus, cingulum bundle, superior and inferior longitudinal fasciculi, and corticospinal tracts. From ages 7 to 15 years, children exposed to prenatal depressive symptoms showed a faster increase in FA in these white matter tracts. Prenatal SSRI exposure was not related to white matter microstructure growth over and above exposure to depressive symptoms. CONCLUSIONS: These results suggest that prenatal exposure to maternal depressive symptoms was negatively associated with white matter microstructure in childhood, but these differences attenuated during development, suggesting catch-up growth.

Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory.

Importance: Clinical decision-making on antidepressant treatment during pregnancy, particularly selective serotonin reuptake inhibitors (SSRIs), is challenging, as both prenatal SSRI exposure and maternal depressive symptoms may be associated with negative outcomes in offspring. Objective: To investigate the association between intrauterine SSRI exposure and maternal depressive symptoms and structural brain development in offspring from mid-childhood to early puberty. Design, Setting, and Participants: This prospective, population-based cohort study was embedded in the Generation R Study in Rotterdam, the Netherlands. All pregnant individuals with an expected delivery date between April 1, 2002, and January 31, 2006, were invited to participate. Data were analyzed from February 1 to September 30, 2022. Exposure: Maternal-reported SSRI use verified by pharmacy records. In mid-pregnancy and 2 and 6 months after delivery, participants reported depressive symptoms using the Brief Symptom Inventory and were divided into 5 groups: SSRI use during pregnancy (n = 41; 80 scans), SSRI use only before pregnancy (n = 77; 126 scans), prenatal depressive symptoms without prenatal SSRI use (n = 257; 477 scans), postnatal depressive symptoms only (n = 74; 128 scans), and nonexposed control individuals (n = 2749; 4813 scans). Main Outcomes and Measures: The main outcome was brain morphometry in offspring, including global and cortical brain volumes, measured at 3 magnetic resonance imaging assessments from 7 to 15 years of age. Results: The study included 3198 mother-child dyads. A total of 3198 mothers (100%) identified as women; mean (SD) age at intake was 31.1 (4.7) years. Children (1670 [52.2%] female) underwent brain imaging assessment from 7 to 15 years of age with 5624 total scans. Most brain gray matter volumes showed an inverted U-shaped trajectory. Compared with nonexposed controls, children prenatally exposed to SSRIs had less cerebral gray matter (ß [SE], -20 212.2 [7285.6] mm3; P = .006), particularly within the corticolimbic circuit, which persisted up to 15 years of age. Children exposed to SSRIs prenatally showed a steeper increase in volumes of the amygdala (age interaction: ß [SE], 43.3 [13.4] mm3; P = .006) and fusiform gyrus (age interaction: ß [SE], 168.3 [51.4] mm3; P = .003) from 7 to 15 years of age. These volumetric differences in the amygdala and fusiform observed in childhood did not persist until early adolescence. Prenatal depression was associated with a smaller volume in the rostral anterior cingulate gyrus (ß [SE], -166.3 [65.1] mm3; P = .006), and postnatal depression was associated with a reduced fusiform gyrus (ß [SE], -480.5 [189.2] mm3; P = .002). No association of SSRI use before pregnancy with brain outcomes was observed. Conclusions and Relevance: The results of this cohort study suggest that prenatal SSRI exposure may be associated with altered developmental trajectories of brain regions involved in emotional regulation in offspring. Further research on the functional implications of these findings is needed.

Association between thyroid autoimmunity and antidepressant treatment-emergent mania in pediatric mood disorders.

Risk factors associated with antidepressant treatment-emergent mania(ATEM) are poorly characterized in child and adolescent populations. To identify better biomarkers, we aimed to explore whether thyroid autoimmunity is associated with ATEM in pediatric mood disorders. We enrolled two groups of pediatric mood disorders, those with ATEM+ (n = 29) and those with ATEM- controls (n = 31). All diagnoses were made according to structured interviews by the clinicians. Autoimmune thyroiditis (anti-thyroid peroxidase antibodies [TPO-abs] and thyroid function (thyroid-stimulating hormone [TSH] and free thyroxin [FT4]) were assessed. Logistic regression was used to explore the relationship between TPO-abs seroprevalence and ATEM+ while controlling for covariates. Group comparisons showed that the patient with ATEM+ had significantly higher seroprevalence and titer of TPO-abs compared to ATEM- controls. In logistic regression analysis adjusting for age, gender, Tanner stage, body mass index, antipsychotic treatments, smoking status and family history of thyroid disorder, the seroprevalence of TPO-abs (>60 U/mL) was significantly associated with ATEM+ (OR = 3.67, 95% confidence interval [CI] = 1.2-11.1, p = 0.022). Our findings demonstrated that seroprevalence and titer of TPO-abs in pediatric mood disorders are associated with ATEM+ status. TPO-abs could potentially serve as a biomarker when assessing the risk of ATEM in the child and adolescent population.

Brain-derived neurotrophic factor in bipolar disorder: Associations with age at onset and illness duration.

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.

Investigation of structure-function correlation among the young offspring of patients with bipolar disorder.

Bipolar disorder (BD) has been associated with impaired executive functioning and integrity of fronto-limbic white matter tracts. The evaluation of these factors in young offspring of patients with BD (BDoff) as a high-risk group offers an opportunity to investigate factors that could predict vulnerability to the disorder. This study aims to examine the correlation between neurocognition and neuroimaging findings to evaluate the potential for these findings as biomarkers for the early recognition of BD. We enrolled BDoff (n = 16) who were aged between 12 and 18. Participants were assessed using clinical and neurocognitive tests. In addition, structural brain magnetic resonance and diffusion tensor imaging data were obtained. Mean fractional anisotropy (FA) and mean diffusivity (MD) values of the superior longitudinal fasciculus (SLF) and cingulum were extracted and correlations with neuropsychological data were analyzed. FA values in the SLF were negatively correlated with Stroop interference, the Wisconsin Card Sorting Test, and the Trail Making Test (B-A) scores. MD values in the cingulum were inversely correlated with the Child and Youth Resilience Measure and positively correlated with higher scores on the Barratt Impulsiveness Scale-Attentional. These findings provide a link between features of the brain and cognitive dysfunction in BDoff.

Regulation of the unfolded protein response through ATF4 and FAM129A in prostate cancer.

Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2α in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target.