Real-world effectiveness of antipsychotic treatment of functional outcomes over 10 years: A national cohort of patients in Denmark with schizophrenia

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Abstract
Background: Antipsychotic medications are recommended for schizophrenia spectrum disorders, yet their long-term effects on functional recovery remain unclear, with conflicting evidence often derived from between-subject comparisons vulnerable to confounding by indication. Methods: We conducted a nationwide register-based cohort study of 65,630 individuals with incident schizophrenia spectrum disorders in Denmark (1998–2023). We modeled antipsychotic exposure against ‘productive engagement’ (employment or education). We used two analytical approaches: (1) within-subject stratified Cox models with time-varying covariates to eliminate time-invariant confounding; and (2) Fine–Gray competing risks models with baseline exposure, accounting for mortality and emigration. Results: Over 26.9 million person-weeks, the overall productive engagement rate was 48.2%. Integration of hospital pharmacy data revealed 6.1% exposure misclassification in studies relying solely on community records. The primary within-subject analysis revealed significant temporal heterogeneity: medication use was associated with reduced engagement rates in the acute (0–2 years; HR = 0.908) and consolidation phases (2–5 years; HR = 0.946), but reversed to a small positive association in the maintenance phase (5+ years; HR = 1.019). The between-subject Fine–Gray model, which estimates cumulative engagement probabilities, yielded an SHR of (95% CI = 0.988–1.015), a population-level average that obscured these phase-specific dynamics. Conclusions: Antipsychotic pharmacotherapy exerts a time-dependent, biphasic impact on vocational recovery. We identified a window of vulnerability during the post-acute ‘consolidation’ phase (years 2–5) where treatment is associated with a transient reduction in productive engagement, before becoming protective after 5 years. These findings challenge the assumption that symptomatic stability automatically facilitates functional reintegration. Danish Lay Summary: I denne undersøgelse har vi set på, hvordan personer kommer tilbage i arbejde eller uddannelse, efter de er startet i medicinsk behandling for skizofreni. Formålet er at forstå, om antipsykotisk medicin øger eller mindsker deres mulighed for at vende tilbage til arbejde eller uddannelse. Resultaterne peger på et udviklingsforløb, som kan forklares i tre faser: De første 2 år har en person i medicinsk behandling 9 % lavere sandsynlighed for at være i arbejde eller uddannelse, sammenlignet med perioder hvor personen er uden behandling. Efter 2–5 år bliver forskellen mindre (omkring 5 %). Medicinen forsinker stadig tilbagevenden til arbejdsmarkedet eller uddannelse, men i mindre grad end før. Efter 5–10 år vender billedet. Her ses en tendens til, at flere som får medicinsk behandling er i arbejde eller uddannelse. Effekten er lille, men den går i en positiv retning. På kort sigt kan antipsykotisk medicin begrænse muligheden for arbejde eller uddannelse. På længere sigt kan medicinen give den stabilitet, der gør det lettere at fastholde eller vende tilbage til arbejde eller uddannelse.
Funding Information
  • Danmarks Nationalbank
  • Margaret Temple, King’s Challenge Fund, and Wellcome Trust (094849/Z/10/Z)
  • Margaret Temple, King’s Challenge Fund, and Wellcome Trust (227867/Z/23/Z)

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