BACKGROUND: Psychosis is a devastating psychiatric condition that consists of abnormal thinking and perceptions. In the majority of adult psychotic illnesses, a cause is neither sought nor identified, despite mounting reports describing autoimmune and inherited metabolic disorders that cause psychosis. Established and emerging therapies in many of these diseases can improve the overall treatment outcome, especially when initiated early. Niemann-Pick disease type C is one of the inborn errors of metabolism that can present with psychosis in adulthood and can go undetected for many years. The measurement of the plasma cholestane-3Î²,5Î±,6Î²-triol levels is a recently discovered reliable and cost-effective method for detecting Niemann-Pick disease type C cases. Whereas the levels of the enzymatically formed oxysterols are understandably affected by medication that interferes with the cytochrome P450 enzymes, it is not known if the levels of the non-enzymatically formed oxysterols, such as the cholestane-3Î²,5Î±,6Î²-triol, are modified by medication like antipsychotics. HYPOTHESIS: Firstly, we hypothesised that the occurrence of autoimmune and inherited metabolic causes of psychosis is greater than clinicians currently believe, and secondly, that the cholestane-3Î²,5Î±,6Î²-triol test utilised in detecting Niemann-Pick disease type C is affected by antipsychotic usage. OBJECTIVES: The primary study aim was to establish the prevalence of several autoimmune disorders (systemic lupus erythematosus, Hashimoto encephalitis, encephalitis due to N-methyl-D-aspartate receptor antibodies, voltage-gated potassium channel antibodies and glutamic acid decarboxylase antibodies) and inborn errors of metabolism (Niemann-Pick disease type C, adrenoleukodystrophy, Wilson disease, metachromatic leukodystrophy, Î±-mannosidosis, Fabry disease, Gaucher disease, GM2-gangliosidosis, homocystinuria and other amino acid disorders) in patients with psychosis admitted to a psychiatric unit. The secondary aim of the study was to determine whether the antipsychotics affect the oxysterol testâs utility in detecting Niemann-Pick disease type C cases. METHODS: This observational, cross-sectional study had 2 arms: The Screening Tests and The Oxysterol Assay. We performed several blood tests and neurological examination in 93 patients with psychosis recruited to The Screening Tests, and we measured the cholestane-3Î²,5Î±,6Î²-triol levels in 194 patients recruited to The Oxysterol Assay. Data regarding antipsychotic use, and possible confounders, including age, gender, BMI, statin use, smoking, and psychosis, were collected for The Oxysterol Assay. The analysis for The Screening Tests was performed using Excel and for The Oxysterol Assay using SPSS. RESULTS: Fifteen patients out of 93 (16.1%) had significantly abnormal autoimmune and metabolic results. However, no positive diagnosis of an autoimmune or inherited metabolic disorder was made to date, as tests to confirm the diagnoses were not included in the study. We found that the antipsychotic medication does not alter the cholestane-3Î²,5Î±,6Î²-triolâ utility as a detecting tool in Niemann-Pick disease type C. Our study showed, for the first time, a statistically significant (p=0.005) positive correlation between age and the cholestane-3Î²,5Î±,6Î²-triol levels: they increase by 0.141 + 0.049 ng/ml with every year (95% CI 0.044 - 0.238). The presence of conditions that have an overpowering effect on the cholestane-3Î²,5Î±,6Î²-triol levels, such as Niemann-Pick disease type C or hepatic disease, possibly shadowed the age impact in previous studies. CONCLUSIONS: Further research to establish the prevalence of organic causes of psychosis is still needed and, based on our findings, researchers can now estimate more precisely the funding required to answer this crucial question. The cholestane-3Î²,5Î±,6Î²-triol tool to detect Niemann-Pick disease type C can be reliably used in patients who receive antipsychotics. We welcome further investigation on the age-dependence mechanism of the cholestane-3Î²,5Î±,6Î²-triol levels.