The premorbid phase of treatment-resistant schizophrenia (TRS) may reveal underlying mechanisms and inform early interventions. According to the neurodevelopmental hypothesis, treatment resistance may be linked to pronounced developmental impairments. We examined school grades and attendance trajectories in children who later developed TRS.

This case-control study analyzed school grade point average and attendance among all individuals born after 1990 and started on clozapine in Chile’s public health system as a proxy for TRS. Control groups included children later diagnosed with treatment-responsive schizophrenia, bipolar disorder, and unaffected classmates. Linear mixed models accounted for individual and school-level confounders.

We included 1072 children (9929 observations, 29.3% female) subsequently diagnosed with TRS, 323 (2802 observations, 25.7% female) with schizophrenia, 175 (1784 observations, 53.8% female) bipolar disorder, and 273,260 (533,335 observations, 47% female) unaffected classmates. Children who later developed TRS had worse grades across levels than their classmates (−0.26 SD [−0.2, −0.4]), but not treatment-responsive schizophrenia. All severe mental illness groups showed grade declines in later school levels, with TRS showing steeper linear decline than treatment-responsive schizophrenia (group×age of −0.03; 95%CI −0.04, −0.01) and steeper quadratic decline than bipolar disorder (group×age2 of −0.005; −0.01, −0.001). Attendance declined over time in the two groups developing schizophrenia compared to their classmates. Those developing TRS experienced the sharpest drop (group×age compared to schizophrenia −0.03; −0.05, −0.01 and bipolar disorder −0.027; −0.049, −0.006).

TRS may stem from a more aggressive pathological process or pronounced late-maturation abnormality, rather than an early premorbid impairment, suggesting an intervention target.