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. 2025 Apr 1;182(4):341-348.
doi: 10.1176/appi.ajp.20240321. Epub 2025 Feb 19.

Continuous Dopamine D2 Receptor Blockade and Long-Term Outcome in First-Episode Schizophrenia

Jari Tiihonen  1 , Antti Tanskanen  1 , Marco Solmi  1 , Jose M Rubio  1 , Christoph U Correll  1 , John M Kane  1 , Heidi Taipale  1
Affiliations

Continuous Dopamine D2 Receptor Blockade and Long-Term Outcome in First-Episode Schizophrenia

Jari Tiihonen et al. Am J Psychiatry. .

Abstract

Objective: It is not known what proportion of patients experience relapse in first-episode schizophrenia despite continuous dopamine D2 receptor blockade and whether breakthrough psychosis is attributable to long-term use of D2-blocking antipsychotics. Using data from a Finnish nationwide cohort, the authors sought to test the hypothesis that the incidence of breakthrough psychosis is accelerated among previously relapse-free patients receiving continuous D2 antagonist treatment beyond 5 years.

Methods: All persons age 45 years or younger with first-episode schizophrenia were identified from the nationwide registry of inpatient care for the years 1996-2014. The primary outcome was a severe relapse leading to hospitalization among those treated continuously with long-acting injectable (LAI) antipsychotics. The secondary outcome was the incidence rate ratio (IRR) of relapse during years 2-10, using year 1 as the reference.

Results: A total of 305 patients initiated ensured LAI use during the first 30 days of follow-up. Kaplan-Meier analysis showed that during the 10-year follow-up, their cumulative probability of relapse was 45% (95% CI=35-57). The annual relapse incidence per person-year decreased from 0.26 (95% CI=0.20-0.35) during the first year to 0.05 (95% CI=0.01-0.19) during the fifth year, corresponding to an IRR of 0.18 (95% CI=0.04-0.74). During years 6-10, only four relapses occurred during 128 person-years, corresponding to an IRR of 0.12 (95% CI=0.03-0.33) compared with year 1.

Conclusions: About 40%-50% of patients with first-episode schizophrenia will relapse despite continuous D2 blockade, apparently due to non-dopaminergic elements of the pathophysiology of the illness, as the results show that long-term dopamine receptor blockade is not associated with an increased risk of breakthrough psychosis.

Keywords: Antipsychotics; Dopamine; First-Episode; Relapse; Schizophrenia Spectrum and Other Psychotic Disorders.

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Conflict of interest statement

Drs. Tiihonen, Tanskanen, and Taipale have participated in research projects funded by grants to their employing institution from Janssen-Cilag and Eli Lilly. Dr. Tiihonen has served as a consultant for or received honoraria or lecture fees from HLS Therapeutics, Janssen, Lundbeck, Orion, Otsuka, and WebMed Global. Dr. Solmi has served as a consultant for AbbVie, Angelini, Boehringer Ingelheim, Lundbeck, and Otsuka. Dr. Rubio has served as a consultant or adviser for or received honoraria from Janssen, Karuna, and TEVA, and he has received grant support from Alkermes and Neurocrine and royalties from UpToDate. Dr. Correll has served as a consultant and/or adviser to or received honoraria from AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, Intra-Cellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, Medincell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris; he has provided expert testimony for Janssen and Otsuka; he has served on data safety monitoring boards for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; he has received grant support from Janssen and Takeda; he receives royalties from UpToDate; and he holds stock options in Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. Dr. Kane has served as a consultant and/or adviser for or received honoraria from Alkermes, Biogen, Boehringer-Ingelheim, Bristol Meyers Squibb, Cerevel, Click Therapies, Dainippon Sumitomo, HLS, Intra-Cellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, Merck, Neurocrine, Newron, Otsuka, Saladax, Sumitomo Pharma America, Sunovion, Takeda, and Teva; he has received grant support from Janssen, Lundbeck, Merck, and Otsuka; and he is a shareholder in Cerevel, Karuna, LB Pharma, Health Rhythms, North Shore Therapeutics, and Vanguard Research Group. Dr. Taipale has received personal fees from Gedeon Richter, Janssen, Lundbeck, and Otsuka.

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