Depression is among the most common psychiatric illnesses, which imposes a major socioeconomic
burden on patients, caregivers, and the public health system. Treatment with classical
antidepressants (e.g. tricyclic antidepressants and selective serotonine reuptake
inhibitors), which primarily affect monoaminergic systems has several limitations,
such as delayed onset of action and moderate efficacy in a relatively large proportion
of depressed patients. Furthermore, depression is highly heterogeneus, and its different
subtypes, including post-partum depression, involve distinct neurobiology, warranting
a differential approach to pharmacotherapy. Given these shortcomings, the need for
novel antidepressants that are superior in efficacy and faster in onset of action
is fully justified. The development and market introduction of rapid-acting antidepressants
has accelerated in recent years. Some of these new antidepressants act through the
GABAergic system. In this review, we discuss the discovery, efficacy, and limitations
of treatment with classic antidepressants. We provide a detailed discussion of GABAergic
neurotransmission, with a special focus on GABAA receptors, and possible explanations
for the mood-enhancing effects of GABAergic medications (in particular neurosteroids
acting at GABAA receptors), and ultimately, we present the most promising molecules
belonging to this family which are currently used in clinical practice or are in late
phases of clinical development.
