Hashimoto’s thyroiditis has been associated with major depression (MD) and schizophrenia (Sz) in epidemiological studies. However, diagnostically relevant antibodies (Abs) against thyroid peroxidase (TPO) and thyroglobulin (Tg) do not act directly on neurons. We hypothesized that an increased prevalence of anti-brain-Abs in thyroid-Ab-carriers could be linked with MD and Sz even without clinically manifest Hashimoto’s thyroiditis. Serum samples from 638 acutely-ill patients with MD, Sz or matched controls were systematically screened for TPO- and Tg-Abs, other endocrine-Abs and a spectrum of specific brain antigens (neuronal cell surface, synaptic, other neuronal or glial proteins). Analyses were based on indirect immunofluorescence in biochip mosaics of frozen tissue sections and transfected HEK293 cells expressing respective recombinant target antigens. Psychopathology was assessed on admission and after 6 weeks treatment by HAMD-21 (in MD) or PANSS (in Sz). Seroprevalence of TPO- and/or Tg-Abs was comparable in ill and healthy individuals (MD ∼10%, Sz ∼7%, controls ∼9%) but thyroid-Abs were associated with neuronal cell surface/synaptic-Abs (p=0.005), particularly in schizophrenia. Thyroid Ab-positive MD patients showed higher HAMD-21 scores (particularly somatic symptoms) at baseline (p=0.026) and better reduction of symptoms after 6 weeks (p=0.049) than thyroid-Ab-negative patients. This was unrelated to antidepressant drug dosage, thyroid hormonal-, inflammation- and anti-brain-Ab-status. No link with PANSS scores was observed in Sz. In conclusion, the co-occurrence of thyroid-Abs and neuronal surface/synaptic-Abs may be associated with Sz. Future cerebrospinal fluid research may be promising to clarify if thyroid-Ab-associated neuronal-Abs reach the brain in Sz patients. Thyroid-Ab-related differences regarding disease-severity and -course in MD are currently unexplained, but may be caused by un-identified anti-brain-Abs or a direct action of TPO-Abs on astrocytes.Copyright © 2020 Elsevier Inc. All rights reserved.