Depakote tremor treatment

Depakote tremor treatment DEFAULT

Risk of Valproic Acid-Related Tremor: A Systematic Review and Meta-Analysis


VPA (valproic acid), a clear, colorless, eight-carbon branched-chain fatty acid, was first produced in 1882 as an organic solvent (1). Then, in 1963, the therapeutic potential of VPA was fortuitously discovered by Carraz et al. (2), who recognized that VPA itself has anticonvulsant properties. VPA has been approved by the Food and Drug Administration (FDA) and is the first-generation broad-spectrum antiepileptic drug (AED) most commonly administered to treat generalized and focal epilepsies in children and adults, and it is also used to treat bipolar disorder, posttraumatic stress disorder (PTSD), schizophrenia, neuropathic pain, and migraine headaches (3–7). It may be useful in novel applications that are currently being researched, such as cancer therapy and prevention (8). Despite its utility, VPA is associated with several common side effects, including tremors, weight gain, alopecia, liver dysfunction, gastrointestinal disturbances, increased triglyceride levels, thrombocytopenia, etc. (9–12).

Tremor, one of the most common neurological symptoms, is defined as an involuntary, rhythmical, oscillatory movement of a body part produced by either synchronous or alternating contractions of antagonist muscles (13). Tremor is the most common side effect involving the central nervous system, occurring in as many as one quarter of chronically treated patients (14, 15). VPA-related tremors are usually action or postural tremors, but sometimes they are rest tremors (16). Tremors do not usually abate with continued treatment (10), so we investigated and diagnosed with the utmost caution, but in some cases, tremors may respond to smaller dosages or changes in the dosing regimen. Additionally, tremors also occur relatively commonly in patients taking antipsychotics, antidepressants, sympathomimetics, antiarrhythmics, AEDs, and other drugs (14, 17), such as lithium, phenytoin (PHT), carbamazepine (CBZ), topiramate (TPM), vigabatrin (VGT), lamotrigine (LTG), and gabapentin (TGB).

However, the relationship between VPA dosage and tremor is currently unclear. In a study by Karas et al., tremors usually appeared with dosages >750 mg per day (16). Patients exhibit tremors with doses exceeding 1,000 mg/d, according to Hyman's reports (18). Additionally, trials have shown that patients with doses of <500 mg also experience tremor (19, 20). In addition, it is not clear whether the dose of VPA compared to other drugs increases the risk of tremors. At present, there is relatively little information about VPA-associated tremors in the existing medical literature, and most of the existing studies are limited to studies with small sample sizes or case reports. To provide more evidence about the incidence of VPA-associated tremor as well as compare the risk of tremor between VPA and other drugs, we systematically reviewed related articles and analyzed them.


Our study did not require ethical approval because patients were not involved. According to the PRISMA (21) principles and MOOSE (22) guidelines, the search strategy, selection criteria, data extraction process, quality assessment, and statistical analysis were predesigned based on the Cochrane Review Methods. The protocol was not registered on any website.

Search Strategy

Two researchers searched online databases, including the PubMed (1977 to February 2, 2020), Embase (1982 to February 2, 2020), and Cochrane Library databases (2001 to February 2, 2020), for potentially relevant studies; there were no language restrictions, but the search was restricted to human studies. The search was conducted with a combination of medical subject headings and term words, including “Valproic acid”[Mesh], “Propylisopropylacetic Acid,” “2-propylpentanoic acid,” “Divalproex,” “Depakene,” “Divalproex Sodium,” “Valproate,” “Valproate Sodium,” “Valproate Calcium,” “VPA,” “Depakine,” “Depakote,” “tremor” [Mesh], “Tremor,” “Tremors,” and “drug-induced tremor.” Additionally, the references of all the included studies or related reviews were screened to avoid accidental omissions.

Selection Criteria

Clinical trials that met the following criteria were included: (1) the design of the trial was an RCT (randomized controlled trial), (2) VPA was the only therapy provided to the control group or test group, and (3) the study provided the original data for VPA-associated tremor and comparisons with the control group. The exclusion criteria were as follows: (1) observational studies (including cross-sectional studies, case–control studies, cohort analyses, and so on), (2) studies in which VPA was combined with one or more other drugs and compared with a control group, (3) comparative studies with two different valproate preparations, (4) studies in which VPA-associated tremor was not mentioned or the data provided were incomplete, and (5) studies based on the same study population. According to the inclusion and exclusion criteria, we identified a total of 29 randomized controlled trials (six studies were placebo-controlled studies).

Data Extraction

Two reviewers independently extracted relevant information from each eligible study, and any discrepancies between the two reviewers were resolved by consulting with the senior author. We established a data extraction form (Table 1), which included the first author's name, publication year, study recruitment method, study field, design, whether the trial include one or multiple centers, sample sizes of the test group and control group, median age of the participants, percentage of females, dose of VPA, duration of treatment, and number of adverse outcomes related to tremor.

Table 1. Characteristics of included studies.

Quality Assessment

The quality of the RCTs was assessed by two authors, and any disagreements were resolved via discussion with a third reviewer, after which the trial was reevaluated. The guidelines for assessing risk of bias provided in the Cochrane handbooks were used to assess the quality of the included studies, and the domains assessed included random sequence generation, allocation concealment, blinding of the participants and personnel, blinding of the assessors, incomplete outcome data, and selective outcome reporting.

Statistical Analysis

We performed statistical analyses using Stata 15.1 software. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) to demonstrate the pooled effects of tremor with VPA compared to other drugs. Forest plots were used to visually display the meta-analysis results. We used fixed-effect models to weight the studies by the amount of available information, whereas a random-effect model was used for heterogeneity between studies, and Cochran's Q statistic and I2 metric statistics were used to assess the level of heterogeneity. For the Cochran Q test, heterogeneity was considered statistically significant when P < 0.05. For I2, if I2 > 50%, the level of heterogeneity was considered unacceptable, and the data were analyzed with a random-effect model. A fixed-effect model was applied when I2 < 50%. P < 0.05 indicated statistical significance, and all tests were two-sided. In our study, we performed analyses of different control groups [AEDs (excluding VPA) and other non-AEDs]. Obvious heterogeneity was assessed by subgroups based on the sample size, VPA dose, and treatment duration.


Included Studies

A total of 1,169 records were retrieved from the Embase, PubMed, and Cochrane library databases. As shown in Figure 1, after duplicates were removed, 1,113 articles remained. During our initial screening process, the titles and abstracts were read, and we eliminated reviews, meta-analyses, single case studies, case series, conference abstracts, commentaries, letters, and editorials. Fifty-three human clinical studies remained. After the full-text review, 24 studies were excluded. Finally, based on the inclusion criteria, 29 RCT studies (a total of 1,986 participants) that presented information on VPA-associated tremor were included in the evaluation of tremor incidence (Table 1).

Figure 1. Flow chart of selection of studies about tremor in patients taking VPA therapy. VPA, valproic acid.

In one study (23), three different doses of VPA were used and compared with a placebo, so we counted this study as three trials. In three studies (24–26), two different AEDs were compared to VPA, so we considered these three studies as six trials. Thus, the total number of comparisons was 34. Most trials were multicenter trials and recruited patients from the USA and Europe, seven trials were conducted in Iran, and other studies were conducted in various countries, such as Korea, Germany, Turkey, and China. These trials included different diseases, all of which were treated by VPA, including epilepsy (15), migraine headache (11), and bipolar disorder (3).

The sample size of the included trials ranged from 33 to 613, and the number of participants treated with VPA ranged from 16 to 244. The age range of the study patients was 6–88 years. The mean VPA dosage ranged from 400 to 2,099 mg/day. The trial performed by Mattson, was the only one in which a 2,099-mg/day dose was tested. The treatment period ranged from 0.75 to 45 months.

Quality Assessment of Included Studies

The results of quality assessments of the included 29 studies are presented in Table 2.

Table 2. Risk of bias table of included studies.

Incidence of Tremor

In one placebo-controlled trial (23), three different doses of VPA were compared with a placebo, so we counted it as three trials. Additionally, two studies did not identify patients who developed tremors (23, 48), so 29 studies were included in our analysis. A random-effect model revealed that the overall incidence of tremor with VPA treatment was 14% [OR = 0.14, 95% CI (0.10–0.17)] (Figure 2).

Figure 2. Pooled analysis of the overall incidence of VPA-related tremor. VPA, valproic acid.

Comparison Between Various Drugs

Twenty-eight articles were included because one prospective study did not clearly determine the incidence of tremor in the control group (46). We independently evaluated the pooled ORs of VPA-induced tremor compared with tremor induced by all other drugs (other AEDs, other non-AEDs) to investigate the specific effect of VPA on tremors. According to our analysis, the use of VPA was significantly associated with an increased risk of tremor compared to that of the control group (Figure 3), including patients taking other drugs [28 articles, OR = 5.40, 95% CI (3.22–9.08)], other AEDs [17 articles, OR = 5.78, 95% CI (3.18–10.50)], and other non-AEDs [11 articles, OR = 4.77, 95% CI (1.55–14.72)]. In addition, we separately compared VPA to other AEDs and found a significant difference in the tremor risk between patients treated with VPA and other AEDs (Figure 4) [LTG OR = 7.46, 95% CI (3.43–16.20); CBZ OR = 3.53, 95% CI (1.91–6.50)]. However, there was no significant difference in the tremor risk between patients treated with VPA and TPM [OR = 4.35, 95% CI (0.681–27.76), P = 0.120]. There was only one article on OXC, LEV, and PHT. These comparisons exhibited heterogeneity, so random-effect models were used.

Figure 3. (A) The pooled OR of VPA-associated tremor compared with all other drugs. (B) The pooled OR of VPA-associated tremor compared with all other AEDs (except VPA), (C) The pooled OR of VPA-associated tremor compared with all other non-AEDs. AEDs, antiepileptic drugs; VPA, valproic acid.

Figure 4. The pooled OR of VPA-associated tremor with other AEDs respectively. VPA, valproic acid; AEDs, antiepileptic drugs; TPM, topiramate; LTG, Lamotrigine; OXC, oxcarbazepine; PHT, phenytoin; CBZ, carbamazepine; LEV, levetiracetam.

Subgroup Analysis

The former comparisons of VPA-induced tremor compared with all drugs exhibited heterogeneity, and we considered that the sample size, VPA dosage, and follow-up time influenced the outcomes. Therefore, subgroup analysis was performed according to the following three factors.

Sample Size

In the subgroup analysis performed by sample size, we used a threshold of 100 patients. It was noted that the risk of VPA-associated tremors in the studies with more than 100 patients differed significantly from the risk of tremors associated with other drugs [OR = 6.23, 95% CI (3.35–11.59)], and this significant difference persisted in the groups with fewer than 100 patients [OR = 3.85, 95% CI (1.41–10.50)] (Figure 5). Among the studies with larger sample sizes, the risk of VPA-related tremors was larger than that in the studies with a small sample size, which reflected the stability of our meta-analysis. Neither group exhibited a significant difference in heterogeneity (I2 = 42.2% and I2 = 66.4%, respectively).

Figure 5. Subgroup analysis of VPA-associated tremor compared with other drugs according to the sample size. VPA, valproic acid.

VPA Doses Used

In the subgroup analysis of the doses, we excluded one study because it did not clearly provide the mean VPA dosage (33). According to the dosage used, we divided the patients into four subgroups: the ≤ 500-mg/d, 500–999-mg/d, 1,000–1,499-mg/d, and ≥1,500-mg/d subgroups. When the dose reached ≥1,500 mg/d, the level of heterogeneity was considered significant (I2 = 81.4% vs. I2 = 59.8%). Considering that dose-related factors may influence the results, we excluded articles that reported doses >1,500 mg/d (23, 27, 30, 36, 48), but the level of heterogeneity did not decrease significantly (I2: 54.6 vs. 59.8%). Therefore, we did not consider studies with a mean dose >1,500 mg/d as a source of heterogeneity. The pooled estimate for VPA-related tremors was significantly different from that of tremors related to other drugs at doses of 500 mg/d [OR = 3.57, 95% CI (1.24–10.26)], 500–999 mg/d [OR = 3.99, 95% CI (1.95–8.20)] and 1,000–1,499 mg/d [OR = 8.82, 95% CI (3.25–23.94)], and there were no statistically significant differences regarding other drugs at doses ≥1,500 mg/d [OR = 2.17, 95% CI (0.38–12.44); P = 0.381] (Figure 6).

Figure 6. Subgroup analysis of VPA-associated tremor compared with other drugs according to the different drug dose. VPA, valproic acid.

Duration Times

Based on the follow-up time, the pooled estimate of VPA-associated tremor was statistically significantly higher than that of tremors associated with other drugs at duration times of ≤ 3 months [OR = 3.06, 95% CI (1.16–8.09)], 3–6 months [OR = 16.98, 95% CI (9.14–31.57)] and 6–12 months [OR = 4.15, 95% CI (2.74–6.29)]. VPA-induced tremor had a higher incidence during treatment durations of 6–12 months than during durations of ≤ 3 and 3–6 months. However, the risk of VPA-related tremor was not significantly different for durations >12 months [OR = 1.53, 95% CI (0.14–16.79); P=0.730] (Figure 7).

Figure 7. Subgroup analysis of VPA-associated tremor compared with other drugs according to the duration time. VPA, valproic acid.

Sensitivity Analysis

The stability of the pooled estimate was assessed by excluding ineligible studies one by one and reconducting the analysis. The outcomes of VPA-associated tremors were not significantly affected, indicating that the results of our analysis were stable (Figure 8).

Figure 8. Sensitivity analysis of VPA-associated tremor compared with other drugs. VPA, valproic acid.

Publication Bias

A funnel plot was used to detect bias in these studies, and the plot seemed to be asymmetrically distributed (Figure 9). Begg's test and Egger's test were conducted, and both tests indicated a lack of publication bias for VPA-associated tremors compared to tremors associated with other drugs (P = 0.922, P = 0.094, Figures 10, 11).

Figure 9. Funnel plot of VPA-associated tremor compared with other drugs. VPA, valproic acid.

Figure 10. Begg's funnel plot test of publication bias for VPA-associated tremor. VPA, valproic acid.

Figure 11. Egger's linear regression test of publication bias for VPA-associated tremor. VPA, valproic acid.


According to previous studies, the evidence for VPA-induced tremor has been well documented. In epilepsy patients, VPA-related tremor is presumed to be one of the most common side effects, with an incidence of 6–64% (36, 39, 50). The mechanism underlying VPA-induced tremors is not completely understood; it has been suggested that the occurrence of tremors with VPA could be explained by the marked changes in the GABA synthesis rate in the substantia nigra and corpus striatum (51), and disturbances of the GABAergic pathways in the basal ganglia system may result in DA inhibition and subsequent changes in catecholamine (NE and E) concentrations (52–54). There is considerable evidence indicating that VPA increases the concentration of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and this mechanism is thought to be a major cause of tremor (55, 56). The increase in transmitters occurs mainly through the following two pathways: (1) inhibition of the activation of glutamate transaminase and succinic acid dehydrogenase to reduce its metabolism and (2) activation and increase glutamate decarboxylase synthesis. At the same time, VPA increased GABA receptor-mediated hyperylation and inhibited the activation of the N-methyl-aspartic acid receptor. The factors of tremor severity may include the patient's sex and age and the dosage and formulations of VPA (55, 56). VPA often exaggerates familial tremor, and this sort of tremor becomes more prevalent and more noticeable as people age. However, whether the relation of VPA-associated tremor with aging is partly a consequence of previously unrecognized essential tremor cases worsening is unknown.

This meta-analysis provides a valuable and relatively complete description of the incidence and risk of VPA-associated tremor compared to tremor associated with other drugs. Our study included 29 RCT trials, and the overall incidence of tremor in patients treated with VPA was estimated to be 14%. According to Farkas et al. (57), the true incidence of VPA-induced tremor may be underestimated, as quantitative methods suggest that motor disturbances may predate symptoms of tremor. Tremor is probably not the first appearing motor adverse effect of valproate treatment. Quantitative methods might reveal a higher incidence of valproate-related motor disturbances than is currently considered (57). Furthermore, we observed a significant difference among patients treated with VPA and all other drugs (other AEDs, non-AEDs). Patients taking VPA had an approximately 4.5-fold higher (17.5 vs. 3.9%) risk of developing tremor than did patients taking other AEDs and an approximately 5-fold higher (11.7 vs. 2.5%) risk than did patients taking other non-AEDs. Compared to a single AED, the risk of VPA-induced tremor was greater than that of LTG- (7.47 times) and CBZ-induced tremor (3.53 times). Since only a few included studies reported the incidence of tremor associated with other AEDs, we were unable to calculate the pooled estimates. This meta-analysis could provide insights into alternative antiepileptic drugs to VPA.

Subgroup analyses were conducted to evaluate the impact of different drug dosages. VPA-induced tremor was found to be dose-related, but the means of the serum levels of VPA were within the normal therapeutic ranges (54). Patients with high blood VPA concentrations tend to develop adverse effects (58). VPA-induced tremor was reported to be reversible upon reduction or withdrawal of the drug and worsened as the dose increased (18, 57). Based on our meta-analysis, we divided the included trials into four groups (≤500 mg/d, 500–999 mg/d, 1,000–1,499 mg/d, ≥1,500 mg/d) according to the mean daily drug dose, and we drew a similar conclusion regarding VPA dose-related. A dose-dependent effect of VPA-related tremor was observed when the four dose groups were compared. Patients taking doses of 1,000–1,500 mg/d had an increased risk of developing tremor compared to patients who were administered both doses ≤ 500 mg/d and doses ranging from 500 to 999 mg/d. It is worth mentioning that VPA is often supplied as a sodium salt, and the molecular weight differed across the included studies. Therefore, future research should provide a more detailed description of the VPA dose.

Medication retention includes all possible reasons for effectiveness and intolerability (59), especially due to the side-effect profile (60). If patients experience VPA-related tremors, clinicians should consider whether the VPA dose is within the therapeutic dosage and whether it is possible to reduce the VPA dose. It may be a wise approach to choose another drug instead of VPA if the effect cannot be maintained after reducing the dosage.

According to the reports of Karas et al. (16), tremors occur as early as within 1 month of therapy. Tremors are present and exacerbated by intentional positions, and as the treatment continues, tremors gradually appear or become more severe. Our meta-analysis confirmed this result. We also divided the studies into four groups according to the follow-up time (≤ 3 m, 3–6 m, 6–12 m, >12 m); when we pooled the results of studies that followed up patients for 6–12 months, the risk of tremor was higher than that in studies that followed up patients for <3 months or from 3 to 6 months. This finding reminds us that the risk of VPA-related tremor may be time-related. At present, no studies have clearly examined the relation between the duration of treatment and risk of tremor. Hence, these data may lay the foundation for future studies, which may be profoundly meaningful for clinical therapy.

Due to the comprehensive search strategy used, high-quality RCTs were included, and the statistical heterogeneity of the outcomes in the pooled estimate analyses and stable sensitivity analysis results suggested our results have good reliability. However, our study also had several limitations. First, in the 29 trials, only 1,986 participants were treated with VPA, and among them, only a small number experienced tremor due to VPA therapy. Second, all the included studies were RCTs, but not all of the studies employed a double-blind design, so the quality of some studies was not relatively high. Third, VPA-related tremor is more common in elderly people and women, but relevant data were unavailable for us to perform a pooled estimation and confirm this conclusion. In addition, the number of the included studies and the AEDs included in comparisons were relatively small; therefore, we need to be cautious when drawing general conclusions.


VPA-associated tremor is more common than many clinicians have realized, with an overall incidence of 14%. VPA poses a higher risk of tremor than do other AEDs. VPA-induced tremor does depend on a dose <1,500 mg/d, and reducing the drug dose can reduce the risk. If the effect cannot be maintained, we recommend replacing VPA with other drugs (such as LTG or CBZ). Additionally, VPA-induced tremor can occur in every period after VPA treatment and gradually worsen over time. Patients taking VPA have a higher risk of experiencing tremor than do patients taking other drugs within 12 months, and patients should be advised about the risk. In summary, these results support more large population-based studies, and longer duration clinical trials are urgently needed to confirm whether VPA increases the risk of developing tremor compared to other drugs and whether the risk is related to dose and duration treatment times.

Data Availability Statement

The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Author Contributions

CqZ and HbS performed the experiments. BmH and HbS supervised the data collection. MlH and HbS wrote the initial draft. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


VPA, valproic aid; RCTs, randomized controlled trials; AEDs, antiepileptic drugs; FDA, Food and Drug Administration; PTSD, posttraumatic stress disorder; CBZ, carbamazepine; TPM, topiramate; VGT, vigabatrin; LTG, lamotrigine; TGB, gabapentin; ORs, odds ratios; CIs, confidence intervals.


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Keywords: valproic aid, tremor, random control trials, meta-analysis, systematic reveiw

Citation: Zhang Cq, He Bm, Hu Ml and Sun Hb (2020) Risk of Valproic Acid-Related Tremor: A Systematic Review and Meta-Analysis. Front. Neurol. 11:576579. doi: 10.3389/fneur.2020.576579

Received: 26 June 2020; Accepted: 09 October 2020;
Published: 15 December 2020.

Copyright © 2020 Zhang, He, Hu and Sun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Hong bin Sun,


Drug - induced tremor is involuntary shaking due to the use of medication . There's two types of common tremors: 1. a neurological tremor- an example would be my grandfather whose hands constantly shake for no reason, and 2. tremor due to anxiety, which is what I have. Involuntary means you shake without trying to do so . I do have what they call "Benign Essential Tremor" which means my hands shake when I am trying to do something, and the harder I try the worse it gets. The shaking occurs when you move or try to hold your arms , hands , or head in a certain position . It is not associated with other symptoms.See also : Essential tremorFamilial tremorTremor Overview
The tremors may affect the hands , arms , head , or eyelids . The tremors rarely affect the lower body and may not affect body sides of the body equally.The shaking usually involves 6 to 10 movements per second.The tremors may be : Episodic -LRB- occuring in discrete bursts -RRB- Intermittent -LRB- come and go with activity , but not always -RRB- Sporadic -LRB- occasional -RRB- They can : Disappear during sleepGet worse with voluntary movement and emotional stressOther symptoms may include : Head nodding Shaking or quivering sound to your voice Symptoms
Drug - induced tremors go away when you stop taking the medicine thats causing the shaking.Treatment or changes in medications may not be required at all if the tremors are mild and do not interfere with daily activity.If the benefit of the medicine is greater than the problems caused by the tremor , different doses or types of medicines may be tried . All 3 types of tremor are with me today!!I also have a mild tremor in my hand. Different doses or similar medications may not cause the tremor.In rare cases , a drug such as propranalol -LRB- Inderol -RRB- or mysoline -LRB- Primadone -RRB- may be added to try and control the tremor . This may be done in the drug causing the tremor cannot be stoppedNever stop taking any medicine without first talking to your doctor . Treatment
Drug - induced tremors are a simple muscle response to certain medications . Certain drugs will cause what is called drug induced parkinson .There are also medications out there that can cause a drug induced Lupus.. what other meds are you (other than the B12 injections)? Drugs that can cause tremors include the following : Anticonvulsants such as valproic acid and divalproex sodium -LRB- Depakote -RRB- Bronchodilators such as theophylline and albuterolImmunosuppressants such as cyclosporineMood stabilizers such as lithium carbonateStimulants such as caffeine Causes
Your doctor can make the diagnosis by performing a physical exam and asking questions about your medical and personal history , especially your medication use.A physical exam will show shaking with movement . Continuous tremors of the left arm; may be Essential Tremor-MRI of brain pending So that is my medical history to date. There are usually no problems with coordination or mental function.Other tests are usually not needed . However , further tests may be done to rule out other reasons for the tremors . Tremors that occur when the muscles are relaxed or that affect the legs or coordination may be a sign of another condition , such as Parkinson 's disease . Other causes of tremors may include : Alcohol withdrawalCigarette smokingHyperthyroidismParkinson 's diseasePheochromocytomaToo much caffeineWilson 's diseaseBlood tests and imaging studies -LRB- such as a CT scan of the head , brain MRI , and x - rays -RRB- are usually normal . Tests & diagnosis
Drug - induced tremor is not a dangerous condition , but some patients find the tremors annoying and embarrassing . Also, I told her that my muscles tremor when i go to use them, even when typing--my fingers tremble, it's annoying!!!!!!!!!!!I got prescribed some new tablets to help with these tremor things and they seem to be having a small impact which is pretty good.I am also starting to wonder, since there is such a thing as Drug Induced Schizophrenia.Side effects include drug induced autoimmune disorders as well...Almost any asthma drug can be used well with exercise induced asthma.Prognosis
Always tell your doctor about the medicines you take . Moist Palms Tremor of Fingers Soft Nails See your doctor and get to the bottom of your fatigue before it gets worse Over - the - counter drugs should be taken with caution , especially those that contain stimulants or a medicine called theophylline.Caffeine can make tremors worse . Avoid caffeinated drinks such as coffee , tea , and soda , and other stimulants . Prevention
Severe tremor can interfere with daily activities , especially fine motor skills such as writing , and other activities such as eating or drinking . I also developed a tremor, especially in my hands.Tremor that gets worse while writing or eating is called kenetic tremor.Complications
Call your health care provider if you are taking a medication and tremors develop that interfere with activity or are accompanied by other symptoms .
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Depakote side effects and how to avoid them

Depakote side effects | Tremors | Weight changes | Rash | Depression | Hair loss | Sexual side effects | How long do side effects last? | Warnings | Interactions | How to avoid side effects

Depakote is a brand-name prescription medicine for the generic drug divalproex sodium or valproic acid. Depakote is in a class of medications called antiepileptic drugs, or anticonvulsants. It works by calming hyperactivity in the brain. It is approved by the Food and Drug Administration (FDA) to prevent and treat seizures, especially in people with epilepsy. Depakote is generally recommended for adults and children 10 years of age and older. It is also used to treat manic episodes associated with bipolar disorder, and to prevent migraine headaches. 

Depakote has a black box warning for hepatotoxicity and should not be taken by people with liver problems. It can cause serious pancreas damage, so people with a history of pancreatitis should not take it. Pregnant women should not take Depakote either. Like any other medication, it is important to be aware of Depakote side effects and its interactions. Let’s look at what you need to know before taking Depakote. 

RELATED: What is Depakote?

Like all medications, Depakote may cause minor and temporary side effects. In patients taking Depakote, the most common side effects include:

  • Headache
  • Nausea
  • Tiredness
  • Swelling of the arms and legs
  • Loss of appetite
  • Abdominal pain 
  • Skin rash
  • Weight gain
  • Vomiting 
  • Weakness
  • Hair loss
  • Tremor
  • Diarrhea 
  • Blurred vision
  • Increased appetite 
  • Decreased platelet count 
  • Confusion
  • Lightheadedness 


Tremors are a known side effect of Depakote. According to a study, about 4% of patients taking Depakote report developing a tremor, which may affect the hands, arms, head, or eyelids. In rare cases, the lower body is affected. The tremor may not affect both sides of the body equally. If patients develop a tremor and it is affecting their ability to function or their quality of life, they should discuss dosage options with their healthcare provider. Tests may be done to rule out other causes of a tremor.

Weight changes 

Depakote often causes an increased appetite, which can lead to weight gain. People taking it to treat migraine headaches may have decreased serotonin levels, which can also lead to cravings and overeating. Depakote can also cause drowsiness, which may decrease activity level. If weight gain is a concern, patients are encouraged to eat a balanced diet and engage in regular physical activity. If the weight gain continues, patients can discuss other medication options with their healthcare provider. 


A mild rash is a common side effect of Depakote and is often not of concern. However, patients should seek immediate medical attention if they develop fever, a red or purple skin rash, hives, sores in the mouth, blistering and peeling of the skin, swelling of the lymph nodes, swelling of the face, eyes, lips, tongue, or throat, trouble swallowing or breathing, as these may be signs of a serious allergic reaction.  

Serious side effects of Depakote

Some side effects of Depakote are more serious and may require medical attention. These include:

  • Pancreatitis
  • Severe liver damage 
  • Suicidal thoughts and depression
  • Severe rash
  • Rapid weight gain
  • Elevated ammonia in the blood
  • Hypothermia (low body temperature) 
  • Bleeding problems 


Patients taking anticonvulsants for any reason may develop depression, and people with a history of mental illness are at an increased risk of worsening depression while taking Depakote. Patients should talk to their healthcare provider if they notice an increase in depressed thoughts, suicidal thoughts, new or worsening irritability, new or worsening anxiety, panic attacks, trouble sleeping, dangerous impulses, or other changes in their mood or behaviors. 

Other Depakote side effects

Hair loss

According to one study, Depakote has been reported to cause hair loss in less than 3% of patients taking it. It is primarily reported in women who are between 40 and 49 years old. If patients are concerned about Depakote and hair loss, they should discuss this with their healthcare provider. Lowering the dosage of Depakote may alleviate this symptom.

Depakote interferes with the endocrine system and, according to one study, can cause reproductive and sexual dysfunction in both men and women. The most common sexual side effects were erectile dysfunction and decreased libido. If patients experience bothersome sexual side effects, they should discuss this with their healthcare provider. 

Most side effects of Depakote are temporary and will go away on their own after the medication is stopped. Since everyone metabolizes medications differently, their bodies will adjust to side effects in their own way. Most common side effects, including nausea and tiredness, will improve after two to four months of taking Depakote. 

Depakote contraindications and warnings 

Liver damage

Depakote should not be taken by people with compromised liver function. It can cause serious liver damage, especially in children younger than two years of age. Children younger than 2 years and patients with hereditary mitochondrial disease are at a considerably increased risk of developing fatal hepatotoxicity. Patients should tell their healthcare provider immediately if they experience stomach pain, dark urine, yellowing of the eyes or skin, decreased appetite, itching, skin rash, vomiting, and/or swelling in their feet, as these are symptoms of liver damage. The risk of getting this serious liver damage is more likely to happen within the first six months of treatment. In some cases, liver damage may continue even after stopping the drug.


Depakote can cause pancreatitis in both children and adults, and should not be taken by people with a history of pancreas disease. Patients should tell their healthcare provider if they experience severe stomach pain, sudden change in body temperature, constipation, or lightheadedness.

Pregnancy and breastfeeding

Depakote has been known to cause serious birth defects, such as spina bifida, and should not be taken by women who are pregnant.According to the manufacturer, these defects occur in 1-2 out of every 100 babies born to mothers who use this medicine during pregnancy. Depakote should not be taken by women who plan on becoming pregnant while taking the medication.

Depakote can be passed through breast milk and should not be taken by women who are breastfeeding.

Other restrictions 

  • Some men have become infertile while taking Depakote.
  • People who have had an allergic reaction to valproate, valproic acid, divalproex sodium, or any of the ingredients in Depakote should not take it. 
  • Patients with certain metabolic diseases such as urea cycle disorders should not take Depakote. 
  • Depakote has the potential to cause blood thinning and should not be taken by people with a history of bleeding problems.


Depakote is generally not considered habit-forming. However, stopping Depakote suddenly can cause serious problems. Patients with epilepsy who suddenly stop a seizure medicine can trigger seizures that will not stop. To avoid withdrawal symptoms, patients should discuss slowly stopping treatment with their healthcare provider. Everyone reacts to medications differently, but possible withdrawal symptoms of Depakote may include seizures, dizziness, tremors, irritability, anxiety, and depression. Patients should seek medical advice if these symptoms worsen. 


Patients should take the dose of Depakote prescribed by their healthcare provider. While everyone responds to medication differently, the maximum recommended dose of Depakote is 60 mg/kg/day. 

It is possible to overdose on Depakote if too much is taken. Symptoms of overdose include sleepiness and irregular heartbeat. A rare symptom of an overdose is a coma. Patients should seek immediate medical attention if they take more than their prescribed dose or experience any of these symptoms. 

Depakote interactions

Like any other medication, there are certain drug interactions that should be avoided. Do not take Depakote with: 

  • Anticoagulants, such as warfarin 
  • Other anticonvulsants, including carbamazepine, ethosuximide, lamotrigine, phenytoin, phenobarbital, and topiramate
  • Antidepressants and anxiolytics, including amitriptyline, bupropion, nortriptyline, and phenelzine
  • Antiemetics, including metoclopramide and over-the-counter medications such as antacids
  • Multiple sclerosis agents, including dalfampridine and amifampridine

1. Take Depakote as prescribed

Read all drug information before starting Depakote, and follow all directions on your prescription label. Depakote is taken orally and comes as a capsule, extended-release tablets called Depakote ER, a delayed-release tablet, a Depakote sprinkle capsule (capsule that contains small beads of medication that can be sprinkled on food), and a syrup (liquid) to take by mouth. 

Dosage will depend on a number of factors including your age, sensitivity to side effects, other medications you are taking, and the reason you are taking Depakote. Take the amount of medication that your healthcare professional has prescribed. The most common Depakote doses are 125 mg tablets, 250 mg tablets, and 500 mg tablets. Take Depakote with food to help prevent the medication from causing stomach pain. 

Take the missed dose as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. 

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. 

Do not stop taking Depakote without talking to your healthcare provider. 

2. Discuss your full medical history with your healthcare provider

Tell your doctor of any medications you are taking, including prescription and over-the-counter drugs, vitamins, and herbal supplements. Discuss any medical conditions you have. Let them know if you are pregnant or breastfeeding or planning on becoming pregnant while taking Depakote. Tell your provider if you have a history of pancreas or liver disease, bleeding problems, or certain metabolic diseases such as urea cycle disorder. It’s also important to discuss a history of depression or mental illness and if you’ve ever experienced suicidal ideation as Depakote may increase these thoughts. While taking Depakote, tell your doctor about any side effects or other symptoms you may develop as he or she may want to adjust the dosage. 

3.  Avoid other medications and substances that could make you drowsy

Depakote may make you drowsy. Do not drive or operate heavy machinery until you know how it will affect you. Some people may also experience impairment in thinking and judgment. Do not drink alcohol while taking Depakote, as this may increase your drowsiness. Do not take sleeping pills, narcotic pain medication, or any other substance that may make you drowsy until you know how Depakote will affect you. Keep Depakote and all medications away from children.

The Approach to Tremor

Drug-Induced Tremor

What Is a Drug-Induced Tremor?

A drug-induced tremor is a tremor that’s caused by taking a drug. A tremor is a rhythmic, uncontrollable movement of part of your body.

The shaking movement created by tremors is usually quick and tends to occur in cycles lasting six to 10 seconds. Drug-induced tremors may also be referred to as drug-induced Parkinson’s (DIP). In fact, 10 percent of Parkinson’s cases at a Parkinson’s disease treatment center turned out to be DIP.

Drug-induced tremors can occur when you move your body a certain way or are in certain positions. Medications that cause the tremors include certain antipsychotics, anticonvulsants, and antidepressants. Certain medications can both cause tremors and worsen any tremors you already have from Parkinson’s disease or another similar disorder.

What Are the Symptoms?

Most tremors occur in the hands. They can also occur in the:

  • arms
  • head
  • face
  • vocal cords
  • trunk
  • legs

Drug-induced tremors may cause your head to shake or nod uncontrollably. The tremors may not happen all of the time, but they’re likely to occur within the first hour of taking medication. If you find that this happens to you, take note of the medications you took before your tremors. This can help you and your doctor figure out which specific medication, or combination of medicines, is causing your symptoms.

Tremors usually stop when you’re asleep, and they can worsen when you’re under stress. You might notice that your voice sounds shaky as well.

Which Drugs Most Often Cause Tremors?

Drug-induced tremors are caused by your brain’s response to the chemicals in certain medications. Drug-induced tremors can also occur as the result of withdrawal from drugs or alcohol.

Anticonvulsant drugs are among the most common causes of drug-induced tremors. Anticonvulsants are used for a variety of medical conditions, including epilepsy and bipolar disorder. Bronchodilators, which are commonly used in the treatment of conditions such as asthma, can also cause tremors.

Immunosuppressants, which are used to prevent the rejection of transplanted organs, can also lead to drug-induced tremors. Drugs used to treat a variety of psychiatric disorders such as antipsychotics, lithium, and certain antidepressants are also potential causes of drug-induced tremors. Caffeine is a stimulant that can also cause you to have tremors or can worsen existing tremors.

How Will My Doctor Diagnose My Symptoms?

Diagnosis of your drug-induced tremors will start with your doctor asking you about your symptoms and medical history. A complete list of the medications you’re taking will be extremely helpful during diagnosis. Telling your doctor how often you’re having tremors can help aid in your diagnosis. The speed of your tremors can also help your doctor determine their cause.

Some important features of drug-induced tremors that distinguish them from Parkinson’s disease include the following:

  • The symptoms are on both the left side and the right side. Parkinson’s disease typically affects primarily one side.
  • The symptoms stop when you stop the medication. Parkinson’s disease is chronic and progressive.
  • There is no brain degeneration. Parkinson’s disease is caused by degeneration in a specific area of the brain.

Your doctor might want to rule out other potential causes of tremors by performing blood tests to check for abnormal levels of certain chemicals in your blood. Problems with your thyroid can also cause tremors, so your levels of thyroid hormones might be checked.

CT and MRI scans are done by a computer and allow your doctor to see your brain. Using these scans, your doctor can potentially rule out defects in your brain that may be causing tremors.

What Can Be Done to Treat My Tremors?

Your doctor will probably ask you to stop taking the drug that’s causing the tremors. This generally happens after talking with your doctor about the potential risks and benefits associated with stopping therapy. Your doctor will also discuss possible alternative treatments with you. Your symptoms may not resolve immediately after stopping the offending medication. Symptoms usually subside in about four months, but in some cases, it may take up to 18 months.

Who Is at Risk for Drug-Induced Tremors?

Anyone can develop tremors from taking medication. But some people are more at risk than others. Among those at increased risk are:

  • the elderly
  • people infected with HIV
  • anyone with a history of dementia
  • women

Preventing Drug-Induced Tremors

Talk to your doctor about the medications you’re taking, and consult them before adding any new over-the-counter medications. Stimulant medications and drugs containing theophylline should be used with caution.

Drinking caffeinated beverages, like coffee and certain teas or sodas, can make your tremors worse. Caffeine can stimulate muscle activity, causing more tremors. Tremors aren’t life-threatening, but they may be embarrassing for you if they happen in public. You might want to go to a support group while you wait for your symptoms to subside.


Tremor treatment depakote

Drug-induced tremor

Drug-induced tremor is involuntary shaking due to the use of medicines. Involuntary means you shake without trying to do so and can't stop when you try. The shaking occurs when you move or try to hold your arms, hands, or head in a certain position. It is not associated with other symptoms.

Drug-induced tremor is a simple nervous system and muscle response to certain medicines. Drugs that can cause tremor include the following:

  • Cancer medicines such as thalidomide and cytarabine
  • Seizure medicines such as valproic acid (Depakote) and sodium valproate (Depakene)
  • Asthma medicines such as theophylline and albuterol
  • Immune suppressing medicines such as cyclosporine and tacrolimus
  • Mood stabilizers such as lithium carbonate
  • Stimulants such as caffeine and amphetamines
  • Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) and tricyclics
  • Heart medicines such as amiodarone, procainamide, and others
  • Certain antibiotics
  • Certain antivirals, such as acyclovir and vidarabine
  • Alcohol
  • Nicotine
  • Certain high blood pressure drugs
  • Epinephrine and norepinephrine
  • Weight loss medicine (tiratricol)
  • Too much thyroid medicine (levothyroxine)
  • Tetrabenazine, a medicine to treat excessive movement disorder

The tremor may affect the hands, arms, head, or eyelids. In rare cases, the lower body is affected. The tremor may not affect both sides of the body equally.

The shaking is usually fast, about 4 to 12 movements per second.

The tremor may be:

  • Episodic (occurring in bursts, sometimes about an hour after taking the medicine)
  • Intermittent (comes and goes with activity, but not always)
  • Sporadic (happens on occasion)

The tremor can:

  • Occur either with movement or at rest
  • Disappear during sleep
  • Get worse with voluntary movement and emotional stress

Other symptoms may include:

  • Head nodding
  • Shaking or quivering sound to the voice

Your health care provider can make the diagnosis by performing a physical exam and asking about your medical and personal history. You will also be asked about the medicines you take.

Tests may be done to rule out other reasons for the tremor. A tremor that occurs when the muscles are relaxed or that affects the legs or coordination may be a sign of another condition, such as Parkinson disease. The speed of the tremor can be an important way to determine its cause.

Other causes of tremors may include:

Blood tests and imaging studies (such as a CT scan of the head, brain MRI, and x-rays) are usually normal.

Drug-induced tremor often goes away when you stop taking the medicine that is causing the shaking.

You may not need treatment or changes in the medicine if the tremor is mild and does not interfere with your daily activity.

If the benefit of the medicine is greater than the problems caused by the tremor, your provider may have you try different dosages of the medicine. Or, you may be prescribed another medicine to treat your condition. In rare cases, a drug such as propranolol may be added to help control the tremor.

Do not stop taking any medicine without first talking to your provider.

Severe tremor can interfere with daily activities, especially fine motor skills such as writing, and other activities such as eating or drinking.

Call your provider if you are taking a medicine and a tremor develops that interferes with your activity or is accompanied by other symptoms.

Always tell your provider about the medicines you take. Ask your provider if it is OK to take over-the-counter medicines that contain stimulants or theophylline. Theophylline is a drug used to treat wheezing and shortness of breath.

Caffeine can cause tremor and make tremor caused by other medicines worse. If you have a tremor, avoid caffeinated drinks such as coffee, tea, and soda. Also avoid other stimulants.

Tremor - drug-induced; Shaking - drug tremor

Morgan JC, Kurek JA, Davis JL, Sethi KD. Insights into pathophysiology from medication-induced tremor. Tremor Other Hyperkinet Mov (N Y). 2017;7:442. PMID: 29204312

O'Connor KDJ, Mastaglia FL. Drug-induced disorders of the nervous system. In: Aminoff MJ, Josephson SA, eds. Aminoff's Neurology and General Medicine. 5th ed. Waltham, MA: Elsevier Academic Press; 2014:chap 32.

Okun MS, Lang AE. Other movement disorders. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine. 26th ed. Philadelphia, PA: Elsevier; 2020:chap 382.

Updated by: Amit M. Shelat, DO, FACP, FAAN, Attending Neurologist and Assistant Professor of Clinical Neurology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M. Editorial team.

Could Tremors Be Just a Vitamin Deficiency? – Dr.Berg

Disabling tremor induced by long-term use of sodium valproate and lamotrigine

Case report

Zhong-Fang He, PhD,a,Jun Chen, MD,bChao-Ning Zhou, MD,bZhi Rao, PhD,a and Xiao-Hua Wang, PhDa

Zhong-Fang He

aDepartment of Pharmacy

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Jun Chen

bDepartment of Neurology, First Hospital of Lanzhou University, Lanzhou, China.

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Chao-Ning Zhou

bDepartment of Neurology, First Hospital of Lanzhou University, Lanzhou, China.

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Zhi Rao

aDepartment of Pharmacy

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Xiao-Hua Wang

aDepartment of Pharmacy

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Author informationArticle notesCopyright and License informationDisclaimer

aDepartment of Pharmacy

bDepartment of Neurology, First Hospital of Lanzhou University, Lanzhou, China.

Correspondence: Zhong-Fang He, Department of Pharmacy, First Hospital of Lanzhou University, Dong-Gang West Road No. 1, Chengguan District, Lanzhou 730000, China (e-mail: [email protected]).

Received 2017 Jul 4; Revised 2017 Oct 26; Accepted 2017 Oct 27.

Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.

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Sodium valproate (VPA) and lamotrigine (LTG) are widely used antiepileptic drugs, disabling postural, and action tremors after using LTG with VPA were reported in 1993. However, in this study, we describe a patient in whom disabling resting-type tremor induced by 2-year use of VPA and LTG.

Patient concerns:

A 50-year old man was referred to department of neurology because of involuntary upper limbs resting-type tremor with high amplitude that had begun 6 months previously and progressively worsened, and he could not work on the day of visit. Furthermore, he had been treated with VPA, LTG, and benzhexol for 2 years as he suffered from twitch of eyelids and facial region, and amantadine, monolithic compound preparation (flupentixol and melitracen) were added in the last 2 months because of tremor and anxiety. However, the treatment had no benefit on improving involuntary movements of the patient.


Drug-induced disabling tremor was diagnosed.

Interventions and outcomes:

LTG, amantadine, and VPA were withdrawn, the remaining 2 drugs, benzhexol and compound preparation (flupentixol and melitracen), were continued to use, and the patient improved in 2.5 months after discontinuation of 3 drugs. There was no recurrence at 6 months follow-up.


Considering the wide and long-term utilization of VPA and LTG, healthcare providers should be aware of them as a possible cause of tremor. When necessary, an attempt of discontinuing the suspected drugs should be made to confirm the diagnosis, instead of symptomatic treatment, especially when the adverse event was severe and fatal.

Keywords: disabling tremor, lamotrigine, long-term use, sodium valproate

1. Introduction

Epilepsy is a common neurological disorder characterized by episodic convulsions associated with transient confusion. More than 50 million people worldwide are affected by epilepsy.[1] It is not only a medical problem, but also an important public health and social problem. Epilepsy is listed as one of the significant neurological and mental diseases requiring prevention and treatment. Although many patients will remain seizure free on the first or second drug, combinations are usually prescribed in those unresponsive to monotherapy.[2] Sodium valproate (VPA) is the most widely used antiepileptic drug worldwide, and lamotrigine (LTG) is a novel antiepileptic agent. A study shows that VPA-LTG comedication exhibits a favorable pharmacodynamic interaction in patients with refractory partial epilepsy.[3]

Generally, VPA is well tolerated, and the most commonly occurring adverse reactions are gastrointestinal disturbances, others are neurologic abnormality, such as ataxia, tremor, sedation, drowsiness, and confusion.[4] Various systemic and neurologic side effects of LTG, such as spasticity, ataxia, nystagmus, and tremor, have also been reported.[4] Reutens et al[5] reported disabling postural and action tremors after LTG with VPA in 1993. However, the study on disabling resting-type tremor secondary to simultaneous administration of the 2 medicines has not been reported. To our knowledge, this is the first report about disabling resting-type tremor caused by VPA and LTG.

2. Case report

A 50-year-old man, weighing 75 kg, was referred to department of neurology because of involuntary upper limbs resting-type tremor with high amplitude that had begun 6 months previously and progressively worsened, and he could not work on the day of visit. Furthermore, he had been treated with VPA, LTG, and benzhexol for 2 years as he suffered from twitch of eyelids and facial region, and amantadine, monolithic compound preparation (flupentixol and melitracen) were added in the last 2 months because of tremor and anxiety. However, the treatment had no benefit on improving involuntary movements of the patient. In lower-grade hospital, the patient had been diagnosed as epilepsy due to twitch of eyelids and facial region, VPA and LTG had been initially given 2 years ago. There was no family history of any neurological disease and clinical features in favor of Wilson disease, he denied hypertension, diabetes mellitus, injury history, and history of drug allergy other than chronic hepatitis B of 30 years. After admission, he was conscious, temperature 36.4°C, pulse was 94 times/min, regular, and blood pressure was 129/91 mm Hg. Neurological examination showed involuntary upper limbs tremor, high muscle tension of extremities, and twitch of eyelids and facial region, the rest of the neurological examination was normal. On further evaluation, routine blood test and other tests such as liver function, kidney function, urine analysis, and random blood glucose were normal. Magnetic resonance imaging of brain, electroencephalography, and neuropsychological examination did not reveal any abnormality.

Disabling tremor induced by drugs was initially diagnosed based on the chronic worsening process, an exposure history of many drugs acting on the central nervous system, and the exclusion of known causes of secondary tremor by above clinical and laboratory evaluation. In treatment, LTG (100 mg qd) and amantadine (100 mg bid) were discontinued immediately; dosage of VPA was gradually reduced (sodium valproate sustained-release tablet: 1000 mg bid for 4 days, subsequently, 500 mg bid for 5 days) and was ceased after 9 days. In other words, within 9 days all of LTG, amantadine, and VPA were withdrawn. The degree of upper limbs tremor was not increased, but somewhat reduced. With that, remaining therapy was benzhexol for 2 mg tid, flupentixol, and melitracen (flupentixol 0.5 mg and melitracen 10 mg) for 1 piece, bid (8 am and noon). At follow-up examination 2.5 months after stopping above 3 drugs, his upper limbs tremor had apparently improved, and twitch of eyelids and facial region also improved except mouth. In addition, his mental state improved compared to 2.5 months ago, and he could work as a security guard according to his wife. There was no recurrence of the upper limbs tremor at 6 months follow-up.

3. Discussion

In this case, we have reported an unusual patient with upper limbs resting-type tremor induced by VPA and LTG, which improved after discontinuation of the culprit drugs. This confirms the initial diagnosis of drug-induced tremor. This case is unusual in 2 regards: firstly, his tremor is disabling and not mild; secondly, this case is the first documented case of resting-type tremor which is different from postural and action tremor caused by LTG with VPA reported in 1993.[5]

Indeed, the patient had been treated initially with VPA and LTG due to epilepsy, approximately 1.5 years later, the patient developed resting-type tremor with high amplitude of the arms and gradually worsened. Therefore, amantadine was added because of upper limbs tremor for 4 months, and compound preparation (flupentixol and melitracen) was also added at that time due to psychosomatic disease with anxiety, but upper limbs tremor did not improve within 2 months.

Firstly, to establish the causal relationship between medication (VPA and LTG) and tremor, we applied WHO Uppsala Monitoring Centre criteria,[6] the result showed that this adverse reaction had “probable” relationship with medication administration. Meanwhile, we assessed severity of this adverse reaction according to the Common Terminology Criteria for Adverse Events[7] in grades 1 to 5 (mild to lethal), the grade of the patient was 4 (disabling).

Secondly, we searched the literature of adverse reactions about tremor and extrapyramidal reaction on VPA, LTG, and amantadine. The results showed: Lautin et al[8] firstly reported a case of tremor with VPA in 1979; Reutens et al[5] reported that 3 patients presented disabling postural and action tremor after LTG with VPA, and their symptoms disappeared after reducing dosage of LTG or VPA. In addition, mild tremor was also observed in patients of VPA monotherapy and VPA-LTG combination.[3,9,10] Pathophysiologic mechanisms of extrapyramidal adverse reaction of VPA remains unknown, although a transient imbalance between functionally reciprocal subgroups of GABA pathways leading to remediable dopamine inhibition might be hypothesized.[11] Another study showed that the number of dopaminergic cells in the substantia nigra was reduced after treatment with VPA in mice.[12] Meanwhile, pharmacokinetic interaction of VPA inhibiting LTG metabolism,[13] pharmacodynamic interaction between VPA and LTG, and individual susceptibility such as chronic hepatitis B may have played a part in extrapyramidal adverse reaction of VPA and LTG.[5] However, amantadine is indicated in the treatment of drug-induced extrapyramidal reactions, and amantadine-induced tremor was not found by literature review.

To our knowledge, we have not found case report of upper limbs disabling tremor induced by VPA, LTG, and amantadine administrated together. In summary, we believe it is not possible to say with certainty if upper limbs tremor of the patient developed as a sole consequence of any one from VPA, LTG, and amantadine or as a consequence of possible synergistic effect of his medications. However, we speculate that simultaneous use of VPA and LTG is a possible culprit cause due to their long-term use of 2 years and antagonism of dopamine. Amantadine is not considered as a main culprit drug in a large part due to its effects on dopamine neurons and short-term use, especially 4 months after developing upper limbs tremor.

4. Conclusion

This case demonstrates that the long-term use of VPA and LTG can lead to disabling tremor. Considering the wide and long-term utilization of VPA and LTG, healthcare providers should be aware of them as a possible cause of tremor. When necessary, an attempt of discontinuing the suspected drugs should be made to confirm the diagnosis, instead of symptomatic treatment, especially when the adverse event was severe and fatal.


Abbreviations: LTG = lamotrigine, VPA = sodium valproate.

Z-FH and JC contributed equally to this work.

This study was supported by Natural Science Foundation of Gansu Province (No. 17JR5RA271).

All interventions given were part of normal health care and therefore ethics approval was not required in this study. However, informed consent was obtained from the patient.

The authors have no conflicts of interest to disclose.


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