Confounding effects of antipsychotics

As discussed by Navari & Dazzan (Reference Navari and Dazzan2009), the potential confounding impact of antipsychotics on progressive brain changes in schizophrenia is considered controversial (DeLisi, Reference DeLisi2008). Although there is evidence for GM loss and ventricular enlargement from prospective studies of patients with first-episode and chronic schizophrenia (Wood et al. Reference Wood, Pantelis, Velakoulis, Yucel, Fornito and McGorry2008), most neuroimaging studies of schizophrenia to date have not included the examination of non-medicated patients, making conclusions about medication effects on neuroimaging measures difficult. Investigation of subjects at the onset of the disease avoids potential confounders such as antipsychotic treatment (Riecher-Rossler et al. Reference Riecher-Rossler, Gschwandtner, Aston, Borgwardt, Drewe, Fuhr, Pfluger, Radu, Schindler and Stieglitz2007). A clinical high-risk status for psychosis (at-risk mental state, ARMS) is associated with a set of neurofunctional abnormalities that are qualitatively similar to those observed in patients with the disorder (Fusar-Poli et al. Reference Fusar-Poli, Perez, Broome, Borgwardt, Placentino, Caverzasi, Cortesi, Veggiotti, Politi, Barale and McGuire2007). As these findings are not attributable to chronic psychotic symptoms or antipsychotic treatment, they may solely represent markers of increased vulnerability to psychotic disorders. Cross-sectional structural MRI studies of non-medicated patients in a prodromal phase of psychosis or ARMS demonstrated that neuroanatomical abnormalities are already evident in the very early phase of psychosis (Wood et al. Reference Wood, Pantelis, Velakoulis, Yucel, Fornito and McGorry2008) whereas longitudinal MRI studies found that the subset of patients who developed psychosis showed a longitudinal reduction in GM in the orbito-frontal, temporal lobe, parietal lobe and cerebellum (Pantelis et al. Reference Pantelis, Velakoulis, McGorry, Wood, Suckling, Phillips, Yung, Bullmore, Brewer, Soulsby, Desmond and McGuire2003; Job et al. Reference Job, Whalley, Johnstone and Lawrie2005; Borgwardt et al. Reference Borgwardt, McGuire, Aston, Gschwandtner, Pfluger, Stieglitz, Radue and Riecher-Rossler2008).

Conclusions and future directions

Neuroimaging studies have provided compelling evidence that despite antipsychotic medication (both typical and atypical) there are detectable anatomical changes at the level of total and regional brain volumes. To date, it remains elusive whether the effects of antipsychotic medication on GM volume are simply beneficial. Experimental studies of macaque monkeys showed that chronic administration of either haloperidol or olanzapine was associated with smaller GM volume (Konopaske et al. Reference Konopaske, Dorph-Petersen, Sweet, Pierri, Zhang, Sampson and Lewis2008). These results, if confirmed, raise ethical questions on antipsychotic use. If antipsychotic medication may lead – at least in some patients – to GM volume reduction careful benefit–risk decisions have to be made for individual patients. Patients with schizophrenia should be very carefully informed about the potential risks (and of course benefits) of antipsychotic medication.

It is questionable whether the effects we are observing are the direct effects of antipsychotics or due to the illness process. Until we have more reliable studies from non-medicated patients, the potential impact of the confounding effect of medication must be borne in mind. For future studies, we therefore suggest focusing on longitudinal designs that represent the gold standard for investigation of medication effects. These studies clearly have the advantage of powerful, within-subject designs. Small sample sizes, heterogeneity in the sociodemographic characteristics of subjects, and lack of consistency between scanning parameters should be addressed by future multi-site studies that have shown the potential to overcome most of these problems and to bridge basic neuroscience with clinical psychiatry. So far, the investigation of patients at risk or with a first episode of schizophrenia seems to be the most promising alternative.