In silico analysis predicts mutational consequences of CITED2, NUDT4, and Ar18B in patients with bipolar disorder.

Bipolar disorder is a mood-related disorder, which can be portrayed as extreme shifts in energy, mood, and activity levels which can also be characterized by manic highs and depressive lows that can be often misdiagnosed as unipolar disorder due to primitive diagnostics techniques based on clinical assessments as well as diagnostic complexities arising due to its heterogeneous nature and overlapping symptoms with conditions like schizophrenia. leading to delays in treatment Strong evidence in support of genetic and epigenetic aspects of bipolar disorder, including mechanisms such as compromised hypothalamic-pituitary-adrenal axis, immune-inflammatory imbalances, oxidative stress, and mitochondrial dysfunction are found. Moreover, some previous research has already stated the role of genes like CITED2, NUDT4, and Arl8B in these processes. The primary goal of this study is to investigate the involvement of the genes in exploring and validating their potential as biomarkers for bipolar disorder. In silico tools like MutationTaster, PolyPhen2, SIFT, GTEx, PhenoScanner, and RegulomeDB were used to perform mutational and gene expression analyses. Results revealed potentially dangerous mutations caused in CITED2, NUDT4, and Arl8B, those which can have diverse outcomes. RegulomeDB, GTEx, and PhenoScanner reveal the involvement of these genes in various brain regions highlighting their relevance to bipolar disorder. This analysis suggests the potential utility of CITED2, NUDT4, and Arl8B as diagnostic markers hence shedding light on their roles to elaborate the molecular range of bipolar disorder. The study also contributes to providing valuable insights into the genetic and molecular basis of bipolar disorders.

A comparison of dislocation risk between dual mobility and traditional constructs used in proximal femoral replacement.

Background: Proximal femoral replacement (PFR) is a reconstruction technique after tumor resection or for revision of failed total hip arthroplasty (THA). However, despite acceptable long-term oncologic and functional outcomes, extensive soft tissue or bone loss increases the risk for prosthetic instability. Instability may depend on the construct chosen for reconstruction, with current options including bipolar, constrained, or dual mobility implants. Clinical studies comparing patient outcomes after PFR with these three different constructs are limited. Methods: This study retrospectively examined a single tertiary academic institution's experience with PFR over a fifteen-year period. The medical records of patients who underwent PFR for indications such as tumor and failed THA with bone loss were reviewed. Patients were stratified into cohorts based on use of bipolar, constrained, or dual mobility implants. Patient demographics, disease characteristics, perioperative data, and data on prosthetic dislocations were recorded. ANOVA and chi-square testing was performed for continuous and categorical variables, respectively. The threshold for statistical significance was set to p < 0.05. Results: 106 patients were identified who underwent PFR. 46 underwent PFR with bipolar prosthesis (follow-up: 20 ± 24.57 months), 42 with constrained liner (follow-up: 30.45 ± 35.32 months), and 18 with dual mobility (follow-up: 15.38 ± 15.67 months). Only BMI (p = 0.036) and smoking history (P = 0.002) differed between groups. Dislocations occurred in 4 (8.7 %) patients who underwent reconstruction with bipolar prosthesis, compared to 8 (19.0 %) with constrained liner, and 3 (16.7 %) patients with dual mobility. Mean time to dislocation was significantly longer in dual mobility patients (P = 0.009). There were no differences in instances of early dislocation between groups (P = 00.238). Conclusion: While study numbers are low, mean time to dislocation was significantly longer with dual mobility. Additional large-scale longitudinal studies are needed to fully elucidate the differences in outcomes amongst these three treatments.

Risk of subsequent Parkinson's disease among patients with bipolar disorder or major depression: A nationwide longitudinal study in Taiwan.

AIM: Bipolar disorder (BD) and major depression have been associated with an increased risk of developing Parkinson's disease (PD); however, few studies have directly compared the risk of PD development between patients with BD and major depression while considering relevant risk factors and psychotropic medications. METHODS: Using the Taiwan National Health Insurance Research Database, 21,186 patients with BD, 21,188 patients with major depression, and 42,374 controls were enrolled between 2001 and 2009, and followed until the end of 2011. Individuals who developed PD during the follow-up period were identified. Cox regression models were used to analyze the hazard ratio (HR) of developing PD, adjusting for demographic factors, comorbidities, and psychotropic medication usage. RESULTS: Both patients with BD [HR 8.63, 95% confidence interval (CI) 6.35-11.72] and those with major depression (HR 5.68, 95% CI 4.15-7.78) had an elevated risk of subsequent PD compared to the controls. Patients with BD were associated with a 51% increased risk of subsequent PD compared with patients with major depression. Long-term treatment with antiepileptic mood stabilizers was associated with increased PD risk among patients with late-onset BD and high Charlson comorbidity index scores. Lithium was not associated with an increased PD risk. CONCLUSIONS: The study highlights an elevated PD risk in patients with BD and major depression compared to the controls, with BD patients at highest risk. Further research is needed to elucidate the complex interplay between psychotropic medications and neurodegenerative processes in BD, aiming to optimize therapeutic strategies and improve patient outcomes.

Mendelian randomisation analysis to explore the association between cathepsins and bipolar disorder.

INTRODUCTION: Bipolar disorder is a psychiatric condition characterized by the coexistence of depression and mania. Diagnosis of this disorder can be challenging due to limited pathologic and experimental tools. Treatment compliance is often poor due to medication side effects. Although cathepsin is known to play a significant role in diseases such as tumors and osteoporosis, its role in psychiatric disorders is not yet fully understood. OBJECTIVE: The aim of this study was to investigate the relationship between cathepsin in the blood circulation and bipolar disorder. METHODS: The causal relationship between cathepsin and different subtypes of bipolar affective disorder was explored using bidirectional Mendelian randomization analysis and multivariate analysis. RESULTS: It was found that cathepsin H level was a protective factor for type II bipolar disorder. No potential causal relationship was found between cathepsin H and type I bipolar disorder, but cathepsin B changes with the development of type I bipolar disorder. A causal relationship was found between cathepsin H and cerebral dopamine neurotrophic factor. CONCLUSIONS: In conclusion, cathepsin H may be a diagnostic target for bipolar II disorder and may play a guiding role in clinical diagnosis. Cathepsin H may have an effect on BD through cerebral dopamine neurotrophic factor.

Mitochondria at the crossroad of dysregulated inflammatory and metabolic processes in bipolar disorders.

In last few decades, considerable evidence has emphasized the significant involvement of mitochondria, often referred to as the "powerhouse of the cell," in the pathophysiology of bipolar disorder (BD). Given crucial mitochondrial functions in cellular metabolism and inflammation, both of which are compromised in BD, this perspective review examines the central role of mitochondria in inflammation and metabolism within the context of this disorder. We first describe the significance of mitochondria in metabolism before presenting the dysregulated inflammatory and metabolic processes. Then, we present a synthetic and hypothetical model of the importance of mitochondria in those dysfunctional pathways. The article also reviews different techniques for assessing mitochondrial function and discuss diagnostic and therapeutic implications. This review aims to improve the understanding of the inflammatory and metabolic comorbidities associated with bipolar disorders along with mitochondrial alterations within this context.

Case report: IORT as an alternative treatment option for breast cancer patients with difficulty staying still.

Background: Administering radiation therapy to individuals with intellectual disabilities (ID) and psychiatric patients taking antipsychotics poses challenges, especially with whole breast irradiation (WBI) due to difficulty staying still (DSS). In such scenarios, intraoperative radiotherapy (TARGIT-IORT) provides an alternative. Although prior studies have shown its applicability in special cases where WBI may be contraindicated, there is a paucity of literature emphasizing its role in patients with ID and psychiatric conditions who have DSS. Therefore, our case series aims to highlight the applicability of administering TARGIT-IORT in such patients. Case reports: Four breast cancer patients underwent lumpectomy and TARGIT-IORT. Among them, two patients had ID, with one experiencing a decreased range of motion. The other two had psychiatric disorders, including schizophrenia and bipolar disorder, both manifesting involuntary movements and DSS. Three patients had invasive ductal carcinoma (IDC), and one had invasive lobular carcinoma (ILC). All patients undergoing TARGIT-IORT tolerated the procedure well. Notably, none of the patients exhibited evidence of disease on follow-up. Conclusion: Our study underscores the potential use of TARGIT-IORT as a viable treatment option for breast cancer patients with intellectual and psychiatric disabilities. Unlike traditional EBRT, TARGIT-IORT offers a single radiation dose, addressing challenges associated with compliance or DSS. Our findings demonstrate positive outcomes and tolerance, especially in patients where standard oncologic procedures are difficult to achieve. TARGIT-IORT could also benefit breast cancer patients with concurrent movement disorders like Parkinson's disease and other movement disorders. Nonetheless, future studies are needed to reinforce its applicability for patients with DSS.

GABAergic dysfunction in postmortem dorsolateral prefrontal cortex: implications for cognitive deficits in schizophrenia and affective disorders.

The microcircuitry within superficial layers of the dorsolateral prefrontal cortex (DLPFC), composed of excitatory pyramidal neurons and inhibitory GABAergic interneurons, has been suggested as the neural substrate of working memory performance. In schizophrenia, working memory impairments are thought to result from alterations of microcircuitry within the DLPFC. GABAergic interneurons, in particular, are crucially involved in synchronizing neural activity at gamma frequency, the power of which increases with working memory load. Alterations of GABAergic interneurons, particularly parvalbumin (PV) and somatostatin (SST) subtypes, are frequently observed in schizophrenia. Abnormalities of GABAergic neurotransmission, such as deficiencies in the 67 kDA isoform of GABA synthesis enzyme (GAD67), vesicular GABA transporter (vGAT), and GABA reuptake transporter 1 (GAT1) in presynaptic boutons, as well as postsynaptic alterations in GABA A receptor subunits further contribute to impaired inhibition. This review explores GABAergic abnormalities of the postmortem DLPFC in schizophrenia, with a focus on the roles of interneuron subtypes involved in cognition, and GABAergic neurotransmission within presynaptic boutons and postsynaptic alterations. Where available, comparisons between schizophrenia and affective disorders that share cognitive pathology such as bipolar disorder and major depressive disorder will be made. Challenges in directly measuring GABA levels are addressed, emphasizing the need for innovative techniques. Understanding GABAergic abnormalities and their implications for neural circuit dysfunction in schizophrenia is crucial for developing targeted therapies.

Depression severity and verbal comprehension in children and adolescents with a major depressive episode.

Introduction: Severe depression is a prevalent psychiatric illness in children and adolescents associated with high levels of morbidity, disability, and a high risk of suicidal behavior. Cognitive factors associated with depression severity in juveniles have been poorly reported. Methods: We investigated the relationship between depression severity and intelligence quotient (IQ)with its subscales in 65 juveniles (aged 10-17 years) with a current major depressive episode evaluated at the Mood Disorder Program of Bambino Gesù Children's Hospital in Rome. Pearson's correlation analyses were followed by a Benjamini-Hochberg correction and linear multivariable regression model. Results: Depression severity measured with the total score of the Children's Depression Rating Scale-Revised (CDRS-R) was positively associated with the Verbal Comprehension Index (VCI; Pearson's r = 0.309 [0.042-0.534]; p = 0.024). The CDRS-R subscales positively associated with VCI by Pearson's correlation were depressed feelings, suicidal ideation, excessive weeping, and reduced facial expressions. Suicidal ideation was the only factor independently and significantly associated with higher VCI in the multivariable linear regression model. Discussion: Suicidal ideation was significantly and independently associated with higher verbal comprehension, indicating that depressed juveniles with better verbal ability may be at a greater risk of showing suicidal ideation.

The major biogenic amine metabolites in mood disorders.

Mood disorders, including major depressive disorder and bipolar disorder, have a profound impact on more than 300 million people worldwide. It has been demonstrated mood disorders were closely associated with deviations in biogenic amine metabolites, which are involved in numerous critical physiological processes. The peripheral and central alteration of biogenic amine metabolites in patients may be one of the potential pathogeneses of mood disorders. This review provides a concise overview of the latest research on biogenic amine metabolites in mood disorders, such as histamine, kynurenine, and creatine. Further studies need larger sample sizes and multi-center collaboration. Investigating the changes of biogenic amine metabolites in mood disorders can provide biological foundation for diagnosis, offer guidance for more potent treatments, and aid in elucidating the biological mechanisms underlying mood disorders.

Obsessive-compulsive symptoms relating to psychosocial functioning for people with schizophrenia, schizoaffective disorder, or bipolar disorder.

To assess the psychosocial functioning concerning obsessive-compulsive symptoms (OCS) and/or obsessive-compulsive disorder (OCD) comorbidity in people with schizophrenia, schizoaffective disorder, or bipolar disorder diagnosed in a large case register database in Southeast London. Data were retrieved from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) register using Clinical Record Interactive Search (CRIS) system, a platform allowing research on full but de-identified electronic health records for secondary and tertiary mental healthcare services. Information of schizophrenia, schizoaffective disorder, bipolar disorder diagnosis and OCS/OCD status was ascertained from structural or free-text fields through natural language processing (NLP) algorithms based on artificial intelligence techniques during the observation window of January 2007 to December 2016. Associations between comorbid OCS/OCD and recorded Health of the Nation Outcome Scales (HoNOS) for problems with activities of daily living (ADLs), living conditions, occupational and recreational activities, and relationships were estimated by logistic regression with socio-demographic confounders controlled. Of 15,412 subjects diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder, 2,358 (15.3%) experienced OCS without OCD, and 2,586 (16.8%) had OCD recorded. The presence of OCS/OCD was associated with more problems with relationships (adj.OR = 1.34, 95% CI: 1.25-1.44), ADLs (adj.OR = 1.31, 95%CI: 1.22-1.41), and living conditions (adj.OR = 1.31, 95% CI: 1.22-1.41). Sensitivity analysis revealed similar outcomes. Comorbid OCS/OCD was associated with poorer psychosocial functioning in people with schizophrenia, schizoaffective disorder, or bipolar disorder. This finding highlights the importance of identification and treatment of comorbid OCS among this vulnerable patient group.

Pathophysiological Mechanisms of Psychosis-Induced Atrial Fibrillation: The Links between Mental Disorder and Arrhythmia.

Atrial fibrillation (AF) is a common phenomenon of sustained arrhythmia leading to heart failure or stroke. Patients with mental disorders (MD), particularly schizophrenia and bipolar disorder, are at a high risk of AF triggered by the dysregulation of the autonomic nervous system, atrial stretch, oxidative stress, inflammation, and electrical or structural remodeling. Moreover, pathophysiological mechanisms underlying MD may also contribute to the genesis of AF. An overactivated hypothalamic-pituitary-adrenal axis, aberrant renin-angiotensin-aldosterone system, abnormal serotonin signaling, disturbed sleep, and genetic/epigenetic factors can adversely alter atrial electrophysiology and structural substrates, leading to the development of AF. In this review, we provide an update of our collective knowledge of the pathophysiological and molecular mechanisms that link MD and AF. Targeting the pathogenic mechanisms of MD-specific AF may facilitate the development of therapeutics that mitigate AF and cardiovascular mortality in this patient population.

Hypothalamic-pituitary-adrenal axis function in the offspring of parents with bipolar disorder and the impact of the family environment: A pilot study of the Reducing Unwanted Stress in the Home (RUSH) prevention program.

BACKGROUND: The home environment of offspring of parents with bipolar disorder (OBD) has been characterized by high levels of stress and disorganization, which may impact development of the hypothalamic-pituitary-adrenal (HPA) axis and their subsequent risk for affective disorders. The present study examined the effects of a family-based preventative intervention on the OBD's HPA axis functioning and whether intervention-related changes in the home environment might have driven change in the HPA axis. METHODS: Fifty-five children (6-11 years) were recruited from families having a parent with bipolar disorder (n=26) or families having two parents with no current mental disorders (n=29). Only those families with a parent having bipolar disorder participated in the preventative intervention. Both groups completed assessments at baseline, post-prevention, 3-, and 6-months post-prevention. At each assessment, family organization, control, cohesion, conflict, and expressiveness, in addition to childhood internalizing problems, were measured, and offspring saliva samples were collected across two consecutive days. RESULTS: Hierarchical Linear Modelling found no significant differences in HPA axis functioning between groups at baseline or across time. Improvements in family organization, however, were associated with elevations in participants' cortisol awakening response (CAR; p =.004) and total daily output (p =.023), and a steepening of their diurnal slope (p =.003) across time. Similar findings were obtained for family cohesion with respect to CAR (p <.001) and, to a lesser degree, diurnal slope (p =.064). DISCUSSION: HPA axis functioning did not differ between the OBD and healthy controls at baseline or in response to the preventative intervention. However, intervention-related improvements in family organization and, to a lesser degree, cohesion, were associated with adaptive changes in HPA functioning over time.

Mood Disorder Public Stigma in Jewish Communities in the United States.

This study employed an experimental vignette design in Jewish communities in the United States (n = 243) to investigate whether public stigma toward target individuals with major depressive disorder or bipolar disorder presenting with either mania or depression was associated with their gender and symptomatology. The Mental Illness Stigma Scale (Day et al., in J Appl Soc Psychol 37(10):2191-2219, 2007) was used to measure the following dimensions of public stigma: (a) anxiety; (b) relationship disruption; (c) hygiene; (d) visibility; (e) treatability; (f) professional efficacy; and (g) recovery. The influence of characteristics of survey respondents on public stigma was also examined. In Jewish communities in the United States, mood disorder symptomatology was associated with the stigma dimensions of recovery, relationship disruption, and hygiene. Among respondents, younger and middle-aged males reported increased treatment efficacy stigma. Research implications include designing stigma reduction interventions tailored to specific diagnostic (e.g., bipolar disorder) and demographic (e.g., younger males) groups within the Jewish community.

Comparison of the Unipolar Electrocautery and the Bipolar Sealer in Reducing Blood Loss in Total Knee Arthroplasty: A Prospective, Randomized, Noninferiority Study.

Background: This was a noninferiority trial to evaluate blood loss during total knee arthroplasty (TKA) when using the unipolar electrocautery system compared to the saline coupled bipolar sealer system in primary TKA. Methods: One hundred sixty-four patients were randomly assigned by a 1:1 ratio to either the unipolar electrocautery system (N = 82) or bipolar sealer system (N = 82). Inclusion criteria included patients scheduled for primary unilateral TKA, preoperative hemoglobin ≥11 mg/dL, preoperative platelet count ≥150,000, age >18 years, and patient willing to complete all study-related procedures. The primary efficacy outcome was estimated blood loss on morning of postoperative day. Secondary efficacy outcomes were comparison between the preoperative hemoglobin and postoperative day 1 hemoglobin, and allogeneic blood transfusions. Additionally, the study collected objective and functional outcomes using the postoperative 2011 Knee Society Score. Results: The unipolar electrocautery system was not found to be less efficacious than the bipolar sealer system. Mean blood loss for the unipolar electrocautery system was 1062.0 cubic centimeters (cc) (95% confidence limit for the mean: 985.2, 1138.7), and for the bipolar sealer system was 929.4 cc (95% confidence limit for the mean: 841.9, 1016.8). The mean difference in blood loss was 132.6 cc, below the margin of inferiority set at 200 cc. Additionally, there was no difference in patient outcomes as measured by the Knee Society Score. Conclusions: The safety, efficacy, and outcomes profile of the unipolar electrocautery system compared to the bipolar sealer system were similar. Use of the bipolar sealer system significantly increases surgical cost without any added benefits.

Psychopathological and Therapeutic Trajectories of Inpatients Affected by Mixed States and Bipolar Spectrum Disorders.

In clinical practice, mental health professionals face diagnostic and therapeutic challenges daily. The diagnostic identification of mixed states allows the management of diagnostic and therapeutic trajectories appropriately. In our study, we evaluated 484 patients at a psychiatric rehabilitation center. The initial pre-admission diagnosis of the mixed state of 3.71% (at baseline) increased to 32.23%. The observation period was three years. The therapeutic efficacy of the pharmacological association of Antidepressants (Ads) or Second Generation Antipsychotics (SGAs) with a mood stabilizer (sodium valproate, lithium, lamotrigine, gabapentin, and pregabalin) was evaluated. An improvement in psychopathological symptoms was observed in different groups analyzed. The most significant differences were observed with the association SGAs + mood stabilizer [olanzapine + valproate sodium (p=0.005); risperidone + pregabalin (p=0.072)] and SSRIs + mood stabilizer [escitalopram + valproate sodium (p=0.005), vortioxetine + mood stabilizers (valproate or gabapentin). However, these are preliminary data and are under evaluation.

Depression, Mood Disorders and Bipolar Spectrum: One or Different Diseases?

The concept of mixity is the essential cognitive cornerstone for quantifying and understanding unstable mood and restlessness, which are components of all mood disorders, diseases that always present fluctuations in mood, from the depressive component to the restless one and to the hypomanic and manic one. The GT-MSRS Mixed States Rating Scale becomes an essential means for early diagnosis.

Linking hearts and minds: understanding the cardiovascular impact of bipolar disorder.

Bipolar disorder is a severe and recurring condition that has become a significant public health issue globally. Studies indicate a heightened risk and earlier onset of cardiovascular diseases among individuals with bipolar disorder, potentially increasing mortality rates. The chronic nature of bipolar disorder leads to disturbances across multiple systems, including autonomic dysfunction, over-activation of the hypothalamic-pituitary-adrenal axis and increased levels of peripheral inflammatory markers. These disruptions cause endothelial damage, the formation of plaques and blood clots, in addition to the medications used to treat bipolar disorder and genetic associations contributing to cardiovascular disease development. Understanding the complex interplay between bipolar disorder and cardiovascular events is essential for the prevention and effective management of cardiovascular conditions in individuals with bipolar disorder.

Bipolar disorder is a mental health condition that affects mood and behavior, significantly impacting the lives of many people around the world. People with this disorder are also at a higher risk for heart diseases, including heart attacks and strokes. Certain lifestyle factors, common among people with bipolar disorder, such as smoking, poor diet and lack of exercise, can cause inflammation and stress, which damage blood vessels and increase the likelihood of heart conditions. The relationship between bipolar disorder and heart disease is complex. The condition affects how the body handles stress and can disrupt normal heart functions. For instance, stress from bipolar disorder can lead to high blood pressure and irregular heartbeats and certain medications taken by those with bipolar disorder can further damage the heart. To better manage these risks, it's important to understand the connection between bipolar disorder and heart disease. Future research should focus on creating guidelines for regular heart health check-ups for people with bipolar disorder and improving overall care to help prevent unfavorable outcomes.

Characterization of Bipolar Disorder I and II: Clinical Features, Comorbidities, and Pharmacological Pattern.

Objective: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition provides precise diagnostic criteria to differentiate between bipolar disorder (BD) type I and II; nevertheless, it can be challenging to come up with the right diagnosis. The aim of this study is to evaluate the sociodemographic differences, clinical features, comorbidities, and pharmacological pattern between patients with BD type I and II. Methods: A total of 680 patients with BD type I and II were consecutively recruited to our psychiatry department. A semi-structured interview was used to collect several information. Results: Patients with BD type I were mostly males, single, with a lower current age, and unemployed compared to patients with BD type II. Furthermore, patients with BD type I showed an earlier age at onset and a significant higher prevalence of psychotic and residual symptoms, a higher number of hospitalizations, and involuntary admissions. On the other hand, patients with BD type II were associated with a significant higher prevalence of lifetime suicide attempts, psychiatric comorbidities, and use of alcohol. Finally, antidepressant drugs were prescribed more often to patients with BD type II, while antipsychotics and mood stabilizers were mostly prescribed in patients with BD type I. Conclusion: the differentiation of the 2 nosologic bipolar diagnosis is in line with the current scientific interest, confirming the existence of a markedly different profile between BD type I and II. This differentiation could reduce the heterogeneity of bipolar presentation in research, optimize clinical assessment, and increase the interest in developing more precise and individualized therapeutic strategies, also implementing psychosocial therapies.

Predicting remission after acute phase pharmacotherapy in patients with bipolar I depression: A machine learning approach with cross-trial and cross-drug replication.

OBJECTIVES: Interpatient variability in bipolar I depression (BP-D) symptoms challenges the ability to predict pharmacotherapeutic outcomes. A machine learning workflow was developed to predict remission after 8 weeks of pharmacotherapy (total score of ≤8 on the Montgomery Åsberg Depression Rating Scale [MADRS]). METHODS: Supervised machine learning models were trained on data from BP-D patients treated with olanzapine (N = 168) and were externally validated on patients treated with olanzapine/fluoxetine combination (OFC; N = 131) and lamotrigine (LTG; N = 126). Top predictors were used to develop a prognosis rule informing how many symptoms should change and by how much within 4 weeks to increase the odds of achieving remission. RESULTS: An AUC of 0.76 (NIR:0.59; p = 0.17) was established to predict remission in olanzapine-treated subjects. These trained models achieved AUCs of 0.70 with OFC (NIR:0.52; p < 0.03) and 0.73 with LTG (NIR:0.52; p < 0.003), demonstrating external replication of prediction performance. Week-4 changes in four MADRS symptoms (reported sadness, reduced sleep, reduced appetite, and concentration difficulties) were top predictors of remission. Across all pharmacotherapies, three or more of these symptoms needed to improve by ≥2 points at Week-4 to have a 65% chance of achieving remission at 8 weeks (OR: 3.74, 95% CI: 2.45-5.76; p < 9.3E-11). CONCLUSION: Machine learning strategies achieved cross-trial and cross-drug replication in predicting remission after 8 weeks of pharmacotherapy for BP-D. Interpretable prognoses rules required only a limited number of depressive symptoms, providing a promising foundation for developing simple quantitative decision aids that may, in the future, serve as companions to clinical judgment at the point of care.

British contributions to the therapeutic use of John Cade's lithium.

Coinciding with the 75th anniversary of John Cade's seminal publication that first reported lithium's antimanic efficacy, we briefly recount the salient findings of the historic paper and draw attention to the important psychiatric research in Britain that reinforced its findings and the critical British opinions that likely impeded its clinical use.