March 25, 2017
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Once-Monthly Aripiprazole Effective in Bipolar Disorder

A long-acting, injectable form of the antipsychotic drug aripiprazole (Abilify, Otsuka) given once a month provides a safe and effective means of maintenance therapy for the treatment of bipolar I disorder, results of a 52-week randomized study suggest.

"The study demonstrated that aripiprazole once-monthly significantly delayed time to recurrence of any mood episodes in patients experiencing a manic episode at screening," senior author Joseph Calabrese, MD, director of the Mood Disorders Program at University Hospitals Case Medical Center, Case Western Reserve School of Medicine, in Cleveland, Ohio, told Medscape Medical News.

"These findings support the potential for once-monthly aripiprazole as a maintenance treatment for the management of adult patients with bipolar I disorder."

The findings were published online January 31 in the Journal of Clinical Psychiatry.

With nonadherence rates in the treatment of bipolar I disorder as high as nearly 80%, a long-acting, injectable antipsychotic is seen as an important tool for improving treatment, the authors note.

Currently, the only long-acting injectable antipsychotic that has been approved by the US Food and Drug Administration for the treatment of bipolar I disorder is risperidone (Risperdal, Janssen). Treatment with risperidone requires an injection every 2 weeks.

Multiple randomized studies have demonstrated that once-monthly aripiprazole (400 mg) has efficacy in the treatment of schizophrenia.

To evaluate the efficacy for treatment of bipolar I disorder, the researchers enrolled 266 participants at sites in seven countries between August 2012 and April 2016. Participants were aged 18 to 65 years and had been diagnosed with bipolar I disorder. At the time of enrollment, they were experiencing a manic episode, determined in accordance with DSM-IV-TR diagnostic criteria, and had a Young Mania Rating Scale (YMRS) total score of 20 or higher.

The participants' conditions had been stabilized with oral aripiprazole. The patients were randomly allocated in a double-blind fashion in a ratio of 1:1 to receive treatment with either once-monthly aripiprazole 400 mg or placebo.

Of the patients, 102 (38.3%) completed the 52-week study, including 48.1% in the aripiprazole group and 28.6% in the placebo group.

The primary outcome measure was time to recurrence of any mood episode after symptoms had remained stable with once-monthly aripiprazole for 8 or more consecutive weeks.

Time to recurrence was found to be significantly delayed in the aripiprazole group compared to the placebo group (P < .0001). The risk of having a recurrence of any mood episode was reduced by nearly a half with aripiprazole (hazard ratio = 0.45; 95% confidence interval, 0.30 - 0.68).

The proportion of patients experiencing a recurrence of any mood episode was significantly lower in the once-monthly aripiprazole group (35 of 132) compared to the placebo group (68 of 133).

The degree of mania symptom severity, as assessed by YMRS at 52 weeks, was reduced in the aripiprazole group, with mean scores of 3.95 in the once-monthly aripiprazole group and 7.99 in the placebo group. The adjusted mean YMRS total score from baseline to week 52 was -3.09 vs -1.17, respectively (P = .002).

Although there were no differences between the groups in terms of recurrence of depressive episodes, the authors note that there was also no increase in depressive episodes.

"This finding contrasts with typical antipsychotics, which, although effective at reducing recurrence of manic episodes, are associated with increased number of depressive episodes," they report.

Dr Calabrese noted that oral aripiprazole is not indicated for the treatment of depression associated with bipolar I disorder and that the results with once-monthly aripiprazole are consistent with results using the oral formulation.

The two groups were similar with respect to use of concomitant anticholinergics (18% in the aripiprazole group vs 14.3% placebo) and benzodiazepines (27.8% aripiprazole vs 24.1% placebo).

During the stabilization phase, 291 (68.5%) of 425 patients receiving once-monthly aripiprazole experienced treatment-emergent adverse events, with 8.5% having one or more serious events, 6.6% having one or more severe events, and 8.7% having events that led to treatment discontinuation.

Rates of treatment-emergent adverse events that occurred at an incidence higher than 5% were higher in the aripiprazole group. These events included weight increase, akathisia, insomnia, and anxiety.

Mean weight gain was low among both groups, with no significant differences between the groups.

Limitations of the study include the fact that patients in the placebo group could have experienced adverse events relating to withdrawal from long-acting aripiprazole that was provided during the stabilization phase.

The efficacy of long-acting, injectable aripiprazole was found to be consistent with the known efficacy of oral aripiprazole in the treatment of bipolar I disorder. The efficacy results were also consistent with the efficacy results for the twice-monthly injectable risperidone, the authors note.

Despite representing a useful tool to prevent nonadherence, long-acting injectables are not as commonly used as might be expected, said Michael Thase, MD, professor of psychiatry and director of the Mood Disorders Program at the University of Pennsylvania's Perelman School of Medicine, in Philadelphia, Pennsylvania.

"Nonadherence to medication is an endemic problem in bipolar disorder and is a big part of the struggle, but these long-acting injectables are not used nearly enough," he told Medscape Medical News.

One reason is that in psychiatry, outpatient practices typically do not have the capacity to provide the injection themselves or to store the medication. As a result, patients need to schedule an appointment at a healthcare center elsewhere.

Furthermore, patients may feel stigmatized by having the medication administered in an injection, Dr Thase explained.

"There can be a feeling of having a loss of control of one's own care," he said. "There's more of a sense of being in control when you know you can stop your drugs whenever you want to."

But with the potentially detrimental effects of relapse in nonadherent patients, including hospitalization or even suicide, a long-acting injectable antipsychotic may be in the best interest of patient and provider in some cases, he noted.

"Given how important adherence is in preventing the risk of relapse, we should be open to the possibility of improvement with long-acting treatments available to us," Dr Thase said.

The study received funding from Otsuka Pharmaceutical Development and Commercialization and H. Lundbeck A/S. Dr Calabrese has received funding from Otsuka and Lundbeck. A full listing of his relationships with industry is provided in the article. Dr Thase has previously consulted for Otsuka and Bristol-Myers Squibb but was not involved in the research on long-acting injectable aripiprazole.

J Clin Psychiatry. Published online January 31, 2017.

SOURCES:

Once-Monthly Aripiprazole Effective in Bipolar Disorder. Medscape. Feb. 14, 2017.



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