Sixty years of neurotransmitter concepts of mood disorders

The year 2025 marks the sixtieth anniversary of the publications that first proposed the neurotransmitter hypothesis of the pathogenesis and treatment of affective disorders. This concept, assuming the dominant function of catecholamines (noradrenaline and dopamine), further added with serotonin, is probably the most important theory regarding the biological pathogenesis and psychopharmacology of affective disorders. A history of the discovery of these neurotransmitters and their role in the central nervous system is presented.The catecholamine hypothesis was proposed in 1965 by American researchers Joseph Schildkraut, William Bunney and John Davis. It concerned a deficiency of noradrenaline in depression and its excess in mania, and later, a similar role of dopamine. The serotonin hypothesis of depression was presented in 1969 by the Briton Alec Coppen and the Soviet researchers Izaslaw Lapin and Grigorij Oxenkrug. The neurotransmitter concepts, especially serotonin theory, contributed to the discovery and introduction of new antidepressants. The selective serotonin reuptake inhibitors have become the most frequently used antidepressants nowadays. The introduction of fluoxetine (Prozac) in the USA at the turn of 1980s/1990s was a cultural event. In the 21st century, serotonin has made a career as a hormone of happiness and has appeared in literary works.Also now, the interpretation of the mechanism of action of the majority of antidepressants concerns their enhancement of noradrenergic, dopaminergic and serotonergic transmission in the central nervous system. The therapeutic effect in mania is associated with an inhibition of dopaminergic transmission. Among other neurotransmitters, acetylcholine can be mentioned as an element of the cholinergic-adrenergic hypothesis of mood disorders. Whereas the introduction of ketamine pointed to the role of glutamatergic neurotransmission in the pathogenesis of depression.