Adjunct Mirtazapine for Negative Symptoms of Schizophrenia

Stephanie V. Phan, Pharm.D.; Tiffany-Jade M. Kreys, Pharm.D.


Pharmacotherapy. 2011;31(10):1017-1030. 

In This Article

Abstract and Introduction


Negative symptoms of schizophrenia are characterized by affective flattening, alogia, avolition, and anhedonia and are often nonresponsive to antipsychotic therapy. Because negative symptoms are predictive of poor occupational and social functioning, as well as poor global outcomes, numerous studies evaluating adjunct therapy to antipsychotics have been conducted. This review focuses on the use of the antidepressant mirtazapine as adjunct therapy to antipsychotics for the treatment of negative symptoms of schizophrenia. A literature search of the MEDLINE database (from inception–March 2011) identified eight relevant articles: six were randomized, double-blind, placebo-controlled trials, and two were open-label trials. Of the six randomized trials reviewed, four studies assessed add-on mirtazapine to second-generation antipsychotics, whereas two studies examined add-on mirtazapine to first-generation antipsychotics. Five of the six randomized trials supported the use of mirtazapine for negative symptoms of schizophrenia. Of the two open-label trials, one naturalistic study demonstrated that mirtazapine add-on therapy to clozapine was not associated with improvements in negative symptoms; however, this study focused primarily on improvements in cognition, not negative symptoms. An open-label extension phase to a randomized controlled trial showed that mirtazapine continued to produce significant improvement in negative symptoms over a longer duration of time, when added to first-generation antipsychotic therapy. Overall, mirtazapine appears to be well tolerated and associated with few drug interactions. Although adjunct mirtazapine to antipsychotics has been shown to be effective at doses of 30 mg/day in most of the trials, limitations of these studies include short study duration and small sample sizes. To improve generalizability, larger multicenter studies with broader inclusion criteria should be conducted. In addition, studies of longer duration that use different mirtazapine dosages are needed to further assess the benefits of mirtazapine for negative symptoms of schizophrenia.


Schizophrenia is a chronic psychotic disorder that affects approximately 2.4 million American adults and has an annual incidence of approximately 1.1%.[1,2] According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), schizophrenia is characterized by at least two or more of the following symptoms that persist for a substantial amount of time during a 1-month period, with some signs of the disorder continuing for at least 6 months: delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, and negative symptoms.[3] The primary goals of treatment are to reduce or eliminate symptoms, maximize quality of life, and maintain recovery.[4] Although antipsychotics can effectively treat positive symptoms and often prevent relapse, many patients remain functionally impaired due to the persistence of negative and/or cognitive symptoms of schizophrenia.[4]

In 2006, the National Institute of Mental Health developed a consensus statement describing the unmet therapeutic need for the treatment of persistent negative symptoms of schizophrenia.[5] Negative symptoms refer to the loss of normal functioning occurring in many patients with schizophrenia.[6] Four core negative symptoms are evaluated in the majority of negative symptom assessment scales and include affective flattening, alogia (poverty of speech; the lessening of speech fluency and productivity, thought to reflect slowing or blocked thoughts, and often manifested as short, empty replies to questions), avolition (reduction, difficulty, or inability to initiate and persist in goal-directed behavior [e.g., no longer interested in meeting with friends]), and anhedonia (absence of pleasure from the performance of acts that would ordinarily be pleasurable [e.g., hobbies, exercise, social interaction, or sexual activity]).[7] These symptoms are predictive of poor occupational and social functioning, as well as poor global outcomes.[8–15]


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