Effects of add-on mirtazapine on neurocognition in schizophrenia

Schizophrenia is a severe, psychiatric illness with neurocognitive deficits as its major component, and affects about 1% of the world population. Improving impaired neurocognitive function is one of the pivotal treatment goals in this patient population. In the treatment of schizophrenia, only a partial treatment response is typically achieved with dopamine antagonists; i.e., antipsychotics . The antidepressant mirtazapine has a unique mechanism of action with, in theory, an ability to enhance neurocognition and provide added value to antipsychotic treatment. This study explored whether or not adjunctive mirtazapine has the potential to improve neurocognitive performance and alleviate clinical symptoms in patients with schizophrenia who demonstrated a suboptimal treatment response to first-generation antipsychotics (FGAs). This study was a neurocognitive arm of a single-center, randomized, add-on, double-blinded, placebo-controlled study, which was carried out in the Karelian Republic, Petrozavodsk, Russia. Patients with schizophrenia or a depressive type schizoaffective disorder, according to the Diagnostic and Statistical Manual of Mental and Behavioral Disorders 4th edition (DSM-IV) criteria, who received stable doses of FGA with inadequate treatment response were enrolled into the trial. Twenty patients were assigned to mirtazapine and 21 to placebo. After a one-week single-blind placebo run-in period, the participants were randomized to receive either 30 mg of mirtazapine or the placebo four times a day (QID) in a double-blind fashion for 6 weeks. Subsequently, those who were eligible to continue entered the following 6-week open-label phase, where they were treated with mirtazapine 30 mg QID. At study weeks 0, 6, and 12, a senior psychologist performed neuropsychological examinations to evaluate neurocognitive functioning. Verbal and visual memory, visuo-spatial and executive functions, verbal fluency and both general mental and psychomotor speeds were assessed by commonly used, validated neuropsychological tests for different neurocognitive domains. Clinical examinations were conducted at week 1 (screening), week 0 (baseline) and after 1, 2, 4, 6, 7, 8, 10, and 12 weeks of treatment. Within group and between group differences were analyzed on a Modified Intent-to Treat (MITT) basis with Last Observations Carried Forward (LOCF). After 6 weeks of treatment, 5/21 neurocognitive parameters (i.e. Wechsler Adult Intelligence Scale Revised (WAIS-R) Block Design, p=0.021; Wechsler Memory Scale (WMS) Logical Memory, p=0.044; WMS Logical Memory Delayed, p=0.044; Stroop Dots, p=0.044; Trail Making Test Part A (TMT-A), p=0.018) were improved with statistical significance in the mirtazapine group. In contrast, only 1 of the 21 parameters changed significantly (WMS Logical Memory, p=0.039) in the placebo group. Add-on 6-week mirtazapine treatment was superior when compared with placebo in the neuropsychological domains of visuo-spatial ability and general mental speed/attentional control (Block Design mirtazapine group vs. placebo and Stroop dots mirtazapine group vs. placebo, p=0.044 for both comparisons). The enhancing effect on the Block Design-measured visuo-spatial functioning was mediated through changes in positive, depressive symptoms and parkinsonism-like side effects, but not via changes in negative symptoms. Moreover, higher doses of FGAs, longer duration of illness and lower initial Block Design scores predicted this effect. During the 6 weeks extension phase, individuals who continued mirtazapine treatment and those who were switched from placebo to mirtazapine showed significant improvements on several neurocognitive tests. Those who switched from placebo to open label mirtazapine treatment achieved similar results in the 6 following weeks as the mirtazapine group during their first 6 weeks of mirtazapine treatment. From week 0 to week 12, the continuation group demonstrated improvements in 17/21 neurocognitive parameters, while the switch group improved in 8/21 of the measured parameters. Twelve weeks of mirtazapine treatment indicated an advantage over a shorter, 6-week mirtazapine treatment on Stroop Dots time (p=0.035) and Trail Making Test part B (TMT-B), and number of mistakes (p=0.043). During the 6-week open-label phase, significant improvements on several clinical parameters, which included the Positive and Negative Syndrome Scale (PANSS) total score, were observed. In the total population (i.e., pooled switch and continuation groups), the effect size was 0.94 (CI 95%=0.45-1.43) as determined by the PANSS total score. Conclusions. Adjunctive mirtazapine treatment might offer added value as a neurocognitive enhancer, and may augment the antipsychotic effect in FGA-treated schizophrenia patients with inadequate treatment response. The ability to generalize these results for a larger population may be limited by the small sample size of the present study. Skitsofrenia on pitkäaikainen ja toimintakykyä voimakkaasti laskeva psykiatrinen sairaus. Skitsofreniassa esiintyy monia tiedonkäsittelyyn liittyviä ns. kognitiivisia oireita, kuten vaikeudet keskittymisessä, uuden oppimisessa ja muistissa. Ne heijastelevat skitsofreniaan liittyviä keskushermoston toiminnan häiriöitä, minkä vuoksi niitä kutsutaan usein myös neurokognitiivisiksi oireiksi. Nykynäkemyksen mukaan neurokognitiiviset oireet ovat merkittävin syy skitsofreniaan liittyvään yleiseen toimintatason laskuun ja ne ovat riippumattomia skitsofrenian muista kliinisistä oireista eivätkä johdu lääkityksestä. Skitsofrenian hoidon keskeisiä haasteita onkin sairauteen liittyvien neurokognitiivisten oireiden kohentaminen. Käsillä olevassa tutkimuksessa tutkittiin tunnetun masennuslääkkeen, mirtatsapiinin ja ensimmäisen sukupolven psykoosilääkkeiden yhdistelmähoidon vaikutuksia pitkäaikaista skitsofreniaa sairastavien neurokognitiivisiin toimintoihin. Tutkimus suoritettiin kaksoissokkoasetelmalla, jossa 39 vapaaehtoista, täysi-ikäistä vakiintunutta ensimmäisen sukupolven neuroleptilääkitystä käyttävää skitsofreniaa sairastavaa sai joko mirtatsapiinia tai lumelääkettä. Mirtatsapiini kohensi hieman näönvaraisen päättelyn kykyjä ja yleistä psyykkistä nopeutta. Lääkkeen suotuisa vaikutus oli sekä itsenäinen että välittyi positiivisten psykoosioireiden vähenemisen, masennusoireiden vähenemisen ja parkinsonismityppisten oireiden vähenemisen kautta. Kaksoissokkoasetelmaa seurasi tutkimuksen avoin vaihe jossa lumelääke vaihdettiin mirtatsapiiniin. Tässä osiossa mirtatsapiinin vaikutukset tehostuivat edelleen. Niillä, jotka saivat nyt lumelääkkeen sijasta mirtatsapiinia, oli havaittavissa samat suotuisat vaikutukset kuin ensimmäisessä tutkimuksessa lääkettä saaneilla. Avoimen tutkimusvaiheen aikana mirtatsapiini lievitti merkittävästi potilaiden psykoosioireita. Johtopäätöksenä on, että ensimmäisen sukupolven antipsykoottiseen lääkitykseen lisätty mirtatsapiini voi kohentaa skitsofreniaa sairastavien neurokognitiivisia toimintoja ja parantaa antipsykootin kliinistä vastetta.