Brain derived neurotrophic factor (BDNF) is reduced in schizophrenia, and this may lead to deleterious down stream consequences as activation of the BDNF-TrkB pathway enhances differentiation of non-pyramidal neurons. BDNF expression is controlled by multiple 5’ promoters which interact with environmental triggers to regulate the amount and the type of BDNF mRNA synthesized. We found widespread cortical reductions in BDNF and/or trkB mRNAs in non-psychotic depression, bipolar disorder and schizophrenia. In the hippocampus, BDNF mRNA levels are decreased in all subfields in schizophrenia and bipolar disorder. TrkB mRNA levels were decreased in all subfields in the schizophrenia and bipolar disorder groups [CA4 (p=0.03)]. Interestingly, ANOVA comparing patients on antidepressants at time of death (N=23), patients free of antidepressants at time of death (N=22), and normal controls (n=15), revealed a significant decrease in both BDNF and TrkB mRNA, in frontal cortex and in hippocampus, in those patients not taking antidepressants as compared to controls. The reduction of BDNF in patients involves transcription from the same promoter that can be induced by antidepressants. Expression from the antidepressant-responsive BDNF gene promoter shuttles BDNF mRNA to dendrites to support the differentiation of dendrite-targeting inhibitory neurons. Correlative evidence suggests that there is a strong relationship between the amount of BDNF and amount of inhibitory neuron markers expressed in brains of the psychiatrically ill. Thus, the present findings demonstrate that the BDNF reduction in mental illness may lead to reduction in inhibitory tone and that these BDNF reductions may be reversed with antidepressant medications.