There is a wealth of evidence that various neuropeptides and their receptor ligands modulate schizophrenia-
related behaviors in preclinical animal models, suggesting that neuropeptide systems may represent potential
novel therapeutic targets for the treatment of schizophrenia. In particular, neurotensin and tachykinins have
been the subject of significant research efforts, generating compelling preclinical data in the schizophrenia field.
However, clinical studies with notably selective tachykinin NK3 receptor antagonists in schizophrenia have been
disappointing, and they were unable to confirm the promising therapeutic potential from animal studies, thereby
questioning the therapeutic utility of these compounds for this condition. This article reviews preclinical and clinical
findings on ligands for neurotensin and tachykinin receptors in schizophrenia, and provides possible explanations
for the failure so far to develop small-molecule neuropeptide ligands for the treatment of schizophrenia.