Aripiprazole (Abilify), the Atypical Atypical Antipsychotic
This is an overview of the drug aripiprazole.
Spectrum of Efficacy
Aripiprazole has now been approved for acute and maintenance treatment of pediatric patients with bipolar disorder from ages 10 to 17. It had already been approved for adult bipolar disorder, schizophrenia, and as an adjunctive treatment for acute unipolar depression inadequately responsive to antidepressants of the serotonin-selective class or the serotonin-norepinephrine reuptake inhibitor venlafaxine. Aripiprazole, along with risperidone, is one of only two drugs FDA-approved for the treatment of irritability in autism.
In a poster presented at the American Psychiatric Association meeting in San Francisco in May 2009, Whitehead and associates indicated that in these pediatric patients with bipolar disorder, not only did their Young Mania Rating score (YMRS) improve, but also their Clinical Global Impresions-Bipolar (CGI-BP) severity score and their quality of life assessments did as well. There was a moderate correlation between subjective improvement in quality of life as measured by the Pediatric Quality of Life Enjoyment and Satisfaction Questionaire (PQLESQ) and the degree of clinical improvement measured by YMRS and CGI-BP. The improvement occurred at both the aripiprazole 10mg/day dose and the 30 mg/day dose when compared with placebo.
Mechanisms of Action
Aripiprazole is what is known as a partial agonist (stimulator) of dopamine D1, D2, and D3 receptors, in contrast to all other typical and atypical antipsychotics, which are full antagonists (blockers) of dopamine receptors. The partial agonism means that when aripiprazole binds to the receptor, it activates the receptor only about 20%, but never any more, no matter how high the dose or blood levels of the drug are.
Since aripiprazole “sits” on the receptor, any degree of excess dopamine that may occur in mania or schizophrenia cannot reach these dopamine receptors, so aripiprazole effectively produces an 80% functional blockade. The 20% stimulation (agonism) of dopamine D2 receptors is sufficient to make aripiprazole the only typical or atypical antipsychotic that significantly lowers prolactin levels. Aripiprazole is also a partial agonist at serotonin 5HT1A receptors, like the drug buspirone (Buspar), which is known for its antidepressant and antianxiety effects. Aripiprazole is a full blocker of 5HT2A receptors, which might also contribute to its antidepressant effects, and (like the antidepressant Trazodone) its ability to increases the deeper phases of sleep known as slow wave sleep.
Side effects: weight gain, but no increases in other metabolic indices
At the American Psychiatric Association meeting in San Francisco in May 2009, Newcomer et al. presented a poster on metabolic measures in pediatric and adolescent patients in the studies that led to the FDA approval. In contrast with schizophrenic patients at six weeks and bipolar patients at four weeks who experienced negligible weight gain, among the bipolar children and adolescents treated with aripiprazole for 30 weeks, there was an approximate 3kg increase in weight compared with 1kg on placebo. However, none of the other indices of the metabolic syndrome showed significant changes when compared with placebo. These included total cholesterol, fasting triglycerides, and fasting glucose.
The metabolic syndrome is considered present if three of five following indices are abnormal. These include: 1. Fasting blood glucose or insulin resistance 2. Increased waist circumference (reflecting weight gain) 3. Increases in cholesterol 4. Increases in triglycerides and 5. Increases in blood pressure. Patients with both unipolar and bipolar affective disorders should take special precautions to have these indices carefully monitored and stabilized by their internist, family practitioner, or directly by their psychiatrist if other specialists are not available. Depression is a risk factor for type II diabetes and vice versa.
The authors of this poster on aripiprazole concluded that these mild weight gain results should inform clinical decisions about the potential use of aripiprazole in children and adolescents, and that the study supports the need for careful management of weight gain and metabolic monitoring of these youngsters.
An acute adjunctive treatment for unipolar patients inadequately responsive to their antidepressant, either an SSRI or an SNRI
Three randomized, placebo-controlled studies all have shown that when aripiprazole (compared with placebo) is added to previously inadequate antidepressant treatment, there is a rapid and highly statistically significant improvement in Montgomery-Asberg Depression Rating Scale (MADRS) scores. Even in studies of only six weeks’ duration, quality of life on the Sheehan Disability Scale (SDS) tended to show improvement as well. There was minimal sedation (approximately 10% of patients on aripiprazole).
Twenty-five percent of patients did experience akathisia (restless legs) and restlessness, but fewer than 2% of the patients discontinued aripiprazole because of these side effects. This editor recommends starting children with bipolar disorder and adults with unipolar depression with 1mg to 2mg of aripiprazole in order to establish better initial tolerability and less akathisia. The weight and metabolic profiles of this study mirror those reported above in the pediatric trials, in that there was significantly greater weight gain on aripiprazole than placebo, but this was of relatively small magnitude (1.3kg), and there was a lack of significant alterations in any of the metabolic indices, including cholesterol, triglycerides, and glucose.
EDITOR’S NOTE: The lack of increase in indices of the metabolic syndrome while on aripiprazole, with the exception of some weight gain, is of substantial clinical importance, because affectively ill patients are already prone to the metabolic syndrome and lose many years of life expectancy (compared with the general population) due to increased medical mortality, predominantly from cardiovascular disease. Thus, it becomes important not to prescribe medications that might exacerbate these problems, such as elevated cholesterol, triglycerides, blood sugar, or blood pressure.
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