By Rif S. El-Mallakh, Sharon Nuss, Dong Gao, Yonglin Gao, Surriya Colleen Ahmad, MD;1 Clare Schrodt, and Caleb Adler


Objectives:  Asenapine, a potent serotonin 7 (5-HT7) receptor antagonist, was examined for efficacy as an antidepressant in depressed bipolar subjects.  It was predicted that subjects with the genetic variant of the short form of the serotonin transporter (5HTTR) would be more likely to respond.

Experimental Design:  A subset of patients participating in a randomized, placebo-controlled study of the efficacy of asenapine in bipolar I depression also underwent genetic testing for the 5HTTR.  Montgomery Åsberg Depression Rating Scale (MADRS) score was ≥26 prior to randomization to asenapine or placebo for 8 weeks.  Gene testing was performed before breaking the blind.

Principal Observations:  Nine patients completing the study also underwent gene testing.  At study end, the average MADRS improvement was -19.80 ± SD 8.59 for the 4 people randomized to asenapine and -3.80 ± 9.01 for the 5 people receiving placebo (P = 0.021, t = 2.88).  Anxiety, as measured by the Hamilton Anxiety Rating Scale (HAM-A), also improved in asenapine-treated patients (-15.40 ± 6.15 vs. -2.80 ± 7.95, P = 0.023, t = 2.803).  Six participants had the short form of the 5HTTR, and it is believed they influenced the significant outcome in this small sample.

Conclusions:  While this is a very small sample, asenapine appears to have a beneficial effect on both depression and anxiety in depressed bipolar I patients compared to treatment with placebo.  Due to the large fraction of subjects with the short form, the hypothesis that the SF-5HTTR might increase asenapine response could not be adequately tested.

Trial Registration: identifier:  NCT01807741