Add-on mirtazapine enhances antipsychotic effect of first generation antipsychotics in schizophrenia: A double-blind, randomized, placebo-controlled trial
Introduction
All antipsychotics are antagonists at dopamine D2 receptors (Butcher, 2000). Clozapine, the prototypical second generation antipsychotic (SGA), demonstrates higher efficacy in treatment-refractory schizophrenia and lower incidence of extrapyramidal symptoms (EPS) than FGAs — features referred to as “atypicality”. These advantages of clozapine are attributed to its high affinity to serotonin 5HT2 receptors and low affinity to dopamine D2 receptors, as opposed to first generation antipsychotics (FGAs), whose D2 affinity is high (Meltzer, 1994). Based on this concept of serotonin dopamine antagonism (SDA), a number of novel SGAs have been developed to replace clozapine, due to its serious adverse effects.
Much optimism accompanied initial reports that favored SGAs over FGAs in a vast majority of important clinical domains. However, the superiority of SGAs has recently been questioned since in large independent studies SGAs failed to outrange FGAs in effectiveness or safety (Jones et al., 2006, Tiihonen et al., 2006). Nevertheless, evidence exists in favor of SGA in terms of e.g., negative symptoms of schizophrenia (Davis et al., 2003), chronic schizophrenia with a history of suboptimal response to treatment (Volavka et al., 2002), adverse effect profile (Dossenbach et al., 2004), compliance (Kahn et al., 2008) and (with olanzapine) discontinuation of treatment (Lieberman et al., 2005).
Like the SGAs, antidepressants trazodone, mianserine, nefazodone and mirtazapine are also inhibitors at 5HT2 receptors. They are, however, lacking D2 receptor affinity and, thus, antipsychotic efficacy. If the SDA theory was true, a combination of these compounds with modestly dosed FGAs could result in a SGA-like receptor blockade profile and improved clinical properties. Indeed, the addition of trazodone, mianserin (Hayashi et al., 1997), or nefazodone (Joffe et al., 1999) to FGAs may reduce negative symptoms of schizophrenia. Moreover, nefazodone (Wynchank and Berk, 2003) and mianserin (Poyurovsky et al., 1999) may alleviate the FGAs-induced EPS, possibly due to the preponderance of serotonin 5HT2 antagonism over dopamine D2 blockade achieved by this combination.
Mirtazapine, in addition to the 5HT2 receptor blockade, demonstrates inhibition at adrenergic α2, serotoninergic 5HT3 and histaminergic H1 receptors, as well as indirect agonism at serotonin 5HT1a receptors (Berendsen and Broekkamp, 1997). Also these receptors appear to be involved in the schizophrenic process (Hertel et al., 1999, Stahl, 2008). In this respect, mirtazapine resembles clozapine (Stahl, 2008), and thus as adjunct might have advantages over antidepressants that exhibit purely 5HT2 inhibition. Indeed, in preclinical studies, adjunctive mirtazapine enhanced the antipsychotic-like effects and tolerability of FGAs drugs in a fashion predictive for atypicality (Berendsen et al., 1998, Pinder et al., 1998). In two recent small RCTs adjunctive mirtazapine was superior to placebo in negative, but not positive symptoms in haloperidol (Berk et al., 2001) and clozapine-treated schizophrenia (Zoccali et al., 2001). Mirtazapine also improved both antipsychotic-induced akatisia (Hieber et al., 2008) and neuro-cognitive performance (Delle Chiaie et al., 2007).
This study was designed to explore the effect of adjunctive mirtazapine on symptoms of schizophrenia in patients who had negligible or sub-optimal response to different FGAs in stable doses. The study was initiated by the investigators and independent of any commercial interests.
Section snippets
Materials and methods
The study protocol and its amendments were approved by the Ethics Committee of the Karelian Republic, Russian Federation and conducted in compliance with the Declaration of Helsinki, Guideline for Good Clinical Practice (ICH_GCP), and the current National Regulations.
This study was a double-blind, RCT of mirtazapine added to on-going FGA treatment. The inclusion criteria were: in-/outpatients, aged 18 to 65 years, diagnosed with schizophrenia or schizoaffective disorder (depressive type)
Results
Of the 46 subjects screened, 41 were randomized. One placebo patient was excluded due to a protocol violation (i.e., too low FGA dose). One more placebo patient was withdrawn immediately after randomization and could not be taken into analyses, as the baseline assessments were not performed. No withdrawals occurred in either group afterwards, and the MITT was thus equal to conventional ITT. Of 14 patients with a previous history of clozapine treatment, clozapine was used in the recommended
Discussion
In this study, a statistically significant favorable effect was found in a wide range of clinical parameters when mirtazapine was added to FGAs. To our knowledge, this is the first RCT reporting an additive antipsychotic effect of an adjunctive antidepressant. Robust statistically significant differences favored mirtazapine treatment when compared to placebo in both within group and between group analyses, despite higher initial psychotic symptom scores in the mirtazapine group. The difference
Conclusions
Adjunctive mirtazapine appears a safe, well tolerable and efficacious option in schizophrenia with sub-optimal response to the FGAs. This is the first RCT reporting a robust additive antipsychotic effect of an adjunctive antidepressant. This finding is important especially due to current re-emerging attention to the FGAs. Mirtazapine/FGAs combination might be worth of a trial prior to clozapine, especially if our findings will be confirmed in larger and longer trials. Further studies should in
Role of funding source
This trial (01T-67) was supported by a grant from the Stanley Medical Research Institute (SMRI), Bethesda, Maryland USA. The SMRI had no role in study design; in gathering or analysis of data; in the writing or publication of the report. The authors report no additional financial or other relationships relevant to the subject of this article.
Contributors
Authors G. Joffe, Terevnikov, Stenberg, M. Joffe and Burkin designed the study and wrote the protocol. Authors Terevnikov and Burkin were responsible for patient interviews and for the design and organizing of the on-site logistics and infrastructure. Authors G. Joffe, M. Joffe and Stenberg were responsible for training of the researchers on the CGP and ratings and (M. Joffe) for the quality monitoring during the data gathering. Author Tiihonen was responsible for the statistical analyses. The
Conflicts of interest
Jari Tiihonen, M.D., Ph.D., reports having served as consultant to Lundbeck, Organon, Janssen-Cilag, Eli Lilly, and Bristol Myers-Squibb, and has received fees for giving expert opinions to Bristol Myers-Squibb and GlaxoSmithKline, and lecture fees from Janssen-Cilag, Bristol Myers-Squibb, Eli Lilly, Pfizer, Lundbeck, GlaxoSmithKline, and Astra Zeneca.
Grigori Joffe, M.D., Ph.D., has served as consultant to Novartis, has received fees for giving expert opinions to Bristo Myers-Squibb, Pfizer,
Acknowledgements
None.
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Location of work: Psychiatric Hospital, Matrosy, Priaža District, Republic of Karelia, Russia, and Day Treatment Unit, Psychoneurological Dispensary, Krsanoflotskaya Street 29, Petrozavodsk, Republic of Karelia, Russia.