BACKGROUND:Depression in both bipolar and major depressive disorder remains a major unmet need due to treatment resistance to the existing treatments. Emerging evidence implicates the renin-angiotensin system in regulating the cellular stress response relevant to depression, suggesting it as a novel therapeutic target for depression. Candesartan, a common hypertension medication, decreases neuroinflammation, oxidative and nitrosative pathway activation, and neurotrophic signalling of angiotensin II by predominantly blocking the angiotensin II type 1 receptors (AT1R). Given AT1R-induced activities are implicated in the pathophysiology of bipolar and major depressive disorder and with supportive pharmacoepidemiology data, candesartan may represent a novel antidepressant strategy. METHODS:The CADET Trials are 2 parallel 16-week double-blind randomized placebo-controlled trials of adjunctive candesartan (or placebo) for the treatment of bipolar depression (CADET-BD) and major depressive disorder (CADET-UD). Each trial aims to recruit 240 adult participants. The primary outcome is the between-group (ie, intervention vs. placebo) differential change from baseline to week 16 in depression symptoms as measured by the Montgomery Åsberg Depression Rating Scale. Secondary outcomes measure depression, mania, anxiety, quality of life, cost-effectiveness, functioning, substance use, cognition, and biological markers. FINDINGS:Findings are not yet available as the trial is ongoing. IMPLICATIONS:The CADET Trials examine the efficacy of candesartan in reducing depressive symptoms in both unipolar and bipolar depression, and whether its effects are mediated through the renin-angiotensin system. Candesartan is affordable, accessible, and well-tolerated. If effective, it could quickly be adopted into clinical practice as a new adjunctive medication for the treatment of these disorders.

There is a need for greater recognition of clinical psychopharmacology endpoints, including instances where specific psychotropic medications may become unnecessary, redundant, contradictory, or otherwise inappropriate and therefore merit deprescribing. To address circumstances warranting psychotropic medication deprescribing. The American Society of Clinical Psychopharmacology convened a panel of 45 international psychopharmacology experts who developed and completed a multiround Delphi survey and conducted a focused literature review between January and May of 2025, in order to identify areas of consensus or disagreement on key aspects of the deprescribing of psychotropic medications. These included collaborative risk-benefit assessments with patients; pharmacokinetic and pharmacodynamic factors; pharmacogenomics; distinguishing redundant or conflictual from complementary mechanisms of action; managing adverse effects; assuring medication adherence; drug tolerance or tachyphylaxis; medication misuse; and the psychological context and ramifications of deprescribing. Consensus was achieved on 44 of 50 final Delphi statements (88%). Panelists unanimously agreed that components of a pharmacotherapy regimen should undergo periodic review to ensure that treatments target relevant symptoms and have favorable risk-benefit ratios. Key points of consensus were that deprescribing: (1) should not occur without first assessing medication adherence; (2) merits consideration if less than partial therapeutic response is apparent, or if treatment goals have been reached and relapse prevention is not a long-term objective; (3) involves psychological ramifications that warrant attention; (4) should be followed by close clinical monitoring; and (5) risk-benefit decisions should ideally involve active patient participation within a shared decision-making model. Through this Consensus Statement, the Task Force identified circumstances in which the selective elimination of certain psychotropic medications may be clinically indicated. Empirical trials are needed to assess the implementation of deprescribing protocols and gauge their safe, effective, and acceptable outcomes.

OBJECTIVE:The investigation focused on differences in the overall network structures of depressive symptoms between patients with bipolar depression (BD) and those with unipolar depression (UD), emphasizing their unique symptom dynamics and centralities. METHODS:Data from the Research on Asian Psychotropic Prescription Patterns for Antidepressants, Phase 3 (REAP-AD3), were used to estimate depressive symptom networks for 240 patients with BD and 2905 patients with UD. A Network Comparison Test (NCT) was conducted to evaluate differences in global strength, edge weights, and node centralities between the two networks. An additional NCT was performed using the same sample size in both groups. RESULTS:Anhedonia emerged as the most central symptom in BD, while persistent sadness was the most central symptom in UD. Global strength was higher in the BD network in the full-sample NCT (p = 0.04), but not in the equal sample-size analysis (p = 0.20). However, no significant differences were identified in overall network structure invariance. CONCLUSIONS:These findings underscore distinct depressive symptom networks in BD and UD. Anhedonia and energy dysregulation were prominent in BD, whereas persistent sadness and self-rumination were more pronounced in UD. Despite the non-significance of other NCT results, the full-sample pairwise network comparison suggested that BD patients exhibit a more integrated symptom structure than UD patients, with stronger overall connectivity between symptoms, which may be linked to neurobiological distinctions such as widespread abnormalities in white matter connectivity and increased within-network connectivity in BD.

Background:Depression in both bipolar and major depressive disorder remains a major unmet need due to treatment resistance to the existing treatments. Emerging evidence implicates the renin-angiotensin system in regulating the cellular stress response relevant to depression, suggesting it as a novel therapeutic target for depression. Candesartan, a common hypertension medication, decreases neuroinflammation, oxidative and nitrosative pathway activation, and neurotrophic signalling of angiotensin II by predominantly blocking the angiotensin II type 1 receptors (AT1R). Given AT1R-induced activities are implicated in the pathophysiology of bipolar and major depressive disorder and with supportive pharmacoepidemiology data, candesartan may represent a novel antidepressant strategy.MethodsThe CADET Trials are 2 parallel 16-week double-blind randomized placebo-controlled trials of adjunctive candesartan (or placebo) for the treatment of bipolar depression (CADET-BD) and major depressive disorder (CADET-UD). Each trial aims to recruit 240 adult participants. The primary outcome is the between-group (ie, intervention vs. placebo) differential change from baseline to week 16 in depression symptoms as measured by the Montgomery & Aring;sberg Depression Rating Scale. Secondary outcomes measure depression, mania, anxiety, quality of life, cost-effectiveness, functioning, substance use, cognition, and biological markers.Findings:Findings are not yet available as the trial is ongoing.Implications:The CADET Trials examine the efficacy of candesartan in reducing depressive symptoms in both unipolar and bipolar depression, and whether its effects are mediated through the renin-angiotensin system. Candesartan is affordable, accessible, and well-tolerated. If effective, it could quickly be adopted into clinical practice as a new adjunctive medication for the treatment of these disorders.

OBJECTIVE:Early economic evaluations (EEE) can evaluate the economic potential of new innovative healthcare solutions. We present a methodological framework for EEE in bipolar disorder and use eLi12 as an illustrative case, a new method to estimate 12-h lithium blood levels when blood sampling deviates from the 12-h timing, enabling more flexibility for patients and better data on 12-h lithium levels. METHODS:A decision-analytic model evaluated the costs and consequences of eLi12 for the treatment of bipolar disorder from a Danish national healthcare payer perspective, assessing the minimum efficacy threshold where eLi12 would be considered cost-effective compared with standard of care. The primary outcome was net monetary benefit (NMB), and we estimated quality-adjusted life-years (QALYs) assuming a willingness-to-pay threshold of €67,000/QALY gained. Costs associated with bipolar disorder and lithium treatment (e.g. hospitalisations, suicides, lost productivity, implementation costs) were estimated from literature, Danish registries, and expert opinion. RESULTS:Assuming 28,000 patients with bipolar disorder whereof 10,000 are treated with lithium, a 2.5% reduction in number of hospitalisations and suicides are sufficient for eLi12 to be considered cost-effective within one year of implementation. When using a longer time horizon, allowing more savings to be included and thus considering a smaller improvement to be sufficient, less than 1% improvement by using eLi12 would be sufficient within a three-year time horizon. CONCLUSION:EEE can evaluate the health economic potential of new innovative methods, supporting early investment decisions and guiding research. eLi12 can have significant healthcare savings, emphasising the relevance of studying clinical implementation.

There is a lack of consensus in the field about the indefinite use of psychostimulants for adult ADHD and the circumstances under which their deprescribing warrants consideration. To address this gap in knowledge, the American Society of Clinical Psychopharmacology (ASCP) convened a Task Force on the deprescribing of psychotropic medications, including stimulant medications for adult ADHD, which entailed a focused literature review and 2-round Delphi survey querying 45 international psychopharmacology experts on factors related to deprescribing. Consensus (≥75% agreement, defined by endorsements of “strongly agree” or “moderately agree”) was reached on 10 of 11 (91%) Delphi statements. Survey responses plus literature review suggest that stimulant deprescribing may be appropriate when 1) the diagnosis of ADHD is deemed incorrect upon reevaluation unless another stimulant-responsive condition is evident; 2) cognitive complaints have other more likely etiologies for which stimulant medications are inappropriate; 3) cognitive benefits are absent; 4) stimulant medications exacerbate medical or other psychiatric comorbidities; 5) adverse effects, if present, are non-remediable; 6) stimulant medications are misused; and 7) untreated comorbid non-cannabis substance use disorders are present. Panelists just fell short of consensus in perceiving regular use of cannabis as an insufficient reason to deprescribe stimulant medications in adult ADHD patients. In sum, clinical circumstances and rationales can be identified that support decisions to deprescribe stimulant medications for adult ADHD. Deliberate stimulant misuse or abuse, comorbid medical or psychiatric contraindications, and diagnostic inaccuracy pose strong reasons to consider deprescribing stimulants, potentially in favor of alternative pharmacotherapies and psychotherapies for adult ADHD.

Objective Approximately 50% of patients with major depressive disorder (MDD) prematurely discontinue their antidepressant medication within 6 months, increasing risk of relapse. Pharmacogenomic (PGx) testing may improve medication adherence by informing treatment based on gene-drug interactions (GDI). Here, we evaluated whether PGx informed treatmentimproved medication adherence in MDD patients. Methods This was an observational, retrospective claims study of adult MDD patients who received a weighted multi-gene PGx test between 1 Jan 2015 and 30 September 2021 and switched medication. PGx results were linked with de-identified administrative claims data from the Optum Labs Data Warehouse. The PGx test report organized psychiatric medications into three categories: no known GDI (congruent), moderate GDI (congruent), and significant GDI (incongruent). Patients were assigned to the following groups based on the medication with the worst congruency 90 days pre- and post-PGx testing: incongruent-to-congruent, no-change-in-congruency, and congruent-to-incongruent. Medication adherence (proportion of days covered [PDC]) and discontinuation (a ≥ 45-day gap in medication fills) were assessed using pharmacy fill data during the 180 days following the date of medication switch (index date). Results Among 6224 patients with PGx testing, those in the incongruent-to-congruent group had the highest adherence (mean PDC 0.65, SD 0.33), compared to the congruent-to-incongruent (mean PDC 0.58, SD 0.34) (p < 0.05) and no-change-in-congruency groups (mean PDC 0.61, SD 0.34) (p < 0.05). The incongruent-to-congruent group also had the lowest discontinuation rate (46%) compared to the congruent-to-incongruent (55%) (p < 0.05) and no-change-in-congruency groups (50%) (p < 0.05). Conclusions Using PGx informed medication selection can improve medication adherence and reduce discontinuation among MDD patients.

OBJECTIVE:Long-acting injectable antipsychotics (LAIAs) can improve adherence, but their optimal use in bipolar disorder needs to be further explored. This study compared LAIAs and oral antipsychotics with respect to health care utilization, illness relapse, and safety in individuals with bipolar disorder. METHODS:A self-controlled case series study was conducted using data from Hong Kong's electronic health records on individuals with bipolar disorder who received prescriptions for both LAIAs and oral antipsychotics during the period of January 1, 2004, through December 31, 2023. Outcomes included measures of health care utilization, illness relapse, and safety. Adjusted incidence rate ratios (aIRRs) for LAIA versus oral antipsychotic treatment periods were estimated using conditional Poisson regression. RESULTS:Among 17,841 people with bipolar disorder, 2,086 (11.7%) received prescriptions for both LAIAs and oral antipsychotics. Compared with oral antipsychotics, LAIAs were associated with statistically significantly lower risks of all-cause emergency department visits (aIRR=0.85, 95% CI=0.81, 0.89), all-cause hospitalizations (aIRR=0.79, 95% CI=0.73, 0.85), psychiatric hospitalizations (aIRR=0.67, 95% CI=0.61, 0.74), hospitalizations for manic episodes (aIRR=0.51, 95% CI=0.44, 0.59), and hospitalizations for mixed episodes (aIRR=0.31, 95% CI=0.14, 0.66). No statistically significant difference was found for hospitalizations for depressive episodes (aIRR=1.34, 95% CI=0.94, 1.93), nonpsychiatric hospitalizations (aIRR=0.97, 95% CI=0.87, 1.08), or cardiovascular hospitalizations (aIRR=0.84, 95% CI=0.62, 1.14). LAIAs were initially associated with an increased risk of extrapyramidal symptoms (aIRR=2.95, 95% CI=1.40, 6.22), but this difference was not statistically significant beyond 90 days of treatment. CONCLUSIONS:LAIAs were associated with substantially less health care utilization and fewer relapses of manic and mixed episodes, and they were not associated with increased risk of nonpsychiatric hospitalizations, notably for cardiovascular disease. These findings support the use of LAIAs for bipolar disorder, with close monitoring for extrapyramidal symptoms during initiation.

This expert opinion paper addresses the critical balance between lithium’s therapeutic efficacy in recurrent mood disorders and its potential renal side effects. The objective is to provide evidence-based guidelines to enhance clinical decision-making, prevent emergence of, and mitigate risks associated with lithium-induced renal impairment. An extensive review of epidemiological, observational, and experimental studies on lithium-induced renal impairment, focusing on its pathophysiology, clinical manifestations, and risk factors was conducted. Expert consensus and recent data were integrated to develop a management algorithm for renal monitoring and intervention. Lithium remains the gold standard for mood stabilization in bipolar disorders, with robust evidence supporting its role in recurrence prevention and suicide risk reduction. While mild to moderate renal impairment is recognized as a risk factor, newer studies show a lower incidence of severe outcomes, such as end-stage kidney disease, necessitating dialysis treatment and renal transplantation, especially with appropriate monitoring, as compared to older studies. This paper addresses pathophysiological mechanisms, including arginine vasopressin resistance and chronic interstitial nephritis, alongside risk factors like rapid initial decline in glomerular filtration rate, early age at treatment initiation, cumulative dosage, mean serum levels of lithium and episodes of lithium intoxication. Effective management strategies, including judicious dosing, routine monitoring, and early nephrology referral, can significantly improve outcomes. Lithium remains an invaluable treatment for recurrent mood disorders, and its benefits often outweigh the risks when managed appropriately. This paper provides a practical framework for clinicians to address renal concerns, emphasizing the importance of systematic monitoring and individualized care. The paper underscores the need for continued research and education of clinicians and patients to optimize lithium use while safeguarding patient health.

PURPOSE/BACKGROUND:Pharmacogenomics (PGx), or the use of genetic information to assess drug-gene interactions, is an important step toward precision medicine. It is unclear if clinician use of PGx yields better outcomes for their patients. This study compared the effectiveness of combinatorial PGx-guided plus guideline-informed treatment (PGx+GIT) with guideline-informed treatment (GIT) alone to improve well-being in individuals with major depressive disorder. METHODS/PROCEDURES:Eligible participants (N=201) were randomized to PGx+GIT or GIT alone. PGx was measured with the proprietary GeneSight combinatorial test. PGx+GIT participant clinicians received test results within 2 business days to inform decisions about medication changes. Participants completed the World Health Organization Well-Being Index (WHO-5), Patient Health Questionnaire (PHQ-9), and PROMIS Profile physical functioning and social roles and activity domains every 2 weeks for 2 months and then every 2 months for the remaining 10 months. Monthly medication changes operationalized as necessary clinical adjustments were tracked with the medication recommendation tracking form. FINDINGS/RESULTS:Both groups improved average well-being over the 12-month study period (model-based change in WHO-5 per log (week) [95% CI]: 4.1 [3.3, 5.0] PGx+GIT and 4.8 [4.0, 5.5] GIT). PGx+GIT did not result in superior improvement in well-being (model-based difference [95% CI]: -0.6 [-1.8, 0.5], P =0.270), or any secondary outcomes. The effect of randomized treatment on well-being was not moderated by depression severity, number of previous failed medications for major depressive disorder, or presence of a comorbid condition. IMPLICATIONS/CONCLUSIONS:These data suggest PGx+GIT was not superior to GIT alone, possibly due to a ceiling effect of GIT, or PGx did not yield better results.

Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

BACKGROUND:Pharmacogenomic (PGx) testing can help improve response and remission rates for patients with major depressive disorder (MDD) and at least one treatment failure. To investigate real-world outcomes, we examined 1) significant gene-drug interactions (GDIs) and 2) healthcare resource utilization (HRU) in a large US insurance claims dataset. METHODS:Weighted multigene PGx testing results in adult patients with MDD were linked with deidentified US claims data. The PGx test report organized medications as congruent (no known or moderate GDI) or incongruent (significant GDI). Medication claims data before and after PGx testing was used to categorize patients as no change in congruency, incongruent-to-congruent, or congruent-to-incongruent. HRU (hospitalizations and emergency department visits) was compared in the 180 days before and after PGx testing. RESULTS:A total of 20,933 patients met inclusion criteria; 16,965 of whom filled medication prescriptions before and after PGx testing. After PGx testing, the proportion of patients filling prescriptions with significant GDIs was reduced (26.1% pretesting vs 15.9% posttesting). All HRU was significantly reduced ( P < 0.001) after PGx testing except for nonpsychiatric hospitalizations ( P > 0.05). Psychiatric hospitalizations were significantly reduced after PGx testing in the incongruent-to-congruent and no change in congruency categories ( P < 0.001), but not in the congruent-to-incongruent category. Conversely, emergency department visits were significantly reduced after PGx testing in all congruency categories ( P < 0.005) and did not differ when compared across congruency categories. CONCLUSIONS:After PGx testing, patients with MDD had decreased prescribing of medications with significant GDI and reduced HRU. PGx testing may have influenced these outcomes, but the retrospective study design limits clarity on its impact.

Bipolar disorder is associated with increased mortality from cardiovascular disease, incidence of Metabolic Syndrome (MetS), and obesity. Adverse childhood experiences (ACEs) may contribute to this increased incidence, but findings have been mixed. We aimed to determine associations between ACEs and cardiometabolic risk markers in people with bipolar disorder, and how they change during pharmacological treatment. Data was analysed from 482 participants with bipolar disorder treated for 24 weeks with lithium or quetiapine, comparing those with and without ACEs across cardiometabolic markers. At baseline, those with ACEs had higher body mass indexes but were similar on all other cardiometabolic measures. During the 24-week treatment period, those with ACEs improved slightly more on continuous metabolic syndrome score (cMetS; p = .004), waist circumference, (p = .041) high density lipoproteins (HDL) cholesterol, (p = .028) and diastolic blood pressure (p = .042) than those without ACEs. Sensitivity analysis exploring the role of ACE type revealed that change in HDL was most strongly associated with sexual abuse; higher diastolic blood pressure with emotional abuse; and increased waist circumference with emotional and physical abuse, and higher cMetS with all three ACE types. There were almost no baseline differences in cardiometabolic markers between the ACE and no ACE groups. Those with ACEs seemingly benefitted more from psychiatric treatment regarding their cardiovascular health compared to the no ACE group. Future research should explore links between ACEs and cardiovascular health in those with bipolar disorder, including benefits of psychiatric treatment, the role of specific ACE types, and longer-term outcomes.