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.

Bipolar DisordersVolume 26, Issue 2 p. 188-189 COMMENTARY A needless contest? Michael J. Gitlin, Corresponding Author Michael J. Gitlin [email protected] orcid.org/0000-0001-7236-9649 Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, California, USA Correspondence Michael J. Gitlin, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA, USA. Email: [email protected]Search for more papers by this author Michael J. Gitlin, Corresponding Author Michael J. Gitlin [email protected] orcid.org/0000-0001-7236-9649 Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, California, USA Correspondence Michael J. Gitlin, Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles (UCLA), Los Angeles, CA, USA. Email: [email protected]Search for more papers by this author First published: 23 January 2024 https://doi.org/10.1111/bdi.13401Citations: 1Read 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 No abstract is available for this article. REFERENCES 1Belmaker RH. Bipolar Disorders. 2023 In press. Google Scholar 2Malhi GS, Bauer M. Lithium first: not merely first line. Bipolar Disord. 2023; 25: 7-8. 10.1111/bdi.13299 PubMedWeb of Science®Google Scholar 3Kishi T, Ikuta T, Matsuda Y, et al. Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials. Mol Psychiatry. 2021; 26: 4146-4157. 10.1038/s41380-020-00946-6 CASPubMedWeb of Science®Google Scholar 4Malhi GS, Bell E, Jadidi M, Gitlin M, Bauer M. Countering the declining use of lithium therapy: a call to arms. Int J Bipolar Disord. 2023; 11(1): 30. doi:10.1186/s40345-023-00310-x 10.1186/s40345-023-00310-x PubMedWeb of Science®Google Scholar 5Gitlin MJ. Why isn't lithium prescribed more often? Here are the reasons why. J Psychiatry Neurol Ser. 2016; 29: 293-297. Google Scholar Citing Literature Volume26, Issue2March 2024Pages 188-189 ReferencesRelatedInformation

Lithium is our oldest continuously prescribed medication in psychopharmacology, with its history as an agent for treating mood disorders extending from the 19th century. Although clinicians prescribe it less frequently than in the past, its utility in treating bipolar disorder is unquestionable. Novel potential indications for its use in psychiatry have created excitement about broader roles for lithium in treating and preventing other disorders. Lithium is effective both in treating acute mania, as an adjunctive antidepressant, and as a maintenance treatment in bipolar disorder. Lithium has also shown some efficacy in treating and preventing unipolar depression, but less clearly than for bipolar maintenance treatment and acute mania. Common side effects include nausea, polyuria, tremor, weight gain and cognitive dulling. These side effects are typically manageable with reasonable clinical strategies. Lithium affects renal, thyroid and parathyroid function. With clinical monitoring, these effects are easily managed although infrequent cases of severe renal insufficiency may occur with long term use. Although not all studies are positive, a consistent database suggests the efficacy of lithium in decreasing suicide attempts and suicides, likely due to its effect on impulsivity and aggression as well as its prophylaxis against depressive and manic recurrences. Recent data have suggested lithium’s potential efficacy for a number of new clinical indications. Lithium’s neuroprotective effects suggest potential efficacy in preventing mild cognitive impairment (MCI) and dementia as well as in aiding recovery from strokes. Higher (but still trace) lithium levels in drinking water are associated with lower rates of dementia. It is still not clear how much lithium-and what serum lithium levels- are required for either of these effects. Other preliminary research suggests that lithium may also have antiviral effects and may decrease cancer risk. Lithium continues to be the mainstay treatment of mood disorders in general and in bipolar disorder specifically. Other potential clinical uses for lithium in psychiatry have re-invigorated excitement for research in other areas such as suicide, preventing cognitive impairment and possibly preventing viral infections and diminishing cancer risk.

The broad acceptance of evidence-based psychosocial interventions as adjuncts to pharmacotherapy for bipolar disorder has been inhibited by the extensive training, supervision, and fidelity requirements of these approaches. Interventions that emphasize evidence-based strategies drawn from these modalities-rather than the full manualized protocols-may broaden the availability of psychotherapy for patients with bipolar disorder. In this article, psychosocial risk factors relevant to the course of bipolar disorder (stressful life events that disrupt social rhythms, lack of social support, family criticism and conflict, and lack of illness awareness or literacy) are reviewed, along with evidence-based psychosocial interventions (e.g., interpersonal and social rhythm therapy, cognitive-behavioral therapy, family-focused therapy, and group psychoeducation) to address these risk factors. The results of a component network meta-analysis of randomized psychotherapy trials in bipolar disorder are discussed. Manualized psychoeducation protocols-especially those that encourage active skill practice and mood monitoring in a family or group format-were found to be more effective, compared with individual psychoeducation or routine care, in reducing 1-year recurrence rates. Cognitive restructuring, regulation of daily and nightly routines, and communication skills training were core components associated with stabilization of depressive symptoms. The authors describe a novel psychoeducational approach-practical psychosocial management (PPM)-that integrates these core strategies into the personalized care of patients with bipolar disorder to reduce recurrences and enhance mood stability. PPM is designed to be implemented, without time-intensive training and oversight, by physician or nonphysician clinicians. Evaluating the efficacy and coverage of PPM will require implementation trials in community settings.

For over half a century, it has been widely known that lithium is the most efficacious maintenance treatment for bipolar disorder. Despite thorough research on the long-term effects of lithium on renal function, a number of important questions relevant to clinical practice remain. The risk of polyuria, reflecting renal tubular dysfunction, is seen in a substantial proportion of patients treated with long term lithium therapy. The duration of lithium may be the most important risk factor for lithium-induced polyuria. Most, but not all, studies find that lithium is associated with higher rates of chronic kidney disease compared to either age matched controls or patients treated with other mood stabilizers. Age, duration of lithium therapy and medical disorders such as hypertension and diabetes mellitus are risk factors for chronic kidney disease in lithium-treated patients. The relationship between polyuria and chronic kidney disease is inconsistent but poorly studied. Although not all studies agree, it is likely that lithium may increase the risk for end stage renal disease but in a very small proportion of treated patients. Patients whose renal function is relatively preserved will show either no progression or improvement of renal function after lithium discontinuation. In contrast, patients with more renal damage frequently show continued deterioration of renal function even after lithium discontinuation. Optimal management of lithium treatment requires obtaining a baseline measure of renal function (typically estimated glomerular filtration rate [eGFR]) and regular monitoring of eGFR during treatment. Should the eGFR fall rapidly or below 60 ml/minute, patients should consider a consultation with a nephrologist. A decision as to whether lithium should be discontinued due to progressive renal insufficiency should be made using a risk/benefit analysis that takes into account other potential etiologies of renal dysfunction, current renal function, and the efficacy of lithium in that individual patient.

Potential nephrotoxicity from long-term lithium use has been well documented for many decades, with the first paper demonstrating structural renal damage, primarily in the form of interstitial nephritis (with scarring of the interstitium, tubular destruction and relative preservation of glomeruli), published in 1977.1 The trajectory of renal function in patients who have had lithium treatment discontinued due to progressive renal impairment (previously measured by serum creatinine, more recently measured by eGFR [estimated glomerular filtration rate]) is still not clear. Studies have shown that, after lithium discontinuation, renal function either stabilizes or improves in many patients while other patients, especially those with worse renal function at the time of lithium discontinuation, show further deterioration in renal function.2 Among the variables that may explain these discrepant results are: (1) the effect of comorbid medical disorders that independently adversely affect renal function such as diabetes or hypertension; (2) the extent of renal damage at the time of lithium discontinuation. As an example, in one recent study, individuals most likely to show progressive deterioration of renal function after lithium discontinuation were those whose eGFR was 32 mL/min or less.2 This finding is consistent with previous studies showing similar results. (3) A final variable, which may be the most important of all, is the length of follow-up after lithium discontinuation. Many studies in this area have followed patients for 1–5 years. However, renal function normally and inevitably deteriorates with age and it may take decades for mild to moderate chronic kidney disease (CKD) (e.g. stage 3, with an eGFR<60) to progress to end-stage renal disease (ESRD). Beyond the frustration of conflicting data, the key issue is that of balancing the risk of treating vs. the risk of not treating, that is removing the treatment that is beneficial. For lithium, the risk of continuing lithium treatment in the face of progressive deterioration in renal function is that of inexorable renal damage. The risk of not treating reflects the frequent observation that, for many patients, treatment with lithium can be either extraordinarily effective or even life-saving given the morbidity of recurrent bipolar episodes. Consistent with this, one recent study demonstrated that patients who discontinued lithium due to CKD stage 3 had more mood episodes, and more psychotropic medication trials compared to those who continued lithium treatment.3 The UCLA Mood Disorders Clinic has been providing longitudinal care to patients with unipolar and bipolar disorder for 45 years. Therefore, we have followed a number of patients for many decades. To illustrate the importance and effect of long-term observation, four brief clinical vignettes of patients with bipolar I disorder treated with lithium are presented, demonstrating both the potential for progression to ESRD in three patients, the toxic effects of dialysis in one of these patients and mood destabilization from discontinuing lithium in another patient. Mr. A, previously reported on 30 years ago as Mr. C in Gitlin, 1993,4 with bipolar I disorder, was treated with lithium. He developed a rising serum creatinine, which was 2.1 mg/100 mL at the time of lithium discontinuation after 12 years of treatment. After lithium discontinuation, he developed a treatment refractory depression. His renal function deteriorated thereafter and he was eventually placed on dialysis treatment. When it was clear that he was inevitably progressing to ESRD and dialysis or renal transplantation, his lithium was restarted with resolution of his depression. However, while on haemodialysis, he continued to have recurrent mood episodes despite the addition of other mood stabilizers to his lithium treatment. The patient refused renal transplantation due to his fear of the requisite corticosteroid treatment post-transplant and its potential to precipitate another manic episode. (He had experienced a hospitalized manic episode in the past associated with corticosteroid use). He eventually developed dialysis-related dementia and died at age 64 of an arrhythmia due to metabolic imbalance related to his dialysis treatment. Ms. B (also previously reported on in Gitlin, 19934 after 6 years of lithium treatment developed a serum creatinine of 2.5 mg/100 mL. After valproate plus bupropion were added, lithium was tapered and discontinued. Over the next 5 years, her serum creatinine decreased to 1.7 mg/100 mL. She did very well for decades on valproate plus bupropion. However, over the next 30+ years, off lithium, her renal function slowly and progressively deteriorated to a current eGFR = 13, meeting diagnostic criteria for ESRD (eGFR<15). Now aged 65 years old, she is preparing for dialysis or renal transplantation. Ms. C, now 51 years old, took lithium with excellent effect for 6 years. In 2000, her lithium was discontinued due to a serum creatinine of 1.8–2.0 ng/100 mL. After 2 years of mood instability, she was eventually well-stabilized on oxcarbazepine plus lamotrigine. Over the next 23 years, her renal function gradually deteriorated. Currently, her eGFR <15, meeting criteria for ESRD and she is preparing for renal transplantation. Ms. D, after very effective long-term treatment with lithium, was evaluated by a nephrologist who recommended discontinuing lithium because of a progressive decrease in her eGFR. Lithium was discontinued when her eGFR was 38 (CKD stage 3b). Despite many other therapies, including other mood stabilizers and ECT, she died by suicide within 1 year of discontinuing lithium. These four cases illustrate a set of difficult clinical decisions regarding long-term lithium use. The absolute risk for ESRD in lithium-treated is very low, even if the relative risk is substantial. Recent estimates of ESRD associated with lithium range between 0.2 and 0.7%, which is an almost eightfold risk compared to the general population.5 But, clinically, how does one weigh the relative risk of end-stage renal disease compared to the potential for a less well-treated bipolar I disorder? Ms. B and Ms. C were both successfully treated with other mood stabilizers after lithium discontinuation. Ms. D was clearly not. Mr. A continued to have recurrent mood cycles both on and off lithium. Despite the cycling while on lithium, he felt that his mood swings, while present were milder when taking lithium. Additionally, how does one accurately and succinctly describe the risk/benefit issues about lithium with bipolar patients as part of informed consent? Does one acknowledge the rare but potentially increased risk for ESRD decades in the future at the time of initiating lithium treatment? Does one discuss this only if and at the time of a progressive decline in eGFR? Finally, at what level of renal function should lithium discontinuation be considered and discussed? The literature suggests that eGFR = 40 mL/min or less is associated with greater risk of further renal function deterioration. Should the discussion occur then or earlier, if/when the patient develops CKD stage 3 (eGFR <60 mL/min)? As a field, we must grapple with these thorny dilemmas, which have no clear answers but real clinical consequences. Most importantly, however, we should at least remind ourselves that short-term (measured in a few years) observations may be reassuring but may underestimate very long-term outcomes that are seen only after decades of observation. Michael Gitlin has conflicts of interest to declare. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

For over half a century, it has been widely known that lithium is the most efficacious treatment for bipolar disorder. Yet, despite this, its prescription has consistently declined over this same period of time. A number of reasons for this apparent disparity between evidence and clinical practice have been proposed, including a lack of confidence amongst clinicians possibly because of an absence of training and lack of familiarity with the molecule. Simultaneously, competition has grown within the pharmacological armamentarium for bipolar disorder with newer treatments promoting an image of being safer and easier to prescribe primarily because of not necessitating plasma monitoring, which understandably is appealing to patients who then exercise their preferences accordingly. However, these somewhat incipient agents are yet to reach the standard lithium has attained in terms of its efficacy in providing prophylaxis against the seemingly inevitable recrudescence of acute episodes that punctuates the course of bipolar disorder. In addition, none of these mimics have the additional benefits of preventing suicide and perhaps providing neuroprotection. Thus, a change in strategy is urgently required, wherein myths regarding the supposed difficulties in prescribing lithium and the gravity of its side-effects are resolutely dispelled. It is this cause to which we have pledged our allegiance and it is to this end that we have penned this article.

APA’s Practice Guideline for the Treatment of Patients With Bipolar Disorder, 2nd Edition, was published in April 2002 (1). Since that time, a number of controlled treatment studies on aspects of bipolar disorder have been completed and published or are in press, including studies of second-generation (atypical) antipsychotics as monotherapy and as adjunctive treatment (with more traditional mood stabilizers) for the acute treatment of mania, studies of antiepileptic agents for the acute treatment of mania, trials for three medications for the acute treatment of bipolar depression, four monotherapy and one combination therapy relapse prevention studies, and studies of psychosocial interventions for maintenance. The evidence from these studies supports a substantially expanded set of options for clinicians who treat patients with bipolar disorder. This guideline watch briefly reviews the most important of the studies. The majority of the studies were industry supported.

Objective In a time of “zero suicide” initiatives and rising suicide rates, resident physicians are particularly susceptible to the psychological and professional ramifications of patient suicide. An adult psychiatry residency program developed and implemented a postvention protocol to address the impact of patient suicide among resident physicians. The current study is a formal evaluation of a training program’s postvention protocol from June 2018 to April 2020. Methods Process and outcome indicators were identified to assess protocol implementation and effectiveness. Process indicators included were postvention protocol adherence. Outcome indicators were perceived helpfulness of postvention protocol–related supports, occupational and general health measures, posttraumatic growth, and posttraumatic stress symptoms following resident participation in the postvention protocol. Results Study response rate was 97% ( n = 57/59) and 81% completed the entire survey ( n = 48/59). Twenty percent of residents ( n = 10/48) experienced patient suicide during residency. Postvention protocol adherence was between 57 and 100%. Protocol-related supports, such as speaking with attendings who had previously experienced an adverse event, were more helpful than other supports ( p < 0.01). Compared to residents who had not experienced patient suicide, mean work empowerment, burnout, mental health, and quality of life scores were not significantly different from residents who participated in the postvention protocol ( p > 0.05). Posttraumatic growth was positively correlated with self-determination at work ( p = 0.01). Conclusions The postvention protocol was helpful to residents and potentially effective at mitigating the psychological and professional consequences of patient suicide. Study findings may inform standardization of postvention protocols among psychiatry training programs.

Despite a resurgence of academic interest in its many therapeutic properties, the clinical use of lithium over the past two decades appears to be declining. The causes of this are multiple but include a diminishing awareness of its true clinical effects, the promotion of other medications with efficacy in bipolar disorder, and also because, over the years, an unfavourable mythology has emerged surrounding its use. The attitudes towards lithium can be likened to those towards the mythological god, Hades; powerful but dangerous, and to be avoided if possible. In this piece that also serves to set the stage for this special issue on lithium, we briefly discuss some of the common myths that we feel need to be dispelled so as to portray lithium accurately.

Back to table of contents Previous article Next article Letters to the EditorFull AccessIs Valproate Reasonable? Response to Leistikow et al.Rita Suri, M.D., Donna Kanar Socol, J.D., Michael Gitlin, M.D.Rita SuriSearch for more papers by this author, M.D., Donna Kanar SocolSearch for more papers by this author, J.D., Michael GitlinSearch for more papers by this author, M.D.Published Online:1 Jan 2021https://doi.org/10.1176/appi.ajp.2020.20030350rAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We appreciate the comments by Drs. Leistikow, Smith, Payne, and Osborne and agree that, in this day and age, the field of reproductive psychiatry views valproate as a last resort for treatment in women of childbearing age, potentially justifiable when it is the only option for treating severe mental illness. We also agree that in utero valproate exposure has been associated with an increased risk of lower IQ, attention deficit hyperactivity disorder, and behavioral issues in exposed children and an increased risk of polycystic ovary syndrome, hyperandrogenism, and menstrual irregularities in women.The case presented in our Clinical Case Conference, “Standard of Care: Reasonable But Not Perfect,” occurred more than 13 years ago, well before the risks of valproate use during pregnancy were understood to the extent that they are today. At the time, valproate was commonly used as a treatment modality, with more than 900,000 prescriptions written annually for women of reproductive age (1). The patient in the case presented was using a reliable form of birth control, placing her risk of having an infant with a neural tube defect at less than one in a thousand. She had severe mental illness, with symptoms of suicidality and thoughts of harming her children and her husband, necessitating a rapid treatment response. Her symptoms had failed to respond to other pharmacologic treatments, and the atypical features of her case suggested a more favorable response to valproate than to lithium (2, 3).At the time this case occurred, the treating clinicians met the standard of care; nevertheless, at trial, they lost the malpractice case. The purpose of our Clinical Case Conference was to clarify that standard of care requires that the threshold of reasonable care, not optimal care, is provided, and to understand the decisions that the treating clinicians made at the time of the case, as well as to highlight areas where alternative decisions, precautions, and actions could have been considered.Drs. Leistikow, Smith, Payne, and Osborne accurately point out “a changing standard of care” regarding the use of valproate in reproductive-age women and suggest that the doctors’ decision, in this case, to “treat with valproate instead of other options, such as lithium, may look less reasonable in years to come.” However, clinicians can be responsible only for making treatment decisions and be held to a standard of care based on the information and the body of knowledge available at the time. Therefore, it may be time for current practice guidelines in the treatment of bipolar disorder to address the issue of whether valproate should be used at all, and if so, the specific circumstances and criteria for use, in the treatment of reproductive-age women.Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California Los Angeles, Los Angeles (Suri, Gitlin); Hughes Socol Piers Resnick & Dym, Ltd., Chicago (Socol).Send correspondence to Dr. Suri ([email protected]).The authors’ disclosures accompany the original article.References1 Meador KJ, Loring DW: Risks of in utero exposure to valproate. JAMA 2013; 309:1730–1731Crossref, Medline, Google Scholar2 Pfennig A, Schlattmann P, Alda M, et al.: Influence of atypical features on the quality of prophylactic effectiveness of long-term lithium treatment in bipolar disorders. Bipolar Disord 2010; 12:390–396Crossref, Medline, Google Scholar3 Bowden CL: Clinical correlates of therapeutic response in bipolar disorder. J Affect Disord 2001; 67:257–265Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 178Issue 1 January 01, 2021Pages 100-100 Metrics KeywordsWomenPre/Peri/Postnatal IssuesEducation-PsychiatricForensic PsychiatryPDF download History Accepted 27 July 2020 Published online 1 January 2021 Published in print 1 January 2021

There has been increasing interest in the use of smartphone applications (apps) and other consumer technology in mental health care for a number of years. However, the vision of data from apps seamlessly returned to, and integrated in, the electronic medical record (EMR) to assist both psychiatrists and patients has not been widely achieved, due in part to complex issues involved in the use of smartphone and other consumer technology in psychiatry. These issues include consumer technology usage, clinical utility, commercialization, and evolving consumer technology. Technological, legal and commercial issues, as well as medical issues, will determine the role of consumer technology in psychiatry. Recommendations for a more productive direction for the use of consumer technology in psychiatry are provided.