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Abstract: Immune and inflammatory mechanisms are detected in a subgroup of treatment resistant hospitalized affective and schizophrenic spectrum disorder patients. We analysed albumin, IgG, IgA, IgM, oligoclonal IgG and specific antibodies in paired cerebrospinal fluid (CSF) and serum samples. Numerical and graphical interpretation of CSF protein data was performed by Reibergrams with a new CSF statistics tool for nonlinear group analysis with reference to a large control group (n =4100). In 41% of the psychiatric patients (n =63) we observed CSF pathologies: 14% displayed intrathecal humoral immune responses, 10% slightly increased CSF cell counts (5–8/μL) and 29% had moderate blood–CSF barrier dysfunctions, in 24% as the only pathological sign with normal IgG, IgA and IgM concentrations in CSF (p =0.9 testing the null hypothesis for intrathecal synthesis with reference to Qmean of the reference group). In the group of affective (n =24) spectrum disorders 20% displayed a systemic immune reaction as detected by oligoclonal IgG. CSF analysis and interdisciplinary clinical approach revealed 6% of psychiatric patients likely to represent a virusspecific, bacterial or autoimmune associated disorder with CNS involvement. Elevated CSF neopterin concentration in 34% of the patients was interpreted as an increased release from astrocytes or from other glia cells. The low level immune response and barrier dysfunctions are discussed on the base of a mild encephalitis pathomechanism in subgroups of psychiatric patients. CSF analysis is shown to be a useful diagnostic tool for differential diagnosis in psychiatric diseases. [Copyright &y& Elsevier]