Lithium and valproate-induced tremors

INTRODUCTION

Tremor is often an unintentional side effect to several psychotropic medications in our treatment arsenal. Tremors often present as involuntary, oscillating movements of muscles located in various parts of the body including head, face, vocal cords, arms, trunk, and legs.¹ The most commonly encountered pathologic tremors in general practice are physiologic and Parkinsonian tremors. Physiologic tremors can be subdivided into several different categories depending on how they occur. Tremors occurring during voluntary contraction of a muscle are known as action tremors and can be categorized as kinetic, postural, or isometric.² A tremor occurring while the body is relaxed and supported is known as a resting tremor. It is important to differentiate pathologic tremors as everyone experiences natural tremors during action and at rest that are of low-amplitude and of high frequency.² Essential tremor is the most common pathologic tremor in the physiologic category. Conversely, Parkinsonian tremors are noted as mostly occurring at rest with a decrease in severity upon voluntary movement and considered asymmetrical in nature.² In general, most tremors commonly occur in the hands leading to embarrassment and difficulty performing activities of daily living.¹ This can lead to patient non-adherence with medications important in the treatment of serious mental illnesses.

LITHIUM TREMOR

Development of a fine hand tremor by patients initiating treatment with lithium is a well-known and anticipated side effect. Incidence of lithium-induced tremor ranges widely from 4–65%.³⁴ It has been estimated that 53% of patients develop tremor during the first week of lithium therapy, yet tremor is present in only 4% of patients who have taken lithium for one to two years.⁵ Estimates of tremor severe enough to impair functioning or be socially embarrassing range from 10–65%.⁵ Tremor may occur in patients taking therapeutic doses of lithium and is also an early sign of toxic lithium levels.

The etiology of lithium tremor is not fully understood. Acute lithium tremor is often noticed when the hand is at rest and increases with voluntary movement. A small study by Pullinger and Tyrer detected an increase in the amplitude of finger tremor early in lithium treatment which decreases after one to two weeks in most patients.⁶ The authors concluded acute lithium-induced tremor was characteristic of exaggerated physiologic tremor and was distinct from the tremor occurring with chronic therapy.⁶ Risk factors identified with increasing the risk of lithium tremor include increasing age, male sex, high serum lithium levels, concurrent antidepressant medications (particularly tricyclic antidepressants) and neuroleptic medications, excessive caffeine intake, personal or family history of tremor, presence of alcoholism, and associated anxiety.³⁵⁷ No evidence supports an association between the occurrence of lithium tremor and the duration of lithium treatment.⁷

Tremor may also occur later on in treatment such as months to years following the initiation of the medication. Tyrer and colleagues measured postural finger tremor of 23 subjects to determine the frequency of the tremor.⁸ The authors concluded lithium in chronic therapy increases the amount of tremor and shifts its frequency from the physiologic range towards Parkinsonian tremor.⁸ Parkinsonian tremor characteristically has a greater amplitude and a lower peak frequency (between 4–7 Hz) than physiologic tremor (between 7–16 Hz). The results signify tremor occurring late in lithium therapy indicates an extrapyramidal symptom and not a toxic side effect from an elevated lithium level.⁸ Fine hand tremor occurring as a side effect of lithium therapy should be distinguished from the coarser hand tremor, which indicates lithium toxicity.⁵

An important rule to follow when managing lithium tremor is to treat the patient, not the level. Cases of lithium toxicity with therapeutic serum concentrations have been reported.⁹ Red blood cells actively exclude lithium and there may be interindividual differences in lithium red blood cell: serum or plasma ratio.⁹¹⁰ Methods for decreasing the frequency and severity of lithium tremor include gradual dose changes, reducing the serum level while maintaining therapeutic efficacy, using single daily dosing, using a sustained-release lithium product, and reducing or eliminating other medications that could worsen the tremor.³⁷¹⁰ Lithium tremor is fully reversible with discontinuation of lithium treatment.

If non-pharmacologic interventions do not adequately improve the tremor, certain medications have demonstrated efficacy for controlling persistent tremors during continued lithium therapy, although results are often mixed. Beta-blockers are often utilized as a first-line pharmacologic intervention for lithium tremor. Multiple case studies have supported the use of propranolol 30–100 mg/day in divided doses while other cases have not shown a benefit.¹¹¹² In a prospective, interventional, non-randomized, unblinded, non-controlled study, six patients treated with nadolol 20 or 40 mg/day showed improvements ranging from moderate to marked.¹³ For patients with asthma or COPD, the selective beta blocker, metoprolol, was effective for patients in two case studies but ineffective in another case study, except at high doses causing bronchospasm.¹⁴¹⁵ In one case study, meprobamate 1200 mg daily was effective.¹² Another study suggested linoleic acid in safflower oil may be a rapid treatment for lithium-induced tremors but a subsequent pilot study using evening primrose oil as the source of linoleic acid was ineffective.¹⁶¹⁷ A small, open-label study (n=5) evaluated the efficacy of vitamin B₆ as a treatment for lithium-induced tremor.⁴ According to the results, one patient reported near total recovery, three patients reported much improvement, and one patient did not notice any change.⁴ Finally, a case of lithium-induced tremor treated with primidone 62.5 mg daily reported dramatic improvement after three days of treatment.¹⁸ The tremor returned when the primidone was held and a subsequent second administration of primidone produced a significant improvement in the tremor.¹⁸

VALPROATE TREMOR

Valproate is one of the most prescribed antiepileptic medications and is also particularly associated with tremors. Incidence of valproate-induced tremor is thought to occur in 6–45% of patients.¹⁹ It is the most common neurologic adverse event observed with valproate. Approximately 25% of patients taking valproate are found to develop a tremor within 3–12 months of initiating therapy.¹ The tremor is often observed with action or postural in nature, although a resting tremor may occur.¹

The tremor is often fine in nature and can affect a patient's head, mouth, tongue, and limbs. It shares clinical and electrophysiological features of an essential tremor and may exacerbate any underlying pathology. The occurrence of tremor is found to be more associated with valproate dose than plasma concentration.¹⁹ Rinnerthaler and colleagues measured rest and postural tremors of patients taking conventional valproate versus controlled-release formulations with accelerometry and surface electromyograms.¹⁹ Through computer tremor analysis they determined controlled-release valproate may cause less tremor activity than immediate conventional valproate. Differences between peak-trough levels in controlled-release valproate versus conventional formulations may attribute to the development of tremors in valproate patients.¹⁹

Valproate is another medication where you have to treat the patient, not the level. It is a medication that is greater than 90% bound to plasma proteins. Binding decreases with increasing valproate concentrations as well as the presence of other plasma protein bound medications.²⁰ Monitoring for such drug interactions may reduce the presence of co-occurring tremors. Newborns as well as elderly eliminate valproate more slowly and are at risk higher risk for adverse events. Valproate is also extensively metabolized in the liver via microsomal glucuronide conjugation, mitochondrial β-oxidation, and cytochrome P450 pathways (2C9, 2A6, 2B6, and 2C19).²⁰ Dose adjusting valproate when given with CYP450 inhibitors may also help with preventing adverse events such as tremors. Other methods for decreasing the frequency and severity of valproate tremor include gradual dose changes and reducing the serum level while maintaining therapeutic efficacy.²¹ Valproate tremor is also fully reversible with discontinuation of valproate treatment.

When the above options fall short in decreasing or discontinuing valproate tremor, there are several pharmacologic treatments that have been examined in literature with mixed efficacy. Beta-blockers are often utilized as a first-line pharmacologic intervention for valproate tremor. In a study conducted by Karas and colleagues, patients with valproate tremors were treated with propranolol, amantadine, diphenhydramine, benztropine, and cyproheptadine.²² Ten patients received propranolol 20mg twice daily and increased to a maximum of 100mg per day. With propranolol therapy, eight of 10 patients experienced diminution of tremor activity.²² Sixty milligrams daily seemed to provide excellent control of the valproate-induced tremor with little sedation. Propranolol mechanism of action is blockade of both peripheral and central β-adrenergic receptors. It is possible that an increase in circulating epinephrine or other catecholamines is important in the development of tremors due to the effectiveness of propranolol in reduction of valproate tremors.²²²³ In the same study, four patients received 100mg twice daily of amantadine and three of the four patients experience moderate decreases in tremor activity.²² The four patients who received cyproheptadine (dose undefined) experienced modest relief from valproate-induced tremor for approximately three hours.²² Two patients received diphenhydramine 50mg twice daily and experienced slight reduction in tremor with marked sedation.²² The two patients who received benztropine 1mg twice daily also experience similar effects as the patients taking diphenhydramine.²² Finally, a case report by Lancman and colleagues utilized acetazolamide 8mg/kg/day initially and advanced to 14mg/kg/day as treatment for valproate induced tremors.²⁴ The patient experienced clinically significant decreases in tremor by day eight.

SUMMARY

Tremor is often an unintentional side effect to several psychotropic medications commonly used to treat psychiatric disorders. Both lithium and valproate-induced tremors are often benign, non-interfering side effects of lithium and valproate treatment. When the tremor becomes bothersome to the patient and begins to affect his or her quality of life, it is important for clinicians to intervene. Many treatment options are available to improve lithium and valproate-induced tremors. Currently, beta-blockers appear to be the mainstay of tremor reduction for both medications.