The neuropsychological hypothesis of antidepressant drug action revisited

Depression is one of the most debilitating disorders of our times. Antidepressant medication, one of the most common (and often first-line) treatments to date, aim to alleviate symptoms, but finding which type of drug benefits which patient remains a daunting task. The underlying mechanism that translates neurochemical effects to symptom improvement is still far from precise. In this review we summarized the evidence on the effects of antidepressants on brain systems and cognitive functioning, and examined the possible value of these correlates as predictors of response. Studies using acute (or sub-chronic) antidepressant administrations in healthy subjects showed effects on affective cognition. In depressed patients, neuroimaging studies examining the effects of antidepressants in pre-post designs have shown changes in the activation of the anterior cingulate cortex and the limbic system after treatment. Increasing evidence shows that baseline anterior cingulate cortex activation could be a possibly critical biomarker of treatment response. The few studies performed to date also indicate potentially different pathways for antidepressants targeting the serotonergic neurotransmitter system versus those targeting the noradrenergic one, but findings are not always consistent. More studies are necessary to establish whether early cognitive effects of drugs are predictive of long-term efficacy in depressed patients. Considering the heterogeneity of depression and in order to approach a more personalized treatment, future studies should also elucidate the effects of antidepressants on different cognitive systems and subsequently on different symptom profiles.