Abstract
It is evident that once psychosis is present in patients with schizophrenia, the underlying biological process of the illness has already been ongoing for many years. At the time of diagnosis, patients with schizophrenia show decreased mean intracranial volume (ICV) as compared with healthy subjects. Since ICV is driven by brain growth, which reaches its maximum size at approximately 13 years of age, this finding suggests that brain development in patients with schizophrenia is stunted before that age. The smaller brain volume is expressed as decrements in both grey and white matter. After diagnosis, it is mainly the grey matter loss that progresses over time whereas white matter deficits are stable or may even improve over the course of the illness. To understand the possible causes of the brain changes in the first phase of schizophrenia, evidence from treatment studies, postmortem and neuroimaging investigations together with animal experiments needs to be incorporated. These data suggest that the pathophysiology of schizophrenia is multifactorial. Increased striatal dopamine synthesis is already evident before the time of diagnosis, starting during the at-risk mental state, and increases during the onset of frank psychosis. Cognitive impairment and negative symptoms may, in turn, result from other abnormalities, such as NMDA receptor hypofunction and low-grade inflammation of the brain. The latter two dysfunctions probably antedate increased dopamine synthesis by many years, reflecting the much earlier presence of cognitive and social dysfunction. Although correction of the hyperdopaminergic state with antipsychotic agents is generally effective in patients with a first-episode psychosis, the effects of treatments to correct NMDA receptor hypofunction or low-grade inflammation are (so far) rather modest at best. Improved efficacy of these interventions can be expected when they are applied at the onset of cognitive and social dysfunction, rather than at the onset of psychosis.
Highlights
When does schizophrenia first manifest itself? Is it at the onset of the first psychosis? Is it at the first signs of psychosis, as in the group of patients referred to as ‘at-risk mental state’ (ARMS)? Or is it even earlier, and not primarily associated with psychosis, but with cognitive decline? This question is essential to address the biology of first-episode schizophrenia, but it is at the core of the schizophrenia concept itself
It is evident that once psychosis is present in patients with schizophrenia, the underlying biological process of the illness has already been ongoing for many years
Poor function of the N-methyl-Daspartate receptor (NMDAr), in turn, renders the gamma-amino-buteric-acid (GABA)ergic interneuron less effective. This loss of GABA-ergic firing provides insufficient inhibition of the secondary glutamatergic neurons, allowing them to fire more often but with less synchrony, directly causing the excessive firing of DA neurons in the mesolimbic pathway.[44]. This hypothesis is based on studies using NMDAr antagonists, such as ketamine and phencyclidine, which were found to induce the full range of schizophrenia symptoms, including psychosis, negative symptoms, and cognitive dysfunction.[45]
Summary
Poor function of the NMDAr, in turn, renders the gamma-amino-buteric-acid (GABA)ergic interneuron less effective This loss of GABA-ergic firing provides insufficient inhibition of the secondary glutamatergic neurons, allowing them to fire more often but with less synchrony, directly causing the excessive firing of DA neurons in the mesolimbic pathway.[44] This hypothesis is based on studies using NMDAr antagonists, such as ketamine and phencyclidine, which were found to induce the full range of schizophrenia symptoms, including psychosis, negative symptoms, and cognitive dysfunction.[45] patients with an autoimmune encephalitis producing antibodies against the NMDAr can have a clinical picture that is indistinguishable from schizophrenia.[46] many of the well-known risk genes, such as DISC-1, dysbindin, SHANK and NRG-1,47,48 and de novo mutations[49] associated with schizophrenia influence glutamatergic neurotransmission. 20 UHR, 14 HCa ((11)C)-labelled raclopride PET PET (18)F-DOPA PET (18)F-DOPA PET (18)F-DOPA PET [11C]-(+)-PHNO
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