Predictors and mediators of add-on mirtazapine-induced cognitive enhancement in schizophrenia--a path model investigation.

We aimed to evaluate predictors and mediators of enhancing effect of adjunctive mirtazapine on cognition in schizophrenia. Patients with difficult-to-treat schizophrenia received either mirtazapine (n = 19) or placebo (n = 18) in a double-blind fashion for six weeks. Mirtazapine outperformed placebo on the Block Design and Stroop Dots. In the present subsidiary study, factors underlying this difference were explored with Path Analysis. Add-on mirtazapine had an independent enhancing effect on the Block Design-measured visuo-spatial functioning. Further, this effect was mediated via changes in positive, depressive and parkinsonism symptoms, but not in negative symptoms. This effect was predicted by higher doses of FGAs, longer duration of illness and lower initial Block Design scores. Path Analysis model fit was good. Mirtazapine may have direct and indirect favorable effects on visuo-spatial functioning, but further research is needed. Path analysis may be a feasible statistical method for further research of neurocognition in psychopharmacological interventions in schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Relationships between pharmacotherapy-induced metabolic changes and improved psychopathology in schizophrenia: data from a mirtazapine and first-generation antipsychotics combination trial.

Clinical efficacy and metabolic side-effects of antipsychotics seem to correlate with each other. In this study, interrelationship of similar metabolic effects of mirtazapine and its earlier reported desirable effects on psychopathology in first-generation antipsychotics (FGAs)-treated schizophrenia were explored. Symptomatic FGAs-treated patients with schizophrenia received a 6-wk double-blind treatment with add-on mirtazapine (n = 20) or placebo (n = 16), followed by a 6-wk open-label mirtazapine treatment. Mirtazapine (but not placebo) induced an increase in body weight and cholesterol levels. The latter was associated with a clinical improvement in all (sub)scales of the Positive and Negative Syndrome Scale [PANSS; an increase of cholesterol by 1 mmol/l predicted 7 points reduction on the PANSS total score (r = 0.85, p = 0.001)]. In schizophrenia, mirtazapine-induced weight gain and increase of total cholesterol are associated with the improved efficacy of mirtazapine-FGAs combination--a novel observation with possible clinical and theoretical implications.

Add-on mirtazapine improves depressive symptoms in schizophrenia: a double-blind randomized placebo-controlled study with an open-label extension phase.

Depression is common in schizophrenia and worsens its course. The role of antidepressants for schizophrenic depression remains unclear. In this study, the efficacy of add-on mirtazapine on depression in schizophrenia was explored in a subsidiary arm of a recent randomized controlled trial. Patients (n = 41) with chronic but stable schizophrenia and inadequate response to stable doses of different first-generation antipsychotics were treated with add-on mirtazapine 30 mg or placebo during a 6-week double-blind phase and with open-label add-on mirtazapine during a 6-week extension phase. Efficacy measures were the Calgary Depression Scale for Schizophrenia (CDSS) and the Positive and Negative Syndrome Scale depression item. During the double-blind phase, both measures' scores decreased significantly in the mirtazapine group but not in the placebo group (for the CDSS, 52.0% vs 19.6%, respectively). During the open­label phase, both groups demonstrated significant improvements. In between­group comparison, a trend favoring mirtazapine did not reach statistical significance. The changes in the CDSS correlated positively with those in the Positive and Negative Syndrome Scale negative, positive and total (sub)scales for mirtazapine­treated patients during the double­blind phase. Depressed patients with schizophrenia may benefit from mirtazapine­first­generation antipsychotics combination, with no increased risk for psychosis. However, more studies are needed.

More evidence on proneurocognitive effects of add-on mirtazapine in schizophrenia.

Enhancement of neurocognition is essential in the treatment of schizophrenia. In our previously reported six-week randomized controlled trial (RCT) mirtazapine added to conventional antipsychotics improved not only negative, but also positive symptoms and neurocognition in difficult-to-treat schizophrenia. The present study aimed to explore whether a prolonged exposure to mirtazapine could further improve neurocognition. Completers of the RCT who were able and willing to proceed to the extension phase received open label mirtazapine for an additional 6 weeks. During the extension phase, both groups (i.e., patients who previously received mirtazapine and those who received placebo) and the whole population showed improvement on a number of neurocognitive tests. Patients who shifted to open label mirtazapine from placebo achieved in the six following weeks similar results as their initially mirtazapine-treated counterparts did during their first 6 weeks of mirtazapine exposure. Middle-term mirtazapine treatment (12 weeks) demonstrated an advantage over short-term mirtazapine treatment (6 weeks) on Stroop Dots time and Trail Making Test, part B, number of mistakes (t = -2.562, p = 0.035 and t = -2.42, p = 0.043, correspondingly). Mirtazapine added to antipsychotics consistently shows desirable effects on neurocognition. Lengthy treatment seems worthwhile. Mirtazapine may become a safe and cost-saving neurocognitive enhancer in schizophrenia, yet more studies are needed.

More evidence on additive antipsychotic effect of adjunctive mirtazapine in schizophrenia: an extension phase of a randomized controlled trial.

OBJECTIVE: Adjunctive mirtazapine improved negative symptoms of schizophrenia in several studies. Recently, we found an improvement also in positive symptoms when mirtazapine was added to first generation antipsychotics (FGAs) in a 6 week randomized controlled trial (RCT). The short duration of that trial was its limitation. This study aimed to explore whether longer treatment is worthwhile. METHOD: Completers of the RCT (n = 39) received open-label add-on mirtazapine for additional 6 weeks. The Positive and Negative Syndrome Scale (PANSS) total score (primary outcome) and several other clinical parameters were measured prospectively. RESULTS: During the open-label phase, significant improvement was achieved in all parameters, with an effect size of 0.94 (CI 95% = 0.45-1.43) on the primary outcome and an impressive additive antipsychotic effect. Patients who received mirtazapine during both phases demonstrated greater improvement in positive symptoms (29.6% versus 21.2%, p = 0.027) than those who received mirtazapine during open-label extension phase only. CONCLUSIONS: These findings support our previous data on the additive antipsychotic effect of mirtazapine in FGAs-treated schizophrenia. Mirtazapine may be effective in other symptom domains, too. Longer duration of mirtazapine treatment may yield additional benefits. If these results will be confirmed in larger studies, add-on mirtazapine may become a feasible option in difficult-to-treat schizophrenia.

Effects of add-on mirtazapine on neurocognition in schizophrenia: a double-blind, randomized, placebo-controlled study.

Mirtazapine added to antipsychotics appears to improve the clinical picture of schizophrenia, including both negative and positive symptoms. This study explored the effect of adjunctive mirtazapine on neurocognition in patients with schizophrenia who had shown an insufficient response to first-generation antipsychotics (FGAs). Thirty-seven schizophrenia patients, who were at least moderately ill despite their FGA treatment, received add-on mirtazapine (n=19) or placebo (n=18) in a 6-wk double-blind, randomized trial. Widely used neuropsychological tests were performed to explore visual-spatial functions, verbal and visual memory, executive functions, verbal fluency and general mental and psychomotor speed. The data were analysed on the modified intent-to-treat basis with last observation carried forward. False discovery rate was applied to correct for multiple testing. Mirtazapine outperformed placebo in the domains of visual-spatial ability and general mental speed/attentional control as assessed by, correspondingly, Block Design and Stroop dots. The difference in the degree of change (i.e. change while on mirtazapine minus that on placebo) was 18.6% (p=0.044) and 11.1% (p=0.044), respectively. Adjunctive mirtazapine might offer a safe, effective and cost-saving option as a neurocognitive enhancer for FGA-treated schizophrenia patients. Mirtazapine+FGA combinations may become especially useful in light of the currently increasing attention towards FGAs. Larger and longer studies that incorporate functional outcomes, as well as comparisons with second-generation antipsychotics are, however, still needed for more definite conclusions.

Add-on mirtazapine enhances antipsychotic effect of first generation antipsychotics in schizophrenia: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Mirtazapine, an antidepressant with a broad spectrum of receptor affinity may, if combined with first generation antipsyhotics (FGAs), improve clinical profile of the FGAs. However, potentiation of the antipsychotic effect by mirtazapine has not been reported thus far. We explored the efficacy of adjunctive mirtazapine on symptoms of schizophrenia in patients having an insufficient response to different FGAs. METHODS: Schizophrenia-diagnosed patients with a prolonged disease and a history of a poor response to numerous antipsychotics, who were at least moderately ill despite their FGAs treatment, received add-on mirtazapine (n=20) or placebo (n=19) in a 6-week double-blind randomized controlled trial (RCT). The analysis was made on a Modified Intent-to-Treat (MITT) basis with Last Observations Carried Forward (LOCF). RESULTS: Mirtazapine outranged placebo on almost all measures. The clear-cut clinical relevance of this finding was demonstrated by a large effect size of 1.00 (95% CI 0.23-1.67, p=0.003) on the total Positive and Negative Syndrome Scale (PANSS) scores (the primary outcome). The PANSS positive subscale scores decreased by 17.2% with mirtazapine vs. 1.6% with placebo (p<0.001), and the PANSS negative subscale scores by 12% and 3% (p<0.001), correspondingly. CONCLUSIONS: This is the first RCT reporting a robust additive antipsychotic effect of an adjunctive antidepressant. Mirtazapine-FGAs combination appears to be a safe, well-tolerated and efficacious treatment option in this challenging population. These findings are important due to the current re-emerging attention to FGAs. The focus of further studies should be expanded to include combinations with or switching to novel antipsychotics, different subpopulations of patients with schizophrenia, finding of optimal doses, and comparison with clozapine.