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Progressive loss of brain gray matter (GM) has been reported in childhood-onset schizophrenia; however, it is uncertain whether these changes are shared by pediatric patients with different psychoses.To examine the progression of brain changes in first-episode early-onset psychosis and their relationship to diagnosis and prognosis at 2-year follow-up.Prospective, multicenter, naturalistic, 2-year follow-up study.Six child and adolescent psychiatric units in Spain.A total of 110 patients and 98 healthy controls were recruited between March 1, 2003, and November 31, 2005. Magnetic resonance imaging of the brain was performed for 61 patients with schizophrenia (n = 25), bipolar disorder (n = 16), or other psychoses (n = 20) and 70 controls (both at baseline and after 2 years of follow-up). Mean age at baseline was 15.5 years (patients) and 15.3 years (controls).The GM and cerebrospinal fluid (CSF) volumes in the total brain and frontal, parietal, and temporal lobes.Compared with controls, patients with schizophrenia showed greater GM volume loss in the frontal lobe during the 2-year follow-up (left: −3.3 vs −0.6 cm3, P = .004; right: −3.7 vs −0.8 cm3, P = .005) and left frontal CSF volume increase (left: 6.7 vs 2.4 cm3, P = .006). In addition to frontal volume, changes for total GM (−37.1 vs −14.5 cm3, P = .001) and left parietal GM (−4.3 vs −2.2 cm3, P = .04) were significantly different in schizophrenic patients compared with controls. No significant differences emerged for patients with bipolar disease. Greater left frontal GM volume loss was related to more weeks of hospitalization, whereas severity of negative symptoms correlated with CSF increase in patients with schizophrenia.Patients with schizophrenia or other psychoses showed greater loss of GM volume and increase of CSF in the frontal lobe relative to controls. Progressive changes were more evident in patients with schizophrenia than those with bipolar disorder. These changes in specific brain volumes after onset of psychotic symptoms may be related to markers of poorer prognosis.