Antipsychotics, brain morphology and duration of untreated illness in schizophrenia

Aims: This thesis addresses the necessity of prophylactic antipsychotic treatment in first-episode schizophrenia patients and the effect of discontinuation of antipsychotics on brain volume and side-effects as well as the usage of these medications in general practice. Furthermore, the influence of the delay of antipsychotic treatment during the prodromal and psychotic phase of schizophrenia on brain volume and outcome in first-episode schizophrenia patients was researched and discussed. Methods and results: Chapter 2 describes a study in which remitted first-episode schizophrenia patients were randomised to discontinuation, or continuation of their antipsychotic treatment. These patients had been clinically stable for at least one year before participation. Additionally a pooled analysis was performed of this and one other study that researched randomised discontinuation in comparable schizophrenia patients. We found a markedly increased risk of a psychotic relapse after gradual discontinuation of antipsychotic medication in these first-episode schizophrenia patients compared to continuation. In Chapter 3 we studied the effect of discontinuation of atypical antipsychotic medication on brain volume change during a one-year interval in remitted and stable first-episode schizophrenia patients. Patients discontinuing atypical antipsychotics decreased in nucleus accumbens and putamen volume over time, but did not change in gray matter volume or any other global brain volume measure compared to continuation. Chapter 4 describes the decrease in body mass index found after discontinuing antipsychotics, while no decrease in extrapyramidal symptoms was identified. In Chapter 5 we investigated the association between duration of untreated illness (DUI), 5-year brain volume change, and clinical outcome at 5-year follow-up in first-episode schizophrenia patients. Mainly, we found no association between DUI and volume change during the first five years of psychotic illness. We did identify correlations of symptom scores after 5-year follow-up with both DUI and brain volume (change). In Chapter 6 a case control study in an electronic database is described, in which initiation of antipsychotic therapy in the general practice was associated to seven International Classification of Primary Care (ICPC) diagnostic categories. We found that general practitioners did not often initiate antipsychotic therapy and in 50% they failed to register the reason for it in terms of an ICPC-code. Initiation of antipsychotics was associated with four ICPC diagnostic categories that are no approved indications for antipsychotic treatment in The Netherlands. GPs mainly prescribed typical antipsychotics, however the incidence of initiating treatment with atypical antipsychotics increased almost threefold over the study period. Conclusions: It appears that the markedly increased risk of relapse after discontinuation of antipsychotic therapy in remitted and stable first-episode schizophrenia patients may not outweigh the advantages of medication discontinuation. Identified advantages are weight loss and possible reversal of atypical antipsychotic-induced putamen and nucleus accumbens increase. Furthermore, the gray matter deficits identified in schizophrenia patients appear to be unrelated to medication. In schizophrenia it seems that excessive tissue loss over time during the first five years of the illness and DUI explain a different part of the variation in symptomatic and functional outcome. Additionally, general practitioners seem to prescribe antipsychotics off-label in part of their patients