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Keywords:

  • lithium;
  • side-effect;
  • bipolar disorder

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References

Objective

Tremor occurs frequently as a side-effect of lithium, and it is, however, easily overlooked in the clinical setting. In this article, we attempt to review the pathophysiology and the clinical approach of lithium tremor.

Method

We searched the Pubmed and Cochrane Library for relevant articles up to the year 2012. Sixty-four articles including 10 review papers, 3 clinical trials, and 12 case reports were reviewed.

Results

Lithium tremor is classified as a postural tremor and subcategorized as an exaggerated physiologic tremor. Differential diagnosis includes metabolic abnormalities, benign essential tremor, Parkinson's disease, and lithium toxicity. Various methods of evaluating lithium tremor and treatment options are discussed.

Conclusion

When lithium tremor has developed, thorough history taking, physical examination, and blood examination including serum lithium level are needed. Pharmacotherapy is indicated only in patients with disabling tremor.

Clinical recommendations
  • When tremor occurs in patients treated with lithium, thorough history taking, physical examination, blood examinations including serum lithium level are needed to exclude lithium toxicity and other possible neurologic disease. In evaluating the severity and progress of tremor, we recommend clinicians use easily administered scales during their physical examination of their patients by asking the patients to draw a spiral or to write a sentence.
  • Clinicians should consider conducting brief neurologic examinations to check their patients' mental alertness and cerebellar function to exclude lithium intoxication and should consider evaluating other possible precipitating factors of lithium toxicity.
  • Modifying potential aggravating factors and using minimal effective dose of lithium are the initial strategy for lithium tremor. If continued lithium treatment is clearly indicated, pharmacotherapy is recommended for patients with lithium tremor associated with moderate-to-severe functional problems.
Additional comments
  • Conclusions are limited by the dearth of studies on the pathophysiology and the treatment of lithium tremor.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References

Tremor is one of the most common adverse effects of lithium that can be observed in the clinical setting. It is thought to be benign, but in some cases, it can be troublesome and socially embarrassing for patients, sometimes leading to non-compliance [1]. But, the mechanism and clinical approach to lithium tremor have been received little attention.

Tremor is an involuntary movement characterized by rhythmic oscillation of a part of the body. Lithium tremor is classified as a postural tremor and subcategorized as an exaggerated physiologic tremor. It is typically produced by voluntary maintenance of a particular posture held against gravity, and it shows a frequency of 8 to 12 Hz in the hands. Essential tremor, which causes postural and action tremor, is closely related to lithium tremor. Some investigators have argued that exaggerated physiologic tremor is a subtype of essential tremor [2].

Non-toxic lithium tremor within the physiologic range needs to be distinguished from other types of tremor related to lithium treatment. In chronic lithium treatment, an infrequent type of tremor with less frequency may develop that has more Parkinsonian features [3]. Also, tremor is one of the initial signs of lithium toxicity.

Aim of the study

The aim of this review was to summarize the accumulated data on the biologic and clinical characteristics of non-toxic lithium tremor and its treatment.

Material and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References

An overview of the current literature on the lithium tremor was undertaken. The search for pertinent publications was carried out using the term ‘lithium’ combine with ‘tremor’. We included literatures that (i) directly evaluate the lithium-related tremor, (ii) were written in English, and (iii) were published until 2012. The Pubmed search for ‘lithium tremor’ retrieved 179 hits; among them, 24 hits were sorted as ‘review’; no meta-analysis was found. A search in the ‘Cochrane Database of Systematic Reviews’ retrieved no hit; side-effect section in ‘Lithium for maintenance treatment of mood disorder’ was reviewed. All abstracts of publications were screened; 64 manuscripts including 10 review articles, 2 placebo controlled studies, 1 cross-over study, and 12 case studies were reviewed for this manuscript. Major textbooks of mood disorder were hand searched. Due to limited studies on the lithium tremor, literatures related to the general drug-induced tremor, and the essential tremor, which is thought to be potentially linked with the lithium tremor, were also reviewed. The potential therapeutic action of these agents in treating mood and related disorders was explored.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References

Characteristics of lithium tremor

Lithium tremor typically appears when started or titrated and decreases over time; it can occur, however, at any time during treatment [4]. It is generally symmetric, related to dose and blood level of lithium [5], and non-progressive. It is usually limited to hands or upper limbs at resting state, but worsens during activities that require fine motor control such as writing or pouring water [6].

When evaluating lithium tremor, clinicians should keep in mind lithium intoxication as a differential diagnosis. In lithium intoxication, tremor is the most common symptom, which is observed to almost half of subjects [7]. The pattern of symptom presentation is different; tremor induced by lithium toxicity is typically irregular, more prominent, and coarser than non-toxic tremor and is often generalized to other parts of the body. Also, it is usually accompanied by other neurologic signs—mental changes (e.g., delirium) are the second most common symptoms of lithium toxicity [7]. Further, non-neurologic symptoms such as gastrointestinal disturbance and changes in electrocardiogram can be observed [8].

Lithium toxicity usually subsides within 3 to 4 days after discontinuation of lithium [9]. However, if lithium is continued, cerebellar tremor due to irreversible neuronal damage—characterized by ataxia, dysarthria, nystagmus, and intention tremor—can occur [10].

The prevalence of lithium tremor

Most studies on the prevalence of lithium tremor were conducted in the 1970s and 1980s. In a review study by Gelenberg and Jefferson [11], the pooled percentage for any complaints of tremor was estimated to be about 27% of patients treated with lithium, with individual studies showing wide variability from 4% to 65%. Between 18 and 53% of patients stop taking lithium, a substantial percentage becomes non-compliant due to side-effects including the tremor [12]. One study found that 32% of patients felt that the lithium tremor resulted in non-compliance and some disability [13].The Cochrane Database of Systematic reviews did not estimate the prevalence of lithium tremor and lithium discontinuation rate due to insufficient data [12].

Such variability could be attributed to several important issues. First, the prevalence of adverse effects can vary depending on the method of evaluation, that is, from non-specified to specified questions (‘Do you suffer any ill effects from the treatment?’ vs. ‘Are you troubled by hand tremor?’) and from subjective questions to physiologic evaluations [14]. Most studies on lithium tremor have relied on a subjective questionnaire with specified questions. In general, investigators have used questions based on a 4-point scale (‘not present’, ‘minimal’, ‘moderate’, and ‘severe’). Prevalence also depends on whether truly troublesome tremor or the entire observable one is counted. Second, previous histories of tremor, comorbid medical conditions, and various risk factors for tremor can affect the prevalence rate. Vestergaard et al. [15] documented that 5% of subjects with lithium tremor had a history of hand tremor, which makes the prevalence rate overestimated. Third, concomitant drugs and a subject's mood state influence the presence of tremor [15, 16]. In a study by Bone et al. [16], tremor was more prevalent in non-euthymic patients than euthymic patients (50.0% vs. 24.6%). In previous studies, these issues have not been perfectly controlled.

The evaluation of lithium tremor

Thorough history taking and physical examination are needed, and underlying medical conditions and histories of tremor should be carefully examined. Tremor at the start or titration of lithium treatment typically suggests lithium tremor. Serum lithium concentration should be checked to exclude possible lithium toxicity. Generally, serum lithium levels ≤1.5 mEq/l are recommended; severe lithium intoxication occurs at serum lithium levels >3.0 mEq/l and death can occur at levels ≥5.0 mEq/l. Yet, neurotoxicity can occur even at therapeutic levels, especially in older patients [8]. Because most lithium intoxication occurs with precipitating factors, that is, dehydration and drug–drug interaction, taking a detailed history is essential; most patients develop lithium toxicity when ill (diarrhea, vomiting, heart failure, renal failure, or surgery) or secondary to a drug interaction that increases lithium levels (e.g., non-steroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors; [17]).Severe tremor should be considered due to lithium toxicity until proven otherwise and could be the first sign of toxicity because no precipitating factors are readily identified in some cases. Also, co-administration or withdrawal of other tremogenic drugs (e.g., alcohol and benzodiazepine) could aggravate the tremor.

Remarkably, clinicians do not use any standard or systematic assessment of lithium tremor. Nevertheless, applying any objective measurement would be useful for clinicians to monitor the progress of tremor. Physiologic tests such as accelerometry or electromyogram can give clinicians more quantitative and precise information on tremor [3, 18]; however, such tests are expensive, inconvenient, and impractical. Most studies used observation of patients' symptoms and simple questionnaires based on a 3- or 4-point scale. We recommend clinicians use easily administered scales during their physical examination of their patients; after observing fine tremor of the affected body part when patients sustain their posture (e.g., hands outstretched and mouth held open; [11]), clinicians can rate the severity of patients' tremor by asking the patients to draw a spiral or to write a sentence [19]. In addition, objective functional performance tests, which are simple to use and inexpensive, help clinicians measure the influence of tremor on daily activities such as pouring water from one cup to another (a bimanual kinetic tremor test) or simply holding a full cup of water for 1 min (which tests for unilateral postural tremor) [19]. Disability, handicap, and quality of life related to lithium tremor also need to be assessed [19].

Even in circumstances when lithium tremor is strongly suspected, other possible neurologic conditions that may be associated with tremor should be ruled out [13]. A neurologic evaluation, routine chemistry, and thyroid function testing are necessary. If other neurologic condition such as Parkinson's disease is suspected, special studies including neuroimaging studies can provide additional clues.

The mechanism of lithium tremor

Surprisingly, the pathophysiology of lithium tremor has never been studied. The two major components of enhanced physiologic tremor are peripheral reflex mechanical oscillation and 8–12 Hz central components [20]. Peripheral mechanical components can be enhanced by sympathomimetics [21]. The origin of the central oscillator is still unclear, but the inferior olive [22, 23] or thalamus [24] is suggested as a possible source. A recent study suggested that oscillator was transmitted through the corticospinal tract [20, 25] and probably located at the cortical level by a mechanism inherent in the organization of the motor system [20, 26].

Given that brain levels of lithium are related to the presence of the tremor [27] and lithium affects neural plasticity [28], lithium tremor is thought to arise from the central nervous system [20, 29]. That is, origins of the central oscillator could be possibly under the influence of lithium. For example, effects on brainstem serotonergic neurons have been hypothesized to affect lithium tremor. Animal studies and a negative synergistic effect in patients with other proserotonergic agents, such as antidepressants, support this hypothesis [22, 29]. Zaninelli et al. [18] found, however, that tremor activity was not influenced by serotonergic affinity of added antidepressants. Additionally, lithium can affect gray matter volume [30, 31] and microstructure of white matter [32], which might have impact on the corticospinal tract.

Contributing/risk factors of lithium tremor

Concomitant use of dopaminergic agents, beta-adrenergic agents, valproate, carbamazepine, proserotonergic agents, and other medications used for medical illnesses (i.e., antiarrythmics, chemotherapeutics, immunosuppressants, methylxanthines, gastrointestinal drugs, and hormones) increases the risk of tremor. Emotional or physical stress, anxiety, medical conditions such as thyrotoxicosis and hypothermia, alcohol withdrawal, and caffeine intake also can exacerbate tremor. Aging and family or personal histories of tremor are important risk factors as well.

Treatment of lithium tremor

For many patients, lithium tremor is tolerable and often improves spontaneously over time [4]. After evaluating the severity of tremor, if tremor is severely troublesome, possible exacerbating factors should be controlled. Caffeine may worsen tremor due to its adrenergic effects; however, as caffeine intake increases renal lithium clearance, sudden discontinuation of caffeine may in fact exacerbated tremor [33]. When possible, reducing the lithium dose can be helpful in any case, but, of course, must be balanced against maintaining a minimally effective dose. Changing the lithium preparation from long acting to short acting or to a different salt—that is, carbonate to citrate—or the use of divided dosing also may be helpful. Note, however, Vestergaard et al. [15] did not observe a correlation between tremor and these factors. Pharmacotherapy should be considered only when a severe disability is present, even after trying non-pharmacologic treatments.

Pharmacotherapy for lithium tremor

Two placebo controlled, cross-over studies with propranolol [34, 35] and one cross-over study between propranolol and metoprolol [36] exist. All other studies, to the best of our knowledge, were open-label case reports [36-48]—see Table 1. A total of 59 patients were included in studies. It was also notable that no objective testing was used except for a study by Kellet et al. [34].Among existing reports, only one study by Schou (linoleic acid) documented negative results [39]. Along with available publications, we also reviewed other agents potentially applicable to lithium tremor. In general, tremorlytic agents, which are used for essential tremor, can be tried. We summarize commonly recommended drugs and dosage in Table 2.

Table 1. Previous reports on pharmacologic treatment of lithium tremor
StudyMedication usedDosageSample size (n)Study typeMain outcome measure
  1. a

    Negative data.

Kirk et al. [35]Propranolol30–80 mg10Single blind, placebo controlled cross-over studySubjective likert scale
Kellet et al. [34]Propranolol vs. practolol

Propranolol 40 mg

Practolol 120 mg

15Placebo controlled, cross-over studyDrawing a line test
Lapierre [42]Propranolol30–40 mg5Case reportsSubjective reporting
Poldinger [46]Oxprenolol160–240 mg10Case reportsSubjective reporting
Van Putten [48]Meprobamate1200 mg1Case reportsSubjective reporting
Lieb [43]Linoleic acidSafflow oil 3000 mg7Case reportsSubjective reporting
Schou [47]aLinoleic acidSafflow oil 3000 mg Case reportsSubjective reporting
Gaby et al. [40]Metoprolol200–400 mg2Case reportsSubjective reporting
Dave and Langbart [39]Naldolol20–40 mg1Case reportsSubjective reporting
Zubenko et al. [36]Metoprolol vs. propranolol

Propranolol 15–80 mg

Metoprolol 200–400 mg

4Cross-over studySubjective reporting
Kruse et al. [38]Naldolol20–40 mg6Case reportsSubjective reporting
Dave [37]Atenolol 1Case reportsSubjective reporting
Goumentouk et al. [41]Primidone62.5 mg1Case reportsSubjective likert scale
Miodownik et al. [45]Vitamin B12900–1200 mg5Case reportsSubjective likert scale
Marks et al. [44]Pregabalin300 mg1Case reportsSubjective reporting
Table 2. The pharmacotherapy for lithium tremor
 Recommended dose (mg)
Propranolol60–320
Naldolol40–80
Primidone

The starting dose 25–75 mg

The maintenance dose 250 mg

Gabapentin

The starting dose 400 mg

The maintenance dose 1200–3600 mg

Topiramate

The starting dose 25 mg

The maintenance dose 200–400 mg

Clonazepam0.5–6 mg
Alprazolam0.125–3 mg
Beta blockers

Although there have been few studies with small sample sizes [34, 35, 42], the effectiveness of beta blockers in treating lithium tremor has been firmly established based on clinical experience [11]. Beta blockers are the treatment of choice for essential tremor, as proved by 12 randomized controlled trials and a recent meta-analytic study [20]. Their mechanism of action is thought to be peripheral, because beta blockers with poor CNS penetration are also effective [36].

Among beta blockers, propranolol is the most commonly prescribed drug, usually in doses between 60 and 320 mg. Some investigators state it should be used on an as-needed basis because it lowers renal lithium clearance [49]. The side-effects of propranolol are light headedness, fatigue, impotence, and bradycardia. It is contraindicated for those with bronchial asthma, sick sinus syndrome, sinus bradycardia, first degree heart block, congestive heart failure, chronic obstructive pulmonary disease, and diabetes. In patients with bronchial disease, selective beta1 blocker, atenolol, or metoprolol can be used [36, 37, 40]. In patients with liver failure, nadolol, which is not metabolized by the liver, can be used [38, 39].

Primidone

Primidone is an antiepileptic medication, which is metabolized to phenyl-ethyl-malonaide and phenobarbital. The exact mechanism of action for tremor is unknown, but possible parent compound and gamma-aminobutyric acid (GABA)-ergic activity of phenobarbital are thought to have tremorlytic effect [50]. Primidone shows a similar effectiveness compared with propranolol in the treatment of essential tremor [20]. Also, there is a case report documenting its dramatic response to tricyclic–lithium-induced tremor [41]. Primidone is usually started at 75 mg, with an adequate dose of around 250 mg/day. However, it has various side-effects including sedation, drowsiness, vertigo, fatigue, ataxia, nausea, vomiting, confusion, and instability.

Gabapentin

Gabapentin has both GABAergic and antiglutaminergic action, and it may modulate sodium and calcium channels. Two cross-over studies demonstrated efficacy of gabapentin in treating essential tremor [51, 52]. Gabapentin treatment is usually started at 400 mg and is maintained between 1200 and 3600 mg/day. It is well tolerated and has fewer adverse effects compared with primidone, but is thought to be less efficacious in the treatment of tremor [53]. The most common adverse effects are dizziness, sedation, and nausea.

Others

Topiramate also has a tremorlytic effect. In a randomized controlled trial for essential tremor, topiramate showed moderate improvement in tremor but with high adverse effects, most commonly paresthesia, nausea, difficulty maintaining concentration or attention, and somnolence [54]. The maintenance dose of topiramate is between 200 and 400 mg/day.

Benzodiazepines, which is thought to related to reduce the anxiety that aggravates tremor, have been used in the treatment of tremor [55]. However, due to adverse effects such as drowsiness and potential risk of dependence and abuse, it is not generally recommend.

Ethanol reduces tremor severity, and its effect lasts 3–4 h. But as the tremor worsens during ethanol withdrawal, and the potential for alcoholism exists [56, 57], it should be avoided. Nimodipine, a L-type calcium channel blocker, may act on tremor, because dopaminergic neurons are L-type calcium channel-dependent autonomous pacemakers [58]. In essential tremor, nimodipine showed efficacy at a dose of 120 mg/day [59]. Vitamin B6 has been suggested to be effective in the treatment of lithium associated [45] and other types of tremor [59], because it takes part in metabolism of almost all possible enzymes associated with the development of movement disorders [60]. Linoleic acid was suggested as a potential agent for the treatment of lithium tremor [43], but a subsequent pilot study was negative[47]. In addition, there was a case report pregabalin [44] and meprobamate [48] in worked to the treatment of lithium tremor.

Non-pharmacotherapy for lithium tremor

In essential tremor non-treatable with pharmacologic agents, botulinum toxin type A and stereotactic surgery including deep brain stimulation are used [53]. Yet, it would be more appropriate for clinicians to reevaluate the need for lithium and consider alternatives before considering those types of treatment.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References

Lithium tremor is one of the most common adverse effects of lithium. It can cause serious problems in patients' daily lives, which might eventually cause non-compliance for treatment. At the current state of knowledge, however, the incidence, pathophysiology, and applicable treatment method still remain unknown. Applying standard evaluation methods would be important in future studies.

Clinicians need to be fully aware of possible risks for tremor and try to modify possible contributing factors before administrating lithium. Also, the nature and severity of the tremor should be regularly examined. We recommend applying simple objective measurements to monitor the progress of tremor. Clinicians should consider conducting brief neurologic examinations to check their patients' mental alertness and cerebellar function to exclude lithium intoxication and should consider evaluating other possible precipitating factors of lithium toxicity. If tremor suddenly becomes worse, serum lithium levels should be checked. To treat lithium tremor, clinicians should, obviously, first modify possible aggravating factors and then consider pharmacotherapy to treat the tremor in patients who have moderate-to-severe functional problems.

Declaration of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References

Dr. Nierenberg served as a consultant to American Psychiatric Association (only travel expenses paid), Appliance Computing Inc. (Mindsite), Basliea, Brain Cells, Inc., Brandeis University, Bristol Myers quibb, Corcept, Dey Pharmaceuticals, Dainippon Sumitomo, Eli Lilly and Company, EpiQ, Forest Research Institute, L.P./Mylan Inc., Novartis, PGx Health, Ridge Diganostics, Shire, Schering-Plough, Sunovian, Takeda Pharmaceuticals, Targacept; consulted for through the MGH Clinical Trials Network and Institute (CTNI), Astra Zeneca, Brain Cells, Inc, Dianippon Sumitomo/Sepracor, Johnson and Johnson, Labopharm, Merck, Methylation Science, Novartis, PGx Health, Shire, Schering-Plough, Targacept, and Takeda/Lundbeck Pharmaceuticals. He received grant/research support through MGH from NIMH, AHRQ, Forest Research Institute, PamLabs, Pfizer Pharmaceuticals, Shire; received honoraria from Belvoir Publishing, University of Texas Southwestern Dallas, Hillside Hospital, American Drug Utilization Review, American Society for Clinical Psychopharmacology, Baystate Medical Center, Columbia University, CRICO, Dartmouth Medical School, IMEDEX, Israel Society for Biological Psychiatry, Johns Hopkins University, MJ Consulting, New York State, Medscape, MBL Publishing, National Association of Continuing Education, Physicians Postgraduate Press, SUNY Buffalo, University of Wisconsin, University of Pisa, University of Michigan, University of Miami, APSARD, ISBD, SciMed, Slack Publishing, Wolters Klower Publishing; is a presenter for the Massachusetts General Hospital Psychiatry Academy (MGHPA). The education programs conducted by the MGHPA were supported through Independent Medical Education (IME) grants from the following pharmaceutical companies in 2008: Astra Zeneca, Eli Lilly, and Janssen Pharmaceuticals; in 2009 Astra Zeneca, Eli Lilly, and Bristol-Myers Squibb; (was) on the advisory boards of Appliance Computing, Inc., Brain Cells, Inc., Eli Lilly and Company, Johnson and Johnson, Takeda/Lundbeck, Targacept, InfoMedic; owns stock options in Appliance Computing, Inc. and Brain Cells, Inc; through MGH, Dr. Nierenberg is named for copyrights to the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery Asberg Depression Scale exclusively licensed to the MGH Clinical Trials Network and Institute (CTNI). Also, through MGH, Dr. Nierenberg has a patent extension application for the combination of buspirone, bupropion, and melatonin for the treatment of depression.

Dr. Kinrys served as a consultant to Astra-Zeneca, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, Janssen Pharmaceutica, Pfizer Inc, Sepracor Inc., UCB Pharma and Wyeth-Ayerst Laboratories; is a presenter for Astra-Zeneca, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, Janssen Pharmaceutica, Pfizer Inc, Sepracor Inc., UCB Pharma and Wyeth-Ayerst Laboratories; received research supports from Astra-Zeneca, Bristol-Myers Squibb Company, Cephalon, Elan Pharmaceuticals, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, Sanofi/Synthelabo, SepracorInc., Pfizer Inc, UCB Pharma and Wyeth-Ayerst Laboratories. Dr. Kinrys reported no equity holding and no royalty/patent. Dr. Baek has no interest to disclosure.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Declaration of interest
  8. References