In reference to a set of main representative manuscripts from each era identified, including the Ottoman Anatolia, this study discusses the historical applications, definitions, and explanations elaborated in the treatment and etiology of depression prior to the development of antidepressive pharmacotherapy, the primary therapeutic modality in use against depression since the 1950s. The conclusions drawn from the texts examined can be abstracted as follows: During the past millennia depressive mood (i) was terminologically referred to by numerous names including “the anger of the heart,” “melancholy,” “neurasthenia,” “hypochondria,” “malihulya,” “vapors,” “the English malady,” “Americanitis,” and “manic depressive psychosis;” (ii) was etiologically explained sometimes absurdly and sometimes relatively plausibly by miscellaneous causes including “blood overflowing the heart,” indigestion of bad foods and drinks, the particular predominance/excess of the “black bile” or a general imbalance between the “humors” constituting the body, overworking and overthinking, underworking and idleness, development of the mass media, women’s participation in intellectual activities, artificial and extravagant lifestyles brought about by civilization, religious liberalism, and rainy, gloomy climates; and (iii) was treated with multifarious therapeutic modalities ranging from futile/harmful practices such as gastrointestinal purgation with various substances for humoral counterbalancing, exposure to electric current, cauterization of the skull, and hydrotherapy with hot/cold water to relatively helpful/harmless methods including phytotherapy with herbal drugs, encouraging for abstaining from strong alcoholic drinks and heavy foods of animal origin and living a moderate life in touch with nature, electroconvulsive therapy, psychotherapy (particularly psychoanalysis), and physical and intellectual occupation or, contrarily, rest.