The global prevalence of depressive disorders is on a rise and it presents one of the most prominent health problems in the modern world. Since the 1950s there was ongoing work in the research for effective antidepressant medication. From the first generation tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), as well as the next generation selective serotonine and norepinephrine reuptake inhibitors (SSRIs and SNRIs), we get remission rates in about two thirds of the patients. To answer the question what should be done with the remaining third that is resistant to therapy and others with inadequate treatment regimen, this review proposes to look into novel pharmacotherapeutical approaches in treating depression. By reviewing different pathophysiological mechanisms of the onset and progress of depressive disorder, directions of antidepressant development will be compared. Focus will be at agents with atypicial mechanisms of action, rapid-acting agents like NMDA receptor antagonists and agents with multireceptor affinities, or those adjuvant to classic treatment. Discussing potential agents pharmacokintetic profile and comparative effectiveness conclusions will be drawn of their ability to control symptoms and duration of depressive episodes.