Chronic Corticosterone Administration-Induced Mood Disorders in Laboratory Rodents: Features, Mechanisms, and Research Perspectives.

Mood disorders mainly affect the patient's daily life, lead to suffering and disability, increase the incidence rate of many medical illnesses, and even cause a trend of suicide. The glucocorticoid (GC)-mediated hypothalamus-pituitary-adrenal (HPA) negative feedback regulation plays a key role in neuropsychiatric disorders. The balance of the mineralocorticoid receptor (MR)/glucocorticoid receptor (GR) level contributes to maintaining the homeostasis of the neuroendocrine system. Consistently, a chronic excess of GC can also lead to HPA axis dysfunction, triggering anxiety, depression, memory loss, and cognitive impairment. The animal model induced by chronic corticosterone (CORT) administration has been widely adopted because of its simple replication and strong stability. This review summarizes the behavioral changes and underlying mechanisms of chronic CORT administration-induced animal models, including neuroinflammatory response, pyroptosis, oxidative stress, neuroplasticity, and apoptosis. Notably, CORT administration at different doses and cycles can destroy the balance of the MR/GR ratio to make dose-dependent effects of CORT on the central nervous system (CNS). This work aims to offer an overview of the topic and recommendations for future cognitive function research.

How we approach steroid-induced affective disorder in pediatric oncology.

High-dose corticosteroids are an essential component of treatment for pediatric cancers. Yet, these agents often cause psychiatric disturbances including sleep disruption, steroid-induced psychosis, and steroid-induced affective disorder (SIAD). SIAD, identified as a specific form of substance/medication-induced mental disorder, can present with various psychiatric symptoms, including mania, depression, irritability, and inconsolability. SIAD's varied presentation can lead to underdiagnosis and complicates clinical care, research, and identification of best practices. Here we highlight three pediatric oncology cases involving SIAD and discuss recommendations for supporting patients with SIAD, while introducing a tiered intervention framework (modified from Kazak) that stratifies responses based on symptom severity.

Efficacy and safety of agomelatine in epilepsy patients with sleep and mood disorders: An observational, retrospective cohort study.

OBJECTIVE: To evaluate the therapeutic efficacy and safety of agomelatine for treating the sleep and mood disorders in epilepsy patients. METHODS: Retrospective data were derived from 113 epilepsy patients for at least 8 weeks. All the subjects were divided into two groups, one was treated with agomelatine, the other was treated with escitalopram. Their depression and anxiety states were assessed by Hamilton Depression (HAMD) and Hamilton Anxiety (HAMA) Scales. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The HAMA, HAMD and PSQI scores in both groups significantly declined after the treatments with agomelatine and escitalopram. However, the agomelatine group exhibited greater improvement in terms of HAMA and PSQI scores compared to the escitalopram group. No severe adverse events were observed in agomelatine group. SIGNIFICANCE: Agomelatine performed better in HAMA and PSQI scores compared to escitalopram, where no significant increase in seizure frequency or side effects were observed. Possibly, agomelatine presents a promising therapeutic option for treating the sleep or mood disorders in epilepsy patients.

Mood changes and clinical decision making in adolescent patients on isotretinoin therapy for acne vulgaris.

Although numerous studies have demonstrated no causal relationship between isotretinoin and depression or suicide, subtle mood changes and idiosyncratic mood symptoms have been reported in patients on isotretinoin treatment for acne vulgaris, and few studies have described the full range of mood symptoms and clinical course after a mood change arises. We reviewed 247 patients, ages 10-25 years, with acne vulgaris on isotretinoin and found that 26/247 (10.5%) patients experienced mood changes, the most common being depressive symptoms, anxiety, aggression, and emotional lability. Regardless of treatment management, 22/25 (88%) patients experienced improvement of mood symptoms to baseline, and 22/25 (88%) were able to complete their isotretinoin course without symptom recurrence. Our findings highlight the importance of monitoring for a broad range of mood changes in patients on isotretinoin, especially those related to a pre-existing mood disorder and including those which do not meet formal criteria for a psychiatric disorder.

Affective disorder and brain alterations in children and adolescents exposed to outdoor air pollution.

BACKGROUND: Childhood and adolescence are critical periods for the development of the brain. However, a limited number of studies have explored how air pollution may associate with affective symptoms in youth. METHODS: We performed a comprehensive review of the existing research on the associations between outdoor air pollution and affective disorders, suicidality, and the evidence for brain changes in youth. PRISMA guidelines were followed and PubMed, Embase, Web of Science, Cochrane Library, and PsychINFO databases were searched from their inception to June 2022. RESULTS: From 2123 search records, 28 papers were identified as being relevant for studying the association between air pollution and affective disorders (n = 14), suicide (n = 5), and neuroimaging-based evidence of brain alterations (n = 9). The exposure levels and neuropsychological performance measures were highly heterogeneous and confounders including traffic-related noise, indoor air pollution, and social stressors were not consistently considered. Notwithstanding, 10 out of the 14 papers provide evidence that air pollution is associated with increased risk of depression symptoms, and 4 out of 5 papers provide evidence that air pollution might trigger suicidal attempts and behaviors. Besides, 5 neuroimaging studies revealed decreased gray-matter volume in the Cortico-Striato-Thalamo-Cortical neurocircuitry, and two found white matter hyperintensities in the prefrontal lobe. CONCLUSIONS: Outdoor air pollution is associated with increased risks of affective disorders and suicide in youth, and there is evidence for associated structural and functional brain abnormalities. Future studies should determine the specific effects of each air pollutant, the critical exposure levels, and population susceptibility.

Heavy metal contamination in Peru: implications on children's health.

Cerro de Pasco, Peru, has been excessively contaminated with heavy metals due to high mining activities in the region. We investigated the presence of chronic exposure to heavy metals in children living in Cerro de Pasco and its effect on health. Heavy metal concentrations were determined in hair samples collected from 78 children living in a region exposed to an open-pit mine (Paragsha region) and from other 16 children unexposed to mine activities (Carhuamayo region). Children exposed to the mine showed statistically significant higher concentration of aluminum, antimony, arsenic, cadmium, chromium, iron, lead, tin and thallium (p < 0.05) than control children. Hair samples collected from the same children in two occasions (2016 and 2018) showed that the exposure is chronic with higher levels of heavy metals observed in 2018. The concentration of heavy metals was higher in hair tip than in hair root samples. Heavy metals are associated with substantial higher risk of nosebleed (odds ratio, OR = 15.40), chronic colic (OR = 7.30), dermatologic alterations (OR = 6.16), mood alterations (OR = 7.07), presence of white lines on nails (OR = 12.10), reduced visual camp (OR = 3.97) and other symptoms (OR = 5.12). Chronic heavy metal exposure implies various negative consequences on children's health. Preventive measures are crucial to protect children's health.

[Intravascular migration of a contraceptive implant]. / Intravasculaire migratie van een hormoonimplantaat.

BACKGROUND: The Implanon NXT is a commonly used contraceptive. Incorrect localization of the implant can cause complications. CASE DESCRIPTION: A 41-year-old woman is seen in the gynaecology outpatient clinic with a request to remove a recently placed Implanon NXT because of worsening mood symptoms. The implant can't be found on physical and ultrasound examination. Duringsurgicalexplorationthe implant is not found at theinsertion site' By means of X-ray scanning the implant becomes visible around the humeral head. The implant appears to be located in the cephalic vein and is subsequently removed. CONCLUSION: In case of a referral due to because of worsening mood symptoms after an Implanon NXT exchange, it is possible that the implant is localized incorrectly. It is recommended to use additional imaging before performing surgical exploration. Furthermore, it is important to insert the Implanon NXT according to the supplied instructions to prevent this complication.

The relationship between antihypertensive medications and mood disorders: analysis of linked healthcare data for 1.8 million patients.

BACKGROUND: Recent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists (AAs) and calcium channel blockers, were associated with reduced risk of new-onset major depressive disorder (MDD) or bipolar disorder (BD). METHOD: Two cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by a receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n = 538 730) included patients with no previous history of mood disorder, whereas the other (n = 262 278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression. RESULTS: For patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For AA monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95% CI 1.04-1.31). Beta blockers' association was stronger (HR 2.68; 95% CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against BD, particularly AAs (HR 0.46; 95% CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD. CONCLUSIONS: There was no evidence that antihypertensive medications prevented new episodes of MDD but AAs may represent a novel treatment avenue for BD.

l-Theanine Prevents Long-Term Affective and Cognitive Side Effects of Adolescent Δ-9-Tetrahydrocannabinol Exposure and Blocks Associated Molecular and Neuronal Abnormalities in the Mesocorticolimbic Circuitry.

Chronic adolescent exposure to Δ-9-tetrahydrocannabinol (THC) is linked to elevated neuropsychiatric risk and induces neuronal, molecular and behavioral abnormalities resembling neuropsychiatric endophenotypes. Previous evidence has revealed that the mesocorticolimbic circuitry, including the prefrontal cortex (PFC) and mesolimbic dopamine (DA) pathway are particularly susceptible to THC-induced pathologic alterations, including dysregulation of DAergic activity states, loss of PFC GABAergic inhibitory control and affective and cognitive abnormalities. There are currently limited pharmacological intervention strategies capable of preventing THC-induced neuropathological adaptations. l-Theanine is an amino acid analog of l-glutamate and l-glutamine derived from various plant sources, including green tea leaves. l-Theanine has previously been shown to modulate levels of GABA, DA, and glutamate in various neural regions and to possess neuroprotective properties. Using a preclinical model of adolescent THC exposure in male rats, we report that l-theanine pretreatment before adolescent THC exposure is capable of preventing long-term, THC-induced dysregulation of both PFC and VTA DAergic activity states, a neuroprotective effect that persists into adulthood. In addition, pretreatment with l-theanine blocked THC-induced downregulation of local GSK-3 (glycogen synthase kinase 3) and Akt signaling pathways directly in the PFC, two biomarkers previously associated with cannabis-related psychiatric risk and subcortical DAergic dysregulation. Finally, l-theanine powerfully blocked the development of both affective and cognitive abnormalities commonly associated with adolescent THC exposure, further demonstrating functional and long-term neuroprotective effects of l-theanine in the mesocorticolimbic system.SIGNIFICANCE STATEMENT With the increasing trend of cannabis legalization and consumption during adolescence, it is essential to expand knowledge on the potential effects of adolescent cannabis exposure on brain development and identify potential pharmacological strategies to minimize Δ-9-tetrahydrocannabinol (THC)-induced neuropathology. Previous evidence demonstrates that adolescent THC exposure induces long-lasting affective and cognitive abnormalities, mesocorticolimbic dysregulation, and schizophrenia-like molecular biomarkers that persist into adulthood. We demonstrate for the first time that l-theanine, an amino acid analog of l-glutamate and l-glutamine, is capable of preventing long-term THC side effects. l-Theanine prevented the development of THC-induced behavioral aberrations, blocked cortical downregulation of local GSK-3 (glycogen synthase kinase 3) and Akt signaling pathways, and normalized dysregulation of both PFC and VTA DAergic activity, demonstrating powerful and functional neuroprotective effects against THC-induced developmental neuropathology.

Risk factors for steroid-induced affective disorder in children with leukemia.

Corticosteroids are essential to treating childhood acute lymphoblastic leukemia (ALL), and can cause significant neuropsychiatric side effects. This retrospective chart review is a preliminary exploration of characteristics associated with psychiatry consultation and steroid-induced affective disorder (SIAD) during ALL treatment. Of 125 ALL patients (ages 1-10 years), 56 (44.8%) received psychiatry consultation. Thirty-nine (31.2%) of the total cohort were diagnosed with SIAD. SIAD was significantly associated with family psychiatric history, but not with steroid exposure, CNS radiation, sociodemographic factors, developmental delay, Trisomy 21, or prior psychiatric history. Gathering family psychiatric history may help identify children at increased risk of SIAD.

Molecular and neuronal mechanisms underlying the effects of adolescent nicotine exposure on anxiety and mood disorders.

Tobacco addiction is highly co-morbid with a variety of mental health conditions, including schizophrenia, mood and anxiety disorders. Nicotine, the primary psychoactive compound in tobacco-related products is known to functionally modulate brain circuits that are disturbed in these disorders. Nicotine can potently regulate the transmission of various neurochemicals, including dopamine (DA), γ-amino-butyric acid (GABA) and glutamate, within various mesocorticolimbic structures, such as the ventral tegmental area (VTA), nucleus accumbens (NAc) and prefrontal cortex (PFC), all of which show pathologies in these disorders. Many neuropsychiatric diseases have etiological origins during neurodevelopment, typically occurring during vulnerable periods of adolescent or pre-natal brain development. During these neurodevelopmental periods, exposure to extrinsic drug insults can induce enduring and long-term pathophysiological sequelae that ultimately increase the risk of developing chronic mental health disorders in later life. These vulnerability factors are of growing concern given rising rates of adolescent nicotine exposure via traditional tobacco use and the increasing use of alternative nicotine delivery formats such as vaping and e-cigarettes. A large body of clinical and pre-clinical evidence points to an important role for adolescent exposure to nicotine and increased vulnerability to developing mood and anxiety disorders in later life. This review will examine current clinical and pre-clinical evidence that pinpoints specific mechanisms within the mesocorticolimbic circuitry and molecular biomarkers linked to the association between adolescent nicotine exposure and increased risk of developing mood and anxiety-related disorders. This article is part of the special issue on 'Vulnerabilities to Substance Abuse'.

Absence of effects of intermittent access to alcohol on negative affective and anxiety-like behaviors in male and female C57BL/6J mice.

Alcohol use disorder is highly comorbid with other neuropsychiatric disorders such as depression and anxiety. Importantly, women and men are affected differentially by heavy drinking, with women experiencing longer negative affective states after intoxication and increased likelihood to present with comorbid mood or anxiety disorders. In rodents, several studies using different alcohol administration models have shown the development of depressive-like or anxiety-like phenotypes that emerge during abstinence. In this study, we compared the emergence of negative affective behaviors during abstinence from 7 weeks of two-bottle choice intermittent access to 20% alcohol in male and female C57BL/6J mice, a drinking paradigm little studied in this context. Half of the mice were tested 24 hours into abstinence on the elevated zero maze and 19-20 days into abstinence in a novel object in the home cage encounter test. The other half of the mice were tested 27-28 days into abstinence with the novelty-suppressed feeding test. As expected, females drank more than males across the 7 weeks of access to alcohol. Drinking history did not affect performance on these tasks, with the exception of increasing the number of open arm entries on the elevated zero maze. Interestingly, in alcohol-naïve mice, females showed fewer anxiety-like behaviors than males in the elevated zero maze and the novelty-suppressed feeding test. Our results suggest that the intermittent access model does not reliably induce negative affective behaviors on these tasks, and that behavior in female and male mice differs across these tests. Rather, intermittent alcohol drinking may induce a mild form of behavioral disinhibition. Thus, the model of alcohol access is a critical factor in determining the appearance of behavioral disturbances that emerge during abstinence.

The synthetic cannabinoid 5F-MDMB-PICA: A case series.

5F-MDMB-PICA has been detected in products sold on the internet as well as in biological samples since 2016. It is associated with serious adverse health and behavioral effects and even death. Herein we report on twelve cases with proven 5F-MDMB-PICA consumption, including three fatalities, four cases of driving under the influence of drugs and five other criminal acts. In these cases, 5F-MDMB-PICA was detected in postmortem blood or serum. Concentrations ranged from 0.1-16ng/mL. In some blood (serum) and urine samples, the hydrolysis metabolite of 5F-MDMB-PICA (M12) could also be detected. In this case series, co-consumption with other drugs occurred in 9 of 12 cases, most commonly alcohol, cannabis and other contemporary SCs. In five cases, 4F-MDMB-BINACA was also detected. The described cases demonstrate various adverse effects that might be associated with 5F-MDMB-PICA. Observed physical adverse effects were mainly balance deficiencies and ocular effects such as reddened conjunctivae, glassy eyes and delayed or unresponsive pupil light reactions. Observed mental and behavioral effects were mainly changing moods, aggression, confusion, erratic behavior, mental leaps, disorientation, slowed reaction, logorrhea and slurred speech. Due to the fast changing market of synthetic cannabinoids, data on such new appearing substances are basically scarce. Because of the limited number of studies on pharmacological properties of synthetic cannabinoids, reports of findings in human samples along with corresponding case history descriptions can be valuable for the interpretation of upcoming routine cases.

Validation of the Serbian version of the Liverpool Adverse Events Profile of antiseizure therapy in patients with epilepsy.

The Liverpool Adverse Event Profile (LAEP) is a useful instrument in assessing the consequences of adverse events in patients using antiseizure medication. The LAEP scale has been validated in several languages to date. The aim of our study was to validate the LAEP scale in the Serbian language (SVLAEP). Validation of the SVLAEP scale was conducted by translating the original English version into the Serbian language and backtranslated into the English language. The translation was accepted when the two versions of the text were compatible. The questionnaire is then given to a group of patients with epilepsy treated with a stable dose of antiseizure medication. For the assessment of the quality of life and depression, we used the Serbian version of the Quality of Life in Epilepsy Inventory-31 (SVQOLIE-31) and the Serbian version of the Neurological Disorders Depression Inventory for Epilepsy (SVNDDI-E). From a total of 166 patients, 118 patients were included, and the remaining 48 were excluded because of other comorbidities and using other psychotropic drugs. Internal consistency (Cronbach's α = 0.87) and test-retest reliability (intraclass correlation coefficient (ICC) = 0.80) were satisfactory. The SVLAEP and SVQOLIE-31 had a strong negative statistical correlation (rs = -0.73; p < 0.001). The SVLAEP and SVNDDI-E final scores had a positive moderate correlation (rs = 0.52; p < 0.001). A moderate negative statistical correlation was found between SVNDDI-E and SVQOLIE-31 (rs = -0.56; p < 0.001). Our study showed that the LAEP scale is a useful indicator for the frequency of the adverse events in antiepileptic drug (AED) usage, despite a minor overlap with the symptoms of depression.

Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis.

Drug-induced Mood- and Cognition-related adverse events (MCAEs) are often only detected during the clinical trial phases of drug development, or even after marketing, thus posing a major safety concern and a challenge for both pharmaceutical companies and clinicians. To fill some gaps in the understanding and elucidate potential biological mechanisms of action frequently associated with MCAEs, we present a unique workflow linking observational population data with the available knowledge at molecular, cellular, and psychopharmacology levels. It is based on statistical analysis of pharmacovigilance reports and subsequent signaling pathway analyses, followed by evidence-based expert manual curation of the outcomes. Our analysis: (a) ranked pharmaceuticals with high occurrence of such adverse events (AEs), based on disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database, and (b) identified 120 associated genes and common pathway nodes possibly underlying MCAEs. Nearly two-thirds of the identified genes were related to immune modulation, which supports the critical involvement of immune cells and their responses in the regulation of the central nervous system function. This finding also means that pharmaceuticals with a negligible central nervous system exposure may induce MCAEs through dysregulation of the peripheral immune system. Knowledge gained through this workflow unravels putative hallmark biological targets and mediators of drug-induced mood and cognitive disorders that need to be further assessed and validated in experimental models. Thereafter, they can be used to substantially improve in silico/in vitro/in vivo tools for predicting these adversities at a preclinical stage.

Mapping the pathways between recreational cannabis use and mood disorders: A Behaviour Sequence Analysis approach.

ISSUES ADDRESSED: Although cannabis use is still illegal in most places around the world, it remains a widely used drug. The recreational use of cannabis has been linked to multiple mental wellbeing issues, including psychosis, depression and anxiety. The objective of this study was to investigate the temporal dynamics of cannabis use in relation to mental health issues. METHODS: The current research uses a novel methodological approach, behaviour sequence analysis, to understand the temporal relationship between recreational cannabis use and surrounding issues related to mental wellbeing, in a sample of 61 participants who had written autobiographical accounts online. RESULTS: The results indicated a bi-directional temporal ordering between cannabis use and mood disorders. Cannabis use preceded psychosis and can also exacerbate symptoms of psychosis, depression and anxiety. Findings also suggested that low self-esteem may be a predictor of future cannabis use. CONCLUSIONS: Research shows a link between mood disorders and recreational cannabis use. The BSA method can be used in applied settings to map pathways in individuals' life histories. SO WHAT?: The current study shows the sequential links between cannabis use and psychosis, depression and anxiety. Results show there is no single clear pathway and clinical practitioners should focus on a wider range of factors in individual's case histories.

Systemic and Local Corticosteroid Use Is Associated with Reduced Executive Cognition, and Mood and Anxiety Disorders.

BACKGROUND: Use of local corticosteroids, especially the inhaled types, has increasingly been associated with systemic uptake and consequent adverse effects. In this study, we assessed the associations between the use of different corticosteroid types with cognitive and neuropsychiatric adverse effects related to high glucocorticoid exposure. METHODS: In 83,592 adults (mean age 44 years, 59% women) of the general population (Lifelines Cohort Study), we analyzed the relationship between corticosteroid use with executive cognitive functioning (Ruff Figural Fluency Test), and presence of mood and anxiety disorders (Mini-International Neuropsychiatric Interview survey). We performed additional exploration for effects of physical quality of life (QoL; RAND-36), and inflammation (high-sensitive C-reactive protein [CRP]). RESULTS: Cognitive scores were lower among corticosteroid users, in particular of systemic and inhaled types, when compared to nonusers. Users of inhaled types showed lower cognitive scores irrespective of physical QoL, psychiatric disorders, and high-sensitive CRP. Overall corticosteroid use was also associated with higher likelihood for mood and anxiety disorders. Users of inhaled corticosteroids were more likely to have mood disorders (OR 1.40 [95% CI 1.19-1.65], p < 0.001) and anxiety disorders (OR 1.19 [95% CI 1.06-1.33], p = 0.002). These findings were independent of physical QoL. A higher likelihood for mood disorders was also found for systemic users whereas nasal and dermal corticosteroid users were more likely to have anxiety disorders. CONCLUSIONS: Commonly used local corticosteroids, in particular inhaled types, and systemic corticosteroids are associated with reduced executive cognitive functioning and a higher likelihood of mood and anxiety disorders in the general adult population.

Neuropsychiatric Immune-related Adverse Events Induced by Pembrolizumab in a Patient with Lung Adenocarcinoma and Systemic Lupus Erythematosus.

The patient was a 73-year-old woman with lung adenocarcinoma and systemic lupus erythematosus (SLE) who was treated with pembrolizumab. After six cycles of pembrolizumab, she developed symptoms suggestive of neuropsychiatric SLE, such as resting tremor, confusional state, depression, mood disorder, and anxiety disorder. In addition, her cerebrospinal fluid level of interleukin-6 was elevated. Her symptoms resolved one month after the discontinuation of pembrolizumab. This is the first report of neuropsychiatric symptoms in a patient with lung cancer and SLE on immune checkpoint blockade therapy.