Antipsychotics, old and new varieties, are effective against positive symptoms such as hallucination and delusions, but are often
of limited value in treating core features of schizophrenia particularly negative symptoms. Developments of new drugs based on current
dogmas have produced similar drugs with no breakthroughs in effectiveness. New knowledge as to which mechanisms are responsible
for symptom productions and treatment is needed.
There is evidence that response may improve when antipsychotics are augmented with selective serotonin reuptake inhibitor (SSRI). This
augmenting effect cannot be explained by summating pharmacological effects of the individual drugs. In a series of laboratory and clinical
studies, we identified unique biochemical effects of the SSRI-Antipsychotic combination, different from each individual drug and
suggested that some of these may mediate the clinical effect. In this paper, we review these studies and propose that modulation of the
gamma-aminobutyric acid (GABA)-A receptor and its regulating system is the mechanism by which SSRI antipsychotic synergism exerts
its clinical efficacy.