Lithium carbonate-induced confusional state in patients with bipolar disorder: identification of case reports and review of the evidence

Christa Lyons¹, Maxine Gossell-Williams²

¹Faculty of Medical Sciences, University of the West Indies, Kingston 7, Jamaica
²Section of Pharmacology and Pharmacy, Department of Basic Medical Sciences, University of the West Indies, Kingston 7, Jamaica

Corresponding Author:
Christa Lyons
Email: [email protected]

DOAJ: 2a450af289904b71a6b652063fe77e22
DOI: https://doi.org/10.48107/CMJ.2024.03.001
Published Online: April 5, 2024

Copyright: This is an open-access article under the terms of the Creative Commons Attribution License which permits use, distribution, and reproduction in any medium, provided the original work is properly cited.

©2024 The Authors. Caribbean Medical Journal published by Trinidad & Tobago Medical Association.

ABSTRACT
Objective: Lithium carbonate is a mood stabilizer used in the treatment of bipolar disorder. However, its narrow therapeutic index (normal = 0.6-1.2 mmol/L) predisposes patients to toxic effects. This study aimed to identify case reports and review the evidence on the frequency, mechanism, risk factors and guidelines associated with a lithium-induced confusional state in patients with bipolar disorder.

Methods: All Databases from the National Center for Biotechnology Information (NCBI) were used to search for lithium AND “confusional state” AND “case report” published in English between 2015 and 2020. This search engine was also used to search for lithium AND “confusional state” AND frequency OR mechanism OR “risk factor” OR guideline published in English.

Results: Case reports showed (1) all patients were treated with lithium for bipolar disorder and hospitalized for a confusional state, (2) most patients took concomitant therapies and recovered after lithium withdrawal, (3) some patients were female and old-aged (65+ years old), and (4) no ethnicities, causality assessments and dose patterns were reported. Other scientific literature showed (1) frequencies of a lithium-induced confusional state varied from very common (>10%) to rare (<0.01%), (2) inhibition of inositol phosphate-phosphatase (IMPase) and glycogen synthase kinase-3 (GSK3) might result in a lithium-induced confusional state, (3) ageing, diseases and concomitant therapies increased the risk of a lithium-induced confusional state, and (4) patients should complete lab tests and diagnostic procedures to monitor and/or prevent a lithium-induced confusional state.

Conclusion: Case reports and other scientific literature elucidated the relationship between lithium and a confusional state.

INTRODUCTION

In 1851, French psychiatrist Jean-Pierre Falret diagnosed a patient with “la folie circulaire [circular insanity]”.¹ Today, this diagnosis is known as bipolar disorder – a psychiatric condition characterized by a cyclical variation in mood. Bipolar disorder can be treated with various compounds such as the inorganic compound, lithium carbonate.

Lithium is widely studied, but its mechanism of action is relatively unknown. More is known about other aspects of its pharmacology: (1) it is an oral drug, (2) it begins working in one to two hours, (3) it has a half-life of 18-36 hours, (4) it has a bioavailability of 80-100%, (5) it can adversely affect the thyroid, kidneys and nervous system, and (6) it is eliminated renally.²

In addition, lithium has a narrow therapeutic index (normal = 0.6-1.2 mmol/L)³; there is a small difference between the minimum effective concentration and the minimum toxic concentration. However, what is effective to one person may be toxic to another. Patients have demonstrated signs and symptoms of lithium toxicity at therapeutic levels (this may be due to factors such as old age, other medications, reduced renal function, dehydration and fever).^4,5

The signs and symptoms of lithium toxicity are as follows: lethargy, nausea and tremors (mild = 1.5-2.5 mmol/L), confusional states, hypotonia and tachycardia (moderate = 2.5-3.5 mmol/L), and hyperthermia, hypotension, seizures and death (severe = >3.5 mmol/L).³ Although the mild and severe signs and symptoms are well-documented, less is known about the moderate signs and symptoms of lithium neurotoxicity, mainly a confusional state (a disturbance in cognition, consciousness or perception).

This study aimed to identify case reports and review the evidence on the frequency, mechanism, risk factors and guidelines associated with a lithium-induced confusional state in patients with bipolar disorder.

METHODS

All databases from the National Center for Biotechnology Information (NCBI) were used to identify case reports on a lithium-induced confusional state. Lithium AND “confusional state” AND “case report” were typed into the search engine. The search was confined to case reports published between 2015 and 2020 in English.

All databases from the NCBI were also used to review the evidence on the frequency, mechanism, risk factors and guidelines associated with a lithium-induced confusional state. Lithium AND “confusional state” AND frequency OR mechanism OR “risk factor” OR guideline were typed into the search engine. Again, the search was confined to journal articles published in English.

RESULTS

Five case reports and 14 other article types on a lithium-induced confusional state were identified (Table 1).

In these five case reports, all patients were treated with lithium for bipolar disorder and hospitalized for a confusional state secondary to lithium toxicity. Four patients took concomitant therapies, while one patient did not report if concomitant therapies were taken. Four patients recovered after lithium withdrawal, while one patient recovered even after continuing lithium. Three patients were over 65 years of age, while two patients were in the 45 to 65 years of age range. Three patients were female and two were male.

Three patients (cases 2 to 4) experienced a confusional state at normal serum lithium levels (0.6, 0.91 and 0.84 mmol/L, respectively), while two patients (cases 1 and 5) experienced a confusional state at mild and severe serum lithium levels (1.69 and 4.3 mmol/L, respectively). Two patients experienced a confusional state years after taking lithium, one patient experienced a confusional state one week after taking lithium and two patients did not report the time of onset of their confusional states. There was no clear dose pattern amongst patients. There were also no ethnicities or causality assessments reported.

Though the frequency of a lithium-induced confusional state was not reported in the five case reports, it was reported in other studies. For example, West identified journal articles and reviewed the evidence on lithium neurotoxicity in patients with schizophrenia and schizoaffective disorder.¹¹ He made mention of three researchers who reported varying frequencies of a lithium-induced confusional state: Johnson found it very common (>10% of n = 7), Prien found it common (1-10% of n = 36), and Zall found it rare (<0.01% of n =10) for patients treated with lithium to experience such a state.^12,13,14

Additional studies attempted to explain the mechanism of a lithium-induced confusional state. Brown and Tracy

provided an overview of the evidence supporting one of the most widely accepted models by Berridge and Irvine – The Inositol Depletion Theory.¹⁵ This model proposed that lithium inhibited inositol phosphate-phosphatase (IMPase) and glycogen synthase kinase 3 (GSK3), which led to a confusional state. This model was further supported by data from the authors demonstrating that the level of inhibition is increased in people with bipolar disorder.

The patients in cases 1, 2, 4 and 5 were over the age of 60. The patients in cases 1, 2 and 3 took lithium along with angiotensin-converting enzyme inhibitors (ACEIs), antipsychotics and/or benzodiazepines. The patients in cases 1, 2 and 5 suffered from cardiac diseases, while the patient in case 4 suffered from hypothyroidism.

In an effort to monitor and/or prevent a lithium-induced confusional state, the Sussex Partnership National Health Service (NHS) Foundation Trust established a set of guidelines.¹⁶ Patients taking lithium should have a physical health and wellness check as recommended by their general practitioner (GP). GPs suggest that patients should complete lab tests and diagnostic procedures such as urea and electrolytes, serum creatinine, thyroid function tests (TFTs), full blood count (FBC), serum lithium, serum calcium and electrocardiograms (ECGs).

Table 1: Case reports on a lithium-induced confusional state. Case numbers 3a and 3b referred to the same patient who was hospitalized on two separate occasions.

DISCUSSION

In summary, case reports and other scientific literature elucidated the relationship between lithium and a confusional state. Case reports showed (1) all patients were treated with lithium for bipolar disorder and hospitalized for a confusional state, (2) most patients took concomitant therapies and recovered after lithium withdrawal, (3) some patients were female and old-aged, and (4) no ethnicities, causality assessments and dose patterns were reported. Other scientific literature showed (1) frequencies of a lithium-induced confusional state varied from very common to rare, (2) inhibition of IMPase and GSK3 might have resulted in a lithium-induced confusional state, (3) ageing, diseases and concomitant therapies might have increased the risk of a lithium-induced confusional state, and (4) patients should complete lab tests and diagnostic procedures to monitor and/or prevent a lithium-induced confusional state.

The case reports and other scientific literature provided a basic understanding of a lithium-induced confusional state in patients. However, a larger sample size of the quoted literature may have provided a better understanding. Using research databases other than NCBI (i.e., Elton B. Stephens Company (EBSCO) or OVID) may have resulted in a larger sample size, a better representation of the population and a collection of accurate data.

The data provided by the case reports showed that all patients with bipolar disorder were treated with lithium and hospitalized for a lithium-induced confusional state. Patients in cases 1 and 5 experienced a confusional state at mild and severe serum lithium levels, respectively, while patients in cases 2 to 4 experienced a confusional state at normal serum lithium levels. The lithium-induced confusional state at varying serum lithium levels may be explained by Forester and his colleagues.¹⁷ They performed a cross-sectional assessment on nine participants before suggesting that brain lithium levels may be elevated even when serum lithium levels are normal. It remained a suggestion, as no brain lithium levels were reported in the case reports.

Patients taking concomitant therapies were at an increased risk of experiencing a confusional state in the case reports. The patient in case 1 took Lisinopril in conjunction with lithium. Lisinopril might have inhibited aldosterone and angiotensin II, leading to natriuresis, decreased renal lithium clearance, increased serum lithium levels and lithium toxicity (as occurred in the patient in the case report by Alderman and Lindsay, as well as the patient in the case report by Krysiak and Okopien).^18,19 The patient in case 2 took Haloperidol and lithium. Lithium might have inhibited striatal dopamine synthesis, thereby increasing the effect of dopamine-receptor blockade by Haloperidol and leading to an encephalopathic syndrome – a condition characterized by extrapyramidal symptoms and severe neurotoxic effects (as occurred in the patient in the case report by Spring, as well as the four patients in the case report by Cohen and Cohen).^20,21 The patients in cases 2 and 3 took Clonazepam along with lithium. There might have been a synergistic effect between both drugs, resulting in central nervous system depressant effects (as occurred in the patient in the case report by Koczerginski and his colleagues, as well as the 21 patients in the cross-sectional study by Divoll and his colleagues).^22,23 The patient in case 3 also took Quetiapine in combination with lithium – two drugs with anticholinergic properties. Competitive antagonism of acetylcholine at muscarinic receptors and anticholinergic intoxication might have occurred as a result (as occurred in the literature review by Glassman and Bigger).²⁴ In all these cases, patients recovered after lithium withdrawal, suggesting that lithium was the offending agent.

Sex and age also increased patients’ risk of experiencing a confusional state. Three out of five patients were female and old-aged. These elderly patients might have experienced pharmacokinetic and pharmacodynamic changes that made them more sensitive to the adverse effects of lithium; pharmacokinetic changes included a reduction in renal clearance and a decrease in volume of distribution of water-soluble drugs, while pharmacodynamic changes included altered sensitivity of receptors to lithium (as was found in the retrospective analysis by Shine and his colleagues).²⁵ Even female patients who were under the age of 60 and treated with lithium were shown to experience renal dysfunction, which might have led to reduced lithium clearance and lithium toxicity (as was found in the letter to the editor by Flint).²⁶

The case reports did not mention patients’ ethnicities, causality assessments and lithium dose patterns. Ethnic data might have revealed differences in susceptibility to lithium toxicity, even though Shelley’s controlled experiment showed that there did not seem to be differences in the pharmacokinetics or side effects of lithium in Caucasians and Afro-Caribbeans.²⁷ Causality assessments might have helped to determine what factors (ethnicity, age, sex, dose and concomitant therapies) caused lithium toxicity. Dose patterns might have also revealed differences in susceptibility to lithium toxicity.

In addition to the case reports, scientific literature evaluated the relationship between lithium and a confusional state. In a 1982 literature review, West reported variations in the frequency of a lithium-induced confusional state in patient.¹¹ He attributed these variations to individual differences in absorption and excretion of lithium, and acute exacerbations of illness. However, other patient characteristics (i.e., sex, age, and concomitant medical illnesses and medications) must be considered.

With regards to the mechanism of a lithium-induced confusional state, it remained to be speculated. Lithium was thought to inhibit IMPase and related enzymes, resulting in direct and indirect depletion of inositol and mood stabilization. One of the related enzymes was GSK3, which played an integral role in energy metabolism, neuroprotection and neuroplasticity signalling pathways (as suggested by the literature review by Gould and Manji).²⁸ Inhibition of GSK3 might have also resulted in a confusional state.

As mentioned earlier, ageing and concomitant therapies increased the risk of a lithium-induced confusional state. Disease also increased this risk. All patients suffered from bipolar disorder, which in itself, can cause an inability to focus and an impairment of cognitive function (especially if patients are untreated or treated with subtherapeutic doses of medications). The patient in case 1 suffered from bipolar disorder, in addition to cardiac and renal diseases (these diseases alone are associated with increased morbidity and mortality); lithium use in the setting of cardiac and renal diseases can result in arrhythmias (i.e., atrial fibrillation, junctional rhythm, ST-T wave changes, supraventricular tachycardia and sinus node arrest) and kidney injury (most commonly nephrogenic diabetes insipidus) (as outlined by the literature review by Reisberg and Gershon).²⁹ The patient in case 4 suffered from hypothyroidism; lithium might have prevented the release of thyroxine (T4) and triiodothyronine (T3), thereby exacerbating the hypothyroid state (as outlined by the letter to the editor by Terao).³⁰ A hypothyroid patient might have experienced symptoms ranging from mild attentional impairment to severe delirium – symptoms mirroring those of a lithium-induced confusional state.

It was recommended that all patients taking lithium should follow certain guidelines to monitor and/or prevent a lithium-induced confusional state (even though this state can occur at normal serum lithium levels).¹⁶ As suggested by an NHS guideline, patients should visit their GP annually for a physical health and wellness check. Vitals, height, weight, smoking status and alcohol use should be assessed, and labs for lipid and plasma glucose levels should be completed. Patients may be prompted to complete additional labs like urea and electrolytes, serum creatinine (every six months or more often if patients suffer from impaired renal function), TFTs (every six months or more often if there is evidence of thyroid dysfunction), FBC (annually), serum lithium (every five to seven days until the desired level is attained and then, every three months), serum calcium (annually) and ECGs (as needed, especially for patients with cardiovascular disease). These labs and screening assessments ensure that patients are healthy and unburdened by illnesses and toxic effects of medications.

CONCLUSION

In conclusion, case reports and other scientific literature elucidated the relationship between lithium and a confusional state. Though the studies were limited by their small sample sizes, they noted that patients experienced a moderate neurotoxicity at normal and abnormal therapeutic ranges of lithium. This may be explained by different patient factors such as age, sex, medications and medical illnesses. These factors must be taken into consideration when physicians prescribe lithium. Then and only then can patients experience the therapeutic effects, not the toxic effects, of lithium.

Acknowledgments: The authors wish to thank the Pharmacovigilance Programme at the University of the West Indies (Mona Campus) without which this research would not be possible.
Competing Interests: Not applicable
Ethical Approval: Not applicable
Funding: Not applicable
Author Contributions: Christa Lyons (research student) was supervised by Professor Maxine Gossell-Williams (research mentor) while conducting and writing this review article.

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