Neuropsychological Effects of Antidepressants: Translational Studies

Pharmacological treatments that improve mood were first identified serendipitously, but more than half a century later, how these drugs induce their antidepressant effects remains largely unknown. With the help of animal models, a detailed understanding of their pharmacological targets and acute and chronic effects on brain chemistry and neuronal function has been achieved, but it remains to be elucidated how these effects translate to clinical efficacy. Whilst the field has been dominated by the monoamine and neurotrophic hypotheses, the idea that the maladaptive cognitive process plays a critical role in the development and perpetuation of mood disorders has been discussed since the 1950s. Recently, studies using objective methods to quantify changes in emotional processing found acute effects with conventional antidepressants in both healthy volunteers and patients. These positive effects on emotional processing and cognition occur without a change in the subjective ratings of mood. Building from these studies, behavioural methods for animals that quantify similar cognitive affective processes have been developed. Integrating these behavioural approaches with pharmacology and targeted brain manipulations, a picture is beginning to emerge of the underlying mechanisms that may link the pharmacology of antidepressants, these neuropsychological constructs and clinical efficacy. In this chapter, we discuss findings from animal studies, experimental medicine and patients investigating the neuropsychological effects of antidepressant drugs. We discuss the possible neural circuits that contribute to these effects and discuss whether a neuropsychological model of antidepressant effects could explain the temporal differences in clinical benefits observed with conventional delayed-onset antidepressants versus rapid-acting antidepressants.