Challenges with lithium use in geriatric patients

ISSN 2397-5628 Journal of Geriatric Care and Research 2017, Vol 4, No 2 Short review Challenges with lithium use in geriatric patients Shiva Shanker Reddy Mukku, Palanimuthu T Sivakumar, Mathew Varghese Abstract Methodology Lithium is the one of the oldest psychotropic used for severe mental illness. It has well proven efficacy in young patients with bipolar disorder. The use of lithium requires regular monitoring of the serum level and checking for adverse effects. When it comes to elderly patients there is always reluctance to use lithium as first choice. The studies done so far in elderly bipolar disorder had proved lithium efficacy similar to valproate and lamotrigine. The pharmacokinetic changes associated with aging, along with decreased functional reserve in elderly put elderly at higher risk of adverse effects and toxicity. This review discusses the challenges of using lithium in elderly patients and the efficacy of lithium in late onset bipolar disorder. We have searched for the articles related to lithium and elderly using different terms such as “lithium and elderly”, “lithium and pharmacokinetic changes with aging”, “lithium and bipolar, lithium and adverse effects in elderly”, “lithium and toxicity in elderly” and “lithium and dosage in elderly”. The search sites used are PUBMED and GOOGLE SCHOLAR. Key words bipolar disorder, elderly, lithium Introduction Lithium is the simplest chemical used as a medication. It was in mid-19th century after an influential paper by John Cade entitled “Lithium salts in the treatment of psychotic excitement” lithium made its entry in to psychiatry. 1 Mogens Schou in Denmark was the first to conduct a randomised trial of lithium in mania showing its effectiveness. Many studies conducted following this trial demonstrated the efficacy of lithium in mania and bipolar illness. Over a period of time, lithium emerged as an alternative to electroconvulsive therapy (ECT) in mania and became established as the drug of choice for maintenance treatment in bipolar disorder.1 Lithium was introduced in India in late 1960. The first study on lithium use in India by Dube et al. evaluated the role of lithium use in 20 patients with hypomania and found that 95% patients showed significant improvement.2 In elderly patients with mood disorder lithium is considered for acute management and for prophylaxis. Limited studies exploring the efficacy of lithium in late onset bipolar disorder / mania have demonstrated positive evidence of efficacy.3,4 Despite this lithium is under used in elderly due to age related changes in pharmacokinetics, associated medical comorbidities and risk for adverse effects. In this review we discuss about the challenges associated with the use of lithium in elderly. Pharmacology Lithium is a soft metal with an atomic number 3. It is monovalent cation with two stable isotopes 6Li and 7Li, the latter being more abundant in nature.5 There are few preparations of lithium, among them lithium bromide and lithium chloride were used in the past but they fell out of use. Currently available are lithium carbonate, lithium citrate, lithium orotate and lithium aspartate. Lithium carbonate is commonly used followed by citrate preparation. Lithium is rapidly and completely absorbed after oral administration with bioavailability of 80-100%. It has no metabolism and excreted unchanged by the renal system. It elimination half-life is 18-36 hours.6 Clinical scenarios where lithium is used in elderly There are few clinical conditions and scenarios where one has to choose or continue lithium in the elderly. The common scenario is where a person with bipolar disorder is on lithium for prophylaxis for many years and now has become elderly.3,7 The second scenario is treatment of resistant depression where the response is partial or little to antidepressants. In this situation lithium is often chosen as augmenting agent.8.9 Lithium is also used in the elderly in situations such as high suicidality,10 and in the prophylaxis of steroid induced psychosis.11 Pharmacokinetic changes in elderly: There are few significant changes in the way lithium is handled in the body with aging. The bioavailability of lithium is not altered with increasing age as lithium is not subject to first-pass metabolism. The composition of the body changes with aging, producing an increase in body fat, and a decrease in total body water. This lead to decrease in volume of distribution of lithium and higher level of serum lithium for a given dose compared to young adults. The clearance of lithium progressively 39 Mukku et al, 2017 decreases with age due to decrease in glomerular filtration. This further leads to gradual increase in serum lithium level.12,13 the 10 year follow-up data reported that the improvement in psychopathology is better with lithium compared to oxcarbazepine and lamotrigine.27 Adverse effects in elderly There only two prospective studies on the lithium use in elderly. In a study done by Murray et al, where lithium use is in elderly is compared with young bipolar patients reported that there is no decline in efficacy of lithium with ageing.18 In another prospective study done by Schaffer and Garvey on 60 elderly patients who were put on lithium reported good response in most of them. 28 Lithium can contribute to side effects related to central nervous system, gastrointestinal system, `endocrine system, cardiovascular system and renal system as in young adults. Most of the studies done on tolerability of lithium have shown that elderly were more prone for side effects and toxicity.3 It is also important to note that these side effects and toxicity can occur at lower doses compared to younger adults. A prospective study of 31 patients aged between 60 and 79 years treated with lithium reported electrocardiogram changes in 58%. 14 In a retrospective study assessing the efficacy and tolerability of lithium therapy in 43 patients aged 65 years and above, lithium toxicity was reported in 26% of patients.15 Lithium use in elderly has been associated with higher frequency (32%) of elevated thyroid-stimulating hormone levels in elderly aged 65 to 85 years.16 This is much higher compared to the 19% subclinical hypothyroidism reported in adults with lithium treatment.17 The prevalence and severity of common side effects like fine hand tremor is also noted to increase with age.18 However in a cross-sectional study, the frequency of nephrogenic diabetes insipidus in elderly was noted to be similar to young adults.19 Dosage requirements in elderly In elderly lower serum concentrations of lithium should be maintained compared to young adults.20 A study on the use of lithium in elderly has shown older patients (aged 70–79 years) required a dose 31% lower than those aged <50 years.21 In an observational study on 110 lithium treated elderly patients, median serum concentration of lithium was 0.55 mmol/l.22 In the same study mean daily doses of lithium carbonate was 464 ± 196 mg in patients taking angiotensin convertase enzyme (ACE) inhibitors, angiotensin receptor blockers, and/or thiazides, the dose was 384 ± 187. The dosage recommended amongst patients aged between 65 and 75 years ranges from 300 to 600 mg/day and rarely exceeds 900 mg/day. For patients aged more than 80 years or frail elderly, the dosage should range from 150 to 300 mg/day and should rarely exceed 450 mg/day.13 Efficacy of lithium in late onset mania/bipolar The studies on lithium efficacy in elderly started in 1970. The initial studies were retrospective studies done by van der Velde; Hewick et al; and Himmelhoch et al.23-25 They have used young bipolar patients as a control group and all these studies suggested that lithium efficacy decreases with age. The later retrospective study by stone et al, contrary to the previous studies said lithium use is effective in elderly and it reduced the number of admissions.15 In the study done by Chen et al, where valproate was used as comparator, found the responsiveness to lithium is better than Valproate. 26 In a recently done retrospective study by Raja et al, included 40 A controlled double blind study done by Sajatovic et al, where the lithium was compared to placebo and lamotrigine found that lithium increases the time to relapse compared to placebo.29 In the GERI-BD study by Young et al, lithium was compared to valproate in randomised controlled trial reported that there is significant decrease in YMRS score in two group.30 The study that said there is no difference between the two groups. Challenges with lithium in elderly 1. In elderly dehydration is very common due to agerelated deficits in thirst mechanism. This will lead to increase in the serum level of lithium in elderly.31 2. Elderly patients have medical comorbidity apart from primary psychiatric disorder. Certain conditions such as hypertension, congestive heart failure and chronic kidney disease will alter the serum lithium level.12 3. Polypharmacy is very common in elderly for various medical conditions. Some of the drugs used in the elderly like diuretics, ACE inhibitors, calcium antagonists and non-steroidal anti-inflammatory drugs (NSAIDs) will alter the serum levels of lithium.31,32 4. Another problem that is commonly encountered in elderly is poor drug compliance. This is very challenging considering the number of medication elderly has to take for the medical conditions. The studies reported that complex regimen and high pill count reduces compliance.33 5. The last but not the least is the risk of overdose with lithium in elderly. The overdose might due to cognitive impairment or self-harm/suicidal attempt in the elderly.34 Overdoses involving lithium could be a serious medical concern. Recommendations for appropriate use of lithium 1. A thorough physical examination of the elderly patient before starting lithium is necessary. The examination should specifically check for goitre, hypertension and signs of congestive cardiac failure. 2. A review of all the medications taken by the patient is needed. Specifically look for NSAIDS, thiazide diuretics and ACE inhibitors. Table 1: Studies done on lithium efficacy in elderly bipolar disorder Sl No 1 Author Study design Sajatovic et al, 2005.29 Placebo controlled, doubleblind trial 2 Young et el, 2010.38 3 Murray et al, 1983.18 Schaffer and Garvey, 1984.28 van der Velde, 1970.24 Hewick et al, 1977.25 Himmelhoch et al, 1980.23 Stone, 1989.15 4 5 6 7 8 9 10 Chen et al, 1999.26 Raja and Raja, 2014.27 Mean age 61.2 Sample size 98 Lithium level 0.8–1.1 Comparator Duration Result Placebo, lamotrigine 6-8 weeks Randomized controlled trial, double-blind parallel group clinical trial (geriBD) Prospective >60 224 0.80– 0.99 Valproate 9 weeks 69 37 NA 2 weeks Prospective 69 14 2 weeks Most elderly patients responded to lithium Retrospective 67 12 2 weeks Lithium efficacy was inversely related to age Retrospective 50-84 46 0.50 to 0.90 0.602.00 NA Young patients NA Lithium significantly delayed time-tointervention for mania /hypomania compared with placebo After 3 weeks of therapy, the YMRS scale scores for those who completed the study improved significantly. No significant differences between the two groups No decline in efficacy of lithium with age 12 weeks Efficacy was obtained at lower levels in elderly Retrospective 63 81 NA Retrospective >65 43 Advanced age has no effect on course or outcome Decrease in no. of admissions in lithium group Retrospective 69 59 Retrospective study >75 NA 0.501.00 0.301.30 NA 3-8 weeks 3.2 weeks 2.3 weeks 480 weeks bipolar Younger bipolar patients Younger bipolar patients Younger bipolar patients Non lithium group Valproate group Oxcarbazepine and lamotrigine Response rates better with lithium than valproate The improvement in psychopathology is greater with lithium than comparators Journal of Geriatric Care and Research 41 Mukku et al, 2017 3. Few blood investigations are recommended prior to starting lithium, which include estimated glomerular filtration rate (eGFR) and thyroid stimulating hormone.35 A baseline electrocardiogram to rule out heart blocks and bradyarrthymias should be done prior to starting lithium.36 4. Start at low dose and titrate gradually. It is safe to keep the dose between 300mg and 600mg. It is particularly not recommended to increase the dose beyond 900mg in elderly.13,37 5. Supervise medication intake in elderly especially with cognitive impairment. 6. Regularly monitor serum lithium level every 3 months, renal functions and serum electrolytes every 6 months.36 7. In lithium treated patients, during the acute medical emergencies, it is advised to liaise with psychiatry team in handling lithium use. Conclusion Lithium is the gold standard drug for patient not only in young onset bipolar patients but also a very effective drug in late onset bipolar disorder. Lithium does not lose its efficacy with aging. The usual rule of start low and go slow when comes to prescribing in elderly should be followed when using lithium. One should aim for slightly lesser dosage and serum level in elderly compared to younger patients. Regular monitoring and proper education of patients for signs of toxicity will ensure safety in elderly. Author information: Shiva Shanker Reddy Mukku, MD, Senior Resident, Department of Psychiatry, Geriatric Clinic & Services, National Institute of Mental Health and Neurosciences, Bangalore, India, Email: shivakmc55@gmail.com; Palanimuthu T Sivakumar, MD, Professor of Psychiatry, Department of Psychiatry, Geriatric Clinic & Services, National Institute of Mental Health and Neurosciences, Bangalore, India, Email: sivakumar.nimhans@gmail.com; Mathew Varghese, MD, Professor of Psychiatry, Department of Psychiatry, Geriatric Clinic & Services, National Institute of Mental Health and Neurosciences, Bangalore, India, Email: mat.varg@yahoo.com Correspondence: Dr Palanimuthu T Sivakumar, Professor of Psychiatry, Department of Psychiatry, Geriatric Clinic & Services, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India, Email: sivakumar.nimhans@gmail.com Competing interests: The authors have declared that no competing interests exist. Received: 11 December 2017; Revised: 21 December 2017; Accepted: 22 December 2017 Copyright © 2017 The Author(s). This is an open-access article distributed under the terms which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Citation: Mukku SSR, Sivakumar PT, Varghese M. Challenges with lithium use in geriatric patients. Journal of Geriatric Care and Research 2017, 4(2): 39-43. 42 References 1. Shorter E. The history of lithium therapy. Bipolar Disord. 2009; 11(2):4–9. 2. Avasthi A, Grover S, Aggarwal M. Research on mood stabilizers in India. Indian J Psychiatry. 2010; 52(Suppl1):S355–61. 3. De Fazio P, Gaetano R, Caroleo M, Pavia M, De Sarro G, Fagiolini A, et al. Lithium in late-life mania: a systematic review. Neuropsychiatr Dis Treat. 2017; 13:755–66. 4. Sajatovic M, Strejilevich SA, Gildengers AG, Dols A, Al Jurdi RK, Forester BP, et al. 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