Clinical Effects of Mirtazapine added to First Generation Antipsychotics in Schizophrenia

Although a number of add-on treatment strategies have been studied to improve the outcome of antipsychotic-treated chronic schizophrenia, none of them have thus far proved to be conclusively effective. Mirtazapine, an antidepressant with a unique receptor profile, improves the clinical effect of first generation antipsychotics (FGAs), in terms of negative and extrapyramidal symptoms (EPS) in some published studies, when used in conjunction with FGAs. The present study aimed to explore the efficacy of adjunctive mirtazapine on the symptoms of schizophrenia in patients with an insufficient response to different FGA monotherapies at adequate stable dosages. Thirtynine patients who met the DSM-IV-TR criteria for schizophrenia or schizoaffective disorder depressive type, and who were at least moderately ill (as measured by the Clinical Global Impression Scale) despite their FGA treatment, received add-on mirtazapine 30 mg/day (n=20) or placebo (n=19) in a 6-week double-blind randomized controlled trial (RCT). Thirtyseven completers of the double-blind phase were treated in an open-label design with mirtazapine 30 mg/day during an additional 6 weeks. Dosages of current antipsychotics remained unchanged. The Positive and Negative Syndrome Scale (PANSS) total score (primary outcome), as well as secondary outcomes, which included PANSS subscales, Simpson-Angus Scale for Extrapyramidal Side-effects (SAS) and Calgary Depression Scale for Schizophrenia (CDSS) were measured prospectively. Patients underwent a physical examination (weight, vital signs) and a range of laboratory measures that included fasting glucose and total cholesterol. Within group and between group differences were compared on the Modified Intent-to-Treat basis with Last Observations Carried Forward. Correlation analyses and regression analyses were used to measure relationships between clinical and metabolic parameters. In the within group analyses, mirtazapine add-on treatment led to a statistically significant improvement of all measured clinical parameters during the double-blind phase. Improvement in PANSS total scores was as large as 12.5% (p less than 0.001), whereas the improvement in PANSS positive symptoms was 17.2% (p less than 0.001) while the improvement in PANSS negative symptoms was 12.0% (p less than 0.001). SAS scores improved by 9.8% (p=0.017) and CDSS scores improved by 52% (p=0.003). The latter change exhibited a direct correlation with several subscales of PANSS. In the mirtazapine group, the effect size was 1.00 (95%CI 0.34-1.67) on the primary outcome parameter. The between-group difference favoured mirtazapine on PANSS total scores (p=0.004), PANSS positive subscale (p=0.001) and PANSS negative subscale (p=0.001). No significant differences were found in other parameters. Mirtazapine treatment led to an increase in body weight and cholesterol levels, and the latter change was associated with a clinical improvement on all PANSS subscales, where an increase in total cholesterol by 1 mmol/L predicted a reduction on the PANSS total score by 7 points [r=0.85, p=0.001]. 8 During the open-label phase, patients who switched to mirtazapine demonstrated an improvement in PANSS (effect size 0.94 on PANSS total scores), CDSS and SAS scores in a manner similar to their mirtazapine-treated counterparts in the double-blind phase. The incidence of adverse events did not differ between mirtazapine and placebo. These findings indicate that add-on mirtazapine to current FGA treatment is significantly more efficacious in the reduction of positive, negative and depressive symptoms than a placebo add-on. This is the first RCT report of a statistically significant additive antipsychotic effect from an adjunctive antidepressant. Mirtazapine induced changes in body weight and lipid metabolism were similar to those seem with the most effective antipsychotics, and this metabolic effect may even contribute to its clinical efficacy. The main limitation of the study was its small sample size. Thus, larger and longer follow up trials are undoubtedly needed to confirm these results. Further research should also consider combinations of mirtazapine with second generation antipsychotics, and especially comparisons with clozapine.Lukuisia lisälääkkeitä on tutkittu hoitotulosta parantavana strategiana psykoosilääkkeitä saavilla skitso-frenia-potilailla. Mikään näistä lisälääkkeistä ei ole tähän asti osoittautunut ratkaisevan tehokkaaksi. Mirtatsapiini, ainutlaatuista reseptoriprofiilia omistava masennuslääke, yhdistettynä ensimmäisen polven psykoosilääkkeisiin paransi niiden kliinisiä vaikutuksia negatiivisiin ja ekstrapyramidaalisiin oireisiin muutamassa aiemmin julkaistussa tutkimuksessa. Tämän tutkimuksen päämääränä oli tutkia mirtatsapiinin vaikutusta skitsofrenian oireisiin skitsofreniaa sairastavilla potilailla, joiden hoitovaste erilaisiin ensimmäisen polven psykoosilääkkeisiin oli riittämätön adekvaatista ja säännöllisestä annostelusta huolimatta. Kolmekymmentä yhdeksän potilasta, joiden oirekuva täytti DSM-IV-TR:n määrittelemät skitsofrenian tai skitsoaffektiivisen häiriön (masennusoireinen muoto) kriteerit ja joiden oireet arvioitiin ainakin keskivai-keaksi (Clinical Global Impression Scale:n mukaan) saivat mirtatsapiinia lisälääkkeenä annoksella 30mg/vrk (n=20) tai lumelääkettä (n=19) kuuden viikon mittaisessa satunnaistetussa kaksoissokko-tutkimuksessa. Kolmekymmentä seitsemän kaksoissokko-faasin käynyttä potilasta saivat mirtatsapiinia 30 mg/vrk avoimessa muodossa toisen 6-viikon mittaisen faasin ajan. Psykoosilääkkeiden annokset pysyivät muutoksetta tutkimuksen molemmissa faaseissa. Positive and Negative Syndrome Scale:n (PANSS) kokonaispistemäärä (primääri tulos), sekä sekundaariset tulokset (PANSS:n ala-asteikot, Simpson-Angus Scale (SAS) ekstrapyramidaalisten oireiden mittarina, ja Calgary Depression Scale for Schizophrenia (CDSS) masennusoireiden mittarina) käytettiin potilaiden psyykkisen tilassa tapahtuvien muutosten arvioimiseksi. Potilaille tehtiin myös fysikaaliset testit (paino, vitaalit funktiot) ja monenlaiset laboratoriotestit, mm. paastosokeriarvo ja kolesteroliarvo. Ryhmien sisäiset ja ryhmien väliset muutok-set verrattiin keskenään Modified Intent-to-Treat perusteella. Korrelaatio ja regressio-analyysit käytettiin analysoidakseen yhteydet kliinisten ja metaboolisten parametrien välillä. Ryhmien sisäisessä analyysissa on tullut esiin että mirtatsapiini lisälääkityksenä aiheutti kaksoissokko faasissa tilastollisesti merkitsevän paranemisen kaikissa analysoiduissa kliinisissä parametreissa. PANSS:n kokonaispistemäärän paraneminen oli 12.5% (p alle 0.001), PANSS:n positiivisen ala-asteikon pistemäärä oli 17.2% (p alle 0.001) ja PANSS:n negatiivisen ala-asteikon pistemäärä oli 12.0% (p alle 0.001). SAS pisteet paranivat 9.8%:lla (p=0.017) ja CDSS pisteet paranivat 52%:lla (p=0.003). Jälkimmäinen muutos suorasti korreloi muutaman PANSS:n ala-asteikon kanssa. Mirtatsapiinin ryhmässä efekti-koko oli 1.00 (95%CI 0.34-1.67) primäärituloksen osalta. Ryhmien välinen vertailu suosi mirtatsapiinia PANSS:n kokonaispistemäärän kannalta (p=0.004), sekä PANSS:n positiivisen (p=0.001) ja PANSS:n negatiivinen (p=0.001) ala-asteikon kannalta. Mitään merkittäviä eroja muissa parametreissa ei löydet-ty. Mirtatsapiini aiheutti painon ja kolesteroli-arvon nousua. Jälkimmäinen muutos korreloi kliinisen pa-ranemisen kanssa siten että kolesterolin nousu 1 mmol/L ennusti PANSS:n pistemäärän laskua 7 pis-teellä [r=0.85, p=0.001]. Avoimessa faasissa mirtatsapiini-hoitoon siirtyneillä potilailla havaittiin paraneminen PANSS- (efekti-koko 0.94 PANSS:n kokonaispistemäärässä), CDSS- ja SAS pistemäärän osalta samalla tavalla, kuin mirtatsapiinia saavilla potilailla kaksoissokko-faasissa. Haittavaikutusten esiintyvyys oli samanlainen mirtatsapiini- ja lumelääkeryhmässä. Nämä löydökset viittaavat siihen että mirtatsapiini lisättynä vanhan polven psykoosilääkkeisiin paljon tehokkaammin helpottaa positiivisia, negatiivisia ja masennusoireita verrattuna lumelääkkeeseen. Tämä on ensimmäinen satunnaistettu kaksoissokko-tutkimus, joka raportoi tilastollisesti merkitsevän antipsykoottisen vaikutuksen, joka on saatu masennuslääkkeestä. Mirtatsapiinin aiheuttamat metabooliset vaikutukset ja painon nousu muistuttavat tehokkaimpien psykoosilääkkeiden aiheuttamia vaikutuksia, joten mirtatsapiinin metaboolinen vaikutusprofiili voi myötävaikuttaa sen kliinistä tehokkuutta. Tämän tutkimuksen päällimmäinen rajoitus oli sen pieni koko. Näin ollen, kooltaan isompia ja kestoltaan pidempiä tutkimuksia tarvitaan vahvistaakseen nämä tulokset. Tulevien tutkimusten aiheena voi olla myös mirtatsapiinin kombinointi uuden polven psykoosilääkkeiden kanssa ja varsinkin sen vertailu klotsapiiniin

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English summar

Add-on mirtazapine improves orgasmic functioning in patients with schizophrenia treated with first-generation antipsychotics

Aim: Sexual dysfunction, common in schizophrenia, may be further exaggerated by antipsychotics, especially those of First Generation (FGAs), and antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRs). Mirtazapine, an antidepressant characterized by its different action mechanism compared with that of the majority of other antidepressants, may improve SSRI-induced sexual dysfunction in patients with depression. It is unknown, however, whether mirtazapine improves sexual functioning in schizophrenia.Methods: This study randomly assigned FGA-treated patients with schizophrenia to receive either an add-on mirtazapine (n=20) or a placebo (n=19) for 6 weeks. Sexual functioning was prospectively measured using five relevant items from the Udvalg for Kliniske Undersogelser side-effect rating scale (UKU-SERS).Results: Orgasmic function improved with statistical significance in the mirtazapine group (p=.03), with no changes in any other sexual functions in either group.Conclusion: Add-on mirtazapine appears to relieve orgasmic dysfunction in FGA-treated patients with schizophrenia.Peer reviewe

Development of self-image and its components during a one-year follow-up in non-referred adolescents with excess and normal weight

Abstract Background The proportion of overweight and obese youths is high. The present study aimed to investigate the development of self-image and its components during a one-year follow-up among non-referred adolescents with excess and normal weight. Furthermore, we separately analyzed the data for girls and boys. Methods Altogether 86 8th grades (41 girls and 45 boys) with a relative weight of 26% or more above the median and 91 controls (43 girls and 48 boys) with normal weight participated the follow-up. The Offer Self-Image Questionnaire, Revised (OSIQ-R) was used to assess self-image at baseline and on follow-up. In the OSIQ-R, a low total raw score implies positive adjustment, while a high raw score implies poor adjustment and a negative self-image. The study design was doubly correlated (pairs and time), and a linear mixed model was used in the statistical analysis. Results In OSIQ-R total scores, a comparative improvement was observed in girls with normal weight. Among these girls, significant change scores compared to zero were seen in impulse control, social functioning, vocational attitudes, self-confidence, self-reliance, body image, sexuality, and ethical values. In girls with excess weight, none of the change scores compared to zero were statistically significant. When the girls with normal and excess weight were compared, the difference in change scores was largest in sexuality and vocational attitudes. Change scores compared to zero were significant in sexuality and idealism for boys with excess weight, and in impulse control, mental health, self-reliance, and sexuality for normal weight boys. When the boys with excess and normal weight were compared, no statistically significant differences emerged in change scores. Conclusion In mid-adolescent girls, the influence of overweight and obesity on the development of self-image is substantial. Weight management programs directed at overweight adolescent girls should include psychological interventions aiming to diminish self-image distress, especially that associated with feelings, attitudes, and behavior towards the opposite sex, as well as future career plans

Randomized Controlled Trials of Add-On Antidepressants in Schizophrenia

Background: Despite adequate treatment with antipsychotics, a substantial number of patients with schizophrenia demonstrate only suboptimal clinical outcome. To overcome this challenge, various psychopharmacological combination strategies have been used, including antidepressants added to antipsychotics. Methods: To analyze the efficacy of add-on antidepressants for the treatment of negative, positive, cognitive, depressive, and antipsychotic-induced extrapyramidal symptoms in schizophrenia, published randomized controlled trials assessing the efficacy of adjunctive antidepressants in schizophrenia were reviewed using the following parameters: baseline clinical characteristics and number of patients, their on-going antipsychotic treatment, dosage of the add-on antidepressants, duration of the trial, efficacy measures, and outcomes. Results: There were 36 randomized controlled trials reported in 41 journal publications (n = 1582). The antidepressants used were the selective serotonin reuptake inhibitors, duloxetine, imipramine, mianserin, mirtazapine, nefazodone, reboxetin, trazodone, and bupropion. Mirtazapine and mianserin showed somewhat consistent efficacy for negative symptoms and both seemed to enhance neurocognition. Trazodone and nefazodone appeared to improve the antipsychotics-induced extrapyramidal symptoms. Imipramine and duloxetine tended to improve depressive symptoms. No clear evidence supporting selective serotonin reuptake inhibitors' efficacy on any clinical domain of schizophrenia was found. Add-on antidepressants did not worsen psychosis. Conclusions: Despite a substantial number of randomized controlled trials, the overall efficacy of add-on antidepressants in schizophrenia remains uncertain mainly due to methodological issues. Some differences in efficacy on several schizophrenia domains seem, however, to exist and to vary by the antidepressant subgroups-plausibly due to differences in the mechanisms of action. Antidepressants may not worsen the course of psychosis. Better designed, larger, and longer randomized controlled trials are needed.Peer reviewe