Schizophrenia: What determines its clinical features and course?

Abstract

Despite more than a century of diagnosing and treating schizophrenia, it is still one of the leading health burdens in the world. Although much research effort in the past decades has led to great progress, there are still challenges in the understanding of this complex disorder. A large body of evidence implicates dysfunction of dopaminergic neurotransmission in the manifestation of positive psychotic symptoms such as hallucinations and delusions. Presynaptic striatal dopamine synthesis and release are consistently reported to be elevated in schizophrenia. Recent studies have also shown that clinical high-risk subjects with subthreshold psychotic symptoms who later developed psychosis have an elevation in presynaptic striatal dopamine synthesis capacity, suggesting that dopaminergic dysfunction is already occurring in the prodrome. Given that high-risk individuals have a wide variety of clinical outcomes, and only a small proportion develop schizophrenia, this finding seems promising for the rational designing of early intervention strategies. Dopaminergic dysfunction, however, is unlikely to explain the full range of clinical features of schizophrenia. Disturbed glutamatergic function may underlie some clinical features other than psychotic symptoms in schizophrenia. Hypofunction of N-methyl-D-aspartate (NMDA) receptors, which are located on parvalbumin-positive GABA interneurons, is hypothesized to be causative of diverse features of schizophrenia including cognitive dysfunction and negative symptoms, as reviewed by Uno and Coyle in this issue of the Journal. The challenge for the theories proposing a neurochemical basis, however, is to explain or to be reconciled with the longitudinal course of schizophrenia. Apart from the neurochemical alterations, schizophrenia is considered a neurodevelopmental disorder. Several structural changes in the brain considered to exist prior to onset have been reported in schizophrenia. Premorbid impairment in cognition is reported to manifest many years before the first psychotic episode. The neurodevelopmental hypothesis proposes that the effects of genetic predisposition and early environmental adverse events impair some of the crucial processes in early brain development. In addition to such initial insults, disturbance of brain maturational processes, including synaptic pruning and myelination during adolescence, might be critical in the manifestation of the first episode of psychosis. Gray matter loss reported to occur during psychosis onset may reflect such a disturbance. Although the precise mechanisms that cause aberrant brain maturation are unknown, an imbalance of excitatory and inhibitory neurons affected by oxidative stress is suggested, which could be a potential target for preventive intervention. Several clinical features of schizophrenia after onset, including relapse, development of treatment resistance, and deteriorating course to poor outcome, cannot be well captured by only the neurodevelopmental perspective. Progressive gray matter loss after onset in several brain regions suggests a neurodegenerative or neurotoxic mechanism, which could also be a potential target for therapeutic intervention to improve long-term outcome. In addition to this, the heterogeneity of pathophysiological mechanisms as well as the epiphenomena associated with several factors, including pharmacological treatment, should be fully taken into account for the further understanding of the determinants of the complex clinical features and course in schizophrenia.