Growing consistent evidence indicates that hypofunction of
N-methyl-D-aspartate (
NMDA) transmission plays a pivotal role in the neuropathophysiology of
schizophrenia. Hence, drugs which modulate
NMDA neurotransmission are promising approaches to the treatment of
schizophrenia. The aim of this article is to review clinical trials with novel compounds acting on the
NMDA receptor (
NMDA-R). This review also includes a discussion and translation of neuroscience into
schizophrenia therapeutics. Although the precise mechanism of action of
minocycline in the brain remains unclear, there is evidence that it blocks the neurotoxicity of
NMDA antagonists and may exert a differential effect on
NMDA signaling pathways. We, therefore, hypothesize that the effects of
minocycline on the brain may be partially modulated by the
NMDA-R or related mechanisms. Thus, we have included a review of
minocycline neuroscience. The search was performed in the PubMed, Web of Science, SciELO, and Lilacs databases. The results of
glycine and D-
cycloserine trials were conflicting regarding effectiveness on the negative and
cognitive symptoms of
schizophrenia. D-
serine and D-
alanine showed a potential effect on negative symptoms and on cognitive deficits.
Sarcosine data indicated a considerable improvement as adjunctive
therapy. Finally,
minocycline add-on treatment appears to be effective on a broad range of psychopathology in patients with
schizophrenia. The differential modulation of
NMDA-R neurosystems, in particular synaptic versus extrasynaptic
NMDA-R activation and specific subtypes of
NMDA-R, may be the key mediators of neurogenesis and neuroprotection. Thus, psychotropics modulating
NMDA-R neurotransmission may represent future monotherapy or add-on treatment strategies in the treatment of
schizophrenia.