 is associate professor of psychiatry at Harvard Medical School and Co-Director, US Department of Veterans Affairs National Bipolar Disorder Telehealth Program. 

David N. Osser, MD

A recent consultation motivated an evaluation of the evidence on when one should monitor electrocardiograms (ECGs) in patients taking 

. Opinions vary and tend to be vague about when and how often to measure the ECG. Mogens Schou, MD, who was perhaps the world’s foremost expert on lithium and a passionate advocate for its use, observed that lithium occasionally changes the function or electrical activity of the heart, but the presence of heart disease rarely should prevent 

 If heart disease was present, however, he recommended a consultation with a cardiologist and serial ECGs might be considered. Much more recently, The Maudsley Prescribing Guidelines in Psychiatry from the United Kingdom recommended getting an ECG if there are risk factors for, or preexisting, cardiac disease—but offered no further details.

In what appears to be the most thorough review of the subject, Mehta and Vannozzi proposed that, though data are limited, routine monitoring of ECGs seems unnecessary. However, if patients are maintained on or develop high lithium levels (eg, 1.2 mEq/L or higher), then the risks of arrhythmias, ST segment changes, and QRS prolongations become significant, and a baseline ECG and periodic repeats are worth doing.

 They also noted that lithium-induced ECG changes are more likely over the age of 60 years. This population has a high prevalence of ischemic 

, and the 2 most common lithium-induced changes (T wave inversions and sinus dysfunctions such as bradycardia) are also common manifestations of cardiac ischemia. Thus, it would be important to delineate the cause if such abnormalities were found. Therefore, Mehta and Vannozzi recommended a baseline ECG and follow-up at least every 6 to 12 months for anyone over age 60 years taking lithium and with risk factors like hypertension, hyperlipidemia, 

, smoking, and a positive family history.

In reviewing the literature since this “complete” literature search (as the authors described it), we only found case reports. In the most recent one, a 52-year-old woman with a complex medical presentation including fever and sepsis had been taking lithium for 10 years. Her ECG showed a wide range of abnormalities that, after excluding other factors, seemed mostly due to lithium as they were present even when her medical problems had resolved.

 There was atrial fibrillation acutely when her lithium level was 2.0 mEq/L (also found in some case reports in the Mehta and Vannozzi review and in another recent case report

), but this converted rapidly when the lithium level came down to normal. Six months later, with normal lithium levels, the patient still had ST segment elevation and inverted T waves. The report’s authors concluded that unpredictable genetic and 

 factors could render a patient vulnerable to life-threatening arrhythmias if the right provocations come along, and the presence of abnormalities at therapeutic levels could predict who is vulnerable. Hence, they recommended that all patients receiving lithium should have a baseline ECG and “regular” monitoring. They noted that these vulnerabilities might be more common in patients taking long-term lithium, hence the need for the continued monitoring.

In summary, it seems that although there are no standardized, officially approved guidelines for serial ECG monitoring with lithium, we probably should be getting more baseline ECGs and repeating them more frequently in patients on long-term lithium and in those who develop cardiac risk factors. Consultation with our cardiology colleagues on any abnormal findings would be prudent.

is an associate professor of psychiatry at Harvard Medical School in Boston, Massachusetts, and codirector of the US Department of Veterans Affairs National Bipolar Disorder Telehealth Program in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

Lithium Treatment of Manic-Depressive Illness: A Practical Guide. 

The Maudsley Prescribing Guidelines in Psychiatry.

Lithium-induced electrocardiographic changes: a complete review. 

4. Diserens L, Porretta AP, Trana C, Meier D. 

Lithium-induced ECG modifications: navigating from acute coronary syndrome to Brugada syndrome.

5. Maddala RNM, Ashwal AJ, Rao MS, Padmakumar R. 

Chronic lithium intoxication: varying electrocardiogram manifestations.

Articles

When should you monitor electrocardiograms in patients taking lithium?

Lithium: Cardiac Adverse Effects and When to Get an ECG

There has been much discussion of the recently published large (519 participants) US Department of Veterans Affairs (VA)–sponsored randomized clinical trial of 

 versus placebo to prevent suicide attempts, hospitalizations to prevent suicide, and deaths after a previous attempt.

 The distinguished group of investigators found no advantage for lithium, and the study was actually interrupted earlier than planned because of the negative results on preliminary analysis.

The authors concluded that “simply” adding lithium to existing medication regimens is unlikely to be effective in preventing a broad range of suicide-related events. An editorial by Baldessarini and Tondo, however, proposed instead that the findings “cannot be taken as evidence that lithium lacks antisuicidal effects” due to numerous serious limitations in the study.

The first of those limitations was that most patients had nonbipolar depression (only 15% had bipolar I or II disorder), a heterogeneous population for which the antisuicidal effects of lithium are perhaps less established. Additionally, the lithium level, which was low overall (0.54 mEq/L), was particularly low in the patients with nonbipolar depression (0.46 mEq/L). Notably, an important previous study (the LiTMUS trial) found no value in general to adding a similar “moderate” dose of lithium for 6 months in patients with bipolar disorder

—so the dose issue could be critical. Length of time on treatment was not much longer in the latest trial: 38 weeks. 

In significant recent support of lithium, a systematic review (not cited in the study or the editorial) evaluated studies involving more than 200,000 participants pertinent to the question of suicide prevention, including patients with mood disorder and others, and concluded that lithium was associated with a significant reduction in suicide behaviors.

Another flaw noted by Baldessarini and Tondo was the large dropout rate of 52%, many of them early in the study. This quantity of dropouts would make any study hard to interpret.

The study was also problematic in having a lot of important comorbidities in the participants. Substance use was present in 85%. This would be likely to reduce the impact of any bipolar treatments applied and is a large factor in suicidal behaviors. It is also very likely to reduce the potential for finding a difference between lithium and placebo. Other conditions associated with suicide (matched in the lithium and control groups as best as possible) were present in large numbers including personality, anxiety, and other disorders—and these would also tend to reduce drug-placebo differences.

Furthermore, the editorial notes that there was no analysis of what other medications the patients were on that might have reduced lithium effectiveness. Antidepressants come to mind because they are often included in the regimens of patients with bipolar disorder, and this use is potentially harmful according to some evidence. For example, the STEP-BD study found that inclusion of an antidepressant in the regimen of rapid-cycling patients with bipolar disorder tripled the rate of recurring depression compared with not taking an antidepressant, even if the patient was on a mood stabilizer.

The study was not totally negative with respect to lithium’s potential benefits for patients with bipolar disorder. In the small number (N = 30) of patients with bipolar disorder in the study for which the primary outcomes were available (first and subsequent suicide-related events), there were 10 events in the lithium group and 20 in the placebo group.

 This was not statistically significant due to the small N, but numerically it is rather impressive in favor of lithium.

In conclusion, despite this new study and the need for further research, the best recommendation at this time regarding lithium in patients with bipolar disorder who are suicidal would be to consider it a worthwhile option. However, it would be important to prioritize treating comorbid substance use disorders and other comorbidities that could affect suicide before—or at least at the same time as—adding lithium to address suicidal thoughts and behaviors. One should not “simply” add lithium.

After adding lithium, if the patient is on an antidepressant, it is advisable to taper off the antidepressant(s). If needed due to persisting or recurrent depression, consider adding evidence-based bipolar depression medications such as lamotrigine, lurasidone, quetiapine, or cariprazine.

 Lumateperone received US Food and Drug Administration (FDA) approval for bipolar depression in December 2021, so that could be considered as well.

 According to a news release, there have been 2 other unpublished lumateperone studies, with one showing no efficacy and the other showing that using lumateperone as an adjunct to lithium or valproate had a small benefit.

 is associate professor of psychiatry at Harvard Medical School in Boston, Massachusetts, and codirector of the US Department of Veterans Affairs National Bipolar Disorder Telehealth Program in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

1. Katz IR, Rogers MP, Lew R; Li+ plus Investigators. 

Lithium treatment in the prevention of repeat suicide-related outcomes in veterans with major depression or bipolar disorder: a randomized clinical trial.

Testing for antisuicidal effects of lithium treatment.

3. Nierenberg AA, Friedman ES, Bowden CL, et al. 

Lithium treatment moderate-dose use study (LiTMUS) for bipolar disorder: a randomized comparative effectiveness trial of optimized personalized treatment with and without lithium.

4. Del Matto L, Muscas M, Murru A, et al. 

Lithium and suicide prevention in mood disorders and in the general population: a systematic review.

5. El-Mallakh RS, Vöhringer PA, Ostacher MM, et al. 

Antidepressants worsen rapid-cycling course in bipolar depression: a STEP-BD randomized clinical trial.

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: an update on bipolar depression.

7. Calabrese JR, Durgam S, Satlin A, et al. 

Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial.

"Despite this new study and the need for further research, the best recommendation at this time regarding lithium in patients with bipolar disorder who are suicidal would be to consider it a worthwhile option."

Lithium and Suicide Prevention: More Thoughts on Recent VA Study

frequently receive polypharmacy, with up to 20% of patients getting 4 or more bipolar medications.

 Problematic drug-drug interactions occur often, impacting effectiveness or safety. They can be pharmacokinetic or pharmacodynamic. Yet these interactions receive little attention in the various practice guidelines and algorithms for the psychopharmacologic management of bipolar disorder. Some of these will be summarized here and in a subsequent article.

—especially olanzapine, quetiapine, and clozapine—can cause even more weight gain when added to valproate.

Lithium is well known to interfere with the synthesis and release of 

 hormones and, in the brain’s effort to compensate for this, thyroid-stimulating hormone will increase. Periodic monitoring is required. What is not so well known is that carbamazepine (CBZ) decreases T4, possibly by induction of the UGT metabolizing enzyme, which exacerbates or hastens the onset of hypothyroidism.

 Thus, the combination of lithium and CBZ may present additive risks. Quetiapine also has some evidence of causing thyroid dysfunction.1

Lithium and anticonvulsants—especially valproate and CBZ—produce a metabolic-type or action tremor (ie, it is worse when doing an action like extending the arms—similar to benign familial essential tremors and tremors associated with hyperthyroidism, electrolyte abnormalities, and alcohol intoxication and withdrawal). When these medicines are used in combination, the severity or likelihood of tremor increases.

Antipsychotics—especially the older neuroleptics and risperidone/paliperidone—produce 

 (resting tremors—slower than metabolic tremors, rhythmic, typically 4 to 6 beats per second).

 Lithium seems to increase antipsychotic-induced Parkinsonian tremors by a not-well-understood mechanism.

Antipsychotics that raise prolactin (eg, risperidone, paliperidone, and most first-generation antipsychotics) increase osteoporosis risk through a pharmacodynamic effect. For this reason and others, guidelines now recommend routine monitoring of 

 Selective serotonin reuptake inhibitors (SSRIs), which are usually not recommended in bipolar patients but often used, also increase osteopenia by a different mechanism involving serotonin. With use of both agents, one can expect an additive harmful effect on bone metabolism.

CBZ also causes osteoporosis through its effect to induce the metabolism of vitamin D. Thus, the combination of CBZ with the prolactin-inducing antipsychotics or with SSRIs, or all three in combination, may produce additive bone harms over the long term.

 But here’s some good news: Lithium may protect from osteoporosis. The use of lithium in combination with antipsychotics and/or SSRIs could reduce the risk associated with the other agents. Better still: Use lithium alone for your patients with bipolar disorder if you can.

Watch out for drug-drug interactions with combinations involving ziprasidone, haloperidol, citalopram, escitalopram, quetiapine, risperidone, and lithium.

is associate professor of psychiatry at Harvard Medical School and codirector, US Department of Veterans Affairs, National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

Possible pharmacodynamic and pharmacokinetic drug-drug interactions that are likely to be clinically relevant and/or frequent in bipolar disorder.

2. Osser DN. Neuroleptic induced pseudoparkinsonism. In: Joseph AB, Young RR, eds. 

Movement Disorders in Neurology and Neuropsychiatry, 2nd Edition

Prolactin monitoring in first-episode psychotic patients.

4. Hindley G, Gall N. QT interval prolongation. In: Taylor DM, Gaughran F, Pillinger T, eds. 

The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Up to 20% of patients with bipolar disorder have 4 or more medications, so it is important to be aware of these common drug-drug interactions.

Drug-Drug Interactions in Patients with Bipolar Disorder

Patients need to be educated frequently about what can increase or decrease their lithium levels, leading to either toxicity or loss of effectiveness. Prescribers need to be reminded as well.

The following are some common circumstances that can increase lithium levels (instruct patients to inform you of any symptoms and get extra levels in these situations):

Dehydration (eg, from vomiting or diarrhea, as may occur in acute gastroenteritis)

Reduced renal filtration rate (eg, in glomerulonephritis and diabetic nephropathy; also age related)

Thiazide diuretics (eg, hydrochlorothiazide) can produce increases from 25% to 400% (very unpredictable).

Nonsteroidal anti-inflammatory drugs (NSAIDs; eg, ibuprofen, naproxen, meloxicam) and probably COX-2 inhibitors (eg, celecoxib, diclofenac) can increase levels 10% to 400% over the course of days to months.

Angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril, enalapril) can induce up to a 400% increase over several weeks.

Angiotensin II inhibitors (eg, losartan, valsartan) probably prompt similar effects to ACE inhibitors.

The following can decrease lithium levels:

Mania may cause levels to go down 50% despite confirmed adherence.

 The mechanism is unclear, but it might be that lithium goes into the intracellular compartment during mania. If you increase dose to improve the plasma level, toxicity symptoms can appear—or they may appear after the mania remits and the lithium returns to the extracellular space.

Caffeine may promote renal excretion of lithium.

The following have little effect on lithium levels

Amiloride is a potassium-sparing diuretic and sometimes does raise levels (need to monitor).

Sulindac is an NSAID that may or may not raise levels (need to monitor).

 we discussed the importance of keeping maintenance lithium levels in the range of 0.6 to 0.8 mEq/L as well as avoiding even brief occurrences of levels more than 1.0 to minimize the risk of long-term kidney impairment.

During meetings with patients, it is important to give frequent reminders of the aforementioned factors that affect levels so that patients will be more likely to call and inform prescribers and to have lithium levels drawn when necessary. Temporary adjustment of doses while waiting for levels (or if it is impossible to get levels) may be advised in some cases.

is associate professor of psychiatry at Harvard Medical School and codirector, US Department of Veterans Affairs, National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. He is also an Editorial Board member for 

. The author reports no conflicts of interest concerning the subject matter of this article.

The Maudsley Prescribing Guidelines in Psychiatry, 14th Edition

Mood-dependent changes of serum lithium concentration in a rapid cycling patient maintained on stable doses of lithium carbonate

3. Mester R, Toren P, Mizrachi I, et al. 

Caffeine withdrawal increases lithium blood levels

4. Ciraulo DA, Shader RI, Greenblatt DJ, Creelman W. 

. Lippincott Williams & Wilkins; 2006:272-275.

Tips for lithium dosing for optimal renal safety

Here are a few reminders to help avoid both toxicity and loss of effectiveness.

Lithium Levels—What Increases and Decreases Them?

Bipolar Disorder: Sorting Out Comorbidities

Slideshows

Because patients with bipolar disorder often have underlying comorbidities, a thorough diagnosis is imperative. 

Nephrotoxicity is a well-known adverse effect of lithium. Monitoring for nephrotoxicity and using 

 with great caution in patients with renal impairment are standards of care.

The estimated glomerular filtration rate (eGFR) has become an easily available routine measure for baseline and periodic monitoring of kidney function in patients on lithium.

 Laboratories report eGFRs of less than 60 mL/minute/1.73 m

 as abnormal and indicating risk of chronic kidney disease (CKD). Stage 3 CKD, associated with an eGFR of 45 plus or minus 14 mL/minute/1.73 m

, is defined as a level of impairment with significant potential for kidney failure and death during a 5-year period. One would usually want to avoid lithium, or consider reducing or discontinuing it, if the eGFR is between 45 and 59 mL/minute/1.73 m

 Bipolar Update, we discussed ways of dosing 

 and maintaining levels of lithium to minimize risk of kidney harm.

 These included using the immediate-release formulation (rather than long-acting versions), prescribing the full dose at night, keeping maintenance levels no higher than 0.6 to 0.8 mEq/L, and avoiding levels higher than 1.0 mEq/L at any time.

GFR decreases with age, so not all reductions of eGFR during long-term lithium use are due to lithium. Questions have been raised about the longstanding adoption of a fixed threshold of less than 60 mL/minute/1.73 m

 for an abnormal eGFR for patients of all ages. It has been proposed that the thresholds should be 75 mL/minute/1.73 m

 for patients under age 40, 60 mL/minute/1.73 m2 for those aged 40 to 65 years, and 45 mL/minute/1.73 m

In a recent study, investigators evaluated outcomes associated with CKD when defined by a fixed (< 60) threshold vs these age-adapted eGFR thresholds.

 Utilizing a population-based cohort of patients in the province of Alberta, Canada, investigators found, as expected, that CKD was diagnosed much more often in older adults using the standard threshold of less than 60 compared with using a 45 mL/minute/1.73 m

 threshold. There were 2356 new cases per 100,000 person-years with the 60 mL/minute/1.73 m

 threshold vs 714 with the 45 mL/minute/1.73 m

 threshold. However, 75% of patients with eGFRs from 45 to 59 mL/minute/1.73 m

 were aged 65 or older and had normal or only mild albuminuria. The 5-year risks of kidney failure and deaths among these older adults were similar to those of a control group of non-CKD elderly patients with eGFRs from 60 to 89 mL/minute/1.73 m

 was 0.12% in both groups. The investigators concluded that the current fixed eGFR criterion seems to result in overdiagnosis of CKD in this aging population. They likely suffered unnecessary evaluations and interventions when their problem was only age-related reduction in eGFR.

 would seem to be that older adults and some other patients with eGFRs of 45 to 59 mL/minute/1.73 m

 do not necessarily have CKD. Clinicians should evaluate these patients for proteinuria before making that diagnosis. Of course, close consultation with a kidney specialist would be advised regarding decisions about lithium use. However, it may be reasonable to start or continue to use lithium in more patients than was done prior to the emergence of this new perspective on the meaning of eGFRs.

Younger patients, in contrast, were often underdiagnosed with CKD using the 60 mL/minute/1.73 m

 threshold. The study found 14 vs 91 new cases of CKD per 100,000 person-years with the 60 and 75 mL/minute/1.73 m

 thresholds, respectively. The absolute rate of CKD was low. Still, it would seem prudent to remember the Alberta data and consult with a renal specialist if the eGFR is below 75 mL/minute/1.73 m

 in younger patients. Notably, however, studies of lithium maintenance in younger patients with bipolar disorder have not found declining eGFRs.

is an associate professor of psychiatry at Harvard Medical School and codirector of the US Department of Veterans Affairs’ National Bipolar Disorder Telehealth Program in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

The Maudsley Prescribing Guidelines in Psychiatry. 14th Edition. 

Lithium and eGFR: a new routinely available tool for the prevention of chronic kidney disease.

Tips for lithium dosing for optimal renal safety.

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CKD: a call for an age-adapted definition.

Accounting for age in the definition of chronic kidney disease.

6. Clos S, Rauchhaus P, Severn A, et al. 

Long term effect of lithium maintenance therapy on eGFR in patients with affective disorders: a population-based cohort study.