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Aripiprazole
See also Neuroleptic drugs
General information
Aripiprazole (Abilify®), an antipsychotic drug, has been said to be the prototype of a new third generation, the so-called “dopamine–serotonin system stabilizers” [ ]. Its mechanism of action differs from previous typical and atypical antipsychotic drugs; it is a partial agonist at D 2 receptors, with properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity respectively, and this is believed to contribute to stabilization rather than blockade of dopaminergic tone; it is also a partial agonist at 5-HT 1A receptors and an antagonist at 5-HT 2A receptors [ ]. Nevertheless, as stated in the Summary of Product Characteristics, “… the mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia, is unknown” [ ]. The most common adverse reactions include restlessness and akathisia, somnolence, and nausea. It can also worsen extrapyramidal symptoms [ ].
Aripiprazole was first approved by the US Food and Drug Administration for the treatment of schizophrenia in 2002, and then by the European Medicines Agency in 2004; finally, it was approved in Japan in 2006. It has been included in recent guidelines on schizophrenia treatment [ ]; thereafter, it was approved for other conditions, such as bipolar disorder, and it is anticipated that many physicians will use it off-label for a similar range of indications to other atypical antipsychotic drugs [ ].
Aripiprazole is supposedly similar in efficacy to other antipsychotic drugs but devoid of their most troublesome adverse reactions; independent reviews, at best, considered aripiprazole as one more to add to the list [ , ]. All in all, it is difficult to know the therapeutic role for aripiprazole, since most of the trials have been conducted to fulfil regulatory requirements and most of the published studies have been supported by the Marketing Authorization Holders, Otsaka Pharmaceuticals and Bristol Myers Squibb; some reanalyses do not add anything new and are in fact redundant publications [ , ]. Most trials have included participants with few comorbidities. Most of the studies were not designed to provide results relevant to daily clinical practice. Adverse effects are reported when they occurring in at least 5–10%, which means that rare serious adverse effects have not [yet] been described.
Drug studies
Observational studies
In 142 adult patients who took aripiprazole (mean final daily dose 16 mg, 0.20 mg/kg) for psychotic, major affective, or other disorders, adverse effects occurred in 16, were three times more likely among women, and most often involved moderate behavioral activation or nausea, with no new episodes of mania [ ].
Resistant schizophrenia
Since a certain proportion of treatment-resistant schizophrenia fails to respond to clozapine, a 6-week open study of the effects of adjunctive aripiprazole has been conducted [ ]. Ten clozapine-treated subjects (mean age 39 years) received aripiprazole augmentation; eight completed the 6-week trial and two ended at week 4. There was no significant change in total PANSS score. There was a significant fall in weight and fasting total serum cholesterol comparing baseline to study end-point. In addition, a retrospective review of case notes of treatment-resistant patients with this condition who took the combination clozapine + aripiprazole for an average of 34 weeks has been carried out [ ]. There was overall improvement in hallucinations and delusions. Clozapine + aripiprazole was associated with a 22% reduction in clozapine dose; 18 of 24 patients lost a mean weight of 5.05 kg. Two patients taking aripiprazole alone were not included in the study as one developed severe dyskinesia affecting the trunk and limbs and the other atypical neuroleptic malignant syndrome.
Three patients with psychotic symptoms despite clozapine and with significant adverse effects received aripiprazole 15 mg/day in combination [ ]. There was general improvement, loss of weight, and reduced obsessive–compulsive symptoms. One patient complained of mild transient nausea. Case series, although of some importance on occasions, cannot be controlled for bias (the most frequent fallacy in these instances being the “post hoc ergo propter hoc” error).
Psychosis associated with Parkinson’s disease
Treatment-induced psychosis affects a significant proportion of patients with idiopathic Parkinson’s disease; treatment options include reducing medications or introducing an atypical antipsychotic drug. Only clozapine has been shown to be efficacious and well tolerated in clinical trials. Now 14 patients (median age 74, range 51–90, years) meeting the entry criteria (Parkinson´s disease and psychosis deemed to be medication-induced for at least 1 month) were given aripiprazole 1 mg/day and titrated up to a maximum dose of 5 mg/day as needed for 6 weeks [ ] in a study supported by the manufacturers. Eight subjects withdrew owing to worse parkinsonism (n = 3), worse psychosis (n = 2), worsening of both (n = 2), and lack of efficacy (n = 1); these findings are similar to those of three other published reports on the use of aripiprazole for psychosis in Parkinson’s disease [ ]. The authors concluded that aripiprazole did not seem to be a promising agent.
Children with developmental disabilities
A retrospective chart review of the first 32 children (age range 5–19 years) treated with aripiprazole at an urban clinic for children with developmental disabilities has been conducted [ ]. Efficacy differed depending on the disorder. There was improvement in aggression in 15 of 28 children, in hyperactivity in 10 of 21, and in impulsivity in 5 of 13. Adverse effects that resulted in withdrawal included sleepiness (n = 4), tics (n = 1), increased aggression (n = 2), stiffness (n = 1), myalgias (n = 1), facial dyskinesia (n = 1), and diarrhea (n = 1). The average daily maintenance dose was 10.5 mg/day (range 1.2–30 mg); the average length of treatment and follow-up was 6.1 months (range 0.2–15 months).
Children with bipolar disorder
A retrospective chart review of 30 children (age range 5–19 years) taking aripiprazole for bipolar disorders has been conducted [ ]. The mean overall psychiatric illness Clinical Global Impression-Severity score significantly improved from baseline to end-point. The most common adverse effect was sedation (n = 10) and the second most common was akathisia (n = 7); most of the patients were taking other medications. The average daily maintenance dose was 9 mg/day (range 5–15 mg); the average length of treatment and follow-up was 4.4 months (range 1–9 months). Most of the patients lost weight (12 of 14 patients for whom there was information on weight gain; mean weight loss, 3 kg).
Comparative studies
Schizophrenia
A comparison of aripiprazole with haloperidol involved two 52-week double-blind trials that were pooled for analysis [ ]. Haloperidol was given in a moderate dose (10 mg/day). These trials were designed to demonstrate the superiority of high-dose aripiprazole (30 mg/day), but failed to do so. The proportion of patients who “responded” during an acute episode, based on an analysis of trial completers (495, 39%, of 1283 patients) were not statistically different (aripiprazole 77%, haloperidol 74%). There was a statistically significant lower rate of discontinuation due to adverse effects with aripiprazole (8.0%) compared with haloperidol (18.4%). Fewer aripiprazole-treated patients (23%) required concomitant medication for extrapyramidal symptoms compared with haloperidol-treated patients (57%).
In an 8-week, multicenter, open study, 1599 outpatients with schizophrenia or schizoaffective disorder were randomly assigned to receive either aripiprazole (n = 1295) or another antipsychotic medication (safety control group; n = 304) [ ]; aripiprazole was begun at 15 mg/day with the option to adjust between 10 and 30 mg/day. The control medication and dosage was specifically selected for each patient by the clinician. The mean aripiprazole dose at the end was 20 mg/day and 65% of the patients completed the study. At the end, the mean Clinical Global Impression–Improvement score of 2.8 showed that aripiprazole was minimally to moderately effective; the mean score for the control group was 3.6, indicating minimal effectiveness to no change. Treatment-related adverse effects were reported in 72% (901/1255) of patients taking aripiprazole and in 64% (170/265) of controls; the most frequent adverse effect in those taking aripiprazole was insomnia (24%). Extrapyramidal symptoms were reported in 10% of patients taking aripiprazole and in 8% of controls. Five patients died during treatment with aripiprazole group or within 30 days after the 8-week phase of the study; three deaths (cardiac death, death of unknown cause 16 days after completing therapy, and homicide) were considered unrelated to the study medication, and the other two deaths (both of unknown cause) were judged by the investigator unlikely to be related to the study medication.
In a 26-week, open, multicenter study, 555 patients were randomized to receive aripiprazole (n = 284) or a control drug (quetiapine, n = 110; olanzapine, n = 75; risperidone, n = 81) [ ]. Aripiprazole was significantly better than control treatment. The incidence of treatment-related adverse effects was similar in the two treatment groups; the most common adverse effects in those taking aripiprazole were insomnia, anxiety, headache, and nausea. One patient taking aripiprazole committed suicide; the two deaths in controls were attributed to lung cancer and to aspiration and cardiac failure.
An open comparative study has been conducted in patients with either acute relapsing or chronic stable schizophrenia [ ]. The patients were randomized to aripiprazole (15–30 mg/day; n = 104) or olanzapine (10–20 mg/day; n = 110). Efficacy improvements were similar between groups at the end. Olanzapine caused more extrapyramidal symptoms (18%) than aripiprazole (10%); mean weight gain with olanzapine was 2.54 versus 0.04 kg with aripiprazole. The increase in prolactin was significantly greater with olanzapine than with aripiprazole (9.3 versus 0.8 ng/ml). One death occurred in the olanzapine group due to heart failure.
Finally, in an independent study, 327 patients were randomized to open treatment with aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, or ziprasidone for a minimum of 3 weeks [ ]. The measure of effectiveness was improvement in mental status so that the patient no longer required acute in-patient care. Haloperidol (89%), olanzapine (92%), and risperidone (88%) were significantly more effective than aripiprazole (64%), quetiapine (64%), and ziprasidone (64%). The difference among the six treatments in rates of withdrawals because of adverse effects was not statistically significant.
Treatment-resistant schizophrenia
In a multicenter, double-blind, randomized study aripiprazole (15–30 mg/day; n = 154) and perphenazine (8–64 mg/day; n = 146) were compared in 300 treatment-resistant patients with schizophrenia [ ]. After 6 weeks both aripiprazole and perphenazine were associated with clinically relevant improvements in PANSS total scores from baseline. More patients needed concomitant medication for extrapyramidal symptoms in the perphenazine group (28%) than in the aripiprazole group (18%). There was abnormal total creatine kinase activity in seven patients taking perphenazine and 12 taking aripiprazole (two of whom withdrew as a result).
Mania
In a double-blind trial, patients with bipolar I disorder were randomized to aripiprazole (n = 175) or haloperidol (n = 172) for an acute manic or mixed episode [ ]. At week 12, significantly more patients taking aripiprazole (50%; average daily dose, 22 mg) were in remission compared with those taking haloperidol (28%; average daily dose, 11 mg). Overall, 208 patients (60%) withdrew during the study period (aripiprazole, 49%; haloperidol, 71%). There were extrapyramidal adverse effects in the two groups (aripiprazole, 24%; haloperidol, 63%); mean change in weight from baseline at week 12 was not significantly different in the two groups (aripiprazole + 0.3 kg, haloperidol -0.1 kg); serum prolactin concentrations fell from baseline with aripiprazole (-13 ng/ml) and rose with haloperidol (+ 7.7 ng/ml). Insomnia was more frequent with aripiprazole (14%) than with haloperidol (7.1%). The non-availability of anticholinergic medication specified in the study protocol and the limited dosage range permitted for haloperidol could have affected the results.
Drug combination studies
A fixed dose of aripiprazole 15 mg/day added to previous clozapine (mean dose 478 mg/day) resulted in significant improvement on PANSS scores in 27 clinically stabilized patients with chronic schizophrenia (22 men; mean age 42 years) in a 16-week open uncontrolled study [ ]. There were no significant changes from baseline to end-point in extrapyramidal symptoms, body weight, or prolactin concentrations; none of the four dropouts were due to adverse events.
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