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Distressing and impairing separation anxiety symptoms with onset in adult life can be diagnosed as an anxiety disorder. Advances in understanding in epidemiology and possible neuropsychobiology make the condition worthy of further detailed consideration, but the absence of robustly evidence-based treatments limits the current utility of diagnosis in clinical practice.
Obsessive-compulsive disorder (OCD) and related disorders (OCRDs) represent a group of conditions in which lack of response to first-line treatments, such as serotonin reuptake inhibitors (SRIs), is common. Therefore, exploring alternative strategies is necessary. We conducted a systematic review of the use of lithium in OCRDs. This systematic review was conducted in accordance with PRISMA guidelines. We included studies evaluating the use of lithium for OCRDs in adults. Eligible designs included case reports, case series, observational studies, and clinical trials. Four databases (PubMed, PsycInfo, Web of Science, and <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>) were searched on January 21, 2025. Response to lithium was defined by improvement on validated scales or, when unavailable, based on clinical descriptions. Twenty-nine studies met inclusion criteria, including 25 case reports or case series and four clinical trials. Most studies focused on OCD (n = 20), followed by trichotillomania (n = 5), tic disorders (n = 3), and body dysmorphic disorder (n = 1). Across the full sample (n = 97), 38.1% of the subjects showed "clinical improvement," although only 54.6% were assessed using validated instruments. Among case reports and case series (n = 37), 89.2% reported "improvement." However, three crossover RCTs found no consistent benefit of lithium, and the only placebo-controlled trial did not detect significant differences between groups in the final pooled analysis. Analysis of individual data showed response to lithium to be more common among younger individuals (p = 0.02), those with comorbid bipolar disorder (p = 0.005), individuals receiving lithium as monotherapy (p < 0.018), and those without prior exposure to SRIs (p < 0.001). Additionally, responders were less likely to have been assessed using standardized instruments (p < 0.001). This is the first systematic review to evaluate lithium as a treatment strategy for OCRDs. While some reports suggest potential benefits, current evidence - largely based on low-quality studies without standardized assessments - does not support its use. Findings from randomized trials remain inconclusive, and further high-quality research is needed.
The role of chemokines in motor abnormalities (MAs) in first-episode psychosis (FEP) is underexplored. Investigating immune biomarker levels in FEP, their association with MAs, and their differences with individuals without FEP may reveal therapeutic targets. Thirty-eight patients and thirty-four controls were included. Primary outcomes assessed group differences in chemokines related immune whole blood biomarkers, including innate (CCL2, CCL3, and CCL11), compensatory (PPARα, CXCL1, and CB2), natural immune chemotaxis biomarkers (CXCL2 and CXCR4), and growth factors (LPAR2, brain-derived neurotrophic factor [BDNF], and vascular endothelial growth factor [VEGF]). Our secondary aim was to examine their association with the total score of five motor scales: the Neurological Evaluation Scale (NES), Simpson Angus Scale (SAS), catatonia symptom of the Comprehensive Assessment of Symptoms and History (CASH), Barnes Akathisia Rating Scale, and Unified Parkinson's Disease Rating Scale (UPDRS). We found significantly higher levels of protein markers (CCL2, VEGF, and CXCL12) and mRNA expression (CXCR4, PPARα, CB2, and LPAR2) in FEP patients compared to the control group. We only observed positive and significant results for CCL2-UPDRS total and CXCR4-SAS associations in post hoc multivariate analyses (β = 0.401, p = 0.036 and β = 0.58, p = 0.001, respectively). Elevated levels of potential neurotoxic (CCL2) and neuroprotective (PPARα and CB2) biomarkers were seen in FEP patients when compared to controls. Moreover, CCL2 levels seem to be directly associated with Parkinsonism in FEP patients, while CXCR4 may be protective against extrapyramidal symptoms. Further research should clarify immune differences between FEP and non-FEP groups, especially in chemotaxis and endocannabinoid pathways.
The study aimed to investigate whether alterations in tryptophan (TRP) metabolites reflect dysregulation of the kynurenine pathway, which has been implicated in bipolar disorder (BD) and to examine their relationship with cognitive functioning by assessing TRP metabolite levels alongside executive performance in non-affected offspring of individuals diagnosed with BD. The study included 32 healthy offspring of parents with BD Type I as the case group and 31 healthy offspring of parents without any psychiatric disorders as controls. Psychiatric screening was conducted using the Turkish adaptation of the Schedule for Affective Disorders and Schizophrenia for School Age Children - Present and Lifetime Version (K-SADS-PL-DSM-5). Executive functioning was examined using a neuropsychological battery that included the Stroop, Serial Digit Learning (SDLT), and Cancellation (CT) tests. Serum levels of TRP, kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HAA), as well as metabolite ratios (KYN/TRP, KYNA/KYN, 3-HK/KYN, and KYNA/3-HK), were measured. Logistic regression analysis was applied as part of the statistical approach to evaluate whether these metabolites and ratios could distinguish the offspring of individuals with bipolar disorder from healthy controls. Neurocognitive performance was significantly poorer in the case group than in the control group. Serum levels of TRP (t=3.568, p=0.001), KYN (t=3.772, p=0.001), KYNA (t=2.797, p=0.007), and the ratios of KYN/TRP (t=2.550, p=0.014) and KYNA/3-HK (z=-2.557, p=0.011) were significantly decreased in cases, whereas KYNA/KYN (t=-2.562, p=0.013) and 3-HK/KYN (z=-3.368, p=0.001) ratios were significantly elevated. Correlation analyses showed significant associations between executive function deficits and TRP (r=0.367, p=0.039), KYN (r=0.380, p=0.032), KYNA (r=0.488, p=0.005), 3-HK (r=0.492, p=0.004), and the 3-HK/KYN ratio (r=0.408, p=0.020). Logistic regression analysis indicated that lower KYN levels distinguished cases from controls (OR=0.986, 95% CI=0.978-0.995, p=0.002). The findings indicate that metabolism within the kynurenine pathway in the offspring of individuals with bipolar disorder shows a shift toward its neurotoxic branch, reflected by increased 3-HK/KYN ratios and decreased KYNA-related indices, and this was associated with deficits in executive functioning. These findings indicate that alterations in TRP metabolism may play a role in altered cognitive processing among individuals with a familial predisposition to BD. Further research employing larger cohorts and dimensional analyses is needed to elucidate these relationships more precisely.
Severe depressive episodes with suicidal ideation present major therapeutic challenges and often require interventions beyond standard antidepressant therapy. Electroconvulsive therapy (ECT) remains a cornerstone treatment for refractory depression, while ketamine, an N-methyl-D-aspartate receptor antagonist, has emerged as a rapid-acting antidepressant with potential benefits in reducing suicidal ideation. This study compares the efficacy, onset of action, and tolerability of intravenous ketamine and ECT as adjunctive treatments in severe major depressive disorder with active suicidal ideation. A randomised controlled trial was conducted at a tertiary care psychiatry department in India, enrolling 64 patients aged 18-60 years with severe depression (HAM-D ≥19, SSI ≥4). Participants were randomly assigned to receive either intravenous ketamine (n = 31) or ECT (n = 33), alongside ongoing oral antidepressants. Both groups underwent six treatment sessions over 2 weeks. Outcomes were assessed at baseline, post-treatment, and 4 weeks after completion. Primary endpoints included changes in depression severity (HAM-D) and suicidal ideation (SSI), while secondary outcomes included response and remission rates, as well as safety and tolerability profiles. Both ECT and ketamine significantly reduced depressive symptoms and suicidal ideation (p < 0.001). HAM-D scores declined from 27 to 1 in the ECT group and from 26 to 2 in the ketamine group by the 4-week follow-up. SSI scores showed parallel improvement, from 12.1 to 1.2 with ECT and 12.6 to 2.0 with ketamine. Ketamine demonstrated a faster onset of clinical improvement, while ECT showed slightly greater durability of response. Side effects were mild in both groups, though ECT was associated with transient cognitive impairment, whereas ketamine produced minor dissociative and urinary symptoms. Ketamine offers a faster reduction in suicidal ideation than ECT, making it a promising acute intervention. Both are effective, safe adjunctive therapies, with treatment choice guided by patient profile and tolerability.
Hypothalamic nuclei are essential for the organisation of fear-induced defensive behaviours oriented to safe places, followed by unconditioned fear-induced antinociception, whereas midbrain tectum structures are associated with non-oriented escape responses. This study aimed to investigate the involvement of the noradrenergic system in both defensive behaviour and fear-induced antinociception. Wistar rats were pre-treated with microinjections of either physiological saline (0.2 µL) or the alpha1-noradrenergic selective antagonist WB4101 (5.0 µg/0.2 µL) into the dorsal raphe nucleus (DRN). After ten minutes, animals received a second microinjection of either physiological saline or bicuculline methiodide (40 ng/200 nL) into one of the following hypothalamic nuclei: dorsomedial (DMH), lateral (LH), or dorsal premammillary (PMd). Fear-induced behaviours were recorded in a circular open-field arena, and nociceptive thresholds were assessed using the tail-flick test for up to 60 min. Microinjections of WB4101 into the DRN resulted in a significant reduction in the frequency and duration of alertness, flat back approach, defensive immobility, and escape behaviours evoked by disinhibition of gamma-aminobutyric acid type A (GABAA) receptors in the hypothalamic nuclei. Furthermore, a significant reduction in defensive antinociception was observed from 0 to 30 min following the end of hypothalamically orchestrated escape behaviours. These findings suggest that alpha1-noradrenergic receptors in the DRN modulate both defensive behaviour and unconditioned fear-induced antinociception elicited by impaired GABAergic neurotransmission in the hypothalamus.
In patients with major depressive disorder (MDD), thyroid dysfunction is highly associated with depression severity and psychotic symptoms such as delusions and hallucinations. However, the prevalence and clinical correlates of psychotic symptomss in older MDD patients with subclinical hypothyroidism are rarely reported in China. We recruited 172 older patients with first-episode and untreated MDD (aged ≥ 50 years). The Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Positive and Negative Syndrome Scale positive subscale, and Global Impression of Severity Scale were used to assess depression, anxiety, psychotic symptoms, and disease severity, respectively. The prevalence of psychotic symptomss was 18.6±0.2% (32/172) in older MDD patients with subclinical hypothyroidism. Thyroid stimulating hormone (TSH) and HAMA scores were clinical correlates for psychotic symptomss in older MDD patients with subclinical hypothyroidism. Our findings suggest that psychotic symptoms is common in older MDD patients with subclinical hypothyroidism. Higher TSH levels may indicate more psychotic symptoms in older MDD patients with subclinical hypothyroidism. Screening of serum thyroid hormones is crucial in older MDD patients.
Throughout time, there has always been a trend connecting stress and tangible damage to one's physical well-being. However, there's a lack of research that elucidates the physical and molecular traits of this stress on organ integrity. Chronic stress disrupts homeostasis, causing oxidative stress, mitochondrial dysfunction, inflammatory markers, and histological damage. In this study, a repeated forced-swim stress was used to induce stress in the C57BL/6 mice model, and its effects on the brain and liver were analyzed at behavioral, biochemical, histological, and genetic marker levels. Behavioral analysis showed reduced mobility duration in experimental mice. This was further supplemented by histopathological data, which revealed mild brain deterioration and moderate liver damage. Biochemical analysis revealed upregulated levels of aminotransferase and alkaline phosphatase (ALP) and decreased levels of mean corpuscular hemoglobin, pointing toward the existence of liver dysfunctionality due to stress. Moreover, we reported the gene expression analysis of stress biomarkers (Bdnf, Fkbp5, Npy, Comt, Ppm1f, Adra2b, and Slc6a4), with a particular focus on Fkbp5, which is associated with depression and cognitive impairment. Similarly, we also studied the expressions of Crp, Cyp2e1, and Irs-2 to gauge liver damage. Results revealed significantly upregulated expression of Npy, Fkbp5, and Ppm1f in stressed mice. Our study identifies that chronic stress shows physical and molecular realizations. Additionally, this offers further incentive to look closely at Fkbp5, Npy, and Ppm1f under similar conditions and highlights their possible roles as markers of stress-induced damage.
Depression and pain share overlapping central neurobiological pathways that represent key pharmacological targets in neuropsychiatric and pain research. However, the neuropharmacological mechanisms by which unpredictable chronic stress (UCS) modulates nociception in translational vertebrate models remains poorly understood. Here, we characterized a zebrafish model of stress-induced sensitization to a visceral chemical challenge by exposing adult fish to a 7- or 14-day UCS protocol (UCS7/UCS14) followed by intraperitoneal acetic acid (AA) injection (1.0-5.0% v/v). In unstressed fish, AA at 1.0% remained subthreshold for inducing the characteristic writhing-like body curvature endpoint, whereas at 5.0% produced a robust response, hence validating the assay. In contrast, UCS exposure revealed a marked nociception-like response to AA 1.0%, reflected by increased body curvature index, indicating a lowered response threshold after chronic stress. Locomotor endpoints exhibited stress-dependent cross-over effects: AA at 1.0% decreased distance traveled in unstressed fish but increased locomotion and reduced immobility in UCS-exposed fish. Pharmacological validation (in UCS7) showed that morphine attenuated the UCS-sensitized body curvature response, whereas diclofenac did not, consistent with an opioidergic contribution to the nociception-like endpoint. Whole-body cortisol levels were elevated by UCS exposure (with or without AA 1.0%) and reduced by morphine in the UCS + AA condition, whereas diclofenac was inactive. Together, these findings establish a pharmacologically tractable adult zebrafish model of stress-induced sensitization with translational relevance for CNS-targeted analgesic discovery and mechanistic studies of stress-pain comorbidity.
Adolescent-onset major depressive disorder (MDD) is associated with high morbidity, recurrence, and suicide risk. However, few studies have prospectively examined its long-term course into emerging adulthood. Ninety-four female adolescents (aged 15-17 years) diagnosed with MDD between January and August 2012 were enrolled. After 10 years, 54 participants were reassessed. Psychiatric diagnoses were established using the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) at baseline and the Structured Clinical Interview for DSM-5 Disorders (SCID-5) at follow-up. Global functioning was rated using the Global Assessment of Functioning (GAF). At both time points, participants completed the Beck Depression Inventory (BDI), Emotional Autonomy Scale (EAS), Parent Adolescent Relationship Questionnaire (PARQ), and Identity Development Assessment Tool (IDAT). Nearly all participants (94.4%) experienced recurrent depressive episodes, and 79.6% met criteria for at least one current psychiatric disorder at the follow-up assessment. The most common current diagnoses were MDD and ADHD (each 35.2%). The mean GAF score at follow-up was 64.2 ± 8.1, indicating moderate functional impairment. Lifetime suicide attempts were reported by 32 participants (59.3%). Runaway behaviour was a significant risk factor for suicidal behaviour (OR = 5.91, 95% CI [1.27-27.54], p = 0.024), while earlier psychiatric contact (OR = 0.40, 95% CI [0.18-0.88], p = 0.027) served as a protective factor. Despite the ongoing need, one fifth of individuals (n=11) was receiving psychiatric care in emerging adulthood. Adolescent-onset Major Depressive Disorder (MDD) is highly recurrent and carries a significant long-term risk for further psychiatric issues and suicide. However, the rigid transition from child to adult services at age 18 appears to disrupt care continuity. Runaway behaviour should be considered a marker of suicide risk, whereas earlier psychiatric contact may be protective. Youth psychiatry programs are needed to bridge the child-adult service gap for adolescents with depression.
Insomnia is one of the most common symptoms of depression, estimated to occur in approximately 75% of adult patients with depression, and it may persist even after remission from depressive episodes. Our objectives were to evaluate the efficacy of mirtazapine in reducing insomnia and depression symptom severity, assess side effects, and compare quality of life (QoL) before and after intervention in major depressive disorder (MDD) patients with insomnia. This was a single-center, prospective, open-label, quasi-experimental pre-post-intervention trial of 6 weeks. The Hamilton Depression Rating Scale (HDRS), Insomnia Severity Index (ISI), Antidepressant Side-Effect Checklist (ASEC), and World Health Organization Quality of Life (WHOQOL-BREF) tools were used during the assessment. Out of the 135 recruited patients, 109 (80.7%) completed the trial. On day 14, with a mean dose of 18.9 mg/day, 24.8% of patients experienced remission for insomnia, while 7.3% showed remission for depression. By day 42, with a mean dose of 18.7 mg/day, these figures increased to 62.4% for insomnia and 41.3% for depression. The reduction in the ISI score (mean ± SD) from baseline to day 14 and day 42 was 8.74 ± 6.16 and 13.55 ± 5.32, respectively. Similarly, the reduction in the HDRS score from baseline on day 14 and 42 was 10.30 ± 6.89 and 17.78 ± 6.26, respectively. The most commonly reported adverse effects (>10%) included increased appetite, drowsiness, weight gain, dry mouth, headache, and constipation. Regarding QoL, the differences were significant for all four domains with the highest improvement observed in the physical (mean difference 25.67 ± 13.95) and psychological domains (mean difference 26.35 ± 16.42) of QoL. Mirtazapine treatment was associated with significant improvements in depression, insomnia, and all QoL parameters, with increased appetite and weight gain being the most common adverse effects. Further randomized controlled comparator studies will be beneficial for healthcare providers to improve the clinical care of MDD patients with insomnia.
Nutrition is an important determinant of health among people with mental disorders; however, barriers to dietary counselling exist. The Eating and Supplementation for Generalized Anxiety Disorder study ("EASe-GAD") was the first trial to assess the impact of these interventions on anxiety symptoms. The primary objective of the present companion qualitative study was to gather and analyze qualitative data about the acceptability, participant experience, impact, barriers and facilitators, strengths, and weaknesses of the EASe-GAD program while also identifying opportunities for improvement. Participants were eligible for this study if they participated in the EASe-GAD trial. Data were collected using focus groups which followed a semi-structured interview approach with a set of predetermined questions. The sessions were recorded and transcribed for data analysis. Data were analyzed by thematic analysis. Three focus groups were completed, involving a total of 12 women. They reported a range of components that they found helpful, such as increased self-efficacy, as well as positive outcomes that they attributed to the intervention, such as improved mental and physical health. They reported components of the program that were less enjoyable, such as having their body weight measured, and also suggested opportunities for improvement. Many participants reported that cost implications of a diet intervention were an important consideration. This project provided valuable insight into the participant experience and impact of the pilot dietary counselling program. Participants reported benefits and opportunities for improvement for subsequent studies aimed at improving nutrition among people with anxiety disorders.
Fear, an adaptive response to danger situation, is vital for the survival of both human beings and rodents. Predator odor-related cues and contextual fear work as valuable models for studying neurobiological circuits, providing insights into unconditioned and conditioned fear-related behavioral and physiological responses, including fear-related antinociception. This study investigated whether a fear paradigm based on predator odor cues could trigger the defensive antinociceptive phenomenon. Our findings indicate that while both the exposure to different predator odor cues and the re-exposure to the experimental context elicit similar defensive behaviors, such as the head-out response (an inhibitory avoidance behavior), only the exposure to the predator odor cues induced defensive antinociception. Notably, during the re-exposure to the experimental context, the endogenous pain modulatory system is not recruited, suggesting that defensive antinociception is not universally elicited by all fear-related reactions. Instead, defensive antinociception appears to be modulated by distinct neural circuits and olfactory perception-dependent mechanisms that adjust dynamically according to threat imminence. Thus, antinociception emerges as part of the immediate defensive response to a threatening odor cue, rather than as a consequence of fear memory retrieval. (PsycInfo Database Record (c) 2026 APA, all rights reserved).
Cognitive impairment is a core feature of bipolar disorder (BD) that impacts functioning and quality of life. This review systematically summarizes the evidence on pharmacological and nutraceutical interventions for cognitive deficits in BD. A systematic search of MEDLINE, Embase, and PsycInfo was conducted to identify studies examining the efficacy of pharmacological or nutraceutical interventions on cognition in individuals aged 18-65 years with euthymic or partially remitted BD from inception to December 29, 2024. This review was registered with PROSPERO (Reference No. CRD42024618397). Risk of bias assessment was conducted using the National Institutes of Health (NIH) quality assessment tools. The extracted data were summarized using a narrative synthesis approach. Sixteen studies were included, evaluating 13 different agents. Working memory, verbal learning and memory, executive functioning, social cognition, and attention/vigilance were improved by multiple agents. Galantamine showed replicated pro-cognitive effects on verbal learning and memory. Lithium, tianeptine, Withania somnifera (ashwagandha), insulin, and lurasidone each demonstrated cognitive benefits in single studies. Erythropoietin and pramipexole showed mixed results across two studies. Methylene blue, JNJ-18038683, docosahexaenoic acid, modafinil, and quetiapine revealed no significant effects. The quality of the studies ranged from good to poor, and the safety and tolerability profiles of the agents were favorable. These results suggest possible approaches for improving cognitive functioning in individuals with BD. Nevertheless, the inconsistency in outcomes and differences in study methodologies highlight the need for larger, rigorously controlled trials with uniform cognitive evaluations to confirm these findings and to assess their clinical relevance.
In recent years, growing attention has been given to the role of sleep disturbances in mental health outcomes, assuming a potential link between sleep problems and suicidality. This study applies a network analysis to examine how sleep quality is interconnected with suicidal thoughts and behaviors, as well as with a range of psychopathological symptoms. A total sample of 1,674 participants (75.3% female, 24.7% male) from the general population were investigated and completed standardized assessments of sleep quality and psychopathological symptoms. A regularized cross-sectional partial correlation network between sleep quality (Pittsburgh Sleep Quality Index [PSQI]), suicidality (Scale for Suicidal Experience and Behavior [SSEV]), and psychopathological symptoms (Brief Symptom Inventory [BSI-18]) was estimated using the EBICglasso algorithm. Node centrality, predictability, and bridge centrality were evaluated, and bootstrap methods were employed to test the stability and significance of the network structure. The network was found to be stable, supporting reliable interpretations. Active suicide thoughts, anxiety, and subjective sleep quality were found to be the most influential nodes within the investigated psychopathological network. Depression and daytime impairment due to poor sleep quality were observed as nodes with the highest bridge centrality. These findings highlight that depression and, importantly, daytime functioning related to poor sleep quality play a central role in linking suicidality and sleep quality. This emphasizes the need to address not only nighttime sleep problems but also daytime impairments as key clinical targets. Prioritizing interventions that improve sleep and restore daytime functioning may therefore be crucial in suicide prevention and clinical care.
Accurate and scalable behavioral annotation remains a challenge in behavioral neuroscience. Manual scoring is time-consuming, variable across annotators, and may overlook transient behaviors critical for phenotyping. By learning from annotated datasets, supervised machine learning (ML) enables automated classification of behavior with high consistency and reduced bias. We benchmarked five supervised ML algorithms, Random Forest, XGBoost, Support Vector Machine, k-Nearest Neighbors, and Multilayer Perceptron (MLP), and compared data against expert human annotations of seizure-like behaviors in adult zebrafish. Twelve trained raters annotated over 43,000 video frames, enabling direct comparison of model performance with human annotation. After frame-level analysis, we also applied behavior-informed filters and then evaluated block-level temporal aggregation. Annotation variability was driven by behavioral complexity, with ambiguous behaviors showing the lowest agreement. Random Forest, XGBoost, and MLP achieved the highest accuracy and post-processing based on posture and velocity improved classification by filtering false positives. Block-level aggregation enhanced accuracy through temporal smoothing but masked short-lived behaviors critical for detecting subtle phenotypes. Most zebrafish seizure studies rely on manual scoring or single-model ML applications. Direct comparisons between multiple ML algorithms and human annotations are rare. Our study uniquely integrates large-scale manual scoring with model benchmarking and temporal resolution strategies, offering insight into reproducibility and scalability in behavioral phenotyping. This study advances automated behavioral analysis in zebrafish by demonstrating the strengths and limitations of machine learning compared to human annotation, and emphasizes how choices in temporal resolution and behavioral classification influence reproducibility and interpretability.
The dorsal hippocampus (DH) encodes contextual memories essential for adaptive responses to environmental threats. The lateral hypothalamus (LH), a primary source of orexinergic neurons in the brain, is also involved in the modulation of defensive behaviors. Although recent research links the orexinergic system to emotional processes, its role in the DH during the organization and expression of learned fear responses remains poorly understood. This study investigates the role of orexin receptor subtypes in DH during contextual fear conditioning. Anatomical tracing techniques revealed a direct projection from the lateral hypothalamus to the DH, providing evidence for a previously unexplored pathway in fear processing. Pharmacological blockade of orexin receptor type 1 (Orx1R) in the DH impaired the acquisition of contextual fear memories, while blockade of orexin receptor type 2 (Orx2R) enhanced memory formation, suggesting opposing roles for these receptors in early memory processing stages. Notably, blocking either receptor before testing did not affect the expression of pre-established fear memories, suggesting that hippocampal orexin receptors are primarily involved in memory formation rather than the expression of learned fear. These findings provide insights into the contribution of the orexinergic system to emotional learning, particularly in hippocampus-dependent fear memories. These findings advance our understanding of the orexin system, specifically the Orx1R and Orx2R functional roles, with implications for developing therapeutic strategies targeting orexin receptors in the treatment of psychiatric disorders like anxiety and post-traumatic stress disorder, which are characterized by disrupted fear processing.
Affective disorders, such as depression and anxiety, pose major challenges to mental health worldwide. Serotonergic dysfunction has been widely implicated in their pathophysiology, although its contribution involves complex and context-dependent mechanisms. To explore the relationship between serotonin depletion and neurobehavioral responses in zebrafish (Danio rerio), animals were treated with para-chlorophenylalanine (pCPA), an inhibitor of tryptophan hydroxylase activity. Fish received two intraperitoneal injections of pCPA (300 mg/kg), with a 24-h interval between injections. Behavioral tests occurred 24 h after the second injection and included the novel tank diving test, tail immobilization, social preference, and shallow water tests. In the novel tank and social preference tests, pCPA-treated fish showed increased geotaxis, with reduced vertical exploration and altered locomotor patterns when facing their conspecifics, suggestive of increased anxiety. Moreover, pCPA exposure increased immobility in both despair-related paradigms, indicative of passive coping in aversive contexts. We also confirmed that pCPA significantly reduced serotonin levels in the brain, showing the effectiveness of the depletion protocol. Overall, these findings expand the behavioral characterization of pCPA-treated adult zebrafish, demonstrating that serotonin depletion modulates multiple behavioral domains. Within a comparative framework, this model provides a platform to investigate multidimensional affective-like phenotypes associated with serotonergic disruption.
Introduction Circadian rhythms are reflected through sleep-wake patterns and chronotype. Patients with bipolar disorder (BD) frequently exhibit disrupted sleep patterns, and a tendency for evening chronotype. Also, genetic risk factors for BD partially overlap with those influencing sleep traits. Lithium (Li), the first-line therapy for BD, stabilizes circadian rhythms and promotes morningness in responders. This study aimed to evaluate whether the polygenic burden of sleep-related traits is associated with Li response in BD patients. Methods A total of 114 European-ancestry BD patients were categorized as Li responders (N=79) or non-responders (N=35), based on the reduction of 50% of the episodes. Polygenic scores (PGS) for chronotype, daytime dozing, ease of getting up, insomnia, morningness, napping, sleep duration, and snoring were calculated using PRS-CS. Associations between each PGS and Li response were tested using logistic regression models. Comparisons were made between the extreme quartiles of each PGS. Results The polygenic score for ease of getting up was significantly associated with Li response, explaining 9.989% of the variance based on Nagelkerke's pseudo-R² (FDR-adjusted p-value= 0.046). Additionally, individuals with a higher genetic predisposition for ease of getting up had increased odds of a good response (FDR-adjusted p-value= 0.039; OR= 5.143; 95% CI= 1.537-17.209). Conclusion The study suggests that a higher genetic predisposition for ease of getting up in the morning may increase the likelihood of responding to Li treatment in BD patients. Our study aligns with previous evidence, highlighting the importance of sleep and chronotype patterns in response to Li in BD patients.
Current predictors of electroconvulsive therapy (ECT) effects rely on static measures. The prognostic value of anxiety evolution during ECT remains unestablished, which impedes personalized treatment. This study aims to investigate the dynamic evolution of anxiety during ECT and its predictive role in treatment effects. We collected 1,053 data points from 117 patients with depression who were undergoing ECT, measuring both the Hamilton Anxiety Rating Scale (HAMA) and the 17-item Hamilton Depression Rating Scale (HAMD-17) at baseline and at each of the first eight ECT sessions. K-means longitudinal clustering identified anxiety evolution patterns, while linear mixed-effects modeling (LMM) and survival analysis were used to assess associations with treatment outcomes. Three distinct anxiety trajectory phenotypes were identified: rapid anxiety remitters (cluster A: 47%), gradual anxiety improvers (cluster B: 41%), and anxiety non-remitters (cluster C: 12%). LMM analysis demonstrated significantly greater HAMD-17 reduction slopes in cluster A (β = -1.32, p = 0.003) and cluster B (β = -1.15, p = 0.007) compared to cluster C. Kaplan-Meier analysis revealed a hierarchical response advantage (cluster A > B > C; log-rank χ2 = 32.15, p < 0.001). Multivariable Cox regression confirmed the superior predictive value of trajectories over baseline HAMA: rapid anxiety remitters showed a 19.77-fold higher response likelihood than anxiety non-remitters (95% CI 8.21-47.63), compared to only a 4% increased probability per HAMA point (hazard ratios = 1.04). Dynamic anxiety trajectories are effective biomarkers for ECT response, offering enhanced predictive value over baseline HAMA scores and enabling personalized treatment strategies for depression.