Several pilot studies were conducted to test different hypotheses regarding the mechanism of action of antidepressant treatments. These were aimed at obtaining preliminary information regarding the potential usefulness of further pursuing these hypotheses. Several studies did indicate the importance of further investigation. These were related to biochemical changes elicited by the most effective antidepressant treatment, namely, electroconvulsive seizures: 1. Electroconvulsive seizures (ECS) caused a rapid and transient increase in the expression of the mRNA and protein for the a-4 subunit of the gama-butyric acid type-A (GABA-A) receptor system. Subcellular distribution studies of the protein strongly suggest that this particular subunit is very different from those thought to compose the well studied GABA-A receptor linked to chloride channels. 2. ECS caused an increase in nitric oxide synthetase mRNA in selective regions of the hippocampus. Tricyclic antidepressants were found to inhibit nitric oxide synthetase enzymatic activity. 3. ECS altered mitochondrial DNA (mtDNA) in a manner suggestive of either increased mtDNA replication or mtDNA transcription. 4. ECS altered the metabolism of neuroactive steroids in a manner that suggests changes in the brain steroid metabolizing enzymes (cytochrome P-450's). The pattern of neuroactive steroid metabolism was tested in human lymphocytes and mimicked the profile of brain metabolism which suggests that lymphocytes may be used to study steroid metabolism in depressed patients.
