A Nationwide Target Trial Emulation Assessing the Risk of Antidepressant-Induced Mania Among Patients With Bipolar Depression.

OBJECTIVE: Antidepressants are commonly used to treat bipolar depression but may increase the risk of mania. The evidence from randomized controlled trials, however, is limited by short treatment durations, providing little evidence for the long-term risk of antidepressant-induced mania. The authors performed a target trial emulation to compare the risk of mania among individuals with bipolar depression treated or not treated with antidepressants over a 1-year period. METHODS: The authors emulated a target trial using observational data from nationwide Danish health registers. The study included 979 individuals with bipolar depression recently discharged from a psychiatric ward. Of these, 358 individuals received antidepressant treatment, and 621 did not. The occurrence of mania and bipolar depression over the following year was ascertained, and the intention-to-treat effect of antidepressants was analyzed by using Cox proportional hazards regression with adjustment for baseline covariates to emulate randomized open-label treatment allocation. RESULTS: The fully adjusted analyses revealed no statistically significant associations between treatment with an antidepressant and the risk of mania in the full sample (hazard rate ratio=1.08, 95% CI=0.72-1.61), in the subsample concomitantly treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.63-2.13), and in the subsample not treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.65-2.07). Secondary analyses revealed no statistically significant association between treatment with an antidepressant and bipolar depression recurrence. CONCLUSIONS: These findings suggest that the risk of antidepressant-induced mania is negligible and call for further studies to optimize treatment strategies for individuals with bipolar depression.

Analysis of Antipsychotic Dosage in Patients With Tardive Dyskinesia: A Case-Control Study Using the Claims Database of the Corporate Health Insurance Association.

PURPOSE: This study aimed to assess the association between antipsychotic doses and the risk of tardive dyskinesia (TD) in clinical practice using a Japanese claims database from 2010 to 2020. METHODS: The study population included patients 15 years or older with a diagnosis record of schizophrenia, depression, or bipolar disorder who were prescribed antipsychotics. Using a case-control design, we categorized patients newly diagnosed with TD as cases, with corresponding 1:10 matching in the control group. The primary endpoint was the relative risk of TD in the >median dose and ≤median dose groups, as determined using conditional logistic regression analysis adjusted for age. RESULTS: The analysis population included 58,452 patients, and the median daily antipsychotic dose was 75 mg/d of chlorpromazine equivalent (CPZE). Of these, 80 were identified as TD cases, and doses >75 mg/d were associated with a significantly increased risk of TD at the last prescription and the maximum dose, respectively, before the date of the first diagnosis of TD. Post-hoc analysis further showed a significant association between doses ≥300 mg/d and the risk of TD compared to doses ≤75 mg/d and doses >75 to <300 mg/d. Comparing ≥300 mg/d versus >75 to <300 mg/d, the odd ratios at the last prescription and maximum dose before the first diagnosis of TD were 3.40 and 3.50, respectively. CONCLUSIONS: In the Japanese medical claims database of patients receiving relatively low doses of antipsychotics, doses >75 mg/d were associated with an increased risk of TD in a dose-dependent manner.

Challenges in the Treatment of Psychotic Bipolar Depression.

BACKGROUND: Psychotic bipolar depression (PBD) is a prevalent yet understudied psychiatric illness, and there are no specific guidelines or Food and Drug Administration-approved medications for its treatment. Recent studies suggest that some antipsychotics and mood stabilizers may be effective in managing bipolar depression; however, their effectiveness for PBD remains unclear. Given the urgent need for more focused research for managing PBD, we conducted a literature review to summarize the existing literature on PBD. METHODS: We conducted an electronic literature search from the 1960s to 2023, utilizing PubMed, MEDLINE, EMBASE, and Google, and selected studies based on their relevance to PBD. FINDINGS: PBD is a complex disorder, with 50%-75% of patients with bipolar disorder exhibiting psychotic features. This likelihood increases among those with a history of psychotic mania. Treatment guidelines often recommend a combination of mood stabilizers, antipsychotics, or electroconvulsive therapy, but they do not specify a first-line treatment. PBD symptoms can be masked by mixed high mood and energy feelings, potentially delaying diagnosis and treatment while increasing suicide risk. Limited research has evaluated outcomes of various treatments for PBD, and despite the lack of evidence for superior efficacy, in clinical practice, antipsychotics are frequently prescribed. Notably, combining an antipsychotic with selective noradrenaline reuptake inhibitors or tricyclic antidepressants may be effective, but including a mood stabilizer is necessary. CONCLUSION: PBD poses a significant challenge in mental health due to its severity and the lack of consensus on optimal treatment approaches. There is a critical need for more dedicated clinical trials and research to answer key questions about the effective treatment of acute PBD, ideal follow-up care, traits of responders to different therapies, and decision models for subsequent treatments.

Targeting inflammasome complexes as a novel therapeutic strategy for mood disorders.

INTRODUCTION: Inflammasome complexes, especially NLRP3, have gained great attention as a potential therapeutic target in mood disorders. NLRP3 triggers a caspase 1-dependent release of the inflammatory cytokines IL-1ß and IL-18, and seems to interact with purinergic and kynurenine pathways, all of which are implicated in mood disorders development and progression. AREAS COVERED: Emerging evidence supports NLRP3 inflammasome as a promising pharmacological target for mood disorders. We discussed the available evidence from animal models and human studies and provided a reflection on drawbacks and perspectives for this novel target. EXPERT OPINION: Several studies have supported the involvement of NLRP3 inflammasome in MDD. However, most of the evidence comes from animal models. The role of NLRP3 inflammasome in BD as well as its anti-manic properties is not very clear and requires further exploration. There is evidence of anti-manic effects of P2×R7 antagonists associated with reduction in the brain levels of IL-1ß and TNF-α in a murine model of mania. The involvement of other NLRP3 inflammasome expressing cells besides microglia, like astrocytes, and of other inflammasome complexes in mood disorders also deserves further investigation. Preclinical and clinical characterization of NLRP3 and other inflammasomes in mood disorders is needed before considering translational approaches, including clinical trials.

Catatonia Due to Lithium Neurotoxicity: A Case Report. / Lityum Nörotoksisitesine Ikincil Gelisen Katatoni Vakasi: Bir Olgu Sunumu.

Lithium may cause toxicity as it has a narrow therapeutic range. Lithium intoxication may manifest in the form of acute, acute on chronic and chronic intoxication. Neurotoxicity is a common component of chronic lithium intoxication and the symptoms include tremor, ataxia, dysarthria, extrapyramidal symptoms, hyperreflexia, seizures and status epilepticus. Although rare, catatonia could as a manifestation of lithium neurotoxicity. In this report, we present a patient with bipolar disorder presenting with catatonic symptoms secondary to lithium intoxication. We will discuss the risk factors, differential diagnosis and the treatment of catatonic symptoms. Lithium neurotoxicity may present with various clinical symptoms including catatonia, and differential diagnosis should be made well in such cases. If lithium neurotoxicity is suspected, rapid and appropriate intervention is required to prevent permanent neurological damage. Keywords: Lithium, Neurotoxicity, Catatonia.

Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity.

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.

D3 Receptor-Targeted Cariprazine: Insights from Lab to Bedside.

Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations and tests to ensure it is safe, potent, and effective. This process is a long and costly endeavor, with many pitfalls and hurdles. The aim of the present review article is to explore what is needed for a molecule to move from the researcher bench to the patients' bedside, presented from an industry perspective through the development program of cariprazine. Cariprazine is a relatively novel antipsychotic medication, approved for the treatment of schizophrenia, bipolar mania, bipolar depression, and major depression as an add-on. It is a D3-preferring D3-D2 partial agonist with the highest binding to the D3 receptors compared to all other antipsychotics. Based on the example of cariprazine, there are several key factors that are needed for a molecule to move from the researcher bench to the patients' bedside, such as targeting an unmet medical need, having a novel mechanism of action, and a smart implementation of development plans.

Pharmacogenomic Characterization of Childbearing-Aged Individuals With Mood Disorders in a Tertiary Care Perinatal Mental Health Clinic.

Objective: The effectiveness of antidepressant treatment for mood disorders is often limited by either a poor response or the emergence of adverse effects. These complications often necessitate multiple drug trials. This clinical challenge intensifies during pregnancy, when medications must be selected to improve the likelihood of response and optimize reproductive outcomes. We determined the distribution of common pharmacogenetic variants, metabolizer phenotypes, past medication responses, and side effects in childbearing-aged individuals seeking treatment in a tertiary care perinatal mental health clinic.Methods: Sixty treatment-seeking women (based on sex at birth) with DSM-5- defined bipolar disorder (n = 28) or major depressive disorder (n = 32) provided DNA samples and completed psychiatric diagnostic and severity assessments between April 2014 and December 2017. Samples were genotyped for single-nucleotide variants in drug metabolizing enzyme genes of commonly prescribed antidepressants (cytochrome P450 [CYP] 1A2, 2B6, 2C9, 2C19, 2D6, 3A4, and 3A5), and the frequency of normative metabolizer status was compared to reference populations data from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The Antidepressant Treatment History Form was used to record historic medication trials and side effects.Results: A significantly greater proportion of extensive metabolizers for CYP2B6 was observed in the study population when compared to CPIC population frequency databases in Caucasians (0.64 vs 0.43 [95% CI: 0.49-0.76]; P value = .006) and African Americans (0.71 vs 0.33 [95% CI: 0.29-0.96]; P value = .045). No significant association was found between metabolizer phenotype and the likelihood of a medication side effect.Conclusion: Pharmacogenomic testing may have value for personalized prescribing in individuals capable of or considering pregnancy.

Comparison of cognitive performance in first-episode drug-naïve schizophrenia, bipolar II disorder, and major depressive disorder patients after treatment.

BACKGROUND: Cognitive impairment is a recognized fundamental deficit in individuals diagnosed with schizophrenia (SZ), bipolar II disorder (BD II), and major depressive disorder (MDD), among other psychiatric disorders. However, limited research has compared cognitive function among first-episode drug-naïve individuals with SZ, BD II, or MDD. METHODS: This study aimed to address this gap by assessing the cognitive performance of 235 participants (40 healthy controls, 58 SZ patients, 72 BD II patients, and 65 MDD patients) using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) before and after 12 weeks of treatment in SZ, BD II, and MDD patients. To clarify, the healthy controls only underwent RBANS testing at baseline, whereas the patient groups were assessed before and after treatment. The severity of symptoms in SZ patients was measured using the Positive and Negative Syndrome Scale (PANSS), and depression in BD II and MDD patients was assessed using the Hamilton Depression Scale-24 items (HAMD-24 items). RESULTS: Two hundred participants completed the 12-week treatment period, with 35 participants dropping out due to various reasons. This group included 49 SZ patients, 58 BD II patients, and 53 MDD patients. Among SZ patients, significant improvements in immediate and delayed memory were observed after 12 weeks of treatment compared to their initial scores. Similarly, BD II patients showed significant improvement in immediate and delayed memory following treatment. However, there were no significant differences in RBANS scores for MDD patients after 12 weeks of treatment. CONCLUSIONS: In conclusion, the findings of this study suggest that individuals with BD II and SZ may share similar deficits in cognitive domains. It is important to note that standardized clinical treatment may have varying degrees of effectiveness in improving cognitive function in patients with BD II and SZ, which could potentially alleviate cognitive dysfunction.

Cross-sectional analysis of pharmaceutical industry payments to authors of clinical practice guidelines for bipolar disorder and major depressive disorder in Japan.

OBJECTIVE: Clinical practice guidelines (CPGs) are essential for standardising patient care based on evidence-based medicine. However, the presence of financial conflicts of interest (COIs) among CPG authors can undermine their credibility. This study aimed to examine the extent and size of COIs among authors of psychiatry CPGs in Japan. METHODS: This cross-sectional analysis of disclosed payments from pharmaceutical companies assesses the prevalence and magnitude of personal payments for lecturing, consulting and writing to CPGs for bipolar disorder and major depressive disorder in Japan between 2016 and 2020. RESULTS: This study found that 93.3% of authors received payments over a 5-year period, with total payments exceeding US$4 million. The median payment per author was US$51 403 (IQR: US$9982-US$111 567), with a notable concentration of payments among a small number of authors, including the CPG chairperson. Despite these extensive financial relationships, only a fraction of authors disclosed their COIs in the CPGs. These large amounts of personal payments were made by pharmaceutical companies manufacturing new antidepressants and sleeping aids listed in the CPGs. CONCLUSIONS: This study found that more than 93% of authors of CPGs for major depressive disorder and bipolar disorder in Japan received considerable amounts of personal payments from the pharmaceutical industry. The findings highlight deviations from international COI management standards and suggest a need for more stringent COI policies for psychiatry CPGs in Japan.

Role of Electroconvulsive Therapy, Ketamine Infusion, and Deep Repetitive Transcranial Magnetic Stimulation in Treatment-Resistant Bipolar Depression: A Case Report.

Background and Objectives: Options for treatment-resistant bipolar depression (TRBPD) are limited. Electroconvulsive therapy (ECT) has shown efficacy in TRBPD. However, the cognitive deficits and memory concerns associated with ECT are problematic for a significant number of patients. It remains unclear what the next step is for patients with TRBPD who fail ECT. Materials and Methods: In this case report, we present a patient with TRBPD who sequentially received 12 sessions of brief-pulse right unilateral ECT, 22 sessions of ketamine infusion at 0.5-0.75 mg/kg for 40 min, and 39 sessions of deep repetitive transcranial magnetic stimulation (dTMS). Results: The patient had some benefit from ECT, but declined continuation of ECT due to memory concerns. The patient tolerated ketamine infusion well but had limited benefit. However, the patient responded well to acute treatment with dTMS and maintained relative stability for more than 2 years. Conclusions: This case suggests that patients with TRBPD who fail ECT and/or ketamine infusion might benefit from dTMS.

Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a multifactorial psychiatric illness affecting ∼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive. METHODS: In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies. FINDINGS: We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na+ conductance. Whole transcriptome sequencing in BD neurons revealed altered gene expression pathways related to glutamate transmission, alterations in cell signalling and ion transport/channel activity. We found altered Akt signalling as a potential therapeutic effect of Li in LR neurons from patients with BD, and that Akt activation mimics Li effect in LR neurons. Furthermore, the increased neural network activity observed in both LR & LNR neurons from patients with BD were reversed by AMP-activated protein kinase (AMPK) activation. INTERPRETATION: These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD. FUNDING: Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.

Lithium Exposure and Risk of Major Neurocognitive Disorders: A Systematic Review and Meta-analysis.

BACKGROUND: Published studies on the association between lithium use and the decreased risk of major neurocognitive disorders (MNCDs) have shown disparities in their conclusions. We aimed to provide updated evidence of this association. METHODS: A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Library from inception until August 31, 2023. All the observational studies evaluating the association between lithium use and MNCD risk were eligible for inclusion. Pooled odds ratios (ORs) and 95% prediction intervals were computed using random-effects models. RESULTS: Eight studies with 377,060 subjects were included in the analysis. In the general population on the association between lithium use versus nonuse and dementia, the OR was 0.94 (95% confidence interval [CI] = 0.77-1.24). Further analysis also demonstrated that lithium use was not associated with an increased risk of Alzheimer's disease (OR = 0.69, 95% CI: 0.31-1.65). When the analysis was restricted to individuals with bipolar disorder to reduce the confounding by clinical indication, lithium exposure was also not associated with a decreased risk of MNCD (OR = 0.9, 95% CI = 0.71-1.15). CONCLUSION: The results of this systematic review and meta-analysis do not support a significant association between lithium use and the risk of MNCD.