Movement disorders, encompassing parkinsonism and tardive dyskinesia, are frequent complications of treatment with antipsychotics.1 Their prevalence is variable within the literature, but drug-induced parkinsonism reportedly affects between 19% and 36% of schizophrenia patients,2 while the prevalence of tardive dyskinesia varies between 13% and 32%,3 depending on whether first or second generation antipsychotics are used. The pathophysiology of antipsychotic-induced parkinsonism and tardive dyskinesia is extremely complex, and is thought to involve, among other factors, blockade of dopamine D2 receptors.4,5
Aripiprazole (Abilify) is an atypical antipsychotic that is approved by the FDA for the treatment of psychosis in schizophrenia, bipolar disorder, major depressive disorder, irritability associated with autistic disorder, Gilles de la Tourette syndrome, as well as agitation associated with schizophrenia or bipolar mania (www.accessdata.fda.gov/drugsatfda_docs/label/2014/021436s038,021713s030,021729s022,021866s023lbl.pdf). Aripiprazole exhibits strong potency and is a partial agonist at serotonin 1A (5-HT1A), 5-HT2C, dopamine D2 and D3 receptors, in addition to being a potent antagonist at 5-HT2A receptors.6 Because its pharmacological profile differs to the mechanism of action of typical antipsychotics, it was initially believed that aripiprazole would have a better tolerability profile and would elicit less movement disorders such as parkinsonism and tardive dyskinesia. However, whereas the literature on this topic remains tenuous, there have been reports of aripiprazole-induced movement disorders such as akathisia,7 tardive dyskinesia,8,9 and acute dystonia.10 Two case-series of aripiprazole-induced movement disorders have been published.11,12 Here, we present 14 patients who were treated with aripiprazole and developed movement disorders while under treatment (Table 1).
Patients treated with aripiprazole and referred to the André Barbeau Movement Disorder Clinic of the Centre Hospitalier de l’Université de Montréal for assessment of abnormal movements are presented here. Patients were seen between September 2013 and January 2016. Their charts were retrospectively reviewed and data pertaining to movement disorders induced while under aripiprazole treatment, or shortly after its discontinuation, are presented. Local Institutional Ethics Committee reviewed and approved this project.
A 59-year-old woman was referred for evaluation of resting and postural tremor. Her medication consisted of aripiprazole 10 mg daily, bupropion XL, paroxetine CR, and quetiapine XR. She exhibited 2 kinds of tremor, one that began a few years ago and was interfering with eating and writing, and another one, present at rest, which had begun 1 year prior to her visit; that is, a few months after aripiprazole had been initiated. The resting tremor affected the lower jaw and both upper limbs, without asymmetry. She also complained of stiffness, difficulty writing and loss of fine motor skills, all of which started shortly after aripiprazole was introduced. In addition to the resting tremor affecting the upper extremities and lower jaw, she exhibited symmetrical postural and kinetic tremor affecting both upper extremities. Muscle tone was increased in both upper extremities and the neck; bradykinesia was present in all 4 limbs. Aripiprazole was gradually tapered. The patient was seen in a follow-up visit 10 months after aripiprazole was discontinued. She was then taking quetiapine XR, paroxetine CR, and bupropion XL. The resting tremor, bradykinesia and rigidity had all disappeared. Bilateral postural and kinetic tremor was still present. The patient was now presenting orobuccolingual stereotypical movements that had begun while aripiprazole was being tapered and that were evocative of tardive dyskinesia. As they were nonbothersome, they were left untreated.
This case suggests that aripiprazole may induce parkinsonism. It also suggests that aripiprazole may induce tardive dyskinesia.
A 63-year-old woman was referred to the movement disorder clinic for tremor and abnormal involuntary movements. She had previously experienced drug-induced parkinsonism in the past while being treated with risperidone and olanzapine for 4 months. Prior to her visit, the 2 drugs had been discontinued for several months had been replaced by quetiapine, resulting in a considerable improvement of the parkinsonian features. Although under quetiapine therapy, she began experiencing repetitive stereotypical chewing movements. Aripiprazole, up to 15 mg daily, was then introduced, presumably to alleviate these jaw movements. A few weeks after being on aripiprazole, parkinsonian features resumed, although repetitive jaw movements disappeared. She was under aripiprazole treatment for 9 months. When seen at the clinic, she exhibited bilateral rest and reemergent tremor, symmetrical bradykinesia, and rigidity. Aripiprazole was discontinued and the parkinsonism disappeared over 8 months, although the jaw movements reappeared; they were improved by propranolol.
This case suggests that aripiprazole may induce parkinsonism. It also suggests that aripiprazole may alleviate tardive dyskinesia. Had the patient been maintained on aripiprazole therapy for a longer period, whether tardive dyskinesia would have resumed while still under treatment is unknown.
A 78-year-old woman with bipolar disorder was seen at the movement disorder clinic for parkinsonism. For 2 years, she had been treated with aripiprazole 15 mg daily, venlafaxine XR and quetiapine. The bipolar disorder was well controlled with this therapeutic regimen, but she was complaining of extreme stiffness, the beginning of which coincided with the start of aripiprazole. On physical examination, the patient was not tremulous, was very bradykinetic and markedly rigid on all 4 extremities and axially. She was also very bradyphrenic. Aripiprazole was discontinued, but it resulted in a relapse of the bipolar disorder, leading to the introduction of lithium. Bradykinesia and rigidity improved following aripiprazole discontinuation.
This case suggests that aripiprazole may induce parkinsonism and may also have cognitive side effects—fot example, bradyphrenia.
A 64-year-old woman was referred to the movement disorder clinic for abnormal involuntary movements. She took aripiprazole, up to 20 mg daily, which was discontinued 3 years prior to the visit. Although taking aripiprazole, she began experiencing repetitive and quasicontinuous flexion/extension movements involving the trunk of moderate amplitude. She also developed stereotypical jaw and tongue movements. She also presented what was reminiscent of akathisia. When seen at the movement disorder clinic, she was on citalopram and tetrabenazine 12.5 mg 3 times daily. On examination, she exhibited constant chewing and lip smacking movements as well as pelvic thrusting. She could not remain seated for more than a few seconds without moving, sometimes she had to get up. She had been taking tetrabenazine for at least 1 year, without improvement of the movements. Tetrabenazine has since then been increased up to 50 mg thrice daily, resulting in a reduction of the akathisia, but is currently being reduced, because the patient developed parkinsonism and bradyphrenia. Propranolol, amantadine, levetiracetam, quetiapine, Ginkgo biloba, and clonazepam have only produced mild relief of the copulatory dyskinesia, which is persisting and debilitating. She is now considering undergoing deep-brain stimulation surgery to provide relief to her dyskinesia.
This case suggests that aripiprazole may induce tardive dyskinesia that is refractory to medical treatment.
A 69-year-old man was referred to the movement disorder clinic for abnormal involuntary movements. When seen at the clinic, he was on quetiapine. Prior to quetiapine, he had been treated with aripiprazole (dose unknown) for about 1 year. Aripiprazole was poorly tolerated and had been discontinued about 1 year prior to the assessment. Aripiprazole reportedly induced severe bilateral resting tremor, unstable balance, gait disturbance, bradyphrenia, dysphagia, and freezing, which we could not demonstrate in our assessment. Moreover, while on aripiprazole, he developed stereotypical orobuccolingual movements. These increased in severity upon aripiprazole discontinuation and persisted despite quetiapine. The patient was seen in a follow-up visit 1-year later. He was not parkinsonian, but oral dyskinesia persisted, despite quetiapine therapy.
This case suggests that aripiprazole may induce tardive dyskinesia. It also suggests, although we could not assess it, that aripiprazole may induce parkinsonism.
A 22-year-old man was seen at the movement disorder clinic for abnormal lingual and facial movements. His psychiatric history was significant for a depression, for which he was treated with lithium and aripiprazole up to 10 mg daily. He was complaining of tongue twisting movements that were sometimes interfering with his speech. The movements started while he was on aripiprazole and had worsened following discontinuation of the drug, 2 years prior to the visit. Trials of trihexyphenidyl, propranolol, gabapentin, and clonazepam were ineffective at reducing these movements. When seen at the clinic, he was on gabapentin, amitriptyline and clonazepam. The movements consisted of stereotypical tongue ondulations accompanied by intermittent eyelid closure. No oromandibular dystonia was noted. Botulinum toxin injections in the tongue muscles partly alleviated the movements.
This case suggests that aripiprazole may induce tardive dyskinesia.
A 61-year-old man was seen at the movement disorder clinic for generalized slowness. When seen, he was on aripiprazole 20 mg daily, mirtazapine and bupropion SR. He had been on this treatment regimen for 9 months when he was seen. He was complaining of generalized slowness and stiffness that was interfering significantly with his activities of daily living. The symptoms had begun a few weeks after aripiprazole was introduced. On physical examination, he exhibited hypomimia, symmetrical rigidity of both upper extremities, bradykinesia affecting the 4 limbs and a shuffling gait. There was no tremor. Aripiprazole was tapered off and replaced by quetiapine XR, which resulted in a significant improvement of parkinsonian features 4 months later. A follow-up visit is planned in a few months to determine if parkinsonism has completely abated.
This case suggests that aripiprazole may induce parkinsonism.
A 66-year-old man was referred to the movement disorder clinic for parkinsonism. His past medical history was significant for a right middle cerebral artery stroke a few years before that resulted in left hemiparesis. He had been followed by a psychiatrist for 4 years for aggressive behavior. His medication had been stable for several months, and consisted of aripiprazole 2 mg daily, paroxetine and baclofen. Despite the stroke, the patient was fully autonomous until about 1 year prior to the visit, time at which aripiprazole was introduced. When seen, he was unable to walk and was wheelchair-bound, hypomimic, and exhibited bilateral resting tremor of both upper extremities. He also had rigidity that was easier to perceive on the right hemibody, as there was superimposed spasticity on the left side of his body. He also complained of dysphagia. The patient was taken off aripiprazole, and was seen in a follow-up visit 5 months later. There was a marked improvement of parkinsonian features, notably resting tremor, which could no longer be demonstrated. Rigidity and bradykinesia had almost completely disappeared. However, shortly after aripiprazole discontinuation, he began exhibiting abnormal movements. He was experiencing stereotypical arrhythmic tongue movements that consisted of up-and-down and side-to-side movements. There was also intermittent opening and closing of the jaw. The head was slightly tilted toward the left. The lower back also appeared to be slightly dystonic, as it was slightly hyperextended and tilted towards the left. He exhibited intermittent flexion and extension movement of the right leg as well. Quetiapine was started and progressively increased to alleviate the hyperkinetic movements. Although they have improved, the dystonic back and neck postures are persisting despite quetiapine therapy.
This case suggests that aripiprazole may induce parkinsonism. It also suggests that discontinuing aripiprazole may lead to the emergence of tardive dyskinesia.
A 66-year-old woman was referred for assessment of a parkinsonian syndrome. Her past psychiatric history was significant for a depressive episode with psychotic features, for which she took risperidone for <year. Risperidone had been discontinued for >2 years prior to her appointment. When seen at the clinic, she was treated with aripiprazole 5 mg daily and sertraline. She had been on this regimen for 2 years. Prior to the introduction of aripiprazole, she had not exhibited any parkinsonian features. However, a few weeks after beginning aripiprazole, she began experiencing bilateral hand resting tremor, stiffness, and micrographia. At the physical examination, she had bilateral resting and reemergent tremor affecting both upper extremities, as well as bradykinesia and rigidity affecting all 4 limbs and the neck. She was also exhibiting stereotypical jaw opening and closing movements, with occasional tongue protrusion. Aripiprazole was discontinued and replaced by quetiapine. The patient was seen in a follow-up visit 9 months later and did not exhibit any signs of parkinsonism. However, the orolingual movements were persisting and had increased in severity. She had also developed choreiform stereotypical movements affecting the trunk and the 4 extremities. She was extremely uncomfortable. A trial of higher dose quetiapine was poorly tolerated by the patient and she had to be put on tetrabenazine, which is currently being titrated.
This case suggests that aripiprazole may induce parkinsonism. It also suggests that aripiprazole may induce tardive dyskinesia, although caution is warranted in this case, as the patient had been on risperidone before aripiprazole. However, the fact that the dyskinesia began while the patient was treated with aripiprazole points towards aripiprazole as the causative agent.
A 68-year-old man was referred to the movement disorder clinic for assessment of parkinsonism. His past medical history was significant for dementia with visual hallucinations. According to his family physician, he had exhibited cognitive decline for a few years prior to the referral, without signs of parkinsonism. The hallucinations had appeared recently and he was put on aripiprazole 2 mg daily shortly after. A few months later, he started presenting bilateral tremor and slowness of movement. When seen at the movement disorder clinic, he had bilateral resting tremor affecting both upper extremities, and exhibited rigidity and bradykinesia affecting mostly the upper limbs. It was suggested to discontinue aripiprazole, but the patient and his spouse both refused as the hallucinations were well controlled with the drug.
This case suggests that aripiprazole may induce parkinsonism. Another possibility is that treatment with aripiprazole might have unmasked a parkinsonian disorder such as Parkinson disease or Lewy body disease. As the patient and his spouse do not want to discontinue aripiprazole, it is not possible to determine whether the parkinsonian phenotype would abate after a few months being off treatment.
A 59-year-old man was referred to the movement disorder clinic for abnormal involuntary movements. When seen, he was not taking any antipsychotic drug. Five years prior to the visit, he took quetiapine, following which he was switched to olanzapine. He was then put on risperidone for a few months, and then on loxapine or 2 months. Loxapine was then discontinued and aripiprazole was started. He took aripiprazole 10 mg daily for 4 months. Although taking aripiprazole, the patient developed akathisia that was “unbearable.” He was seen 3 months after aripiprazole discontinuation. Although in the waiting room, he was walking around, incapable of remaining seated and exhibited stereotypical pedaling leg movements upon sitting. He also had stereotypical orolingual chewing movements. He did not exhibit bradykinesia or rigidity; he had a slight postural tremor. The akathisia, pedaling and chewing movements all began while he was taking aripiprazole. Trials of benzodiazepines, propranolol, gabapentin and benztropine were ineffective at reducing the akathisia and the stereotypical leg and mouth movements. The patient had to be put on tetrabenazine to alleviate his symptoms. Akathisia disappeared with tetrabenazine, but the stereotypical leg and mouth movements still persist, despite being milder. Depression is now treated with mirtazapine.
This case suggests that aripiprazole may induce akathisia and tardive dyskinesia. However, the interpretation of this case is limited because the patient took antipsychotics prior to aripiprazole, which could play a role in the akathisia and tardive dyskinesia. However, the emergence of both akathisia and tardive dyskinesia while being under aripiprazole treatment tends to orient toward aripiprazole as the drug that caused the phenomena.
A 72-year-old woman was referred to the movement disorder clinic for evaluation of a parkinsonian syndrome. Her medication consisted of aripiprazole 5 mg daily, olanzapine and quetiapine XR. Aripiprazole was added to olanzapine and quetiapine XR a few years prior to the visit, shortly after which she began experiencing bilateral resting tremor affecting both upper extremities, stiffness affecting all 4 limbs and slowness of movement. Aripiprazole was discontinued, olanzapine was reduced and quetiapine XR was increased. One year later, the patient did not exhibit any signs of parkinsonism. However, she had developed mild stereotypical chewing movements that were nonbothersome.
This case suggests that aripiprazole may induce parkinsonism and that tardive dyskinesia may emerge upon withdrawal. However, as the patient was taking olanzapine concurrently with aripiprazole, olanzapine might have played a role in both parkinsonism and tardive dyskinesia and this case needs to be interpreted with caution.
A 43-year-old man was referred to the movement disorder clinic for abnormal movements affecting the jaw and hands. When seen, he was on aripiprazole 10 mg twice a day and clozapine 100 mg daily. He had previously taken loxapine and lithium, but had been off these medications for a few years. The movements began to appear a few days after aripiprazole was reduced from 15 mg twice daily to 10 mg twice daily. The patient did not notice these movements and they were not bothersome. He exhibited stereotypical jaw opening and closing movements, as well as lateral tongue movements. He also had rotational bilateral wrist movements. He did not have akathisia or parkinsonism. Aripiprazole was reincreased to 15 mg twice daily by the psychiatrist, leading to a reduction of the abnormal movements.
This case suggests that aripiprazole may induce tardive dyskinesia, and that increasing aripiprazole to a dose where there was no tardive dyskinesia previously may alleviate these abnormal involuntary movements.
A 69-year-old woman was referred to the movement disorder clinic for evaluation of a parkinsonian syndrome. She had been treated with monthly paliperidone injections for 1 year, after which it was discontinued, because of tremor and stiffness that developed after a few injections. When she was seen, she had been on aripiprazole 5 mg daily for 1 year. She had bilateral upper and lower extremity resting tremor. She exhibited rigidity and bradykinesia affecting the 4 limbs, in addition to hypomimia and hypophonia. She also had nocturnal akathisia that was reducing the duration of her sleep. In a follow-up visit 8 months later, aripiprazole had been discontinued and replaced by quetiapine XR and lurasidone. At this time, the patient’s parkinsonian phenotype was essentially unchanged.
This case suggests that the patient developed drug-induced parkinsonism while being treated with antipsychotics. Although it does not allow to incriminate aripiprazole as the etiological agent, it suggests that replacing an antipsychotic that caused parkinsonism with aripiprazole may not lead to a reduction of the parkinsonian disability. The persistence of the parkinsonian phenotype after aripiprazole might be due to treatment with lurasidone.13 Whether the antipsychotics unmasked an underlying Parkinson’s disease or whether the patient is afflicted by drug-induced parkinsonism remains uncertain at this time.
The cases presented here add to the existing literature on aripiprazole-induced movement disorders. As mentioned in the Introduction, aripiprazole has a unique mechanism of action, as a partial agonist at 5-HT1A, 5-HT2C, dopamine D2 and D3 receptors, and as an antagonist at 5-HT2A receptors.6 Several articles have now been published that report that aripiprazole may induce movement disorders, the breadth of which is varied, encompassing akathisia,7 tardive dyskinesia,8,9 acute dystonia,10 and parkinsonism.11,12 The mechanisms underlying aripiprazole-induced movement disorders have not been clearly defined, but likely involve an interaction with dopamine D2 receptors14
Here, we present 14 cases encompassing individuals of both sexes, and an age span from 22 to 78 years old. Here, doses as low as 2 mg daily were sufficient to induce movement disorders. A limitation of our article is that some patients were not antipsychotic naïve at the time they took aripiprazole, which, in these cases, must be kept in mind when interpreting the contribution of aripiprazole to the emergence of the abnormal movements. Nevertheless, the cases presented here suggest that:
- aripiprazole may induce parkinsonism;
- if an antipsychotic other than aripiprazole has induced parkinsonism, the parkinsonian phenotype may persist while being treated with aripiprazole;
- aripiprazole may induce tardive dyskinesia encompassing orobuccolingual dyskinesia, appendicular dyskinesia, as well as truncal dyskinesia.
The cases presented here suggest that aripiprazole may induce the same side effects as first generation antipsychotics. Further articles like ours will help to further define the spectrum of aripiprazole-induced movement disorders, and to have a better idea of the prevalence of these motor complications. Clinicians should be aware of these potential extra-pyramidal side effects when prescribing aripiprazole.