Reboxetine add-on to clozapine in treatment of negative symptoms of schizophrenia: a preliminary open-label study

Background Negative symptoms, including blunted emotional responsiveness, social skills deficits, impoverished content of thought and speech, and lack of motivation, constitute hallmarks of chronic schizophrenia and contribute more than positive symptoms to poor functional outcome and quality of life. Furthermore, cognitive deficits, mainly in working memory and executive functions domains, are core features of schizophrenia, usually persisting even during otherwise successful treatment with antipsychotic drugs. Antidepressant drugs added to ongoing antipsychotic treatment are currently used with the aim of addressing negative and residual symptoms [1]. Reboxetine, a selective noradrenaline reuptake inhibitor broadly used as an antidepressant, has showed positive effects on cognitive functioning in depressed patients. Based on the therapeutic rationale that dysfunctional noradrenergic system plays a key role in both cognitive impairment and lack of motivation [2], we evaluated the effect of reboxetine add-on on negative symptoms and cognitive deficits in a sample of chronic schizophrenia patients in stable clozapine treatment. Method This study was a 12-week open-label trial on 12 outpatients (8 males and 4 females) who met DSM-IV criteria for schizophrenia and demonstrated persistent negative symptoms despite an adequate trial of clozapine. Patients had been on clozapine monotherapy, for at least 1 year; the dose had been stable for at least 1 month before the trial and remained unchanged during the entire study period. All subjects received 4 mg of reboxetine/day. A clinical assessment including PANSS, CDSS, BPRS, and a neuropsychological assessment including Stroop colour-word interference, phonemic and semantic verbal fluency tests, before and after treatment with reboxetine were performed. Outcome was measured as mean ±SD and differences in scores between baseline and endpoint (week-12) were analysed by the Wilcoxon rank sum test; a p value of < .05 was selected. Results Significant decreases in severity of depressive symptoms (CDSS scores baseline vs. week-12: 3.17±3.09 vs. .91±1.22, p=.012) but no significant changes in schizophrenic clinical symptoms (PANSS-N scores baseline vs. week 12: 18.67±6.54 vs. 19.33±5.96, p=.506; PANSS-P scores baseline vs. week-12: 9.83±2.72 vs. 9.33±2.06, p=.506; PANSS-G scores baseline vs. week-12: 34±10.11 vs. 32.5±8.59, p=.581; BPRS scores baseline vs. week-12: 32.5±5.77 vs. 32.17±7.64, p=.937) were observed. Furthermore, no significant differences in the neuropsychological profile were found, except worse performance at phonemic verbal fluency task (scores baseline vs. week-12: 26.67±8.94 vs. 21.83±6.48, p .012). Finally, reboxetine add-on was safe and well-tolerated. Conclusion Reboxetine augmentation of clozapine treatment in chronic schizophrenia was effective in reducing severity of depressive symptoms, whereas it had no impact on negative symptoms. Noteworthy, the hypothesis of a strong contribution of depression to negative symptoms was not supported by results. Moreover, a worsening of neurocognitive performance in phonemic verbal fluency task was observed. Our findings confirmed previous published data regarding no reboxetine effect at diminishing neuropsychological dysfunctions [3]. Affective but not cognitive improvement merits further investigation. The development of treatment strategies to improve functional outcome in schizophrenia, even at those times when antipsychotic drugs effectively control positive symptoms, remains a therapeutic challenge.