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Mirtazapine Plus Clozapine Appears to Improve Negative Symptoms of Schizophrenia

The addition of mirtazapine to clozapine for treatment of schizophrenia appears to improve negative symptoms associated with schizophrenia, report Italian researchers.

Developing effective treatment of negative symptoms associated with schizophrenia is a primary treatment goal, with recent studies suggesting an efficacy with dual action compounds, the noradrenergic and specific serotonergic antidepressants (NaSSa).

To test the safety and efficacy of mirtazapine, the first drug of this new class of NaSSa, in this setting, Rocco Zoccali, MD, Psychiatric and Anaesthesiological Sciences, University of Messina, and colleagues conducted an 8-week, double-blind, placebo-controlled trial in which 12 outpatients diagnosed with schizophrenia were randomised to mirtazapine (30 mg/day) and 12 to placebo after at least 1 year of clozapine monotherapy (150-650 mg/day). All patients remained on clozapine throughout the study. Patients were included in the study because they exhibited negative symptoms that persisted despite adequate clozapine treatment.

Efficacy was assessed using the Brief Psychiatric Rating Scale (BPRS) administered at baseline and at 8 weeks, as well as the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) administered at baseline and at the end of weeks 2, 4, and 8.

Of the 24 patients, 10 from each group were available for analysis. At 8 weeks, patients in the mirtazapine group had significantly lower SANS scores than those in the placebo group (39.0 vs. 51.0, respectively; P < .01) and had significant improvement in the SANS subscales avolition/apathy (6.3 vs. 9.7, respectively; P < .05) and anhedonia/asociality (8.0 vs. 10.6, respectively; P < .05). These significant improvements in negative symptoms with mirtazapine were also significant after 4 weeks of treatment compared to baseline values (P < .01). Mirtazapine also showed superiority over placebo in reducing negative symptoms based on the total BPRS score at 8 weeks (25.4 vs. 44.7, respectively; P < .01). Positive symptoms as measured by SAPS were not changed in either group at the end of the 8 week study period.

Overall, mirtazapine was well tolerated with only mild and transient drowsiness seen in 3 patients and weight gain in 2 patients.

Despite limitations of this study that included small sample size, limited trial duration, and inter-individual variability in clinical response, the authors conclude that "the addition of mirtazapine to clozapine treatment is well tolerated and may be proposed as an useful therapeutic strategy to improve negative symptoms in chronic schizophrenic patients."

Int Clin Psychopharmacol 2004 Mar;19:2:71-6. "The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study"

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