Since the introduction of the antidepressant fluvoxamine in 1999, pharmacotherapy has been recognised as the center of treatment for depression. However, recently, the relationship between a depressive state and using antidepressants is not as clear as it used to be. The treatment goal has changed from response to remission and recovery, and treatment adherence appears to be almost the same as that for schizophrenia. Regarding side effects, our research revealed that sleepiness and fatigue were ranked as the top two most burdensome side effects, and sometimes antidepressants cause anxiety and agitation, so clinicians are recommended to distinguish sedative antidepressants from non-sedatives. After the year 2000, the debate regarding underdiagnosing bipolar disorder emerged. Finally, looking at major treatment guidelines for depression around the world, for moderate depression, pharmacotherapy remains the first-line treatment, but, for mild depression, the guidelines recommend guided self-help, walking, and problem-solving techniques, etc., which can be understood as tools to promote resilience. So,treating depression now seems more complicated and difficult compared to the 1990’s.