Adjunctive armodafinil for negative symptoms in adults with schizophrenia: A double-blind, placebo-controlled study John M. Kane a, ⁎, Ronghua Yang b , James M. Youakim c a Department of Psychiatry, The Zucker Hillside Hospital, 75–59 263rd Street, Kaufmann Bldg, Suite 103, Glen Oaks, NY 11004, USA b Cephalon, Inc., 41 Moores Road, Frazer, PA 19355, USA c Formerly of Cephalon, Inc. abstract article info Article history: Received 23 June 2011 Received in revised form 1 November 2011 Accepted 7 November 2011 Available online 16 December 2011 Keywords: Armodafinil Negative symptoms PANSS Tolerability Schizophrenia Objective: A prior 4-week, proof-of-concept study suggested that adjunctive therapy with armodafinil 200 mg/day decreases negative symptoms in patients with clinically stable schizophrenia. This study inves- tigated the efficacy and tolerability of adjunctive armodafinil for treatment of negative symptoms in adults with schizophrenia receiving antipsychotic medications. Methods: This parallel-group, 24-week study enrolled adults with schizophrenia who were receiving oral olanzapine, risperidone, or paliperidone for ≥6 weeks, and had a Positive and Negative Syndrome Scale (PANSS) negative symptom subscale score of ≥15. Patients received one of 3 doses of once-daily armodafinil (150 mg, 200 mg, or 250 mg) or placebo. The primary efficacy measure was the change from baseline to final visit in the PANSS negative symptom subscale score. Secondary measures included the PANSS total score, Clinical Global Impression of Severity, Personal and Social Performance Scale, and CNSVitalSigns cognitive battery. Results: Of 285 randomized patients, 213 received armodafinil and 72 received placebo. The mean (SD) changes in PANSS negative symptom subscale score were -1.9 (3.8) for armodafinil 150 mg (n= 70), –2.3 (3.6) for armodafinil 200 mg (n= 69), –2.0 (3.3) for armodafinil 250 mg (n=71), and -2.2 (4.1) for placebo (n=70) (p ≥0.70 for each armodafinil group versus placebo). Secondary measures were generally not different between groups. Armodafinil was generally well tolerated, without worsening positive symptoms. Conclusions: This study found no benefit of adjunctive armodafinil versus placebo for negative symptoms in pa- tients with schizophrenia receiving treatment with olanzapine, risperidone, or paliperidone. Armodafinil was generally well tolerated in these patients. © 2011 Elsevier B.V. All rights reserved. 1. Introduction The negative symptoms of schizophrenia may impair social and occupational function to a greater extent than positive symptoms, but effective treatment for these symptoms remains an unmet clinical need (Ross et al., 2006; Biedermann and Fleischhaker, 2011). Since the current antipsychotic medications used to treat schizophrenia generally reduce positive symptoms but have demonstrated only modest effects on negative symptoms, the persistence of negative symptoms disproportionately limits a patient's recovery and function (Erhart et al., 2006; Kirkpatrick et al., 2006; Laughren and Levin, 2006; Buchanan, 2007). Therefore, a substantial unmet need remains for more effective treatments of negative symptoms of schizophrenia (Erhart et al., 2006; Kirkpatrick et al., 2006). Negative symptoms of schizophrenia may be associated with low dopaminergic activity in the prefrontal cortex (Apud and Weinberger, 2007). In patients with schizophrenia, stimulants such as amphet- amines, which increase dopaminergic transmission, have been ob- served to alleviate negative symptoms; however, amphetamines may worsen psychosis through nonselective stimulation of dopaminergic neurotransmission in the subcortical areas of the brain responsible for positive symptoms (Apud and Weinberger, 2007). In addition, standard nonstimulant antipsychotics such as clozapine or olanzapine do not offer effective alternatives, as they have demonstrated no benefits for negative symptoms in studies in patients with schizophrenia (Buchanan, 2007). Armodafinil, a non-amphetamine stimulant, is the R- and longer- lasting isomer of modafinil (Dinges et al., 2006). Although the mech- anism of action of armodafinil remains unclear, one of its many effects is increased catecholaminergic signaling (Volkow et al., 2009; Rosenberg and Bogan, 2010; Schwartz et al., 2010), which may stim- ulate dopamine activity more selectively in the mesocortical pathway and the prefrontal cortex, and thus may have improved tolerability Schizophrenia Research 135 (2012) 116–122 ⁎ Corresponding author at: Department of Psychiatry, The Zucker Hillside Hospital, 75–59 263rd Street, Kaufmann Bldg, Suite 103, Glen Oaks, NY 11004–1150, USA. Tel.: +1 718 470 8141 (Office); fax: +1 718 343 7739. E-mail addresses: JKane2@NSHS.edu (J.M. Kane), ryang@cephalon.com (R. Yang). 0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2011.11.006 Contents lists available at SciVerse ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres