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.

The diagnosis of bipolar disorder (BD) in young children has been a topic of debate, in part owing to varied interpretation of manic-like symptoms. We examined how expert academic clinicians participating in the pediatric bipolar biobank varied in their interpretation and application of Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria and diagnoses. Study co-investigators reviewed 12 standardized narratives and for each marked a visual analog scale with their confidence in the presence of manic episodes and criteria. We analyzed raters’ confidence and inter-rater agreement using interclass correlation (ICC). Symptoms with good ICC ranging from 0.60 to 0.74 included inflated self-esteem/grandiosity and decreased need for sleep. Diagnoses and episodes with poor ICCs (< 0.4) included Hypomania and Bipolar Not Elsewhere Classified/Not Otherwise Specified. Despite efforts made to refine BD criteria with DSM-5, there was substantive variation in diagnostic interpretation among investigators working with children presenting with manic-like symptoms.

Background While bipolar disorder is strongly linked to an increased risk of suicide, recent evidence has challenged the assumption that mixed symptoms play a distinct role in suicidal ideation beyond depressive severity. This study examines how depressive, hypo/manic, and mixed features influence suicidal ideation in individuals with bipolar disorder. Data from 903 participants in the Stanley Foundation Bipolar Network (1995–2002) were analyzed to assess associations between mood states, classified by the Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C) and the Young Mania Rating Scale (YMRS), and suicidal ideation, measured using IDS-C item 18, using generalized estimating equations. Results Depressive symptoms were strongly associated with suicidal ideation (OR = 21.98, 95% CI: 15.31–31.54). Moderate hypo/manic symptoms also conferred risk (OR = 3.11, 95% CI: 1.51–6.49), and milder hypo/mania showed a weaker but significant association (OR = 1.74, 95% CI: 1.05–2.89). The highest suicidal ideation was observed in individuals with hypo/mania featuring mixed symptoms (OR = 29.43), exceeding that of depression or depression with mixed features (OR = 21.98). However, findings diverged based on modeling approach: in continuous predictor models, SI was driven solely by depressive symptom severity, with no significant association observed for hypo/mania or its interaction with depression. In contrast, when mood states were categorized using clinically meaningful thresholds, hypo/mania with mixed features emerged as a distinct contributor to suicidal ideation risk. Conclusion These findings underscore the need for integrating both dimensional and categorical approaches to mood state classification in research on suicidality in bipolar disorder.

Lithium is a classic, primary treatment for bipolar disorder that has paradoxically been used less over time, especially in North America, which goes against the accumulating evidence for its efficacy. Bipolar disorder is increasingly conceptualised as a chronic, potentially progressive condition worsened and accelerated by each mood episode, which might resemble multiple sclerosis or rheumatoid arthritis as a condition that requires disease-modifying treatments to change illness trajectory. In this Personal View, we argue that lithium acts like a disease-modifying drug in bipolar disorder. Although the pathophysiology of bipolar disorder remains unclear, many of the mechanisms implicated in bipolar disorder, and the surrogate markers associated with this condition, are uniquely affected by lithium treatment from the DNA and cellular levels to the structure and function of the brain and other body systems. Clinical trial and cohort study evidence shows that lithium is effective and probably superior to other medications used to treat bipolar disorder, and that long-term outcomes are better with lithium than non-lithium regimens. Conceptualisation of lithium as a disease-modifying agent might help to increase clinical use by doctors, especially early in the disease course to better serve our patients.

INTRODUCTION:Bipolar disorder (BD), characterized by extreme mood shifts between mania and depression, can manifest in childhood, and pose treatment challenges. Treatment for full-criteria BD I or II in children has been partially described in the literature, but major uncertainties exist regarding non-classic presentations, which were originally designated as bipolar "not otherwise specified" (BP-NOS) in DSM-IV and in DSM-5 and ICD-11 as either other specified or unspecified BD (S-USBD). This review aims to provide literature-based recommendations on the treatment of S-USBD, with a focus on a fear of harm (FOH) subtype, now termed temperature and sleep dysregulation disorder (TSDD). METHODS:A broad systematic literature review with AI assistance was conducted to identify all articles in PubMed providing data on the treatment of children with either atypical BD, BD-NOS, USBD, specified BD, rapid cycling BD, or a phenotype of BD. AIMS:Given the paucity of pharmacological treatment literature on any of the earliest forms of BD prior to their achieving a BP I or BP II diagnosis, it was felt that there was a critical need to review the existent literature on the earliest presentations and prodromes, which now fall under the rubric of specified (BD S-USBD). Here, the focus is on the prevalent BP-NOS subtype, which meets all the classical presentations of BP except for the brief durations of mania, and a more newly recognized form of S-USBD called TSDD. RESULTS:Eleven family-focused psychotherapy studies were identified, including nine randomized controlled trials (RCTs) with uniformly positive results versus the comparative group, which was treatment as usual (TAU) for unclear subtypes and subtypes of S-USBD. Only three psychopharmacological RCTS were reported, and only one on aripiprazole in unspecified subtypes of S-USBD in high-risk children showed a significant difference from placebo. None of the controlled trials and only two case series provided separate outcome data on the S-USBD subtypes, except for one that focused exclusively on the TSDD subtype. These two case series reports preliminarily defined the TSDD subtype and provided novel pharmacological treatment data, including lithium, clonidine, and ketamine, which led to good outcomes. CONCLUSION:Good support was provided in the 11 studies for the use of adjunctive family-focused psychotherapeutic approaches, and this approach should be considered an important part of any treatment regimen. The pharmacological treatment landscape for S-USBD lacks a systematic research base, warranting further exploration with controlled clinical trials. Case series indicate promising treatment outcomes for TSDD with high-dose lithium, clonidine, ketamine, and other cooling measures. Validation of this novel treatment strategy in controlled trials is needed to advance the management of the S-USBD variants.

Bipolar disorder often starts on childhood or adolescence but is too often poorly recognized and treated leading to the evolution of an illness with considerable disability. While lithium is widely recognized a first line treatment option its use is declining in comparison to other less effective agents. Here we review the major assets of lithium a drug that can prevent many aspects of illness progression as a function of increased numbers of episodes experienced. More episodes are related to faster and more severe recurrences cognitive deficits, and treatment refractoriness. Many of the side effects of lithium, such as renal dysfunction, are based on earlier and uncontrolled literature and are over emphasized. Given lithium's unique therapeutic profile, a re-evaluation of its under-utilization is definitely indicated.

Lithium is the superior first-line treatment for bipolar disorder (BD). Yet the percentage of patients receiving lithium is abysmally low, especially in the US. Since psychiatrists have failed to place lithium in its appropriate role, we make the case that patients with BD themselves need to be better educated about the unique characteristics and pre-eminence of the drug so that it can be used more often and appropriately. Lithium has a highly unfavorable popular reputation among would-be patients and many psychiatrists. Thus, a direct appeal to patients with BD appears appropriate to try to remediate this situation. The unique assets of lithium are underappreciated or not well known. Conversely, the side effects profile of lithium are overestimated. Here, we make the case that lithium’s image needs to be revised not only with better and more accurate information but also with a wholesale renaming and rebranding of the drug. We will not only outline the unique qualities and new information about the side effects of the drug but attempt to change some of the terminology conventionally used to refer to lithium so that its use may be appropriately applied earlier and at an increased frequency for patients with BD.

Bipolar DisordersEarly View EDITORIAL Early intervention, relapse prevention, and neuroprogression in bipolar disorder: The evidence matters Lakshmi N. Yatham, Corresponding Author Lakshmi N. Yatham [email protected] orcid.org/0000-0002-7405-0954 Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada Correspondence Lakshmi N. Yatham, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. Email: [email protected]Search for more papers by this authorAyal Schaffer, Ayal Schaffer orcid.org/0000-0001-6220-5042 Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorLars V. Kessing, Lars V. Kessing orcid.org/0000-0001-9377-9436 Copenhagen Affective disorder Research Center (CADIC), Psychiatric Center Copenhagen, Department of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkSearch for more papers by this authorKamilla Miskowiak, Kamilla Miskowiak Neurocognition and Emotion in Affective Disorders (NEAD) Centre, University of Copenhagen, Copenhagen, Denmark Department of Psychology, and Mental Health Services, Capital Region of Denmark Psychiatric Centre Copenhagen, Frederiksberg Hospital, Frederiksberg, DenmarkSearch for more papers by this authorFlavio Kapczinski, Flavio Kapczinski orcid.org/0000-0001-8738-856X Federal University - UFRGS, Porto Alegre, Brazil McMaster University, Hamilton, Ontario, CanadaSearch for more papers by this authorEduard Vieta, Eduard Vieta orcid.org/0000-0002-0548-0053 Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, SpainSearch for more papers by this authorRobert M. Post, Robert M. Post orcid.org/0000-0002-4246-524X Department of Psychiatry, George Washington School of Medicine, Washington, District of Columbia, USASearch for more papers by this authorMichael Berk, Michael Berk Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Melbourne, AustraliaSearch for more papers by this author Lakshmi N. Yatham, Corresponding Author Lakshmi N. Yatham [email protected] orcid.org/0000-0002-7405-0954 Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada Correspondence Lakshmi N. Yatham, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada. Email: [email protected]Search for more papers by this authorAyal Schaffer, Ayal Schaffer orcid.org/0000-0001-6220-5042 Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, CanadaSearch for more papers by this authorLars V. Kessing, Lars V. Kessing orcid.org/0000-0001-9377-9436 Copenhagen Affective disorder Research Center (CADIC), Psychiatric Center Copenhagen, Department of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkSearch for more papers by this authorKamilla Miskowiak, Kamilla Miskowiak Neurocognition and Emotion in Affective Disorders (NEAD) Centre, University of Copenhagen, Copenhagen, Denmark Department of Psychology, and Mental Health Services, Capital Region of Denmark Psychiatric Centre Copenhagen, Frederiksberg Hospital, Frederiksberg, DenmarkSearch for more papers by this authorFlavio Kapczinski, Flavio Kapczinski orcid.org/0000-0001-8738-856X Federal University - UFRGS, Porto Alegre, Brazil McMaster University, Hamilton, Ontario, CanadaSearch for more papers by this authorEduard Vieta, Eduard Vieta orcid.org/0000-0002-0548-0053 Hospital Clinic, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, SpainSearch for more papers by this authorRobert M. Post, Robert M. Post orcid.org/0000-0002-4246-524X Department of Psychiatry, George Washington School of Medicine, Washington, District of Columbia, USASearch for more papers by this authorMichael Berk, Michael Berk Deakin University, IMPACT – the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Melbourne, AustraliaSearch for more papers by this author First published: 25 April 2024 https://doi.org/10.1111/bdi.13435Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat CONFLICT OF INTEREST STATEMENT Yatham LN: reports consultant/speaker fees from Alkermes, Allergan (currently Abbvie) Dainippon Sumitomo Pharma, Gedeon Richter, GSK, Intracellular Therapies, Merck, Sanofi, and Sunovion, and grants from Allergan (now AbbVie), CIHR, and Dainippon Sumitomo, outside the submitted work, over the last 3 years. Schaffer A has received consultant/speaker fees from Allergan/Abbvie, GSK, Lundbeck, Otsuka in the past 3 years. Kessing LV has been a consultant for Teva and Lundbec during the last 3 years. Miskowiak KW reports consultancy fees from Lundbeck, Angelini, Gedeon Richter, and Janssen-Cilag in the past 3 years. Kapczinski F received grants or participated in the board or as speaker for the following entities: Johnson & Johnson, Daiichi Sankyo, Ache, and Janssen. Vieta E has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Johnson & Johnson, Lundbeck, Medincell, Merck, Newron, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. Post RM: Speaker for Sunovion and Abbvie. Berk M: Grant/Research Support: MRFF, NHMRC, Congressionally Directed Medical Research Programs (CDMRP) USA, AEDRTC Australian Eating Disorders Research and Translation Centre, Patient-Centered Outcomes Research Institute (PCORI), Baszucki Brain Research Fund, Danmarks Frie Forskningsfond. Psykiatrisk Center Kobenhavn, Stanley Medical Research Institute, Victorian Government Department of Jobs, Precincts and Regions, Wellcome Trust, Victorian Medical Research Acceleration Fund, Controversias Psiquiatria Barcelona, CRE, Victorian COVID-19 Research Fund, Consultancies: Lundbeck, Sandoz, Servier, Medisquire, HealthEd, ANZJP, EPA, Janssen, Medplan, RANZCP, Abbott India, ASCP, International Society of Bipolar Disorder, Precision Psychiatry, Penn State College of Medicine, Shanghai Mental Health Centre. (Last 3 years)—all unrelated to this work. Open Research DATA AVAILABILITY STATEMENT Data sharing not applicable to this article as no datasets were generated or analysed during the current study. REFERENCES 1Berk M, Brnabic A, Dodd S, et al. Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention. 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Amazingly, the National Institute of Mental Health (NIMH) has stopped funding clinical trials in favor of basic research.No other institute in the National Institutes of Health has taken this approach, and none can understand the destruction of the

BACKGROUND:Lithium remains the gold-standard medication for acute and prophylactic treatment of bipolar disorder. Understanding clinicians' practices and patients' experiences, knowledge and attitudes about lithium may improve its clinical use.METHODS:Online anonymous surveys collected information about clinician's practices and level of confidence in managing lithium and patients' experiences with lithium treatment and information received about benefits and side effects. Knowledge and attitudes regarding lithium were assessed with the Lithium Knowledge Test (LKT) and the Lithium Attitudes Questionnaire (LAQ).RESULTS:Among 201 clinicians, 64.2% endorsed often treating patients with lithium and reported high levels of confidence in assessing and managing lithium. Practices concerning clinical indications, drug titration, and serum levels were guideline-concordant, but compliance with monitoring recommendations was less frequent. Practitioners were interested in receiving more education about lithium. The patients' survey recruited 219 participants with 70.3% being current lithium users. Most patients (68%) found lithium helpful and 71% reported experiencing any kind of side effect. Most responders did not receive information about side effects or other benefits of lithium. Patients with higher scores on the LKT were more likely to have positive attitudes about lithium.LIMITATIONS:Cross-sectional design with predominantly English-speaking participants from Brazil and North America.CONCLUSIONS:There is a discrepancy between guidelines, clinician confidence and knowledge of lithium use and practice. A deeper understanding of how to monitor, prevent and manage long-term side effects and which patients are most likely to benefit from lithium may narrow the gap between knowledge and use.

Objective: Bipolar patients in the United States (US) compared to those from the Netherlands and Germany (here abbrev. as "Europe") have more Axis I comorbidities and more poor prognosis factors such as early onset and psychosocial adversity in childhood. We wished to examine whether these differences also extended to Axis II personality disorders (PDs).Methods: 793 outpatients with bipolar disorder diagnosed by SCID gave informed consent for participating in a prospective longitudinal follow up study with clinician ratings at each visit. They completed detailed patient questionnaires and a 99 item personality disorder inventory (PDQ-4). US versus European differences in PDs were examined in univariate analyses and then logistic regressions, controlling for severity of depression, age, gender, and other poor prognosis factors.Results: In the univariate analysis, 7 PDs were more prevalent in the US than in Europe, including antisocial, avoidant, borderline, depressive, histrionic, obsessive compulsive, and schizoid PDs. In the multivariate analysis, the last 4 of these PDs remained independently greater in the US than Europe.Conclusions: Although limited by use of self report and other potentially confounding factors, multiple PDs were more prevalent in the US than in Europe, but these preliminary findings need to be confirmed using other methodologies. Other poor prognosis factors are prevalent in the US, including early age of onset, more childhood adversity, anxiety and substance abuse comorbidity, and more episodes and rapid cycling. The interactions among these variables in relationship to the more adverse course of illness in the US than in Europe require further study.(c) 2022 Published by Elsevier B.V.

Bipolar disorder is heterogeneous in phenomenology, illness trajectory, and response to treatment. Despite evidence for the efficacy of multimodal-ity interventions, the majority of persons affected by this disorder do not achieve and sustain full syndromal recovery. It is eagerly anticipated that combining datasets across various information sources (e.g., hierarchical "multi-omic" measures, electronic health records), analyzed using advanced computational methods (e.g., machine learning), will inform future diagnosis and treatment selection. In the interim, identifying clinically meaningful subgroups of persons with the disorder having differential response to specific treatments at point-of-care is an empirical priority. This paper endeavours to synthesize salient domains in the clinical characterization of the adult patient with bipolar disorder, with the overarching aim to improve health outcomes by informing patient management and treatment considerations. Extant data indicate that characterizing select domains in bipolar disorder provides actionable information and guides shared decision making. For example, it is robustly established that the presence of mixed features - especially during depressive episodes - and of physical and psychiatric comorbidities informs illness trajectory, response to treatment, and suicide risk. In addition, early environmental exposures (e.g., sexual and physical abuse, emotional neglect) are highly associated with more complicated illness presentations, inviting the need for developmentally-oriented and integrated treatment approaches. There have been significant advances in validating subtypes of bipolar disorder (e.g., bipolar I vs. II disorder), particularly in regard to pharmacological interventions. As with other severe mental disorders, social functioning, interpersonal/family relationships and internalized stigma are domains highly relevant to relapse risk, health outcomes, and quality of life. The elevated standardized mortality ratio for completed suicide and suicidal behaviour in bipolar disorder invites the need for characterization of this domain in all patients. The framework of this paper is to describe all the above salient domains, providing a synthesis of extant literature and recommendations for decision support tools and clinical metrics that can be implemented at point-of-care.