At the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, Fung et al. presented a meta-analysis of treatments for autism that ranked them in terms of statistical effect size, ranging from 0.9 (large), to 0.5 to 0.8 (medium), to <0.4 (small). The only drug with a large effect size was risperidone, at 0.9. Most effect sizes were medium, including aripiprazole at 0.8 and N-acetylcysteine (NAC) at 0.7. Both clonidine and methylphenidate had effect sizes of 0.6, and tianeptine’s was 0.5.
Fung and colleagues noted that the first two on the list, the atypical antipsychotics risperidone and aripiprazole, often have problematic side effects (such as sedation, weight gain, and motor symptoms) that must be balanced against their effectiveness. In contrast, NAC is well tolerated with few side effects, and two placebo controlled studies showed that it was effective both alone and as an adjunctive treatment to the antipsychotic risperidone.
In a poster at the 9th International Conference on Bipolar Disorder (ICBD) held in Pittsburgh in 2011, Rahman and colleagues reported that in patients being treated for bipolar disorder, the addition of atypical antipsychotic aripiprazole to maintenance treatment with lamotrigine was more effective than the addition of placebo to the same maintenance treatment with lamotrigine. Improvements in Young Mania Rating Scores (YMRS) with the combination of aripiprazole plus lamotrigine were significantly greater than that of lamotrigine plus placebo.
Editor’s note: These data add to a growing literature that shows that an atypical antipsychotic added to a mood stabilizer is associated with better prophylactic effects than use of the mood stabilizer alone. Previously, most of the studies of this type of combination used lithium or valproate as the mood stabilizer and, to our knowledge, this is the first to demonstrate that long-term prevention with lamotrigine is enhanced by the addition of an atypical antipsychotic.
Many of the atypical antipsychotics are FDA-approved as adjunctive treatments to mood stabilizers in the long-term treatment of bipolar disorder. The controlled clinical trial data that led to this FDA approval support the practice of many clinicians who prescribe combination treatment rather than monotherapy in order to achieve a more rapid onset of anti-manic stabilization and longer-term maintenance effects. The use of aripiprazole and quetiapine as adjuncts to lithium and valproate is particularly common in bipolar disorder since the same atypical antipsychotics are FDA-approved as adjunctive treatments in unipolar depression, and clinicians are familiar with prescribing them to improve ineffective acute antidepressant treatment.
EDITOR’S NOTE: Dr. Gagin Joshi of Massachusetts General Hospital, who presented the work on carbamazepine and lamotrigine on page 1 provided us with his own general treatment algorithm for youngsters with bipolar disorder.
Joshi typically starts with 0.5 to 2 gms of omega-3 fatty acids because of their benign side-effects profile, the many studies suggesting they are effective in adult mood disorders, and a recent article indicating that they were effective in preventing the conversion of prodromal schizophrenia into full-blown illness in a randomized double-blind controlled study in Australia.
After the omega-3 fatty acids, Joshi’s second choice is typically the atypical antipsychotic aripiprazole (Abilify) because of its lesser degree of weight gain compared to atypicals quetiapine (Seroquel) or risperidone (Risperidol). Risperidone can be a third option if aripiprazole is not effective or tolerated.
We’ve recently posted about some of the reasons aripiprazole and ziprasidone can make good choices for treatment.
Read about ziprasidone here.
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.
Adding aripiprazole to the drug regimen of a patient with major depression was significantly superior to adding placebo on most of the core symptom items of major depression in a pooled analysis of several studies. Martin et al. presented these data in a poster at the American Psychiatric Association meeting in San Francisco in May 2009. The improved areas included: trouble falling asleep, feeling sad, low mood, decreased appetite, view of the self, view of the future, thoughts about death/suicide, general interest, capacity for pleasure/enjoyment, interest in sex, and interpersonal sensitivity.
These improvements were accompanied by improvements at a trend or significance level in quality of life after just six weeks of treatment, as well as a generally good side-effects tolerability profile. The most common side effects are akathisia (restless legs) and restlessness, which appear to be less prominent if one starts with very low (pediatric) doses, i.e. 1mg to 2mg/day. The metabolic profile of the drug is relatively benign, with only weight gain occurring significantly more on aripiprazole than on placebo, while there were no significant changes in cholesterol or triglycerides.
In a recent study, children 6-12 years old with autism were treated with aripiprazole and showed improvement in irritability. The study lasted 52 weeks and had an open-label flexible-dose design (ranging from 2-15 mg/day) with an average dose of 9.6 mg/day. Few discontinuations occurred due to adverse effects, suggesting that aripiprazole is generally safe for use in this patient cohort. Increase in weight gain was the reason seven subjects (2%) discontinued the drug, although weight gain appeared to plateau with continued treatment.
Aripiprazole is already FDA-approved for the treatment and prevention of mania in adults and children (10-17 years). It is also approved as an adjunct (add-on) to poorly effective antidepressants in adults with unipolar (non-psychotic) major depression.
EDITOR’S NOTE: The general safety and tolerability of aripiprazole for the treatment of irritability in children with autistic disorder in this study means the drug can be added to the list of potential treatments for patients with autism. Previously, only risperidone had shown strong placebo-controlled data for efficacy in autism. A study by Hollander published in Neuropsychopharmacology this year indicated that valproate was also significantly better than placebo in treating irritability in children with autism spectrum disorders.