ICNS_May-June13_CoverRandy A. Sansone, MD, and Robert J. Sawyer, MD
Dr. Sansone is a Professor in the Departments of Psychiatry and Internal Medicine at Wright State University School of Medicine in Dayton, Ohio, and Director of Psychiatry Education at Kettering Medical Center in Kettering, Ohio. Dr. Sawyer is the Medical Director of Sycamore Primary Care Center, which is affiliated with Kettering Medical Center in Kettering, Ohio.

Innov Clin Neurosci. 2013;10(5–6):10–13

Funding/financial disclosures: No funding was received for the preparation of this article. The authors have no conflicts relevant to the content of this article.

Dear Editor:

Atypical antipsychotics, including aripiprazole, are effective medications for the treatment of psychotic disorders as well as the augmentation of antidepressants in the treatment of major depression.[1] In support of mood augmentation, aripiprazole has this indication through the United States Food and Drug Administration (FDA). Despite the broad use of atypical antipsychotics for various clinical syndromes, discontinuation syndromes related to these second-generation drugs are not well characterized.[2]

It appears that discontinuation symptoms from atypical antipsychotics may be grouped into three general categories: 1) withdrawal supersensitivity psychosis (i.e., abrupt psychotic relapses associated with the acute decrease or cessation of an atypical antipsychotic[3]), 2) abnormal movement disorders, and 3) various mixed symptoms. Withdrawal supersensitivity psychosis has been reported with ziprasidone,[4] olanzapine,[5] and clozapine.[6] Likewise, various abnormal movement disorders have been associated with the abrupt withdrawal of aripiprazole (e.g., abnormal jaw, tongue, and hand movements[7]), ziprasidone (e.g., akathisia[8]), risperidone (e.g., tics,[9] akathisia,[10] dyskinesias,[11] rabbit syndrome[12]), quetiapine (e.g., hyperkinesis,[13] dyskinesias,[14] chorea[15]), and clozapine (e.g., oculogyric crisis,[16] catatonia,[17] dystonias, and dyskinesias[18]).

As for the third group of discontinuation symptoms, according to infrequent reports, various mixed symptoms may emerge following the cessation of atypical antipsychotics. Case reports document such symptoms for both quetiapine (reported withdrawal symptoms of nausea, vomiting, lightheadedness, diaphoresis, lightheadedness, tachycardia, anxiety[19,20]) and olanzapine (reported withdrawal symptoms of tremulousness, body aches, headache, insomnia, piloerection, blurred vision, nightmares[21]). However, we were not able to locate a single case report in the PubMed database regarding aripiprazole withdrawal and various mixed symptoms. In addition, the Gold Pharmacology reference source did not identify a discontinuation syndrome associated with aripiprazole.[22] However, the package insert for aripiprazole indicated the presence of withdrawal symptoms in monkeys after abrupt cessation of the drug.[23] In addition, the internet revealed a number of individuals who reported withdrawal symptoms from aripiprazole, such as nausea, lightheadedness, tachycardia, diaphoresis, and anxiety,[24] as well as insomnia.[25] Likewise, consumers reported headaches, tremulousness, and flu-like symptoms.[26] In the following case report, we describe a 61-year-old man who abruptly discontinued aripiprazole and experienced a number of unpleasant symptoms highly suggestive of withdrawal.

Case report. Mr. A. was a 61-year-old, normal-weight, white man with diabetes, hypertension, hypercholesterolemia, gastroesophageal reflux, restless legs syndrome, and chronic depression (dysthymic disorder). He had previously been on a number of different courses of antidepressants (e.g., sertraline, fluoxetine, citalopram, escitalopram, bupropion, venlafaxine extended-release) as well as several augmentation strategies (e.g., buspirone, gabapentin, lamotrigine) that were prescribed by various physicians. However, the patient had been prescribed duloxetine 40 to 60mg per day since 2007, in addition to several ongoing medications for his medical conditions (humalog insulin via insulin pump, losartan 25mg, omeprazole 40mg). Due to continuing refractory depressive symptoms, the patient was prescribed aripiprazole in September of 2010, and remained on a dosage between 2mg and 5mg since initiation. In January of 2013, the patient abruptly discontinued aripiprazole 5mg per day as the prescription had expired and he was on vacation. Within two days of cessation, the patient began to experience sudden-onset lightheadedness, intermittent nausea, severe insomnia (i.e., difficulty falling and staying asleep), irritability, generalized muscular twitches, intense anxiety, worry, rumination, and dysphoria. The symptoms waxed and waned over the initial days, but gradually began to dissipate after two weeks. Before and during this time, all concomitant medications remained unchanged in prescription and dose.

Discussion. This patient’s experience mimics the reports by consumers, which are described on the internet. However, it is important to note that some of these symptoms may be attributable to depression relapse, such as dysphoria, rumination, insomnia, and irritability, whereas other symptoms are more suggestive of withdrawal (e.g., nausea, lightheadedness, muscle twitching).
Ariprazole and its active metabolite, dehydro-aripiprazole, have half-lives of 75 and 94 hours, respectively, and are seemingly unaffected by age or gender.[22] Given these lengthy half-lives, it would seem less likely that aripiprazole would cause withdrawal symptoms. However, fluoxetine and its active metabolite, norfluoxetine, have half-lives of 96 hours and 384 hours, respectively (i.e., longer than aripiprazole), and may cause discontinuation symptoms in the week following abrupt cessation—a finding that was confirmed in a prospective study.[27]

As for the contribution of other medications to the patient’s abrupt-onset symptoms, this possibility is less likely. There had been no recent changes in either medications or dosages, eliminating the possibility of any synergism.
A physiological explanation for the cause of withdrawal symptoms with aripiprazole remains elusive. According to Canas,[24] aripiprazole influences D1 as well as 5-HT1 and 5-HT2A receptors, but not cholinergic, adrenergic, or histaminic receptors. Some of these latter receptors might readily explain several of the reported withdrawal symptoms experienced by this patient. However, a number of the reported withdrawal symptoms resemble discontinuation symptoms associated with selective serotonin reuptake inhibitors and suggest serotonergic mechanisms.[19] As reported by Goudie and Cole, “…the understanding of antipsychotic drug psychopharmacology in terms of…discontinuation effects at the basic science level is limited, if not virtually absent.”[2]

Conclusion. We report a case of probable aripiprazole withdrawal characterized by various mixed symptoms, which to our knowledge has not been previously reported in the empirical literature. In this case, these various symptoms gradually receded over time. Therefore, it appears that on rare occasion, aripiprazole can cause a discontinuation syndrome characterized by various mixed symptoms that are likely to dissolve over time—a reminder to clinicians to always taper psychotropic medications when administered long-term. This rare risk is of clinical importance due to the current broad role of aripiprazole in the augmentation of mood disorders.

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