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Table of Contents
REVIEW ARTICLES
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 86-98

Bupropion-associated movement disorders: A systematic review


Department of Neurology, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil; Department of Medicine, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil

Date of Submission11-Dec-2019
Date of Decision02-Jan-2020
Date of Acceptance10-Jan-2020
Date of Web Publication28-Jul-2020

Correspondence Address:
Dr. Jamir Pitton Rissardo
Rua Roraima, Santa Maria, Rio Grande do Sul.
Brazil
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AOMD.AOMD_35_19

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  Abstract 

Bupropion (BPP) was originally an antidepressant, but now it is also used for seasonal affective disorder and smoking cessation. The aim of this systematic review was to evaluate the clinical epidemiological profile, pathological mechanisms, and management of BPP-associated movement disorders. Relevant reports in six databases were identified and assessed by two reviewers without language restriction. A total of 63 reports of 710 cases from 16 countries were assessed. The movement disorders associated with BPP found clearly defined were: dyskinesia (8), dystonia (7), parkinsonism (7), myoclonus (6), tic (6), stuttering (3), rapid eye movement sleep disorders (2), and ballism (1); the not clearly defined cases included 488 tremors, 80 slurred speech, 48 ataxia, 20 abnormal movements, 19 falls, 4 akathisia, 3 dyskinesia, 2 hyperkinesia, 2 poor coordination, and the rest was only reported once (dystonia, myoclonus, motor tic, and rigidity). The mean age was 46 years (7–85 years). The male was predominant sex (52.77%). The mean BPP dose was 248.38 mg, and the most common indication was a major depressive disorder (73.68%). The average time of onset was 3.47 weeks and of recovery was 2.71 weeks. The most common management was BPP withdrawal. In the literature, the majority of the cases did not clearly report the clinical neurological examination and lacked electrodiagnostic studies. Future studies about adverse effects with BPP should describe at least the clinical characteristics and the physical exam of the individuals, especially when fall and slurred speech are observed.

Keywords: Amfebutamone, bupropion, drug induced, movement disorder, systematic review


How to cite this article:
Pitton Rissardo J, Fornari Caprara AL. Bupropion-associated movement disorders: A systematic review. Ann Mov Disord 2020;3:86-98

How to cite this URL:
Pitton Rissardo J, Fornari Caprara AL. Bupropion-associated movement disorders: A systematic review. Ann Mov Disord [serial online] 2020 [cited 2020 Sep 24];3:86-98. Available from: http://www.aomd.in/text.asp?2020/3/2/86/291079




  Key messages: Top


  1. BPP-induced dyskinesia (DKN) is probably a dose-dependent central nervous system side effect.


  2. The pathophysiological mechanism associated with the movement disorders are dopaminergic, noradrenergic, or the combination of these two neurotransmitters.


  3. If BPP is needed maybe before the withdrawal of the drug, a dose adjustment based on the benefits and DKN symptoms with careful evaluation case-by-case can be carried out.



  Introduction Top


Bupropion (BPP), also known as amfebutamone, is an aminoketone that belongs to the class of substituted cathinone and is similar to phenethylamines [Figure 1]. The first chemical studies with this drug started in 1960; in the following decade, studies with animal models showed a probable efficacy for the adjunctive management of depression.[1] In December 1985, BPP was first approved by the Food and Drug Administration (FDA) and marketed under the name Wellbutrin for the treatment of the major depressive disorder.[2] But, many case reports about BPP-induced seizures led to prompt removal of this drug from the market.[3] During 1985–1989, studies have shown that the greatest risk of seizure with this aminoketone occurs in individuals with bulimia and epilepsy.[4] In 1989, BPP was reintroduced by FDA with a warning in this subgroup and advice of starting in lower doses with a gradual increase.[5] The formulation approved was an immediate-release (IR) tablet, which required three times daily dosing.
Figure 1: Skeletal formula of bupropion

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Throughout 1989–1995, a sustained-release (SR) formulation was being developed due to some drawbacks of the IR. First, the inconvenience of the dose scheduled although clinical efficacy has been proven.[6] Second, some reports about the association of the peak plasma concentration of BPP and the adverse events at the same time.[7] In 1996, BPP SR was developed and marketed. The original name amfebutamone was led in the best, and after 2000, the chemical compound 3-chloro-N-tert-butyl-β-keto-α-methylphenethylamine was only called BPP. Head-to-head studies of BPP and selective serotonin reuptake inhibitors revealed a greater frequency of noncompliance with BPP, in which the complaints were again about the frequency of the doses.[6] In 2003, an extended-release formulation of BPP was released. Also, in the next years, the assessment of the efficacy for new uses of BPP was performed.

BPP is approved for major depressive disorder, seasonal affective disorder, and smoking cessation. This drug is also being prescribed off-label for the treatment of antidepressant-induced sexual dysfunction, attention deficit hyperactivity disorder, depression associated with bipolar disorder, generalized anxiety disorder, neuropathic pain, post-traumatic stress disorder, and obesity.[8] The main mechanism of action is probably the inhibition of dopamine and norepinephrine reuptake. Also, a noncompetitive antagonist of nicotinic acetylcholine receptors and negative allosteric modulation of the serotonin 5-HT3A receptor were already observed [Figure 2].[9],[10]
Figure 2: Schematic diagram of the mechanism of action of bupropion (BPP). Inhibition of dopamine and norepinephrine uptake. Also, BPP is a competitive antagonist of nicotinic acetylcholine receptors in the pineal gland that causes disinhibition of the melatonin synthesis, which leads to a decrease of depression symptom severity and possible enhancement of the efficacy of other neurotransmitters. Thus, these three pathways combined are possibly responsible for the antidepressant effect of BPP

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There are several adverse effects related to BPP. The most commonly reported and occurring in more than 10% of the patients are headache, dry mouth, nausea, weight loss, insomnia, agitation, dizziness, and pharyngitis. There is a black box warning about suicidal behavior, and that the FDA did not approve this medication for bipolar depression.[8],[11] In this context, the aim of this systematic review was to evaluate the clinical epidemiological profile, pathological mechanisms, and management of BPP-associated movement disorders.


  Materials and Methods Top


Search strategy

We searched six databases in an attempt to locate any and all existing reports on movement disorders secondary to BPP published between 1984 and 2019 in electronic form. Excerpta Medica (Embase), Google Scholar, Latin American and Caribbean Health Sciences Literature (LILACS), MEDLINE, Scientific Electronic Library Online (SciELO), and ScienceDirect were searched. Search terms were “tic,  Parkinsonism More Details, dystonia, restless legs syndrome, periodic limb movement disorder, akathisia, dyskinesia, tremor, chorea, restlessness, ataxia, hyperkinetic, hypokinetic, bradykinesia, movement disorder, movement, side effect, myoclonus, ballism, adverse effect, and idiosyncratic.” These terms were combined with “Bupropion, amfebutamone.”

Inclusion and exclusion criteria

Case reports, case series, original articles, letters to the editor, bulletins, and poster presentations published from 1984 to 2019 were included in this review with no language restriction. The two authors independently screened the titles and abstracts of all papers found from the initial search. Disagreements between the authors were resolved through discussion.

We excluded cases where movement disorder was already known and the individual motor symptoms were not worsened by or were not related to BPP. For tremors, clinical trials wherein other drugs such as naltrexone or stimulants were used together with BPP or the management of BPP for smoking cessation were removed from the analysis due to lack of possible better explanation of the abnormal movement. Also, cases that were not accessible by electronic methods, including after a request to the authors of the study by e-mail, were excluded.

Data extraction

A total of 7654 papers were found; of which, 7346 were irrelevant [Figure 3]. When provided, we extracted author, department, year of publication, country of occurrence, number of patients affected, BPP indication including off-label uses, time from first BPP dose till movement disorder onset, time from BPP withdrawal to symptoms improvement, patient’s status at follow-up, and important findings of clinical history and management. An important percentage of the reports did not clearly describe the case. In addition, the description of the follow-up lacked information. The data were extracted by two independent authors, double-checked to ensure matching, and organized by whether the movement disorder was a side effect of the BPP use.
Figure 3: Flow chart of the screening process

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Definitions

The clinical characteristics and definitions of the movement disorders such as dystonia (DTN), restless legs syndrome, periodic limb movement disorder, akathisia, dyskinesia (DKN), tremor, parkinsonism (PKN), tic, chorea, ballism, and myoclonus (MCL) were obtained from the reference Jankovic and Tolosa.[12] The clinical diagnosis for the psychiatric conditions was obtained from the Diagnostic and Statistical Manual of Mental Disorders.[13]


  Results Top


For the years 1984 and 2019, a total of 63 reports containing 710 cases that developed movement disorders after the use of BPP from 16 different countries were reported [Table 1].[3],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75] The origin was North American (674 cases), Asian (29 cases), European (6 cases), and South American (1 case). The movement disorders associated with BPP found were DKN (8 cases), DTN (7 cases), PKN (7 cases), MCL (6 cases), tic (6 cases), stuttering (3 cases), rapid eye movement sleep disorders (2 cases), ballism (1 case); the not clearly defined cases included 488 tremors, 80 slurred speech, 48 ataxia, 20 abnormal movements, 19 falls, 4 akathisia, 3 DKN, 2 hyperkinesia, 2 poor coordination, and the rest was only reported once (DTN, MCL, motor tic, and rigidity).
Table 1: Clinical reports of bupropion-associated movement disorders

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The rest of the results only described the group with clearly defined cases without ataxia or tremor that involved 40 individuals. The mean reported age was approximately 46 years (age range, 7–85 years). Male was the predominant sex with a percentage of 52.77% (19 of 36). The most common indication of BPP was major depressive disorder 73,68% (28 of 38), followed by smoking cessation (5), attention deficit hyperactivity disorder (4), and obsessive-compulsive disorder (1).

The mean BPP dose when the movement disorder occurred was 248.38 mg (dose range, 75–400 mg); the individuals separated by dose were 2 at 75 mg, 7 at 150 mg, 1 at 200 mg, 2 at 225 mg, 17 at 300 mg, 1 at 350 mg, and 1 at 400 mg. The time from the BPP start to abnormal movement onset was specified in 24 reports; of which, in 19, it was less than 1 month. The average onset time was 3.47 weeks (onset range, 0.14–16 weeks). The time from BPP withdrawal to symptoms recovery was specified in 19 reports; of which, in 17, it was less than 1 month. The mean time till recovery was 2.71 weeks (recovery range, 0.14–20 weeks).

The management was BPP withdrawal in 83.78% (31 of 37) cases. The other options were reduction or increase of BPP dose. Four cases reported rechallenge of the BPP with recurrence of the symptoms. Also, some reports described the use of benzodiazepines, anticonvulsants, typical antipsychotics, and cabergoline in an attempt to speed the recovery time.


  Discussion Top


General

On the basis of the results, we can suppose that the majority of the cases presented a middle-aged adult male of North American origin who was prescribed BPP 150–300 mg for the management of the major depressive disorder. Within 1 month of the BPP start, the individual began to develop orofacial and limb abnormal movements. When he searched for medical assistance, BPP was withdrawn, and a benzodiazepine was started. In the follow-up within less than 1 month, the patient had a full recovery.

The most common movement disorder reported was tremor, and in the majority of the cases, it was not clearly described. We hypothesized that the tremor, which was probably action, occurred due to an enhancement of the physiological tremor by the plasmatic increase of norepinephrine.[76] Slurred speech was the second most frequently observed and was included in [Table 1] because of the possibility of an association with a movement disorder. The clinical trials did not specify the characteristics of these individuals, but they could be diagnosed as movement disorders such as oromandibular DTN, subcortical MCL, ataxia, or even bradykinesia.[77] Falls were also commonly reported, and they need to be cautiously evaluated in the clinical practice when present; we believe that some of the cases could have been diagnosed with parkinsonian syndromes, which is supported by case reports of BPP-induced PKN presenting with falls.[16] However, both fall and slurred speech could only be supposed to be cases of movement disorders due to the insufficient data found in the literature. Therefore, these adverse events need to be better elucidated and described in future studies.

Herein, we would like to discuss some of the movement disorders in subtopics to give a better comprehension of the data. [Figure 4] shows a resume of the neurotransmitters involved in the BPP-associated movement disorders.
Figure 4: Schematic diagram showing the receptors involved in the mechanism of bupropion-associated movement disorders

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Dyskinesia

In all the reported cases about DKN secondary to BPP, the patients presented with orofacial symptoms; in those cases where BPP was maintained, after weeks, limb involvement was observed.[23] Also, the DKN subgroup had the longest periods, in months, of abnormal movement onset and its recovery.

We hypothesized that BPP-induced DKN is probably a dose-dependent central nervous system side effect. First, Gardos[23] reported two patients with neuroleptic tardive DKN where BPP aggravated their symptoms, which alleviated after BPP removal. Second, Kohen and Sarcevic[43] increased BPP dose in their patient diagnosed BPP-induced DKN, and the DKN worsened. Moreover, they prescribed mirtazapine that decreased the severity of the abnormal movement; after, an increase of the mirtazapine dose was carried out, and the individual had a full recovery.[43] Thus, we can imply that increasing the dose of mirtazapine possibly counterbalanced the BPP side effect.

One of the most common assumptions for the pathophysiological mechanism of drug-induced DKN is an abnormal adaptation of the striatal organization, leading to overactivation of the direct pathway.[78] This hypothesis is a possible explanation for the development in the BPP-induced DKN in the reported cases and may be supported by the time since drug start until the abnormal movement onsetThis hypothesis is a possible explanation for the development in the BPP-induced DKN in the reported cases and may be supported by the time since drug start until the abnormal movement onset. However, we can postulate another theory based on new studies with norepinephrine and rat models, in which the DKN temporally coincided with the extracellular striatal norepinephrine efflux.[79] This happened even after a significant loss of central norepinephrine, which can suggest that the norepinephrine transmitter itself probably influences the pathogenesis.[80] It is worth noting that as BPP is found to have antagonistic action on dopamine receptors at certain doses, the dopaminergic hypothesis cannot be excluded.[29],[44]

The most common management was the BPP withdrawal or dose decrease. Also, in an attempt to accelerate recovery, some authors proposed to prescribe mirtazapine and benzodiazepines. But, the recovery time of these reports was the same or was longer than the other studies. In this way, if BPP is needed maybe before the withdrawal of the drug, a dose adjustment based on the benefits and adverse events with careful evaluation case-by-case can be performed.

Dystonia

The most common presentation was the oromandibular DTN followed by cervical involvement. Interesting findings in this group when compared to the general movement disorders associated with BPP: none of the reports analyzed showed axial involvement, which is a common feature in drug-induced DTN; the individuals were younger; the BPP doses were lower; and the onset time was shorter. With this background, we can assume that DTN after BPP is a model of drug-induced movement disorder,[81] which is only found in susceptible individuals so the best management is its sudden withdrawal along with the start of biperiden or benzodiazepines for a short time. But, Detweiler and Harpold[35] reported a subject who on BPP rechallenge in a small dose did not develop new DTN symptoms.

One important fact was that even though BPP can induce DTN, its cessation may also cause this movement disorder due to a rapid decrease in dopamine availability, in a situation similar to dopamine-blocking drugs.[46]

A possible mechanism for the development of DTN secondary to BPP is related to a synergistic relationship between dopamine and norepinephrine.[82] In susceptible individuals, the increasing levels of dopamine led to an activation of the direct pathway, and the norepinephrine excess could act at β-adrenergic receptors on cerebellar Purkinje cells, which in experimental models caused ipsilateral leaning and postures reminiscent of human DTN.[83]

Parkinsonism

It is worth mentioning that some of the data found in patients with PKN were the opposite of data from patients with DTN when both compared to the mean features. In this context, the individuals were older and the BPP doses were higher in the PKN-induced patients. On the basis of these data, we can note that probably the age was an important component for the development of PKN in this group of individuals.[84] Therefore, the finding of PKN in these individuals could be more related to Parkinson’s disease itself than a drug’s adverse event.However, all the individuals had a complete recovery after BPP withdrawal. In addition, Grandas and Lopez-Manzanares[44] reported a case of a patient that the I-123 ioflupane single-photon emission computed tomography showed normal striatal uptake.[85]

BPP has a complex pharmacological effect on dopaminergic neurotransmission. In some patients with Parkinson’s disease, modest improvement in motor symptoms has already been reported,[86] albeit it has shown a very low affinity for dopamine uptake sites.[87] We believe that an explanation for the PKN could be related to the norepinephrine in a similar mechanism to the BPP-induced DKN;[80] the presence of DKN at the same time of PKN, in the reports by Grandas and Lopez-Manzanares[44] and Lam,[57] supports this hypothesis.

Myoclonus

The majority of reports about MCL occurred during BPP overdose; in only three reports, the occurrence was with normal BPP doses. There was a variable presentation of MCL in the literature: palatal, multifocal, and cranial[52] (MCL type proposed by Gupta and Lang). We hypothesized that the source of MCL was probably subcortical based on the segmental MCL.[88] However, the case reports lacked information about the neurological examination and electrodiagnostic studies.

Hohler and Hartmann[36] proposed that the palatal jerks occurred due to inhibitory release of serotonin, norepinephrine, and dopamine by BPP causing oscillation of the inferior olivary nucleus. The dopaminergic innervation of the inferior olive in animals, observed by light microscopic and ultrastructural investigation, revealed that the ventrolateral outgrowth receives dopaminergic input from the mesodiencephalic junction.[89] Therefore, maybe this dopaminergic input, when increased by BPP, to the inferior olive can lead to the palatal MCL.

The most common management was the BPP withdrawal. Also, even though only one report described the use of benzodiazepines, we believe that short-term prescriptions of these drugs should be considered as they can lead to fast recovery decreasing the social impairment caused by the jerks.[90]

Tics

Since the discoveries of the pharmacological mechanism and results in animal studies, BPP has been accused of being significantly associated with tics. However, in the literature, we have a few reports with this side effect. Also, the majority of the reports are with Tourette’s syndrome or previously known tic disorder; we only have one report with BPP-induced tics in a person without a tic disorder. Thereby, even if tics secondary to BPP are well-known; this adverse event is rare. It is worth mentioning that except for one case, all cases were observed in kids or teens.

An interesting fact is that the reports appear to be related to the drug formulations. The first reports occurred with IR drugs, and the worsening of tic occurred almost at the same time as the plasmatic peak of BPP.[17] The last two individuals were in use of extended-release formulations.[62],[75] Thus, it seems that this abnormal movement was directly associated with concentration and the time exposure.

One of the hypotheses to explain tics is the striatal dopaminergic activation.[91] BPP increases dopamine neurotransmission in both the nucleus accumbens and the prefrontal cortex.[10] In this way, tics secondary to BPP administration probably occur due to an increase of the dopaminergic activation in the striatum.

Stuttering and ballism

We included the stuttering cases induced by BPP due to possible misdiagnosis. The differential diagnosis of stutter should include at least psychogenic source, DTN, and MCL. We believe that the cases reported in the literature could be diagnosed among these three disorders. This hypothesis can be supported by some facts. First, none of the cases was clinically examined by a movement disorder specialist, which probably contributed to a general description of the features without a minute portrait of the neurological examination or even of the oral cavity.[92] Second, electrodiagnostic studies are lacking, which could have contributed to some pathological pathways or other diagnoses.[93] Third, stuttering when secondary to medication is more common to have the recovery in weeks, but the reports with BPP were within days.[94] Four, in all the cases, the patients had a severe major depressive disorder that may be contributed to a misdiagnosis.[95]

The mechanism of stutter is believed to be related to the dopamine system in the brain regions that modulate verbalization.[96] The effectiveness of dopamine antagonists[97] to treat this disorder and the increased marker of presynaptic dopamine activity in the ventral limbic and subcortical regions support this theory.[98] So, the increase of dopamine by BPP, which mainly occurs in the prefrontal cortex,[10] can explain the BPP-induced stuttering.

de Graaf et al.[38] reported a case of ballism associated with BPP. The management was through drug withdrawal, and haloperidol combined with benzodiazepine was started due to the severity of the movement disorder. In the same way as stuttering, the increase of dopamine is probably related to the BPP-induced ballism/chorea. This is supported by the symptomatic treatment efficacy with blockers of striatal D2 dopamine receptors.[99]


  Conclusion Top


BPP is associated with DKN, DTN, PKN, MCL, tic, stuttering, rapid eye movement sleep disorders, and ballism. In the literature, the number of reports about BPP-associated movement disorder is probably underestimated; however, in general, this drug is uncommonly related to abnormal movements. The majority of the cases did not clearly report the clinical neurological examination and lacked electrodiagnostic studies. BPP-induced DKN is probably a dose-dependent central nervous system side effect. The possible pathophysiological mechanisms associated with the movement disorders are dopaminergic, noradrenergic, or the combination of these two neurotransmitters. If BPP is needed maybe before the withdrawal of the drug, a dose adjustment based on the benefits and DKN symptoms with careful evaluation case-by-case can be carried out. Future studies about adverse effects with BPP should describe at least the clinical characteristics and the physical exam of the individuals, especially when fall and slurred speech are observed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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