Lithium and Medical Comorbidity

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CASE VIGNETTE

“Ms Price” is a 58-year-old Caucasian female with a history of bipolar disorder with psychotic features and borderline intellectual function. Her psychotropic medication regimen has included lithium 300 mg BID for more than a decade, with good clinical response. She was recently diagnosed with breast cancer in situ, which is being treated with a 5-year course of tamoxifen.

Ms James has chronic kidney disease, with a current eGFR of 47 mL/min per 1.73 m². The patient and her sister (primary caretaker) are aware of the adverse effects of lithium on kidney function. However, they request to continue therapy, as Ms Price has a history of illness exacerbation—requiring inpatient psychiatric hospitalization—when lithium was discontinued in the past.

Lithium is a common, widely used mood stabilizer in the treatment of bipolar disorder.¹ Cardiovascular disease is the leading cause of death in bipolar disorder.² There is also some evidence of an increased risk of dementia in patients with bipolar disorder.³

Although associations between lithium treatment and somatic complications are well known, there is also growing evidence for its neuroprotective effects.^4-6 A systematic review found that 4 of 6 included studies found a protective effect of lithium on the development of dementia.⁷

Other studies have found some evidence for decreased cardiovascular disease morbidity and mortality with lithium.^8,9 However, the relationship between long-term lithium treatment and health outcomes is still unclear.

The Current Study

Ponzer and colleagues¹⁰ performed a nationwide register-based study in Finland of long-term lithium treatment and disease risk, particularly vascular and neurological disorders. Cases were defined as at least 1 dispensation of lithium for 3 or more consecutive years from 1995 to 2016, based on a national prescription medicine register.

The authors selected 10 age-, sex-, and municipality-matched controls per case from the general Finnish population. Cases and controls were followed in the national Care Register for Health Care until the end of 2016 for somatic diagnosis outcomes, primarily cardiovascular, cerebrovascular, venous thromboembolic disorders, and neurodegenerative disorders, as well as kidney disease and suicide. Data on smoking, alcohol abuse, hypertension, hyperlipidemia, diabetes, and use of antipsychotic medication were also obtained.

The authors investigated effects of lithium of somatic diagnosis outcomes using Cox proportional hazards models, controlling for the above covariates. A sub-cohort of controls with a history of a diagnosis of mood or psychotic disorder, but not treated with lithium, was identified to consider the effects of psychiatric illness on overall health.

The authors identified 9698 lithium-treated cases and 96,507 controls without lithium prescription for the analyses. Sub-cohort analyses consisted of 8762 lithium-treated cases and 8786 controls. The mean participant age was 45 years, and the sample was 46% male.

In the full cohort, lithium was associated with an increased risk for cardiovascular and cerebrovascular disorders (HR=1.15, 99% CI 1.07–1.23), driven by a higher risk for myocardial infarction, cerebral infarction, and transient cerebral ischemic attacks, and after controlling for common cardiovascular risk factors.

Lithium was also associated with an increased risk for venous thromboembolic events (HR=2.29, 99% CI 2.04–2.58). There was an increased risk of dementia (HR=2.64, 99% CI 2.38–2.94), Parkinson disease (HR=3.82, 99% CI 3.13–4.66), and seizures (HR=2.32, 99% 2.04–2.63) with lithium use. Furthermore, lithium was associated with increased risk of kidney disorders (HR=4.86, 99% CI 4.30–5.50) and suicide (HR=4.18, 99% CI 3.29–5.30) compared to the general population.

In the sub-cohort with psychiatric illness, lithium users had a lower risk for cardiovascular and cerebrovascular disorders as a group (HR=0.80, 99% CI 0.73–0.89), including cerebral infarction (HR= 0.84, 99% CI 0.70–0.99), again after controlling for common cardiovascular risk factors. Risk for venous thromboembolic events remained increased (HR=1.42, 99% CI 1.20-1.69), albeit at a lower magnitude.

This similar pattern was also observed for Parkinson disease (HR=1.58, 99% CI 1.18-2.13), dementia (HR=1.15, 99% CI 0.99-1.33) and kidney orders (HR=3.28, 99% CI 2.63-4.08). The association with suicide was no longer significant.

Study Conclusions

The authors concluded that this was the largest study of associations between long-term lithium treatment and a broad spectrum of somatic health outcomes, compared to both the general population and individuals with mood or psychotic disorders not treated with lithium.

Notably, lithium-treated patients had an increased risk of cardiovascular and cerebrovascular disorders compared to the general population, but a lower risk compared to non-lithium-treated patients. They also found no indication that lithium significantly reduced the risk of dementia or thromboembolic events, and lithium was associated with an increased risk of renal disease.

The primary strength of the study was the large population-based sample, including patients with psychiatric illness not treated with lithium. Limitations included the lack of data on the time on lithium treatment, potential underreporting of smoking and alcohol use, and lack of data on nutrition and physical activity. In order to address the risk of multiple testing, the authors reported 99% (instead of 95%) confidence intervals to decrease the risk of false positive findings.

The Bottom Line

Psychiatric illness is associated with an increased burden of somatic disease. Lithium use was associated with a lower risk of cardiovascular and cerebrovascular disease, but not dementia in individuals with a mood or psychotic disorder diagnosis. Venous thromboembolism, Parkinson disease, and kidney disease were significantly more prevalent in lithium-treated individuals compared to both the general population and individuals with a similar psychiatric background.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Tondo L, Alda M, Bauer M, et al. Clinical use of lithium salts: guide for users and prescribers. Int J Bipolar Disord. 2019;7(1):16.

2. Osby U, Brandt L, Correia N, et al. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry. 2001;58(9):844-850.

3. Diniz BS, Teixeira AL, Cao F, et al. History of bipolar disorder and the risk of dementia: a systematic review and meta-analysis. Am J Geriatr Psychiatry. 2017;25(4):357-362.

4. Hibar DP, Westlye LT, Doan NT, et al. Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Mol Psychiatry. 2018;23(4):932-942.

5. Matsunaga S, Kishi T, Annas P, et al. Lithium as a treatment for Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis. 2015;48(2):403-410.

6. Mohammadianinejad SE, Majdinasab N, Sajedi SA, et al. The effect of lithium in post-stroke motor recovery: a double-blind, placebo-controlled, randomized clinical trial. Clin Neuropharmacol. 2014;37(3):73-78.

7. Velosa J, Delgado A, Finger E, et al. Risk of dementia in bipolar disorder and the interplay of lithium: a systematic review and meta-analyses. Acta Psychiatr Scand. 2020;141(6):510-521.

8. Prosser JM, Fieve RR. Patients receiving lithium therapy have a reduced prevalence of neurological and cardiovascular disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2016;71:39-44.

9. Ahrens B, Müller-Oerlinghausen B, Schou M, et al. Excess cardiovascular and suicide mortality of affective disorders may be reduced by lithium prophylaxis. J Affect Disord. 1995;33(2):67-75.

10. Ponzer K, Millischer V, Schalling M, et al. Lithium and risk of cardiovascular disease, dementia and venous thromboembolism [published online ahead of print, 2023 Jan 18]. Bipolar Disord. 2023;10.1111/bdi.13300.