Antidepressants: current mechanisms and new hopes

Abstract

Modern drugs for depression—including tricyclic antidepressants, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors—improve mood and motivation by influencing a relatively small repertoire of ‘monoamine’ neurotransmitters released from pre-synaptic nerve terminals. While current antidepressants prevent considerable suffering, around 30% of patients do not respond adequately to treatment. Furthermore, patients usually need to take conventional antidepressants for several weeks before the hopelessness, helplessness and suicidal ideation of depression abate. Against this background, the recognition that ketamine, used as an anaesthetic and a ‘recreational’ drug, rapidly improved severe depression that did not respond to other antidepressants was, according to Science, ‘arguably the most important discovery [in depression] in half a century’. Studies into the mode of action of ketamine along with investigations to ascertain why total sleep deprivation alleviates depression in about 60% of patients, raise the prospect of overcoming the frustrating and potentially dangerous delay in the onset of action with conventional antidepressants and offer new hope to patients resistant to current drugs. Moreover, these studies help to characterise the subtle neurochemical basis of this common psychiatric condition. This article examines the pharmacology of current antidepressants, as well as some of the research that promises to transform the prospects for people living with this devastating disease who do not respond to current agents.