Advances in the understanding and challenges facing the management of first-episode schizophrenia

Abstract

Symptoms of schizophrenia typically first appear in adolescence, a time of transition involving biological, social and emotional changes. Schizophrenia and related psychotic illnesses can significantly impair educational and social development; consequently, early identification and treatment is paramount and can affect long-term outcome. Singh (2010) states that early intervention is cost effective and does ameliorate the course of early psychosis, referring specifically to specialist early intervention teams, and their impact on longterm disease outcome and prognosis. Much research is now available in this area, and the papers selected for this supplement focus on intervention at this critical stage, related side effects as well as mortality risk factors associated with schizophrenia. The stress–vulnerability model for schizophrenia suggests that the onset and course of schizophrenia may be determined by an underlying vulnerability, with clinical manifestation being modulated by environmental stressors. It has long been recognized, since the days of Kraepelin (1913), that people with schizophrenia are more likely to be obese and to suffer from metabolic problems such as diabetes mellitus. Leonard et al. review evidence concerning a disordered immune system in schizophrenia and postulate that the relationship between the therapeutic benefits of antipsychotics, the pathology of schizophrenia and these metabolic syndromes are linked to chronic, low-grade inflammation. As maternal infections have been implicated as a causative factor, the resulting inflammatory changes could contribute to neurodevelopmental difficulties, and a sensitized immune system that activates in adolescence. Leonard et al. also discuss the important role played by pro-inflammatory cytokines which modulate neuronal action, differentiation and survival during neurodevelopment, and more specifically influence activity and survival of neurons that utilize neurotransmitters such as serotonin, glutamate and dopamine. Interleukin-6 is particularly important in schizophrenia as it could augment dopaminergic function which, in turn, would affect psychotic symptoms. In addition to the dopaminergic system, some pro-inflammatory cytokines enhance the activity of the glutamatergic system, via the tryptophan–kynurenine pathway, and this might contribute to the cognitive decline sometimes seen in schizophrenia. The inflammation hypothesis of schizophrenia raises the possibility of using anti-inflammatory drugs, such as COX-2 inhibitors, as adjuncts to traditional antipsychotic medication. Van Haren et al. find further evidence to suggest that schizophrenia is a progressive brain disease, and that the most significant decline in grey matter volume occurs in the critical first year of illness. Indeed, there appears to be a linear correlation of grey matter loss with age in schizophrenia, as opposed to the exponential decline seen in healthy individuals. Van Haren et al. also suggest there is a link between the extent of volume loss and severity of symptoms and social functioning, but do acknowledge other studies refute this theory. Although antipsychotic medication remains a confounding factor for grey matter loss, studies in first-degree relatives and at-risk individuals show that cumulative antipsychotic intake can only explain some of these brain volume changes. This review highlights the need for further large studies that follow patients over a long period of time, to further clarify the relationship between brain volume change, antipsychotic intake and outcome. Indeed, the potential to attenuate brain volume changes could potentially improve long-term outcome, which again highlights the need for early intervention and effective treatment in this morbid disease. The advent of ‘atypical’, or second generation antipsychotics, engendered a therapeutic optimism in the treatment of first-episode patients (NICE, 2002). Taylor et al. reviewed the effectiveness of antipsychotic medications in first episode schizophrenia and found traditional randomized controlled trials (RCTs), whilst being necessary, lacked generalizability to real-world clinical scenarios. A need for long-term observational studies to complement the RCTs was recognized, and several high-profile studies have now been published, often using discontinuation rate of antipsychotic medication as the primary outcome. The rationale behind this is that a