Background: The initial prodromal state of psychosis (IPS) is defined as an early disease stage prior to the onset of overt psychosis characterized by sub-threshold or more unspecific psychiatric symptoms. Little is known regarding the biochemical changes during this period. Methodology/Principal Findings: We investigated the metabolic/proteomic profiles of cerebrospinal fluid (CSF) of first onset drug naïve paranoid schizophrenía patients (n=54) and individuals presenting with initial prodromal symptoms (n=24), alongside healthy volunteers (n=70) using proton nuclear magnetic resonance (1H-NMR) spectroscopy and surface enhanced laser desorption ionization (SELDI) mass spectrometry, respectively. Partial least square discriminant analysis (PLS-DA) showed that 36%/29% of IPS patients displayed proteomic/metabolic profiles characteristic of first-onset, drug naïve schizophrenia, i.e., changes in levels of glucose and lactate as well as changes in a VGF-derived peptide (VGF23-62) and transthyretin protein concentrations. However, only 29% (n=7) of the investigated IPS patients (who to date have been followed up for up to three years) have so far received a diagnosis of schizophrenia, The presence of biochemical alterations in the IPS group did not correlate with the risk to develop schizophrenia. Conclusions/Significance: Our results imply that schizophrenia-related biochemical disease processes can be traced in CSF of prodromal patients. However, the biochemical disturbances identified in IPS patients, at least when measured at a single time point, may not be sufficient to predict clinical outcome.