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Efficacy of add-on mirtazapine on clinical and neuropsychologic parameters in schizophrenic patients treated with conventional antipsychotics: a double-blind, placebo-controlled trial with an open-label extension phase
DOI 10.1186/ISRCTN00721331
ClinicalTrials.gov identifier
EudraCT number
Public title Efficacy of add-on mirtazapine on clinical and neuropsychologic parameters in schizophrenic patients treated with conventional antipsychotics: a double-blind, placebo-controlled trial with an open-label extension phase
Scientific title
Acronym N/A
Serial number at source 7183
Study hypothesis Mirtazapine will improve negative, possibly positive and extrapyramidal symptoms, as well as neurocognition, if added to a conventional antipsychotic.
Lay summary Not provided at time of registration
Ethics approval Approved by the Republican Commision on Medical Ethics, Petrozavodsk (Session #6, Sept 9, 2004)
Study design Double-blind, placebo-controlled trial with an open-label extension phase
Countries of recruitment Finland
Disease/condition/study domain Schizophrenia
Participants - inclusion criteria Male or female in- or out-patients will be recruited if:
1. They are aged 18-65 years
2. Have schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) (APA, 1994); defined schizophrenia (disorganized, catatonic, paranoid, residual, or undifferentiated) or schizo-affective disorder, depressive type
3. Receiving one or more conventional antipsychotics at cumulative daily dose of at least 400 mg chlorpromazine equivalents (e.g. haloperidol 12 mg daily) (see Table of Antipsychotic Equivalents), which has remained unchanged (also in terms of dosage) during at least 6 last weeks prior to screening baseline (8 weeks for depot antipsychotics).
Table of antipsychotic equivalents (Basire, 2000) oral mg/day: chlorpromazine 100 mg (= 25-50 mg intramuscular (IM) or 250 mg rectal), fluphenazine 2 mg, levomeptromazine - not known, pericyazine 24 mg, perphenazine 8 mg, prochlorperazine 15 mg, promazine 100 mg, thioridazine 100 mg, trifluoperazine 5 mg, benperidol 2 mg, droperidol 4 mg (Short t1/2) or 3 mg IM/intravenous (IV), haloperidol 3 mg or 1.5 mg IM/IV for doses up to 150 mg/day, trifluoperidol 2 mg, flupentixol 2 mg, zuclopentixol 25 mg up to 150 mg/day, pimozide 2 mg (Long t1/2), remoxiprid 75 mg, amisulpride 100 mg, sulpiride 200 mg, loxapine 10 mg depot (mg/week), fluphenazine 5-10 mg (1-12.5 mg), pipothiazine 10 mg (5-12.5 mg), haloperidol 15 mg (5-12.5 mg), flupentixol 10 mg (8-20 mg), zuclopentixol 100 mg (40-100 mg), fluspirilene 2 mg - not fully established.
4. Demonstrating less than optimal clinical outcome i.e. experiencing either positive or negative symptoms (disability due to only general symptoms will be insufficient for inclusion) resulting in the illness of at least moderate severity (i.e. 4, moderately ill, or more on the clinical global impression (CGI), severity item) (Guy, 1970)
5. The clinical condition has remained stable during the last 6 weeks prior to the baseline visit
6. The patient has a level of understanding that enables reasonable cooperation with the investigator and the ability to fulfil the neurocognitive tests
7. The patient has given written informed consent
Participants - exclusion criteria 1. History of allergy or serious adverse events due to mirtazapine
2. Previous lack of response to a trial with mirtazapine in daily doses of 30 mg or more during four or more weeks, added to the patientís current or earlier conventional antipsychotic medication
3. Previous lack of response to another antidepressant with affinity to postsynaptic (5-hydroxytryptamine) 5HT2 receptors (e.g. mianserine, trazodone, or nefazodone) used in adequate doses during four or more weeks
4. Current atypical antipsychotic medication (e.g. clozapine, risperidone, olanzapine, sertindole, quetiapine, zotepine, ziprasidone, etc.)
5. History of non-response to either clozapine or other atypical antipsychotics
6. Medical or neurological condition or drug treatment that might put patients at serious risk or bias the assessment of their clinical or mental status (e.g. serious unstable physical illness, epilepsy, organic brain syndrome etc.)
7. History of or current bipolar disorder or schizoaffective disorder, bipolar type (patients with schizoaffective disorder, depressive type can participate in the study)
8. Substance addiction or abuse within the last three months prior to screening
9. Clearly predictable poor compliance
10. For females of child-bearing potential: pregnancy, lactation, or inability or unwillingness to use medically acceptable methods of contraception during the study
11. Treatment with any antidepressant, mood stabilizer, regular (i.e. four or more times within 1 week) use of sumatriptan, naratriptan, zolmitriptan, or drugs with similar mechanism of action, or buspiron or drugs with similar mechanism of action - within four weeks (for fluoxetine, six weeks) prior to baseline. Accidental use of the drugs for treatment of migraine listed above is forbidden on the day of clinical assessment before the assessment.
12. Treatment with antipsychotics other than those currently in use within six weeks prior to baseline
13. Treatment with benzodiazepines as follows:
a. Regular use (i.e. four or more times weekly) of any benzodiazepines at any doses during any of the last four weeks prior to baseline, if they have being received for less than two months. However, regular use of benzodiazepines is permitted if they are absolutely necessary and have been received during two or more months prior to baseline in stable daily doses not exceeding 30 mg of diazepam or comparable doses of other benzodiazepines, as determined by the table of equivalents (Bazire, 2000).
b. Accidental use (i.e. three or less times weekly) of benzodiazepines in daily doses exceeding 30 mg of diazepam or comparable doses of other benzodiazepines (see table of equivalents) (i.e. accidental use of 30 mg or less of diazepam or comparable doses of other benzodiazepines is not a criterion for exclusion). Use of benzodiazepines on the day of clinical assessment is forbidden before the assessment.
14. Electroconvulsive therapy (ECT) within three months prior to baseline
15. Any clinically relevant abnormality detected during the physical examination or laboratory screening tests and likely to interfere with the conduct of the study
Anticipated start date 10/10/2004
Anticipated end date 31/12/2006
Status of trial Completed
Patient information material
Target number of participants 40
Interventions Add-on mirtazapine versus placebo.
Primary outcome measure(s) Positive and negative syndrome scale (PANSS) total scores.
Secondary outcome measure(s) 1. Number of responders (20% or more decline on PANSS total or subscores)
2. Change in standard neurocognitive tests
Sources of funding Stanley Medical Research Institute
Trial website
Publications 1. 2012 results in http://www.ncbi.nlm.nih.gov/pubmed/22750079
Contact name Dr  Grigori  Joffe
  Address Hospital of Kellokoski
  City/town Kellokoski
  Zip/Postcode 04500
  Country Finland
  Tel +358 (0)40 5136500
  Fax +358 (0)98 1956676
  Email grigori.joffe@kolumbus.fi
Sponsor Stanley Medical Research Institute (USA)
  Address 5430 Grosvenor Lane

Suite 200
  City/town Bethesda
  Zip/Postcode MD 20814-2142
  Country United States of America
  Tel +1 301 571 0760 ext 124
  Fax +1 301 571 0769
  Email herrerax@stanleyresearch.org
  Sponsor website: http://www.stanleyresearch.org
Date applied 19/09/2005
Last edited 20/11/2012
Date ISRCTN assigned 25/05/2006
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