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SENSITIZATION IN THE AFFECTIVE DISORDERS Stressor and Episode Sensitization in the Unmedicated State At the beginning of the twentieth century, Kraepelin (1921) laid out the fundamentals of the sensitization hypothesis of affective disorders: the attacks begin not infrequently after the illness or death of near relatives … we must regard all alleged injuries as possibly sparks for the discharge of individual attacks, but the real cause of the malady must be sought in permanent internal changes , which at least very often, perhaps always, are innate … in spite of the removal of the discharging cause, the attack follows its independent development. But, finally, the appearance of wholly similar attacks on wholly dissimilar occasions or quite without external occasion shows that even there where there has been external influence, it must not be regarded as a necessary presupposition for the appearance of the attack. (pp. 180–181) In this terse and insightful paragraph, he outlines four different components of the sensitization hypothesis: (1) initial episodes of affective illness are often precipitated by psychosocial stressors; (2) as recurrences emerge, later episodes do not require the same psychosocial precipitation, but may occur more spontaneously; (3) episodes tend to occur with a characteristic similarity; and (4) innate neurobiological mechanisms mediate these vulnerabilities and recurrences, and presumably these could occur both on an inherited and an experiential basis. Other aspects of this sensitization hypothesis are outlined in additional passages from his work.