Episodes Of Bipolar Disorder Research Articles

Cariprazine in Bipolar Disorder and Substance Use: A Dual Approach to Treatment?

Bipolar disorder (BD) is characterized by recurrent episodes of mania, hypomania, and depression and is often complicated by comorbid substance use disorders (SUDs). Up to 60% of individuals with BD experience SUDs, which exacerbate mood instability and increase the risk of rapid cycling, suicide, and poor clinical outcomes. Current treatment strategies, including lithium and valproate, show limited efficacy in treating both BD and SUD. Psychotherapeutic approaches such as cognitive behavioral therapy (CBT) offer benefits but lack a specific focus on substances such as cannabis and cocaine. Since there is still debate on how to treat this comorbidity, there is a need to find new therapeutic options; this mini-review examines the pharmacological properties of cariprazine and its emerging role in the treatment of comorbid BD and SUD. Cariprazine, an atypical antipsychotic with partial agonism at dopamine D2 and D3 receptors, has shown promise in treating both mood symptoms and cognitive dysfunction in BD. Its unique affinity for D3 receptors, which are involved in motivation and reward processing, may offer advantages in reducing drug craving. Clinical trials indicate that cariprazine effectively treats manic, depressive, and mixed episodes in BD with a favorable side effect profile, particularly at lower doses. Preliminary results suggest its potential to reduce craving and substance use in individuals with co-occurring BD and SUD. Therefore, cariprazine, with its unique pharmacodynamic mechanism, could be further studied for the treatment of BD in comorbidity with SUD. However, evidence on the role of cariprazine in the treatment of SUDs remains limited, based primarily on case reports and animal studies. Further research, including large-scale clinical trials, is needed to determine its full efficacy in this dual diagnosis.

A Bayesian analysis of heart rate variability changes over acute episodes of bipolar disorder

Bipolar disorder (BD) involves autonomic nervous system dysfunction, detectable through heart rate variability (HRV). HRV is a promising biomarker, but its dynamics during acute mania or depression episodes are poorly understood. Using a Bayesian approach, we developed a probabilistic model of HRV changes in BD, measured by the natural logarithm of the Root Mean Square of Successive RR interval Differences (lnRMSSD). Patients were assessed three to four times from episode onset to euthymia. Unlike previous studies, which used only two assessments, our model allowed for more accurate tracking of changes. Results showed strong evidence for a positive lnRMSSD change during symptom resolution (95.175% probability of positive direction), though the sample size limited the precision of this effect (95% Highest Density Interval [−0.0366, 0.4706], with a Region of Practical Equivalence: [-0.05; 0.05]). Episode polarity did not significantly influence lnRMSSD changes.

Aripiprazole/Sertraline Combination: Clinical and Cost-Effectiveness in Comparison With Quetiapine for the Treatment of Bipolar Depression (ASCEnD Trial)-Protocol for a Nested Qualitative Study.

Bipolar disorder is a recurrent mental health disorder with a prevalence rate of 1.4%. On average, there can be a delay of 9.5 years from the initial presentation of symptoms to a confirmed diagnosis. Individuals living with bipolar disorder have a reduced life expectancy. There is limited evidence regarding the effectiveness of antidepressants in treating bipolar disorder. The ASCEnD clinical trial will test the clinical and cost-effectiveness of the aripiprazole/sertraline combination in comparison with quetiapine for the treatment of bipolar depression (individuals who suffer from depressive episodes in bipolar disorder) and will include a nested qualitative study. The qualitative study will use semi-structured interviews to explore pilot trial participants' and clinicians' perspectives on recruitment procedures, the acceptability of the intervention, the management of bipolar disorder and attitudes to medication combinations. Findings will inform recruitment strategies and optimise training for the participating sites in the ASCEnD full trial. They will also help to illuminate the lived experience of people with bipolar disorder and the clinicians who work with people with bipolar disorder. The discussion will explore perspectives on the delay in diagnosis, having a diagnosis, the impact of living with bipolar disorder and attitudes to treatment, including drug combinations. A Lived Experience Advisory Panel (LEAP) has been convened with the support of the McPin Foundation, which will contribute to the ASCEnD trial and its nested qualitative study to provide input on the design and delivery of the trial and qualitative study, analysis of qualitative data and dissemination of findings.

The experience of mood change over time for people diagnosed with bipolar disorder: a longitudinal interpretative phenomenological analysis

ABSTRACT Living with episodes of mania and depression is recognised to instil profound instability in people diagnosed with bipolar disorder, but little is known about how these mood changes arise through a person’s trajectory over time. This longitudinal study aimed to investigate the experience of mood change within and between bipolar disorder episodes. Semi-structured interviews were conducted with three women at two time points and were analysed using longitudinal interpretative phenomenological analysis to form idiographic trajectories. Three longitudinal themes illustrated the changing experiences of participants during periods of depression, euthymia (stability) and mania: (i) Extreme changes in activity and agency, (ii) Changes in feelings and connectivity, (iii) Shifting sense of the future disrupts momentum. The findings highlighted trajectories of change in key areas of the participants’ lives including activity levels, routine and agency, intensity of feelings and connectivity, and their sense of the future and progression. Changes experienced during episodes were cumulative, impacting participants’ ability to reconnect, take control and move forward during euthymia. The clinical value of mapping a client’s sense of change across BD phases is indicated, along with the need to build agency, progression and connectivity during euthymic periods. Suggestions for research and practice are discussed.

Adjunctive use of mindfulness-based mobile application in depression: randomized controlled study.

Mindfulness-based interventions (MBI) are effective in relapse prevention in Major Depressive Disorder (MDD). Internet-based interventions have been demonstrated to be effective in the treatment of MDD. Consequently, the integration of MBI through mobile applications emerges as a promising supplementary intervention for MDD, contributing to the augmentation of mental health services, particularly within ambulatory care contexts. The current randomized controlled study is designed to evaluate the efficacy of adjunctive MBI delivered via a mobile app in mitigating symptom severity and stress levels. This assessment involves a comparison with standard treatment practices in an ambulatory setting among individuals diagnosed with MDD. A total of 83 patients diagnosed with MDD (depressive episode, recurrent depression or depressive phase of bipolar disorder) were randomly allocated to the intervention (41 patients) or control condition (42 patients). The intervention consisted of the daily use of the mindfulness mobile application "Headspace" for thirty days. The control condition was treatment as usual (TAU) only. The symptom severity has been assessed by the Beck Depression Inventory (BDI-II) as well as the Hamilton Depression Rating Scale (HDRS-17). Blood pressure and resting heart rate have been assessed as secondary outcome. Upon hospital discharge, the mean scores on the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS) signaled partial remission of MDD in both treatment arms. In both groups, a subsequent decrease in both self-reported and expert-rated scores was evident after a 30-day period. However, the decrease in depression severity as measured by HDRS was significantly higher in the MBI group compared to the control group after 30days. For secondary outcomes, systolic blood pressure was lower in the intervention group compared to control group. The total drop-out rate was 29%. Short term mindfulness intervention via mobile application (30days) can be beneficial as adjunctive therapy to treatment as usual in patients with MDD.

Changes in the medial prefrontal cortex metabolites after 6 months of medication therapy for patients with bipolar disorder: A 1H-MRS study.

The study aimed to assess brain metabolite differences in the medial prefrontal cortex (mPFC) between acute and euthymic episodes of bipolar disorder (BD) with both mania and depression over a 6-month medication treatment period. We utilized 1H-MRS technology to assess the metabolite levels in 53 individuals with BD (32 in depressive phase, 21 in manic phase) and 34 healthy controls (HCs) at baseline. After 6 months of medication treatment, 40 subjects underwent a follow-up scan in euthymic state. Metabolite levels, including N-acetyl aspartate (NAA), glutamate (Glu), and Glutamine (Gln), were measured in the mPFC. Patients experiencing depressive and manic episodes exhibited a notable reduction in NAA/Cr + PCr ratios at baseline compared to healthy controls (p = 0.004; p = 0.006) in baseline, compared with HCs. Over the 6-month follow-up period, the manic group displayed a significant decrease in Gln/Cr + PCr compared to the initial acute phase (p = 0.03). No significant alterations were found in depressed group between baseline and follow-up. This study suggests that NAA/Cr + PCr ratios and Gln/Cr + PCr ratios in the mPFC may be associated with manic and depressive episodes, implicating that Gln and NAA might be useful biomarkers for distinguishing mood phases in BD and elucidating its mechanisms.

Machine Learning-Driven Comparative Analysis of Quetiapine and Olanzapine for Managing Depressive Episodes in Bipolar Disorder

Background Bipolar disorder (BD) necessitates effective management of both manic and depressive episodes. Quetiapine and olanzapine are antipsychotic medications commonly used in the treatment of BD, but their relative efficacy as antidepressants is a topic of ongoing research. Objective This case series aims to evaluate the greater efficacy of quetiapine compared to olanzapine as an antidepressant in the treatment of bipolar disorder. Methods Two patients with bipolar disorder were treated with either quetiapine or olanzapine. Clinical assessments were conducted using the Mood Disorder Questionnaire (MDQ), Clinical Global Impression-Severity (CGI-S), Hamilton Depression Rating Scale (HDRS), and Global Assessment of Functioning (GAF) before and after the treatment. Results Quetiapine showed greater efficacy in reducing depressive symptoms and improving overall functioning compared to olanzapine. MDQ scores decreased, CGI-S scores improved, HDRS scores reduced, and GAF scores increased more significantly in the patient treated with quetiapine. Conclusion Quetiapine appears to be a more effective antidepressant than olanzapine in the treatment of bipolar disorder. These findings suggest that quetiapine could be considered a preferred option for managing depressive episodes in BD patients.

Prevalence and Risk by Age and Sex of Sleep Dysregulation and Depressive Episodes in Bipolar and Depressive Disorders in a Community Survey in Sardinia, Italy.

Background/Objectives: Sleep disturbances often accompany mood disorders and persistent insomnia after mood symptoms have resolved may be a marker of poor outcome. The association between sleep symptoms and mood disorders seems to change with age and sex. This study aims to assess the frequency of depressive episodes and sleep disorders in the general population through an agile screening questionnaire and to evaluate the association of depressive episodes and sleep symptoms by sex and age categories. Methods: 774 women and 728 men from Sardinia aged > 16 years old were enrolled. The Patient Health Questionnaire (PHQ-9) was administered through a computer-assisted telephonic interview. Results: The frequency of depressive episodes was double in women (10.6% vs. 4.4%; p < 0.0001), with the highest values in women > 75 yo (17.4%). The frequency of sleep dysregulation was double in women (18.7% vs. 9.6%; p < 0.0001), with the highest values in women > 75 yo (35.9%) and the lowest in the group of men > 75 yo. The group of young males showed the lowest frequency of depressive episodes (1.4%) and a frequency of sleep dysregulation (9.1%) similar to that of the other groups of age and sex. Sleep dysregulation without depressive episodes presented a higher distribution in the elderly, both in males (20.7%) and in females (18.5%). No significative differences were found across sex and age groups in the distribution of depressive episodes without sleep dysregulation. Conclusions: The use of an agile screener such as PHQ9 in the general population and/or in populations at risk can be a valuable tool in finding those individuals in whom sleep dysregulation may represent an early warning signal, one that may be thoroughly evaluated to identify and treat possible sleep disorders early.

The mediating effects of school bullying victimization in the relationship between childhood trauma and NSSI among adolescents with mood disorders

BackgroundNonsuicidal self-injury (NSSI) is a serious problem in the adolescent population worldwide. Childhood trauma and bullying have been identified as risk factors for NSSI. We explored the relationships among Childhood trauma, Bullying victimization and the severity of NSSI behaviours, and test the effect of Bullying victimization in mediating the association between Childhood trauma and the NSSI behaviours.MethodsA total of 123 adolescents were recruited. They were diagnosed with depression or depressive episodes of bipolar disorder and had experienced NSSI in the last year. They were assessed using the Chinese version of the Childhood Trauma Questionnaire (CTQ-C), the Revised Olweus Bullying Victimization Questionnaire (OBVQ-R), and the Adolescent Self-Harm Questionnaire (ASHQ).ResultsFemales presented a significantly greater prevalence of sexual abuse and relationship bullying than boys. Individuals in the younger age group (10–14 years) presented a greater incidence of emotional neglect, verbal bullying, relationship bullying, and total bullying, and their NSSI score was also higher than that of those in the older age group (15–19 years). Only children show a greater prevalence of sexual abuse than nononly children. Single-parent families scored higher on emotional abuse, emotional neglect, physical neglect and physical bullying than two-parent families. There was a significant positive correlation between each dimension of childhood trauma and all the dimensions of bullying, between childhood trauma and NSSI, and between bullying and NSSI. Childhood trauma can not only directly affect the severity of NSSI but also indirectly aggravate the severity of NSSI through bullying victimization. The mediating effects of bullying victimization on emotional abuse, physical abuse, emotional neglect and physical neglect were 14%, 21%, 20%, 13% and 20%, respectively.ConclusionThere was a significant positive correlation between childhood trauma and bullying, between childhood trauma and NSSI, and between bullying and NSSI. Childhood trauma can not only directly affect the severity of NSSI but also indirectly aggravate the severity of NSSI through bullying victimization. Bullying victimization played the partial mediating effects between Childhood trauma and NSSI.

Pharmacological Treatment of Binge Eating Disorder and Frequent Comorbid Diseases.

Binge eating disorder (BED) is the most common specific eating disorder (ED). It is frequently associated with attention deficit hyperactivity disorder (ADHD), depression, bipolar disorder (BD), anxiety disorders, alcohol and nicotine use disorder, and obesity. The aim of this narrative review was to summarize the evidence for the pharmacological treatment of BED and its comorbid disorders. We recommend the ADHD medication lisdexamfetamine (LDX) and the antiepileptic and antimigraine drug topiramate for the pharmacological treatment of BED. However, only LDX is approved for the treatment of BED in some countries. Medications to treat diseases frequently comorbid with BED include atomoxetine and LDX for ADHD; citalopram, fluoxetine, sertraline, duloxetine, and venlafaxine for anxiety disorders and depression; aripiprazole for manic episodes of BD; lamotrigine, lirasidone and lumateperone for depressive episodes of BD; naltrexone for alcohol use disorder; bupropion for nicotine use disorder; and liraglutide, semaglutide, and the combination of bupropion and naltrexone for obesity. As obesity is a frequent health consequence of BED, weight gain-inducing medications, such as the atypical antipsychotics olanzapine or clozapine, the novel antidepressant mirtazapine and tricyclic antidepressants, and the mood stabilizer valproate should be avoided where possible. It is currently unclear whether the novel and promising glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptor agonists like tirzepatide and retatrutide help with BED and its comorbidities. However, these compounds have been reported to reduce binge eating in individuals with obesity or overweight.

Recent Advances in representative small-molecule DRD2 inhibitors: Synthetic Routes and clinical applications

The dopamine D2 receptor (DRD2) represents a pivotal target for therapeutic intervention in the treatment of neuropsychiatric disorders, including schizophrenia, bipolar disorder, and Parkinson's disease. The successful discovery of numerous effective DRD2 inhibitors has led to their clinical application and ongoing evaluation in various clinical trials. This review explores the synthetic approaches and clinical applications of prototypical small-molecule DRD2 inhibitors that have received approval or are currently undergoing clinical trials, highlighting their therapeutic potential and challenges. The synthesis of these inhibitors employs various chemical strategies, including modifications of phenothiazine and butyrophenone structures, which have yielded significant antipsychotic agents like chlorpromazine and haloperidol. Additionally, newer classes of inhibitors, such as aripiprazole, exhibit partial agonist activity at DRD2, offering a unique therapeutic profile. Clinically, DRD2 inhibitors demonstrate efficacy in managing positive symptoms of schizophrenia, manic episodes in bipolar disorder, and dopaminergic imbalance in Parkinson's disease. However, the emergence of adverse effects, including tardive dyskinesia, extrapyramidal symptoms and metabolic syndrome, presents substantial challenges. Advances in the development of second-generation antipsychotics aim to balance efficacy with a better side effect profile by targeting additional neurotransmitter receptors. This review aims to deliver an overview of the synthesis and clinical applications of representative small-molecule DRD2 inhibitors across various clinical phases, thereby offering strategic insights for the advancement of DRD2 inhibitor development.

The Transition Between Depressive Episode and Manic Episode During the Treatment of Bipolar Disorder

Bipolar disorder (BD) is characterized by periodic alternations between depressive and manic episodes. It belongs to a complex group of severe and persistent conditions. This category includes bipolar I disorder (BDI) and bipolar II disorder (BDII). The definition of BDI hinges primarily on the manifestation of a syndromal manic episode. Conversely, BDII is characterized by the occurrence of both a syndromal hypomanic episode and a major depressive episode, which jointly constitute its defining features. BDI is the most common type in clinics. The duration of episodes and the time spent in the manic phases and depressive periods of bipolar disorder are not clearly defined for subtypes of the disorder. This paper analyzes the duration of manic episodes and depressive episodes in bipolar disorder, and explores the switch from major depression to bipolar depression. By analyzing and comparing the data and results in essays, it is still hard to tell the exact duration and the occurrence of the episodes. But the effects of drugs can be summarized during the treatment of bipolar disorders. At the same time, it discovers that during treatment of major depression, bipolar disorder occurs. In conclusion, the duration is different for different people, and it depends on many subjective influences. During treatment of major depression, the transition from major depression to bipolar depression will happen indeed, but the probability is very small. This research may provide a new concern that doctors and scientists should pay more attention to the treatment of such mental diseases and keep an eye on the switch.

A large-scale study on uric acid-related biomarkers in patients with bipolar disorder

Objective: Recent research has provided strong evidence supporting the use of uric acid-related ratios as potential biomarkers for disease diagnosis. Notable ratios among these include uric acid-to-albumin ratio (UAR), uric acid-to-creatinine ratio (UCR), uric acid-to-high-density lipoprotein ratio (UHR), and uric acid-to-lymphocyte ratio (ULR). The aim of the study is to analyze these biomarkers in bipolar disorder (BD) patients. Methods: 5465 BD patients were enrolled in this study and 6629 healthy subjects served as controls. We compared differences of the above ratio indicators among different BD diagnostic groups and analyzed factors leading to the onset of BD. Results: BD-M (manic episodes of BD) group had higher ULR, UHR, UCR, UAR than HC (Heathy Controls) and BD-D (depressive episodes of BD) groups, while BD-D group showed lower ULR and UCR than HC group. P-BD-M (BD-M with psychotic symptoms) group displayed higher ULR, UHR, UCR, UAR than HC group, while even higher ULR, UHR, UAR than NP-BD-M (BD-M without psychotic symptoms) group. High UAR was risk factor in BD-M. Conclusions: Our study suggests BD-M has more intense inflammatory response than BD-D. Furthermore, there is heterogeneity in the pathogenesis of psychotic symptoms between BD-M and BD-D. Additionally, High UAR was risk factor in BD-M.

Up-to-Date on clinical and preclinical studies of psilocybin therapy

Major Depressive Disorder (MDD) poses a significant global health burden, with 30-40% patients developing resistance to standard clinical antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants. In 2016, Carhart-Harris and colleagues reported that psilocybin, the hallucinogenic compound derived from magic mushrooms, exhibits rapid and enduring antidepressant effects in patients with treatment-resistant depression. Subsequent clinical studies have found the therapeutic potential of psilocybin in MDD, depressive episode in bipolar disorder, anorexia, and drug addiction. In 2018 and 2019, the U.S. Food and Drug Administration designated psilocybin as a "breakthrough medicine" for treatment-resistant depression and MDD, respectively. Notably, the side effects of psilocybin are limited to transient and mild issues, such as headache and fatigue, suggesting its safety. In 2023, we published a review on the role of serotonin 5-HT2A receptors in the antidepressant effects of serotonergic psychedelics (Nihon Yakurigaku Zasshi, Volume 158, Issue 3, Page 229-232). Here, we present our study alongside the latest clinical and preclinical research on the antidepressant effects of psilocybin and provide an overview of the potential and issues related to psilocybin therapy.

Endoxifen dual benefits, alleviating symptoms of bipolar disorder, and a potential novel anticraving agent for alcohol dependence: A case series

Abstract: Substance use may be a risk factor and precipitator in episodes of bipolar affective disorder (BPAD). BPAD increases vulnerability to substance use as a part of increased risk behavior and/or self-medication, ultimately leading to dependence. Endoxifen is an active metabolite of tamoxifen with a four-fold protein kinase C inhibitory activity. The efficacy of endoxifen is shown in reducing manic symptoms faster and has a safe adverse effect profile.[1] This case series explores the effectiveness of endoxifen in reducing both manic symptoms and alcohol cravings in patients with mania and comorbid alcohol dependence. The severity of mania was monitored using the Young Mania Rating Scale, while alcohol cravings were evaluated using the Alcohol Use Disorders Identification Test (AUDIT)[2] scores before and after the intervention. All three patients showed a significant reduction in manic symptoms following endoxifen treatment. In addition, there was a significant decrease in AUDIT scores, indicating a reduction in alcohol cravings. These findings suggest that endoxifen may have dual benefits in managing mania and may be a potential anticraving agent.

Serum Vitamin D, Mania and Depression-Related Scores: A Comparison among Mixed Bipolar, Mania, and Healthy Subjects.

Objective: Manic and mixed episodes of bipolar disorder are important episodes of this disorder. The aim of the current study was to assess serum vitamin D (SVD) levels in patients with mania and mixed bipolar disorder, compared to healthy subjects. Method : The current cross-sectional study was conducted on 75 subjects, including healthy subjects (n = 25), patients with acute-phase mania (n = 25), and patients with mixed bipolar disorder (n = 25). The SVD levels were measured in all of the enrolled subjects. The Hamilton Depression Rating Scale (HDRS), Young Mania Rating Scale (YMRS), and Clinical Global Impression- Severity (CGI-S) were used to assess disease activity in patient groups. Data analysis was performed using SPSS version 18. For statistical analysis, analysis of variance (ANOVA), independent-sample t test, Pearson correlation, and Chi-square tests were utilized. P-values < 0.05 were considered statistically significant. Results: The results showed that the mean of SVD was significantly lower in mania and mixed bipolar patients compared to healthy subjects (P < 0.05). In addition, the number of subjects with SVD ≥ 20 ng/ml was higher in the healthy group compared to the patient groups (P < 0.05). Also, SVD was negatively correlated with the CGI-S (r = -0.311; P = 0.028), YMRS (r = -0.464; P = 0.001), and HDRS (r = -0.393; P = 0.005) in the total patient subjects. Conclusion: Prevalence of low SVD was considerably high in mania and mixed bipolar patients compared to healthy subjects. Additionally, meaningful negative correlations were found between SVD and disease activity-related variables including the HDRS, YMRS, and CGI-S.

Bipolar disorder and Lewy body dementia: case report and literature review.

Depressive episodes with psychotic symptoms are prevalent among the older adults, emphasizing the need to differentiate them from dementia with Lewy bodies (DLB), in which depressive and psychotic symptoms commonly coexist. In contrast, psychotic symptoms occur more frequently in depressive episodes of bipolar disorder (BD) than in major depressive disorder (MDD). Although MDD is a significant risk factor for dementia, studies exploring the relationship between BD and dementia are lacking. This report details the case of a 74-year-old female who experienced severe psychotic depression that led to suicide attempts during a long-term course of young-onset BD. Ultimately, she was diagnosed with DLB based on her neurocognitive symptoms and results of the neuroimaging examination. She had experienced multiple relapses in the past, predominantly characterized by depressive episodes in her old age. Notably, she had never undergone lithium treatment, which is known for its potential efficacy in preventing relapse and dementia. Recent systematic reviews and meta-analyses have suggested that patients with BD have a higher risk of dementia than the general population, and that lithium usage is associated with a reduced risk. Moreover, patients with BD have been suggested to have an elevated risk of developing Parkinson's disease (PD), and the pathophysiological relationship between BD and PD may be attributed to dopamine dysregulation resulting from multiple relapses. Future research is imperative to identify strategies for preventing dementia in patients with BD and to develop interventions for the comorbidities of BD and DLB.

Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Towards a natural treatment for mania: red onion husk extract modulates neuronal resilience, redox signalling, and glial activation

BackgroundRed onion husk, a readily available agricultural waste material, contains diverse bioactive compounds with potential health benefits. This study aimed to assess the safety and therapeutic potential of red onion husk extract in managing manic-like symptoms and associated neurochemical dysfunctions.MethodsAcute and repeated oral dose studies were conducted in mice and rats to evaluate the safety profile of the extract. FT-IR analysis identified functional groups in the extract, while GC-MS analysis identified specific bioactive compounds in the flavonoid-rich fraction. A ketamine-induced manic behaviour model in Wistar rats was employed to assess the extract’s efficacy in attenuating manic-like symptoms. Behavioural and neurochemical analyses were performed to further investigate the extract’s effects.ResultsThe extract demonstrated a favourable safety profile in both acute and repeated dose studies. FT-IR analysis revealed a complex mixture of organic compounds, including hydroxyl groups, alkynes/nitriles, aromatic and non-aromatic C = C bonds, amines, and polysaccharides. GC-MS analysis identified 17 bioactive compounds, including five-methyl-2-phenylindolizine, methadone N-oxide, and 3-phenylthiane, S-oxide. Ketamine administration significantly increased oxidative stress markers, TBARS, and suppressed antioxidant enzyme activities (SOD, GPx, CAT) in both the cerebral cortex and hippocampus, alongside elevated acetylcholinesterase (AchE) activity, indicating enhanced neuronal excitability. Pre-treatment with FRF (25 mg/kg) effectively mitigated ketamine-induced oxidative stress, as evidenced by reduced TBARS levels and partially restored SOD and GPx activities. Interestingly, FRF significantly increased CAT activity (p < 0.001), potentially suggesting an additional compensatory mechanism. Notably, FRF pre-treatment also counteracted ketamine-upregulated AchE activity, offering neuroprotection against heightened neuronal excitability.ConclusionRed onion husk extract exhibits a favourable safety profile and exerts potent antioxidant and neuroprotective effects, possibly through modulating Nrf2 signalling pathways. Its ability to counteract ketamine-induced oxidative stress and neuronal hyperactivity highlights its potential as a complementary therapeutic strategy for managing manic episodes in bipolar disorder. Further research is warranted to elucidate the precise molecular mechanisms underlying FRF’s action and explore its clinical efficacy in human studies.

Acupuncture at five Zang-shu and Ge-shu for bipolar depression: study protocol for a randomized controlled pilot trial

Background: Bipolar disorder is a very common, often misdiagnosed mental disorder strongly associated with comorbidity, disability, and premature mortality. Bipolar depression (i.e., depressive episode in bipolar disorder) is poorly responsive to available treatments. Acupuncture at five Zang-shu and Ge-shu, a prescription from Dr. Leting Wang, is a popular therapy for depression in China. Its effectiveness and safety for bipolar depression is yet to be verified by clinical study. Methods/design: The study is a single-center, prospective, randomized controlled trial involving 72 patients diagnosed with bipolar depression. Participants will be randomized either to the study group or the control group in a 1:1 ratio. All participants will receive mood stabilizer therapy. In addition, the study group will receive acupuncture therapy at five Zang-shu and Ge-shu, three times per week. The control group will orally take the antidepressant bupropion. Observation and intervention will last for 8 consecutive weeks. Outcome measurements include Hamilton Depression Rating Scale-17 (HAMD-17), Hamilton Anxiety Rating Scale (HAMA), Clinical Global Impression Scale (CGI), Young Manic Rating Scale (YMRS), Treatment Emergent Symptom Scale (TESS), serum levels of anti-inflammatory cytokines (IL-4, IL-10, TGF-β), pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), brain-derived neurotrophic factor (BDNF) and C-Reactive Protein (CRP). Assessments will be conducted at baseline, 1st, 2nd, 4th and 8th week after randomization. Safety assessments will be performed throughout the study. Discussion: The results of this study are expected to verify the effectiveness and safety of acupuncture at five Zang-shu and Ge-shu for bipolar depression, and explore its therapeutic mechanisms from the point of anti- inflammation.