{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T13:47:31Z","timestamp":1793281651971,"version":"4.5.0"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["World Psychiatry"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:p>Although clozapine is the most effective medication for treatment\u2010resistant schizophrenia, response is inadequate in over half of people with that condition. There is limited guidance available on effective clozapine augmentation strategies. We studied the comparative effectiveness of specific doses of oral olanzapine, quetiapine, risperidone and aripiprazole augmentation of clozapine treatment on the risk of hospitalization due to a psychotic episode, as a marker for severe relapse, among patients with schizophrenia or schizoaffective disorder. In this population\u2010based study, patients with one of those diagnoses receiving clozapine were identified from Finnish (years 1995\u20102017, N=14,053) and Swedish (years 2006\u20102021, N=8,743) nationwide registers. The risk of hospitalization due to a psychotic episode associated with periods of antipsychotic augmentation of clozapine treatment vs. same\u2010dose clozapine monotherapy was assessed by a within\u2010individual design, using each individual as his\/her own control to eliminate selection bias, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately; then results were combined using a random\u2010effect meta\u2010analysis. Secondary outcomes were somatic hospitalization, and hospitalization for psychosis or a somatic cause. The only augmentation associated with a significantly decreased risk of hospitalization due to psychosis in both countries was medium\u2010dose (9 to &lt;16.5 mg\/day) aripiprazole combined with high\u2010dose (\u2265330 mg\/day) clozapine, and this combination was associated with the best outcome in the meta\u2010analysis (adjusted hazard ratio, aHR=0.68, 95% CI: 0.62\u20100.75, p&lt;0.0001). Among patients using medium\u2010dose (180 to &lt;330 mg\/day) clozapine, medium\u2010dose aripiprazole augmentation was the only treatment more effective than clozapine monotherapy after Bonferroni correction (aHR=0.79, 95% CI: 0.70\u20100.91, p=0.0006). The use of all high\u2010dose augmentations was associated with an increased risk of hospitalization due to psychosis. Only aripiprazole augmentations were associated with a decreased risk of hospitalization for psychosis or a somatic cause, and the lowest risk was observed for medium\u2010dose aripiprazole plus high\u2010dose clozapine (aHR=0.70, 95% CI: 0.58\u20100.84, p=0.0001). This meta\u2010analysis of two nationwide cohorts, totaling almost 23,000 patients using clozapine, indicates that medium\u2010dose aripiprazole augmentation of clozapine treatment is associated with a 20\u201030% decreased risk of severe relapse compared with clozapine monotherapy within the same individuals, while augmentation with higher doses of aripiprazole (as well as with high doses of all other antipsychotics) is associated with an increased relapse risk.<\/jats:p>","DOI":"10.1002\/wps.21316","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T11:00:38Z","timestamp":1747306838000},"page":"250-259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Effectiveness of clozapine augmentation with specific doses of other antipsychotics in schizophrenia: a meta\u2010analysis from two nationwide cohorts"],"prefix":"10.1002","volume":"24","author":[{"given":"Jari","family":"Tiihonen","sequence":"first","affiliation":[{"name":"Department of Forensic Psychiatry University of Eastern Finland, Niuvanniemi Hospital  Kuopio Finland"},{"name":"Department of Clinical Neuroscience Karolinska Institutet  Stockholm Sweden"},{"name":"Center for Psychiatry Research Stockholm City Council  Stockholm Sweden"},{"name":"Neuroscience Center, University of Helsinki  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antti","family":"Tanskanen","sequence":"additional","affiliation":[{"name":"Department of Forensic Psychiatry University of Eastern Finland, Niuvanniemi Hospital  Kuopio Finland"},{"name":"Department of Clinical Neuroscience Karolinska Institutet  Stockholm Sweden"},{"name":"Center for Psychiatry Research Stockholm City Council  Stockholm Sweden"},{"name":"Population Health Unit Finnish Institute for Health and Welfare  Helsinki 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Charit\u00e9 Universit\u00e4tsmedizin Berlin  Berlin Germany"},{"name":"German Center for Mental Health (DZPG)  partner site Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Siskind","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Queensland  Brisbane QLD Australia"},{"name":"Addiction and Mental Health Metro South Health  Brisbane QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Taipale","sequence":"additional","affiliation":[{"name":"Department of Forensic Psychiatry University of Eastern Finland, Niuvanniemi Hospital  Kuopio Finland"},{"name":"Department of Clinical Neuroscience Karolinska Institutet  Stockholm Sweden"},{"name":"Center for Psychiatry Research Stockholm City Council  Stockholm Sweden"},{"name":"School of Pharmacy University of Eastern Finland  Kuopio 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