Aripiprazole and Tardive Dyskinesia

Vol 2 # 4

In this edition of the journal we call attention to the accumulating evidence that Abilify/aripiprazole can cause tardive dyskinesia.


This contrasts with early claims by the manufacturer that such risks were minimal (Berman; Marcus below).


Earlier publications claimed that aripiprazole could be used to treat tardive dyskinesia (Margolese).

Such claims were clearly suspect at the time as it is well known that any antipsychotic dopamine blocking agent can temporarily suppress signs of tardive dyskinesia that the cost of long-term exacerbation.


The first case report of TD associated with aripiprazole was published over 10 years ago.


Epidemiology of tardive dyskinesia before and during the era of modern

antipsychotic drugs.

Tarsy D, Lungu C, Baldessarini RJ.

Handb Clin Neurol. 2011;100:601-16.


Department of Neurology, Harvard Medical School and Beth Israel Deaconess

Medical Center, Boston, MA 02215, USA.

Late or tardive dyskinesias/dystonias (TD), contrary to expectation, have not

disappeared with the use of expensive, modern antipsychotic drugs (APDs). Risk

appears to be substantially lower than with older neuroleptics, and there is

sparing of most acute movement disorders traditionally associated with APD



However, risks of TD with modern APDs have been reduced much less than

expected, by perhaps two- to threefold or even less, with substantial risks in

the elderly. Major challenges in assessing prevalence or, preferably, incidence

of TD arise from prolonged and erratic past exposure to various APDs, relatively

recent use of modern APDs, and the occurrence of spontaneous movement disorders

(about 5% and more in the elderly).


TD risks associated with modern APDs may be similar to some older neuroleptics, especially those of low-moderate potency.

Risperidone (and its active metabolite paliperidone), at high doses, may carry

unusually high TD risk, whereas TD risk is low with clozapine, and perhaps

quetiapine and aripiprazole.


Optimistic expectations for the efficacy and neurological safety of modern APDs have encouraged their wide use in many conditions, sometimes off-label or in combinations, with little research support, increasing the chance of a higher prevalence of TD, especially at older ages.


Measures to limit TD risk include: (1) critical, objective indications for APD

use; (2) long-term use only for compelling or research-supported indications,

primarily chronic psychotic illness that worsens when APD is slowly discontinued;

(3) avoiding off-label indications; (4) using alternative treatments when APD

treatment is elective, or early dyskinesia is identified; (5) using low but

effective doses of single APDs, especially in the elderly; and (6) regular and

specific examination for early TD.


Movement Disorders Induced by the “Atypical” Antipsychotic Aripiprazole.

Selfani K, Soland VL, Chouinard S, Huot P.

Neurologist. 2017 Jan;22(1):24-28.


Unité des Troubles du Mouvement André Barbeau Division of Neurology, Centre

Hospitalier de l’Université de Montréal


OBJECTIVES: Aripiprazole is an antipsychotic that acts as a partial agonist at

dopamine D2 receptors. Because of its partial agonist activity, it was believed

that aripiprazole would be less susceptible than typical antipsychotics to induce

extrapyramidal side effects. However, a few case-reports and case-series

detailing aripiprazole-induced movement disorders have been published, suggesting

that aripiprazole-induced movement disorders may arise. Here, we report

further cases of aripiprazole-induced movement disorders to raise the awareness

of clinicians on this adverse effect.


METHODS: Patients referred to the André-Barbeau Movement Disorder clinic treated

with aripiprazole were enrolled in this study. Their charts were retrospectively

reviewed and data regarding past psychiatric history, past antipsychotic

medication, duration of aripiprazole treatment, daily dose of aripiprazole

administered, and resulting movement disorders were collected.


RESULTS: We report 14 cases of parkinsonism, tardive dyskinesia and akathisia

induced by aripiprazole. Some of these, mostly the parkinsonian phenotype, abated

spontaneously following drug discontinuation, whereas others, mostly related to

tardive phenomena, persisted after aripiprazole was discontinued, and required



CONCLUSIONS: This case-series adds to the existing literature that suggests that

movement disorders may arise following treatment with aripiprazole. Clinicians

should be aware of this potential side effect when prescribing aripiprazole to




Tardive Dyskinesia and Covert Dyskinesia with Aripiprazole: A Case Series.


Patra S


Curr Drug Saf. 2016;11(1):102-3.


Department of Psychiatry, All India Institute of Medical Sciences,

Bhubaneswar, Odisha, India.


Aripiprazole, a dopamine stabilizing atypical antipsychotic is used in treatment

of tardive dyskinesia caused by other neuroleptics. Tardive dyskinesia is rarely

caused by Aripiprazole and has only been documented in high risk patients i.e.,

female gender, advanced age, affective illness, coexisting neurological



The author describes two atypical cases of tardive dyskinesia

associated with Aripiprazole. First case of tardive dyskinesia was observed in a

neuroleptic naïve young adult male with paranoid illness after six months of

treatment with Aripiprazole upon addition of Fluoxetine and the second case was a

middle aged female with affective illness where dyskinetic movements appeared

after stopping Aripiprazole. The role of Fluoxetine in causing tardive dyskinesia

with Aripiprazole and covert dyskinesia due to Aripiprazole with appropriate

management is discussed.



A Case of Aripiprazole-Induced Tardive Dyskinesia with Dramatic Evolution.

Heitzmann E, Javelot H, Weiner L, Michel B.


Case Rep Psychiatry. 2016;2016:7031245.


North Alsace Mental Health Clinic (Etablissement Public de Santé Alsace Nord

(EPSAN)), Brumath, France.


Aripiprazole is reported to be a good clinical safety profile antipsychotic.

However, recent data suggest that the risk of tardive dyskinesia could be higher

than initially thought. We report the case of aripiprazole-induced tardive

dyskinesia with dramatic evolution in a patient with several risk factors,

including older age and exposure to antipsychotic over a period longer than six

months. This case and its dramatic evolution, associated with other cases

recently published, suggest reconsidering the real risk of tardive dyskinesia

associated with aripiprazole, particularly in the elderly.


A case of aripiprazole induced tardive dyskinesia in a neuroleptic-naïve patient

with two years of follow up.

Goyal R Devi SH


Clin Psychopharmacol Neurosci. 2014 Apr;12(1):69-71.


Institute of Living/Hartford Hospital, Hartford, CT, USA. (2)Department of

Psychiatry, Lady Hardinge Medical College and Hospitals, New Delhi, India.


Tardive dyskinesia (TD) is arguably the most serious and potential irreversible

side effect of antipsychotic medication. Traditionally first generation

antipsychotics are the neuroleptics considered to have higher risk of TD as

compared to second and third generation antipsychotics. Aripiprazole is a

third-generation antipsychotic with a novel mechanism of action. Risk of

developing TD with use of aripiprazole has been unknown.


Recently many cases of aripiprazole associated TD have been reported.


A case of 52 year old woman is discussed who presented to us with first manic episode. Patient had never been treated with any antipsychotic medication in her life before. During

current episode, she was treated with aripiprazole 30 mg/day. During follow up,

patient was found to have developed dyskinetic oro-facial movements within 2

months of starting aripiprazole. She was not taking any other

antipsychotic/anti-dopaminergic medication at that time. Patient’s abnormal

oro-facial movements could not be reversed in spite of immediate discontinuation

of aripiprazole. Multiple medications tried over the next 2 years but her

movement disorder never remitted.


Above case (along with other recent reports) suggest that risk of movement disorder with aripiprazole use could be higher than previously thought.

Further studies are required to find out incidence of

movement disorder with aripiprazole. Aripiprazole use should be preferably

restricted to FDA approved indications. Clinician needs to be very vigilant about

emergence of any movement disorder while using aripiprazole, especially in

patients with risk factors for TD.




Tardive dyskinesia and other movement disorders secondary to aripiprazole.

Peña MS, Yaltho TC, Jankovic J.

Mov Disord. 2011 Jan;26(1):147-52.


Department of Neurology, Parkinson’s Disease Center and Movement Disorders

Clinic, Baylor College of Medicine, Houston, Texas.


The objective of this report is to draw attention to tardive dyskinesia (TD)

caused by aripiprazole, a third generation antipsychotic. TD has been

traditionally attributed to typical (first-generation) antipsychotics, but other

dopamine receptor blocking drugs and atypical (second- and third-generation)

neuroleptics are emerging as an important cause of TD.


We reviewed the medical records of patients with TD seen at the Baylor College of Medicine Movement Disorders Clinic between 2002 and 2010 to identify patients with TD associated

with aripiprazole.


Among 236 patients with TD seen over the specified period, 8

(3.4%) were found to have aripiprazole-associated TD. In 5 patients, TD occurred

after exclusive exposure to aripiprazole. The mean age at onset was 55.8 ± 14.8

years with a female predominance. The average duration of treatment with

aripiprazole was 18.4 ± 26.4 months. Oro-bucco-lingual stereotypy was seen in all

patients. In most patients, TD did not spontaneously improve after stopping

aripiprazole. Of the 5 patients treated with tetrabenazine, 4 improved during



Although aripiprazole, a third generation antipsychotic, has been

promoted to have a low risk of TD, the drug accounts for about 3.5% of patients

with TD evaluated in a movement disorders clinic. This largest reported series

draws attention to the growing incidence of TD and other drug-induced movement

disorders associated with “atypical antipsychotics.”



Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2:

Incidence and management strategies in patients with schizophrenia.


Margolese HC Chouinard G, Kolivakis TT, Beauclair L, Miller R, Annable L.


Can J Psychiatry. 2005 Oct;50(11):703-14.

Department of Psychiatry, McGill University, Montreal, Quebec.

METHODS: We conducted a review of TD incidence and management literature from

January 1, 1965, to January 31, 2004, using the terms tardive dyskinesia,

management, therapy, neuroleptics, antipsychotics, clozapine, olanzapine,

risperidone, quetiapine, ziprasidone, and aripiprazole. Additional articles were

obtained by searching the bibliographies of relevant references. We considered

articles that contributed to the current understanding of both the incidence of

TD with atypical antipsychotics and management strategies for TD.


RESULTS: The incidence of TD is significantly lower with atypical, compared with

typical, antipsychotics, but cases of de novo TD have been identified. Evidence

suggests that atypical antipsychotic therapy ameliorates long-standing TD. This

paper outlines management strategies for TD in patients with schizophrenia.


CONCLUSION: The literature supports the recommendation that atypical

antipsychotics should be the first antipsychotics used in patients who have

experienced TD as a result of treatment with conventional antipsychotic agents.

The other management strategies discussed may prove useful in certain patients.



Safety and tolerability of aripiprazole for irritability in pediatric patients

with autistic disorder: a 52-week, open-label, multicenter study.


Marcus RN, Owen R, Manos G, Mankoski R, Kamen L, McQuade RD, Carson WH,

Findling RL.

J Clin Psychiatry. 2011 Sep;72(9):1270-6.


Department of Research and Development, Bristol-Myers Squibb, 5 Research

Parkway, Wallingford, CT


OBJECTIVE: Evaluate the long-term safety and tolerability of aripiprazole in the

treatment of irritability in pediatric subjects (6-17 years) with autistic



METHOD: A 52-week, open-label, flexibly dosed (2-15 mg/d) study of the safety and

tolerability of aripiprazole in outpatients with a DSM-IV-TR diagnosis of

autistic disorder who either had completed 1 of 2 antecedent, 8-week randomized

trials or were enrolled de novo (ie, not treated in the randomized trials).

Safety and tolerability measures included incidences of adverse events,

extrapyramidal symptoms, weight, metabolic measures, vital signs, and other

clinical assessments.


RESULTS: Subjects were enrolled between September 2006 and June 2009. Three

hundred thirty subjects entered the treatment phase: 86 de novo, 174 prior

aripiprazole, and 70 prior placebo. A total of 199 (60.3%) subjects completed 52

weeks of treatment. Adverse events were experienced by 286/330 subjects (86.7%).

Common adverse events included weight increase, vomiting, nasopharyngitis,

increased appetite, pyrexia, upper respiratory tract infection, and insomnia.

Discontinuations due to adverse events occurred in 35/330 randomized subjects

(10.6%)-most commonly aggression and weight increase. One patient discontinued

from the study due to a laboratory-related adverse event (moderately increased

alanine transaminase and aspartate transaminase). Nine subjects experienced

serious adverse events-most frequently aggression. Extrapyramidal

symptoms-related adverse events occurred in 48/330 subjects (14.5%)-most commonly tremor (3.0%), psychomotor hyperactivity (2.7%), akathisia (2.4%), and dyskinesia (not tardive, 2.4%).


At > 9 months’ aripiprazole exposure (n = 220), mean change

in body weight z score was 0.33 and body mass index z score was 0.31. The

percentages of subjects with clinically significant fasting metabolic

abnormalities at > 9 months were 2% for glucose, 5% for total cholesterol, 7% for

low-density lipoprotein cholesterol, 30% for high-density lipoprotein

cholesterol, and 5% for triglycerides.


CONCLUSIONS: Aripiprazole was generally safe and well tolerated in the long-term

treatment of irritability associated with autistic disorder in pediatric

subjects. Weight should be proactively monitored during long-term treatment.



Aripiprazole-related tardive dyskinesia.

Maytal G, Ostacher M, Stern TA.

CNS Spectr. 2006 Jun;11(6):435-9.



Psychiatric Consultation Service, Massachusetts General Hospital, Boston, MA

02114, USA.


The low prevalence of extrapyramidal symptoms associated with atypical

antipsychotics has led to their widespread use during the past decade.

Aripiprazole, the newest medication in this class, has been associated with

extrapyramidal symptoms (eg, akathisia) and with improvement of tardive

dyskinesia (TD), but to date it has not been associated with the development of


We report a case of TD associated with the use of aripiprazole 15 mg/day for

18 months for refractory depression. Symptoms of TD resolved within several weeks

of discontinuation of aripiprazole.



Long-term safety and tolerability of open-label aripiprazole augmentation of

antidepressant therapy in major depressive disorder.


Berman RM, Thase ME, Trivedi MH, Hazel JA, Marler SV, McQuade RD, Carson W,

Baker RA, Marcus RN.


Neuropsychiatr Dis Treat. 2011;7:303-12.


Neuroscience Global Clinical Research Bristol-Myers Squibb, Wallingford, CT,



BACKGROUND: Effective management of major depressive disorder often includes the

long-term use of multiple medications, and the longer-term utility and safety of

adjunctive aripiprazole has not been evaluated in a controlled setting.

PATIENTS AND METHODS: Patients (n = 706) completing one of two 14-week

double-blind studies of aripiprazole augmentation, as well as de novo patients (n

= 296) nonresponsive to current antidepressant therapy, were enrolled in this

open-label study. Patients received open-label aripiprazole for up to 52 weeks.

RESULTS: Open-label treatment was completed by 323 patients (32.2%). At endpoint

(n = 987), the mean dose of aripiprazole was 10.1 mg/day. Common (>15% of

patients) spontaneously reported adverse events were akathisia (26.2%), fatigue

(18.0%), and weight gain (17.1%).


The incidence of serious adverse events was

4.0%. Four spontaneous reports of possible tardive dyskinesia were submitted

(0.4%); all resolved within 45 days of drug discontinuation. Mean weight change

was 4.4 kg; 36.6% experienced ≥7% increase in weight from baseline (observed case

analysis, n = 303). No clinically relevant changes in other metabolic parameters

were seen. At the end of open-label treatment, 221 patients (69.7%) had a

Clinical Global Impression-Severity of Illness score of 1 (not at all ill) or 2

(borderline ill).


CONCLUSION: Long-term adjunctive aripiprazole therapy was well tolerated with an

acceptable long-term safety and tolerability profile in patients with major

depressive disorder who had not responded to treatment with one or more

antidepressant therapies. Clinically significant weight gain was observed in

about one-third of patients. Overall, the adverse event profile was consistent

with that reported in the short-term trials and readily managed clinically.



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