Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis Eric Michael Hecht ⁎, David C. Landy University of Miami Miller School of Medicine, United States abstract article info Article history: Received 19 October 2011 Received in revised form 20 November 2011 Accepted 28 November 2011 Available online xxxx Keywords: Schizophrenia Alpha-2 antagonists Meta-analysis Mirtazapine Mianserin Introduction: Reduced dopaminergic activity in the pre-frontal cortex may partially explain the negative symp- toms of schizophrenia. Animal models have shown that adding an alpha-2 adrenergic receptor antagonist to a D2 antagonist can efflux dopamine into the frontal cortex increasing dopaminergic activity. Trials of alpha-2 antagonist add-on therapy in humans have been limited by small sample sizes. Therefore, a meta-analysis was conducted to determine if adding an alpha-2 antagonist to a D2 antagonist improves schizophrenia treatment by reducing negative symptoms. Methods: Randomized, placebo-controlled trials of the addition of an alpha-2 antagonist to a D2 antagonist were identified through a PubMed search. Treatment effects were measured using schizophrenia rating scales and meta-analyzed as standardized mean differences using random effects models. Results: Eight unique studies were identified, each including 18 to 41 patients and lasting four to eight weeks. The overall effect size of add-on alpha-2 therapy across the eight trials was an improvement of 0.16 (95% C.I., -.30 to 0.62) for positive symptoms, 0.84 (95% C.I., .17 to 1.51) for negative symptoms, 0.28 (95% C.I., -.08 to 0.64) for general symptoms, and .80 (95% C.I., .15 to 1.46) for symptoms overall. Negative symptom improvements were independent of improvements in depressive symptoms, measured using the Hamilton depression rating scale, for 3 of the 5 studies. Conclusions: Add-on agents with alpha-2 antagonist activity appear to improve the efficacy of D2 antago- nists for the treatment of schizophrenia by reducing negative symptoms. These results support conducting a more definitive confirmatory clinical trial. © 2011 Elsevier B.V. All rights reserved. 1. Introduction The treatment of schizophrenia remains inadequate, with over 75% of patients failing to achieve pharmacological remission, despite the introduction of second generation (SGA) antipsychotic medica- tions (Miyamoto et al., 2005; Beitinger et al., 2008; Leucht et al., 2009). These patients experience significantly higher rates of homelessness, hospitalization, and suicidality which are associated with increased mortality and societal burdens (Kooyman et al., 2007; Seeman, 2007). Despite insufficient evidence, attempts to improve these outcomes have many clinicians prescribing add-on medications (Zink et al., 2010). In this report, we highlight the potential benefits of alpha-2 antagonist add-on therapy. First and second generation anti-psychotic agents primarily alter the function of the D2 receptor in the subcortical regions of the brain (Seeman, 1987). Nevertheless, evidence suggests a regional dysfunction of the dopaminergic system throughout the brain including the pre-frontal cortex (Svensson, 2003; Howes and Kapur, 2009). Poor dopaminergic transmission and chronic low levels of dopamine in the prefrontal cortex have been linked to cognitive impairment and nega- tive symptoms in schizophrenia (Abi-Dargham, 2004; Devoto and Flore, 2006). Clozapine has been shown to cause the efflux of dopamine into the pre-frontal cortex, an action thought to be mediated by its alpha-2 receptor antagonism (Marcus et al., 2005). A similar effect occurs with other alpha-2 antagonists in combination with D2 antagonists which are administered to rodents (Hertel et al., 1999; Wadenberg et al., 2006). Mirtazapine and mianserin are structural analogs and used as monotherapy in the treatment of major depression. Both agents act as antagonists at central a2-adrenergic autoreceptors and heteroceptors, and have been shown to efflux dopamine into the pre-frontal cortex in rodents when combined with D2 antagonists (Millan et al., 2000; Wiker et al., 2005). Trials in schizophrenic patients have been performed, combining these agents with D2 antagonists, but have been limited by small sample sizes and have reached inconsistent results. A prior meta- analysis of add-on therapy was conducted before all of these trials Schizophrenia Research xxx (2011) xxx–xxx ⁎ Corresponding author. Tel.: + 1 646 236 7500. E-mail address: ehecht@med.miami.edu (E.M. Hecht). SCHRES-04835; No of Pages 5 0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2011.11.030 Contents lists available at SciVerse ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres Please cite this article as: Hecht, E.M., Landy, D.C., Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis , Schizophr. Res. (2011), doi:10.1016/j.schres.2011.11.030