Questions about medication and episode effects on brain anatomy were addressed using statistical approaches that controlled for some factors using regression approaches while testing for effects of factors of interest. This approach is relatively straightforward when factors are independent, but when they are correlated, as illness severity and drug dosage are, causal inferences are less certain. It is hard to fully confirm whether sicker patients with greater brain abnormalities receive more medication (and thus the causes of anatomic changes precede or even lead indirectly to higher drug dosages), or whether brain atrophy reflects a pharmacological effect of antipsychotic drugs. The authors recognize this issue, but it is an important caveat. Other statistical issues include potential nonlinearities in the relationships of interest, such that, for example, drug dosage may be associated with brain volume reductions primarily at higher dosages or with longer relapse durations. Another question is whether a subgroup of individuals, perhaps defined by genetic or epigenetic factors, are more likely to show atrophic changes in relation to relapse duration or drug treatment intensity.