[Treatment strategy of refractory depression and its presynaptic mechanism of action]

Most antidepressants used in Japan are reuptake inhibitors of monoamine, such as noradrenaline and serotonin. Incidence of refractory depression, which is resistant to at least two monoamine reuptake inhibitors, is 10-20%. ECT and the addition of lithium, thyroid hormones or dopamine agonists is used for the treatment of refractory depression. Bupropion and MAO inhibitors are also effective for refractory depression but not approved in Japan. The presynaptic mechanism of action of these antidepressants has been studied by in vivo microdialysis studies. Serotonin reuptake inhibitors increase extracellular serotonin concentrations in the brain. Noradrenaline reuptake inhibitors increase extracellular noradrenaline concentrations in the brain, and increase extracellular dopamine concentrations in the frontal cortex, but not in the nucleus accumbens or striatum. ECT and MAO inhibitors increase extracellular serotonin concentrations in the brain, and ECT, bupropion and MAO inhibitors increase extracellular noradrenaline concentrations in the brain. In contrast to monoamine reuptake inhibitors, ECT, bupropion and MAO inhibitors increase extracellular dopamine concentrations not only in the frontal cortex but also in the nucleus accumbens and striatum. The facilitation of mesolimbic or nigrostriatal dopamine neurotransmission may be the mechanism of action behind these treatments' efficacies for refractory depression. Although there are only a few studies concerning the mechanism of action of augmentation therapy, recent studies demonstrated that subchronic lithium treatment increases basal concentrations of extracellular serotonin in the frontal cortex and hippocampus. Subchronic lithium further increases SSRI-induced increases in extracellular serotonin concentrations, and this effect is suggested to be the mechanism of action for lithium augmentation of antidepressants.