Lithium therapy in patients on dialysis: A systematic review

Abstract

Background

Lithium is a first-line pharmacotherapy for the treatment of bipolar disorder, but long-term use is associated with nephrotoxicity. However, as dialysis effectively eliminates lithium, it remains a pharmacotherapeutic option for patients on dialysis. This systematic review seeks to evaluate the dosing, safety, efficacy, and monitoring of lithium in patients receiving dialysis.

Method

A PubMed database search performed May 5th, 2020, identified 535 article titles. After exclusion criteria were applied, a total of 15 articles were included in this systematic review.

Results

In 18 patients receiving dialysis, lithium was primarily used for the treatment of mood disorders. The majority of patients received 300–900 mg lithium carbonate thrice-weekly following dialysis, but several alternative lithium salts and dosing strategies were utilized. The pharmacokinetic properties of lithium in dialysis are not well understood and can be complicated by a serum lithium “rebound effect” following dialysis, due to a two-compartment volume of distribution. Additionally, presence of residual diuresis in some patients may be reason to administer lithium more frequently than thrice-weekly following dialysis. Lithium was shown to be an effective pharmacotherapy in all patients, with many demonstrating rapid improvement after drug initiation. Five patients experienced an adverse event on lithium, but only one patient required lithium discontinuation.

Conclusion

Lithium may be used in patients on dialysis, with close monitoring of pre-dialysis serum lithium concentrations for at least two weeks after treatment initiation, followed by a lower frequency after stabilization to ensure therapeutic concentrations and reduce toxicity risk.

Keywords

bipolar disorder end-stage renal disease hemodialysis lithium renal replacement

Introduction

Bipolar disorder is a mental illness with significant morbidity and mortality which affects approximately 2.4% of people across the lifespan.¹ According to the 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) bipolar disorder guidelines, lithium is considered a first-line monotherapy for the treatment of acute mania and depression in bipolar disorder, as well as maintenance therapy.¹ Therapeutic utilization of lithium, an alkali metal first discovered in 1818, can be considered one of the most important advances in modern psychiatry, with over 60 years experience in clinical practice.^2,3 Additionally, lithium has been shown to decrease the risk of suicide in patients with bipolar disorder.⁴ General adverse event monitoring with lithium should include nausea, increased body weight, increased thirst and urination, QT-interval prolongation, hypothyroidism, reduced cognitive processing, sedation, tremor, and dermatologic reactions (e.g. acne, rash, hair loss, psoriasis).¹ As lithium has a narrow therapeutic window, which is a U.S. Food and Drug Administration boxed warning, patients should have individualized medication dosing and frequent concentration monitoring (i.e. 3–5 days after the most recent dose titration) during acute therapy.¹ Generally, serum lithium concentrations and renal function monitoring are recommended at a minimum of every 3–6 months in stable patients, with goal serum lithium trough concentrations in acute depression or mania between 0.8–1.2 mmol/L in general adults and 0.4–0.8 mmol/L in older adults.¹

Unfortunately, lithium use is also strongly correlated with nephrotoxicity, including nephrogenic diabetes insipidus, chronic tubulointerstitial nephropathy, and acute tubular necrosis.¹ Chronic lithium therapy (i.e. duration greater than ten years) has been shown to decrease the estimated glomerular filtration rate (eGFR) and increase the risk for progression to chronic kidney disease (CKD).¹ Lithium use in patients over the age of 66 has been shown to double the risk for the development of CKD, although data suggest the progression to end-stage renal disease (ESRD) remains low.¹ While there is no strict estimated glomerular filtration rate (eGFR) cut-off to determine when a patient should discontinue lithium, a nephrology consult is recommended for patients who experience a rapid decline in eGFR (>5 mL/min/1.73 m² over one year or >10 mL/min/1.73 m² over five years) or have an eGFR < 45 mL/min/1.73 m² on two consecutive readings.¹ The risk of declining renal function or requirement of dialysis must also be balanced against the therapeutic benefits of lithium.^5,6

If the decision is made to continue or initiate lithium in patients receiving dialysis, multiple challenges must be addressed. These include variability of dosing in dialysis, accounting for residual diuresis, lack of consensus recommendations for serum lithium monitoring, and the potential for a rebound in serum lithium concentration post-dialysis. Therefore, it is critical to consider the tolerability of therapy in this population, as well as age-related changes in pharmacokinetics, pharmacodynamics, and drug-drug interactions. These challenges are not insurmountable, as multiple case reports demonstrated safety and efficacy of lithium treatment in dialysis.^3,4,6–18 Pharmacokinetically, lithium remains as a metal cation in the body with over 90% bioavailability, has minimal protein binding, follows a two-compartment model of distribution, and is almost entirely renally eliminated; the goal for dialysis patients is to maintain therapeutic serum concentrations between dialysis sessions.^7,16 Lithium distributes via total body water, first into the extracellular fluid, and then into the intracellular fluid within 5–10 days.⁴ It is suggested that approximately 80% of lithium is removed from the extracellular fluid during a dialysis treatment.⁶ Lithium slowly re-equilibrates back into the serum following dialysis, but ingestion of the next dose is required to achieve therapeutic serum concentrations following dialysis.⁶ This re-distribution can cause a fluctuation in lithium concentrations known as a post-dialysis rebound.⁴ The clearance of lithium has also been found to be inversely related to hematocrit, as lithium is not removed from erythrocytes during dialysis.⁹

Given a lack of consensus guiding lithium use in patients on dialysis, this systematic review seeks to summarize available literature involving the safety and efficacy of lithium in this context, lithium dosing strategies, and appropriate monitoring of serum lithium concentrations. To our knowledge, this is the first systematic review of the therapeutic use of lithium therapy in patients on maintenance dialysis and beyond the scope of other related articles published on the topic.

Methods

A PubMed database search on May 5th, 2020 using the search terms “Lithium AND (dialysis OR hemodialysis OR renal replacement)” identified five hundred and thirty-five article titles. The search included case reports, case series, and clinical trials in the English language for adults receiving lithium while on dialysis. Reports utilizing dialysis specifically for the treatment of lithium intoxication were excluded. After careful consideration by the senior authors (IM and MS), a total of twenty-one potentially interesting titles were identified. One article was excluded due to non-English language, and full-text articles were obtained for the others. Four potentially interesting articles were obtained from the reference lists of the interesting articles. A total of 15 articles were included in the systematic review (Figure 1).

Figure 1.

Flow leading to articles included in the systematic review for lithium use in dialysis.

Results

As detailed in Table 1, this systemic review included a total of 18 patients, from 15 articles. The average age was 54 (interquartile range 19.5, range 25–69) years old. Lithium was primarily initiated for the treatment of bipolar disorder but also for major depression, unspecified personality disorder, and cluster headaches. Seventeen patients received hemodialysis, and one received continuous ambulatory peritoneal dialysis. A thrice-weekly hemodialysis regimen was most common, with dialysis duration ranging between three to five hours. Oral lithium carbonate was the most commonly used salt form, although the formulation (e.g. immediate- or extended- release) was often not specified. Therapeutic lithium carbonate doses ranged between 300 mg to 900 mg and were most commonly administered as a single oral dose immediately following dialysis (e.g. thrice-weekly dosing). Three patients received oral lithium daily due to better symptom control and residual diuresis.^6,13,18 Two patients received lithium through the dialysate solution, one via peritoneal dialysis and the other via hemodialysis; the dialysate administration route was used due to poor adherence and difficulty reaching stable therapeutic serum levels with oral dosing.^8,13 In patients with major depression or bipolar disorder, therapeutic pre-dialysis lithium concentrations ranged from 0.3–1.3 mmol/L in patients under 60 years of age^{3,4,8–10,13–15} and 0.5–0.9 mmol/L in patients age 60 years and greater.^6,7,11,12,16 Adverse effects were reported included uncomfortable thirst (n = 1), elevated serum parathyroid hormone and decreased serum calcium (n = 1), somnolence and slurred speech (n = 1), vomiting and myoclonic twitching (n = 1), and broad-based gait, unsteadiness, and ataxia which led to lithium discontinuation (n = 1).^7,9,11,13,14 The other patients were successfully managed with close serum level monitoring and dose adjustment. Two patients had progressive physical deterioration during lithium therapy, but lithium improved symptoms of bipolar disorder.^8,12 Three patients eventually underwent renal allograft and some required lithium dose increases following this.^6,10

Table 1.

Cases of lithium use in patients on dialysis.

Author	Patient characteristics; Lithium indication	Dialysis characteristics; Patient residual renal function	Lithium formulation	Lithium dose; Corresponding serum concentration	Adverse events	Clinical outcome
Bjarnason et al.⁷	62 yo F; MDD	HD 3 x/week; 3.5 hour sessions RRF GFR: 0.9 ml/min/1.73 m²	Carbonate; Release NR	1. 150 mg x 2 DFD; ∼0.25 mmol/L 2. 300 mg x 1 DFD; ∼0.45 mmol/L 3. 450 mg x 1 DFD; ∼0.55 mmol/L 4. 600 mg 3xW; ∼0.9 mmol/L (12-hour trough at Css) 5. 450 mg 3xW; ∼0.7 mmol/L (12-hour trough at Css)	Uncomfortable thirst taking 600 mg 3xW	Continued lithium with “relief of severe depressive symptoms”; Continued lithium with at least 32 weeks of reported observation
Chang et al.⁴	56 yo F; BD	HD; “initially erratic” schedule HD 3 x/week; session hours NR RRF NR	Carbonate; CR	1. 400-600 mg daily with “erratic” HD schedule; 0.5–1.2 mmol/L 2. 400 mg 3xW; ∼0.3 mmol/L (pre-dialysis trough at Css)	NR	BD stabilized at lower lithium concentration along with olanzapine 10 mg daily; Continued lithium at least 2 years after discharge
Engels et al.⁶	69 yo F; BD	HD 3 x/week; 3 hour sessions RRF GFR: 10 ml/min/1.73 m²	Carbonate; Release NR	1. 300 mg 3xW; 0.33 mmol/L 2. 200 mg daily; 0.6 mmol/L	None	Patient had “marked improvement” in depression after 1 month; Continued lithium for 52 weeks before receiving a renal allograft
Flynn et al.⁸	56 yo F; BD	PD 3 x/day; 2 liter exchanges RRF NR	Chloride; IR	1. 0.7–0.89 mmol/L dialysate (2 liters, 3x/day); ∼0.75–1.3 mmol/L (serum)	NR	Patients’ mania improved; Continued lithium for approximately 16 weeks before physical decompensation and death
Gruner et al.⁹	59 yo M; BD	HD 3 x/week; 4 hour sessions RRF urine output: 200 ml/day	Carbonate; CR	1. 600 mg 3xW; 0.7 mmol/L 2. 400 mg 3xW; ∼ 0.5–0.77 mmol/L (pre-dialysis trough at Css)	No “common” adverse events; Elevated serum parathyroid hormone; Decreased serum calcium	Patients’ aggression reduced in several days, delusions ceased within 2 weeks; Symptom free after continued lithium for 3 years of reported observation
Knebel et al.¹¹	68 yo M; BD	HD 3 x/week; 3 hour sessions RRF NR	Carbonate; Release NR	1. 600 mg 3xW; 0.6-0.8 mmol/L (pre-dialysis trough at Css) 2. 900 mg 3xW; 1.42 mmol/L (pre-dialysis trough at Css) 3. 600 mg 3xW; 1.41 mmol/L after first HD, 0.75 mmol/L after 2 additional HD	Somnolence and slurred speech at 900 mg dose	Patient’s BD symptoms improved; Adverse effects resolved after dose reduction; Continued lithium at least 2 years of reported observation
Koecheler et al.¹⁰	41 yo M; BD 28 yo F; Unspecified personality disorder	HD 3x/week; session hours NR RRF negligible	Carbonate; Release NR	1. 300 mg daily; 1.3 mmol/L 2. 600 mg 3xW; 1.0 mmol/L	NR	Both patients received renal allograft and lithium was subsequently increased to 300 mg thrice-daily and 300 mg twice daily with trough lithium concentrations of 1.2-1.3 mmol/L and 1.0 mmol/L respectively
Lipperman et al.¹²	65 yo F; BD	HD 3 x/week; session hours NR RRF negligible	Salt and release NR	1. 300 mg 3xW; ∼0.5-0.6 mmol/L (pre-dialysis trough at Css)	NR	Patients’ behavior and mental status “fairly good”; Gradual physical decompensation; Continued lithium for at least 3 years of reported observation
Oakley et al.¹³	47 yo F; BD	HD times per week NR; session hours NR RRF Scr: 14.5 mg/dl	Oral; Salt and release NR Chloride; Added to dialysate	1. ∼550 mg (oral) daily; ∼1.0 mmol/L average (range 0.2-1.8 mmol/L) 2. 0.9-1.0 mmol/L (dialysate); 0.7 - 0.8 mmol/L (serum) 3. 0.7-0.8 mmol/L (dialysate); 0.6-0.8 mmol/L (serum)	Vomiting with oral lithium; Myoclonic twitching with dialysate lithium (0.9-1 mmol/L)	Oral lithium not tolerated with fluctuating concentrations; Lower dialysate lithium dosing reduced myoclonic twitching; BD symptoms “successfully controlled”; Lithium therapy duration NR
Port et al.¹⁴	53 yo M; BD	HD 3 x/week; 4 hour sessions RRF NR	Carbonate; Release NR	1. 300 mg x 2 DFD; ∼0.4 mmol/L 2. 600 mg x 2 DFD; ∼0.75 mmol/L 3. 900 mg x 1 DFD; ∼1.0 mmol/L	Broad-based gait; Unsteadiness; Mild ataxia	Hamilton Depression Rating Scale score reduced from 17 to 2 after one month of lithium use; Lithium discontinued due to toxicity after one month; Continued improvement in depressive symptoms after discontinuation
Procci²	25 yo F; BD vs. SAFD	HD 3 x/week; 5 hour sessions RRF negligible	Carbonate; Release NR	1. 300 mg x NR DFD; ∼0.3 mmol/L 2. 450 mg 3xW; ∼0.6- 0.7 mmol/L 3. 600 mg 3xW; ∼0.7-0.8 mmol/L	NR	Regained psychiatric stability after 2 weeks of lithium use; Continued lithium therapy for at least 26 weeks of reported observation
Quentzel et al.¹⁵	44 yo M; BD vs. SAFD	HD 3 x/week; session hours NR RRF NR	NR	1. 600 mg x 1 DFD; “barely detextable” concentration 2. 1200 mg x 1 DFD; 1.4 mmol/L 3. 900 mg x 2 DFD; ∼1.1-1.2 mmol/L 4. 900 mg 3xW; 0.8-1.0 mmol/L (pre-dialysis trough at Css)	NR	Regained psychiatric stability after 1.5 weeks of lithium use along with haloperidol and clonazepam; Continued lithium for at least “several months” observed as ambulatory patient
Walcher et al.¹⁶	60 yo sex NR; MDD	HD 3 x/week; 4.5 hour sessions RRF CrCl:1.4 ml/min/1.73 m²; Urine output: 400 ml/day	Acetate; IR	1. 1608 mg 3xW; ∼0.7-0.9 mmol/L	None	Clinical outcomes NR; Continued lithium over 40 weeks of reported observation
Zetin et al.¹⁷	57 yo M, 68 yo F, 68 yo M; Diagnosis NR	HD 3 x/week; session hours NR RRF negligible	Carbonate; Release NR	1. 300 mg 3xW; 0.2, 0.3, and 0.5 mmol/L 2. 600 mg 3xW; 0.5-0.9 mmol/L	None	Clinical outcomes NR; Continued lithium for at least 4 weeks of reported observation
Zuddas et al.¹⁸	54 yo M; CH	HD 3 x/week, 5 hour sessions RRF NR	Carbonate; Release NR	1. 150 mg prior to dialysis; 150 mg after dialysis; 150 mg morning of non-dialysis days; 0.13-0.17 mmol/L 2. 150 mg x1 DFD, 150 mg x1 night DFD, 150 mg non-dialysis mornings; Average 0.51 mmol/L, range 0.45 - 0.73 mmol/L	None	Lithium concentrations > 0.46 mmol/L led to “remarkably reduced” frequency and intensity of CH; Continued lithium 50 days and had no CH reoccurrence 3 months after discontinuation

3xW: thrice-weekly dosing after dialysis; BD: bipolar disorder; CH: cluster headache; CrCl: creatinine clearance; Css: concentration steady state; DFD: dose(s) following dialysis; F: female; GFR: glomerular filtration rate; HD: hemodialysis; IR: immediate release; M: male; MDD: major depressive disorder; NR: not reported; PD: peritoneal dialysis; RRF: residual renal function; SAFD: schizoaffective disorder; SR: slow-release; yo: year old.

Discussion

Lithium continues to be a first-line pharmacotherapy for patients with bipolar disorder,¹ however, there are no specific pharmacotherapy guidelines in these patients who also have ESRD. It is well-known lithium is highly dialyzable, with hemodialysis removing ∼80% of lithium from the extracellular volume.⁶ The dose of lithium chosen should therefore be sufficient enough to replace the drug that is removed from the extracellular fluid during dialysis, as it is assumed there is negligible transfer to the intracellular fluid during a dialysis treatment.⁷ The 15 reports included in the systematic review did not offer a uniform lithium dosing procedure in dialysis (Table 1). A study of three hemodialysis patients with no residual renal clearance achieved therapeutic serum lithium concentrations (range of 0.5–0.9 mmol/L) on a maintenance dose of 600 mg lithium thrice-weekly following dialysis.¹⁷ Data from these patients was used to develop a line of best fit for lithium dosing: target serum concentration = 0.4 × (# of 300 mg lithium capsules) – 0.07 [17]. Another report recommended starting all patients at 600 mg lithium carbonate thrice-weekly after each dialysis.¹⁶ A third report advocated for aggressive initial lithium dosing to rapidly achieve control of manic and psychotic symptoms.¹⁵ A fourth report recommended the desired lithium concentration steady-state (mmol/L) = 15 × 0.0001 × (lithium dose (mg)), with emphasis that changes in the length of dialysis treatments may impact serum concentrations, with longer sessions (≥5 hours) leading to lower serum concentrations and vice versa.⁹ Finally, a report analyzed three different lithium dosing methods in hemodialysis: a maintenance and loading dose based on volume of distribution (Vd), a renal function (eGFR) method, and a two-compartment model of distribution method. Of the three approaches, a maintenance dose based on Vd yielded the most accurate serum concentration for their patient with limited residual renal function.⁷ This volume of distribution method is summarized below, with a 300 mg dose of lithium carbonate being equivalent to 8.1 mmol of lithium:

0.8 L/kg * Bodyweight (kg) = Volume of Distribution (Vd)

Vd (L) * Target lithium serum concentration (mmol/L) = Loading dose (mmol) given once after first dialysis

0.333 * Vd = Central compartment volume (CCV)

CCV * Target lithium serum concentration (mmol/L) = Maintenance Dose (mmol) given after subsequent dialysis

Another consideration when determining an appropriate lithium dose is whether the patient has residual renal function (RRF), which is common in lithium-associated nephropathy.^6,16 The presence of RRF means Vd alone cannot be used to estimate the dose, as the dose will likely need to be increased for these patients.^6,7 In one report, a patient received 300 mg lithium carbonate thrice-weekly following dialysis but was unable to reach the target serum concentration of 0.6 mmol/L. This patient’s dose was increased to 200 mg lithium carbonate daily to account for RRF and reached a therapeutic lithium serum concentration.⁶ Another potential reason for lithium clearance outside of hemodialysis and RRF includes lithium excretion through excessive body sweat, though no studies are available to make recommendations related to this intrinsic factor.⁹

Therapeutic drug monitoring is clearly a priority when using lithium in dialysis patients; however, there is not a consensus recommendation for goal trough (i.e. pre-dialysis) lithium concentrations. As there is not enough information available to confidently recommend a goal trough lithium concentration specifically for dialysis patients, we suggest initially using age and clinical condition-specific recommendations from the 2018 CANMAT bipolar disorder guideline.¹ At the same time, patients on maintenance lithium treatment may benefit from lower-than-recommended lithium concentrations.⁴ The frequency of lithium concentration monitoring has been suggested to be performed daily during the first two weeks of treatment and reduced to thrice-weekly pre-dialysis after three consecutive concentrations have been stable on the same dose. Following this period, monitoring frequency may be extended to every one to three months if clinically indicated.^4,9 The clinical value of post-dialysis lithium concentration monitoring may be limited. Reports which obtained post-dialysis concentrations assessed patient-specific pharmacokinetic parameters, determined the specific amount of lithium cleared during dialysis, and investigated signs of lithium toxicity.^6,11,14,16

The pharmacokinetic properties of lithium in hemodialysis are not well understood.⁶ In dialysis patients, the maximum serum concentration (Cmax) of lithium carbonate has been suggested to be ∼30% higher than the trough concentrations immediately prior to the next dialysis session.¹⁴ The general elimination half-life of lithium in dialysis patients is unknown, but may be over 100 hours,¹⁴ and the elimination half-life specifically during active hemodialysis sessions may be 1–1.3 hours.¹⁶ Available data suggest lithium steady-state concentration may be reached in approximately one week for patients on dialysis,^3,11 but concentration fluctuations may occur despite unchanged lithium doses.^3,7,9 Since lithium follows a two-compartment model of distribution, a rebound effect after dialysis can occur, resulting in drug re-distribution from the intracellular to the extracellular compartment, which may affect time to steady-state concentration.^6,11 It has been suggested the type of dialysate (i.e. acetate or bicarbonate) may influence the rebound effect.¹⁹ While both acetate and bicarbonate dialysate eliminate total body lithium relatively equally, acetate dialysate removes lithium almost exclusively from the extracellular fluid, while bicarbonate removes lithium from both intracellular and extracellular space. Therefore, it is plausible that use of bicarbonate dialysate could reduce the rebound effect.¹⁹ Finally, there may be lithium trough concentration variability based on dialysis frequency. One report suggests lithium trough concentrations may be 15% higher after short-interval dialysis frequency (i.e. 48 hour interval) than after long-interval dialysis frequency (i.e. 72 hour interval), which may be due to RRF or other forms of excretion (e.g. sweat).⁹

Lithium is available in multiple salt formulations: acetate, carbonate, chloride, citrate, and oxalate. Lithium carbonate was the most commonly utilized formulation in patients on dialysis, although many reports did not specify whether the immediate (IR) or extended-release (ER) formulation was used. The oral bioavailability of lithium is approximately 80–100%, with Cmax reached in ∼1–2 hours and ∼4–6 for the IR and ER formulations, respectively.² In general populations, a longer time to peak lithium concentration can lessen some adverse events (e.g. tremor, cramping, nausea, rash, urinary frequency, neuromuscular slowing), sometime at the expense of more gastrointestinal adverse events,² but it is unknown if this is consistent in patients on dialysis taking lithium. Given the rapid elimination of lithium during dialysis, it would be logical to use the IR formulation to quickly increase the drug to a therapeutic concentration. However, based on available reports, the optimal oral lithium formulation to use in patients on dialysis is unclear. Additionally, some patients may benefit from lithium acetate or chloride to be added directly to their dialysate solution in the event of refusing oral medications, significant lithium concentration fluctuations, or during outpatient peritoneal dialysis.^8,13

Among the 18 patients represented by this systematic review, many of whom had failed alternative pharmacotherapies, lithium generally improved clinical symptoms (Table 1). Patients often had a clinical response (e.g. decreased mania or depression, achievement of euthymia) within one to two weeks and had sustained remission and stability for up to three years^{3–6,9,12,14,15}. Five patients were reported to have adverse effects from lithium therapy which include increased thirst, somnolence and slurred speech, vomiting and myoclonic twitching, ataxia and broad-based gait, and increased serum parathyroid hormone and decreased serum calcium (Table 1).^7,9,11,13,14 Most of these adverse events subsided with lithium dose reduction, but none of these patients’ lithium concentrations exceeded 1.5 mmol/L, which is generally considered a threshold for higher toxicity risk. Two patients had progressive physical deterioration during lithium treatment, but lithium improved overall symptoms of bipolar disorder.^8,12 Two patients may have developed symptoms of mania with the initiation of dialysis.^9,14 While the exact relationship is not known, it is thought dialysis may trigger mania by removal of uro-toxins from the blood or due to dialysis being viewed as a positive life event.⁹ Conversely, one patient developed transient depressive symptoms when initiating hemodialysis.³ Since lithium remains relatively contraindicated in patients with advanced renal disease, the risks and benefits of initiating or continuing lithium in dialysis must be weighed carefully. This systematic review demonstrates lithium can be an effective treatment in patients on dialysis, and the risk of adverse events can largely be mitigated with appropriate dosing and serum concentration monitoring.

As adverse events can occur despite stable and therapeutic lithium concentrations, some patients on dialysis will not have a favorable risk-benefit ratio for lithium use. In the context of treating bipolar disorder, there are no guidelines available for pharmacotherapy management in these patients. Fortunately, some mood stabilizing agents and atypical antipsychotics are not contraindicated in patients on dialysis, or undergo primary renal elimination. Anticonvulsant mood stabilizing agents such as carbamazepine, lamotrigine, oxcarbazepine, and valproic acid could be considered therapies.²⁰ However, lamotrigine may require post-dialysis supplementation, valproic acid can be removed by high-flux dialyzers, and patients taking a highly protein bound medication (e.g. valproic acid) may have increased free-drug concentrations when hypoalbuminemia is present.²⁰ Atypical antipsychotics which could be considered for the treatment of bipolar disorder in patients on dialysis include aripiprazole, asenapine, clozapine, quetiapine, and ziprasidone.²¹ Olanzapine, paliperidone, and risperidone should be avoided or used with high caution as adverse events and reduced clearance have been reported in patients on dialysis.²¹ As scientific knowledge is limited regarding the safety and efficacy of these agents in dialysis, their use should be critically assessed by prescribing clinicians and pharmacists. The use of therapeutic drug monitoring of neuropsychiatric medications in patients on dialysis, among other special populations, is of critical importance to safely treat patients and advance scientific knowledge regarding appropriate medication choice and dosing recommendations.²²

Conclusion

Lithium is a first-line therapy for the treatment of bipolar disorder, yet its use is relatively contraindicated in patients with severe renal disease.¹ However, multiple case reports demonstrate dialysis patients can safely and effectively be treated with lithium. The dosing strategy for lithium in dialysis is not standardized, but a variety of methods have been proposed. Lithium carbonate thrice-weekly following dialysis is the most utilized regimen in dialysis patients, but it is possible to add lithium to dialysate when indicated. Additionally, patients with residual diuresis may require higher lithium doses or more frequent administration. Regardless of dose, careful monitoring of lithium concentrations is crucial to achieve a therapeutic response and avoid toxicity. Some patients taking lithium developed adverse events consistent with lithium toxicity when serum trough concentrations were less than 1.5 mmol/L, suggesting the need for careful clinical monitoring. While the serum lithium trough concentration which is therapeutic in dialysis patients may be slightly lower than non-dialysis patients, we do not find evidence to be compelling enough to recommend dialysis-specific serum trough lithium concentrations. Therefore, we recommend using age and condition-specific lithium concentration troughs as outlined by the 2018 CANMAT bipolar guidelines.¹ The pharmacokinetic profile of lithium in dialysis patients remains an area of further research; however, it appears patients may achieve lithium steady-state concentration in approximately one week. Rebound lithium concentration increases have been reported, but more research is needed to determine the clinical significance of this event. While this review highlights potential strategies for lithium dosing in ESRD patients, further research is indicated to discern how treatment strategies compare to each other in terms of safety and efficacy for this population.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: IRM receives royalties from Hogrefe Publishing Corp. FAO, NFM, and MDS have no conflicts of interest.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Ian R McGrane

Michael D Shuman

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