Psychopharmacology Reviews: High-Dose Aripiprazole for Treatment-Resistant Schizophrenia

David L. Ginsberg, MD

Dr. Ginsberg is Director of Outpatient Services, Tisch Hospital’s Department of Psychiatry, New York University Medical Center

Aripiprazole is an atypical neuroleptic with a unique mechanism of action. According to the package insert, the maximum recommended dose for aripiprazole is 30 mg/day. In clinical practice, off-label prescribing of medications, including the use of doses that exceed the manufacturer’s recommendations, is not uncommon. Most premarketing studies are designed principally to demonstrate safety, efficacy, and tolerability and often exclude many patients who are treated after a drug has been released. Now comes a report on the use of aripiprazole, in an individual with treatment-resistant schizophrenia, at a dose of 75 mg/day.

A 21 year-old woman was diagnosed in 2004 with paranoid schizophrenia of 7 months’ duration. She presented with command auditory hallucinations of a derogatory nature that were interfering with her social and academic functioning. Past and family histories were unremarkable. The patient had sequential trials of trifluoperazine up to 25 mg/day and haloperidol up to 15 mg/day, each for 4 weeks, but experienced no improvement. At this point, aripiprazole 10 mg/day was initiated then increased by 10 mg/day every 2 weeks until achieving a dosage of 30 mg/day by the end of the first month. The patient showed a partial response, with an approximately 30% reduction in the hallucinations. When no further improvement accrued over the next 3 weeks, after obtaining informed consent from the patient to exceed the maximum recommended dose, the dose of aripiprazole was increased further to 45 mg/day then after another 3 weeks, to 60 mg/day. By this time the hallucinations had decreased by about 75%. An electrocardiogram (ECG) was normal. Laboratory testing indicated the absence of hyperglycemia or dyslipidemia. Three weeks later, aripiprazole was increased to 75 mg/day. Within a month, the hallucinations completely resolved. Moreover, academic performance and social functioning improved as well. A repeat ECG revealed sinus tachycardia at 100-110 beats per minute. Over the next 10 weeks, the patient was maintained on 75 mg/day of aripiprazole with sustained complete remission of symptoms, and no adverse effects such as extrapyramidal symptoms, akathisia, nausea, vomiting, orthostatic hypotension, seizure, or weight gain. As this was her first psychotic episode, aripiprazole was tapered and subsequently stopped over the next 10 months with no relapse of symptoms.

In the case described above, high-dose aripiprazole was a safe and effective treatment. An unresolved question is whether or not the clinical improvements seen would have occurred had aripiprazole been maintained at a lower dosage. The authors of the report chose 2 weeks as an appropriate interval for increasing dose since this is the time needed to achieve steady state concentrations of the drug. Finding the right dose of a psychotropic medication is often difficult due to the myriad factors that impact on the issue and the wide variability among individuals. Until more precise means are established, determining the right dose of a drug for an individual patient will remain largely an empiric exercise.

Disclosure: Dr. Ginsberg is a speaker for AstraZeneca, Cyberonics, Forest, and GlaxoSmithKline; and has received research support from Cyberonics.