The long-term effect of schizophrenia on the brain: dementia praecox?

Kraepelin’s use of the term “dementia praecox” for the condition we now know as schizophrenia encouraged the view that his patients had a progressive decline in behavioral function associated with (and probably caused by) progressive changes in brain anatomy and function over the course of illness. This viewwas challenged first by the failure of early postmortemhistopathology studies to identify gross anatomic changes. Later, it was challenged by models proposing that neurodevelopmental alterations caused the disorder and that the primary diseaserelateddamage tobrain organizationwas largely inplace at illness onset. Enthusiasm for “progressive” and “neurodevelopmental”models has varied over time and across countries (1), and establishing the validity of these models and their mechanisms remains one of the major challenges of schizophrenia research. Interest in demonstrating and establishing the mechanisms for progressive disease was an important reason for several schizophrenia programs to start longitudinal studies, including MRI protocols, of “first-episode” schizophrenia more than two decades ago. In brief, they hoped to identify progressive encephalopathy that might explain a decline in function. These were very challenging studies. The 202 patients reported by Andreasen et al. in this issue (2) were recruited over 18 years and underwent scanning on average three times. Additional challenges in these studies were maintaining patients’ study participation and keeping funding and investigative teams together over long follow-up periods. That 67% of the patients in this study remained involved over so long a period represents a remarkable achievement. Theprimary focus of theAndreasen et al. study is on clinical associations of atrophic anatomic changeswith duration of persistent psychosis and intensity of antipsychotic treatment. Regional hypermetabolic activity during acute psychosis (3) and glutamate excitotoxicity (4, 5) represent potential mechanisms for a neurotoxicity of psychosis. Indirect evidence suggests that antipsychotic medications may have adverse effects on brain anatomy and function. Persistent adverse effects of antipsychotics on some cognitive processes supported by frontostriatal brain systems are well established in preclinical models (6). Studies using similar cognitive paradigms with schizophrenia patients show similar adverse effects (7). Reduced prefrontal connectivity in resting-state fMRI studies has also been demonstrated after initiation of antipsychotic treatment (8). Thus, evidence for potential adverse effects of antipsychotics outside the domain of motor systems has grown in recent years. The greatest reason for concern about adverse neuroanatomic effects of antipsychotic treatment stems from data showing a robust reduction in brain volume in monkeys treated with clinically relevant dosages of conventional and atypical antipsychotics (9). This remains a troubling observation on clinical grounds given the lack of therapeutic alternatives to antipsychotics. Patients with recurring psychosis may experience cumulative, persistent atrophic brain changes