Mirtazapine add-on improves olanzapine effect on negative symptoms of schizophrenia.

To the Editors: Negative symptoms are core manifestations of schizophrenia that remain largely resistant to current treatments. Involvement of dopamine in the pathophysiology of schizophrenia has been hypothesized since the introduction of antipsychotics. These drugs fundamentally act by blocking dopamine D2 receptors. 2 Current antipsychotics are beneficial for treating positive symptoms that may be associated with excess of dopamine release. However, antipsychotics may be less effective in treating cognitive deficits and negative symptoms of schizophrenia. Indeed, even though only weakly correlated, both these symptom clusters may be related to reduced prefrontal dopamine levels. This hypothesis is consistent with imaging findings and with pharmacological data suggesting that dopamine agonists temporarily ameliorate negative symptoms in patients. Moreover, second-generation antipsychotics compared with first-generation antipsychotics seem to have some advantage on negative symptoms and cognitive deficits, possibly by also increasing dopamine levels in the prefrontal cortex. Therefore, pharmacological approaches aimed at further increasing dopamine in the prefrontal cortex may result in additional benefits for prefrontal symptoms in patients with schizophrenia. Mirtazapine is the first of a new class of dual-action compounds, the noradrenergic and specific serotonergic antidepressants. Its activity is related to enhancement of noradrenergic and serotonergic signaling, respectively, by presynaptic >2 antagonism and postsynaptic 5-HT2 and 5-HT3 antagonism. Dopamine projections to prefrontal cortex are subject to tonic inhibition by >2 noradrenergic autoreceptors. Therefore, blockade of >2 receptors may increase dopamine in the prefrontal cortex. Consistent with this hypothesis, 2 studies have shown that noradrenergic neurons from the locus coeruleus projecting to the prefrontal cortex also release dopamine along with noradrenaline and that mirtazapine increases dopamine release in the prefrontal cortex, preventing the effects of stress. The potential use of mirtazapine as an add-on for treatment of negative symptoms of schizophrenia has been already suggested in a double-blind, randomized, placebo-controlled study. This study demonstrated a significant decrease in negative symptoms when mirtazapine was added to haloperidol in a group of schizophrenic patients. More recent studies have also demonstrated consistent results. Based on this background, we designed a double-blind, placebo-controlled study, to assess the efficacy of mirtazapine in addon to an ongoing treatment with olanzapine for treating negative symptoms and working memory deficits in patients with schizophrenia. We enrolled 28 white patients with schizophrenia (mean age, 29.3 [SD, 7.4]; 21 males) from the Psychiatric Inpatient Unit at the Department of Neuroscience and Sense Organs, University of Bari ‘‘Aldo Moro,’’ Italy. Inclusion criteria were diagnosis of schizophrenia with recent exacerbation of psychotic symptoms requiring hospitalization. Exclusion criteria were history of alcohol or drug abuse in the last 12 months and any diagnosable systemic or neurological condition. All patients gave a detailed informed consent for participation to the present protocol that had been approved by the local institutional review board. Starting from the first day of admission to the hospital, patients were enrolled and were treated for 8 weeks with olanzapine in monotherapy (mean dose, 16.5 [SD, 7] mg). After 8 weeks, patients were randomized with a 1:1 ratio into 2 groups in a double-blind fashion. Both groups were treated for another 8 weeks as follows: 1 group received mirtazapine (n = 14) at recommended dosage (30 mg/d), whereas the other group received placebo (n = 14). Olanzapine treatment was held at stable dose level (the dose reached before randomization at the end of the first 8 weeks of the study) during all the second 8-week period. Symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale (CDS) by a certified psychiatrist (G.C.). Evaluations were performed at times 0 (before starting olanzapine treatment) and after 1, 2, 4, 8 (when treatment with mirtazapine was started, T0), 12 weeks (T1), and 16 weeks (T2) of treatment. Increasing loads of working memory were evaluated with the 1and 2-back conditions within the N-back task at 1, 4, 8 (T0), and 16 weeks (T2), as in earlier reports. At the end of the study, the blind condition was broken, and repeated measures analyses of variance were used to evaluate the effect of treatment with mirtazapine on PANSS total scores and related subscale scores, as well as on CDS scores. t Tests for dependent samples were used for post hoc analyses. As some patients withdrew before study end, the missing psychopathological evaluations were treated with mixed model for repeated measures. Spontaneously reported adverse events were collected during the study, although no laboratory test was systematically collected during and for the purpose of the study. Treatment groups did not differ in terms of sex, age, length of illness, drugfree period before entering the trial, or dose of olanzapine (all P 9 0.1). For demographic and clinical characteristics, see Table 1. Eighteen of the patients concluded the study at 16 weeks (8 patients treated with mirtazapine and 10 with placebo), whereas 2 interrupted the study at 12 weeks (1 treated with mirtazapine and 1 with placebo), thus allowing us to include them in our mixed model for repeated measures analysis. Eight patients dropped out before T1 (5 treated with mirtazapine and 3 with placebo). All the previously mentioned patients interrupted the study for reasons unrelated to treatment. There were no significant differences between treatment groups in terms of PANSS total scores and related subscale scores before olanzapine treatment (all P 9 0.2) as well as at T0 (when placebo/ mirtazapine was added on) (all P 9 0.6). Analysis of variance indicated a significant effect of treatment with mirtazapine on negative symptoms from T0 to T2 (F2,46 = 3.20, P = 0.04). In particular, post hoc analysis performed with t test for dependent samples indicated that the mirtazapine group had a statistically significant reduction of PANSS negative scores from T0 to T2 (t = 3.82, P G 0.002), whereas this effect was not significant in the placebo group (t = 1.22, P 9 0.2). No statistically significant effect was found on PANSS total, positive symptoms, and general psychopathology scores (all P 9 0.3) as well as on CDS score (P = 0.26) as a function of treatment with mirtazapine. No serious adverse events were reported during olanzapine and mirtazapine treatments. No statistically significant difference was found between the 2 treatment groups in terms of accuracy and reaction time (RT) at the working memory loads investigated, 1-back (P = 0.1; P = 0.4) and 2-back (P = 0.8; P = 0.1). In the LETTERS TO THE EDITORS