“…The literature includes a large number of naturalistic studies and overall it suggests that there is some brain volume loss over time both in medicated and in unmedicated patients with schizophrenia (Ahmed et al, 2015; Andreasen et al, 2013; Baaré et al, 2001; Boonstra et al, 2011; Chaves et al, 2015; Gur et al, 1998; Ho et al, 2003b; Hu et al, 2020; Kraguljac et al, 2019; Kubota et al, 2015; Li et al, 2019; Lin et al, 2019; Lyall et al, 2021; Narr et al, 2005, Van Haren et al, 2011; Veijola et al, 2014; Vita et al, 2012; Xiao et al, 2018). An important problem in the interpretation of findings is that a significant number of patients with schizophrenia are complete or partially treatment resistance already since the first episode (Demjaha et al, 2017), while the natural history of the disease is highly heterogeneous (Ciompi, 1980; Dragioti et al, 2017; Fountoulakis et al, 2019, 2021a,b). Duration of untreated psychosis seems to have an adverse impact also (Correll et al, 2018; Howes et al, 2021).…”