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Importance: Schizophrenia is a leading cause of disability worldwide, with an illness course that putatively deteriorates over time. Whether the notion of a progressive brain disease holds in its chronic stage is debated. Objective: To investigate brain volume change and the impact of iatrogenic factors in chronic schizophrenia patients (duration of illness at baseline 16.17 ± 8.14 years) and controls over 13 years. Design: Participants were recruited as part of the Human Brain Informatics study. Data acquisition took place between 1999 and 2018, including baseline, 5- and 13-years follow-up. Setting: Naturalistic longitudinal case-control study. Participants: The sample consisted of 143 participants, of whom 64 were patients with chronic schizophrenia (20% female, mean age at baseline 40.5 ± 7.7 years) and 79 healthy controls (37% female, mean age at baseline 42.8 ± 8.4 years). T1-weighted structural imaging and information about medication use were obtained at each time point. Exposure: Antipsychotic medication and other prescribed drugs. Main Outcome(s) and Measure(s): Individual total and tissue-specific brain volumes, as well as two-time point percentage brain and ventricle volume change. Results: Patients had lower total brain volume at baseline. Yet, trajectories in total brain volume and gray matter volume loss as well as ventricular enlargement did not differ relative to controls. White matter volume was similar between groups at baseline and 5-year but diverged between 5-year and 13-year follow-up, with accelerated loss in patients. While antipsychotic exposure did not show an association with brain volume loss over time, higher medication load was associated with lower brain volume across time points. Patients on second-generation antipsychotics alone showed lowest total brain volume, only after accounting for add-on drug use. Conclusion and Relevance: We found limited evidence for progressive brain volume loss in chronic schizophrenia, beyond normal aging. Stable differences in patient brain volumes relative to controls may primarily occur during the first years of illness. All prescribed drugs need to be considered when examining the impact of antipsychotic medication on brain structure.
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