For over 20 years, studies have tried to measure the association between the duration of untreated psychosis (DUP) and changes in brain morphology. A hypothesis that untreated psychosis is neurotoxic has been postulated, but the mechanisms of that toxicity have not been described. We re-analyzed papers collected for a systematic review to extract data on the hypotheses that have been generated on the potential mechanisms by which DUP could impact brain morphology in first-episode psychosis. Dopaminergic hyperactivity, prolonged hypothalamic-pituitary-adrenal activation, and persistent activity of catecholamines have been hypothesized as mechanisms to explain these associations. However, the question remains as to whether the observed structural changes are permanent or may be reversed via antipsychotic treatment.