The Role of Serum Lithium Concentration on Pill Burden in Psychiatric Populations

Innov Clin Neurosci. 2020;17(4–6): Early Release, Ahead of Issue

Lithium has been considered a mainstay for the treatment of bipolar disorder for more than 60 years.¹ It has proven effectiveness in depression, mania, and suicide prevention.² Despite lithium’s proven efficacy, it has remained underutilized, in part as a result of prescriber reluctance to use lithium due to its narrow therapeutic index, risk of toxicity, and frequent need for monitoring recommended by major guidelines.^3,4 The targeted narrow therapeutic window within which lithium is considered effective and with a decreased risk of toxicity is 0.6 to 1.2mEq/L.⁵

Despite its long history of use, there continues to be debate among health care providers regarding appropriate lithium dosing and serum concentrations in order to control symptoms while minimizing potential adverse effects and decreasing pill burden. Many studies have highlighted the importance of monitoring serum lithium concentrations to assess adherence and screen for potential toxicity. However, current research does not establish the efficacy of lithium based on differences in serum concentration.⁵ There are few studies available evaluating whether psychiatric pill burden is influenced by serum lithium concentration. This study examined the serum lithium concentrations of psychiatric inpatients and considered whether these concentrations are associated with the need for additional psychiatric polypharmacy.

Literature Review

Lithium has long been considered the gold-standard and most effective agent in the treatment of bipolar disorder. Additionally, it is used in the treatment of other psychiatric disorders, including treatment-resistant depression and acute mania.^4,6–8 Relative to other agents used for the treatment of bipolar disorder—including but not limited to valproate, olanzapine and quetiapine—lithium has been found to be superior due to its decreased rate of treatment failure.⁹ Lithium has also been shown to decrease the risk of attempted suicide, suicidal ideation, and suicide-related death in individuals with a mood disorder diagnosis.^6,10 In individuals receiving lithium therapy for the treatment of bipolar disorder or other major affective disorders, an 80-percent decreased risk of attempted or actual death by suicide was reported.¹¹

Manufacturer guidelines recommend lithium be dosed to a serum lithium concentration range of 0.6 to 1.2mEq/L.¹² Daily doses of 900mg or less can result in therapeutic serum concentrations that are effective in some individuals, while others might require upwards of 1,800mg daily.¹³ Lithium can be dosed once, twice, or three times daily.¹⁴ To determine an accurate serum lithium concentration, the trough serum concentration is typically drawn 12 hours after the last dose.¹³

Within the recommended therapeutic range, lithium can affect both the endocrine and renal systems, resulting in potential adverse effects on renal and thyroid function.⁴ Adverse effects associated with lithium are generally dose-dependent and can involve the central nervous system (CNS), gastrointestinal (GI) tract, kidneys, and thyroid. Although these side effects can be observed at 12-hour steady-state lithium concentrations greater than 1mEq/L, CNS side effects have been reported at lower concentrations, especially in more vulnerable populations such as geriatric and pediatric patients.

Nephrogenic diabetes insipidus, which manifests as polydipsia and polyuria, is reported in roughly 30 to 50 percent of patients and preliminary studies have demonstrated that the incidence of these renal effects might be less in patients receiving a once-daily versus divided dose; however, once-daily dosing potentially contributes to the worsening of other adverse effects.¹⁵ Adverse GI side effects occur frequently when lithium is initiated at any dosing frequency, with nausea, anorexia, diarrhea, and vomiting reported in up to 30 percent of patients. While these GI effects generally decrease with continued therapy, they are most notably associated with high peak serum concentrations of lithium. To minimize GI adverse effects, lithium can be administered with food, as the liquid formulation, or extended release formulation to allow once-daily dosing.^4,15 Regardless of dose, lithium has been reported to cause clinically evident hypothyroidism in up to four percent of patients with therapeutic concentrations.

Other side effects can include but are not limited to cardiac, dermatologic, and hematologic consequences.¹⁵ Hematologic side effects of lithium include acute and chronic leukocytosis and neutrophilia.¹⁶ Neutrophilia occurs when serum lithium concentrations are between 0.4 and 1.1mEq/L.¹⁷ White blood cell (WBC) values can increase 30 to 40 percent as compared with those before lithium treatment. This side effect has led to the concomitant use of lithium with clozapine in patients at risk for neutropenia. In combination with clozapine, lithium dosed in the range of 300 to 900mg daily and upwards of 1,200mg to 1,500mg daily has been effective in maintaining adequate neutrophil counts.^18–20 Individuals should be monitored closely during lithium dosing changes due to the narrow therapeutic window around which adverse effects are most likely to occur.¹³

Acute toxicity, which includes nausea and diarrhea, can appear when lithium reaches a serum concentration greater than 1.2mEq/L.¹⁵ However, the risk of toxicity might still occur with individuals who have a lower serum lithium concentration.²¹ As serum lithium concentrations increase, individuals can experience blurred vision or other neurologic symptoms.¹³ Supratherapeutic serum lithium concentrations can lead to signs and symptoms of toxicity such as confusion, impaired coordination, and seizures, with coma or death occurring at serum concentrations as low as 2mEq/L.^3,13 Organ system damage including renal insufficiencies has been reported at serum concentrations of greater than 3mEq/L.¹³ In other cases, treatment-resistant individuals might require and tolerate higher serum lithium concentrations.²²

Current guidelines do not recommend the use of more than three concurrent psychotropic medications for the treatment of bipolar disorder.^23–26 Despite these recommendations, individuals with bipolar disorder are often prescribed multiple psychotropic medications, leading to polypharmacy.²⁷ Up to 36 percent of individuals with bipolar disorder were found to have a complex pharmacotherapeutic regimen consisting of at least four psychotropic medications.²⁸ An increase in the number of prescribed medications can lead to decreased adherence, and increased risks of adverse effects, drug interactions, and cost to the individual and health care system alike, which must be evaluated when preparing an individual for discharge from a psychiatric hospital.^29–31 Lithium might decrease the need for or associated risks of polypharmacy, but it is unknown at what serum lithium concentration this effect is found.²⁷

Objectives

Our primary outcome was to determine whether serum lithium concentrations were associated with additional psychiatric polypharmacy. It was hypothesized that psychiatric inpatients with a lower serum lithium concentration would have an increased pill burden, while individuals with a high serum lithium concentration would have a decreased pill burden. Currently, there is no clinical application for the use of serum lithium concentration to predict the pill burden of psychiatric inpatients. Secondary outcomes measured the use of concomitant psychiatric medications at doses above the established FDA MDD as well as a reported increased use of pro re nata (PRN) psychiatric medications.

Methods

This study was conducted at a state psychiatric inpatient facility in Buffalo, NY and approved by the facility’s Institutional Review Board. For hypothesis testing, a retrospective chart review was conducted utilizing the computerized patient record system, bar code medication administration, and mental health automated health record system of inpatients 18 years of age or older who received lithium, regardless of diagnosis, and had a serum lithium concentration drawn while hospitalized at the psychiatric facility between April 1, 2016 and December 31, 2018.

Pharmacologic endpoints included serum lithium concentration and number of concurrent medical or psychiatric medications, PRN medications prescribed and/or given, dosing of psychiatric and medical medications, STAT medications given, psychiatric medication changes after serum lithium concentrations were evaluated, and psychiatric medications dosed over the FDA-recommended MDD.

Data were analyzed by evaluating each individual serum lithium concentration as its own case control. By reviewing individual serum lithium concentration, the data reflect the psychiatric pill burden throughout the long-term course of treatment. This approach can be viewed as more precise than examining a limited snapshot of one distinct time in an individual’s treatment.

A one-way analysis of variance (ANOVA) was completed using Minitab (Pennsylvania State University, State College, PA, USA) to compare the number of medical and psychiatric medications prescribed, psychiatric medications dosed over the FDA-recommended MDD, psychiatric medication doses, and PRN and STAT medications given based on the serum lithium concentration. The serum concentration for statistical significance was selected at p less than 0.05 with significant outcomes relevant to clinical outcomes and to minimize the risk of making a type 1 error.

The following were included in this study: inpatients present at the facility any time during April 1, 2016 to December 31, 2018 aged at least 18 years old who were prescribed and received lithium and who had at least one serum lithium concentration measured and recorded between April 1, 2016 and December 31, 2018. Individuals with a Criminal Procedure Law designation were excluded.

Results

The charts of 38 patients with a total of 192 individual serum lithium concentrations were reviewed. Data were analyzed via one-way ANOVA to examine how the independent variable “serum lithium concentration” impacts or predicts the dependent variable “pill burden of psychiatric medications.” Serum lithium concentrations were stratified into four distinct categories (A, B, C, D) based on a predetermined range (Figure 1). Pill burden of psychiatric medications was determined based on a count of all psychiatric medications prescribed following the draw and evaluation of each serum lithium concentration.

It was observed that differences in the overall burden of psychiatric medications relative to serum lithium concentration were not statistically significant. The number of prescribed psychiatric medications did not significantly increase (p=0.187) or decrease (p=0.178) following the draw and evaluation of serum lithium concentrations, regardless of value. Additionally, the number of scheduled psychiatric medication doses also did not significantly increase (p=0.279) or decrease (p=0.396).

When examining the number of psychiatric medications prescribed over the MDD, there was a statistically significant increase in the number of medications prescribed at doses that exceed the FDA-recommended MDD following the draw and evaluation of serum lithium concentrations as compared with prior to the evaluation of serum lithium concentration (p=0.018). The results additionally suggested that, when individuals had a serum lithium concentration of less than 0.6mEq/L, they were significantly more likely to have received more psychiatric medications that exceeded the MDD relative to categories B (p=0.006), C (p=0.021), and D (p=0.031).

The increase in the frequency of PRN medications administered following a draw and evaluation of lab results of the lowest serum lithium concentration (category A) when compared with the next lowest serum lithium concentration (category B) was a statistically significant outcome (p=0.034).

There was an unequal number of serum lithium concentrations within each of the four categories of serum lithium concentration. Category D (>1.2mEq/L) contained the fewest number of serum lithium concentrations with eight values, while category B contained the most with 89 values. Of note, category D is outside of the recommended therapeutic range and would not be a therapeutic goal for prescribers. If a serum concentration was drawn and measured within category D, the individual would be considered to be approaching or to have reached a toxic serum concentration, thus resulting in a need for urgent intervention to quickly adjust the dose to achieve a safe therapeutic range. Overall, category B accounted for nearly half of the sample (46%).

Discussion

A statistically significant increase was seen in the number of psychiatric medications prescribed over the MDD when comparing categories of serum lithium concentrations. Individuals with a serum lithium concentration of less than 0.6mEq/L were most likely to receive concomitant psychiatric medications at doses over the MDD. There was also a statistically significant increase in the frequency of PRN medications administered (cumulative dose) when comparing the serum lithium concentration of categories A and B. Both of these findings might represent a greater degree of residual symptomatology requiring additional intervention.

The differences in the overall burden of psychiatric medications prescribed was not statistically significant following serum lithium concentration when examining all serum lithium concentrations. This might be due to routine prescribing practices of the facility’s medical staff for the treatment of refractory mental illness; however, this assumption requires further investigation to confirm. As some symptoms are addressed, such as mood stability, other symptoms might emerge as well as psychosocial issues that were previously eclipsed by the treated symptom. Overall, psychiatric medications need to properly and thoroughly treat mental illness and promote skill building for coping with psychosocial issues.

Our findings might support a goal of lower serum lithium concentrations since individuals with lower serum lithium concentrations did not require a greater number of medications—just higher doses of concomitant psychiatric medications when compared with individuals with higher serum lithium concentrations. The need for increased frequency of PRN medications among patients in serum lithium concentration category A might be associated with individuals who were recently initiated on lithium and, thus, the duration of lithium use and the value of serum lithium concentrations should be further investigated for clinical usefulness.

Categories A (<0.6mEq/L) and C had 49 and 46 values, respectively. Serum lithium concentrations were examined with consideration that low levels might be reported in patients who were newly initiated and who remain problematically symptomatic. However, a lower serum lithium concentration might be indicated in special populations such as in the elderly or those benefiting from lithium’s hematologic side effects in combination with clozapine.^32,33 Concentrations might change based on fluid and salt intake. There are also racial and ethnic differences in that those of Asian ancestry might be more sensitive to lithium and might experience greater therapeutic benefit at lower doses than individuals of European or African descent.^34,35 Efforts to manage the serum concentration and symptomatology involve adjustments to medication dose, administration time, formulation, and adjunctive psychopharmacology.

Conclusion

Serum lithium concentrations help the prescriber to track progress toward mood stabilization. Therefore, a serum lithium concentration in the low range could indicate the establishment of a new medication regimen. In such a case, one would expect a low serum lithium concentration to indicate the need for a higher dose of lithium or the prescribing of additional psychiatric medications.

Lithium has a narrow therapeutic index and can lead to toxicity and serious adverse outcomes including death if an individual is not monitored closely. We hypothesized that individuals with lower serum lithium concentrations would have an increased pill burden, while individuals with higher serum lithium concentrations would have a decreased pill burden.

We can conclude that serum lithium concentrations might be associated with an increase in the frequency of PRN medications administered as well as an increase in the use of cumulative doses that exceed the FDA MDD. However, serum lithium concentrations were not associated with an increase or decrease in an individual’s psychiatric pill burden. This might be due to the need for more symptom management and additional awareness for the need to prevent polypharmacy. Therefore, it is hypothesized that doses are increased and maybe even exceeded beyond the recommended MDD to ensure that patients do not need to take multiple medications, which subsequently could result in an increased risk of adverse effects and drug interactions. Instead, if lithium doses were optimized, decreased psychotropic doses might be necessary. Given the number of interactions associated with lithium (e.g., consider salt, water, coffee), prescribers are potentially cautious in titrating lithium doses. Prescribers should continue to monitor their patients’ serum lithium concentrations on a regular basis to ensure safety and efficacy.

This study found that targeting a lower serum lithium concentration might decrease the risk of toxicity and not lead to an increase in the number of psychiatric medications an individual is prescribed. The study was limited by the small population and uneven distribution in the number of serum lithium concentration records. Additionally, researchers did not review the date on which lithium was initiated. More studies are needed to confirm this association and to understand whether psychiatric stabilization and the number of discharges are not significantly different if an individual has a lower serum lithium concentration as compared with a higher serum lithium concentration.

References

1. Machado-Vieira R, Manji HK, Zarate Jr C. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord.
   2009;11(Suppl 2):92–109.
2. Post RM. The new news about lithium: an underutilized treatment in the United States. Neuropsychopharmacology. 2017;43(5):1174–1179.
3. Baird-Gunning J, Lea-Henry T, Hoegberg LCG, et al. Lithium poisoning. J Intensive Care Med. 2017;32(4):249–263.
4. Nikolova V, Pattanaseri K, Hidalgo-Mazzei D, et al. Is lithium monitoring NICE? Lithium monitoring in a UK secondary care setting. J Psychopharmacol. 2018;32(4):408–415.
5. Hopkins H, Gelenberg A. Serum lithium levels and the outcome of maintenance therapy of bipolar disorder. Bipolar Disord. 2000;2(3 Pt 1):174–179.
6. Malhi G, Adams D, Berk M. Is lithium in a class of its own? A brief profile of its clinical use. Aust N Z J Psychiatry. 2009;43:1096–1104.
7. Bauer M, Adli M, Bschor T, et al. Lithium’s emerging role in the treatment of refractory major depressive episodes: augmentation of antidepressants. Neuropsychobiology. 2010;62(1):36–42.
8. Malhi G, Outhred T. Therapeutic mechanisms of lithium in bipolar disorder: recent advances and current understanding. CNS Drugs. 2016;30(10):931–949.
9. Hayes J, Marston L, Walters K, et al. Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records. World Psychiatry. 2016;15(1):53–58.
10. Lewitzka U, Severus E, Bauer R, et al. The suicide prevention effect of lithium: more than 20 years of evidence—a narrative review. Int J Bipolar Disord. 2015;3(1):1–16.
11. Baldessarini R, Tondo L, Davis P, et al. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord. 2006;8(5 Pt 2):625–639.
12. Lithium [package insert]. Columbus, OH: Roxane Laboratories, Inc; 2011.
13. Richardson T, Macaluso M. Clinically relevant treatment considerations regarding lithium use in bipolar disorder. Expert Opin Drug Metab Toxicol. 2017;13(11):1105–1113.
14. Singh L, Nizamie S, Akhtar S, Praharaj S. Improving tolerability of lithium with a once-daily dosing schedule. Am J Ther. 2011;18(4):288–291.
15. McEvoy G, et al. AHFS: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2019.
16. Lapierre G, Stewart R. Lithium carbonate and leukocytosis. Am J Hosp Pharm.
    1980,37(11):1525–1528.
17. Esposito D, Ruillon F, Limosin F. Continuing clozapine treatment despite neutropenia. Eur J Clin Pharmacol. 2004;60(11):759–764.
18. Mattai A, Fung L, Bakalar J, et al. Adjunctive use of lithium carbonate for the management of neutropenia in clozapine-treated children. Hum Psychopharmacol. 2009;24(7):584–589.
19. Brunoni A, Ferreira L, Gallucci-Neto J, et al. Lithium as a treatment of clozapine-induced neutropenia: a case report. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(8):2006–2007.
20. Kanaan R, Kerwin R. Lithium and clozapine rechallenge: a retrospective case analysis. J Clin Psychiatry. 2006;67(5):756–760.
21. Medić B, Stojanović M, Štimec B, et al. Lithium—pharmacological and toxicological aspects: the current state of the art. Curr Med Chem. 2018 Sep 4. [Epub ahead of print].
22. Oruch R, Elderbi M, Khattab H, et al. Lithium: a review of pharmacology, clinical uses, and toxicity. Eur J Pharmacol. 2014;740:464–473.
23. Paton C, Barnes T, Shingleton-Smith A, et al. Lithium in bipolar and other affective disorders: prescribing practice in the UK. J Psychopharmacol. 2010;24(12):1739–1746.
24. Yatham L, Kennedy S, Parikh S, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2012;15(1):1–44.
25. Goodwin G. Evidence-based guidelines for treating bipolar disorder: revised second edition—recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2009;23(4):346–388.
26. Grunze H, Vieta E, Goodwin G, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania. World J Biol Psychiatry. 2009;10(2):85–116.
27. Suppes T, Dennehy E, Hirschfeld R, et al. TThe Texas implementation of medication algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66(7):870–886.
28. Golden J, Goethe J, Woolley S. Complex psychotropic polypharmacy in bipolar disorder across varying mood polarities: a prospective cohort study of 2712 inpatients. J Affect Disord. 2017;221:6–10.
29. Weinstock L, Gaudiano B, Epstein-Lubow G, et al. Medication burden in bipolar disorder: A chart review of patients at psychiatric hospital admission. Psychiatry Res. 2014;216(1):24–30.
30. Mukattash T, Alzoubi K, El-Rub E, et al. Prevalence of non-adherence among psychiatric patients in Jordan, a cross sectional study. Int J Pharm Pract. 2016;24(3):217–221.
31. Sachs G, Peters A, Sylvia L, Grunze H. Polypharmacy and bipolar disorder: whats personality got to do with it? Int J Neuropsychopharmacol. 2013;17(7):1053–1061.
32. Gören J, Tewksbury A. Drug interactions and polypharmacy. In: Ritsner, MS. Polypharmacy in Psychiatry Practice, Volume I: Multiple Medication Use Strategies. New York, NY: Springer. 2012:45–74.
33. De Fazio P, Gaetano R, Caroleo M, et al. Lithium in late-life mania: a systematic review. Neuropsychiatr Dis Treat. 2017;13:755–766.
34. Platman SR. Lithium retention and excretion. Arch Gen Psychiatry. 1969;20(3):285.
35. Lin KM, Cheung F. Mental health issues for Asian Americans. Psychiatr Serv. 1999;50(6):774–780.